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    • 专利摘要:
    The present invention provides a compound represented by theformula   wherein A represents (1) a bond, (2) a group represented bythe formula -CRa=CRb- (Ra and Rb each represent a hydrogen atom orC1-6 alkyl) and the like; R1 represents (1) cyano or (2) anoptionally esterified or amidated carboxyl group; R2 represents (1) a hydrogen atom, (2) an optionally substituted hydroxy group, (3) an optionally substituted amino group and the like; R3 and R4each represent a hydrogen atom and the like; R5 represents ahydrogen atom and the like; R6 represents an optionallysubstituted hydroxy group and the like; R7and R8 each representan optionally substituted hydrocarbon group and the like; R9 andR10 each represent (1) a hydrogen atom and the like; Y representsan optionally substituted methylene group; and n represents 0 or 1,or a salt thereof, which has an excellent phosphodiesterase IVinhibiting action.
    公开号:EP1541576A1
    申请号:EP03741560
    申请日:2003-07-24
    公开日:2005-06-15
    发明作者:Yoshihisa c/o Takeda Pharmaceutical Co.Ltd. INOUE；Nobuhiro c/o Takeda Pharmaceutical Co.Ltd. FUJII；Michiyo c/o Takeda Pharmaceutical Co. Ltd. GYOTEN；Tatsumi c/oTakeda Pharmaceutical Co.Ltd MATSUMOTO
    申请人:Takeda Pharmaceutical Co Ltd；
    IPC主号:C07D491-00
    专利说明:
    [0001] The present invention relates to a novel furoisoquinolinederivative which has a phosphodiesterase IV-inhibiting action, andis useful as a prophylactic and/or therapeutic agent againstinflammatory diseases, atopic dermatitis, allergic rhinitis,asthma, chronic obstructive pulmonary diseases, chronic rheumatoidarthritis, autoimmune diseases, depression, Alzheimer's dementia,memory disorders, osteoporosis, diabetes, atherosclerosis and thelike, and use thereof. BACKGROUND ART
    [0002] These days, a large number of hormones and neurotransmittersfunction to increase or decrease the intracellular level of cyclicadenosine-3',5'-monophosphate (cAMP) which is an intracellularsecond messenger, whereby regulating the cellular functions. Theintracellular cAMP level is regulated by a synthesizing enzyme anda degrading enzyme. Thus, cAMP is produced by adenyl cyclases anddegraded by phosphodiesterase. This degrading enzyme alsoregulate the degradation of cyclic guanosine-3',5'-monophosphate(cGMP).
    [0003] Eleven isozymes of the phosphodiesterase have been found sofar [Proceedings of the National Academy of Sciences of the UnitedStates of America), Vol. 97, p. 3702 (2000)], and each functionsto regulate the intracellular CAMP and cGMP levels in variouscells such as those in central nervous system, circulatory organs,respiratory organs, digestive organs, genital organs, blood cellsand tracheal smooth muscles, whereby controlling the cellularfunctions. It is also known that a phosphodiesterase isozymereferred to as phosphodiesterase IV exists predominantly in theinflammatory cells such as an eosinophil, neutrophil, monocyte, T-lymphocyteand macrophage [Clinical and Experimental Allergy,Vol.22, p. 337 (1992)].
    [0004] Therapeutic agents against a bronchial asthma can be broadlyclassified into three groups. That is, the three groups include bronchodilators (e.g., β-adrenaline receptor agonists), theantiinflammatory agents (e.g., corticosteroids) and xanthinederivatives having both of the bronchodilating effect and theantiinflammatory effect (e.g., theophylline). Among these,theophylline has been used as a therapeutic agent against asthmafor a long time. Theophylline has drawn attention recently sinceits bronchodilating effect has been found to be based on thephosphodiesterase-inhibiting effect. However, theophylline is anon-selective phosphodiesterase inhibitor and sometimes exhibits acardiovascular side effect. Thus, its blood level should strictlybe controlled to reduce the side effect. Accordingly, amedicament for treating an inflammatory disease such as asthma isdesired to be one which inhibits the phosphodiesterase IVselectively and which has no effects on other isozymes of thephosphodiesterase.
    [0005] A study result was reported to show a possibility that aphosphodiesterase IV-selective inhibitor is an effectivetherapeutic agent against an inflammatory disease such as asthma[Pulmonary Pharmacology, Vol. 7, p. 1 (1994)]. The compoundswhich are known to be evaluated clinically to have thephosphodiesterase IV-selective inhibiting action includeArofylline, Cilomilast, Roflumilast, V-11294A, CDC-801, BAY 19-8004,Cipamfylline, SCH-351591, PD 189659 and the like (AnnualReports in Medicinal Chemistry, Vol. 36, p41-56, (2001)).
    [0006] Furthermore, as a compound having the phosphodiesterase IV-selectiveinhibiting action, a nicotinamide derivative isdescribed in WO 01/57036, and a furoisoquinoline derivative in WO01/70746 and WO 03/000695.
    [0007] As a furoisoquinoline derivative, WO 02/04455 discloses acompound represented by the formula
    [0008] A potent selective phosphodiesterase IV inhibitor is expectedto have a sufficient prophylactic or therapeutic effect in a widerange of diseases accompanied with inflammations. The objective of the invention is to provide a novel heterocyclic compound whichhas selective phosphodiesterase IV-inhibiting effect and increasesthe intracellular cAMP level whereby exhibiting bronchodilatingand antiinflammatory effects and which is also excellent in termsof safety, etc. DISCLOSURE OF INVENTION
    [0009] The present inventors have made extensive studies, andfirstly synthesized a novel furo[2,3-h]isoquinoline compoundrepresented by having the formula
    [0010] That is, the present invention relates to: [1] A compound represented by the formula
    [0011] In the above formulae, A is (1) a bond, (2) a grouprepresented by the formula -CRa=CRb- (Ra and Rb each represent a hydrogen atom or a C1-6 alkyl group), (3) a group represented bythe formula -(CONH)p-(C(Rc)(Rd))q- (Rc and Rd each represent ahydrogen atom or a C1-6 alkyl group, p represents 0 or 1 and qrepresents 1 or 2), (4) a group represented by the formula-CH2OCH2-or (5) a group represented by the formula -OCH2-.
    [0012] The C1-6 alkyl group represented by Ra, Rb, Rc and Rd includes,for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl and the like.
    [0013] The group represented by the "formula -CRa=CRb- (Ra and Rbeach represent a hydrogen atom or a C1-6 alkyl group)" includes,for example, a group represented by -CH=CH-, -C(C1-6 alkyl)=CH-,-CH=C(C1-6alkyl) - or -C(C1-6 alkyl)=C(C1-6 alkyl)-, and among these,preferably -CH=CH-, -C(C1-6 alkyl)=CH-, -CH=C(C1-6 alkyl)-,particularly preferably a group represented by -CH=CH-,-C(methyl)=CH-or -CH=C (methyl)-.
    [0014] The group represented by the "formula -(CONH)p-(C(Rc)(Rd))q-(Rc and Rd each represent a hydrogen atom or a C1-6 alkyl group, pis 0 or 1 and q is 1 or 2)" includes, for example, a grouprepresented by -CH2-, -CH(C1-6 alkyl)-, -C(C1-6 alkyl) (C1-6 alkyl)-,-(CH2)2-, -(CH(C1-6 alkyl))2-, -(C(C1-6 alkyl) (C1-6 alkyl))2-, -CONH-CH2-,-CONH-CH(C1-6 alkyl)-, -CONH-C(C1-6 alkyl) (C1-6 alkyl)-, -CONH-(CH2)2-,-CONH-(CH(C1-6 alkyl))2- or -CONH-(C(C1-6 alkyl) (C1-6alkyl))2-, and among these, preferably -CH2-, -C(C1-6 alkyl) (C1-6alkyl)-, -(CH2)2-, -CONH-CH2-, -CONH-C(C1-6 alkyl) (C1-6 alkyl)-,particularly a group represented by -CH2-, -C(methyl)2-, -(CH2)2-,-CONH-CH2- or -CONH-C (methyl)2-.
    [0015] A is preferably (1) a bond, (2) a group represented by theformula -CH=CH-, (3) a group represented by the formula-C(Rc)(Rd)- (Rc and Rd each represent a hydrogen atom or a C1-6 alkylgroup) or (4) a group represented by the formula -CH2OCH2-, andamong these, more preferably (1) a bond, (2) a group representedby the formula -CH=CH-, (3) a group represented by the formula-C(methyl)2-or (4) a group represented by the formula -CH2OCH2-.
    [0016] In the above formulae, R1 is (1) a cyano group or (2) anoptionally esterified or amidated carboxyl group.
    [0017] The "optionally esterified or amidated carboxyl group"represented by R1 includes, for example, (i) a carboxyl group,(ii) a C1-6 alkoxy-carbonyl group which may have 1 to 5substituents selected from (1) a halogen atom, (2) a C1-3alkylenedioxy group, (3) a nitro group, (4) a cyano group, (5) anoptionally halogenated C1-6 alkyl group, (6) an optionallyhalogenated C2-6 alkenyl group, (7) an optionally halogenated C2-6alkynyl group, (8) a C3-8 cycloalkyl group, (9) a C6-14 aryl group,(10) an optionally halogenated C1-6 alkoxy group, (11) anoptionally halogenated C1-6 alkylthio group, (12) a hydroxyl group,(13) an amino group, (14) a mono-C1-6 alkylamino group, (15) amono-C6-14 arylamino group, (16) a di-C1-6 alkylamino group, (17) adi-C6-14 arylamino group, (18) an acyl group selected from formyl,carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl,C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, sulfino, sulfo, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, (19) an acylamino group selected from formylamino,C1-6 alkyl-carboxamide, C6-14 aryl-carboxamide, C1-6 alkoxy-carboxamide,C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino, (20) an acyloxy group selected from C1-6 alkyl-carbonyloxy, C6-14aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy,di-C1-6 alkyl-carbamoyloxy, mono-C6-14 aryl-carbamoyloxy,di-C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) a5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, (22) a phosphono group, (23) aC6-14 aryloxy group, (24) a di-C1-6 alkoxy-phosphoryl group, (25) aC6-14 arylthio group, (26) a hydrazino group, (27) an imino group,(28) an oxo group (except the case that it forms a ring togetherwith a hydrocarbon group), (29) a ureido group, (30) a C1-6 alkyl-ureidogroup, (31) a di-C1-6 alkyl-ureido group, (32) an oxidegroup and (33) a group formed by binding of 2 or 3 groups selectedfrom (1) to (32) listed above and the like a group consisting of(hereinafter, abbreviated as Substituent group A), (iii) a C3-8cycloalkyloxy-carbonyl group which may have 1 to 5 substituentsselected from Substituent group A described above, (iv) a C7-16aralkyloxy-carbonyl group which may have 1 to 5 substituentsselected from Substituent group A described above, (v) a C6-14aryloxy-carbonyl group which may have 1 to 5 substituents selectedfrom Substituent group A described above, (vi) a carbamoyl group,(vii) a mono-C1-6 alkyl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above,(viii) a di-C1-6 alkyl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above,(ix) a mono-C6-14 aryl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above or(x) a di-C6-14 aryl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above andthe like.
    [0018] The "halogen atom" in the above-mentioned Substituent group Aincludes, for example, fluorine, chlorine, bromine and iodine.
    [0019] The "C1-3 alkylenedioxy group" in the above-mentionedSubstituent group A includes, for example, methylenedioxy,ethylenedioxy and propylenedioxy.
    [0020] The "optionally halogenated C1-6 alkyl group" in the above-mentionedSubstituent group A is, for example, a C1-6 alkyl group(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, hexyl and the like) which may have 1 to3 halogen atoms (e.g., fluorine, chlorine, bromine and iodine) andthe like, and specifically methyl, chloromethyl, difluoromethyl,trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl,propyl, 3,3,3-trifluoropropyl, isopropyl, butyl,4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexylor the like.
    [0021] The "optionally halogenated C2-6 alkenyl group" in the above-mentionedSubstituent group A includes, for example, a C2-6 alkenylgroup (e.g., vinyl, allyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl,4-pentenyl, 5-hexenyl and the like) which may have 1 to3 halogen atoms (e.g., fluorine, chlorine, bromine and iodine) andthe like.
    [0022] The "optionally halogenated C2-6 alkynyl group" in the above-mentionedSubstituent group A includes, for example, a C2-6 alkynylgroup (e.g., propargyl, ethynyl, 2-butynyl, 2-hexynyl and thelike) which may have 1 to 3 halogen atoms (e.g., fluorine,chlorine, bromine and iodine) and the like.
    [0023] The "C3-8 cycloalkyl group" in the above-mentioned Substituentgroup A includes, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
    [0024] The "C6-14 aryl group" in the above-mentioned Substituentgroup A includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl,2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl,4-phenanthryl, 9-phenanthryl and the like.
    [0025] The "optionally halogenated C1-6 alkoxy group" in the above-mentioned Substituent group A includes, for example, a C1-6 alkoxygroup (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy,neopentyloxy and the like) which may have 1 to 3 halogen atoms(e.g., fluorine, chlorine, bromine and iodine) and the like, andspecifically methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, trichloromethoxy, 3,3,3-trifluoropropoxy,4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy,6,6,6-trifluorohexyloxy and the like.
    [0026] The "optionally halogenated C1-6 alkylthio group" in theabove-mentioned Substituent group A includes, for example, a C1-6alkylthio group (e.g., methylthio, ethylthio, propylthio,isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthioand the like) which may have 1 to 3 halogen atoms (e.g.,fluorine, chlorine, bromine and iodine) and the like, andspecifically methylthio, difluoromethylthio, trifluoromethylthio,ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio,pentylthio, hexylthio and the like.
    [0027] The "mono-C1-6 alkylamino group" in the above-mentionedSubstituent group A includes, for example, methylamino, ethylamino,propylamino, isopropylamino, butylamino and the like.
    [0028] The "mono-C6-14 arylamino group" in the above-mentionedSubstituent group A includes, for example, phenylamino, 1-naphthylamino,2-naphthylamino and the like.
    [0029] The "di-C1-6 alkylamino group" in the above-mentionedSubstituent group A includes, for example, dimethylamino,diethylamino, dipropylamino, diisopropylamino, dibutylamino,ethylmethylamino and the like.
    [0030] The "di-C6-14 arylamino group" in the above-mentionedSubstituent group A includes, for example, diphenylamino, di(2-naphthyl)aminoand the like.
    [0031] The "C1-6 alkyl-carbonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl andthe like.
    [0032] The "C3-8 cycloalkyl-carbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,cyclopropyl-carbonyl, cyclobutyl-carbonyl, cyclopentyl-carbonyl,cyclohexyl-carbonyl, cycloheptyl-carbonyl, cyclooctyl-carbonyl andthe like.
    [0033] The "C1-6 alkoxy-carbonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example, methoxy-carbonyl,ethoxy-carbonyl, propoxy-carbonyl, isopropoxy-carbonyl,n-butoxy-carbonyl, isobutoxy-carbonyl, sec-butoxy-carbonyl, tert-butoxy-carbonyl,pentyloxy-carbonyl, isopentyloxy-carbonyl,neopentyloxy-carbonyl and the like.
    [0034] The "C6-14 aryl-carbonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example, benzoyl, 1-naphthoyl,2-naphthoyl and the like.
    [0035] The "C7-16 aralkyl-carbonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example, phenylacetyl,3-phenylpropionyl and the like.
    [0036] The "C6-14 aryloxy-carbonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,phenoxycarbonyl, 2-naphthyloxycarbonyl and the like.
    [0037] The "C7-16 aralkyloxy-carbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,benzyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
    [0038] The "5- or 6-membered heterocyclic carbonyl containing 1 to 3hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms" as the "acyl group" inthe above-mentioned Substituent group A includes, for example, 1-pyrrolidinylcarbonyl,4-piperidylcarbonyl, 1-piperazinylcarbonyl,2-morpholinylcarbonyl, 4-pyridylcarbonyl, 3-thienylcarbonyl, 2-furylcarbonyl,2-thiazolylcarbonyl and the like.
    [0039] The "mono-C1-6 alkyl-carbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,methylcarbamoyl, ethylcarbamoyl and the like.
    [0040] The "di-C1-6 alkyl-carbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example, dimethylcarbamoyl, diethylcarbamoyl and the like.
    [0041] The "mono-C6-14 aryl-carbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,phenylcarbamoyl, 2-naphthylcarbamoyl and the like.
    [0042] The "di-C6-14 aryl-carbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,diphenylcarbamoyl and the like.
    [0043] The "5- or 6-membered heterocyclic carbamoyl containing 1 to3 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms" as the "acyl group" inthe above-mentioned Substituent group A includes, for example, 1-pyrrolidinylcarbamoyl,4-piperidylcarbamoyl, 1-piperazinylcarbamoyl,2-morpholinylcarbamoyl, 4-pyridylcarbamoyl,3-thienylcarbamoyl, 2-furylcarbamoyl, 2-thiazolylcarbamoyl and thelike.
    [0044] The "C1-6 alkyl-thiocarbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,methylthiocarbonyl, ethylthiocarbonyl and the like.
    [0045] The "C3-8 cycloalkyl-thiocarbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,cyclopentylthiocarbonyl, cyclohexylthiocarbonyl and the like.
    [0046] The "C1-6 alkoxy-thiocarbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,methoxythiocarbonyl, ethoxythiocarbonyl, propoxythiocarbonyl,butoxythiocarbonyl and the like.
    [0047] The "C6-14 aryl-thiocarbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,phenylthiocarbonyl, 2-naphthylthiocarbonyl and the like.
    [0048] The "C7-16 aralkyl-thiocarbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,benzylthiocarbonyl, phenethylthiocarbonyl and the like.
    [0049] The "C6-14 aryloxy-thiocarbonyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,phenoxythiocarbonyl, 2-naphthyloxythiocarbonyl and the like.
    [0050] The "C7-16 aralkyloxy-thiocarbonyl" as the "acyl group" in the above-mentioned Substituent group A includes, for example,benzyloxythiocarbonyl, 2-naphthylmethyloxythiocarbonyl and thelike.
    [0051] The "5- or 6-membered heterocyclic thiocarbonyl containing 1to 3 hetero atoms selected from a nitrogen atom, a sulfur atom andan oxygen atom in addition to carbon atoms" as the "acyl group" inthe above-mentioned Substituent group A includes, for example, 1-pyrrolidinylthiocarbonyl,4-piperidylthiocarbonyl, 1-piperazinylthiocarbonyl,2-morpholinylthiocarbonyl, 4-pyridylthiocarbonyl,3-thienylthiocarbonyl, 2-furylthiocarbonyl,2-thiazolylthiocarbonyl and the like.
    [0052] The "mono-C1-6 alkyl-thiocarbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,methylthiocarbamoyl, ethylthiocarbamoyl and the like.
    [0053] The "di-C1-6 alkyl-thiocarbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,dimethylthiocarbamoyl, diethylthiocarbamoyl and the like.
    [0054] The "mono-C6-14 aryl-thiocarbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,phenylthiocarbamoyl, 2-naphthylthiocarbamoyl and the like.
    [0055] The "di-C6-14 aryl-thiocarbamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,diphenylthiocarbonyl and the like.
    [0056] The "5- or 6-membered heterocyclic thiocarbamoyl containing 1to 3 hetero atoms selected from a nitrogen atom, a sulfur atom andan oxygen atom in addition to carbon atoms" as the "acyl group" inthe above-mentioned Substituent group A includes, for example, 1-pyrrolidinylthiocarbamoyl,4-piperidylthiocarbamoyl, 1-piperazinylthiocarbamoyl,2-morpholinylthiocarbamoyl, 4-pyridylthiocarbamoyl,3-thienylthiocarbamoyl, 2-furylthiocarbamoyl,2-thiazolylthiocarbamoyl and the like.
    [0057] The "mono-C1-6 alkylsulfamoyl" as the "acyl group" in theabove-mentioned Substituent group A includes, for example,methylsulfamoyl, ethylsulfamoyl and the like.
    [0058] The "di-C1-6 alkylsulfamoyl" as the "acyl group" in the above-mentioned Substituent group A includes, for example,dimethylsulfamoyl, diethylsulfamoyl and the like.
    [0059] The "C6-14 arylsulfamoyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,phenylsulfamoyl and the like.
    [0060] The "C1-6 alkylsulfonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,methylsulfonyl, ethylsulfonyl and the like.
    [0061] The "C6-14 arylsulfonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,phenylsulfonyl, 2-naphthylsulfonyl and the like.
    [0062] The "C1-6 alkylsulfinyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,methylsulfinyl, ethylsulfinyl and the like.
    [0063] The "C6-14 arylsulfinyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,phenylsulfinyl, 2-naphthylsulfinyl and the like.
    [0064] The "C1-6 alkoxysulfinyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,methoxysulfinyl, ethoxysulfinyl and the like.
    [0065] The "C6-14 aryloxysulfinyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,phenoxysulfinyl and the like.
    [0066] The "C1-6 alkoxysulfonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,methoxysulfonyl, ethoxysulfonyl and the like.
    [0067] The "C6-14 aryloxysulfonyl" as the "acyl group" in the above-mentionedSubstituent group A includes, for example,phenoxysulfonyl and the like.
    [0068] The "C1-6 alkyl-carboxamide" as the "acylamino group" in theabove-mentioned Substituent group A includes, for example,acetamide, propionamide and the like.
    [0069] The "C6-14 aryl-carboxamide" as the "acylamino group" in theabove-mentioned Substituent group A includes, for example,benzamide, 2-naphthylcarboxamide and the like.
    [0070] The "C1-6 alkoxy-carboxamide" as the "acylamino group" in theabove-mentioned Substituent group A includes, for example,methoxycarboxamide, ethoxycarboxamide, isopropoxycarboxamide,tert-butoxycarboxamide and the like.
    [0071] The "C1-6 alkylsulfonylamino" as the "acylamino group" in theabove-mentioned Substituent group A includes, for example,methylsulfonylamino, ethylsulfonylamino and the like.
    [0072] The "C6-14 arylsulfonylamino" as the "acylamino group" in theabove-mentioned Substituent group A includes, for example,phenylsulfonylamino, 2-naphthylsulfonylamino and the like.
    [0073] The "C1-6 alkyl-carbonyloxy" as the "acyloxy group" in theabove-mentioned Substituent group A includes, for example,acetyloxy, propionyloxy and the like.
    [0074] The "C6-14 aryl-carbonyloxy" as the "acyloxy group" in theabove-mentioned Substituent group A includes, for example,benzoyloxy, 2-naphthoyloxy and the like.
    [0075] The "C1-6 alkoxy-carbonyloxy" as the "acyloxy group" in theabove-mentioned Substituent group A includes, for example,methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy,tert-butoxycarbonyloxy and the like.
    [0076] The "mono-C1-6 alkyl-carbamoyloxy" as the "acyloxy group" inthe above-mentioned Substituent group A includes, for example,methylcarbamoyloxy, ethylcarbamoyloxy and the like.
    [0077] The "di-C1-6 alkyl-carbamoyloxy" as the "acyloxy group" in theabove-mentioned Substituent group A includes, for example,dimethylcarbamoyloxy, diethylcarbamoyloxy and the like.
    [0078] The "mono-C6-14 aryl-carbamoyloxy" as the "acyloxy group" inthe above-mentioned Substituent group A includes, for example,phenylcarbamoyloxy, 2-naphthylcarbamoyloxy and the like.
    [0079] The "di-C6-14 aryl-carbamoyloxy" as the "acyloxy group" in theabove-mentioned Substituent group A includes, for example,diphenylcarbamoyloxy and the like.
    [0080] The "5- to 14-membered heterocyclic group containing 1 to 4hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms" in the above-mentioned Substituent group A includes, for example, 4-pyridyl, 2-thienyl,2-furyl, 2-thiazolyl, 3-indolyl, morpholino, piperazin-1-yl,piperidino, pyrrolidin-1-yl, 2-isoindolinyl and the like.
    [0081] The "C6-14 aryloxy group" in the above-mentioned Substituentgroup A includes, for example, phenoxy.
    [0082] The "di-C1-6 alkoxy-phosphoryl group" in the above-mentionedSubstituent group A includes, for example, dimethoxyphosphoryl,diethoxyphosphoryl and the like.
    [0083] The "C6-14 arylthio group" in the above-mentioned Substituentgroup A includes, for example, phenylthio and the like.
    [0084] The "C1-6 alkyl-ureido group" in the above-mentionedSubstituent group A includes, for example, methylureido,ethylureido and the like.
    [0085] The "di-C1-6 alkyl-ureido group" in the above-mentionedSubstituent group A includes, for example, dimethylureido,diethylureido and the like.
    [0086] The "C1-6 alkoxy-carbonyl group" of the "C1-6 alkoxy-carbonylgroup which may have 1 to 5 substituents selected from the above-mentionedSubstituent group A " as the "optionally esterified oramidated carboxyl group" represented by R1 includes, for example,for example, methoxy-carbonyl, ethoxy-carbonyl, propoxy-carbonyl,isopropoxy-carbonyl, n-butoxy-carbonyl, isobutoxy-carbonyl, sec-butoxy-carbonyl,tert-butoxy-carbonyl, pentyloxy-carbonyl,isopentyloxy-carbonyl, neopentyloxy-carbonyl and the like.
    [0087] The "C3-8 cycloalkyloxy-carbonyl group" of the "C3-8cycloalkyloxy-carbonyl group which may have 1 to 5 substituentsselected from Substituent group A described above" as the"optionally esterified or amidated carboxyl group" represented byR1 includes, for example, cyclopropyloxy-carbonyl, cyclobutyloxy-carbonyl,cyclopentyloxy-carbonyl, cyclohexyloxy-carbonyl,cycloheptyloxy-carbonyl, cyclooctyloxy-carbonyl and the like.
    [0088] The "C7-16 aralkyloxy-carbonyl group" of the "C7-16 aralkyloxy-carbonylgroup which may have 1 to 5 substituents selected fromSubstituent group A described above" as the "optionally esterifiedor amidated carboxyl group" represented by R1 includes, for example, benzyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
    [0089] The "C6-14 aryloxy-carbonyl group" of the "C6-14 aryloxy-carbonylgroup which may have 1 to 5 substituents selected fromSubstituent group A described above" as the "optionally esterifiedor amidated carboxyl group" represented by R1 includes, forexample, phenoxycarbonyl, 2-naphthyloxycarbonyl and the like.
    [0090] The "mono-C1-6 alkyl-carbamoyl group" of the "mono-C1-6 alkyl-carbamoylgroup which may have 1 to 5 substituents selected fromSubstituent group A described above" as the "optionally esterifiedor amidated carboxyl group" represented by R1 includes, forexample, methylcarbamoyl, ethylcarbamoyl and the like.
    [0091] The "di-C1-6 alkyl-carbamoyl group" of the "di-C1-6 alkyl-carbamoylgroup which may have 1 to 5 substituents selected fromSubstituent group A described above" as the "optionally esterifiedor amidated carboxyl group" represented by R1 includes, forexample, dimethylcarbamoyl, diethylcarbamoyl and the like.
    [0092] The "mono-C6-14 aryl-carbamoyl group" of the "mono-C6-14 aryl-carbamoylgroup which may have 1 to 5 substituents selected fromSubstituent group A described above" as the "optionally esterifiedor amidated carboxyl group" represented by R1 includes, forexample, phenylcarbamoyl, 2-naphthylcarbamoyl and the like.
    [0093] The "di-C6-14 aryl-carbamoyl group" of the "di-C6-14 aryl-carbamoylgroup which may have 1 to 5 substituents selected fromSubstituent group A described above" as the "optionally esterifiedor amidated carboxyl group" represented by R1 includes, forexample, diphenylcarbamoyl and the like.
    [0094] R1 is preferably (1) a cyano group, (2) a carboxyl group, (3)a C1-6 alkoxycarbonyl group, (4) a carbamoyl group, (5) an N-mono-C1-6alkylcarbamoyl group, and among these, R1 is preferablycarboxyl group or carbamoyl group.
    [0095] In the above formulae, R2 is (1) a hydrogen atom, (2) anoptionally substituted hydroxyl group, (3) an optionallysubstituted amino group, (4) an optionally substituted alkyl group,(5) an optionally esterified or amidated carboxyl group or (6) anitro group.
    [0096] The "optionally substituted hydroxyl group" represented by R2includes, for example, a group represented by the formula -OR12(R12 is (a) a hydrogen atom, (b) a C1-6 alkyl group, a C2-6 alkenylgroup, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8cycloalkenyl group, a C6-14 aryl group or a C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A, or (c) an acyl group selected from formyl, carbamoyl, C1-6alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, each of which may have 1 to 5 substituentsselected from Substituent group A described above).
    [0097] The C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group,a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 arylgroup or a C7-16 aralkyl group of the "C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group, the C3-8 cycloalkyl group,the C3-8 cycloalkenyl group, the C6-14 aryl group or the C7-16 aralkylgroup, each of which may have 1 to 5 substituents selected fromSubstituent group A" represented by R12 includes, for example, thefollowings: a C1-6 alkyl group: methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like; a C2-6 alkenyl group: vinyl, allyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl,4-pentenyl, 5-hexenyl and the like; a C2-6 alkynyl group: propargyl, ethynyl, 2-butynyl, 2-hexynyland the like; a C3-8 cycloalkyl group: cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl and the like; a C3-8 cycloalkenyl group: 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl,1-cyclohexenyl and the like; a C6-14 aryl group: phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl,2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl,4-phenanthryl, 9-phenanthryl and the like; and a C7-16 aralkyl group: benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl,2-naphthylmethyl, 2-phenethyl, 2,2-diphenylethyl,1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl,biphenylylmethyl, biphenylylethyl, biphenylylpropyl,biphenylylbutyl and the like.
    [0098] The "C1-6 alkyl-carbonyl", the "C3-8 cycloalkyl-carbonyl", the"C1-6 alkoxy-carbonyl", the "C6-14 aryl-carbonyl", the "C7-16 aralkyl-carbonyl",the "C6-14 aryloxy-carbonyl", the "C7-16 aralkyloxy-carbonyl",the "5- or 6-membered heterocyclic carbonyl containing1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atomand an oxygen atom in addition to carbon atoms", the "mono-C1-6alkyl-carbamoyl", the "di-C1-6 alkyl-carbamoyl", the "mono-C6-14aryl-carbamoyl", the "di-C6-14 aryl-carbamoyl", the "5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms", the "C1-6 alkyl-thiocarbonyl", the "C3-8cycloalkyl-thiocarbonyl", the "C1-6 alkoxy-thiocarbonyl", the "C6-14 aryl-thiocarbonyl", the "C7-16 aralkyl-thiocarbonyl", the "C6-14aryloxy-thiocarbonyl", the "C7-16 aralkyloxy-thiocarbonyl", the "5-or 6-membered heterocyclic thiocarbonyl containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms", the "mono-C1-6 alkyl-thiocarbamoyl",the "di-C1-6 alkyl-thiocarbamoyl", the "mono-C6-14aryl-thiocarbamoyl", the "di-C6-14 aryl-thiocarbamoyl", the "5- or6-membered heterocyclic thiocarbamoyl containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms", the "mono-C1-6 alkylsulfamoyl",the "di-C1-6 alkylsulfamoyl", the "C6-14 arylsulfamoyl", the "C1-6alkylsulfonyl", the "C6-14 arylsulfonyl", the "C1-6 alkylsulfinyl",the "C6-14 arylsulfinyl", the "C1-6 alkoxysulfinyl", the "C6-14aryloxysulfinyl", the "C1-6 alkoxysulfonyl" and the "C6-14aryloxysulfonyl" as the acyl group of the "acyl group which mayhave 1 to 5 substituents selected from Substituent group Adescribed above" represented by R12, includes those such as the"C1-6 alkyl-carbonyl", the "C3-8 cycloalkyl-carbonyl", the "C1-6alkoxy-carbonyl", the "C6-14 aryl-carbonyl", the "C7-16 aralkyl-carbonyl",the "C6-14 aryloxy-carbonyl", the "C7-16 aralkyloxy-carbonyl",the "5- or 6-membered heterocyclic carbonyl containing1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atomand an oxygen atom in addition to carbon atoms", the "mono-C1-6alkyl-carbamoyl", the "di-C1-6 alkyl-carbamoyl", the "mono-C6-14aryl-carbamoyl", the "di-C6-14 aryl-carbamoyl", the "5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms", the "C1-6 alkyl-thiocarbonyl", the "C3-8cycloalkyl-thiocarbonyl", the "C1-6 alkoxy-thiocarbonyl", the "C6-14aryl-thiocarbonyl", the "C7-16 aralkyl-thiocarbonyl", the "C6-14aryloxy-thiocarbonyl", the "C7-16 aralkyloxy-thiocarbonyl", the "5-or 6-membered heterocyclic thiocarbonyl containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms", the "mono-C1-6 alkyl-thiocarbamoyl",the "di-C1-6 alkyl-thiocarbamoyl", the "mono-C6-14 aryl-thiocarbamoyl", the "di-C6-14 aryl-thiocarbamoyl", the "5- or6-membered heterocyclic thiocarbamoyl containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms", the "mono-C1-6 alkylsulfamoyl",the "di-C1-6 alkylsulfamoyl", the "C6-14 arylsulfamoyl", the "C1-6alkylsulfonyl", the "C6-14 arylsulfonyl", the "C1-6 alkylsulfinyl",the "C6-14 arylsulfinyl", the "C1-6 alkoxysulfinyl", the "C6-14aryloxysulfinyl", the "C1-6 alkoxysulfonyl" and the "C6-14aryloxysulfonyl" in the acyl group of the above-mentionedSubstituent group A.
    [0099] The "optionally substituted amino group" represented by R2includes, for example, (1) a group represented by the formula-NR13R14(R13 and R14 each represent (i') a hydrogen atom, (ii') a C1-6alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group or aC7-16 aralkyl group, each of which may have 1 to 5 substituentsselected from Substituent group A, (iii') an acyl group selectedfrom formyl, carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl,C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl,C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or6-membered heterocyclic carbamoyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, C1-6 alkoxysulfinyl, C6-14aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14 aryloxysulfonyl, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above or (iv') a 5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above, or R13 and R14 may be taken together withthe adjacent a nitrogen atom to form a 5- to 14-membered ring),(2) a C1-6 alkylideneamino group which may have 1 to 5 substituentsselected from Substituent group A described above (e.g.,methylideneamino, ethylideneamino and the like) and the like.
    [0100] "The C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynylgroup, the C3-8 cycloalkyl group, the C3-8 cycloalkenyl group, theC6-14 aryl group or the C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A" representedby R13 and R14 includes those such as the above-mentioned "C1-6alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14 aryl group or aC7-16 aralkyl group, each of which may have 1 to 5 substituentsselected from Substituent group A" represented by R12.
    [0101] The "acyl group which may have 1 to 5 substituents selectedfrom Substituent group A described above" represented by R13 andR14 includes those such as the above-mentioned "acyl group whichmay have 1 to 5 substituents selected from Substituent group Adescribed above" represented by R12.
    [0102] The "5- to 14-membered heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms " of the "5- to 14-memberedheterocycle containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, each of which may have 1 to 5 substituents selectedfrom Substituent group A described above" represented by R13 andR14 includes, for example, 4-pyridyl, 2-thienyl, 2-furyl, 2-thiazolyl,3-indolyl, morpholino, piperazin-1-yl, piperidino,pyrrolidin-1-yl, 2-isoindolinyl and the like.
    [0103] The 5- to 14-membered ring which R13 and R14 may form togetherwith the adjacent nitrogen atom includes, for example, 1-pyrrolidinyl,1-piperidyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl,1,2-dihydropyridin-1-yl, 1-imidazolidinyl and thelike.
    [0104] The "optionally substituted alkyl group" represented by R2includes, for example, a C1-6 alkyl group which may have 1 to 5substituents selected from Substituent group A described above andthe like. The C1-6 alkyl group includes, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl and the like.
    [0105] The "optionally esterified or amidated carboxyl group"represented by R2 includes, for example, those such as the"optionally esterified or amidated carboxyl group" represented byR1.
    [0106] R2 is preferably (1) a hydrogen atom, (2) a hydroxyl group,(3) a C1-6 alkoxy group, (4) a C7-16 aralkyloxy group, (5) an aminogroup, (6) a mono-C1-6 alkylamino group which may have onesubstituent selected from carboxyl, carbamoyl, quinolyl, phenoxyand pyridyl, (7) a mono-C7-16 aralkylamino group which may have onesubstituent selected from a halogen atom, cyano, C1-6 alkoxy,carboxyl and C1-6 alkoxycarbonyl, (8) a mono-C6-14 arylamino group,(9) a mono-C1-6 alkylcarbonylamino group which may have 1 to 3substituents selected from a halogen atom, thienyl and C1-6alkoxycarbonyl-C1-6 alkylthio, (10) a mono-C1-6 alkylsulfonylaminogroup, (11) a mono-C6-14 arylcarbonylamino group which may have onesubstituent selected from C1-6 alkoxy and C1-6 alkylcarbonylamino,(12) a quinolylcarbonylamino group, (13) a pyridylcarbonylaminogroup which may have 1 or 2 halogen atoms, (14) anindolylcarbonylamino group, (15) a N-C1-6 alkyl-N-C1-6 alkylcarbonylamino group which may have 1 to 4 substituentsselected from a halogen atom, C1-6 alkoxycarbonyl and quinolyl,(16) a N-C1-6 alkylcarbonyl-N-C7-16 aralkylamino group which mayhave 1 to 3 halogens, (17) a N-C1-6 alkyl-N-pyridylcarbonylaminogroup, (18) a C1-6 alkylideneamino group which may have one di-C1-6alkylamino, (19) a mono-C1-6 alkylureido group which may have oneC1-6 alkoxycarbonyl, (20) a di-C1-6 alkylureido group, (21) a mono-C6-14arylureido group, (22) a 1-imidazolidinyl group which mayhave 1 to 3 substituents selected from C1-6 alkyl and oxo, (23) aC1-6 alkyl group, (24) a C1-6 alkoxycarbonyl group, (25) a nitrogroup or (26) a 1-pyrrolidinyl group. Among these, R2 ispreferably (1) a hydrogen atom, (2) a C1-6 alkoxy group, (3) amono-C1-6 alkylamino group, (4) a mono-C7-16 aralkylamino group, (5)a quinolylcarbonylamino group or (6) a pyridylcarbonylamino group.
    [0107] The ring which R2 and A or R1 may form together with theadjacent nitrogen atom includes, for example, a 5- to 8-memberedheterocycle which may have 1 to 5 substituents selected fromSubstituent group A described above.
    [0108] The "5- to 8-membered heterocycle" is a 5- to 8-memberedheterocycle (preferably a 5- to 7-membered aliphatic heterocycle)containing one or more (e.g., 1 to 4, preferably 1 to 3) heteroatoms of one or two kinds selected from a nitrogen atom, a sulfuratom and an oxygen atom in addition to carbon atoms and the like.
    [0109] Specifically, a partial structure represented by the formula
    [0110] The substituent which the ring that R2 and A or R1 may formtogether with the adjacent nitrogen atom, may have is preferably,for example, (1) a hydroxyl group, (2) a C1-6 alkyl group which mayhave one C1-6 alkoxy-carbonyl (e.g., methyl, ethyl, propyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl,methoxycarbonylmethyl, ethoxycarbonylmethyl and the like), (3) aC7-16 aralkyl group (e.g., benzyl and the like), (4) a C6-14 arylgroup (e.g., phenyl and the like), (5) an oxo group and the like.
    [0111] R3 and R4 each represent (1) a hydrogen atom, (2) anoptionally substituted hydrocarbon group or (3) an acyl group, andR3 and R4 may be taken together with the adjacent carbon atom toform an optionally substituted 3- to 8-membered ring.
    [0112] The "optionally substituted hydrocarbon group" represented byR3 and R4 includes, for example, a C1-6 alkyl group (e.g., methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, hexyl and the like), a C2-6 alkenyl group (e.g., vinyl,allyl, isopropenyl, 2-butenyl, 2-methyl-2-propenyl, 4-pentenyl, 5-hexenyland the like), a C2-6 alkynyl group (e.g., propargyl,ethynyl, 2-butynyl, 2-hexynyl and the like), a C3-8 cycloalkylgroup (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like), a C3-8 cycloalkenyl group(e.g., 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 1-cyclohexenyland the like), a C6-14 aryl group (e.g. , phenyl, 1-naphthyl,2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl,2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryland the like) or a C7-16 aralkyl group (e.g., benzyl,phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-phenethyl, 2,2-diphenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,4-phenylbutyl and 5-phenylpentyl), each of which mayhave 1 to 5 substituents selected from Substituent group Adescribed above and the like.
    [0113] The "acyl group" represented by R3 and R4 includes those suchas the above-mentioned "acyl group" represented by Substituentgroup A.
    [0114] The 3- to 8-membered ring which R3 and R4 form together withthe adjacent carbon atom includes, for example, a 3- to 8-memberedhomocycle or heterocycle.
    [0115] The 3- to 8-membered homocycle which R3 and R4 form togetherwith the adjacent carbon atom includes 3- to 8-membered cyclichydrocarbon comprising carbon atoms and hydrogen atoms, andspecifically C3-8 cycloalkane (e.g., cyclobutane, cyclopentane,cyclohexane, cycloheptane and cyclooctane), C3-8 cycloalkene (e.g.,cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene)and the like. Among these, the 3- to 8-membered homocycle ispreferably C3-8 cycloalkane, particularly a 5- or 6-memberedhomocycle such as cyclopentane, cyclohexane and the like(particularly, cyclohexane).
    [0116] The 3- to 8-membered heterocycle which R3 and R4 formtogether with the adjacent carbon atom includes a 5- to 8-memberedaliphatic heterocycle (preferably a 5- or 6-membered aliphaticheterocycle) containing one or more (e.g., 1 to 4, preferably 1 to3) hetero atoms of one or two kinds selected from a nitrogen atom,a sulfur atom and an oxygen atom in addition to carbon atoms andthe like.
    [0117] More specifically, it is, for example, a 5- to 8-membered(preferably 5- or 6-membered) aliphatic heterocycle containing 1to 3 hetero atoms selected from a nitrogen atom, an oxygen atomand a sulfur atom such as piperidine, piperazine, morpholine,thiomorpholine, pyrrolidine, imidazolidine and the like such as inaddition to carbon atoms and nitrogen atoms and the like.
    [0118] R3 and R4 are preferably a C1-6 alkyl group, particularlymethyl, respectively.
    [0119] In the above formulae, R5 is (1) a hydrogen atom, (2) a cyanogroup, (3) an optionally substituted hydrocarbon group, (4) anacyl group or (5) an optionally substituted hydroxyl group.
    [0120] The "optionally substituted hydrocarbon group" represented byR5 includes those such as the above-mentioned "optionallysubstituted hydrocarbon group" represented by R3 and R4.
    [0121] The "acyl group" represented by R5 includes those such as theabove-mentioned "acyl group" represented by Substituent group A.
    [0122] The "optionally substituted hydroxyl group" represented by R5includes, for example, a group represented by the formula -OR15(R15 is (a) a hydrogen atom, (b) a C1-6 alkyl group, a C2-6 alkenylgroup, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8cycloalkenyl group, a C6-14 aryl group or a C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A, or (c) an acyl group selected from formyl, carbamoyl, C1-6alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, each of which may have 1 to 5 substituentsselected from Substituent group A described above) and the like.
    [0123] "The C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynylgroup, the C3-8 cycloalkyl group, the C3-8 cycloalkenyl group, theC6-14 aryl group or the C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A" and the "acylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above" represented by R15 include those such asthe above-mentioned "the C1-6 alkyl group, the C2-6 alkenyl group,the C2-6 alkynyl group, the C3-8 cycloalkyl group, the C3-8cycloalkenyl group, the C6-14 aryl group or the C7-16 aralkyl group,each of which may have 1 to 5 substituents selected fromSubstituent group A" and the "acyl group which may have 1 to 5substituents selected from Substituent group A described above"represented by R12.
    [0124] R5 is preferably a hydrogen atom or a C1-6 alkyl groupoptionally substituted with a cyano group, particularly preferablya hydrogen atom.
    [0125] In the above formulae, R6 is (1) a hydrogen atom, (2) anoptionally substituted hydrocarbon group, (3) an acyl group, (4)an optionally substituted heterocyclic group, (5) a halogen atom,(6) an optionally substituted hydroxyl group, (7) an optionallysubstituted thiol group, (8) a group represented by the formula-S(O)rR11(R11 represents an optionally substituted hydrocarbongroup or an optionally substituted heterocyclic group, and rrepresents 1 or 2) or (9) an optionally substituted amino group.
    [0126] The "optionally substituted hydrocarbon group" represented byR6 includes those such as the above-mentioned "optionallysubstituted hydrocarbon group" represented by R3 and R4.
    [0127] The "acyl group" represented by R6 includes those such as theabove-mentioned "acyl group" represented by Substituent group A.
    [0128] The "heterocyclic group" of the "optionally substituted heterocyclic group" represented by R6 includes, for example, a 5-to 14-membered heterocyclic group containing 1 to 4 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms (e.g., 4-pyridyl, 2-thienyl, 2-furyl, 2-thiazolyl,3-indolyl, morpholino, piperazin-1-yl, piperidino,pyrrolidin-1-yl, 2-isoindolinyl and the like).
    [0129] The "substituent" of the "optionally substituted heterocyclicgroup" represented by R6 includes 1 to 5 substituents selectedfrom the above-mentioned Substituent group A.
    [0130] The "halogen atom" represented by R6 includes, for example,fluorine, chlorine, bromine and iodine.
    [0131] The "optionally substituted hydroxyl group" represented by R6includes, for example, a group represented by the formula -OR16(R16 is (i') a hydrogen atom, (ii') a C1-6 alkyl group, a C2-6alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8cycloalkenyl group, a C6-14 aryl group or a C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A, (iii') an acyl group selected from formyl, carbamoyl, C1-6alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-membered heterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, each of which may have 1 to 5 substituentsselected from Substituent group A described above or (iv') a 5- to14-membered heterocycle containing 1 to 4 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, each of which may have 1 to 5 substituentsselected from Substituent group A described above) and the like.
    [0132] "The C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynylgroup, the C3-8 cycloalkyl group, the C3-8 cycloalkenyl group, theC6-14 aryl group or the C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A" and the "acylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above" represented by R16 include those such asthe above-mentioned "C1-6 alkyl group, a C2-6 alkenyl group, a C2-6alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, aC6-14 aryl group or a C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A" and the "acylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above" represented by R12.
    [0133] The "5- to 14-membered heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, each of which may have 1 to 5substituents selected from Substituent group A described above"represented by R16 includes, for example, 4-pyridyl, 2-thienyl, 2-furyl,2-thiazolyl, 3-indolyl, morpholino, piperazin-1-yl,piperidino, pyrrolidin-1-yl, 2-isoindolinyl and the like, each ofwhich may have 1 to 5 substituents selected from Substituent groupA described above.
    [0134] The "optionally substituted thiol group" represented by R6includes, for example, a group represented by the formula -SR17 (R17 is (i') a hydrogen atom, (ii') a C1-6 alkyl group, a C2-6alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8cycloalkenyl group, a C6-14 aryl group or a C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A, (iii') an acyl group selected from formyl, carbamoyl, C1-6alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, each of which may have 1 to 5 substituentsselected from Substituent group A described above or (iv') a 5- to14-membered heterocycle containing 1 to 4 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, each of which may have 1 to 5 substituentsselected from Substituent group A described above).
    [0135] "The C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group, the C3-8 cycloalkyl group, the C3-8 cycloalkenyl group, theC6-14 aryl group or the C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A", the "acylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above" and the "5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above" represented by R17 include those such asthe above-mentioned "C1-6 alkyl group, a C2-6 alkenyl group, a C2-6alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, aC6-14 aryl group or a C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A", the "acylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above" and the "5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above" represented by R16.
    [0136] The "optionally substituted hydrocarbon group" represented byR11 in the group represented by the "formula -S(O)rR11 (R11represents an optionally substituted hydrocarbon group or anoptionally substituted heterocyclic group, and r represents 1 or2)" represented by R6 includes, for example, a C1-6 alkyl group, aC2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkyl group, aC3-8 cycloalkenyl group, a C6-14 aryl group or a C7-16 aralkyl group,each of which may have 1 to 5 substituents selected fromSubstituent group A, and includes those such as the above-mentioned"C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynylgroup, a C3-8 cycloalkyl group, a C3-8 cycloalkenyl group, a C6-14aryl group or a C7-16 aralkyl group, each of which may have 1 to 5substituents selected from Substituent group A" represented by R16.
    [0137] The "optionally substituted heterocyclic group" representedby R11 in the group represented by the "formula -S(O)rR11 (R11represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and r represents 1 or2)" represented by R6 is a 5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above and the like, and includes those such asthe above-mentioned "5- to 14-membered heterocycle containing 1 to4 hetero atoms selected from a nitrogen atom, a sulfur atom and anoxygen atom in addition to carbon atoms, each of which may have 1to 5 substituents selected from Substituent group A describedabove" represented by R16.
    [0138] The "optionally substituted amino group" represented by R6includes, for example, a group represented by the formula -NR18R19(R18 and R19 each represent (i') a hydrogen atom, (ii') a C1-6 alkylgroup, a C2-6 alkenyl group, a C2-6 alkynyl group, a C3-8 cycloalkylgroup, a C3-8 cycloalkenyl group, a C6-14 aryl group or a C7-16aralkyl group, each of which may have 1 to 5 substituents selectedfrom Substituent group A, (iii') an acyl group selected fromformyl , carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl, 5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, C1-6 alkoxysulfinyl, C6-14aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14 aryloxysulfonyl, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above or (iv') a 5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above) and the like.
    [0139] "The C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynylgroup, the C3-8 cycloalkyl group, the C3-8 cycloalkenyl group, theC6-14 aryl group or the C7-16 aralkyl group, each of which may have 1to 5 substituents selected from Substituent group A", the "acylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above" and the "5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above" represented by R18 and R19 include thosesuch as the above-mentioned "C1-6 alkyl group, a C2-6 alkenyl group,a C2-6 alkynyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkenylgroup, a C6-14 aryl group or a C7-16 aralkyl group, each of which mayhave 1 to 5 substituents selected from Substituent group A", the"acyl group which may have 1 to 5 substituents selected fromSubstituent group A described above" and the "5- to 14-memberedheterocycle containing 1 to 4 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, each of which may have 1 to 5 substituents selectedfrom Substituent group A described above" represented by R16.
    [0140] R6 is preferably an optionally substituted hydroxyl group, agroup represented by the formula -S(O)rR11 (R11 represents an optionally substituted hydrocarbon group or an optionallysubstituted heterocyclic group, and r represents 1 or 2) or anoptionally substituted amino group.
    [0141] Among these, R6 is preferably (1) a group represented by theformula -OR16 wherein R16 is a C1-6 alkyl group, (2) a grouprepresented by the formula -S(O)rR11 wherein r is 1 and R11 is a C1-6alkyl group or (3) a group represented by the formula -NR18R19wherein R18 is C1-6 alkyl-carbonyl and R19 is a hydrogen atom.
    [0142] R6 is particularly preferably a group represented by theformula -OR16 wherein R16 is a C1-6 alkyl group, particularly a C2-6alkyl group, and specifically ethyl.
    [0143] Namely, R6 is preferably a C1-6 alkoxy group, more preferablya C2-6 alkoxy group, particularly ethoxy.
    [0144] In the above formulae, R7 and R8 are each (1) a hydrogen atomor (2) an optionally substituted hydrocarbon group, or R7 and R8may be taken together with the adjacent carbon atom to form anoptionally substituted 3- to 8-membered ring.
    [0145] The "optionally substituted hydrocarbon group" represented byR7 and R8 includes those such as the above-mentioned "optionallysubstituted hydrocarbon group" represented by R3 and R4.
    [0146] The "optionally substituted 3- to 8-membered ring" which R7and R8 form together with the adjacent carbon atom includes thosesuch as the above-mentioned "optionally substituted 3- to 8-memberedring" which R3 and R4 form together with the adjacentcarbon atom, preferably optionally substituted 3- to 8-memberedhomocycle, more preferably C3-8 cycloalkane (e.g., cyclobutane,cyclopentane, cyclohexane, cycloheptane, cyclooctane),particularly preferably 5- or 6-membered homocycle such ascyclopentane, cyclohexane and the like (particularly,cyclopentane) .
    [0147] R7 and R8 are each preferably a C1-6 alkyl group (e.g., methyl,ethyl and the like) and the like, particularly preferably a methylgroup.
    [0148] In the above formulae, R9 and R10 are each (1) a hydrogen atomor (2) an optionally substituted hydrocarbon group.
    [0149] The "optionally substituted hydrocarbon group" represented byR9 and R10 includes those such as the above-mentioned "optionallysubstituted hydrocarbon group" represented by R3 and R4.
    [0150] R9 and R10 each represent preferably a hydrogen atom.
    [0151] In the above formulae, Y is an optionally substitutedmethylene group. The substituent of the methylene group is agroup selected from the above-mentioned Substituent group A.
    [0152] Among these, Y is preferably methylene.
    [0153] In the above formulae, n is 0 or 1. Among these, n ispreferably 0.
    [0154] The preferable compound of the present invention is asfollows: a compound represented by the formula
    [0155] R2 is (1) a hydroxyl group, (2) a C1-6 alkoxy group, (3) a C7-16aralkyloxy group, (4) an amino group, (5) a mono-C1-6 alkylaminogroup which may have one substituent selected from carboxyl,carbamoyl, quinolyl, phenoxy and pyridyl, (6) a mono-C7-16aralkylamino group which may have one substituent selected from ahalogen atom, cyano, C1-6 alkoxy, carboxyl and C1-6 alkoxycarbonyl,(7) a mono-C6-14 arylamino group, (8) a mono-C1-6 alkylcarbonylamino group which may have 1 to 3 substituents selected from a halogenatom, thienyl and C1-6 alkoxycarbonyl-C1-6 alkylthio, (9) a mono-C1-6alkylsulfonylamino group, (10) a mono-C6-14 arylcarbonylamino groupwhich may have one substituent selected from C1-6 alkoxy and C1-6alkylcarbonylamino, (11) a quinolylcarbonylamino group, (12) apyridylcarbonylamino group which may have 1 or 2 halogen atoms,(13) an indolylcarbonylamino group, (14) a N-C1-6 alkyl-N-C1-6alkylcarbonylamino group which may have 1 to 4 substituentsselected from a halogen atom, C1-6 alkoxycarbonyl and quinolyl,(15) a N-C1-6 alkylcarbonyl-N-C7-16 aralkylamino group which mayhave 1 to 3 halogens, (16) a N-C1-6 alkyl-N-pyridylcarbonylaminogroup, (17) a C1-6 alkylideneamino group which may have one di-C1-6alkylamino, (18) a mono-C1-6 alkylureido group which may have oneC1-6 alkoxycarbonyl, (19) a di-C1-6 alkylureido, (20) a mono-C6-14arylureido group, (21) a 1-imidazolidinyl group which may have 1to 3 substituents selected from C1-6 alkyl and oxo, (22) a C1-6alkyl group, (23) a C1-6 alkoxycarbonyl group, (24) a nitro groupor (25) a 1-pyrrolidinyl group, or R2 and A or R1 may be takentogether with the adjacent carbon atom to form a nitrogen-containing5- to 7-membered ring which may have 1 to 3substituents selected from (1) a hydroxyl group, (2) C1-6 alkylwhich may have one C1-6 alkoxy-carbonyl, (3) C7-16 aralkyl, (4) C6-14aryl and (5) oxo,   R3 and R4 each represent a C1-6 alkyl group,   R5 is a hydrogen atom,   R6 is a C2-6 alkoxy group,   R7 and R8 are each a C1-6 alkyl group,   R9 and R10 are each a hydrogen atom,   Y is a methylene group, and   n is 0, or a salt thereof.
    [0156] Among these, the compound of the present invention ispreferably a compound represented in Examples 1 to 32, 35 to 92,98, 99, 102, 103, 111 to 113 or 121 to 168 or a salt thereof asdescribed below, particularly 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoic acid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoicacid, (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methoxyphenyl]-2-propenoicacid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylcarbonyl)amino]benzoicacid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzeneacetic acid, N-[2-(aminocarbonyl)-5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinecarboxamideor a salt thereof.
    [0157] Furthermore, in the same manner, the compound of the presentinvention is preferably a compound represented by the formula
    [0158] Among these, the compound of the present invention is preferably a compound represented in below-described Examples 33,34, 93 to 97, 100, 101, 104 to 110 or 114 to 120 or a salt thereof,particularly [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]aceticacid,4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneacetic acid or a saltthereof, particularly [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]aceticacidhydrochloride or 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneaceticacid hydrochloride hydrate.
    [0159] Salts of the compounds of the present invention include apharmacologically acceptable salt, etc., for example, a salt withan inorganic base, an ammonium salt, a salt with an organic base,a salt with an inorganic acid, a salt with an organic acid, a saltwith a basic or acidic amino acid, etc. Suitable examples of thesalt with an inorganic base include an alkali metal salt such as asodium salt, potassium salt, etc.; an alkaline earth metal saltsuch as a calcium salt, a magnesium salt, etc.; an aluminum salt;etc. Suitable examples of the salt with an organic base include asalt with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine,etc. Suitable examples of the salt with an inorganic acid includea salt with hydrochloric acid, hydrobromic acid, nitric acid,sulfuric acid, phosphoric acid, etc. Suitable examples of thesalt with an organic acid include a salt with formic acid, aceticacid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalicacid, tartaric acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc. Suitable examples of the salt with abasic amino acid include a salt with arginine, lysine, ornithine,etc. Suitable examples of the salt with an acidic amino acidinclude a salt with aspartic acid, glutamic acid, etc.
    [0160] Among those, a pharmacologically acceptable salt is preferred, and the examples thereof include, in the case of having a basicfunctional group, a salt with an inorganic acid such ashydrochloric acid, hydrobromic acid, nitric acid, sulfuric acidand phosphoric acid, etc., a salt with an organic acid such asacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaricacid, maleic acid, citric acid, succinic acid, methanesulfonicacid and p-toluenesulfonic acid, etc. and, in the case of havingan acidic functional group, an alkaline metal salt such as asodium salt, a potassium salt, etc., an alkaline earth metal saltsuch as a calcium salt, magnesium salt, etc., and an ammonium salt.
    [0161] The prodrug of the compound of the present invention or asalt thereof means a compound which is converted to the compoundof the present invention under the physiological condition or withreaction in vivo by an enzyme, a gastric acid or the like, that is,a compound which is converted to the compound of the presentinvention by enzymatic oxidation, reduction, hydrolysis, etc.; acompound which is converted to the compound of the presentinvention with hydrolysis by gastric acid, etc.; etc. Examples ofthe prodrug of the compound of the present invention include acompound wherein an amino group of the compound of the presentinvention is substituted with acyl, alkyl or phosphoric acid (e.g.a compound wherein an amino group of the compound of the presentinvention is substituted with eicosanyl, alanyl,pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl,tetrahydrofuranyl, pyrrolidylmethyl,pivaloyloxymethyl or tert-butyl, etc.); a compound wherein ahydroxyl group of the compound of the present invention issubstituted with acyl, alkyl, phosphoric acid or boric acid (e.g.a compound wherein a hydroxyl group of the compound of the presentinvention is substituted with acetyl, palmitoyl, propanoyl,pivaloyl, succinyl, fumaryl, alanyl or dimethylaminomethylcarbonyl,etc.); a compound wherein a carboxyl group of the compound of thepresent invention is substituted with ester or amide (e.g. acompound wherein a carboxyl group of the compound of the presentinvention is substituted with ethyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethylester, ethoxycarbonyloxyethyl ester, phthalidyl ester, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylester, cyclohexyloxycarbonylethylester or methyl amide, etc.); etc. These prodrugs can bemanufactured by a per se known method from the compound of thepresent invention.
    [0162] In addition, the prodrug of the compound of the presentinvention may be a compound which is converted into the compoundof the present invention under the physiological conditions asdescribed in "Pharmaceutical Research and Development", Vol.7(Molecular Design), pp. 163-198, published in 1990 by HirokawaPublishing Co.
    [0163] Furthermore, the compound in Reference Examples 27 to 115 asdescribed below has also a phosphodiesterase IV inhibiting actionin the similar manner to the compound of the present invention.
    [0164] The compound of the present invention or a salt thereof canbe prepared based on Reaction Formula 1 to Reaction Formula 4 asdescribed below and modifications thereof.
    [0165] Symbols of the compounds in the following Reaction Formulaschemes are as described above unless otherwise stated.Furthermore, when Compounds (III), (VI) and (VIII) which areincluded in the compound of the present invention, and Compounds(I), (II), (IV), (V) and (VII) which are corresponding tointermediates thereof in the Reaction Formulae, form salts thereof,and the salts include, for example, those such as the above-mentionedsalts of the compound of the present invention.
    [0166] Compounds (I), (IV) and (V) can be prepared by, for example,the method described in WO 01/70746 or JP-A-2001-335579, or amodification thereof.
    [0167] Compound (II) is commercially available, or can be preparedaccording to a per se known method or a modification thereof.
    [0168] For the general solvent used in the following reactions,alcohols represent methanol, ethanol, 1-propanol, 2-propanol,tert-butyl alcohol and the like; ethers represent diethyl ether,diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like; hydrocarbons represent benzene,toluene, cyclohexane, hexane and the like; amides represent N,N-dimethylformamide,N,N-dimethylacetamide, hexamethylphosphorictriamide and the like; halogenated hydrocarbons representdichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethaneand the like; organic acids represent formic acid,acetic acid, propionic acid, trifluoroacetic acid, methanesulfonicacid and the like; esters represent methyl acetate, ethyl acetate,propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate,tert-butyl acetate, pentyl acetate, hexyl acetate and the likeunless otherwise described.
    [0169] Compound (III) [wherein Y represents CH2 or CH(OH)] isprepared by reacting Compound (I) with Compound (II) under thepresence of an acid or a halogenating reagent.
    [0170] The amount of Compound (II) to be used is about 0.5 to about5 moles, preferably about 0.5 to about 2 moles, relative to 1 moleof Compound (I).
    [0171] The "acid" includes mineral acids such as sulfuric acid,hydrogen chloride, hydrogen bromide, hydrogen iodide, perchloricacid, etc., Lewis acids such as a boron trifluoride diethyl ethercomplex, zinc chloride, aluminum chloride and the like organicacids such as methanesulfonic acid, trifluoromethanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acidand the like and the like. The amount of the acid to be used isabout 1 to about 10 moles, preferably about 1 to about 6 moles,relative to 1 mole of Compound (I).
    [0172] The "halogenating reagent" includes halogens such as bromine, chlorine, iodine, etc., imides such as N-bromosuccinimide, etc.,halogen adducts such as benzyltrimethylammonium dichloroiodate,benzyltrimethylammonium tribromide, etc. and the like. The amountof the halogenating reagent to be used is about 1 to about 5 moles,preferably about 1 to about 2 moles, relative to 1 mole ofCompound (I).
    [0173] This reaction is conducted advantageously using a solventwhich is inert to the reaction. Such solvent is not particularlylimited as long as the reaction proceeds, but preferably, forexample, hydrocarbons, organic acids, halogenated hydrocarbons,esters or a mixture thereof and the like.
    [0174] The reaction time is usually about 10 minutes to about 48hours, preferably about 15 minutes to about 24 hours. Thereaction temperature is usually about -20 to about 150°C,preferably about 0 to about 100°C.
    [0175] Compound (III) [wherein Y represents CH2 or CH(OH)] isprepared by reacting Compound (IV) [wherein Z is an optionallysubstituted hydroxyl group or a halogen atom] with Compound (II)under the presence of an acid or a halogenating reagent.
    [0176] The "optionally substituted hydroxyl group" represented by Zincludes, for example, (1) a hydroxyl group, (2) an optionallyhalogenated C1-6 alkylcarbonyloxy (e.g., acetyloxy,trifluoroacetyloxy, propionyloxy and the like), (3) an optionallyhalogenated C1-6 alkylsulfonyloxy (e.g., methanesulfonyloxy,trifluoromethanesulfonyloxy, ethanesulfonyloxy and the like) and(4) C6-10 arylsulfonyloxy which may have 1 to 3 substituentsselected from halogen, C1-6 alkyl, C1-6 alkoxy and nitro (e.g., phenylsulfonyloxy, naphthylsulfonyloxy, p-chlorophenylsulfonyloxy,m-nitrophenylsulfonyloxy, p-toluenesulfonyloxy and the like).
    [0177] The "halogen atom" represented by Z includes, for example,fluorine, chlorine, bromine and iodine.
    [0178] The amount of Compound (II) to be used is about 0.5 to about5 moles, preferably about 0.5 to about 2 moles, relative to 1 moleof Compound (I).
    [0179] The "acid" includes mineral acids such as sulfuric acid,hydrogen chloride, hydrogen bromide, hydrogen iodide, perchloricacid, etc., Lewis acids such as a boron trifluoride diethyl ethercomplex, zinc chloride, aluminum chloride, etc., organic acidssuch as methanesulfonic acid, trifluoromethanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,etc. and the like. The amount of the acid to be used is about 1to about 10 moles, preferably about 1 to about 6 moles, relativeto 1 mole of Compound (I).
    [0180] The "halogenating reagent" includes halogens such as bromine,chlorine, iodine, etc., imides such as N-bromosuccinimide, etc.,halogen adducts such as benzyltrimethylammonium dichloroiodate,benzyltrimethylammonium tribromide, etc. and the like. The amountof the halogenating reagent to be used is about 1 to about 5 moles,preferably about 1 to about 2 moles, relative to 1 mole ofCompound (I).
    [0181] This reaction is conducted advantageously using a solventwhich is inert to the reaction. Such solvent is not particularlylimited as long as the reaction proceeds, but preferably, forexample, hydrocarbons, organic acids, halogenated hydrocarbons,esters or a mixture thereof and the like.
    [0182] The reaction time is usually about 10 minutes to about 48hours, preferably about 15 minutes to about 24 hours. Thereaction temperature is usually about -20 to about 150°C,preferably about 0 to about 100°C.
    [0183] Compound (VI) is prepared by reacting Compound (V) [whereinR4a is a divalent group formed by removing one hydrogen atom fromR4] with Compound (II) under the presence of an acid or ahalogenating reagent.
    [0184] The amount of Compound (II) to be used is about 0.5 to about5 moles, preferably about 0.5 to about 2 moles, relative to 1 moleof Compound (I).
    [0185] The "acid" includes mineral acids such as sulfuric acid,hydrogen chloride, hydrogen bromide, hydrogen iodide, perchloricacid, etc., Lewis acids such as boron trifluoride diethyl ethercomplex, zinc chloride, aluminum chloride, etc., organic acidssuch as methanesulfonic acid, trifluoromethanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid,etc. and the like. The amount of the acid to be used is about 1to about 10 moles, preferably about 1 to about 6 moles, relativeto 1 mole of Compound (I).
    [0186] The "halogenating reagent" includes halogens such as bromine,chlorine, iodine, etc., imides such as N-bromosuccinimide, etc.,halogen adducts such as benzyltrimethylammonium dichloroiodate,benzyltrimethylammonium tribromide, etc. and the like. The amountof the halogenating reagent to be used is about 1 to about 5 moles,preferably about 1 to about 2 moles, relative to 1 mole ofCompound (I).
    [0187] This reaction is conducted advantageously using a solventwhich is inert to the reaction. Such solvent is not particularlylimited as long as the reaction proceeds, but preferably, forexample, hydrocarbons, organic acids, halogenated hydrocarbons,esters or a mixture thereof and the like.
    [0188] The reaction time is usually about 10 minutes to about 48hours, preferably about 15 minutes to about 24 hours. Thereaction temperature is usually about -20 to about 150°C,preferably about 0 to about 100°C.
    [0189] Compound (VII) is prepared by reducing Compound (III).
    [0190] The reducing method includes, for example, reduction with ametal hydrogen complex such as sodium borohydride, etc., reductionwith borane complexes such as a borane tetrahydrofuran complex, aborane dimethylsulfide complex, etc., reduction with alkylboranessuch as thexyl borane, disiamyl borane, etc., reduction withdiborane, reduction with metals such as zinc, aluminum, tin, iron,etc., reduction with alkali metals such as sodium, lithium,etc./liquid ammonia (Birch reduction), reduction by hydrogenationreaction and the like.
    [0191] In the case of reduction with the metal hydrogen complex, theamount is about 1 to about 10 moles, preferably about 1 to about 3moles, relative to 1 mole of Compound (III).
    [0192] In the case of reduction with the borane complexes,alkylboranes or diborane, the amount is about 1 to about 10 moles,preferably about 1 to about 5 moles, relative to 1 mole ofCompound (III).
    [0193] In the case of reduction with metals or alkali metals, theamount is about 1 to about 20 equivalents, preferably about 1 toabout 5 equivalents to 1 mole of Compound (III).
    [0194] In this reaction, if desired, Lewis acid may be used. The"Lewis acid" includes, for example, aluminum chloride, aluminumbromide, titanium (IV) chloride, tin (II) chloride, zinc chloride, boron trichloride, boron tribromide, boron trifluoride and thelike. The amount of the Lewis acid to be used is about 1 to about5 moles, preferably about 1 to about 2 moles, relative to Compound(III) .
    [0195] A hydrogenation reaction may also be used for the reduction,and in such a case, the catalyst includes palladium carbon,platinum (IV) oxide, Raney nickel, Raney cobalt and the like. Theamount of the catalyst to be used is about 5 to about 1000% byweight, preferably about 10 to about 300% by weight to Compound(III).
    [0196] This reaction is conducted advantageously using a solventwhich is inert to the reaction. Such solvent is not particularlylimited as long as the reaction proceeds, but preferably, forexample, a solvent such as alcohols, ethers, hydrocarbons, amides,organic acids and the like or a mixed solvent thereof and the like.
    [0197] The reaction time varies depending on kinds and amount of areducing agent to be used or activity or amount of a catalyst, butusually about 1 hour to about 100 hours, preferably about 1 hourto about 50 hours. The reaction temperature is usually about -20to about 120°C, preferably about 0 to about 80°C. When ahydrogenation catalyst is used, the hydrogen pressure is usuallyabout 1 to about 100 atm.
    [0198] Compound (VIII) is prepared by oxidizing Compound (VII).
    [0199] The oxidizing agent used in oxidation includes, for example,hydrogen peroxide and the like. The amount of the oxidizing agentto be used is about 1 to about 20 moles, preferably about 1 toabout 5 moles, relative to 1 mole of Compound (VII).
    [0200] In this reaction, it is preferable to use a catalyst such assodium tungstate (VI) and the like. The amount of the catalyst tobe used is about 0.05 to about 1 mole, preferably about 0.05 toabout 0.5 mole, relative to 1 mole of Compound (VII).
    [0201] This reaction is conducted advantageously using a solventwhich is inert to the reaction. Such a solvent is notparticularly limited as long as the reaction proceeds, butpreferably, for example, a solvent such as alcohols, hydrocarbons, amides, halogenated hydrocarbons, water and the like or a mixedsolvent thereof and the like.
    [0202] The reaction time is usually about 30 minutes to about 48hours, preferably about 1 hour to about 24 hours. The reactiontemperature is usually about -20 to about 150°C, preferably about0 to about 100°C.
    [0203] In each of the reactions described above, a starting compoundhaving an amino, carboxy or hydroxy as its substituent may bepresent as a compound in which a protective group used ordinarilyin a peptide chemistry has been introduced into such a substituent,and an objective compound can be obtained by deprotection ifnecessary after the reaction.
    [0204] A protective group for amino includes, for example, formyl,or C1-6 alkyl-carbonyl (e.g., acetyl, propionyl and the like),benzoyl, C1-6 alkoxy-carbonyl (e.g., methoxycarbonyl,ethoxycarbonyl and the like), phenyloxycarbonyl, C7-10 aralkyloxy-carbonyl(e.g., benzyloxycarbonyl and the like), trityl andphthaloyl, each of which may have a substituent, etc. Thesubstituent includes a halogen atom (e.g., fluorine, chlorine,bromine and iodine and the like), C1-6 alkyl-carbonyl (e.g., acetyl,propionyl, valeryl and the like), nitro and the like. The numberof substituents is 1 to 3 or so.
    [0205] A protective group for carboxyl includes, for example, C1-6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyland the like), phenyl, trityl and silyl, each of which may have asubstituent, etc. The substituent includes a halogen atom (e.g.,fluorine, chlorine, bromine and iodine and the like), formyl, C1-6alkyl-carbonyl (e.g., acetyl, propionyl, butylcarbonyl and thelike), nitro, C1-6 alkyl (e.g., methyl, ethyl, tert-butyl and thelike), C6-10 aryl (e.g., phenyl, naphthyl and the like) and thelike. The number of substituents is 1 to 3 or so.
    [0206] A protective group for hydroxy includes, for example, formyl,or C1-6 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyland the like), phenyl, C7-11 aralkyl (e.g., benzyl and thelike), C1-6 alkyl-carbonyl (e.g., acetyl, propionyl and the like), phenyloxycarbonyl, C7-11 aralkyloxy-carbonyl (e.g.,benzyloxycarbonyl and the like), tetrahydropyranyl,tetrahydrofuranyl and silyl, each of which may have a substituent,etc. The substituent includes a halogen atom (e.g., fluorine,chlorine, bromine and iodine and the like), C1-6 alkyl (e.g.,methyl, ethyl, tert-butyl and the like), C7-11 aralkyl (e.g.,benzyl and the like), C6-10 aryl (e.g., phenyl, naphthyl and thelike), nitro and the like. The number of substituents is 1 to 4or so.
    [0207] A deprotection method may be a per se known method or amodification thereof such as a treatment with an acid, base, UV,hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate,tetrabutylammonium fluoride, palladium (II) acetate and the like,as well as a reduction.
    [0208] In any case, deprotection, acylation, alkylation,hydrogenation, oxidation, reduction, carbon chain elongation andsubstituent exchange reaction are further used if necessary, aloneor in combination thereof to synthesize the compound of thepresent invention. These reactions may employ the methodsdescribed for example in New Course of Experimental Chemistry,Vols. 14 and 15, 1977 (MARUZEN) and the like.
    [0209] When an objective product is obtained in a free form by areaction described above, and it may be then converted into a saltin accordance with an ordinary method, and when it is obtained asa salt then it may be converted into a free form or another saltin accordance with an ordinary method. The compound of thepresent invention thus obtained can be isolated and purified froma reaction solution by a known method such as solvent conversion,concentration, solvent extraction, fraction distillation,crystallization, recrystallization, chromatography and the like.
    [0210] When the compound of the present invention is present as aconfiguration isomer, a diastereomer, a conformer and the like,and it can be then isolated, if desired, by a separation orpurification procedure described above. When the compound of thepresent invention is present as a racemate, it can be resolved into an S form and an R form by an ordinary optical resolutionmethod.
    [0211] When the compound of the present invention has itsstereoisomers, then individual isomers or a mixture thereof mayalso be encompassed in the invention.
    [0212] The compound of the present invention may be hydrated or non-hydrated.
    [0213] The compound of the present invention may be labeled with anisotope (e.g., 3H, 14C and 35S) and the like.
    [0214] Since the compound of the present invention or a salt thereofhas an excellent phosphodiesterase inhibiting effect, particularlya phosphodiesterase IV-inhibiting effect and a low toxicity andalso is safe, it can be used as a prophylactic or therapeuticagent in mammals (for example, human, mouse, dog, rat, cattle,etc.) against inflammatory diseases, autoimmune disease, diabetes,atherosclerosis, graft versus host disease, multiple sclerosis,sepsis, psoriasis, osteoporosis, depression, central dysfunctionafter cerebrovascular occlusion, cerebrovascular dementia,Alzheimer's dementia, memory disorders, obesity, cardiacinsufficiency, pulmonary fibrosis, allergic diseases (e.g., atopicdermatitis, allergic rhinitis, urticaria), angina pectoris,myocardial infarction, hypertension, pulmonary hypertension, renaldiseases, brain function diseases, immunity deficiency,ophthalmological diseases, male or female sexual disorders and thelike, as well as a phosphodiesterase IV inhibitor. Especially,the compound of the present invention or a salt thereof can beused as a prophylactic or therapeutic agent against inflammatorydiseases, atopic dermatitis, allergic rhinitis, asthma, chronicobstructive pulmonary diseases, chronic rheumatoid arthritis,autoimmune diseases, depression, Alzheimer's dementia, memorydisorders, osteoporosis, diabetes, atherosclerosis and the like,as well as a phosphodiesterase IV inhibitor. The administrationroute may be oral or parenteral.
    [0215] Particularly, the compound of the present invention can beused, by inhibiting phosphodiesterase IV A, as a prophylactic or therapeutic agent against asthma, atopic dermatitis, allergicrhinitis, chronic obstructive pulmonary diseases, rheumatoidarthritis, depression, Alzheimer's dementia, memory disorders,multiple sclerosis or osteoporosis, by inhibitingphosphodiesterase IV B, as a prophylactic or therapeutic agentagainst asthma, atopic dermatitis, allergic rhinitis, chronicobstructive pulmonary diseases, rheumatoid arthritis, depression,Alzheimer's dementia, memory disorders, multiple sclerosis orosteoporosis, by inhibiting phosphodiesterase IV C, as aprophylactic or therapeutic agent against asthma, atopicdermatitis, allergic rhinitis, chronic obstructive pulmonarydiseases, rheumatoid arthritis, multiple sclerosis or osteoporosis,and by inhibiting phosphodiesterase IV D, as a prophylactic ortherapeutic agent against asthma, atopic dermatitis, allergicrhinitis, chronic obstructive pulmonary diseases, rheumatoidarthritis, depression, Alzheimer's dementia, memory disorders,multiple sclerosis or osteoporosis.
    [0216] Specific examples of formulation include a tablet (includinga sugar-coated tablet and a film-coated tablet), pills, capsules(including microcapsules), granules, fine powders, powders, syrups,emulsions, suspensions, injectable preparations, inhalationpreparations, ointments, eye drops, aerosols, ophthalmic ointments,hard ointments, suppositories, troches, poultices, liniments andthe like. Any of these formulations can be prepared in accordancewith an ordinary method (for example a method described inJapanese Pharmacopoeia).
    [0217] The amount of the compound of the present invention in aformulation according to the invention may vary depending on theformulation, and it is usually 0.01 to 100% by weight, preferably0.1 to 50% by weight, more preferably 0.5 to 20% by weight basedon the whole formulation.
    [0218] Specifically, a tablet is produced by mixing a medicament asit is with an excipient, binder, disintegrating agent or othersuitable additives to form a homogenous mass, granulating by asuitable method, combining with a lubricant and the like, and then compression-molding it, or by mixing a medicament as it is with anexcipient, a binder, a disintegrating agent or other suitableadditives to form a homogenous mass and then compression-moldingit, or by preparing a granule first and then compression-moldingit directly or after mixing it with suitable additives to form ahomogenous mass. The formulation can further contain a coloringagent, a flavoring agent and the like, if necessary. Theformulation can further be film-coated by a suitable coating agent.
    [0219] In a method for producing an injection formulation, a certainamount of a medicament is dissolved, suspended or emulsified in aninjection solvent, physiological saline, Ringer's solution and thelike when the medicament is water-soluble, or usually in vegetableoils and the like when the medicament is water-insoluble, wherebyobtaining a certain quantity, or a certain amount of themedicament is sealed in a vial for an injection formulation.
    [0220] A carrier for an oral formulation includes a materialcustomarily used in the pharmaceutical field, such as starch,mannitol, crystalline cellulose, sodium carboxymethylcellulose andthe like. A carrier for the injectable preparation, for example,distilled water, physiological saline, a glucose solution, aninfusion solution and the like. Other additives generally used ina formulation may also be added properly.
    [0221] The dose of such a formulation may vary depending on the age,the body weight, the condition, the administration route, theadministration frequency and the like, but for example, a dailydose in an adult suffering from asthma is generally 0.01 to 100mg/kg, preferably 0.1 to 50 mg/kg, more preferably 0.5 to 10 mg/kgas an active ingredient (the compound of the present invention),which is given orally once or twice divided a day.
    [0222] While the compound of the invention can exhibit an excellentphosphodiesterase IV-inhibiting activity even when being givenalone, it can also be used in combination (multi-medicamentcombination) with other pharmaceutical components other than thecompound of the present invention (hereinafter abbreviated as acombination drug).
    [0223] Such a combination drug includes, for example, an anti-chronicobstructive pulmonary disease agent (e.g., a β stimulant:fenoterol, salbutamol, terbutaline, formoterol, salmeterol, amucolytic agent: ambroxol, erdosteine, carbocisteine, anexpectorant: fudosteine, an antioxidant: N-acetyl cysteine and thelike), an anti-asthma agent (for example, fluticasone propionate,beclomethasone propionate, theophylline, aminophylline, procaterol,ketotifen, azelastine, seratrodast, etc.), an anti-allergic agent(for example, fexofenadine, epinastine, ebastine, etc.), ananticholinergic agent (for example, thiotropium bromide,ipratropium bromide, flutropium bromide, oxitropium bromide, etc.),an anti-inflammatory agent (for example, diclofenac sodium,ibuprofen, indomethacin, loxoprofen sodium, etc.), anantibacterial agent (for example, cefixime, cefdinir, ofloxacin,tosufloxacin tosylate, levofloxacin, etc.), an antifungal agent(for example, fluconazole, itraconazole, etc.), a diabetes-treatingagent (for example, pioglitazone, nateglinide, voglibose,acarbose, etc.) and the like.
    [0224] In combination of the compound of the present invention andthe combination drug, the administration time of the compound ofthe present invention and the combination drug is not restricted,and the compound of the present invention or the combination drugcan be administered to the subject simultaneously, or may beadministered at different times. The dosage of the combinationdrug may be determined according to the administration amountclinically used, and can be appropriately selected depending onthe subject to be administered, the administration route, thedisease, the combination and the like.
    [0225] The administration mode of the compound of the presentinvention and the combination drug is not particularly limited,and it may be sufficient that the compound of the presentinvention and the combination drug are combined in administration.Examples of such administration mode include the followingmethods: (1) a method wherein the compound of the present invention and the combination drug are simultaneously produced to give asingle preparation which is administered; (2) a method wherein the compound of the present inventionand the combination drug are separately produced to give two kindsof preparations which are administered simultaneously through thesame administration route; (3) a method wherein the compound of the present inventionand the combination drug are separately produced to give two kindsof preparations which are administered through the sameadministration route at different times; (4) a method wherein the compound of the present inventionand the combination drug are separately produced to give two kindsof preparations which are administered simultaneously by differentadministration routes; (5) a method wherein the compound of the present inventionand the combination drug are separately produced to give two kindsof preparations which are administered by different administrationroutes at different times (for example, the compound of thepresent invention and the combination drug are administered inthis order, or in the reverse order) and the like. Hereinafter,these administration modes are referred to as the combinationpreparation of the present invention.
    [0226] The combination preparation of the present invention has lowtoxicity, and for example, the compound of the present inventionand/or the above-mentioned combination drug can be mixed with apharmacologically acceptable carrier according to a per se knownmethod to give a pharmaceutical composition, for example, a tablet(including a sugar-coated tablet and a film-coated tablet),powders, granules, capsules (including a soft capsule), solutions,injections, suppositories, sustained release agents and the like,each of which can be safely administered orally or parenterally(e.g., locally, rectally, intravenously and the like). Theinjection can be administered by intravenous, intramuscular,subcutaneous, intra-organ, intranasal, intradermal, instillation,intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, juxtaposition of tumor and administration directlyto the lesion.
    [0227] The pharmacologically acceptable carrier which may be used inproduction of the combination preparation includes those used forthe above-mentioned pharmaceutical composition of the presentinvention.
    [0228] The compounding ratio of the compound of the presentinvention to the combination drug in the combination preparationof the present invention can be appropriately selected dependingon the administration subject, the administration route, thediseases and the like.
    [0229] For example, the content of the compound of the presentinvention in the combination preparation varies depending on theform of preparation, and is usually from about 0.01% by weight toabout 100% by weight, preferably from about 0.1% by weight toabout 50% by weight, more preferably from about 0.5% by weight toabout 20% by weight, relative to the total of the preparation.
    [0230] The content of the combination drug in the combinationpreparation of the present invention varies depending on the formof preparation, and is usually from about 0.01% by weight to about100% by weight, preferably from about 0.1% by weight to about 50%by weight, more preferably from about 0.5% by weight to about 20%by weight, to the total of the preparation.
    [0231] The content of additives such as a carrier and the like inthe combination preparation of the present invention variesdepending on the form of preparation, and is usually from about 1%by weight to about 99.99% by weight, preferably from about 10% byweight to about 90% by weight, to the total of the preparation.
    [0232] When the compound of the present invention and thecombination drug are formulated separately, the same contents maybe adopted.
    [0233] These preparations can be manufactured by a per se knownmethod commonly used in the pharmaceutical manufacturing process.
    [0234] For example, the compound of the present invention and thecombination drug can be provided as an injectable preparation such as an aqueous injection together with a dispersing agent (e.g.,Tween 80 (manufactured by Atlas Powder, US), HCO 60 (manufacturedby Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose,sodium alginate, hydroxypropylmethyl cellulose, dextrin and thelike), a stabilizer (e.g., ascorbic acid, sodium pyrosulfite andthe like), a surfactant (e.g., Polysorbate 80, Macrogol and thelike), a solubilizer (e.g., glycerin, ethanol and the like), abuffer (e.g., phosphoric acid and an alkali metal salt thereof,citric acid and an alkali metal salt thereof and the like), anisotonizing agent (e.g., sodium chloride, potassium chloride,mannitol, sorbitol, glucose and the like), a pH regulator (e.g.,hydrochloric acid, sodium hydroxide and the like), a preservative(e.g.', ethyl p-oxybenzoate, benzoic acid, methylparaben,propylparaben, benzyl alcohol and the like), a dissolving agent(e.g., cone. glycerin, meglumine and the like), a solubilizingagent (e.g., propylene glycol, sucrose and the like), a soothingagent (e.g., glucose, benzyl alcohol and the like) and the like,or an oily injection by dissolving, suspending or emulsifying themin a vegetable oil such as olive oil, sesame oil, cotton seed oil,corn oil and the like or a solubilizing agent such as propyleneglycol.
    [0235] In the case of a preparation for oral administration, thecompound of the present invention and the combination drug can beprovided as a preparation for oral administration according to aper se known method by adding an excipient (e.g., lactose, sucrose,starch and the like), a disintegrating agent (e.g., starch,calcium carbonate and the like), a binder (e.g., starch, arabicgum, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropylcellulose and the like), a lubricant (e.g., talc, magnesiumstearate, polyethylene glycol 6000 and the like) and the like, tothe compound of the present invention or the combination drug, andcompression-molding the mixture, then if desired, coating themolded product by a per se known method for the purpose of maskingof taste, enteric property or sustained release. The coatingagent includes, for example, hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (methacrylic acid/acrylicacid copolymer, manufactured by Rohm, Germany), pigment (e.g.,iron oxide red, titanium dioxide and the like) and the like. Thepreparation for oral administration may be either a rapid releasepreparation or a sustained release preparation.
    [0236] For example, in the case of a suppository, the compound ofthe present invention and the combination drug can be provided asan oil or aqueous solid, semisolid or liquid suppository accordingto a per se known method. The oily substrate used in the above-mentionedcomposition includes, for example, glycerides of higherfatty acids [e.g., cacao butter, Witepsol (manufactured by DynamitNobel, Germany) and the like], intermediate grade fatty acids[e.g., Myglyol (manufactured by Dynamit Nobel, Germany) and thelike], or vegetable oils (e.g., sesame oil, soy bean oil, cottonseed oil and the like) and the like. Further, the aqueous baseincludes, for example, polyethylene glycols and propylene glycol,and the aqueous gel base includes, for example, natural gums,cellulose derivatives, vinyl polymers, acrylic acid polymers andthe like.
    [0237] The above-mentioned sustained release agent includessustained release microcapsules and the like. For obtaining asustained release microcapsule, a per se known method can beadopted. For example, it is preferable to mold into a sustainedrelease preparation shown in [2] below.
    [0238] A compound of the present invention is preferably molded intoan oral administration preparation such as a solid preparation(e.g., powder, granule, tablet, capsule and the like) and the like,or molded into a rectal administration preparation such as asuppository. Particularly, an oral administration preparation ispreferable.
    [0239] The combination drug can be provided as the above-mentioneddrug form depending on the kind of the drug.
    [0240] In the following, there will be shown specifically [1] aninjection of the compound of the present invention or thecombination drug and a production method thereof, [2] a rapidrelease preparation or sustained release preparation of thecompound of the present invention or the combination drug and aproduction method thereof and [3] a sublingual tablet, a buccal oran intraoral rapid integrating agent of the compound of thepresent invention or the combination drug or a production methodthereof. [1] Injectable preparation and a production method thereof
    [0241] It is preferred that an injectable preparation is prepared bydissolving the compound of the present invention or thecombination drug in water. This injectable preparation may beallowed to contain a benzoate and/or a salicylate.
    [0242] The injection is obtained by dissolving the compound of thepresent invention or the combination drug, and if desired, abenzoate and/or a salicylate, into water.
    [0243] The above-mentioned salts of benzoic acid and salicylic acidinclude, for example, salts of alkali metals such as sodium,potassium and the like, salts of alkaline earth metals such ascalcium, magnesium and the like, ammonium salts, meglumine salts,organic acid salts such as tromethamol and the like.
    [0244] The concentration of the compound of the present invention orthe combination drug in the injection is from 0.5 w/v% to 50 w/v%,preferably from about 3 w/v% to about 20 w/v%. The concentrationof a salt of benzoic acid or/and a salt of salicylic acid is from0.5 w/v% to 50 w/v%, preferably from 3 w/v% to 20 w/v%.
    [0245] Conventional additives to be used in an injection may beappropriately added in a preparation of the present invention.Examples of the additives include a stabilizer (e.g. ascorbic acid,sodium pyrosulfite and the like), a surfactant (e.g., Polysorbate80, macrogol and the like), a solubilizer (e.g., glycerin, ethanoland the like), a buffer (e. g., phosphoric acid and an alkalimetal salt thereof, citric acid and an alkali metal salt thereofand the like), an isotonizing agent (e.g., sodium chloride, potassium chloride and the like), a dispersing agent (e.g.,hydroxypropylmethyl cellulose, dextrin and the like), a pHregulator (e.g., hydrochloric acid, sodium hydroxide and the like),a preservative (e.g., ethyl p-oxybenzoate, benzoic acid and thelike), a dissolving agent (e.g., conc. glycerin, meglumine and thelike), a solubilizing agent (e.g., propylene glycol, sucrose andthe like), a soothing agent (e.g., glucose, benzyl alcohol and thelike) and the like. These additives are blended in a usualproportion generally used in an injection.
    [0246] It is advantageous that the pH of the injection is controlledfrom 2 to 12, preferably from 2.5 to 8.0 by addition of a pHregulator.
    [0247] An injectable preparation is obtained by dissolving thecompound of the present invention or the combination drug and ifdesired, a salt of benzoic acid and/or a salt of salicylic acid,and if necessary, the above-mentioned additives into water. Thesemay be dissolved in any order, and can be appropriately dissolvedby the method similar to that in a conventional method ofproducing an injection.
    [0248] An aqueous solution for injection may be advantageouslyheated, alternatively, for example, filter sterilization, highpressure heat sterilization and the like can be conducted in thesame manner as those for a usual injection, to provide aninjection.
    [0249] It may be advantageous that an aqueous solution for injectionis subjected to high pressure heat sterilization at 100°C to 121°Cfor 5 minutes to 30 minutes.
    [0250] Further, a preparation endowed with the antibacterialproperty of a solution may also be produced so that it can be usedas a preparation which is divided and administered multiple-times. [2] A sustained release preparation or a rapid releasepreparation, and a production method thereof
    [0251] Preferred is a sustained release preparation which isobtained, by coating a core containing the compound of the presentinvention or the combination drug with a film forming agent such as a water-insoluble substance, swellable polymer and the like, ifdesired. For example, a sustained release preparation for oraladministration of once administration a day type is preferable.
    [0252] The water insoluble substance used in film forming agentincludes, for example, cellulose ethers such as ethyl cellulose,butyl cellulose and the like; cellulose esters such as celluloseacetate, cellulose propionate and the like; polyvinyl esters suchas polyvinyl acetate, polyvinyl butyrate and the like; an acrylicacid/methacrylic acid copolymer, a methyl methacrylate copolymer,an ethoxyethyl methacrylate/cinnamoethyl methacrylate/aminoalkylmethacrylate copolymer, polyacrylic acid, polymethacrylic acid,methacrylic acid alkyl amide copolymer, poly(methyl methacrylate),polymethacrylate, polymethacryl amide, amino alkyl methacrylatecopolymer, poly(methacrylic acid anhydride), glycidyl methacrylatecopolymer, and specially an Eudragits (manufactured by RohmPharma) such as Eudragit RS-100, RL-100, RS-30D, RL-30D, RL-PO,RS-PO (a copolymer of ethyl acrylate/methylmethacrylate/chlorotrimethylmethacrylate/ethyl ammonium), EudragitNE-30D (a copolymer of methyl methacrylate/ethyl acrylate) and thelike, a hydrogenated oil such as hardened caster oil (e.g., Lubriwax (Freund Corporation) and the like) and the like; a wax such ascarnauba wax, fatty acid glycerin ester, paraffin and the like;polyglycerin fatty acid ester and the like.
    [0253] The swellable polymer is preferably a polymer having acidicdissociating group and pH-dependent swelling property, and apolymer having an acidic dissociating group which swells little inan area such as the stomach and swells in a neutral area such asthe small intestine or the large intestine.
    [0254] The polymer having the acidic dissociating group and pH-dependentswelling property includes, for example, crosslinkablepolyacrylic polymer such as Carbomer 934P, 940, 941, 974P, 980,1342 and the like, polycarbophil, calcium polycarbophil (allmanufactured by BF Goodrich.), Hibiswako 103, 104, 105, 304 (allmanufactured by Wako Pure Chemical Co., Ltd.) and the like.
    [0255] The film forming agent used in a sustained release preparation may further contain a hydrophilic substance.
    [0256] The hydrophilic substance includes, for example, apolysaccharide optionally having sulfuric acid group such aspullulans, dextrin, alginic acid alkali metal salt and the like; apolysaccharide having a hydroxyalkyl group or a carboxyalkyl groupsuch as hydroxypropyl cellulose, hydroxypropyl methyl cellulose,sodium carboxymethyl cellulose and the like; methyl cellulose;polyvinyl pyrrolidone; polyvinyl alcohol; polyethylene glycol; andthe like.
    [0257] The content of the water-insoluble substance in the filmforming agent of the sustained release preparation is about30%(w/w) to about 90%(w/w), preferably about 35%(w/w) to about80%(w/w), and more preferably about 40%(w/w) to about 75%(w/w).The content of the swellable polymer is about 3%(w/w) to about30%(w/w), preferably about 3%(w/w) to about 15%(w/w). The filmforming agent may further contain a hydrophilic substance, in thiscase, the content of the hydrophilic substance in the film formingagent is about 50%(w/w) or less, preferably about 5%(w/w) to about40%(w/w), and more preferably about 5%(w/w) to about 35%(w/w).This %(w/w) indicates % by weight based on a film forming agentcomposition which is obtained by removing a solvent (e.g., water,lower alcohols such as methanol, ethanol, etc. and the like) froma solution of the film forming agent.
    [0258] The sustained release preparation is manufactured bypreparing a core containing drugs as exemplified below, then,coating the resulted core with a liquid of the film forming agentprepared by heating and dissolving a water-insoluble substance, aswellable polymer and the like or by dissolving or dispersing itin a solvent. I. Preparation of a core containing a drug
    [0259] The form of a core containing a drug to be coated with a filmforming agent (hereinafter, sometimes simply referred to as acore) is not particularly limited, and preferably the core isformed into particles such as granules or fine particles.
    [0260] When the core is composed of granules or fine particles, the average particle size thereof is preferably from about 150 toabout 2,000 µm, further preferably, from about 500 µm to about1,400 µm.
    [0261] Preparation of the core can be conducted by a usualproduction method. For example, it can be prepared by mixing asuitable excipient, a binder, a disintegrating agent, a lubricant,a stabilizer and the like with a drug, and subjecting the mixtureto wet-extrusion granulation, fluidized-bed granulation or thelike.
    [0262] The content of the drugs in the core is from about 0.5%(w/w)to about 95%(w/w), preferably from about 5%(w/w) to about 80%(w/w),further preferably from about 30%(w/w) to about 70%(w/w).
    [0263] The excipient contained in the core includes, for example,saccharides such as sucrose, lactose, mannitol, glucose and thelike, starch, crystalline cellulose, calcium phosphate, cornstarch and the like Among them, crystalline cellulose and cornstarch are preferable.
    [0264] The binders include, for example, polyvinyl alcohol,hydroxypropyl cellulose, polyethylene glycol, polyvinylpyrrolidone, Pluronic F68, arabic gum, gelatin, starch and thelike. The disintegrating agents include, for example,carboxymethyl cellulose calcium (ECG505), croscarmellose sodium(Ac-Di-Sol), crosslinkable polyvinyl pyrrolidone (crospovidone),low-substituted hydroxypropyl cellulose (L-HPC) and the like.Among these, hydroxypropyl cellulose, polyvinyl pyrrolidone andlow-substituted hydroxypropyl cellulose are preferable. Thelubricant or the aggregation inhibitor includes, for example, talc,magnesium stearate and an inorganic salt thereof. The lubricantincludes a polyethylene glycol and the like. The stabilizingagent includes an acid such as tartaric acid, citric acid,succinic acid, fumaric acid, maleic acid and the like.
    [0265] In addition to the above-mentioned preparation methods, thecore can also be prepared by, for example, a rolling granulationmethod in which a drug or a mixture of the drug with an excipient,a lubricant and the like is added portionwise to an inert carrier particle which is the center of the core while spraying a binderdissolved in a suitable solvent such as water, lower alcohols(e.g., methanol, ethanol, etc.) and the like, a pan coating method,a fluidized bed coating method or a melt granulating method. Theinert carrier particle includes, for example, those made ofsucrose, lactose, starch, crystalline cellulose or waxes, and theaverage particle size thereof is preferably from about 100 µm toabout 1,500 µm.
    [0266] For the purpose of separating the drug contained in the corefrom the film forming agent, the surface of the core may be coatedwith a protective agent. The protective agent includes, forexample, the above-mentioned hydrophilic substances, water-insolublesubstances and the like. The protective agent ispreferably polyethylene glycol, and polysaccharides having ahydroxyalkyl group or carboxyalkyl group, more preferablyhydroxypropylmethyl cellulose and hydroxypropyl cellulose. Theprotective agent may contain a stabilizer such as acids such astartaric acid, citric acid, succinic acid, fumaric acid, maleicacid and the like, and a lubricant such as talc and the like.When the protective agent is used, the coating amount is fromabout 1%(w/w) to about 15% (w/w), preferably from about 1%(w/w) toabout 10%(w/w), further preferably from about 2%(w/w) to about8%(w/w), based on the core.
    [0267] The coating of the protective agent can be carried out by ausual coating method, and specifically the coating can be carriedout by spraying the protective agent by a fluidized bed coatingmethod, a pan coating method and the like. II. Coating of a core with a film forming agent
    [0268] A core obtained in the above-mentioned step I is coated witha solution of the film forming agent obtained by heating anddissolving the above-mentioned water-insoluble substance and a pH-dependentswellable polymer and a hydrophilic substance, or bydissolving or dispersing them in a solvent, to give a sustainedrelease preparation.
    [0269] The method for coating a core with a solution of the film forming agent includes, for example, a spray coating method andthe like.
    [0270] The composition ratio of a water-insoluble substance, aswellable polymer and a hydrophilic substance in a solution of thefilm forming agent is appropriately selected so that the contentsof these components in a coated film are those as described above,respectively.
    [0271] The coating amount of the film forming agent is from about1%(w/w) to about 90%(w/w), preferably from about 5%(w/w) to about50%(w/w), further preferably from about 5%(w/w) to about 35%(w/w),based on the core (not including coating amount of the protectiveagent).
    [0272] The solvent in the solution of the film forming agentincludes water or an organic solvent alone or in admixture thereof.In the case of use in admixture, the mixing ratio of water to theorganic solvent (water/organic solvent: ratio by weight) can bevaried in the range from 1 to 100%, and preferably from about 1%to about 30%. The organic solvent is not particularly limited aslong as it dissolves a water-insoluble substance, and for example,it includes lower alcohols such as methanol, ethanol, 2-propanol,1-butanol and the like, lower alkanones such as acetone and thelike, acetonitrile, chloroform, dichloromethane and the like.Among them, lower alcohols are preferable, and ethanol and 2-propanolare particularly preferable. Water, and a mixture ofwater with an organic solvent are preferably used as a solvent fora film forming agent. In this case, if necessary, an acid such astartaric acid, citric acid, succinic acid, fumaric acid, maleicacid and the like may also be added into a solution of the filmforming agent for stabilizing the solution of the film formingagent.
    [0273] The operation in the case of coating by a spray coatingmethod can be conducted by a usual coating method, andspecifically it can be conducted by spray-coating a solution ofthe film forming agent onto a core, for example, by a fluidizedbed coating method, a pan coating method and the like. In this case, if necessary, talc, titanium oxide, magnesium stearate,calcium stearate, light anhydrous silicic acid and the like mayalso be added as a lubricant, and glycerin fatty esters, hardenedcastor oils, triethyl citrate, cetyl alcohol, stearyl alcohol andthe like may also be added as a plasticizer.
    [0274] After coating with a film forming agent, if necessary, anantistatic agent such as talc and the like may be mixed.
    [0275] The rapid release preparation may be liquid (a solution, asuspension, an emulsion and the like) or solid (particles, a pill,a tablet and the like). It may be an oral preparation or aparenteral preparation such as an injectable preparation and thelike, and preferably an oral preparation.
    [0276] The rapid release preparation may usually also contain acarrier, an additive and an excipient customarily used in thefield of formulation (hereinafter, sometimes abbreviated as theexcipient) in addition to the drug as an active component. Thepreparation excipient used is not particularly limited as long asit is an excipient ordinarily used as a preparation excipient.For example, the excipient for an oral solid preparation includeslactose, starch, corn starch, crystalline cellulose (Avicel PH101,manufactured by Asahi Chemical Industry Co., Ltd. and the like),powdered sugar, granulated sugar, mannitol, light anhydroussilicic acid, magnesium carbonate, calcium carbonate, L-cysteineand the like, and preferably corn starch, mannitol and the like.These excipients can be used alone or in combinations of two ormore. The content of the excipient is, for example, from about4.5 w/w% to about 99.4 w/w%, preferably from about 20 w/w% toabout 98.5 w/w%, further preferably from about 30 w/w% to about 97w/w%, based on the total amount of the rapid release preparation.
    [0277] The content of a drug in the rapid release preparation can beappropriately selected in the range from about 0.5% to about 95%,preferably from about 1% to about 60% based on the total amount ofthe rapid release preparation.
    [0278] When the rapid release preparation is an oral solidpreparation, it usually contains a disintegrating agent in addition to the above-mentioned components. The disintegratingagent includes, for example, carboxymethyl cellulose calcium (ECG-505,manufactured by Gotoku Yakuhin), croscarmellose sodium (forexample, Actisol, manufactured by Asahi Chemical Industry Co.,Ltd.), crospovidone (for example, Kollidon CL, manufactured byBASF), low-substituted hydroxypropyl cellulose (manufactured byShin-Etsu Chemical Co., Ltd.), carboxymethyl starch (manufacturedby Matsutani Kagaku K.K.), carboxymethyl starch sodium (Exprotab,manufactured by Kimura Sangyo), partially pregelatinized starch(PCS, manufactured by Asahi Chemical Industry Co., Ltd.) and thelike, and for example, includes those which disintegrate a granuleby contacting with water and absorbing water, causing swelling, ormaking a channel between an effective ingredient constituting thecore and an excipient. These disintegrating agents can be usedalone or in combinations of two or more. The amount of thedisintegrating agent used is appropriately selected depending onthe kind and the compounding amount of a drug used, formulationdesign for release property and the like, and for example, fromabout 0.05 w/w% to about 30 w/w%, preferably from about 0.5 w/w%to about 15 w/w%, based on the total amount of the rapid releasingagent.
    [0279] When the rapid release preparation is an oral solidpreparation, it may further contain if desired, additivesconventional in solid preparations in addition to the above-mentionedcomposition. Such an additive includes, for example, abinder (e.g., sucrose, gelatin, arabic gum powder, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,carboxylmethyl cellulose, polyvinylpyrrolidone, pullulans, dextrinand the like), a lubricant (e.g., polyethylene glycol, magnesiumstearate, talc, light anhydrous silicic acid (for example, Aerosil(Nippon Aerosil Co., Ltd.)), a surfactant (e.g., anionicsurfactants such as sodium alkylsulfate and the like, nonionicsurfactants such as polyoxyethylene fatty acid ester andpolyoxyethylene sorbitan fatty acid ester, polyoxyethylene castoroil derivatives and the like), a coloring agent (e.g., a tar-based pigment, caramel, iron oxide red, titanium oxide and riboflavins),and if necessary, an appetizing agent (e.g., a sweetening agent, aflavoring agent and the like), an adsorbent, a preservative, awetting agent, an antistatic agent and the like. Further, astabilizer such as an organic acid such as tartaric acid, citricacid, succinic acid, fumaric acid and the like may also be added.
    [0280] The above-mentioned binder includes preferably hydroxypropylcellulose, polyethylene glycol and polyvinylpyrrolidone and thelike.
    [0281] The rapid releasing preparation can be prepared by mixing theabove-mentioned components, and if necessary, further kneading themixture, and molding it based on a usual technology of producingpreparations. The above-mentioned mixing is conducted bygenerally used methods, for example, mixing, kneading and the like.Specifically, when a rapid release preparation is formed, forexample, into a particle, it can be prepared, according to thesame means as in the above-mentioned method for preparing a coreof a sustained release preparation, by mixing the components usinga vertical granulator, a universal kneader (manufactured by HataTekkosho), a fluidized bed granulator FD-5S (manufactured byPulek) and the like, and then subjecting the mixture to wetextrusion granulation, fluidized bed granulation and the like.
    [0282] Thus obtained rapid releasing preparation and sustainedreleasing preparation may be themselves provided as the products,or provided appropriately together with preparation excipients andthe like, separately, by an ordinary method to a preparation, andthen they may be administered simultaneously or may beadministered in combination at any administration interval, orthey may be themselves provided as one oral preparation (e.g.,granules, fine particles, tablets, capsules and the like) orprovided as one oral preparation together with preparationexcipients and the like. It may also be permissible that they areprovided as granules or fine particles, and filled in the samecapsule to be used as a preparation for oral administration. [3] Sublingual, buccal or intraoral rapid disintegrating agent and a production method thereof
    [0283] Sublingual, buccal or intraoral rapid disintegrating agentsmay be a solid preparation such as a tablet and the like, or maybe an oral mucosa membrane patch (film).
    [0284] The sublingual, buccal or intraoral rapid disintegratingagent is preferably a preparation containing the compound of thepresent invention or the combination drug and an excipient. Itmay contain also auxiliary agents such as a lubricant, anisotonizing agent, a hydrophilic carrier, a water-dispersiblepolymer, a stabilizer and the like. Further, for easy absorptionand increased bioavailability, β-cyclodextrin or β-cyclodextrinderivatives (e.g., hydroxypropyl-β-cyclodextrin and the like) andthe like may also be contained.
    [0285] The above-mentioned excipient includes lactose, sucrose, D-mannitol,starch, crystalline cellulose, light anhydrous silicicacid and the like. The lubricant includes magnesium stearate,calcium stearate, talc, colloidal silica and the like, andparticularly preferably magnesium stearate and colloidal silica.The isotonizing agent includes sodium chloride, glucose, fructose,mannitol, sorbitol, lactose, saccharose, glycerin, urea and thelike, and particularly preferably mannitol. The hydrophiliccarrier includes a swellable hydrophilic carrier such ascrystalline cellulose, ethyl cellulose, crosslinkablepolyvinylpyrrolidone, light anhydrous silicic acid, silicic acid,dicalcium phosphate, calcium carbonate and the like, andparticularly preferably crystalline cellulose (e.g., finecrystalline cellulose and the like). The water-dispersiblepolymer includes gums (e.g., gum tragacanth, acacia gum andcyamoposis gum), alginates (e.g., sodium alginate), cellulosederivatives (e.g., methyl cellulose, carboxymethyl cellulose,hydroxymethyl cellulose, hydroxypropyl cellulose andhydroxypropylmethyl cellulose), gelatin, water-soluble starch,polyacrylic acids (e.g., Carbomer), polymethacrylic acid,polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbophil, ascorbate, palmitates and the like, and preferably hydroxypropylmethyl cellulose, polyacrylic acid, alginate, gelatin,carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycoland the like, particularly preferably hydroxypropylmethylcellulose. The stabilizer includes cysteine, thiosorbitol,tartaric acid, citric acid, sodium carbonate, ascorbic acid,glycine, sodium sulfite and the like, and particularly preferablycitric acid and ascorbic acid.
    [0286] The sublingual, buccal or intraoral rapid disintegratingagent can be manufactured by mixing the compound of the presentinvention or the combination drug and an excipient by a per seknown method. Further, if desired, an auxiliary agent such as alubricant, an isotonizing agent, a hydrophilic carrier, a water-dispersiblepolymer, a stabilizer, a coloring agent, a sweeteningagent, a preservative and the like may be mixed. The sublingual,buccal or intraoral rapid disintegrating agent is obtained bymixing the above-mentioned components simultaneously or at timeintervals, and then subjecting the mixture to tablet-makingmolding under pressure. For obtaining suitable hardness, it mayalso be permissible that the materials are moistened by using asolvent such as water, alcohol and the like if desired before andafter the tablet making process, and after the molding, thematerials are dried, to obtain a product.
    [0287] In the case of molding into a mucosa membrane patch (film),the compound of the present invention or the combination drug andthe above-mentioned water-dispersible polymer (preferably,hydroxypropyl cellulose and hydroxypropylmethyl cellulose), anexcipient and the like are dissolved in a solvent such as waterand the like, and the resulted solution is cast to give a film.Further, additives such as a plasticizer, a stabilizer, anantioxidant, a preservative, a coloring agent, a buffer, asweetening agent and the like may also be added. For impartingsuitable elasticity to the film, glycols such as polyethyleneglycol, propylene glycol and the like may be contained, or forenhancing adhesion of the film to an intraoral mucosa membranelining, a bio-adhesive polymer (e.g., polycarbophil, carbopol) may also be contained. In the casting, a solution is poured on thenon-adhesive surface, spread to uniform thickness (preferably,about 10 micron to about 1,000 micron) by an application tool suchas a doctor blade and the like, and the solution is then dried toform a film. It may be advantageous that thus formed film isdried at room temperature or under heat, and cut into desiredsurface area.
    [0288] The intraoral rapid disintegrating preparation is preferablysolid rapid diffuse preparation composed of a network bodycomprising the compound of the present invention or thecombination drug, and a water-soluble or water-diffusible carrierwhich is inert to the compound of the present invention or thecombination drug. This network body is obtained by sublimating asolvent from the solid composition constituted of a solutionprepared by dissolving the compound of the present invention orthe combination drug in a suitable solvent.
    [0289] The composition of an intraoral rapid disintegrating agentpreferably contains a matrix forming agent and a secondarycomponent in addition to the compound of the present invention orthe combination drug.
    [0290] The matrix forming agent includes animal proteins orvegetable proteins such as gelatins, dextrins, soybean, wheat,psyllium seed protein and the like; rubber substances such asarabic gum, guar gum, agar, xanthan gum and the like;polysaccharides; alginic acids; carboxymethyl celluloses;carrageenans; dextrans; pectins; synthetic polymers such aspolyvinylpyrrolidone and the like; substances derived from agelatin-arabic gum complex and the like. Further, it includessaccharides such as mannitol, dextrose, lactose, galactose,trehalose and the like; cyclic saccharides such as cyclodextrinand the like; inorganic salts such as sodium phosphate, sodiumchloride, aluminum silicate and the like; amino acids having 2 to12 carbon atoms such as glycine, L-alanine, L-aspartic acid, L-glutamicacid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanineand the like.
    [0291] One or more of the matrix forming agent(s) can be introducedin a solution or a suspension before solidification. Such matrixforming agent may be present in addition to a surfactant, or maybe present with the surfactant excluded. The matrix formingagents may help to keep the compound of the present invention orthe combination drug diffused in the solution or the suspension,in addition to formation of the matrix.
    [0292] The composition may contain secondary components such as apreservative, an antioxidant, a surfactant, a thickening agent, acoloring agent, a pH controlling agent, a flavoring agent, asweetening agent, a food taste masking agent and the like. Thecoloring agent includes red, black and yellow iron oxides, and FD& C dyes such as FD & C Blue 2, FD & C Red 40 and the likemanufactured by Elis and Eberald. Examples of the suitableflavoring agent include mint, raspberry, licorice, orange, lemon,grapefruit, caramel, vanilla, cherry, grape flavor andcombinations thereof. Examples of the suitable pH controllingagent include citric acid, tartaric acid, phosphoric acid,hydrochloric acid and maleic acid. Examples of the suitablesweetening agent include aspartame, acesulfame K and thaumatineand the like. Examples of the suitable food taste-masking agentinclude sodium bicarbonate, ion exchange resin, cyclodextrin-inclusioncompounds, adsorbent substances and microcapsulatedapomorphine.
    [0293] The preparation contains the compound of the presentinvention or the combination drug in an amount of usually fromabout 0.1% by weight to about 50% by weight, preferably from about0.1% by weight to about 30% by weight, and is preferably apreparation (such as the above-mentioned sublingual agent, buccaland the like) which can dissolve 90% or more of the compound ofthe present invention or the combination drug (into water) withinthe time range of about 1 minute to about 60 minutes, preferablyof about 1 minute to about 15 minutes, more preferably of about 2minutes to about 5 minutes, and intraoral rapid disintegratingpreparations which are disintegrated within the range of 1 second to 60 seconds, preferably of 1 to 30 seconds, further preferablyof 1 to 10 seconds after being placed in the oral cavity.
    [0294] The content of the above-mentioned excipient in the wholepreparation is from about 10% by weight to about 99% by weight,preferably from about 30% by weight to about 90% by weight. Thecontent of the β-cyclodextrin or β-cyclodextrin derivative in thewhole preparation is from 0 to about 30% by weight. The contentof the lubricant in the whole preparation is from about 0.01% byweight to about 10% by weight, preferably from about 1% by weightto about 5% by weight. The content of the isotonizing agent inthe whole preparation is from about 0.1% by weight to about 90% byweight, preferably from about 10% by weight to about 70% by weight.The content of the hydrophilic carrier agent in the wholepreparation is from about 0.1% by weight to about 50% by weight,preferably from about 10% by weight to about 30% by weight. Thecontent of the water-dispersible polymer in the whole preparationis from about 0.1 to about 30% by weight, preferably from about10% by weight to about 25% by weight. The content of thestabilizer in the whole preparation is from about 0.1% by weightto about 10% by weight, preferably from about 1% by weight toabout 5% by weight. The above-mentioned preparation may furthercontain additives such as a coloring agent, a sweetening agent, apreservative and the like, if necessary.
    [0295] The dose of a combination preparation of the presentinvention varies depending on the kind of the compound (I) of thepresent invention, the age, the body weight, the symptoms, thedrug form, the administration method, the administration time andthe like, and for example, to a patient (adult, body weight: about60 kg), the combination preparation is administered intravenouslyat a dose of about 0.01 to about 1,000 mg/kg/day, preferably about0.01 to about 100 mg/kg/day, more preferably about 0.1 to about100 mg/kg/day, particularly about 0.1 to about 50 mg/kg/day,particularly about 1.5 to about 30 mg/kg/day in terms of thecompound of the present invention or the combination drug,respectively, once or several times divided a day. Of course, since the dose as described above varies depending on variousconditions, it may be sometimes sufficient to administer smalleramounts than the above-mentioned dosage, and further it may besometimes necessary to administer greater amounts than that.
    [0296] The amount of the combination drug can be set at any valueunless side effects are problematical. The daily dosage in termsof the combination drug varies depending on the severity ofsymptoms, the age, the sex, the body weight, the sensitivitydifference of the subject, the administration time and interval,the property, formulation and kind of the pharmaceuticalpreparation, the kind of effective ingredient and the like, butnot particularly limited thereto; for example, in the case of oraladministration, the dose of the drug is usually from about 0.001mg to 2,000 mg, preferably from about 0.01 mg to 500 mg, furtherpreferably from about 0.1 mg to 100 mg, per 1 kg body weight of amammal, which is usually administered once to four times divided aday.
    [0297] In administration of the combination preparation, thecompound of the present invention may be administered afteradministration of the combination drug or the combination drug maybe administered after administration of the compound of thepresent invention, though they may be administered simultaneously.When administered at a time interval, the interval variesdepending on the effective ingredient, the drug form and theadministration method. For example, when the combination drug isadministered first, the compound of the present invention isadministered within time range of from 1 minute to 3 days,preferably from 10 minutes to 1 day, more preferably from 15minutes to 1 hour after administration of the combination drug.When the compound of the present invention is administered first,the combination drug is administered within time range of from 1minute to 1 day, preferably from 10 minutes to 6 hours, morepreferably from 15 minutes to 1 hour after administration of thecompound of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION
    [0298] The present invention is further detailed in the followingReference Examples, Examples, Formulation Examples andExperimental Examples, any of which are for illustrative purposeonly and is not intended to restrict the invention and can bemodified without departing from the scope of the invention.
    [0299] In the following Reference Examples and Examples, the term"room temperature" usually means a temperature from about 10 toabout 35°C. % means a mol/mol% when used for a yield andotherwise it means % by weight. A basic silica gel used was NH-DM1020manufactured by FUJI SILYSIA CHEMICAL LTD. Anyunidentifiable broad peak such as those of OH and NH protons ineach proton NMR spectrum are not included in the data.
    [0300] Corn starch, hydroxypropylcellulose, magnesium stearate,lactose, croscarmellose sodium, hydroxypropylmethyl cellulose,iron (III) oxide and titanium oxide to be used in the followingFormulation Examples were appropriate products for JapanesePharmacopoeia revision 14th.
    [0301] Abbreviations shown below are defined as follows: s: Singlet d: Doublet t: Triplet q: Quartet m: Multiplet J: Coupling constant Hz: Hertz CDCl3: chloroform-d DMSO-d6: dimethylsulfoxide-d6 1H NMR: Proton nuclear magnetic resonance
    [0302] To a solution of 1-methyl 2-aminoterephthalate (8.0 g, 41.0mmol) in N,N-dimethylformamide (40 ml) were added 1-hydroxy-1H-benzotriazole·ammoniumsalt (6.86 g, 45.1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (8.64 g, 45.1 mmol)under ice-cooling, and the mixture was stirred at the same temperature for 1.5 hours and at room temperature for 30 minutes.The reaction mixture was combined with ice water, and theprecipitated crystals were taken by filtration, and washed withwater and diethyl ether. The filtrate was neutralized with sodiumhydrogen carbonate, and extracted four times with a mixed solutionof tetrahydrofuran-ethyl acetate. The combined organic layer wasdried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was crystallized from water-ethylacetate to give the title compound (7.32 g, yield 92%).1H NMR (DMSO-d6) δ 3.80 (3H, s), 6.74 (2H, s), 6.94 (1H, dd, J =8.4, 1.8 Hz), 7.24 (1H, d, J = 1.8 Hz), 7.37 (1H, br s), 7.72 (1H,d, J = 8.4 Hz), 7.91 (1H, br s). Reference Example 2 Methyl 4-cyano-2-[(trifluoroacetyl)amino]benzoate
    [0303] To a solution of methyl 2-amino-4-(aminocarbonyl)benzoate(4.02 g, 20.7 mmol) in tetrahydrofuran (40 ml) were addedtriethylamine (6.43 ml, 45.5 mmol) and trifluoroacetic anhydride(6.34 ml, 45.5 mmol) under ice-cooling, and the mixture wasstirred at the same temperature for 30 minutes. The reactionmixture was combined with ice water, and extracted twice withethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried overmagnesium sulfate, filtered, and concentrated under reducedpressure. The residue was subjected to a silica gel columnchromatography (hexane/ethyl acetate, 10:1) to give the titlecompound (5.65 g, quantitative).1H NMR (CDCl3) δ 4.03 (3H, s), 7.53 (1H, dd, J = 8.2, 1.4 Hz), 8.22(1H, d, J = 8.2 Hz), 9.04 (1H, d, J = 1.4 Hz), 12.30 (1H, br s). Reference Example 3 Methyl 2-amino-4-cyanobenzoate
    [0304] To a suspension of methyl 4-cyano-2-[(trifluoroacetyl)amino]benzoate(108 g, 397 mmol) in methanol(850 ml) was added potassium carbonate (60.3 g, 436 mmol), and themixture was stirred for 2 hours at 50°C. After cooling, methanolwas distilled off under reduced pressure, the residue was combined with water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with 0.5 M hydrochloric acid, and asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-diisopropyl ether togive the title compound (53.9 g, yield 76%).1H NMR (CDCl3) δ 3.90 (3H, s), 5.93 (2H, br s), 6.87 (1H, dd, J =8.4, 1.8 Hz), 6.94 (1H, d, J = 1.8 Hz), 7.93 (1H, d, J = 8.4 Hz). Reference Example 4 Methyl 4-cyano-2-(ethylamino)benzoate
    [0305] To a solution of methyl 2-amino-4-cyanobenzoate (3.04 g, 17.3mmol) in acetic acid (10 ml) were added acetaldehyde (90%) (10 ml)and sodium triacetoxy borohydride (7.71 g, 36.4 mmol) under ice-cooling,and the mixture was stirred at the same temperature for 1hour and at room temperature for 2 hours. The reaction mixturewas combined with ice water, neutralized with sodium hydrogencarbonate, and extracted with ethyl acetate. The combined organiclayer was washed with water and a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The resultant crystals werewashed with diisopropyl ether-hexane to give the title compound(800 mg, yield 23%). The mother liquor was concentrated underreduced pressure, the residue was subjected to a silica gel columnchromatography (hexane/ethyl acetate, 50:1 followed by 30:1), andthe obtained crystals were washed with hexane to give the titlecompound (920 mg, yield 26%).1H NMR (CDCl3) δ 1.34 (3H, t, J = 7.0 Hz), 3.16-3.29 (2H, m), 3.88(3H, s), 6.77-6.82 (1H, m), 6.90 (1H, s), 7.77 (1H, br s), 7.95(1H, d, J = 7.6 Hz). Reference Example 5 Methyl [(4-cyanophenyl)methoxy]acetate
    [0306] To a solution of 4-cyanobenzenemethanol (5.02 g, 37.7 mmol)in tetrahydrofuran (30 ml) was added sodium hydride (66%dispersion in oil) (1.51 g, 41.5 mmol), and the mixture wasstirred for 1.5 hours at 60°C. Under ice-cooling, methyl bromoacetate (3.93 ml, 41.5 mmol) was added thereto, and themixture was stirred for 30 minutes at 60°C. After cooling, methylbromoacetate (1.07 ml, 11.3 mmol) was further added thereto, andthe mixture was stirred for 1 hour at 60°C. The reaction mixturewas poured into a saturated aqueous solution of ammonium chlorideunder ice-cooling, and extracted twice with ethyl acetate. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residuewas subjected to a silica gel column chromatography (hexane/ethylacetate 5:1) to give the title compound (4.42 g, yield 57%).1H NMR (CDCl3) δ 3.78 (3H, s), 4.17 (2H, s), 4.69 (2H, s), 7.49 (2H,d, J = 8.1 Hz), 7.65 (2H, d, J = 8.1 Hz). Reference Example 6 4-Iodo-3-methoxybenzonitrile
    [0307] To a solution of 3-hydroxy-4-iodobenzonitrile (946 mg, 3.86mmol) in N,N-dimethylformamide (6 ml) were added iodomethane (0.26ml, 4.25 mmol) and sodium hydride (66% dispersion in oil) (155 mg,4.25 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was combined withice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate, andconcentrated under reduced pressure to give the title compound(790 mg, yield 79%).1H NMR (CDCl3) δ 3.93 (3H, s), 6.97-7.02 (2H, m), 7.90 (1H, d, J =8.4 Hz). Reference Example 7 4-Cyano-2-methoxyphenyl trifluoromethanesulfonate
    [0308] To a solution of 4-hydroxy-3-methoxybenzonitrile (10.9 g,73.1 mmol) in ethyl acetate (75 ml) were added pyridine (13.0 ml,161 mmol) and trifluoromethanesulfonic anhydride (22.7 g, 80.4mmol) under ice-cooling, and the mixture was stirred for 1 hour atthe same temperature. The reaction mixture was combined with icewater, and extracted twice with ethyl acetate. The combined organic layer was washed with 1 M hydrochloric acid, 1 M aqueoussolution of sodium hydroxide, water and a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate,concentrated under reduced pressure, and crystallized from ethylacetate-hexane to give the title compound (15.7 g, yield 76%).1H NMR (CDCl3) δ 3.98 (3H, s), 7.30-7.35 (3H, m). Reference Example 8 Methyl (E)-3-(4-cyano-2-methoxyphenyl)-2-propenoate
    [0309] To a solution of 4-iodo-3-methoxybenzonitrile (790 mg, 3.05mmol) in N,N-dimethylformamide (7 ml) were added methyl acrylate(0.57 ml, 6.30 mmol) dicyclohexylmethylamine (1.67 ml, 6.33 mmol),tris(2-methylphenyl)phosphine (118 mg, 0.338 mmol) and palladium(II) acetate (22 mg, 0.0980 mmol), and the mixture was stirred for13 hours at 90°C. After cooling, the reaction mixture wascombined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resultantcrystals were washed with hexane to give the title compound (550mg, yield 83%). Alternative synthetic method
    [0310] To a suspension of 4-cyano-2-methoxyphenyltrifluoromethanesulfonate (5.03 g, 17.9 mmol), palladium (II)acetate (40 mg, 0.179 mmol) and sodium carbonate (2.28 g, 21.5mmol) in N,N-dimethylacetamide (30 ml) were added triethylphosphite (0.31 ml, 1.79 mmol) and methyl acrylate (3.22 ml, 35.8mmol), and the mixture was stirred for 20 hours under nitrogenatmosphere at 100°C. After cooling, the reaction mixture wascombined with water, and extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resultantcrystals were washed with diisopropyl ether to give the titlecompound (610 mg, yield 16%). The mother liquor was concentratedunder reduced pressure, the residue was subjected to a silica gel column chromatography (hexane/ethyl acetate, 10:1 followed by 3:1)to give the title compound (560 mg, yield 14%).1H NMR (CDCl3) δ 3.82 (3H, s), 3.93 (3H, s), 6.58 (1H, d, J = 16.1Hz), 7.14 (1H, d, J = 1.5 Hz), 7.27 (1H, dd, J = 8.2, 1.5 Hz),7.57 (1H, d, J = 8.2 Hz), 7.94 (1H, d, J = 16.1 Hz). Reference Example 9 4-Iodo-3-(phenylmethoxy)benzonitrile
    [0311] With benzyl bromide, the title compound was obtained by themethod similar to that in Reference Example 6. Yield 77%.1H NMR (CDCl3) δ 5.19 (2H, s), 6.98-7.04 (2H, m), 7.35-7.46 (5H, m),7.90 (1H, d, J = 7.8 Hz). Reference Example 10 Methyl (E)-3-[4-cyano-2-(phenylmethoxy)phenyl]-2-propenoate
    [0312] From 4-iodo-3-(phenylmethoxy)benzonitrile, the title compoundwas obtained by the method similar to that in Reference Example 8.Yield 74%.1H NMR (CDCl3) δ 3.81 (3H, s), 5.19 (2H, s), 6.60 (1H, d, J = 16.3Hz), 7.19 (1H, s), 7.27 (1H, d, J = 8.0 Hz), 7.60 (1H, d, J = 8.0Hz), 8.01 (1H, d, J = 16.3 Hz). Reference Example 11 Methyl 5-cyano-2-[(E)-3-methoxy-3-oxo-1-propenyl]benzoate
    [0313] From methyl 5-cyano-2-iodobenzoate, the title compound wasobtained by the method similar to that in Reference Example 8.Yield 73%.1H NMR (CDCl3) d 3.84 (3H, s), 3.97 (3H, s), 6.36 (1H, d, J = 16.0Hz), 7.69 (1H, d, J = 8.0 Hz), 7.81 (1H, dd, J = 8.0, 1.4 Hz),8.28 (1H, d, J = 1.4 Hz), 8.43 (1H, d, J = 16.0 Hz). Reference Example 12 Methyl 4-cyano-α,α-dimethylbenzeneacetate
    [0314] To a solution of methyl 4-cyanobenzeneacetate (2.646 g, 15.1mmol) and iodomethane (2.4 ml) in N,N-dimethylformamide (50 ml)was slowly added 60% oily sodium hydride (1.55 g, 38.8 mmol) underice-cooling. The reaction mixture was stirred for 2 hours at roomtemperature. The reaction solution was slowly added to ice water,and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The residue was subjected toa silica gel column chromatography (ethyl acetate/hexane 3:1) togive the title compound (2.996 g, yield 98%).1H NMR (CDCl3) δ 1.59 (6H, s), 3.67 (3H, s), 7.42-7.47 (2H, m),7.61-7.65 (2H, m). Reference Example 13 Methyl 4-cyano-2-nitrobenzeneacetate
    [0315] To a solution of 4-cyano-2-nitrobenzeneacetic acid (4.236 g,20.5 mmol) in methanol (80 ml) was added dropwise thionyl chloride(1.5 ml) under ice-cooling. The reaction mixture was stirred atroom temperature for 2 hours, and concentrated under reducedpressure. The residue was combined with a saturated aqueoussolution of sodium hydrogen carbonate, and extracted with ethylacetate. The extracts were washed with a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure to give the title compound (4.40 g, yield 97%).1H NMR (CDCl3) δ 3.74 (3H, s), 4.11 (2H, s), 7.53 (1H, d), 7.88 (1H,dd), 8.42 (1H, d). Reference Example 14 Methyl 2-amino-4-cyanobenzeneacetate
    [0316] To a solution of methyl 4-cyano-2-nitrobenzeneacetate (2.793g, 12.7 mmol) in toluene (40 ml) were added magnesium sulfate (770mg) and 10% palladium/carbon (50% water-containing product) (268mg), and the mixture was subjected to catalytic reduction at roomtemperature for 6 hours under hydrogen atmosphere. The catalystand magnesium sulfate were separated by filtration, and thefiltrate was concentrated under reduced pressure to give the titlecompound (2.293 g, yield 95%).1H NMR (CDCl3) δ 3.60 (2H, s), 3.71 (3H, s), 4.28 (2H, br s), 6.94-7.04(2H, m), 7.16 (1H, d). Reference Example 15 Methyl 4-cyano-2-(trifluoroacetylamino)benzeneacetate
    [0317] To a solution of methyl 4-cyano-2-nitrobenzeneacetate (2.241g, 10.2 mmol) in toluene (30 ml) were added magnesium sulfate (636 mg) and 10% palladium/carbon (50% water-containing product) (110mg), and the mixture was subjected to catalytic reduction underhydrogen atmosphere at room temperature for 5 hours. The catalystand magnesium sulfate were separated by filtration, and thefiltrate was concentrated under reduced pressure. To a solutionof the residue and triethylamine (1.7 ml) in toluene (10 ml) wasadded dropwise a solution of trifluoroacetic anhydride (1.6 ml) intoluene (5 ml) under ice-cooling, and the reaction mixture wasstirred at 0°C for 30 minutes. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extracts werewashed with a saturated aqueous solution of sodium chloride, dried,and concentrated under reduced pressure to give the title compound(2.288 g, yield 79%).1H NMR (CDCl3) δ 3.75 (2H, s), 3.80 (3H, s), 7.38 (1H, d), 7.51 (1H,dd), 8.28 (1H, d), 10.32 (1H, br s). Reference Example 16 Methyl 4-cyano-2-[(2-pyridinylcarbonyl)amino]benzeneacetate
    [0318] To a solution of methyl 2-amino-4-cyanobenzeneacetate (1.155g, 6.07 mmol) and 4-(dimethylamino)pyridine (2.234 g, 18.2 mmol)in N,N-dimethylformamide (50 ml) was added picolinic acid chloridehydrochloride (1.628 g, 9.15 mmol) and the mixture was stirred for2 hours at room temperature. Picolinic acid chloridehydrochloride (0.527 g, 2.96 mmol) was further was added to thereaction mixture, and the mixture was stirred at room temperaturefor 1 hour. The obtained mixture was combined with water, andalkalified with an aqueous solution of 10% potassium carbonate,and extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The resultant crude crystalswere recrystallized from ethyl acetate-hexane to give the titlecompound (1.034 g, yield 58%).1H NMR (CDCl3) δ 3.78 (3H, s), 3.79 (2H, s), 7.36-7.56 (3H, m),7.94 (1H, dt), 8.27-8.34 (1H, m), 8.64-8.69 (1H, m), 10.70 (1H, brs) . Reference Example 17 Methyl 4-cyano-α,α-dimethyl-2-nitrobenzeneacetate
    [0319] To a solution of methyl 4-cyano-2-nitrobenzeneacetate (1.69 g,7.68 mmol) and iodomethane (1.9 ml) in N,N-dimethylformamide (30ml) was slowly added 60% oily sodium hydride (937 mg, 23.4 mmol)under ice-cooling. The reaction mixture was stirred at roomtemperature for 3 hours. The reaction solution was slowly addedto ice water, and extracted with ethyl acetate. The extracts werewashed with a saturated aqueous solution of sodium chloride, dried,and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography (ethylacetate/hexane 3:1) to give the title compound (1.864 g, yield98%).1H NMR (CDCl3) δ 1.70 (6H, s), 3.66 (3H, s), 7.76 (1H, d), 7.89 (1H,dd), 8.21 (1H, d). Reference Example 18 6-Cyano-1,3-dihydro-3,3-dimethyl-2H-indol-2-one
    [0320] To a solution of methyl 4-cyano-α,α-dimethyl-2-nitrobenzeneacetate(1.237 g, 4.98 mmol) in methanol (20 ml) wasadded 10% palladium/carbon (50% water-containing product) (252mg) under hydrogen atmosphere at room temperature for 14 hours,and the mixture was subjected to catalytic reduction. Thecatalyst was separated by filtration, and the filtrate wasconcentrated under reduced pressure to give the title compound(915 mg, yield 99%).1H NMR (CDCl3) δ 1.34 (6H, s), 7.24-7.32 (2H, m), 7.41 (1H, dd). Reference Example 19 Methyl (E)-3-(4-cyano-2-nitrophenyl)-2-propenoate
    [0321] To a solution of methyl diethylphosphonoacetate (4.2 ml) intetrahydrofuran (10 ml) was added 60% oily sodium hydride (633 mg,15.8 mmol) at 0°C, and the mixture was stirred at room temperaturefor 30 minutes. To the reaction mixture solution was added 4-formyl-3-nitrobenzonitrile(2685 mg, 15.2 mmol) at roomtemperature, and the mixture was further stirred at roomtemperature for 2.5 hours. The reaction mixture was combined with20% ammonia water, and extracted with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride,dried, and concentrated under reduced pressure. The resultantcrude crystals were recrystallized from ethyl acetate-hexane togive the title compound (2695 mg, yield 76%).1H NMR (CDCl3) δ 3.86 (3H, s), 6.45 (1H, d), 7.77 (1H, d), 7.89-7.96(1H, m), 8.10 (1H, d), 8.35 (1H, d). Reference Example 20 Ethyl (E)-3-(4-cyano-2-nitrophenyl)-2-propenoate
    [0322] With ethyl diethylphosphonoacetate, the title compound wasobtained by the method similar to that in Reference Example 19.Yield 40%.1H NMR (CDCl3) δ 1.36 (3H, t, J = 7.2 Hz), 4.31 (2H, q, J = 7.2 Hz),6.45 (1H, d, J = 15.4 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.93 (1H, d,J = 7.8 Hz), 8.09 (1H, d, J = 15.4 Hz), 8.35 (1H, s). Reference Example 21 Methyl (E)-3-(2-amino-4-cyanophenyl)-2-propenoate
    [0323] A mixed solution of methyl (E)-3-(4-cyano-2-nitrophenyl)-2-propenoate(2.695 g, 11.6 mmol) and tin (II) chloride (11.01 g,58.1 mmol) in ethanol (50 ml) and ethyl acetate (50 ml) wasstirred for 2 hours at 70°C. The reaction mixture was cooled, andneutralized by adding a saturated aqueous solution of sodiumhydrogen carbonate, and the insolubles were separated byfiltration. The organic layer was separated, washed with asaturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure to give the title compound(1.771 g, yield 76%).1H NMR (CDCl3) δ 3.82 (3H, s), 4.14 (2H, br s), 6.42 (1H, d), 6.94-7.05(2H, m), 7.42 (1H, d), 7.74 (1H, d). Reference Example 22 Ethyl (E)-3-(2-amino-4-cyanophenyl)-2-propenoate
    [0324] From ethyl (E)-3-(4-cyano-2-nitrophenyl)-2-propenoate, thetitle compound was obtained by the method similar to that inReference Example 21. Yield 79%.1H NMR (CDCl3) δ 1.35 (3H, t, J = 7.2 Hz), 4.18 (2H, br s), 4.28(2H, q, J = 7.2 Hz), 6.42 (1H, d, J = 16.1 Hz), 6.97 (1H, s), 7.02 (1H, d, J = 8.0 Hz), 7.42 (1H, d, J = 8.0 Hz), 7.74 (1H, d, J =16.1 Hz). Reference Example 23 Methyl (4-cyano-2-nitrophenoxy)acetate
    [0325] To a solution of 4-cyano-2-nitrophenol (8.21 g, 50.0 mmol)and methyl bromoacetate (5.2 ml, 55 mmol) in N,N-dimethylformamide(50 ml) was added potassium carbonate (8.30 g, 60.1 mmol), and themixture was stirred for 2 hours at room temperature. The reactionmixture was combined with water, and extracted twice with ethylacetate. The combined organic layer was washed twice with water,0.5 M hydrochloric acid and water, and concentrated under reducedpressure. The residue was washed with a mixed solution of ethylacetate-diisopropyl ether to give the title compound (6.41 g,yield 54%).1H NMR (CDCl3) δ 3.83 (3H, s), 4.89 (2H, s), 7.06 (1H, d, J = 8.9Hz), 7.81 (1H, dd, J = 8.9, 2.1 Hz), 8.19 (1H, d, J = 2.1 Hz). Reference Example 24 Methyl (2-amino-4-cyanophenoxy)acetate
    [0326] To a solution of methyl (4-cyano-2-nitrophenoxy)acetate (1.00g, 3.80 mmol) in tetrahydrofuran (10 ml) was added 10%palladium/carbon (50% water-containing product) (0.10 g), and themixture was stirred at 0°C for 2 hours and at room temperature for1 hour under hydrogen atmosphere. The catalyst was filtered off,and the filtrate was concentrated under reduced pressure. Theresidue was washed with diisopropyl ether to give the titlecompound (731 mg, yield 93%).1H NMR (CDCl3) δ 3.82 (3H, s), 4.14 (2H, br s), 4.71 (2H, s), 6.69(1H, d, J = 8.3 Hz), 6.95 (1H, d, J = 1.9 Hz), 7.01 (1H, dd, J =8.3, 1.9 Hz). Reference Example 25 Methyl (E)-3-(4-cyano-2-methylphenyl)-2-propenoate
    [0327] A suspension of 4-bromo-3-methylbenzonitrile (1.96 g, 10.0mmol), methyl acrylate (1.1 ml, 12 mmol), palladium (II) acetate(90 mg, 0.40 mmol) and tris(2-methylphenyl)phosphine (488 mg, 1.60mmol) in triethylamine (10 ml) was stirred under nitrogen atmosphere at 100°C for 14 hours. The reaction mixture wascombined with ethyl acetate, and the mixture was filtered throughHyflo Super-Cel (trade name), and the filtrate was concentratedunder reduced pressure. The residue was subjected to a silica gelcolumn chromatography (hexane/ethyl acetate, 100:1, 10:1 followedby 5:1), and recrystallized from ethyl acetate-hexane to give thetitle compound (423 mg, yield 21%).1H NMR (CDCl3) δ 2.47 (3H, s), 3.84 (3H, s), 6.43 (1H, d, J = 15.9Hz), 7.48-7.53 (2H, m), 7.61 (1H, d, J = 8.4 Hz), 7.91 (1H, d, J =15.9 Hz). Reference Example 26 Ethyl (E)-3-(4-cyanophenyl)-2-butenoate and ethyl (Z)-3-(4-cyanophenyl)-2-butenoate
    [0328] To a solution of ethyl diethylphosphonoacetate (2.71 g, 12.1mmol) in tetrahydrofuran (20 ml) was added sodium hydride (66%dispersion in oil) (0.44 g, 12 mmol) under ice-cooling, and themixture was stirred at the same temperature for 10 minutes. Tothe obtained mixture was added portionwise 4-acetylbenzonitrile,and the mixture was stirred at room temperature 24 hours. Thereaction mixture was poured into a saturated aqueous solution ofammonium chloride, and the mixture was extracted twice with ethylacetate. The combined organic layer was washed twice with water,and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography (hexane/ethylacetate, 15:1 followed by 5:1) to give (E)-form (748 mg, yield 34%,crystallized from diisopropyl ether-hexane) and (Z)-form (341 mg,yield 16%, oil).(E)-form: 1H NMR (CDCl3) δ 1.33 (3H, t, J = 7.1 Hz), 2.57 (3H, d, J= 1.5 Hz), 4.23 (2H, q, J = 7.1 Hz), 6.15 (1H, q, J = 1.5 Hz),7.56 (2H, d, J = 8.7 Hz), 7.68 (2H, d, J = 8.7 Hz).(Z)-form: 1H NMR (CDCl3) δ 1.11 (3H, t, J = 7.2 Hz), 2.17 (3H, d, J= 1.7 Hz), 4.01 (2H, q, J = 7.2 Hz), 5.97 (1H, q, J = 1.7 Hz),7.30 (2H, d, J = 8.4 Hz), 7.65 (2H, d, J = 8.4 Hz). Reference Example 27 [4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methyl acetate
    [0329] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1.26 g, 4.78 mmol) and 4-cyanobenzenemethanol(530 mg, 3.98 mmol) in toluene (3.5 ml) andacetic acid (2 ml) was added conc. sulfuric acid (0.53 ml, 9.95mmol), and the mixture was stirred for 1 hour at 80°C. Ethanol(35.9 ml) was added dropwise thereto at the same temperature andthe mixture was stirred for 30 minutes. After cooling, thereaction mixture was poured into ice water, and washed withdiisopropyl ether. The aqueous layer was neutralized with sodiumhydrogen carbonate, and extracted three times with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wassubjected to a basic silica gel column chromatography(hexane/ethyl acetate, 10:1 followed by 5:1), and crystallizedfrom diisopropyl ether-hexane to give the title compound (614 mg,yield 37%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.28 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.11 (3H, s), 2.20 (2H, s), 2.66 (2H, s), 4.18 (2H, q, J =7.0 Hz), 5.15 (2H, s), 6.60 (1H, s), 7.34-7.42 (4H, m). Reference Example 28 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenemethanol
    [0330] To a solution of [4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methylacetate (881mg, 2.09 mmol) in methanol (4 ml) was added 5 M aqueous solution(1 ml) of sodium hydroxide, and the mixture was stirred for 1 hourat room temperature. Methanol was distilled off under reducedpressure, the residue was combined with water and diisopropylether, and neutralized with 5 M hydrochloric acid. Theprecipitated crystals were taken by filtration, and washed withwater and diisopropyl ether to give the title compound (666 mg,yield 84%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0 Hz), 2.21 (2H, s), 2.66 (2H, s), 4.18 (2H, q, J = 7.0 Hz), 4.72(2H, s), 6.60 (1H, s), 7.33 (2H, d, J = 8.6 Hz), 7.38 (2H, d, J =8.6 Hz). Reference Example 29 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol
    [0331] To a solution of 4-cyanophenol (3.00 g, 25.2 mmol) and 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(8.66 g, 32.8 mmol) in acetic acid (30 ml)-toluene(40 ml) was added conc. sulfuric acid (3.49 ml, 65.5 mmol),and the mixture was stirred at 80°C for 1 hour. The reactionsolution was cooled with ice, water was added thereto, and themixture was washed with diisopropyl ether. The aqueous layer wasagain ice-cooled and alkalified with conc. ammonia water, andextracted with ethyl acetate. The extracts were washed with water,and concentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (ethyl acetate/methanol19:1), and crystallized from ethyl acetate-hexane to give thetitle compound (1.47 g, yield 16%).1H NMR (CDCl3) δ 1.28 (6H, s), 1.30 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.24 (2H, s), 2.69 (2H, s), 4.18 (2H, q, J = 7.0 Hz), 6.45(2H, d, J = 8.6 Hz), 6.59 (1H, s), 7.03 (2H, d, J = 8.6 Hz), 8.01(1H, br s). Reference Example 30 3-[6-(Ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid
    [0332] To a solution of 1-methylethyl 3-[6-(ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoate(2.28 g, 5.05 mmol) in methanol (10 ml) was added 5 M aqueoussolution (5 ml) of sodium hydroxide, and the mixture was stirredat room temperature for 15 hours. The reaction solution wasadjusted at pH 4.5 with 5 M hydrochloric acid, methanol was addedthereto, and the solvent was distilled off under reduced pressure.The residue was dissolved in water, and extracted three times withethyl acetate. The combined organic layer was concentrated under reduced pressure, the residue was recrystallized from ethylacetate-diisopropyl ether to give the title compound (1.50 g,yield 73%).1H NMR (CDCl3) δ 1.28 (6H, s), 1.39 (3H, t, J = 7.2 Hz), 1.52 (6H,s), 2.17 (2H, s), 2.92 (2H, s), 3.04 (2H, q, J = 7.2 Hz), 6.95 (1H,s), 7.46 (1H, t, J = 7.4 Hz), 7.61 (1H, d, J = 7.4 Hz), 8.03 (1H,d, J = 7.4 Hz), 8.13 (1H, s). Reference Example 31 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[6-(ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0333] To a solution of 3-[6-(ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzaicacid (1.76 g, 4.30mmol), α,α-dimethylglycine amide hydrochloride (655 mg, 4.73 mmol),1-hydroxy-1H-benzotriazole monohydrate (724 mg, 4.73 mmol) andtriethylamine (1.50 ml, 10.8 mmol) in N,N-dimethylformamide (8 ml)was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (1.07 g, 5.59 mmol) under ice-cooling, and themixture was stirred at room temperature for 15 hours. To thereaction mixture was poured ice water, and the mixture wasextracted three times with ethyl acetate. The combined organiclayer was washed with an aqueous solution of sodium chloride and asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-diisopropyl ether togive the title compound (2.01 g, yield 95%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.30 (6H, s), 1.34 (3H, t, J = 7.4Hz), 1.71 (6H, s), 2.17 (2H, s), 2.68 (2H, s), 3.00 (2H, q, J =7.4 Hz), 5.51 (1H, br s), 6.45 (1H, br s), 6.93 (1H, s), 7.02 (1H,s), 7.42-7.52 (2H, m), 7.85-7.89 (2H, m). Reference Example 32 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[6-(ethylsulfinyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0334] To a suspension of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[6-(ethylthio)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide (826 mg, 1.67 mmol) in methanol (7ml) was added a solution of sodium periodate (895 mg, 4.18 mmol)in water (5 ml) under ice-cooling, and the mixture was stirred atroom temperature for 40 hours. The solvent was distilled offunder reduced pressure, and the residue was combined with anaqueous solution of sodium chloride, and extracted three timeswith tetrahydrofuran. The combined organic layer was dried oversodium sulfate, and concentrated under reduced pressure. Theresidue was subjected to a basic silica gel column chromatography(hexane/ethyl acetate 1:3 followed by ethyl acetate) to give thetitle compound (85 mg), and a mixture of the starting materialsand the title compound (528 mg). The mixture was dissolved inmethanol (6 ml), a solution of sodium periodate (450 mg, 2.10mmol) in water (2.5 ml) was added thereto, and the mixture wasstirred at room temperature for 18 hours. The solvent wasdistilled off under reduced pressure, and the residue was combinedwith an aqueous solution of sodium chloride, and extracted twicewith ethyl acetate-tetrahydrofuran. The combined organic layerwas dried over sodium sulfate, and concentrated under reducedpressure. The residue was subjected to a basic silica gel columnchromatography (hexane/ethyl acetate 1:3 followed by ethylacetate), collected with those previously obtained, andrecrystallized from ethyl acetate-diisopropyl ether to give thetitle compound (292 mg, yield 34%).1H NMR (CDCl3) δ 1.20-1.31 (15H, m), 1.73 (6H, s), 2.18 (2H, s),2.77 (2H, s), 2.83-3.18 (2H, m), 5.48 (1H, br s), 6.37 (1H, br s),7.05 (1H, s), 7.44 (1H, s), 7.48-7.56 (2H, m), 7.83-7.88 (2H, m). Reference Example 33 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[6-(ethylsulfonyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0335] To a suspension of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[6-(ethylsulfinyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide(588 mg, 1.19 mmol) in methanol (6 ml) was added a solution of sodium periodate (1.27 g, 5.96 mmol)in water (5 ml) under ice-cooling, and the mixture was stirred at60°C for 18 hours. After cooling, solvent was distilled off underreduced pressure, to the residue were added an aqueous solution ofsodium chloride, sodium hydrogen carbonate and ethyl acetate, andthe precipitated crystals were taken by filtration to give thetitle compound (265 mg, yield 50%). The filtrate was extractedtwice with a mixed solution of ethyl acetate-tetrahydrofuran, thecombined organic layer was dried over sodium sulfate, andconcentrated under reduced pressure. The residue was subjected toa basic silica gel column chromatography (hexane/ethyl acetate 1:3followed by ethyl acetate), and recrystallized from ethyl acetateto give the title compound (185 mg, yield 30%).1H NMR (CDCl3+DMSO-d6 5 drops) δ 1.26 (6H, s), 1.30 (3H, t, J = 7.5Hz), 1.30 (6H, s), 1.72 (6H, s), 2.24 (2H, s), 2.75 (2H, s), 3.34(2H, q, J = 7.5 Hz), 6.11 (1H, br s), 6.89 (1H, br s), 7.49-7.52(3H, m), 7.75 (1H, s), 7.90-7.94 (2H, m). Reference Example 34 Ethyl 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0336] To a solution of 2,3-dihydro-7-methoxy-2,2-dimethyl-a-(1-methylethyl)-5-benzofuranmethanol(16.0 g, 63.9 mmol) and 3-cyanobenzoicacid (7.84 g, 53.3 mmol) in toluene (60 ml) andacetic acid (35 ml) was added conc. sulfuric acid (7.10 ml, 133mmol), and the mixture was stirred for 1 hour at 80°C. Ethanol(35.9 ml) was added dropwise thereto at the same temperature andthe mixture was stirred for 30 minutes. After cooling, thereaction mixture was poured into ice water, and washed withdiethyl ether. The aqueous layer was neutralized with conc.ammonia water, and extracted twice with diethyl ether. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wassubjected to a basic silica gel column chromatography(hexane/ethyl acetate 20:1), and the obtained crystals were washed with pentane to give the title compound (2.11 g, yield 10%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.30 (6H, s), 1.49 (3H, t, J = 7.2Hz), 2.17 (2H, s), 2.70 (2H, s), 3.93 (3H, s), 4.38 (2H, q, J =7.2 Hz), 6.63 (1H, s), 7.43-7.64 (2H, m), 8.06-8.11 (2H, m). Reference Example 35 3-(3,4,8,9-Tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrobromide
    [0337] A solution of 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid (840 mg, 2.21mmol) in 48% hydrobromic acid (6 ml) was stirred at 110°C for 36hours. After ice-cooling, the precipitated crystals were taken byfiltration, and washed with water and diethyl ether to give thetitle compound (676 mg, yield 69%).1H NMR (DMSO-d6) δ 1.22 (6H, s), 1.43 (6H, s), 2.07 (1H, d, J =14.6 Hz), 2.18 (1H, d, J = 14.6 Hz), 3.09 (2H, s), 6.78 (1H, s),7.73-7.87 (2H, m), 8.14-8.28 (2H, m), 11.29 (1H, br s), 12.32 (1H,br s). Reference Example 36 3,4,8,9-Tetrahydro-6-methoxy-α,α,3,3,8,8-hexamethyl-1-phenylfuro[2,3-h]isoquinoline-5-acetonitrile
    [0338] To a solution of 3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline-5-acetonitrile(215 mg,0.574 mmol) in N,N-dimethylformamide (2 ml) iodomethane (0.079 ml,1.26 mmol) was added sodium hydride (66% dispersion in oil) (46 mg,1.26 mmol) under ice-cooling, and the mixture was stirred at thesame temperature for 30 minutes and at room temperature for 20hours. The reaction mixture was combined with ice water, andextracted twice with ethyl acetate. The combined organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, and concentrated underreduced pressure. The residue was subjected to a basic silica gelcolumn chromatography (hexane/ethyl acetate 20:1), andrecrystallized from hexane to give the title compound (77 mg,yield 33%).1H NMR (CDCl3+DMSO-d6 5 drops) δ 1.20 (6H, s), 1.29 (6H, s), 1.94 (6H, s), 2.15 (2H, s), 2.88 (2H, s), 3.95 (3H, s), 7.39-7.45 (5H,m) . Reference Example 37 1-Methylethyl3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzoate
    [0339] To a solution of 1.57 M n-butyllithium/hexane (42.3 ml, 66.4mmol) were added dropwise a solution of N,N,N',N'-tetramethylethylenediamine(10.0 ml, 66.4 mmol) in tetrahydrofuran(15 ml), a solution of 7-bromo-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran(4.68 g, 16.6 mmol) intetrahydrofuran (15 ml) and a solution of n-propyl disulfate (20 g,133 mmol) in tetrahydrofuran (15 ml) at -78°C in this order, andthe mixture was stirred for 15 hours with elevating thetemperature naturally to room temperature. The reaction mixturewas poured into a saturated aqueous solution of ammonium chloride,and the mixture was extracted twice with ethyl acetate. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residuewas subjected to a silica gel column chromatography (hexanefollowed by hexane/ethyl acetate 50:1) to give a mixture of 2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)-7-(propylthio)benzofuranand 2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuranat about 15:2 (4.11 g).
    [0340] To a suspension of the obtained mixture (3.10 g) and 3-cyanobenzoate1-methylethyl (1.83 g, 9.65 mmol) in acetic acid (6ml) and toluene (13 ml) was added dropwise conc. sulfuric acid(1.29 ml, 24.1 mmol) under ice-cooling, and the mixture wasstirred for 1.5 hours at 60°C. Conc. sulfuric acid (0.51 ml, 9.65mmol) and 2-propanol (11.7 ml) were further added dropwise thereto,and the mixture was heated under reflux for 5 hours. To thereaction mixture was poured ice water, the mixture was neutralizedwith sodium hydrogen carbonate, and extracted twice with ethylacetate. The combined organic layer was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residuewas dissolved in N,N-dimethylformamide (20 ml). 2-iodopropane(0.48 ml, 4.83 mmol) and potassium carbonate (668 mg, 4.83 mmol)were added thereto, and the mixture was stirred for 15 hours atroom temperature. To the reaction mixture was poured ice water,and the mixture was extracted twice with ethyl acetate. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography (hexane/ethylacetate, 10:1 followed by 5:1) to give the title compound (1.00 g,yield 22%) .Oily matter. Reference Example 38 3-[3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzoicacid
    [0341] From 1-methylethyl 3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzoate,the titlecompound was obtained by the method similar to that in ReferenceExample 30. Yield 17%.Melting point: 206-208°C (ethyl acetate-diisopropyl ether).1H NMR (CDCl3) δ 1.11 (3H, t, J = 7.5 Hz), 1.25 (6H, s), 1.51 (3H,s), 1.74-1.86 (2H, m), 1.91 (3H, s), 2.10 (2H, s), 2.92 (1H, d, J= 13.0 Hz), 3.04 (2H, t, J = 7.2 Hz), 3.41 (1H, d, J = 13.0 Hz),6.97 (1H, s), 7.66 (1H, dd, J = 7.8, 7.5 Hz), 7.68 (1H, s), 8.00(1H, d, J = 7.5 Hz), 8.12 (1H, d, J = 7.8 Hz). Reference Example 39 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0342] From 3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzoicacid, the titlecompound was obtained by the method similar to that in ReferenceExample 31. Yield 57%.Melting point:195-197°C (diisopropyl ether). 1H NMR (CDCl3) d 1.05 (3H, t, J = 7.2 Hz), 1.25 (6H, s), 1.30 (6H,s), 1.62-1.78 (2H, m), 1.71 (6H, s), 2.17 (2H, s), 2.68 (2H, s),2.95 (2H, t, J = 7.3 Hz), 5.49 (1H, br s), 6.43 (1H, br s), 6.92(1H, s), 6.96 (1H, s), 7.43-7.52 (2H, m), 7.85-7.89 (2H, m). Reference Example 40 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylsulfinyl)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0343] From N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(propylthio)furo[2,3-h]isoquinolin-1-yl]benzamide,the title compound was obtained bythe method similar to that in Reference Example 32. Yield 87%.1H NMR (CDCl3) δ 1.07 (3H, t, J = 7.5 Hz), 1.23-1.35 (12H, m),1.60-2.05 (2H, m), 1.72 (6H, s), 2.19 (2H, s), 2.75-3.05 (2H, m),2.80 (2H, s), 5.51 (1H, br s), 6.39 (1H, br s), 7.12 (1H, br s),7.44-7.55 (2H, m), 7.85-7.92 (2H, m). Reference Example 41 α-Fluoro-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline-5-acetonitrile
    [0344] To a solution of 3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline-5-acetonitrile(301 mg,0.804 mmol) in tetrahydrofuran (5 ml) was added dropwise asolution of 1.54 M tert-butyllithium/pentane (1.15 ml, 1.77 mmol)at -78°C, and the mixture was stirred for 1 hour at the sametemperature. A solution of N-fluorobenzenesulfonimide (634 mg,2.01 mmol) in tetrahydrofuran (5 ml) was added dropwise at -78°Cthereto, and the mixture was stirred with elevating thetemperature naturally to room temperature for 3 hours. Thereaction mixture was combined with ice water, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a basic silica gel column chromatography(hexane/ethyl acetate, 30:1 followed by 10:1), and crystallizedfrom pentane to give the title compound (198 mg, yield 63%). 1H NMR (CDCl3) δ 1.27 (6H, s), 1.30 (6H, s), 2.13 (1H, d, J = 14.0Hz), 2.22 (1H, d, J = 14.0 Hz), 2.82 (1H, d, J = 15.6 Hz), 2.98(1H, dd, J = 15.6, 3.6 Hz), 4.04 (3H, s), 6.66 (1H, d, J = 45.2Hz), 7.39 (5H, s). Reference Example 42 α,α-Difluoro-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline-5-acetonitrile
    [0345] To a solution of α-fluoro-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline-5-acetonitrile(89 mg, 0.227 mmol) in tetrahydrofuran (1 ml) was added dropwise asolution of 1.54 M tert-butyllithium/pentane (0.16 ml, 0.249 mmol)at -78°C, and the mixture was stirred for 1 hour at the sametemperature. A solution of N-fluorobenzenesulfonimide (93 mg,0.295 mmol) in tetrahydrofuran (5 ml) was added dropwise at -78°Cthereto, and the mixture was stirred for 15 hours with elevatingthe temperature naturally to room temperature. The reactionmixture was combined with ice water, and extracted twice withethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was subjected to a silica gel column chromatography(hexane/ethyl acetate, 10:1 followed by 5:1), and crystallizedfrom diisopropyl ether-hexane to give the title compound (14 mg,yield 15%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.30 (6H, s), 2.19 (2H, t, J = 1.8Hz), 2.85 (2H, t, J = 2.8 Hz), 4.08 (3H, s), 7.40 (5H, s). Reference Example 43 Ethyl 3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride
    [0346] To a solution of ethyl 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(117 mg,0.278 mmol) in 1,2-dichloroethane (2 ml) were addedtrichloroacetyl chloride (0.037 ml, 0.333 mmol) and aluminumchloride (44 mg, 0.333 mmol) under ice-cooling, and the mixturewas stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, neutralized with 5 M aqueous solutionof sodium hydroxide, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over sodium sulfate,and concentrated under reduced pressure. The residue wassubjected to a basic silica gel column chromatography (ethylacetate) to give the title compound as free base. This wasdissolved in ethyl acetate, a solution of 4 M hydrogenchloride/ethyl acetate was added thereto, and the mixture wasconcentrated under reduced pressure, and the residue wascrystallized from ethyl acetate to give the title compound (43 mg,yield 36%).1H NMR (DMSO-d6) δ 1.22 (6H, s), 1.33 (3H, t, J = 6.9 Hz), 1.43 (6H,s), 2.05-2.20 (2H, m), 3.07 (2H, s), 4.37 (2H, q, J = 6.9 Hz),6.84 (1H, s), 7.78 (1H, t, J = 7.8 Hz), 7.88 (1H, d, J = 7.8 Hz),8.15 (1H, d, J = 1.2 Hz), 8.27 (1H, dd, J = 7.8, 1.2 Hz), 11.43(1H, br s). Reference Example 44 1-Methylethyl 3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)furo[2,3-h]isoquinolin-1-yl]benzoatehydrochloride
    [0347] From 7-bromo-2,3-dihydro-2,2-dimethyl-5-(2-methyl-1-propenyl)benzofuran,the title compound was obtained as free baseby the method similar to that in Reference Example 37. This wasdissolved in ethyl acetate, a solution of 4 M hydrogenchloride/ethyl acetate was added thereto, and the mixture wasconcentrated under reduced pressure, and the residue wascrystallized from hexane to give the title compound. Yield 8.9%.1H NMR (DMSO-d6) δ 1.26 (6H, s), 1.30 (6H, s), 1.36 (6H, d, J = 6.3Hz), 2.17 (2H, s), 2.51 (3H, s),2.70 (2H, s), 5.20-5.33 (1H, m),7.47 (1H, t, J = 7.7 Hz), 7.61 (1H, dt, J = 7.7, 1.5 Hz), 8.04 (1H,t, J = 1.5 Hz), 8.08 (1H, dt, J = 7.7, 1.5 Hz). Reference Example 45 3-[3,4,8,9-Tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)furo[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride
    [0348] From 1-methylethyl 3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)furo[2,3-h]isoquinolin-1-yl]benzoate, the titlecompound was obtained as free base by the method similar to thatin Reference Example 30. This was dissolved in ethyl acetate, anda solution of 4 M hydrogen chloride/ethyl acetate was addedthereto. The mixture was concentrated under reduced pressure, andthe residue was crystallized from ethanol-ethyl acetate-diisopropylether to give the title compound. Yield 95%.1H NMR (DMSO-d6) δ 1.23 (6H, s), 1.45 (6H, s), 2.10-2.25 (2H, m),2.57 (3H, s), 3.17 (2H, s), 7.19 (1H, s), 7.77 (1H, t, J = 7.5 Hz),7.87 (1H, d, J = 7.5 Hz), 8.19 (1H, s), 8.27 (1H, d, J = 7.5 Hz). Reference Example 46 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0349] From 3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)furo[2,3-h]isoquinolin-1-yl]benzoicacid hydrochloride,the title compound was obtained by the method similar to that inReference Example 31. Yield 71%.1H NMR (CDCl3) δ 1.26 (6H, s), 1.30 (6H, s), 1.71 (6H, s), 2.17 (2H,s), 2.50 (3H, s), 2.70 (2H, s), 5.41 (1H, br s), 6.43 (1H, br s),6.86 (1H, s), 6.97 (1H, s), 7.43-7.49 (2H, m), 7.85-7.89 (2H, m). Reference Example 47 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylsulfinyl)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0350] From N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylthio)furo[2,3-h]isoquinolin-1-yl]benzamide,the title compound was obtained bythe method similar to that in Reference Example 32. Yield 59%.1H NMR (CDCl3) δ 1.20-1.43 (12H, m), 1.69 (6H, s), 2.19 (2H, s),2.78 (2H, s), 2.83 (3H, s), 5.44 (1H, br s), 6.36 (1H, br s), 7.06(1H, s), 7.48-7.57 (3H, m), 7.80-7.90 (2H, m). Reference Example 48 2-[3-(3,4,8,9-Tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-5,5-dimethyl-1,5-dihydro-4H-imidazol-4-one
    [0351] To a solution of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide(546 mg, 1.18 mmol) in 1,2-dichloroethane(3 ml) were added trichloroacetyl chloride (0.21 ml,2.94 mmol) and aluminum chloride (392 mg, 2.94 mmol) under ice-cooling,and the mixture was stirred at room temperature for 60hours. Trichloroacetyl chloride (0.20 ml, 2.83 mmol) and aluminumchloride (472 mg, 3.54 mmol) were added thereto under ice-cooling,and the mixture was stirred at room temperature for 87 hours. Thereaction mixture was poured into ice water, neutralized with 5 Maqueous solution of sodium hydroxide, and the precipitate wastaken by filtration. The filtrate was extracted with a mixedsolution of tetrahydrofuran-ethyl acetate, the combined organiclayer was washed with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, and concentrated underreduced pressure. The residue was subjected to a basic silica gelcolumn chromatography (ethyl acetate followed by ethylacetate/methanol 10:1), and the obtained crystals were washed withdiisopropyl ether to give the title compound (163 mg, yield 32%).1H NMR (CDCl3+ DMSO-d6 5 drops) δ 1.24 (6H, s), 1.29 (6H, s), 1.80(6H, s), 2.16 (2H, s), 2.63 (2H, s), 6.60 (1H, s), 7.45-7.55 (2H,m), 7.80 (1H, br s), 7.91-7.98 (2H, m). Reference Example 49 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide
    [0352] To a solution of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide(10.1 g, 21.8 mmol) in 1,2-dichloroethane(60 ml) were added trichloroacetyl chloride (1.55ml, 21.8 mmol) and aluminum chloride (10.2 g, 76.3 mmol) underice-cooling, and the mixture was stirred at room temperature for60 hours. Trichloroacetyl chloride (1.55 ml, 21.8 mmol) andaluminum chloride (4.36 g, 32.7 mmol) were added thereto underice-cooling, and the mixture was stirred for 15 hours at roomtemperature. The reaction mixture was combined with ice water, ethyl acetate and tetrahydrofuran, and neutralized with 5 Maqueous solution of sodium hydroxide. The aqueous layer wasseparated, and extracted with a mixed solution of tetrahydrofuran-ethylacetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, and concentrated under reduced pressure. The residue wassubjected to a basic silica gel column chromatography (ethylacetate/methanol 10:1), and the obtained crystals were washed withdiisopropyl ether to give the title compound (8.17 g, yield 83%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.28 (6H, s), 1.69 (6H, s), 2.15 (2H,s), 2.63 (2H, s), 5.97 (1H, br s), 6.59 (1H, s), 6.83 (1H, br s),7.44-7.52 (2H, m),7.60 (1H, s), 7.87-7.91 (2H, m). Reference Example 50 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[6-(2-fluoroethoxy)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0353] To a solution of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamidehydrochloride (148 mg, 0.305 mmol) inN,N-dimethylformamide (2 ml) were added potassium carbonate (89 mg,0.641 mmol) and 1-bromo-2-fluoroethane (0.025 ml, 0.335 mmol), andthe mixture was stirred at room temperature for 1 hour and at 60°Cfor 2 hours. After cooling, the reaction mixture was poured intoice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with an aqueous solution of sodiumchloride and a saturated aqueous solution of sodium chloride,dried over sodium sulfate, and concentrated under reduced pressure.The residue was subjected to a basic silica gel columnchromatography (ethyl acetate), and the obtained crystals werewashed with diisopropyl ether to give the title compound (64 mg,yield 42%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.30 (6H, s), 1.72 (6H, s), 2.17 (2H,s), 2.69 (2H, s), 4.39 (2H, dt, J = 27.8, 4.4 Hz), 4.78 (2H, dt, J= 46.4, 4.4 Hz), 5.30 (1H, br s), 6.43 (1H, br s), 6.67 (1H, s),6.93 (1H, br s), 7.46-7.50 (2H, m), 7.85-7.90 (2H, m). Reference Example 51 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylsulfonyl)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0354] From N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(methylsulfinyl)furo[2,3-h]isoquinolin-1-yl]benzamide,the title compound was obtained bythe method similar to that in Reference Example 33. Yield 65%.1H NMR (CDCl3) δ 1.27 (6H, s), 1.36 (6H, s), 1.74 (6H, s), 2.23 (2H,s), 2.75 (2H, s), 3.21 (3H, s), 5.43 (1H, br s), 6.30 (1H, br s),7.05 (1H, s), 7.48-7.53 (2H, m), 7.57 (1H, s), 7.85-7.92 (2H, m). Reference Example 52 N-(2,Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(2,2,2-trifluoroethoxy)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0355] To a solution of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide(359 mg, 0.799 mmol) in N,N-dimethylformamide(3 ml) were added potassium carbonate (121 mg,0.878 mmol) and 1,1,1-trifluoro-2-iodoethane (0.087 ml, 0.878mmol), and the mixture was stirred at room temperature for 2 hoursand at 50°C for 4 hours. Potassium carbonate (121 mg, 0.878 mmol)and 1,1,1-trifluoro-2-iodoethane (0.17 ml, 1.76 mmol) were addedthereto, and the mixture was stirred at room temperature for 60hours and at 50°C for 4 hours. 1,1,1-trifluoro-2-iodoethane (0.087ml, 0.878 mmol) was added thereto, and the mixture was stirred at50°C for 4 hours. 1,1,1-trifluoro-2-iodoethane (0.17 ml, 1.76mmol) was added thereto, and the mixture was stirred at 50°C for18 hours. After cooling, the reaction mixture was combined withice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, and concentrated underreduced pressure. The residue was subjected to a basic silica gelcolumn chromatography (hexane/ethyl acetate 1:2 followed by ethylacetate), and crystallized with diethyl ether-diisopropyl ether to give the title compound (102 mg, yield 24%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.30 (6H, s), 1. 72 (6H, s), 2.17 (2H,s), 2.67 (2H, s), 4.54 (2H, q, J = 8.4 Hz), 5.38 (1H, br s), 6.43(1H, br s), 6.71 (1H, s), 6.97 (1H, s), 7.44-7.49 (2H, m), 7.84-7.88(2H, m). Reference Example 53 1-(3-Bromophenyl)-3,4,8,9-tetrahydro-N,3,3,8,8-pentamethylfuro[2,3-h]isoquinolin-6-aminedihydrochloride
    [0356] To a solution of [1-(3-bromophenyl)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-6-yl]trifluoromethanesulfonate (183 mg, 0.345 mmol) in 40%methylamine/methanol was added a solution (3 ml) of ammoniumchloride (37 mg, 0.690 mmol), and the mixture was stirred undernitrogen atmosphere in a sealed tube at 150°C for 18 hours. Aftercooling, the solvent was distilled off under reduced pressure, andthe residue was dissolved by adding water and ethyl acetate. Theaqueous layer was separated, and extracted with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, andconcentrated under reduced pressure. The residue was subjected toa basic silica gel column chromatography (hexane/ethyl acetate,10:1) to give the title compound as free base. This was dissolvedin ethyl acetate, a solution of 4 M hydrogen chloride/ethylacetate was added thereto, and the mixture was concentrated underreduced pressure to give the title compound (34 mg, yield 20%).Amorphous.1H NMR (DMSO-d6) δ 1.27 (6H, s), 1.37 (3H, s), 1. 42 (3H, s), 2.08(1H, d, J = 15.5 Hz), 2.20 (1H, d, J = 15.5 Hz), 2.88 (3H, d, J =4.8 Hz), 2.98 (1H, d, J = 16.2 Hz), 3.18 (1H, d, J = 16.2 Hz),6.53 (1H, s), 7.15-7.25 (1H, m), 7.45-7.60 (2H, m), 7.84 (1H, s),7.85-7.95 (1H, m), 11.44 (1H, s). Reference Example 54 2-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-5,5-dimethyl-1,5-dihydro-4H-imidazol-4-one
    [0357] From 2-[3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-5,5-dimethyl-1,5-dihydro-4H-imidazol-4-oneand iodoethane, the title compound wasobtained by the method similar to that in Reference Example 50.Yield 83%.1H NMR (CDCl3) δ 1.25 (6H, s), 1.31 (6H, s), 1.47 (3H, t, J = 7.0Hz), 1.80 (6H, s), 2.16 (2H, s), 2.68 (2H, s), 4.19 (2H, q, J =7.0 Hz), 6.60-6.62 (2H, m), 7.48-7.50 (2H, m), 7.85 (1H, s), 7.92-7.96(1H, m). Reference Example 55 5-(Bromomethyl)-1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline
    [0358] To a suspension of 1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethyl-1-phenylfuro[2,3-h]isoquinoline(1.47g, 3.55 mmol), paraformaldehyde (94%) (170 mg, 5.32 mmol) andsodium bromide (603 mg, 5.86 mmol) in acetic acid (1.02 ml, 17.8mmol) was added conc. sulfuric acid (0.57 ml, 10.7 mmol), and themixture was stirred for 20 hours at 100°C. After cooling, thereaction mixture was combined with ice water, neutralized withconc. ammonia water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography (hexane/ethylacetate, 10:1) to give the title compound (673 mg, yield 37%).Amorphous.1H NMR (CDCl3) δ 1.27 (6H, s), 1.32 (6H, s), 2.19 (2H, s), 2.70 (2H,s), 4.05 (3H, s), 4.63 (2H, s), 7.26-7.35 (2H, m), 7.50-7.56 (2H,m). Reference Example 56 1-(3-Bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline-5-acetonitrile
    [0359] To a solution of 5-(bromomethyl)-1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline(670 mg, 1.32 mmol) in N,N-dimethylformamide (7 ml) was added a solution of sodium cyanate (65 mg, 1.32 mmol) in water (2 ml), andthe mixture was stirred at room temperature for 2 hours. Thereaction mixture was combined with water, and extracted twice withethyl acetate. The combined organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried oversodium sulfate, filtered, and concentrated under reduced pressure.The residue was subjected to a basic silica gel columnchromatography (hexane/ethyl acetate, 10:1), and crystallized fromhexane to give the title compound (131 mg, yield 49%).1H NMR (CDCl3) δ 1.28 (6H, s), 1.32 (6H, s), 2.20 (2H, s), 2.68 (2H,s), 3.73 (2H, s), 4.05 (3H, s), 7.25-7.36 (2H, m), 7.50-7.57 (2H,m). Reference Example 57 1-(3-Aminophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline-5-acetonitrile
    [0360] To a solution of 1-(3-bromophenyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinoline-5-acetonitrile(170 mg, 0.375 mmol) in toluene (1.5 ml) were addedbenzophenoneimine (0.075 ml, 0.450 mmol) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(17.5 mg, 0.0281 mmol),sodium tert-butoxide (50.4 mg, 0.525 mmol) andtris(dibenzylideneacetone)dipalladium(0) (8.6 mg, 0.00938 mmol),and the mixture was stirred for 15 hours under nitrogen atmosphereat 80°C. After cooling, the reaction mixture was combined withice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was dissolved intetrahydrofuran (3 ml), 1 M hydrochloric acid (1 ml) was addedthereto, and the mixture was stirred for 30 minutes at roomtemperature. The reaction mixture was combined with ice water,and extracted twice with ethyl acetate. The combined organiclayer was washed with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was subjected to a basic silica gel column chromatography (hexane/ethyl acetate 2:1) togive the title compound (94 mg, yield 64%).Oily matter.1H NMR (CDCl3) δ 1.26 (6H, s), 1.31 (6H, s), 2.30 (2H, s), 2.66 (2H,s), 3.73 (2H, s), 4.02 (3H, s), 6.67 (3H, m), 7.10-7.18 (1H, m). Reference Example 58 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-propoxyfuro[2,3-h]isoquinolin-1-yl)benzamide
    [0361] With 1-iodopropane, the title compound was obtained by themethod similar to that in Reference Example 50. Yield 62%.1H NMR (CDCl3) δ 1.04 (3H, t, J = 7.5 Hz), 1.26 (6H, s), 1.30 (6H,s), 1.75-1.91 (2H, m), 2.17 (2H, s), 2.69 (2H, s), 4.07 (2H, q, J= 6.9 Hz), 5.40 (1H, br s), 5.47 (1H, br s), 6.62 (1H, s), 7.02(1H, s), 7.45-7.50 (2H, m), 7.86-7.89 (2H, m). Reference Example 59 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[6-(2-amino-2-oxoethoxy)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamidehydrochloride
    [0362] With 2-iodoacetamide, the title compound was obtained as freebase by the method similar to that in Reference Example 50. Thiswas dissolved in ethyl acetate, a solution of 4 M hydrogenchloride/ethyl acetate was added thereto, and the mixture wasconcentrated under reduced pressure. The resultant crystals werewashed with ethyl acetate to give the title compound was obtained.Yield 68%.1H NMR (DMSO-d6) δ 1.25 (6H, s), 1.48 (12H, s), 2.20-2.30 (2H, m),3.05-3.20 (2H, m), 4.70 (2H, s), 6.91 (1H, s), 6.91 (1H, s), 6.94(1H, s), 7.20 (1H, s), 7.41 (1H, s), 7.54 (1H, s), 7.70-7.74 (2H,m), 8.15-8.30 (2H, m), 8.47 (1H, s). Reference Example 60 3-[5-(Cyanomethyl)-3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-methylbenzamide
    [0363] To a solution of 3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-methylbenzamidehydrochloride (529 mg, 1.13 mmol) in 1,2-dichloroethane (3 ml) was added aluminum chloride (452 mg, 3.39mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 4.5 hours. Aluminum chloride (301 mg, 2.26 mmol)was further added thereto, and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was combined withice water, ethyl acetate and tetrahydrofuran, and alkalified with5 M aqueous solution of sodium hydroxide, and the precipitate wastaken by filtration. The aqueous layer was separated, andextracted twice with a mixed solution of ethyl acetate-tetrahydrofuran.The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, and concentrated under reduced pressure. The resultantcrystals were washed with diisopropyl ether to give the titlecompound (280 mg, yield 59%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.35 (6H, s), 2.14 (2H, s), 2.76 (2H,s), 2.97 (3H, d, J = 4.8 Hz), 3.72 (2H, s), 6.80-6.85 (1H, m),7.47-7.50 (2H, m), 7.85-7.93 (2H, m). Reference Example 61 3-[5-(Cyanomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-methylbenzamide
    [0364] From 3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]-N-methylbenzamideandiodoethane, the title compound was obtained by the method similarto that in Reference Example 50. Yield 79%.1H NMR (CDCl3) δ 1.26 (12H, s), 1.39 (3H, t, J = 7.0 Hz), 2.10 (2H,s), 2.68 (2H, s), 3.00 (3H, d, J = 4.8 Hz), 3.76 (2H, s), 4.34 (2H,q, J = 7.0 Hz), 6.40-6.53 (1H, br), 7.44-7.50 (2H, m), 7.75 (1H,s), 7.83-7.89 (1H, m). Reference Example 62 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-6-(2-hydroxyethoxy)-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0365] To a solution of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide(438 mg, 0.974 mmol) in N,N-dimethylformamide (4 ml) were added potassium carbonate (148 mg,1.07 mmol), potassium iodide (16 mg, 0.0974 mmol) and 2-bromoethanol(0.076 ml, 1.07 mmol), and the mixture was stirred at60°C for 5 hours. 2-bromoethanol (0.035 ml, 0.487 mmol) wasfurther added thereto, and the mixture was stirred for 15 hours at60°C. After cooling, the reaction mixture was combined with icewater, and extracted twice with ethyl acetate. The combinedorganic layer was washed with an aqueous solution of sodiumchloride and a saturated aqueous solution of sodium chloride,dried over sodium sulfate, and concentrated under reduced pressure.The residue was subjected to a basic silica gel columnchromatography (hexane/ethyl acetate, 50:1 followed by 20:1), andcrystallized from ethyl acetate to give the title compound (209 mg,yield 44%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.30 (6H, s), 1.71 (6H, s), 2.18 (2H,s), 2.68 (2H, s), 3.95 (2H, t, J = 4.4 Hz), 4.21 (2H, t, J = 4.4Hz), 5.43 (1H, br s), 6.45 (1H, br s), 6.66 (1H, s), 7.01 (1H, s),7.42-7.49 (2H, m), 7.84-7.90 (2H, m). Reference Example 63 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-6-(2-propynyloxy)furo[2,3-h]isoquinolin-1-yl]benzamide
    [0366] With 3-bromo-1-propyne, the title compound was obtained bythe method similar to that in Reference Example 50. Yield 76%.1H NMR (CDCl3) δ 1.25 (6H, s), 1.30 (6H, s), 1.71 (6H, s), 2.18 (2H,s), 2.59 (1H, t, J = 2.2 Hz), 2.70 (2H, s), 4.83 (2H, d, J = 2.2Hz), 5.81 (1H, br s), 6.78 (1H, br s), 7.41-7.49 (2H, m), 7.86-7.91(2H, m). Reference Example 64 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[6-(difluoromethoxy)-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0367] To a suspension of N-(2-amino-1,1-dimethyl-2-oxoethyl)-3-(3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide(451 mg, 1.00 mmol) in 1,4-dioxane (4ml) were added chlorobenzyltriethyl ammonium (11 mg, 0.050 mmol) and a solution of sodium hydroxide (120 mg, 3.01 mmol) in water(0.12 ml). Chlorodifluoromethane was bubbled under ice-coolingfor 10 minutes and the mixture was stirred at room temperature for5 hours. Chlorodifluoromethane was bubbled again, and the mixturewas stirred for 15 hours at room temperature. The reactionmixture was combined with ice water, and extracted twice withethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography (ethylacetate/methanol, 50:1 followed by 10:1), and crystallized fromdiethyl ether-hexane to give the title compound (276 mg, yield55%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.30 (6H, s), 1.72 (6H, s), 2.20 (2H,s), 2.69 (2H, s), 5.41 (1H, br s), 6.40 (1H, br s), 6.57 (1H, d, J= 74.2 Hz), 6.87 (1H, s), 7.01 (1H, s), 7.47-7.50 (2H, m), 7.85-7.90(2H, m). Reference Example 65 Methyl 3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoate
    [0368] From methyl 3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoate,the titlecompound was obtained by the method similar to that in ReferenceExample 60. Yield 40%.1H NMR (CDCl3) δ 1.27 (12H, s), 2.16 (2H, s), 2.72 (2H, s), 3.76(2H, s), 3.93 (3H, s), 5,75 (1H, br s), 7.47-7.51 (1H, m), 7.58-7.61(1H, m),8.05 (1H, s), 8.15-8.12 (1H, m). Reference Example 66 Methyl 3-[5-(cyanomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoate
    [0369] From methyl 3-[5-(cyanomethyl)-3,4,8,9-tetrahydro-6-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoateandiodoethane, the title compound was obtained by the method similarto that in Reference Example 50. Yield 64%.1H NMR (CDCl3) δ 1.27 (6H, s), 1.28 (6H, s), 1.39 (3H, t, J = 7.2 Hz), 2.11 (2H, s), 2.69 (2H, s), 3.76 (2H, s), 3.93 (3H, s), 4.34(2H, q, J = 7.2 Hz), 7.49 (1H, t, J = 7.5 Hz), 7.59-7.62 (1H, m),8.06-8.11 (2H, m). Reference Example 67 N-(2-Amino-1,1-dimethyl-2-oxoethyl)-3-[5-(cyanomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzamide
    [0370] From methyl 3-[5-(cyanomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoate,3-[5-(cyanomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl]benzoicacid was obtainedby the method similar to that in Reference Example 30. From theresultant benzoic acid derivative, the title compound was obtainedby the method similar to that in Reference Example 31. Yield 72%.1H NMR (CDCl3) δ 1.32-1.50 (15H, m), 1.73 (6H, s), 2.28 (2H, s),2.92 (2H, s), 3.77 (3H, s), 4.52 (2H, q, J = 7.0 Hz), 5.35 (1H, brs), 6.50 (1H, br s), 7.41 (1H, d, J = 8.0 Hz), 7.55 (1H, t, J =8.0 Hz), 8.09 (1H, d, J = 8.0 Hz), 8.34 (1H, br s), 8.44 (1H, s). Reference Example 68 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide
    [0371] From 7-ethoxy-2,3-dihydro-2,2-dimethyl-a-(1-methylethyl)-5-benzofuranmethanoland 4-cyano-N-methylbenzamide, the titlecompound was obtained by the method similar to that in ReferenceExample 34. Yield 50%.1H NMR (CDCl3) δ 1.25 (6H, s), 1.29 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.16 (2H, s), 2.67 (2H, s), 3.04 (3H, d, J = 5.0 Hz), 4.18(2H, q, J = 7.0 Hz), 6.29 (1H, t, J = 5.0 Hz), 6.61 (1H, s), 7.45(2H, dd, J = 6.8, 1.8 Hz), 7.78 (2H, dd, J = 6.8, 1.8 Hz). Reference Example 69 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride
    [0372] From 7-ethoxy-2,3-dihydro-2,2-dimethyl-a-(1-methylethyl)-5-benzofuranmethanoland 4-aminobenzonitrile, the title compound wasobtained as free base by the method similar to that in Reference Example 34. This was dissolved in ethyl acetate, and a solutionof 4 M hydrogen chloride/ethyl acetate was added thereto. Themixture was concentrated under reduced pressure, and the residuewas crystallized from ethanol-diisopropyl ether to give the titlecompound. Yield 31%.1H NMR (DMSO-d6) δ 1.29 (6H, s), 1.36 (6H, s), 1.36 (3H, t, J = 7.0Hz), 2.50 (2H, s), 3.04 (2H, s), 4.21 (2H, q, J = 7.0 Hz), 6.76(2H, d, J = 8.4 Hz), 7.02 (1H, s), 7.08 (2H, br s), 7.36 (2H, d, J= 8.4 Hz), 11.66 (1H, br s). Reference Example 70 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]acetamide
    [0373] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride(323 mg, 0.738 mmol) in tetrahydrofuran (3 ml) were addedtriethylamine (0.34 ml, 2.44 mmol) and acetyl chloride (0.058 ml,0.812 mmol) under ice-cooling, and the mixture was stirred at roomtemperature for 2 hours. The reaction mixture was combined withice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wassubjected to a basic silica gel column chromatography(hexane/ethyl acetate, 2:1 followed by 1:1), and crystallized fromdiethyl ether-hexane to give the title compound (191 mg, yield64%).1H NMR (CDCl3) δ 1.22 (6H, s), 1.31 (6H, s), 1.45 (3H, t, J = 7.0Hz), 2.18 (3H, s), 2.25 (2H, s), 2.65 (2H, s), 4.17 (2H, q, J =7.0 Hz), 6.58 (1H, s), 7.34 (2H, d, J = 8.0 Hz), 7.40 (1H, s),7.52 (2H, d, J = 8.0 Hz). Reference Example 71 3,4,8,9-Tetrahydro-N,3,8,8-tetramethyl-6-(methylamino)-1-phenylfuro[2,3-h]isoquinoline-3-methanamine
    [0374] A mixture of 3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride (0.50 g, 1.08 mmol) and 40% methylamine/methanol a solution of (4ml) was stirred for 15 hours at 160°C under nitrogen atmosphere ina sealed tube. The reaction solution was concentrated underreduced pressure, and the residue was alkalified with an aqueoussolution of sodium hydrogen carbonate, and extracted with ethylacetate. The extracts were washed with water, and concentratedunder reduced pressure. The residue was subjected to a silica gelcolumn chromatography (from ethyl acetate/methanol 19:1 to ethylacetate/methanol/triethylamine 92:5:3), then purified with a basicsilica gel column chromatography (hexane/ethyl acetate 3:1), andrecrystallized from ethyl acetate-diisopropyl ether to give thetitle compound (0.18 g, yield 46%).Melting point: 126 to 128°C.1H NMR (CDCl3) δ 1.08 (3H, s), 1.22 (3H, s), 1.28 (3H, s), 2.10 (1H,d, J = 15.8 Hz), 2.19 (1H, d, J = 15.8 Hz), 2.46 (3H, s), 2.47 (1H,d, J = 15.2 Hz), 2.67 (1H, d, J = 10.8 Hz), 2.81 (1H, d, J = 10.8Hz), 2.91 (3H, d, J = 5.0 Hz), 3.05 (2H, d, J = 15.2 Hz), 3.98 (1H,br d, J = 5.0 Hz), 6.31 (1H, s), 7.37 (5H, s). Reference Example 72 2-[(6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-isoindol-1,3(2H)-dione
    [0375] A solution of 3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolinehydrochloride(0.80 g, 1.72 mmol) in N,N-dimethylformamide (15 ml) was cooledwith ice, and to this solution were added sodium hydride (66%dispersion in oil) (62.6 mg, 1.72 mmol) and potassium phthalimide(0.414 g, 2.24 mmol). The mixture was stirred under nitrogenatmosphere at 170°C for 3 hours and cooled to room temperature.The reaction solution was combined with water, and extracted withethyl acetate. The extracts were washed with water, andconcentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (from hexane/ethyl acetateto 3:2 ethyl acetate), and recrystallized from ethyl acetate-hexaneto give the title compound (0.53g, yield 62%).Melting point: 187 to 189°C. 1H NMR (CDCl3) δ 1.18 (3H, s), 1.21 (3H, s), 1.37 (3H, s), 1.44 (3H,t, J = 7.0 Hz), 2.04 (1H, d, J = 16.4 Hz), 2.11 (1H, d, J = 16.4Hz), 2.79 (1H, d, J = 15.8 Hz), 3.00 (1H, d, J = 15.8 Hz), 3.84(1H, d, J = 13.6 Hz), 3.95 (1H, d, J = 13.6 Hz), 4.13 (2H, q, J =7.0 Hz), 6.53 (1H, s), 7.36-7.44 (5H, m), 7.63-7.78 (4H, m). Reference Example 73 6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-acetonitrile
    [0376] To a solution of 3-(bromomethyl)-6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline(3.00 g, 7.00mmol) in dimethylsulfoxide (24 ml) was added sodium cyanate (0.378g, 7.70 mmol), and the mixture was stirred for 15 hours undernitrogen atmosphere at 80°C. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extracts werewashed with water, and concentrated under reduced pressure. Theresidue was purified with a silica gel column chromatography (fromhexane/ethyl acetate 4:1 to 7:3) to give the title compound (0.51g, yield 19%).Amorphous.1H NMR (CDCl3) δ 1.30 (3H, s), 1.33 (3H, s), 1.36 (3H, s), 1.48 (3H,t, J = 6.9 Hz), 2.21 (2H, s), 2.58 (1H, d, J = 16.5 Hz), 2.71 (1H,d, J = 16.5 Hz), 2.81 (1H, d, J = 15.6 Hz), 2.91 (1H, d, J = 15.6Hz), 4.20 (2H, q, J = 6.9 Hz), 6.66 (1H, s), 7.40 (5H, s). Reference Example 74 6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-acetamide
    [0377] To a solution of ice-cooled 6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-acetonitrile(0.41 g, 1.09 mmol) in methanol (5 ml) were added 1 M aqueoussolution of sodium hydroxide (1.64 ml, 1.64 mmol) and 30% hydrogenperoxide water (0.186g, 1.64 mmol), and the mixture was stirred atroom temperature for 24 hours. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extracts werewashed with water, and concentrated under reduced pressure. Theresidue was purified with a silica gel column chromatography (ethyl acetate/methanol 19:1) to give the title compound (0.31 g,yield 72%).Amorphous.1H NMR (CDCl3) δ 1.13 (3H, s), 1.28 (3H, s), 1.36 (3H, s), 1.47 (3H,t, J = 7.0 Hz), 2.15 (1H, d, J = 16.2 Hz), 2.31 (1H, d, J = 16.2Hz), 2.53 (1H, d, J = 14.4 Hz), 2.56 (1H, d, J = 15.4 Hz), 2.68(1H, d, J = 14.4 Hz), 2.88 (1H, d, J = 15.4 Hz), 4.19 (2H, q, J =7.0 Hz), 5.48-5.50 (1H, m), 6.63 (1H, s), 7.41 (5H, s), 7.90 (1H,br d, J = 4.0 Hz). Reference Example 75 6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-methanamine
    [0378] To a suspension of 2-[(6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-isoindol-1,3(2H)-dione(2.44 g, 4.93 mmol) in ethanol (20 ml) was addedhydrazine monohydrate (0.550 ml, 11.3 mmol), and the mixture washeated under reflux for 3 hours. The reaction solution was cooledto room temperature, alkalified with 1 M aqueous solution ofsodium hydroxide, and extracted with ethyl acetate. The extractswere washed with 1 M aqueous solution of sodium hydroxide andwater, and concentrated under reduced pressure. The residue waspurified with a basic silica gel column chromatography (ethylacetate/methanol 97:3) to give the title compound (1.71 g, yield95%).Amorphous.1H NMR (CDCl3) δ 1.06 (3H, s), 1.28 (3H, s), 1.33 (3H, s), 1.46 (3H,t, J = 7.0 Hz), 2.14 (1H, d, J = 16.2 Hz), 2.24 (1H, d, J = 16.2Hz), 2.47 (1H, d, J = 15.6 Hz), 2.79 (1H, d, J = 12.8 Hz), 2.88(1H, d, J = 12.8 Hz), 2.91 (1H, d, J = 15.6 Hz), 4.19 (2H, q, J =7.0 Hz), 6.62 (1H, s), 7.39 (5H, s). Reference Example 76 N-[(6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]benzamide
    [0379] To a solution of ice-cooled 6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-methanamine (0.20 g, 0.55 mmol) in tetrahydrofuran (3 ml) was added 1 Maqueous solution of sodium hydroxide (1.4 ml, 1.4 mmol), andfurther benzoyl chloride (0.096 ml, 0.82 mmol) was added dropwisethereto. The mixture was stirred under ice-cooling for 30 minutes,combined with water, and extracted with ethyl acetate. Theextracts were washed with water, and concentrated under reducedpressure to give the title compound (0.24 g, yield 93%).Amorphous.1H NMR (CDCl3) δ 1. 07 (3H, s), 1.27 (3H, s), 1.33 (3H, s), 1.46 (3H,t, J = 7.0 Hz), 2.12 (1H, d, J = 16.2 Hz), 2.24 (1H, d, J = 16.2Hz), 2.57 (1H, d, J = 15.6 Hz), 2.94 (1H, d, J = 15.6 Hz), 3.61-3.70(1H, m), 3.78-3.88 (1H, m), 4.18 (2H, q, J = 7.0 Hz), 6.64(1H, s), 6.97-7.02 (1H, m), 7.41-7.51 (8H, m), 7.75-7.79 (2H, m). Reference Example 77 2-Chloro-N-[(6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]acetamide
    [0380] To a solution of ice-cooled 6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-methanamine(0.540 g, 1.48 mmol) in tetrahydrofuran (7 ml) was added 1 Maqueous solution of sodium hydroxide (3.7 ml, 3.7 mmol), andfurther chloroacetyl chloride (0.177 ml, 2.22 mmol) was addeddropwise thereto. The mixture was stirred under ice-cooling for15 minutes, combined with water, and extracted with ethyl acetate.The extracts were washed with water, and concentrated underreduced pressure to give the title compound (0.64 g, yield 98%).Amorphous.1H NMR (CDCl3) δ 1.04 (3H, s), 1.28 (3H, s), 1.35 (3H, s), 1.47 (3H,t, J = 6.9 Hz), 2.15 (1H, d, J = 16.2 Hz), 2.27 (1H, d, J = 16.2Hz), 2.54 (1H, d, J = 12.0 Hz), 2.85 (1H, d, J = 12.0 Hz), 3.39-3.46(1H, m), 3.63-3.70 (1H, m), 4.07 (2H, s), 4.18 (2H, q, J =6.9 Hz), 6.63 (1H, s), 7.32-7.42 (6H, m). Reference Example 78 N-[(6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-1H-imidazole-1-acetamide
    [0381] To a solution of 2-chloro-N-[(6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]acetamide (0.340 g, 0.771 mmol) in N,N-dimethylformamide(5 ml) were added sodium hydride (66% dispersion in oil) (33.6 mg,0.925 mmol) and imidazole (0.157 g, 2.31 mmol), and the mixturewas stirred at room temperature for 30 minutes. The reactionsolution was combined with water, and extracted with ethyl acetate.The extracts were washed with water, and concentrated underreduced pressure. The residue was purified with a basic silicagel column chromatography (ethyl acetate/methanol 19:1) to givethe title compound (0.262 g, yield 72%).Amorphous.1H NMR (CDCl3) δ 0.91 (3H, s), 1.26 (3H, s), 1.36 (3H, s), 1.46 (3H,t, J = 7.0 Hz), 2.13 (1H, d, J = 16.2 Hz), 2.31 (1H, d, J = 16.2Hz), 2.46 (1H, d, J = 15.2 Hz), 2.75 (1H, d, J = 15.2 Hz), 3.23-3.33(1H, m), 3.59-3.70 (1H, m), 4.18 (2H, q, J = 7.0 Hz), 4.67(2H, s), 6.50-6.58 (1H, m), 6.61 (1H, s), 6.93 (1H, s), 7.08-7.10(2H, m), 7.28-7.31 (2H, m), 7.41-7.44 (2H, m), 7.52 (1H, s). Reference Example 79 N-[(6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]methanesulfonamide
    [0382] To a solution of ice-cooled 6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-methanamine(0.200 g, 0.549 mmol) in tetrahydrofuran (3 ml) was added 1 Maqueous solution of sodium hydroxide (1.4 ml, 1.4 mmol), andfurther methanesulfonyl chloride (0.064 ml, 0.82 mmol) was addeddropwise thereto. The mixture was stirred under ice-cooling for30 minutes, combined with water, and extracted with ethyl acetate.The extracts were washed with water, concentrated under reducedpressure, and further the residue was washed with hexane and driedto give the title compound (0.17 g, yield 70%).Amorphous.1H NMR (CDCl3) δ 1.05 (3H, s), 1.27 (3H, s), 1.35 (3H, s), 1.47 (3H,t, J = 7.0 Hz), 2.13 (1H, d, J = 16.2 Hz), 2.28 (1H, d, J = 16.2Hz), 2.46 (1H, d, J = 15.4 Hz), 2.96 (3H, s), 3.05 (1H, d, J =15.4 Hz), 3.18-3.26 (1H, m), 3.37-3.44 (1H, m), 4.19 (2H, q, J = 7.0 Hz), 5.04-5.10 (1H, m), 6.63 (1H, s), 7.40 (5H, s). Reference Example 80 N-[(6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]-2-(dimethylamino)acetamide
    [0383] To a solution of 2-chloro-N-[(6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]acetamide(0.300 g, 0.680 mmol) in tetrahydrofuran (4ml) was added an aqueous solution of 40% dimethylamine (1 ml), andthe mixture was stirred at room temperature for 1 hour. Thereaction solution was combined with water, and extracted withethyl acetate. The extracts were washed with water, andconcentrated under reduced pressure to give the title compound(0.230 g, yield 75%).Amorphous.1H NMR (CDCl3) δ 1.05 (3H, s), 1.27 (3H, s), 1.33 (3H, s), 1.46 (3H,t, J = 7.0 Hz), 2.12 (1H, d, J = 16.4 Hz), 2.23 (1H, d, J = 16.4Hz), 2.26 (6H, s), 2.53 (1H, d, J = 15.8 Hz), 2.84 (1H, d, J =15.8 Hz), 2.97 (2H, s), 3.43-3.62 (2H, m), 4.18 (2H, q, J = 7.0Hz), 6.62 (1H, s), 7.38-7.44 (5H, m), 7.67-7.75 (1H, m). Reference Example 81 N-[(6-Ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinolin-3-yl)methyl]acetamide
    [0384] From 6-ethoxy-3,4,8,9-tetrahydro-3,8,8-trimethyl-1-phenylfuro[2,3-h]isoquinoline-3-methanamineand acetic anhydride,the title compound was obtained by the method similar to that inReference Example 79. Yield 63%.Amorphous.1H NMR (CDCl3) δ 1.01 (3H, s), 1.27 (3H, s), 1.34 (3H, s), 1.46 (3H,t, J = 7.0 Hz), 2.00 (3H, s), 2.12 (1H, d, J = 16.2 Hz), 2.24 (1H,d, J = 16.2 Hz), 2.49 (1H, d, J = 15.6 Hz), 2.86 (1H, d, J = 15.6Hz), 3.40-3.51 (1H, m), 3.53-3.63 (1H, m), 4.18 (2H, q, J = 7.0Hz), 6.17-6.24 (1H, m), 6.62 (1H, s), 7.41 (5H, s). Reference Example 82 3-(6-Ethoxy-3,4,8,9-tetrahydro-4-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide
    [0385] A mixture of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide(2.78 g,6.84 mmol), N-bromosuccinimide (1.46 g, 8.21 mmol) and 2,2'-azobis(isobutyronitrile)(0.112 g, 0.684 mmol) was heated underreflux for 1 hour. The reaction solution was cooled to roomtemperature, and concentrated under reduced pressure. The residuewas combined with an aqueous solution of sodium hydrogen carbonateand extracted with ethyl acetate. The extracts were washed withwater, and concentrated under reduced pressure. The residue waspurified with a basic silica gel column chromatography (ethylacetate), and recrystallized from ethyl acetate-hexane to give thetitle compound (0.400 g, yield 14%).Melting point: 186 to 188°C.1H NMR (CDCl3) δ 1.18 (3H, s), 1.26 (3H, s), 1.30 (6H, s), 1.47 (3H,t, J = 6.9 Hz), 2.14 (2H, s), 2.94 (3H, d, J = 4.8 Hz), 4.12 (2H,q, J = 6.9 Hz), 4.38 (1H, br s), 6.90 (1H, s), 6.96 (1H, br s),7.41-7.46 (2H, m), 7.71 (1H, s), 7.84-7.88 (1H, m). Reference Example 83 3-(6-Ethoxy-4-fluoro-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide
    [0386] A solution of 3-(6-ethoxy-3,4,8,9-tetrahydro-4-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide(0.100 g, 0.237 mmol) in dichloromethane (3 ml) was cooled to-78°C,to this solution was added diethylaminosulfur trifluoride(41.7 µl, 0.284 mmol), and the mixture was slowly cooled to roomtemperature with stirring the mixture. The reaction solution wascombined with an aqueous solution of sodium hydrogen carbonate,and extracted with ethyl acetate. The extracts were washed withwater, and concentrated under reduced pressure. The residue waspurified with a silica gel column chromatography (ethyl acetate),and recrystallized from ethyl acetate-hexane to give the titlecompound (79.0 mg, yield 79%).Melting point: 172 to 173°C.1H NMR (CDCl3) δ 1.12 (3H, s), 1.28 (3H, s), 1.33 (3H, s), 1.47 (3H,t, J = 7.0 Hz), 1.48 (3H, s), 2.13 (1H, d, J = 16.2 Hz), 2.22 (1H, d, J = 16.2 Hz), 2.97 (3H, d, J = 4.6 Hz), 4.22 (2H, q, J = 7.0Hz), 5.10 (1H, d, J = 50.8 Hz), 6.43-6.53 (1H, m), 6.87-6.89 (1H,m), 7.42-7.50 (2H, m), 7.79 (1H, s), 7.85-7.93 (1H, m). Reference Example 84 3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethyl-4-oxofuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide
    [0387] To a solution of 3-(6-ethoxy-3,4,8,9-tetrahydro-4-hydroxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide(0.450 g, 1.07 mmol) in chloroform (5 ml) was added manganesedioxide (1.5 g), and the mixture was stirred for 15 hours at roomtemperature. The reaction solution was filtered, and the filtratewas concentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (ethyl acetate) andrecrystallized from ethyl acetate-hexane to give the titlecompound (0.289 g, yield 64%).Melting point: 233 to 235°C.1H NMR (CDCl3) δ 1.33 (6H, s), 1.49 (3H, t, J = 7.0 Hz), 1.50 (6H,s), 2.16 (2H, s), 2.98 (3H, d, J = 4.4 Hz), 4.25 (2H, q, J = 7.0Hz), 6.47 (1H, br d, J = 4.4 Hz), 7.42-7.52 (2H, m), 7.56 (1H, s),7.75-7.79 (1H, m), 7.86-7.92 (1H, m). Reference Example 85 3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N,N-dimethylbenzamide
    [0388] To a solution of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride(0.200 g, 0.465 mmol) and 1-hydroxy-1H-benzotriazole monohydrate(78.4 mg, 0.512 mmol) in N,N-dimethylformamide (2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.116 g,0.605 mmol) under ice-cooling, and the mixture was stirred underice-cooling for 30 minutes. To this mixture was added an aqueoussolution of 50% dimethylamine (1 ml), and the mixture was furtherstirred for 1 hour under ice-cooling. The reaction solution wascombined with water, and extracted with ethyl acetate. Theextracts were washed with water and concentrated under reducedpressure to give the title compound (0.188 g, yield 96%). Oily matter.1H NMR (CDCl3) δ 1.24 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.23 (2H, s), 2.67 (2H, s), 3.00-3.08 (6H, m), 4.18 (2H, q, J= 7.0 Hz), 6.60 (1H, s), 7.42-7.49 (4H, m). Reference Example 86 1-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]pyrrolidine
    [0389] To a suspension of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride(0.20 g, 0.465 mmol), 1-hydroxy-1H-benzotriazole monohydrate (78.4mg, 0.512 mmol) and pyrrolidine (58.2 µl, 0.698 mmol) in N,N-dimethylformamide(2 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.116 g, 0.605mmol) and triethylamine (0.195 ml, 1.40 mmol), and the mixture wasstirred at room temperature for 1 hour. The reaction solution wascombined with water, and extracted with ethyl acetate. Theextracts were washed with water and concentrated under reducedpressure to give the title compound (0.175 g, yield 84%).Oily matter.1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0Hz), 1.82-1.99 (4H, m), 2.22 (2H, s), 2.67 (2H, s), 3.44 (2H, t, J= 6.2 Hz), 3.63 (2H, t, J = 6.4 Hz), 4.18 (2H, q, J = 7.0 Hz),6.60 (1H, s), 7.38-7.60 (4H, m). Reference Example 87 1-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]piperidine
    [0390] From 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochlorideand piperidine, the title compound was obtained by the methodsimilar to that in Reference Example 86. Yield 79%.Oily matter.1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0Hz), 1.48-1.71 (6H, m), 2.22 (2H, s), 2.67 (2H, s), 3.39 (2H, brs), 3.68 (2H, br s), 4.18 (2H, q, J = 7.0 Hz), 6.60 (1H, s), 7.38-7.50(4H, m). Reference Example 88 1,1-Dimethylethyl 3-[[[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]-1-piperidinecarboxylate
    [0391] To a solution of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(3.50 g, 9.60mmol), 1-hydroxy-1H-benzotriazole monohydrate (1.62 g, 10.6 mmol)and 1-[[(1,1-dimethylethyl)oxy]carbonyl]-3-piperidinecarboxylicacid (2.20 g, 9.60 mmol) in N,N-dimethylformamide (30 ml) wereadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(2.39 g, 12.5 mmol) and triethylamine (4.02 ml, 28.8 mmol), andthe mixture was stirred at 50°C for 2 hours. The reactionsolution was combined with water, and extracted with ethyl acetate.The extracts were washed with water, and concentrated underreduced pressure. The residue was purified with a silica gelcolumn chromatography (from hexane/ethyl acetate 1:4 to ethylacetate) and recrystallized from ethyl acetate-hexane to give thetitle compound (3.04 g, yield 55%).Melting point: 202 to 203°C.1H NMR (CDCl3) δ 1.19 (3H, s), 1.24 (3H, s), 1.31 (6H, s), 1.38-1.72(2H, m), 1.45 (9H, s), 1.46 (3H, t, J = 7.0 Hz), 1.91 (2H, brs), 2.26 (2H, s), 2.45 (1H, br s), 2.65 (2H, s), 3.09 (1H, br s),3.38 (1H, br s), 3.72 (1H, br s), 3.90-3.98 (1H, m), 4.18 (2H, q,J = 7.0 Hz), 6.58 (1H, s), 7.03 (1H, d, J = 7.8 Hz), 7.22-7.30 (1H,m), 7.48 (1H, s), 7.75 (1H, d, J = 8.2 Hz), 8.52 (1H, br s). Reference Example 89 N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-piperidinecarboxamidedihydrochloride
    [0392] To a solution of 1,1-dimethylethyl 3-[[[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]carbonyl]-1-piperidinecarboxylate(2.48 g, 4.31mmol) in ethanol (30 ml) was added a solution of 4 M hydrogenchloride/ethyl acetate (2.5 ml), and the mixture was stirred for 1hour at 60°C. The reaction solution was cooled to roomtemperature and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound(2.18 g, yield 92%).Melting point: 256 to 257°C (Decomposed).1H NMR (DMSO-d6) δ 1.18 (3H, t, J = 7.1 Hz), 1.24 (6H, s), 1.46 (6H,br s), 1.59-1.80 (3H, m), 2.06-2.10 (1H, m), 2.22-2.43 (2H, m),2.86-3.48 (7H, m), 4.24 (2H, q, J = 7.1 Hz), 7.08 (1H, s), 7.32(1H, d, J = 7.8 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.88 (1H, br s),7.99 (1H, s), 9.18-9.29 (1H, m), 9.33-9.48 (1H, m). Reference Example 90 N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]urea
    [0393] To a suspension of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride(0.800 g, 1.83 mmol) in tetrahydrofuran (10 ml) was addedtriethylamine (0.510 ml, 3.66 mmol), and the mixture was stirreduntil the red color was dissipated. To this mixture was addedsodium cyanate (0.238 g, 3.66 mmol) and the mixture was cooledwith ice, and trifluoroacetic acid (0.705 ml, 9.15 mmol) was addeddropwise thereto. The mixture was stirred for 2 hours at roomtemperature, combined with an aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The extracts werewashed with water, and concentrated under reduced pressure. Theresidue was recrystallized from ethyl acetate-hexane to give thetitle compound (0.470 g, yield 63%).Melting point: 202 to 205°C.1H NMR (CDCl3) δ 1.24 (6H, s), 1.30 (6H, s), 1.45 (3H, t, J = 7.0Hz), 2.27 (2H, s), 2.67 (2H, s), 4.17 (2H, q, J = 7.0 Hz), 4.92(2H, br s), 6.58 (1H, s), 6.94 (1H, d, J = 7.2 Hz), 7.19 (1H, d, J= 8.2 Hz), 7.25-7.28 (1H, m), 7.36 (1H, d, J = 7.2 Hz), 7.75 (1H,br s). Reference Example 91 2-Methyl-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-[(trifluoroacetyl)amino]propanamide
    [0394] To a suspension of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine dihydrochloride(1.50 g, 3.43 mmol), 2-methyl-2-[(trifluoroacetyl)amino]propionicacid (0.683 g, 3.43 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (0.525 g, 3.43 mmol) in N,N-dimethylformamide (10 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (0.855 g, 4.46 mmol) and triethylamine (1.67 ml,12.0 mmol), and the mixture was stirred at room temperature for 15hours. The reaction solution was combined with water, andextracted with ethyl acetate. The extracts were washed with water,and concentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (ethyl acetate/methanol97:3) to give the title compound (1.32 g, yield 71%).Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 7.0Hz), 1.76 (6H, s), 2.29 (2H, s), 2.66 (2H, s), 4.18 (2H, q, J =7.0 Hz), 6.60 (1H, s), 7.15 (1H, d, J = 7.8 Hz), 7.37 (1H, t, J =7.8 Hz), 7.45-7.49 (1H, m), 7.64-7.71 (1H, m), 7.80 (2H, s). Reference Example 92 N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-5-oxo-2-pyrrolidinecarboxamide
    [0395] From 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochlorideand 5-oxo-2-pyrrolidinecarboxylic acid, the title compound wasobtained by the method similar to that in Reference Example 91.Yield 78%.Amorphous.1H NMR (CDCl3) δ 1.22 (6H, br s), 1.30 (6H, s), 1.46 (3H, t, J =7.0 Hz), 2.00 (2H, br s), 2.21 (2H, s), 2.28-2.55 (4H, m), 4.08-4.23(3H, m), 6.58 (1H, s), 7.07 (1H, d, J = 8.0 Hz), 7.15-7.30(2H, m), 7.54 (1H, s), 7.71 (1H, d, J = 8.0 Hz), 8.71 (1H, br s). Reference Example 93 2-Amino-2-methyl-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide
    [0396] To a solution of 2-methyl-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-[(trifluoroacetyl)amino]propanamide (1.25 g, 2.29 mmol) intetrahydrofuran (10 ml) was added 2 M aqueous solution (5 ml) ofsodium hydroxide, and the mixture was stirred at 90°C for 24 hours.The reaction solution was combined with water, and extracted withethyl acetate. The extracts were washed with water andconcentrated under reduced pressure to give the title compound(0.98 g, yield 95%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.43-1.48 (9H, m),2.28 (2H, s), 2.65 (2H, s), 4.18 (2H, q, J = 7.8 Hz), 6.59 (1H, s),7.07 (1H, d, J = 7.8 Hz), 7.33 (1H, t, J = 7.8 Hz), 7.54 (1H, s),7.82 (1H, d, J = 7.8 Hz), 9.97 (1H, s). Reference Example 94 5,5-Dimethyl-3-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione
    [0397] To a solution of 2-amino-2-methyl-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide(0.890 g, 1.98 mmol) in N,N-dimethylformamide(10 ml) was added N,N'-carbonyldiimidazole(0.685 g, 4.22 mmol), and the mixture was stirred for 20 hours atroom temperature. The reaction solution was combined with asaturated aqueous solution of sodium hydrogen carbonate, andextracted with ethyl acetate. The extracts were washed with water,and concentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (from hexane/ethyl acetate1:1 to ethyl acetate), and recrystallized from ethyl acetate-hexaneto give the title compound (0.370 g, yield 39%).Melting point: 237 to 238°C.1H NMR (CDCl3) δ 1.25-1.32 (18H, m), 1.47 (3H, t, J = 6.9 Hz), 2.37(2H, br s), 2.69 (2H, s), 4.19 (2H, q, J = 6.9 Hz), 6.60 (1H, s),7.28-7.34 (1H, m), 7.42-7.48 (2H, m), 7.55 (1H, br s), 7.62 (1H,s). Reference Example 95 3-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione
    [0398] To a suspension of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride(0.800 g, 1.83 mmol) in tetrahydrofuran (12 ml) was addedtriethylamine (0.561 ml, 4.03 mmol), and the mixture was stirreduntil the red color was dissipated. To this mixture was addedethyl isocyanatoacetate (0.215 ml, 1.92 mmol), and the mixture wasstirred at 60°C for 1.5 hours. The reaction solution wasconcentrated under reduced pressure, and the residue was combinedwith 5 M hydrochloric acid (14 ml), and stirred for 2 hours at85°C. The reaction solution was combined with an aqueous solutionof sodium hydrogen carbonate, and extracted with ethyl acetate.The extracts were washed with water, and concentrated underreduced pressure. The residue was purified with a basic silicagel column chromatography (from hexane/ethyl acetate 1:4 to ethylacetate/methanol 97:3), and recrystallized from ethyl acetate-hexaneto give the title compound (0.695 g, yield 85%).Melting point: 202 to 204°C.1H NMR (CDCl3) δ 1.25 (6H, br s), 1.33 (6H, s), 1.46 (3H, t, J =7.0 Hz), 2.36 (2H, br s), 2.66 (2H, s), 3.98 (2H, s), 4.18 (2H, q,J = 7.0 Hz), 6.59 (1H, s), 7.41-7.52 (4H, m). Reference Example 96 3-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1-methyl-2,4-imidazolidinedione
    [0399] To a solution of ice-cooled 3-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,4-imidazolidinedione(0.567 g, 1.27 mmol) in tetrahydrofuran (5ml) was added sodium hydride (66% dispersion in oil) (55.3 mg,1.52 mmol), and the mixture was stirred under ice-cooling for 20minutes. To this mixture was added dropwise iodomethane (94.6 µl,1.52 mmol), and the mixture was further stirred for 1 hour underice-cooling. The reaction solution was combined with sodiumhydrogen carbonate water, and extracted with ethyl acetate. Theextracts were washed with water, and concentrated under reducedpressure. The residue was purified with a basic silica gel column chromatography (hexane/ethyl acetate 1:4) to give the titlecompound (0.375 g, yield 64%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.33 (6H, s), 1.45 (3H, t, J = 7.0Hz), 2.36 (2H, br s), 2.65 (2H, s), 3.06 (3H, s), 4.00 (2H, s),4.18 (2H, q, J = 7.0 Hz), 6.58 (1H, s), 7.48-7.52 (4H, m). Reference Example 97 1-Acetyl-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-piperidinecarboxamide
    [0400] A suspension of N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-piperidinecarboxamidedihydrochloride (0.400 g, 0.729 mmol) intetrahydrofuran (3 ml) was cooled with ice, 2 M aqueous solutionof sodium hydroxide (1.5 ml, 3.0 mmol) was added thereto, and themixture was stirred. To this mixture was added dropwise aceticanhydride (0.103 ml, 1.09 mmol), and the mixture was stirred atroom temperature for 1 hour. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extracts werewashed with water and concentrated under reduced pressure to givethe title compound (0.38 g, quantitative).Amorphous.1H NMR (CDCl3) δ 1.16 (3H, s), 1.23 (3H, s), 1.30 (6H, s), 1.45 (3H,t, J = 7.0 Hz), 1.50-1.55 (1H, m), 1.62-1.81 (1H, m), 1.99 (2H, s),2.13 (3H, s), 2.25 (2H, s), 2.62-2.75 (3H, m), 3.28-3.47 (2H, m),3.59-3.66 (0.7H, m), 3.87-3.93 (0.3H, m), 4.11-4.21 (2.7H, m),4.47-4.55 (0.3H, m), 6.56-6.60 (1H, m), 6.98-7.04 (1H, m), 7.21-7.25(1H, m), 7.35 (0.3H, s), 7.53 (0.7H, s), 7.64-7.68 (0.7H, m),7.87-7.92 (0.3H, m), 8.70 (0.3H, br s), 8.98 (0.7H, br s). Reference Example 98 N3-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-1,3-piperidinedicarboxamide
    [0401] From N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-piperidinecarboxamidedihydrochloride and sodium cyanate, the title compound was obtained by the method similar to that inReference Example 90. Yield 75%.Melting point: 119 to 121°C (recrystallized from ethyl acetate).1H NMR (DMSO-d6) δ 1.13 (6H, s), 1.22 (6H, s), 1.32 (3H, t, J = 7.0Hz), 1.50-1.66 (2H, m), 1.81-2.01 (1H, m), 2.28 (2H, s), 2.31-2.48(1H, m), 2.53-2.66 (4H, m), 2.70-2.81 (1H, m), 3.83-3.95 (1H, m),4.00-4.13 (3H, m), 5.96 (2H, s), 6.75 (1H, s), 7.03 (1H, d, J =7.5 Hz), 7.34 (1H, t, J = 7.5 Hz), 7.60-7.71 (2H, m), 10.07 (1H,s). Reference Example 99 N3-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-N1-methyl-1,3-piperidinedicarboxamide
    [0402] To a suspension of N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-3-piperidinecarboxamidedihydrochloride (0.500 g, 0.912 mmol) intetrahydrofuran (10 ml) was added triethylamine (0.280 ml, 2.01mmol), and the mixture was stirred at room temperature for 15minutes. To this mixture was added dropwise methyl isocyanate(64.5 µl, 1.09 mmol), and the mixture was stirred at roomtemperature for 1.5 hours. The reaction solution was combinedwith water, and extracted with ethyl acetate. The extracts werewashed with water and concentrated under reduced pressure to givethe title compound (0.30 g, yield 62%).Amorphous.1H NMR (DMSO-d6) δ 1.12 (6H, s), 1.22 (6H, s), 1.33 (3H, t, J = 7.0Hz), 1.56-1.64 (2H, m), 1.91 (1H, br d, J = 10.4 Hz), 2.28 (2H, s),2.33-2.45 (1H, m), 2.50-2.67 (7H, m), 2.76 (1H, t, J = 12.6 Hz),3.90 (1H, br d, J = 12.6 Hz), 4.01-4.13 (3H, m), 6.37-6.47 (1H, m),6.77 (1H, s), 7.01 (1H, d, J = 7.6 Hz), 7.32 (1H, t, J = 7.6 Hz),7.60-7.65 (2H, m), 10.01 (1H, s). Reference Example 100 N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,2,2-trifluoroacetamide
    [0403] To a suspension of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenaminedihydrochloride (0.800 g, 1.83 mmol) in tetrahydrofuran (10 ml) was addedtriethylamine (1.27 ml, 9.15 mmol), and the mixture was stirreduntil the red color was dissipated. This was cooled with ice,trifluoroacetic anhydride (0.387 ml, 2.75 mmol) was added dropwisethereto, and the mixture was stirred for 1 hour. The reactionsolution was combined with water, and extracted with ethyl acetate.The extracts were washed with water, and concentrated underreduced pressure. The residue was and recrystallized from ethylacetate-hexane to give the title compound (0.65 g, yield 77%).1H NMR (CDCl3) δ 1.29 (12H, s), 1.46 (3H, t, J = 6.9 Hz), 2.21 (2H,br s), 2.69 (2H, s), 4.18 (2H, q, J = 6.9 Hz), 6.59 (1H, s), 7.10-7.12(2H, m), 7.24-7.29 (1H, m), 7.35 (1H, d, J = 8.1 Hz), 10.06(1H, br s). Reference Example 101 N-[3-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzenemethanamine
    [0404] To a solution of ice-cooled N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2,2,2-trifluoroacetamide(0.500 g, 1.09 mmol) andbenzyl bromide (0.155 ml, 1.31 mmol) in tetrahydrofuran (5 ml) wasadded sodium hydride (66% dispersion in oil) (47.4 mg, 1.31 mmol),and the mixture was stirred at 60°C for 15 hours. The reactionsolution was poured into 0.2 M hydrochloric acid, and washed withdiisopropyl ether. The aqueous layer was alkalified with anaqueous solution of sodium hydrogen carbonate, and extracted withethyl acetate. The extracts were washed with water, andconcentrated under reduced pressure. The residue was purifiedwith a basic silica gel column chromatography (hexane/ethylacetate 9:1 from 17:3) to give the title compound (0.310 g, yield63%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.32 (6H, s), 1.45 (3H, t, J = 7.0Hz), 2.31 (2H, s), 2.65 (2H, s), 4.02 (1H, br s), 4.17 (2H, q, J =7.0 Hz), 4.34 (2H, s), 6.57-6.71 (4H, m), 7.15 (1H, t, J = 8.0 Hz),7.29-7.35 (5H, m). Reference Example 102 4-Oxo-4-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]butyricacid
    [0405] To a solution of succinic anhydride (503 mg, 5.03 mmol) intetrahydrofuran (5 ml) was added a solution of 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(1.76 g, 5.02 mmol) in tetrahydrofuran (5 ml), andthe mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was combined with diethyl ether, and the crystalswere taken by filtration to give the title compound (2.09 g, yield92%).1H NMR (CDCl3) δ 1.30 (6H, s), 1.41 (6H, br s), 2.30 (2H, br s),2.52 (4H, s), 2.84 (2H, s), 3.94 (3H, s), 6.64 (1H, s), 7.03 (1H,d, J = 7.5 Hz), 7.21-7.28 (1H, m), 7.58 (1H, d, J = 7.5 Hz), 7.71(1H, s), 9.83 (1H, s). Reference Example 103 N-Methyl-N'-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]butanediamide
    [0406] To a solution of 4-oxo-4-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]butyricacid (226 mg, 0.502 mmol) and 1-hydroxy-1H-benzotriazole·ammoniumsalt (92 mg, 0.60 mmol) in N,N-dimethylformamide(1 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (125 mg, 0.652mmol), and the mixture was stirred at room temperature for 15hours. The reaction mixture was combined with water and asaturated aqueous solution of sodium hydrogen carbonate, andextracted three times with chloroform. The combined organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was crystallized from ethylacetate-diethyl ether to give the title compound (142 mg, yield63%).1H NMR (CDCl3) δ 1.23 (6H, br s), 1.31 (6H, s), 2.26 (2H, s), 2.60-2.75(6H, m), 3.92 (3H, s), 5.58 (1H, br s), 5.91 (1H, br s), 6.59 (1H, s), 7.02 (1H, d, J = 7.7 Hz), 7.26 (1H, t, J = 7.7 Hz), 7.44(1H, t, J = 1.7 Hz), 7.65-7.70 (1H, m), 8.64 (1H, br s). Reference Example 104 N-[3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]butanediamide
    [0407] To 4-oxo-4-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]butyricacid(226 mg, 0.502 mmol), a solution of 40% methylamine/methanol (55mg, 0.71 mmol) and a solution of 1-hydroxy-1H-benzotriazolemonohydrate (85 mg, 0.56 mmol) in N,N-dimethylformamide (1 ml) wasadded 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(125 mg, 0.652 mmol), and the mixture was stirred at roomtemperature for 15 hours. The reaction mixture was combined withwater and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-diethyl ether to give the titlecompound (187 mg, yield 80%).1H NMR (CDCl3) δ 1.23 (6H, br s), 1.31 (6H, s), 2.28 (2H, s), 2.53-2.60(2H, m), 2.64-2.72 (4H, m), 2.77-2.82 (3H, m), 3.92 (3H, s),5.95-6.08 (1H, m), 6.60 (1H, s), 7.04 (1H, d, J = 7.2 Hz), 7.25-7.34(1H, m), 7.48 (1H, s), 7.64-7.70 (1H, m), 8.48-8.68 (1H, m). Reference Example 105 1,1-Dimethylethyl [3-oxo-3-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]propyl]carbamate
    [0408] A solution of 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(701 mg, 2.00mmol), 3-(tert-butoxycarbonylamino)propionic acid (417 mg, 2.20mmol), 1-hydroxy-1H-benzotriazole monohydrate (337 mg, 2.20 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(499 mg, 2.60 mmol) in N,N-dimethylformamide (4 ml) was stirred atroom temperature for 24 hours. The reaction mixture was combined with water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combinedorganic layer was washed twice with water, and concentrated underreduced pressure. The residue was purified with a basic silicagel column chromatography (ethyl acetate) to give the titlecompound (1.0 g, yield 96%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, br s), 1.32 (6H, s), 1.43 (9H, s), 2.29(2H, s), 2.56 (2H, t, J = 5.9 Hz), 2.68 (2H, s), 3.47 (2H, q, J =5.9 Hz), 3.92 (3H, s), 5.12-5.24 (1H, m), 6.60 (1H, s), 7.04-7.10(1H, m), 7.30 (1H, t, J = 8.0 Hz), 7.46-7.51 (1H, m), 7.63-7.68(1H, m), 7.96-8.05 (1H, m). Reference Example 106 3-Amino-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide
    [0409] To a solution of 1,1-dimethylethyl [3-oxo-3-[[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]amino]propyl]carbamate(930 mg, 1.84 mmol) in ethanol (5ml) was added a solution of conc. hydrochloric acid (0.50ml)/ethanol (1 ml), and the mixture was stirred at 80°C for 5hours. The reaction mixture was concentrated under reducedpressure. The residue was combined with water and ethyl acetate,neutralized with a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combinedorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried through sodium sulfate-basic silica gel(eluting with ethyl acetate followed by chloroform/methanol 5:1),and concentrated under reduced pressure to give the title compound(280 mg, yield 36%).1H NMR (CDCl3) δ 1.24 (6H, br s), 1.32 (6H, s), 2.30 (2H, s), 2.40-2.49(2H, m), 2.68 (2H, s), 3.08-3.14 (2H, m), 3.92 (3H, s), 6.60(1H, s), 7.06 (1H, dt, J = 7.9, 1.4 Hz), 7.32 (1H, t, J = 7.9 Hz),7.39 (1H, t, J = 1.8 Hz), 7.82 (1H, ddd, J = 7.9, 2.2, 0.8 Hz),10.14 (1H, br s). Reference Example 107 3-(Acetylamino)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide
    [0410] To a solution of 3-amino-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]propanamide(191 mg, 0.453 mmol) and triethylamine (82 µl, 0.59 mmol) intetrahydrofuran (3 ml) was added dropwise acetyl chloride (38 µl,0.54 mmol) under ice-cooling, and the mixture was stirred at thesame temperature for 10 minutes. The reaction mixture wascombined with water and a saturated aqueous solution of sodiumhydrogen carbonate, and extracted twice with ethyl acetate. Thecombined organic layer was washed twice with water, andconcentrated under reduced pressure. The residue was crystallizedfrom ethyl acetate-hexane to give the title compound (188 mg,yield 90%).1H NMR (CDCl3) δ 1.24 (6H, br s), 1.32 (6H, s), 1.97 (3H, s), 2.29(2H, s), 2.54 (2H, m), 2.69 (2H, s), 3.53-3.62 (2H, m), 3.92 (3H,s), 6.35-6.42 (1H, m), 6.60 (1H, s), 7.08 (1H, d, J = 8.0 Hz),7.31 (1H, t, J = 8.0 Hz), 7.56 (1H, s), 7.60 (1H, d, J = 8.0 Hz),8.07 (1H, br s). Reference Example 108 N-[2-(Acetylamino)ethyl]-3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzamide
    [0411] To a solution of 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride(208 mg, 0.500 mmol), N-acetylethylenediamine (61 mg, 0.60 mmol)and 1-hydroxy-1H-benzotriazole monohydrate (92 mg, 0.60 mmol) inN,N-dimethylformamide (1 ml) were added triethylamine (0.21 ml,1.5 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (125 mg, 0.652 mmol), and the mixture was stirred atroom temperature for 15 hours. The reaction mixture was combinedwith water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combinedorganic layer was washed twice with water, and concentrated underreduced pressure. The residue was crystallized from ethylacetate-diethyl ether to give the title compound (169 mg, yield 73%).1H NMR (CDCl3) δ 1.25 (6H, br s), 1.30 (6H, s), 2.00 (3H, s), 2.18(2H, s), 2.69 (2H, s), 3.43-3. 59 (4H, m), 3.93 (3H, s), 6.42-6.50(1H, m), 6.62 (1H, s), 7.30-7.36 (1H, m), 7.41-7.50 (2H, m), 7.83(1H, dt, J = 6.5, 2.2 Hz), 7.88-7.90 (1H, m). Reference Example 109 3-(Acetylamino)-N-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzamide
    [0412] To a solution of 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine(351 mg, 1.00mmol), 3-(acetamido)benzoic acid (198 mg, 1.11 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (169 mg, 1.10 mmol) in N,N-dimethylformamide(1 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (250 mg, 1.30 mmol),and the mixture was stirred at room temperature for 14 hours. Thereaction mixture was combined with water and a saturated aqueoussolution of sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried throughsodium sulfate-basic silica gel (eluting with ethyl acetatefollowed by ethyl acetate/methanol 5:1), and concentrated underreduced pressure. The residue was purified with a basic silicagel column chromatography (hexane/ethyl acetate 1:1, ethyl acetatefollowed by ethyl acetate/methanol 5:1) to give the title compound(505 mg, yield 99%).Amorphous.1H NMR (CDCl3) δ 1.25 (6H, br s), 1.32 (6H, s), 2.09 (3H, s), 2.33(2H, s), 2.69 (2H, br s), 3.92 (3H, s), 6.60 (1H, s), 7.07 (1H, d,J = 7.8 Hz), 7.28-7.38 (2H, m), 7.50 (1H, d, J = 7.8 Hz), 7.62 (1H,s), 7.70-7.77 (2H, m), 7.89 (1H, s), 8.30 (1H, br s), 8.43 (1H, brs). Reference Example 110 3-(Acetylamino)-N-[3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]benzamide
    [0413] To a solution of 3-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenamine dihydrochloride(438 mg, 1.00 mmol), 3-(acetamido)benzoic acid (198 mg, 1.11 mmol)and 1-hydroxy-1H-benzotriazole monohydrate (169 mg, 1.10 mmol) inN,N-dimethylformamide (1.5 ml) were added triethylamine (0.51 ml,3.7 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (250 mg, 1.30 mmol), and the mixture was stirred atroom temperature for 40 hours. The reaction mixture was combinedwith water and a saturated aqueous solution of sodium hydrogencarbonate, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried through sodium sulfate-basicsilica gel (eluting with ethyl acetate), and concentrated underreduced pressure. The residue was crystallized from ethylacetate-diisopropyl ether to give the title compound (331 mg,yield 63%).1H NMR (CDCl3) δ 1.25 (6H, br s), 1.32 (6H, s), 1.46 (3H, t, J =7.0 Hz), 2.12 (3H, s), 2.31 (2H, s), 2.67 (2H, br s), 4.18 (2H, q,J = 7.0 Hz), 6.59 (1H, s), 7.06-7.11 (1H, m), 7.33 (1H, t, J = 8.0Hz), 7.37 (1H, t, J = 8.0 Hz), 7.53 (1H, d, J = 8.1 Hz), 7.61 (1H,t, J = 1.8 Hz), 7.70-7.80 (2H, m), 7.92 (1H, s), 8.21 (1H, br s),8.24 (1H, s). Reference Example 111 Methyl [3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]acetate
    [0414] To a solution of 3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol(479 mg, 1.36 mmol)and methyl bromoacetate (0.15 ml, 1.6 mmol) in N,N-dimethylformamide(3 ml) was added potassium carbonate (245 mg,1.77 mmol), and the mixture was stirred at room temperature for 23hours. The reaction mixture was combined with water, andextracted twice with ethyl acetate. The combined organic layerwas washed twice with water, and concentrated under reducedpressure. The residue was purified with a silica gel columnchromatography (hexane/ethyl acetate 2:1) to give the titlecompound (550 mg, yield 95%). Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.32 (6H, s), 2.23 (2H, s), 2.69 (2H,s), 3.79 (3H, s), 3.92 (3H, s), 4.66 (2H, s), 6.60 (1H, s), 6.92(1H, dd, J = 2.3, 1.4 Hz), 6.96 (1H, ddd, J = 8.2, 2.6, 1.0 Hz),7.01 (1H, dt, J = 7.8, 1.2 Hz), 7.27-7.34 (1H, m). Reference Example 112 [3-(3,4,8,9-Tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]aceticacid
    [0415] To a solution of methyl [3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]acetate(545 mg, 1.29 mmol) in methanol (3 ml) was added 5 M aqueoussolution of sodium hydroxide (0.64 ml, 3.2 mmol), and the mixturewas heated under reflux for 15 minutes. The reaction mixture wascombined with 1 M hydrochloric acid (3.2 ml, 3.2 mmol) under ice-cooling,and the mixture was twice extracted with chloroform. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,concentrated under reduced pressure to give the title compound(0.52 g, yield 98%).Amorphous.1H NMR (DMSO-d6) δ 1.15 (6H, s), 1.22 (6H, s), 2.23 (2H, s), 2.66(2H, s), 3.81 (3H, s), 4.72 (2H, s), 6.79-6.83 (2H, m), 6.93 (1H,d, J = 8.0 Hz), 7.00 (1H, dd, J = 8.0, 2.4 Hz), 7.33 (1H, t, J =8.0 Hz). Reference Example 113 N-Methyl-2-[3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]acetamide
    [0416] To a solution of [3-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]aceticacid (544 mg,1.33 mmol), 40% methylamine/methanol a solution of (0.23 g, 3.0mmol) and 1-hydroxy-1H-benzotriazole monohydrate (244 mg, 1.46mmol) in N,N-dimethylformamide (4 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (331 mg, 1.73 mmol),and the mixture was stirred at room temperature for 44 hours. Thereaction mixture was combined with water and a saturated aqueous solution of sodium hydrogen carbonate, and extracted twice withethyl acetate. The combined organic layer was washed twice withwater, and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-diisopropyl ether to give thetitle compound (412 mg, yield 73%).1H NMR (CDCl3) δ 1.24 (6H, br s), 1.32 (6H, s), 2.23 (2H, s), 2.69(2H, s), 2.91 (3H, d, J = 5.1 Hz), 3.93 (3H, s), 4.53 (2H, s),6.55-6.68 (1H, m), 6.61 (1H, s), 6.92 (1H, ddd, J = 8.2, 2.7, 0.9Hz), 6.99-7.04 (2H, m), 7.32 (1H, t, J = 8.2 Hz). Reference Example 114 Methyl 2-bromo-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0417] With methyl 2-bromo-4-cyanobenzoate, the title compound wasobtained by the method similar to that in Reference Example 29.Yield 37%.Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.34 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.24 (2H, s), 2.66 (2H, s), 3.95 (3H, s), 4.18 (2H, q, J =7.0 Hz), 6.61 (1H, s), 7.41 (1H, dd, J = 1.2, 8.0 Hz), 7.73 (1H, d,J = 1.2 Hz), 7.84 (1H, d, J = 8.0 Hz). Reference Example 115 Methyl 2-bromo-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0418] From 2,3-dihydro-7-methoxy-2,2-dimethyl-a-(1-methylethyl)-5-benzofuranmethanoland methyl 2-bromo-4-cyanobenzoate, the titlecompound was obtained by the method similar to that in ReferenceExample 29. Yield 31%.Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.35 (6H, s), 2.26 (2H, s), 2.68 (2H,s), 3.93 (3H, s), 3.96 (3H, s), 6.62 (1H, s), 7.41 (1H, d, J = 8.1Hz), 7.74 (1H, d, J = 1.2 Hz), 7.85 (1H, dd, J = 1.2, 8.1 Hz). Reference Example 116 Methyl 4-(aminocarbonyl)-2-nitrobenzoate
    [0419] A solution of methyl 2-nitroterephthalate (50 g) in 1-methyl-2-pyrrolidone(150 ml) was cooled to 10°C, and thionyl chloride (39.6 g) was added dropwise thereto at 10°C. The mixture wasstirred at 10°C for 1 hour to prepare a solution of acid chloride.Separately, a mixed solution of 25% ammonia water (350 ml) andtoluene (250 ml) was cooled to -10°C. The previously obtainedsolution of acid chloride was added dropwise thereto -at 10°C.The solution of acid chloride was washed well with 1-methyl-2-pyrrolidone(50 ml), while keeping the temperature at -10°C. Themixture was stirred at -10°C for 30 minutes, and the temperaturewas elevated to 0°C. Then, water (250 ml) was added dropwisethereto at 0 to 10°C. The mixture was stirred at 0 to 10°C for 2hours, and the precipitated crystals were taken by filtration, andwashed with water (500 ml) to give the title compound (45.16 g,yield 91%).1H NMR (DMSO-d6) δ 3.86 (3H, s), 7.81 (1H, s), 7.94 (1H, d, J = 7.9Hz), 8.26 (1H, d, J = 7.9 Hz), 8.35 (1H, s), 8.47 (1H, s). Reference Example 117 Methyl 4-(aminocarbonyl)-2-(ethylamino)benzoate
    [0420] To a solution of methyl 4-(aminocarbonyl)-2-nitrobenzoatemethyl (20 g) in tetrahydrofuran (200 ml), methanol (200 ml) andacetic acid (100 ml) was added 90% acetaldehyde (13.1 g). Then,5% palladium carbon (hydrate, 2 g) was added thereto. Thereaction was conducted under 0.8 MPa of hydrogen pressure at 45 to55°C for 1 hour. The catalyst was filtered off while keeping thetemperature of the reaction solution at 45 to 55°C. The crystalswere washed with tetrahydrofuran/methanol=1/1 (100 ml). Themixture was concentrated under reduced pressure to the volume of200 ml. Water (200 ml) was added dropwise thereto at 20 to 30°C.The mixture was stirred at 20 to 30°C for 30 minutes, cooled, andstirred for 1 hour at 0 to 10°C. The precipitated crystals weretaken by filtration, and washed with water (200 ml) to give thetitle compound (18.58 g, yield 94%).1H NMR (CDCl3) δ 1.32 (3H, t, J = 7.2 Hz), 3.25-3.34 (2H, m), 3.88(3H, s), 5.75 (1H, br), 6.08 (1H, br), 6.83 (1H, dd, J = 1.6, 8.3Hz), 7.17 (1H, d, J = 1.6 Hz), 7.68 (1H, br), 7.94 (1H, d, J = 8.3Hz). Reference Example 118 Methyl 4-cyano-2-(ethylamino)benzoate
    [0421] Methyl 4-(aminocarbonyl)-2-(ethylamino)benzoate (71.82 g) wassuspended in pyridine (718 ml). Phosphorus oxychloride (54.5 g)was added dropwise thereto while keeping the temperature at 20 to30°C. The mixture was stirred for 1 hour at 20 to 30°C. Themixture was cooled to 0 to 10°C, and water (1436 ml) which wascooled to 0 to 10°C, was added dropwise thereto while keeping thetemperature at 0 to 10°C. The mixture was stirred at 0 to 10°Cfor 2 hours, the crystals were taken by filtration, and washedwith water (719 ml) to give the title compound (61.5 g, yield 93%).1H NMR (CDCl3) δ 1.34 (3H, t, J = 7.1 Hz), 3.18-3.27 (2H, m), 3.89(3H, s), 6.79 (1H, dd, J = 1.4, 8.2 Hz), 6.91 (1H, s), 7.76 (1H,br), 7.94 (1H, d, J = 8.2 Hz). Reference Example 119 Methyl 4-cyano-2-pyrrolidinylbenzeneacetate
    [0422] To a mixed solution of methyl 2-amino-4-cyanobenzeneacetate(478 mg, 2.51 mmol), 2,5-dimethoxytetrahydrofuran (468 mg, 3.54mmol) and sulfuric acid (2.8 ml) in methanol (3 ml) andtetrahydrofuran (7 ml) was added portionwise sodium borohydride(485 mg, 12.8 mmol). The reaction mixture solution was stirred atroom temperature for 14 hours. The reaction mixture was combinedwith water, and extracted with ethyl acetate. The extracts werewashed with a saturated aqueous solution of sodium chloride, dried,and concentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (ethyl acetate/hexane 3:1)to give the title compound (279 mg, yield 45%).1H NMR (CDCl3) δ 1.90-1.98 (4H, m), 3.12-3.18 (4H, m), 3.70 (3H, s),3.73 (2H, s), 7.14-7.24 (3H, m). Example 1 Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0423] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-a-(1-methylethyl)-5-benzofuranmethanol(11.3 g, 42.9 mmol) and methyl 2-amino-4-cyanobenzoate (6.30 g, 35.8 mmol) in toluene (40 ml) andacetic acid (25 ml) was added conc. sulfuric acid (5.92 ml, 111mmol) under ice-cooling, and the mixture was stirred for 2 hoursat 80°C. Methanol (18 ml) was added dropwise thereto, and themixture was stirred for 30 minutes at 65°C. After cooling, thereaction mixture was combined with ice water, neutralized withsodium hydrogen carbonate, and extracted three times with ethylacetate. The combined organic layer was extracted three timeswith 1 M hydrochloric acid, and the combined aqueous layer wasneutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Tothe residue was added ethyl acetate, and the precipitated crystalswere removed. The mother liquor was concentrated under reducedpressure, and the residue was purified with a basic silica gelcolumn chromatography (hexane/ethyl acetate, 5:1 followed by 3:1)to give the title compound (7.33 g, yield 49%).Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.33 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.36 (2H, s), 2.66 (2H, s), 3.89 (3H, s), 4.18 (2H, q, J =7.0 Hz), 5.76 (2H, s), 6.59 (1H, s), 6.62 (1H, dd, J = 7.8, 1.5Hz), 6.73 (1H, d, J = 1.5 Hz), 7.85 (1H, d, J = 7.8 Hz). Example 2 Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride
    [0424] Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(7.33 g, 17.3mmol) was dissolved in ethyl acetate, and a solution of 4 Mhydrogen chloride/ethyl acetate (8.7 ml) was added thereto. Themixture was concentrated under reduced pressure, and the residuewas crystallized from ethanol-ethyl acetate to give the titlecompound (7.16 g, yield 90%).1H NMR (DMSO-d6) δ 1.27 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.43 (6H,s), 2.39 (2H, s), 3.15 (2H, s), 3.85 (3H, s), 4.24 (2H, q, J = 7.0 Hz), 6.90 (1H, d, J = 8.2, 1.4 Hz), 6.97 (1H, d, J = 1.4 Hz), 7.08(1H, s), 7.91 (1H, d, J = 8.2 Hz). Example 3 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate
    [0425] To a solution of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(5.54 g, 13.1 mmol) in tetrahydrofuran (50 ml) were addedtriethylamine (2.01 ml, 14.4 mmol) and trifluoroacetic anhydride(1.94 ml, 13.8 mmol) under ice-cooling, and the mixture wasstirred for 1 hour at room temperature. The reaction mixture wascombined with ice water, and extracted twice with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wascrystallized from diisopropyl ether to give the title compound(4.14 g, yield 61%). The mother liquor was concentrated underreduced pressure, and again crystallized from diisopropyl ether togive the title compound (590 mg, yield 8.7%). Further, the motherliquor was concentrated under reduced pressure, and crystallizedfrom hexane to give the title compound (1.08 g, yield 16%).1H NMR (CDCl3) δ 1.32 (12H, s), 1.47 (3H, t, J = 7.2 Hz), 2.29 (2H,s), 2.74 (2H, s), 4.01 (3H, s), 4.21 (2H, q, J = 7.2 Hz), 6.63 (1H,s), 7.36 (1H, dd, J = 8.0, 1.4 Hz), 8.15 (1H, d, J = 8.0 Hz), 8.70(1H, d, J = 1.4 Hz), 12.28 (1H, s). Example 4 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)(trifluoroacetyl)amino]benzoatehydrochloride
    [0426] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(104 mg, 0.201 mmol) in N,N-dimethylformamide(1 ml) were added potassium tert-butoxide (25 mg,0.221 mmol) and benzyl bromide (0.026 ml, 0.221 mmol) under ice-cooling,and the mixture was stirred at room temperature for 3 hours. The reaction mixture was combined with ice water, andextracted twice with ethyl acetate. The combined organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified with a silicagel column chromatography (hexane/ethyl acetate, 5:1 followed by3:1) to give the title compound as free base. This was dissolvedin ethyl acetate and a solution of 4 M hydrogen chloride/ethylacetate was added thereto. The mixture was concentrated underreduced pressure, and the residue was crystallized from ethylacetate-diisopropyl ether to give the title compound (73 mg, yield56%).1H NMR (DMSO-d6) δ 1.20 (6H, s), 1.37 (3H, t, J = 6.8 Hz), 1.44 (3H,s), 1.54 (3H, s), 2.13 (2H, s), 3.07 (1H, d, J = 19.5 Hz), 3.23(1H, d, J = 19.5 Hz), 3.51 (3H, s), 4.24 (2H, q, J = 6.8 Hz),4.61-4.75 (1H, br), 5.15-5.30 (1H, br), 7.08 (1H, s), 7.10-7.20(2H, m), 7.27-7.29 (3H, m), 7.78-8.07 (3H, m). Example 5 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoate
    [0427] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)(trifluoroacetyl)amino]benzoate(1.11 g, 1.82 mmol)in methanol (6 ml) was added potassium carbonate (504 mg, 3.65mmol), and the mixture was stirred for 1 hour at 65°C. Aftercooling, methanol was distilled off under reduced pressure, andthe residue was combined with water, and extracted twice withethyl acetate. The combined organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried oversodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate, 10:1 followed by 5:1) togive the title compound (697 mg, yield 75%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.33 (6H, s), 1.46 (3H, t, J = 7.0 Hz), 2.25 (2H, s), 2.65 (2H, s), 3.87 (3H, s), 4.17 (2H, q, J =7.0 Hz), 4.44 (2H, d, J = 5.4 Hz), 6.57-6.60 (2H, m), 6.72 (1H, s),7.25-7.34 (5H, m), 7.92 (1H, d, J = 8.1 Hz), 8.13 (1H, t, J = 5.4Hz). Example 6 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoicacid
    [0428] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoate(586 mg, 1.14 mmol) in methanol (5ml) was added 5 M aqueous solution (1 ml) of sodium hydroxide, andthe mixture was stirred at room temperature for 1.5 hours and at60°C for 2.5 hours. Methanol was distilled off under reducedpressure, and the residue was neutralized with 5 M hydrochloricacid, and extracted twice with ethyl acetate. The combinedorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified with a silica gelcolumn chromatography (hexane/ethyl acetate 1:2 followed by ethylacetate), and recrystallized from ethyl acetate-diethyl ether-diisopropylether to give the title compound (159 mg, yield 28%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.47 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.20 (2H, br s), 2.83 (2H, s), 4.20 (2H, q, J = 7.0 Hz), 4.29(2H, s), 6.39 (1H, d, J = 8.0 Hz), 6.50 (1H, s), 6.60 (1H, s),7.15-7.25 (5H, m), 7.79 (1H, d, J = 8.0 Hz), 8.40-9.00 (1H, br). Example 7 Ethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoate
    [0429] To ethanol (2 ml) was added dropwise thionyl chloride (0.095ml, 1.30 mmol) under ice-cooling, and the mixture was stirred atthe same temperature for 10 minutes. 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoicacid (180 mg, 0.361 mmol) was addedthereto, and the mixture was stirred at 80°C for 36 hours. Aftercooling, ethanol was distilled off under reduced pressure, and the residue was combined with water, and neutralized with 1 M aqueoussolution of sodium hydroxide. The mixture was extracted twicewith ethyl acetate, the combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was purified with a basic silica gel column chromatography(hexane/ethyl acetate, 10:1), and crystallized from diisopropylether-hexane to give the title compound (84 mg, yield 44%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.30 (6H, s), 1.36-1.49 (6H, m),2.26 (2H, s), 2.66 (2H, s), 4.17 (2H, q, J = 7.0 Hz), 4.32 (2H, q,J = 7.0 Hz), 4.43 (2H, d, J = 5.4 Hz), 6.56-6.59 (2H, m), 6.71 (1H,s), 7.25-7.35 (5H, m), 7.93 (1H, d, J = 8.2 Hz), 8.14 (1H, t, J =5.4 Hz). Example 8 Ethyl 2-[acetyl(phenylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0430] To a solution of ethyl 4-(6-ethoxy-3,3,8,8-tetramethyl-3,4,8,9-tetrahydrofuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoate(610 mg, 1.16 mmol) intetrahydrofuran (6 ml) were added triethylamine (0.18 ml, 1.27mmol) and acetyl chloride (0.091 ml, 1.27 mmol) under ice-cooling,and the mixture was stirred at room temperature for 2 hours and at60°C for 2 hours. After cooling, sodium hydride (66% dispersionin oil) (46 mg, 1.27 mmol) and acetyl chloride (0.091 ml, 1.27mmol) were added thereto, and the mixture was stirred at roomtemperature for 15 hours. The reaction mixture was combined withice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (hexane/ethyl acetate, 5:1followed by 3:1), and crystallized from diisopropyl ether-hexaneto give the title compound (283 mg, yield 43%).1H NMR (CDCl3) δ 1.17 (3H, s), 1.25 (3H, s), 1.30 (6H, s), 1.30 (3H,t, J = 7.4 Hz), 1.46 (3H, t, J = 7.0 Hz), 1.89 (3H, s), 2.15 (2H, s), 2.65 (2H, s), 4.10 (2H, q, J = 7.0 Hz), 4.19 (2H, q, J = 7.4Hz), 4.64 (1H, d, J = 14.2 Hz), 4.96 (1H, d, J = 14.2 Hz), 6.60(1H, s), 7.04 (1H, d, J = 1.6 Hz), 7.20-7.30 (5H, m), 7.45 (1H, dd,J = 8.0, 1.6 Hz), 7.96 (1H, d, J = 8.0 Hz). Example 9 2-[Acetyl(phenylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0431] To a solution of ethyl 2-[acetyl(phenylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(369 mg, 0.649 mmol) in methanol (3ml) was added 5 M aqueous solution (1 ml) of sodium hydroxide, andthe mixture was stirred at room temperature for 3 hours. Methanolwas distilled off under reduced pressure, and the residue wasneutralized with 5 M hydrochloric acid. The precipitated crystalswere taken by filtration, and washed with water and diethyl etherto give the title compound (183 mg, yield 52%). The filtrate wasconcentrated under reduced pressure, and to the residue water wereadded ethyl acetate and tetrahydrofuran. The aqueous layer wasseparated, and extracted three times with tetrahydrofuran-ethylacetate. The combined organic layer was washed with a saturatedaqueous solution of sodium chloride, dried over sodium sulfate,filtered, and concentrated under reduced pressure to give thetitle compound (148 mg, yield 42%).1H NMR (CDCl3) δ 1.22 (3H, s), 1.26 (6H, s), 1.41 (3H, s), 1.46 (3H,t, J = 7.0 Hz), 1.70 (2H, s), 2.63-2.90 (5H, m), 4.04 (1H, d, J =13.8 Hz), 4.19 (2H, q, J = 7.0 Hz), 5.58 (1H, d, J = 13.8 Hz),6.59 (1H, s), 6.80 (1H, br s), 7.19 (5H, s), 7.43 (1H, d, J = 7.9Hz), 7.99 (1H, d, J = 7.9 Hz). Example 10 7-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methyl-1-(phenylmethyl)-4(1H)-quinazolinone
    [0432] To a solution of 2-[acetyl(phenylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid (221 mg, 0.409 mmol), 1-hydroxy-1H-benzotriazole·ammoniumsalt (68 mg, 0.450 mmol) and triethylamine (0.063 ml, 0.450 mmol) in N,N-dimethylformamide (2 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg,0.450 mmol), and the mixture was stirred at room temperature for15 hours. The reaction mixture was combined with ice water, andextracted twice with ethyl acetate. The combined organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified with a basicsilica gel column chromatography (hexane/ethyl acetate 1:2followed by ethyl acetate), and crystallized from ethyl acetate-diisopropylether to give the title compound (132 mg, yield 62%).1H NMR (CDCl3) δ 1.22 (12H, s), 1.44 (3H, t, J = 7.0 Hz), 1.85 (2H,br s), 2.65 (5H, s), 4.16 (2H, q, J = 7.0 Hz), 5.42 (2H, s), 6.57(1H, s), 7.05 (2H, dd, J = 8.0, 2.8 Hz), 7.30-7.35 (4H, m), 7.42(1H, dd, J = 8.0, 1.0 Hz), 8.41 (1H, d, J = 8.0 Hz). Example 11 Methyl 2-(benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0433] To a suspension of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (978 mg, 2.13 mmol) in tetrahydrofuran (10 ml) wereadded triethylamine (0.88 ml, 6.30 mmol) and benzoyl chloride(0.25 ml, 2.17 mmol), and the mixture was stirred for 1 hour at70°C. After cooling, the reaction mixture was combined with icewater, neutralized with sodium hydrogen carbonate, and extractedtwice with ethyl acetate. The combined organic layer was washedwith a saturated aqueous solution of sodium chloride, dried oversodium sulfate, filtered, and concentrated under reduced pressure.The residue was crystallized from ethyl acetate-diisopropyl etherto give the title compound (593 mg, yield 53%).1H NMR (CDCl3) δ 1.32 (6H, s), 1.36 (6H, s), 1.48 (3H, t, J = 7.0Hz), 2.40 (2H, br s), 2.76 (2H, br s), 4.00 (3H, s), 4.21 (2H, q,J = 7.0 Hz), 6.63 (1H, s), 7.28-7.35 (1H, m), 7.50-7.60 (3H, m),8.03 (2H, d, J = 8.4 Hz), 8.17 (1H, d, J = 8.4 Hz), 9.00 (1H, s),12.07 (1H, s). Example 12 2-(Benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0434] To a solution of methyl 2-(benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(574 mg, 1.09 mmol) in methanol (5 ml) was added 5 M aqueoussolution (2 ml) of sodium hydroxide, and the mixture was stirredfor 1 hour at 60°C. After cooling, the residue was adjusted at pH5.5 with 5 M hydrochloric acid, and methanol was distilled offunder reduced pressure. The resultant crystals were washed withwater and diethyl ether to give the title compound (517 mg, yield93%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.50 (3H, t, J = 7.0 Hz), 1.67 (3H,s), 1.80 (3H, s), 2.19 (1H, d, J = 17.2 Hz), 2.44 (1H, d, J = 17.2Hz), 3.00-3.20 (2H, m), 4.20 (2H, q, J = 7.0 Hz), 6.69 (1H, s),6.82-6.87 (1H, m), 7.30-7.50 (3H, m), 7.70-7.82 (1H, m), 7.90-8.05(2H, m), 8.79 (1H, s). Example 13 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(4-pyridinylcarbonyl)amino]benzoate
    [0435] To a solution of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (854 mg, 1.86 mmol) in N,N-dimethylformamide (8 ml)were added 4-(dimethylamino)pyridine (1.05 g, 8.60 mmol) andisonicotinic acid chloride hydrochloride (614 mg, 3.45 mmol), andthe mixture was stirred at room temperature for 3 hours and at50°C for 1 hour. Isonicotinic acid chloride hydrochloride (153 mg,0.86 mmol) was further added thereto, and the mixture was stirredfor 1 hour at 50°C. After cooling, the reaction mixture wascombined with ice water, and extracted twice with ethyl acetate.The combined organic layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The resultantcrystals were washed with diisopropyl ether to give the titlecompound (630 mg, yield 64%). 1H NMR (CDCl3) δ 1.32 (12H, s), 1.48 (3H, t, J = 7.0 Hz), 2.37 (2H,br s), 2.75 (2H, s), 4.02 (3H, s), 4.21 (2H, q, J = 7.0 Hz), 6.64(1H, s), 7.30-7.35 (1H, m), 7.87-7.89 (2H, m), 8.18 (1H, d, J =8.1 Hz), 8.85 (2H, d, J = 6.3 Hz), 8.95 (1H, d, J = 1.2 Hz), 12.27(1H, s) . Example 14 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(4-pyridinylcarbonyl)amino]benzoicacid
    [0436] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(4-pyridinylcarbonyl)amino]benzoate,the title compound was obtainedby the method similar to that in Example 9. Yield 45%.1H NMR (CDCl3+ DMSO-d6 4 drops) δ 1.28 (6H, s), 1.36 (6H, s), 1.47(3H, t, J = 7.0 Hz), 2.32 (2H, s), 2.79 (2H, s), 4.21 (2H, q, J =7.0 Hz), 6.65 (1H, s), 7.06 (1H, dd, J = 8.0, 1.2 Hz), 7.99 (2H, d,J = 6.0 Hz), 8.17 (1H, d, J = 8.0 Hz), 8.72 (2H, d, J = 6.0 Hz),8.81 (1H, d, J = 1.2 Hz). Example 15 Methyl 2-[[3-(acetylamino)benzoyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0437] To a solution of 3-(acetamido)benzoic acid (486 mg, 2.71mmol) in toluene (2 ml) were added thionyl chloride (0.33 ml, 4.52mmol) and N,N-dimethylformamide (1 drop), and the mixture wasstirred for 1 hour at 80°C. After cooling, the solvent wasdistilled off under reduced pressure, and the residue wasdissolved in N,N-dimethylformamide (6 ml). Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (1.12 g, 2.44 mmol) andtriethylamine (1.25 ml, 9.00 mmol) were added thereto, and themixture was stirred at room temperature for 1 hour and at 60°C for5 hours. To the obtained mixture were added triethylamine (0.47ml, 3.39 mmol), and the acid chloride which was prepared with 3-(acetamido)benzoicacid (607 mg, 3.39 mmol), thionyl chloride(0.49 ml, 6.78 mmol) and toluene (2 ml) in the same method asdescribed above, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was combined with ice water,and extracted twice with ethyl acetate. The combined organiclayer was washed with water and a saturated aqueous solution ofsodium chloride, dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (hexane/ethyl acetate, 3:1followed by 1:1), and crystallized from ethyl acetate-diisopropylether to give the title compound (326 mg, yield 23%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.20 (3H, s), 2.36 (2H, s), 2.68 (2H, s), 4.00 (3H, s), 4.19(2H, q, J = 7.0 Hz), 6.61 (1H, s), 7.17 (1H, dd, J = 8.2, 1.4 Hz),7.44-7.52 (2H, m), 7.74 (1H, d, J = 8.2 Hz), 7.90 (1H, s), 7.98-8.02(1H, m), 8.10 (1H, d, J = 8.0 Hz), 8.96 (1H, s), 12.01 (1H,s). Example 16 2-[[3-(Acetylamino)benzoyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0438] To a suspension of methyl 2-[[3-(acetylamino)benzoyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(175 mg, 0.300 mmol) in methanol (1ml) was added 5 M aqueous solution of sodium hydroxide (0.16 ml,0.80 mmol), and the mixture was heated under reflux for 30 minutes.The reaction mixture was cooled, and diluted with water. 1 Mhydrochloric acid (0.80 ml, 0.80 mmol) was added dropwise thereto,and the precipitated crystals were taken by filtration, and washedwith water to give the title compound (159 mg, yield 93%).1H NMR (DMSO-d6) δ 1.23 (6H, s), 1.25 (6H, br s), 1.35 (3H, t, J =6.9 Hz), 2.08 (3H, s), 2.32-2.52 (2H, m), 2.80 (2H, br s), 4.15(2H, q, J = 6.9 Hz), 6.90 (1H, s), 7.22 (1H, d, J = 8.1 Hz), 7.50(1H, t, J = 8.0 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.80 (1H, d, J =8.1 Hz), 8.13 (1H, d, J = 8.1 Hz), 8.23 (1H, s), 8.76 (1H, s),10.22 (1H, s). Example 17 Methyl 2-(acetylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0439] To a solution of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (1.20 g, 2.61 mmol) in N,N-dimethylformamide (8 ml)were added triethylamine (1.18 ml, 8.47 mmol) and acetyl chloride(0.19 ml, 2.66 mmol) under ice-cooling, and the mixture wasstirred at room temperature for 1 hour and at 60°C for 3 hours.After cooling, triethylamine (0.91 ml, 6.53 mmol) and acetylchloride (0.47 ml, 6.53 mmol) were added thereto, and the mixturewas stirred at room temperature for 24 hours. The reactionmixture was combined with ice water, and extracted twice withethyl acetate. The combined organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried oversodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified with a silica gel column chromatography(hexane/ethyl acetate, 3:1 followed by 1:1), and crystallized fromdiisopropyl ether-hexane to give the title compound (264 mg, yield22%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.22 (3H, s), 2.30 (2H, s), 2.66 (2H, s), 3.95 (3H, s), 4.18(2H, q, J = 7.0 Hz), 6.59 (1H, s), 7.11 (1H, dd, J = 8.2, 1.4 Hz),8.04 (1H, d, J = 8.2 Hz), 8.73 (1H, d, J = 1.4 Hz), 11.04 (1H, s). Example 18 2-(Acetylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0440] From methyl 2-(acetylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate,the titlecompound was obtained by the method similar to that in Example 12.Yield 89%.1H NMR (CDCl3) δ 1.27 (6H, s), 1.49 (3H, t, J = 7.0 Hz), 1. 62 (6H,s), 2.13 (3H, s), 2.14 (1H, d, J = 24.0 Hz), 2.38 (1H, d, J = 24.0Hz), 2.99 (2H, s), 4.25 (2H, q, J = 7.0 Hz), 6.66 (1H, s), 6.80(1H, d, J = 8.0 Hz), 7.67-7.90 (1H, br), 8.58 (1H, s), 9.70 (1H,br s). Example 19 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(methylsulfonyl)amino]benzoate
    [0441] To a solution of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (1.01 g, 2.20 mmol) in pyridine (4 ml) was addedmethanesulfonyl chloride (0.24 ml, 3.06 mmol), and the mixture wasstirred at room temperature for 15 hours. After cooling, thereaction mixture was combined with ice water, and extracted twicewith ethyl acetate. The combined organic layer was washed withwater and a saturated aqueous solution of sodium chloride, driedover sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate 5:1), and crystallized fromdiethyl ether-hexane to give the title compound (445 mg, yield40%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.33 (6H, s), 1.46 (3H, t, J = 6.9Hz), 2.26 (2H, s), 2.68 (2H, s), 3.09 (3H, s), 3.96 (3H, s), 4.18(2H, q, J = 6.9 Hz), 6.60 (1H, s), 7.18 (1H, dd, J = 8.1, 1.2 Hz),7.27 (1H, d, J = 1.2 Hz), 8.09 (1H, d, J = 8.1 Hz). Example 20 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(methylsulfonyl)amino]benzoicacid
    [0442] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(methylsulfonyl)amino]benzoate,the title compound was obtainedby the method similar to that in Example 12. Yield 93%.1H NMR (CDCl3) δ 1.29 (3H, s), 1.32 (3H, s), 1.51 (3H, t, J = 7.0Hz), 1.62 (3H, s), 1.74 (3H, s), 2.13 (1H, d, J = 17.0 Hz), 2.38(1H, d, J = 17.0 Hz), 2.93 (3H, s), 2.99 (1H, d, J = 15.4 Hz),3.18 (1H, d, J = 15.4 Hz), 4.27 (2H, q, J = 7.0 Hz), 6.70 (1H, s),7.04 (1H, d, J = 7.7 Hz), 7.49 (1H, s), 7.87 (1H, d, J = 7.7 Hz). Example 21 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoate
    [0443] To a solution of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate hydrochloride (813 mg, 1.77 mmol) in N,N-dimethylformamide (6 ml)were added 4-(dimethylamino)pyridine (1.10 g, 9.02 mmol) andpicolinic acid chloride hydrochloride (730 mg, 4.10 mmol), and themixture was stirred for 1 hour at room temperature. The reactionmixture was combined with ice water, and extracted twice with amixed solution of ethyl acetate-tetrahydrofuran. The combinedorganic layer was washed with an aqueous solution of sodiumchloride and a saturated aqueous solution of sodium chloride,dried over sodium sulfate, filtered, and concentrated underreduced pressure. The resultant crystals were washed withdiisopropyl ether-hexane to give the title compound (738 mg, yield79%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.30 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.33 (2H, s), 2.69 (2H, s), 4.04 (3H, s), 4.19 (2H, q, J =7.0 Hz), 6.60 (1H, s), 7.20 (1H, dd, J = 8.2, 1.6 Hz), 7.49 (1H,ddd, J = 7.8, 4.8, 1.2 Hz), 7.91 (1H, td, J = 7.8, 1.3 Hz), 8.13(1H, d, J = 8.2 Hz), 8.26 (1H, dd, J = 7.8, 1.2 Hz), 8.79 (1H, dd,J = 4.8, 1.3 Hz), 9.05 (1H, d, J = 1.6 Hz). Example 22 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoicacidhydrochloride
    [0444] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoate(444 mg, 0.842 mmol) in methanol(4 ml) was added 5 M aqueous solution (1 ml) of sodium hydroxide,and the mixture was stirred at room temperature for 2 hours.Methanol was distilled off under reduced pressure, and the residuewas neutralized with 5 M hydrochloric acid, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was dissolved in ethyl acetate, and a solution of 4 Mhydrogen chloride/ethyl acetate (0.64 ml) was added thereto. Themixture was concentrated under reduced pressure, and the residue was crystallized from ethanol-diisopropyl ether to give the titlecompound (432 mg, yield 93%).1H NMR (DMSO-d6) δ 1.23 (6H, s), 1.38 (3H, t, J = 7.0 Hz), 1.44 (3H,s), 1.50 (3H, s), 2.30 (1H, d, J = 14.4 Hz), 2.44 (1H, d, J = 14.4Hz), 3.13 (1H, d, J = 14.8 Hz), 3.27 (1H, d, J = 14.8 Hz), 4.26(2H, q, J = 7.0 Hz), 7.11 (1H, s), 7.48 (1H, d, J = 8.2 Hz), 7.70-7.76(1H, m), 8.07-8.20 (2H, m), 8.29 (1H, d, J = 8.2 Hz), 8.77(1H, d, J = 4.4 Hz), 9.03 (1H, s). Example 23 N-[2-(Aminocarbonyl)-5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinecarboxamide
    [0445] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoicacid hydrochloride (228 mg, 0.415mmol), 1-hydroxy-1H-benzotriazole·ammonium salt (70 mg, 0.539mmol) and triethylamine (0.14 ml, 1.04 mmol) in N,N-dimethylformamide(2 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (103 mg, 0.539mmol), and the mixture was stirred at room temperature for 2 hoursand at 50°C for 4 hours. After cooling, the reaction mixture wascombined with ice water, and extracted twice with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium hydrogen carbonate, water and a saturatedaqueous solution of sodium chloride, dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residuewas purified with a silica gel column chromatography (hexane/ethylacetate 1:2 followed by ethyl acetate), and crystallized fromethyl acetate-hexane to give the title compound (141 mg, yield66%).1H NMR (CDCl3) δ 1.27 (6H, s), 1.29 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.31 (2H, br s), 2.68 (2H, s), 4.18 (2H, q, J = 7.0 Hz), 6.59(1H, s), 7.07 (1H, dd, J = 8.0, 1.8 Hz), 7.39 (1H, ddd, J = 7.5,4.8, 1.2 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.82 (1H, td, J = 7.5, 1.8Hz), 8.19 (1H, ddd, J = 7.5, 1.2, 0.9 Hz), 8.65 (1H, ddd, J = 4.8, 1.8, 0.9 Hz), 8.96 (1H, d, J = 1.8 Hz). Example 24 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-pyridinylcarbonyl)amino]benzoate
    [0446] With nicotinic acid chloride hydrochloride, the titlecompound was obtained by the method similar to that in Example 13.Yield 67%.1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.35 (2H, s), 2.68 (2H, s), 4.00 (3H, s), 4.19 (2H, q, J =7.0 Hz), 6.61 (1H, s), 7.20 (1H, dd, J = 8.2, 1.6 Hz), 7.47 (1H,dd, J = 8.0, 4.8 Hz), 8.12 (1H, d, J = 8.2 Hz), 8.32 (1H, dt, J =8.0, 1.8 Hz), 8.80 (1H, dd, J = 4.8, 1.8 Hz), 8.96 (1H, d, J = 1.6Hz), 9.29 (1H, d, J = 1.8 Hz), 12.21 (1H, s). Example 25 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-pyridinylcarbonyl)amino]benzoicacid
    [0447] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-pyridinylcarbonyl)amino]benzoate,the title compound was obtainedby the method similar to that in Example 9. Yield 90%.1H NMR (CDCl3) δ 1.25 (6H, s), 1. 51 (3H, t, J = 6.9 Hz), 1.73 (3H,s), 1.80 (3H, s), 2.20 (1H, d, J = 16.6 Hz), 2.37 (1H, d, J = 16.6Hz), 3.09 (1H, d, J = 16.6 Hz), 3.18 (1H, d, J = 16.6 Hz), 4.28(2H, q, J = 6.9 Hz), 6.17 (1H, s), 6.87 (1H, d, J = 7.2 Hz), 7.30-7.38(1H, m), 7.78-7.90 (1H, m), 8.10-8.25 (1H, m), 8.67-8.72 (2H,m), 9.05-9.13 (1H, m). Example 26 Methyl 2-[(2-chloro-4-pyridinylcarbonyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0448] To a suspension of 2-chloroisonicotinic acid (678 mg, 4.30mmol) in toluene (2 ml) were added thionyl chloride (0.38 ml, 5.16mmol) and N,N-dimethylformamide (1 drop), and the mixture wasstirred for 1 hour at 80°C. After cooling, the solvent wasdistilled off under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (3 ml). Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (852 mg, 1.86 mmol) and4-(dimethylamino)pyridine (1.16 g, 9.46 mmol) were added thereto,and the mixture was stirred at room temperature for 2 hours. Thereaction mixture was combined with ice water, and extracted twicewith ethyl acetate. The combined organic layer was washed withwater and a saturated aqueous solution of sodium chloride, driedover sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified with a silica gel columnchromatography (hexane/ethyl acetate 5:1), and the obtainedcrystals were crystallized from diisopropyl ether-hexane to givethe title compound (694 mg, yield 66%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.33 (2H, s), 2.68 (2H, s), 4.00 (3H, s), 4.20 (2H, q, J =7.0 Hz), 6.61 (1H, s), 7.24 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J =5.2 Hz), 7.92 (1H, s), 8.14 (1H, d, J = 8.6 Hz), 8.61 (1H, d, J =5.2 Hz), 8.91 (1H, s), 12.28 (1H, s). Example 27 2-[(2-Chloro-4-pyridinylcarbonyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride
    [0449] To a solution of methyl 2-[(2-chloro-4-pyridinylcarbonyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(466 mg, 0.829mmol) in methanol (4 ml) was added 5 M aqueous solution (1 ml) ofsodium hydroxide, and the mixture was stirred at room temperaturefor 5 hours and at 50°C for 1 hour. After cooling, methanol wasdistilled off under reduced pressure, and the residue wasneutralized with 5 M hydrochloric acid, and extracted twice withethyl acetate. The combined organic layer was dried over sodiumsulfate, and concentrated under reduced pressure. This wasdissolved in ethyl acetate, and a solution of 4 M hydrogenchloride/ethyl acetate was added thereto. The mixture wasconcentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give a mixture. To asuspension of 2-chloroisonicotinic acid (152 mg, 0.966 mmol) intoluene (1 ml) were added thionyl chloride (0.078 ml, 1.06 mmol)and N,N-dimethylformamide (1 drop), and the mixture was stirredfor 1 hour at 80°C. After cooling, the solvent was distilled offunder reduced pressure, and the residue was dissolved in N,N-dimethylformamide(1 ml). Previously obtained crystals and 4-(dimethylamino)pyridine(177 mg, 1.45 mmol) were added theretounder ice-cooling, and the mixture was stirred for 1 hour at roomtemperature. The reaction mixture was combined with ice water,neutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed withwater and a saturated aqueous solution of sodium chloride, driedover sodium sulfate, put through silica gel layer, andconcentrated under reduced pressure. The residue was dissolved inmethanol (1 ml), 5 M aqueous solution (0.5 ml) of sodium hydroxidewas added thereto, and the mixture was stirred for 1 hour at roomtemperature. Methanol was distilled off under reduced pressure.The residue was combined with ethyl acetate, neutralized with 5 Mhydrochloric acid, and concentrated under reduced pressure. Tothe residue was added ethanol, the insolubles were taken byfiltration, and the filtrate was concentrated under reducedpressure. This procedure was repeated twice, and the residue wascrystallized from ethanol-ethyl acetate to give the title compound(142 mg, yield 29%).1H NMR (DMSO-d6) δ 1.24 (6H, s), 1.38 (3H, t, J = 7.0 Hz), 1.44 (6H,s), 2.30 (1H, d, J = 14.0 Hz), 2.45 (1H, d, J = 14.0 Hz), 3.14 (2H,s), 4.24 (2H, q, J = 7.0 Hz), 7.08 (1H, s), 7.51 (1H, d, J = 8.0Hz), 7.86 (1H, d, J = 5.6 Hz), 7.94 (1H, s), 8.24 (1H, d, J = 8.0Hz), 8.59 (1H, s), 8.70 (1H, d, J = 5.6 Hz), 12.36 (1H, s). Example 28 Methyl 2-[(2,6-dichloro-4-pyridinylcarbonyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0450] With 2,6-dichloro-4-pyridine carboxylic acid, the title compound was obtained by the method similar to that in Example 26.Yield 46%.1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.32 (2H, s), 2.68 (2H, s), 4.03 (3H, s), 4.19 (2H, q, J =7.0 Hz), 6.61 (1H, s), 7.25 (1H, dd, J = 8.0, 1.6 Hz), 7.82 (2H,s), 8.14 (1H, d, J = 8.0 Hz), 8.86 (1H, d, J = 1.6 Hz), 12.29 (1H,s). Example 29 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylcarbonyl)amino]benzoate
    [0451] To a solution of 2-quinolinecarboxylic acid (656 mg, 3.79mmol) in toluene (3 ml) were added thionyl chloride (0.41 ml, 5.67mmol) and N,N-dimethylformamide (1 drop), and the mixture wasstirred for 30 minutes at 80°C. After cooling, the solvent wasdistilled off under reduced pressure, and the residue wasdissolved in N,N-dimethylformamide (6 ml). Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(800 mg, 1.89 mmol) and 4-(dimethylamino)pyridine(924 mg, 7.56 mmol) were added thereto,and the mixture was stirred for 1.5 hours at room temperature.The reaction mixture was combined with ice water, and extractedtwice with ethyl acetate. The combined organic layer was washedwith water and a saturated aqueous solution of sodium chloride,dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified with a silica gelcolumn chromatography (hexane/ethyl acetate, 3:1 followed by 2:1),and the obtained crystals were washed with hexane to give thetitle compound (831 mg, yield 76%).1H NMR (CDCl3) δ 1.27 (6H, s), 1.30 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.34 (2H, s), 2.69 (2H, s), 4.09 (3H, s), 4.20 (2H, q, J =7.0 Hz), 6.61 (1H, s), 7.21 (1H, dd, J = 8.0, 1.4 Hz), 7.62-7.70(1H, m), 7.80-7.93 (2H, m), 8.16 (1H, d, J = 8.0 Hz), 8.33-8.35 (3H,m), 9.09 (1H, d, J = 1.8 Hz). Example 30 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylcarbonyl)amino]benzoic acid
    [0452] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylcarbonyl)amino]benzoate(563 mg, 0.975 mmol) in methanol(4 ml) was added 5 M aqueous solution (0.39 ml) of sodiumhydroxide, and the mixture was stirred at room temperature for 1.5hours and at 55°C for 3 hours. After cooling, methanol wasdistilled off under reduced pressure, and the residue was combinedwith water and acetone, and neutralized with 5 M hydrochloric acid.The precipitated crystals were washed with water and diethyl etherto give the title compound (481 mg, yield 88%).1H NMR (CDCl3) δ 1.22 (6H, s), 1.50 (3H, t, J = 7.0 Hz), 1.75 (6H,s), 2.17 (1H, d, J = 17.7 Hz), 2.42 (1H, d, J = 17.7 Hz), 3.06 (2H,s), 4.26 (2H, q, J = 7.0 Hz), 6.70 (1H, s), 7.10-7.20 (1H, m),7.55 (1H, t, J = 7.5 Hz), 7.67-7.79 (2H, m), 8.00-8.15 (3H, m),8.34 (1H, d, J = 4.7 Hz), 8.93 (1H, s). Example 31 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylamino)benzoate
    [0453] To a suspension of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (815 mg, 1.78 mmol) in xylene (4 ml) were addedbromobenzene (0.21 ml, 1.97 mmol), cesium carbonate (2.15 g, 6.60mmol), palladium (II) acetate (11 mg, 0.0495 mmol) and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl(46 mg, 0.0743 mmol), andthe mixture was stirred at 140°C for 7 hours. After cooling, thereaction mixture was combined with ice water, neutralized withsodium hydrogen carbonate, and extracted twice with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The residuewas purified with a silica gel column chromatography (hexane/ethylacetate, 10:1 followed by 5:1), and crystallized from diisopropylether-hexane to give the title compound (369 mg, yield 42%).1H NMR (CDCl3) δ 1.20 (6H, s), 1.33 (6H, s), 1.45 (3H, t, J = 7.0 Hz), 2.35 (2H, s), 2.63 (2H, s), 3.93 (3H, s), 4.16 (2H, q, J =7.0 Hz), 6.56 (1H, s), 6.73 (1H, dd, J = 8.0, 1.4 Hz), 7.02-7.10(1H, m), 7.21-7.35 (5H, m), 7.98 (1H, d, J = 8.0 Hz), 9.55 (1H, s). Example 32 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylamino)benzoicacid
    [0454] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylamino)benzoate,the title compound was obtained by the method similar to that inExample 9. Yield 87%.1H NMR (CDCl3) δ 1.30 (6H, s), 1.47 (3H, t, J = 7.0 Hz), 1.56 (6H,s), 2.36 (2H, s), 2.92 (2H, s), 4.20 (2H, q, J = 7.0 Hz), 6.52 (1H,dd, J = 7.6, 1.6 Hz), 6.93 (1H, br s), 7.12 (1H, d, J = 1.6 Hz),7.21-7.27 (5H, m), 7.82 (1H, d, J = 7.6 Hz). Example 33 Methyl [4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]acetate
    [0455] A solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenol(0.500 g, 1.37 mmol)in N,N-dimethylformamide (5 ml) was cooled with ice, sodiumhydride (66% dispersion in oil) (59.7 mg, 1.64 mmol) was addedthereto, and the mixture was stirred at room temperature for 1hour. To this was added methyl bromoacetate (0.155 ml, 1.64 mmol),and the mixture was further stirred at 80°C for 3 hours. Thereaction solution was cooled to room temperature, combined withwater, and extracted with ethyl acetate. The extracts were washedwith water, and concentrated under reduced pressure. The residuewas purified with a silica gel column chromatography (hexane/ethylacetate, 1:1 followed by 1:2), and crystallized from diisopropylether to give the title compound (0.570 g, yield 55%).1H NMR (CDCl3) δ 1.22 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.23 (2H, s), 2.65 (2H, s), 3.81 (3H, s), 4.18 (2H, q, J =7.0 Hz), 4.67 (2H, s), 6.59 (1H, s), 6.92 (2H, dd, J = 6.8, 2.0Hz), 7.35 (2H, dd, J = 6.8, 2.0 Hz). Example 34 [4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]aceticacid hydrochloride
    [0456] From methyl [4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenoxy]acetate,the titlecompound was obtained as free base by the method similar to thatin Example 9. This was dissolved in ethyl acetate, a solution of4 M hydrogen chloride/ethyl acetate was added thereto, and themixture was concentrated under reduced pressure to give the titlecompound. Yield 88%.Amorphous.1H NMR (DMSO-d6) δ 1.26 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.41 (6H,s), 2.28 (2H, s), 3.11 (2H, s), 4.23 (2H, q, J = 7.0 Hz), 4.97 (2H,s), 7.06 (1H, s), 7.17 (1H, d, J = 8.4 Hz), 7.19 (1H, d, J = 8.4Hz), 7.57 (2H, d, J = 8.4 Hz), 12.32 (1H, s). Example 35 Methyl 2-[[[(2-ethoxy-2-oxoethyl)amino]carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0457] To a suspension of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride (2.11 g, 4.60 mmol) in tetrahydrofuran (16 ml) wereadded triethylamine (1.25 ml, 8.95 mmol) and ethylisocyanatoacetate (0.57 ml, 5.11 mmol) under ice-cooling, and themixture was heated under reflux for 4 hours. Ethylisocyanatoacetate (0.42 ml, 3.84 mmol) was further added in threeportions, and the mixture was heated under reflux for 15 hours.The reaction mixture was combined with water, and extracted twicewith a mixed solution of ethyl acetate-tetrahydrofuran. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The resultant crystalswere washed with diisopropyl ether to give the title compound (393mg, yield 85%).1H NMR (CDCl3) δ 1.23-1.32 (15H, s), 1.46 (3H, t, J = 7.0 Hz), 2.34(2H, s), 2.64 (2H, s), 3.93 (3H, s), 3.98-4.28 (6H, m), 5.23 (1H, t, J = 5.2 Hz), 6.57 (1H, s), 7.00 (1H, dd, J = 8.0, 1.6 Hz), 7.99(1H, d, J = 8.0 Hz), 8.56 (1H, d, J = 1.6 Hz), 10.51 (1H, s). Example 36 Methyl 2-(2,5-dioxo-1-imidazolidinyl)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0458] A solution of methyl 2-[[[(2-ethoxy-2-oxoethyl)amino]carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(1.94 g,3.52 mmol) in 5 M hydrochloric acid (5 ml) was stirred at 80°C for7 hours. The solution was dissolved in methanol (10 ml), conc.sulfuric acid (0.56 ml, 10.6 mmol) was added thereto, and themixture was stirred at 70°C for 15 hours. After cooling, methanolwas distilled off under reduced pressure, the residue wasneutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified with a silica gel column chromatography (hexane/ethylacetate, 3:1 followed by 1:1), and crystallized from diethyl etherto give the title compound (812 mg, yield 46%).1H NMR (CDCl3) δ 1.32 (6H, s), 1.35 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.28 (2H, s), 2.75 (2H, s), 3.78 (3H, s), 4.20 (2H, q, J =7.0 Hz), 4.78 (2H, s), 6.63 (1H, s), 7.16 (1H, dd, J = 8.2, 1.4Hz), 7.21 (1H, d, J = 1.4 Hz), 8.05 (1H, d, J = 8.2 Hz), 9.62 (1H,s). Example 37 2-(2,5-Dioxo-1-imidazolidinyl)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacidhydrochloride
    [0459] To a solution of methyl 2-(2,5-dioxo-1-imidazolidinyl)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(279 mg, 0.552 mmol) in methanol (2ml) was added 1 M aqueous solution (1.16 ml) of sodium hydroxide,and the mixture was stirred at room temperature for 18 hours. Thereaction solution was acidified with 5 M hydrochloric acid, and the solvent was distilled off under reduced pressure. The residuewas combined with ethanol and acetone, and the insolubles weretaken by filtration. The filtrate was concentrated under reducedpressure, and this procedure was repeated twice to give the titlecompound (271 mg, yield 93%).Amorphous.1H NMR (DMSO-d6) δ 1.25 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.44 (6H,s), 2.30 (2H, s), 3.15 (2H, s), 4.24 (2H, q, J = 7.0 Hz), 4.61 (2H,s), 7.08 (1H, s), 7.40 (1H, d, J = 8.0 Hz), 7.43 (1H, s), 8.15 (1H,d, J = 8.0 Hz), 12.00 (1H, s). Example 38 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)benzoate
    [0460] From methyl 2-(2,5-dioxo-1-imidazolidinyl)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoateand iodomethane, the title compound was obtained bythe method similar to that in Example 33. Yield 86%.1H NMR (CDCl3) δ 1.26 (6H, s), 1.35 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.24 (2H, s), 2.70 (2H, s), 3.65 (3H, s), 3.80 (3H, s), 4.20(2H, q, J = 7.0 Hz), 4.88 (2H, s), 6.63 (1H, s), 7.27 (1H, d, J =8.0 Hz), 7.31 (1H, s), 8.22 (1H, d, J = 8.0 Hz). Example 39 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)benzoicacid
    [0461] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(3-methyl-2,5-dioxo-1-imidazolidinyl)benzoate,the title compound was obtained by themethod similar to that in Example 12. Yield 77%.1H NMR (DMSO-d6) δ 1.33 (6H, s), 1.49 (6H, s), 1.49 (3H, t, J = 7.0Hz), 2.08-2.15 (2H, m), 2.72-3.00 (2H, m), 3.61 (3H, s), 4.23 (2H,q, J = 7.0 Hz), 4.58-4.85 (2H, m), 6.67 (1H, s), 7.26 (1H, d, J =8.0 Hz), 7.42 (1H, s), 8.32 (1H, d, J = 8.0 Hz). Example 40 Methyl 2-[[(dimethylamino)carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0462] To a solution of methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(869 mg, 2.06 mmol) in N,N-dimethylacetamide (5 ml) were addedtriethylamine (0.14 ml, 1.03 mmol) and 4-nitrophenylchlorocarbonate (598 mg, 2.97 mmol), and the mixture was stirredfor 1.5 hours at room temperature. A solution (2.6 ml, 5.15 mmol)of 2 M dimethylamine/tetrahydrofuran was added thereto under ice-cooling,and the mixture was stirred at room temperature for 15hours. The reaction mixture was combined with ice water,neutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium hydrogen carbonate, water anda saturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was purified with a silica gel column chromatography(hexane/ethyl acetate 1:1), and crystallized from diisopropylether-hexane to give the title compound (281 mg, yield 28%). Themother liquor was again purified with a silica gel columnchromatography (hexane/ethyl acetate 1:1), and crystallized fromdiethyl ether-hexane to give the title compound (257 mg, yield25%).1H NMR (CDCl3) δ 1.22 (6H, s), 1.31 (6H, s), 1.45 (3H, t, J = 6.9Hz), 2.35 (2H, br s), 2.64 (2H, s), 3.07 (6H, s), 3.93 (3H, s),4.17 (2H, q, J = 6.9 Hz), 6.56 (1H, s), 6.97 (1H, dd, J = 8.1, 1.8Hz), 7.99 (1H, d, J = 8.1 Hz), 8.63 (1H, d, J = 1.8 Hz), 10.65 (1H,s). Example 41 2-[[(Dimethylamino)carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0463] From methyl 2-[[(dimethylamino)carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate,the title compound was obtained by the method similarto that in Example 12. Yield 60%. 1H NMR (DMSO-d6) δ 1.18 (6H, s), 1.22 (6H, s), 1.34 (3H, t, J = 6.9Hz), 2.35 (2H, br s), 2.69 (2H, s), 2.95 (6H, s), 4.11 (2H, q, J =6.9 Hz), 6.82 (1H, s), 6.99 (1H, d, J = 8.1 Hz), 7.99 (1H, d, J =8.1 Hz), 8.44 (1H, s), 11.27 (1H, br s). Example 42 Methyl 2-[[(phenylamino)carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0464] With aniline, the title compound was obtained by the methodsimilar to that in Example 40. Yield 69%.1H NMR (CDCl3) δ 1.14 (6H, s), 1.23 (6H, s), 1.33 (3H, t, J = 6.9Hz), 2.42 (2H, br s), 2.62 (2H, s), 3.92 (3H, s), 4.09 (2H, q, J =6.9 Hz), 6.79 (1H, s), 6.94-6.99 (1H, m), 7.07 (1H, d, J = 8.2 Hz),7.23-7.28 (2H, m), 7.47 (1H, d, J = 7.8 Hz), 7.98 (1H, d, J = 8.2Hz), 8.33 (1H, s), 9.85 (1H, s), 10.06 (1H, s). Example 43 7-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-3-phenyl-2,4(1H,3H)-quinazolinedione
    [0465] From methyl 2-[[(phenylamino)carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate,the title compound was obtained by the method similarto that in Example 9. Yield 58%.1H NMR (CDCl3) δ 1.35 (12H, s), 1.48 (3H, t, J = 7.0 Hz), 2.31 (2H,s), 2.75 (2H, br s), 4.20 (2H, q, J = 7.0 Hz), 6.63 (1H, s), 7.17(1H, dd, J = 8.1, 1.5 Hz), 7.24-7.29 (3H, m), 7.42-7.54 (3H, m),8.08 (1H, d, J = 8.1 Hz), 9.80 (1H, s). Example 44 Methyl 2-[[2-(1,1-dimethylethoxy)-2-oxoethyl](trifluoroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0466] From tert-butyl bromoacetate, the title compound was obtainedby the method similar to that in Example 4. Yield 43%.1H NMR (CDCl3) δ 1.16 (3H, s), 1.28 (3H, s), 1.31 (3H, s), 1.32 (3H,s), 1.46 (3H, t, J = 7.2 Hz), 1.49 (9H, s), 2.62 (1H, d, J = 15.8Hz), 2.74 (1H, d, J = 15.8 Hz), 3.67 (1H, d, J = 16.8 Hz), 3.91(3H, s), 4.19 (2H, q, J = 7.2 Hz), 4.85 (1H, d, J = 16.8 Hz), 6.61 (1H, s), 7.50 (1H, dd, J = 8.0, 1.4 Hz), 7.70 (1H, d, J = 1.4 Hz),8.09 (1H, d, J = 8.0 Hz). Example 45 N-[5-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(methoxycarbonyl)phenyl]glycine
    [0467] To a solution of methyl 2-[[2-(1,1-dimethylethoxy)-2-oxoethyl](trifluoroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(1.91 g,3.02 mmol) in methanol (15 ml) was added potassium carbonate (835mg, 6.04 mmol), and the mixture was stirred for 1 hour at 60°C.After cooling, methanol was distilled off under reduced pressure.The residue was combined with water, adjusted at pH 5 with 1 Mhydrochloric acid, and extracted three times with ethyl acetate.The extract was concentrated under reduced pressure, and theobtained crystals were washed with diisopropyl ether to give thetitle compound (1.04 g, yield 72%).1H NMR (CDCl3) δ 1.31 (6H, s), 1.49 (3H, t, J = 7.0 Hz), 1.54 (6H,s), 2.36 (2H, s), 2.95 (2H, s), 3.64 (2H, s), 3.83 (3H, s), 4.25(2H, q, J = 7.0 Hz), 6.52 (1H, s), 6.54 (1H, d, J = 8.0 Hz), 6.67(1H, s), 7.94 (1H, d, J = 8.0 Hz), 8.07 (1H, br s). Example 46 Methyl 2-[(2-amino-2-oxoethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0468] From N-[5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(methoxycarbonyl)phenyl]glycine,the title compound was obtainedby the method similar to that in Example 10. Yield 78%.1H NMR (CDCl3) δ 1.25 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.27 (2H, s), 2.68 (2H, s), 3.91 (3H, s), 3.97 (2H, d, J =5.9 Hz), 4.19 (2H, q, J = 7.0 Hz), 5.37 (1H, br s), 6.40 (1H, brs), 6.60 (1H, s), 6.64 (1H, d, J = 1.4 Hz), 7.72 (1H, dd, J = 8.2,1.4 Hz), 7.96 (1H, d, J = 8.2 Hz), 8.29 (1H, t, J = 5.9 Hz). Example 47 2-[(Carboxymethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0469] From N-[5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(methoxycarbonyl)phenyl]glycine,the title compound was obtainedby the method similar to that in Example 12. Yield 68%.1H NMR (DMSO-d6) δ 1.15 (6H, s), 1.23 (6H, s), 1.33 (3H, t, J = 6.8Hz), 2.32 (2H, s), 2.66 (2H, s), 3.99 (2H, s), 4.06 (2H, q, J =6.8 Hz), 6.51 (1H, s), 6.56 (1H, d, J = 8.0 Hz), 6.79 (1H, s),7.85 (1H, d, J = 8.0 Hz), 8.24 (1H, br s). Example 48 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[ethyl(trifluoroacetyl)amino]benzoate
    [0470] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(3.04 g, 5.86 mmol) in N,N-dimethylformamide(20 ml) were added potassium tert-butoxide (724mg, 6.45 mmol) and iodoethane (0.52 ml, 6.45 mmol), and themixture was stirred at room temperature for 2 hours and at 50°Cfor 3 hours. Iodoethane (0.094 ml, 1.17 mmol) was further addedthereto, and the mixture was stirred at 50°C for 5 hours. Thereaction mixture was combined with ice water, and extracted twicewith ethyl acetate. The combined organic layer was washed withwater and a saturated aqueous solution of sodium chloride, driedover sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified with a silica gel columnchromatography (hexane/ethyl acetate, 5:1 followed by 3:1) to givethe title compound (1.76 g, yield 55%).Amorphous.1H NMR (CDCl3) δ 1.13-1.43 (15H, m), 1.46 (3H, t, J = 7.0 Hz), 2.11(1H, d, J = 16.1 Hz), 2.22 (1H, d, J = 16.1 Hz), 2.65 (1H, d, J =15.5 Hz), 2.73 (1H, d, J = 15.5 Hz), 3.35-3.55 (0.6 H, m), 3.88(0.9H, s), 3.90 (2.1H, s), 3.96-4.16 (1.4H, m), 4.19 (2H, q, J =7.0 Hz), 6.61 (1H, s), 7.25 (0.3H, d, J = 1.4 Hz), 7.30 (0.7H, d,J = 1.4 Hz), 7.52 (0.7H, dd, J = 7.8, 1.4 Hz), 7.63 (0.3H, dd, J =7.8, 1.4 Hz), 8.12 (0.7H, d, J = 7.8 Hz), 8.19 (0.3H, d, J = 7.8Hz). Example 49 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoate (Method 1)
    [0471] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[ethyl(trifluoroacetyl)amino]benzoate(1.70 g, 3.11 mmol) inmethanol (10 ml) was added potassium carbonate (645 mg, 4.67 mmol),and the mixture was stirred at 60°C for 10 hours. After cooling,methanol was distilled off under reduced pressure, and the residuewas combined with water, and extracted twice with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purifiedwith a basic silica gel column chromatography (hexane/ethylacetate, 10:1), and crystallized from pentane to give the titlecompound (528 mg, 38%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.26-1.34 (9H, m), 1.46 (3H, t, J =7.0 Hz), 2.36 (2H, s), 2.68 (2H, s), 3.17-3.30 (2H, m), 3.87 (3H,s), 4.18 (2H, q, J = 7.0 Hz), 6.57 (1H, dd, J = 8.0, 1.4 Hz), 6.59(1H, d, J = 1.4 Hz), 6.67 (1H, s), 7.64 (1H, t, J = 5.5 Hz), 7.89(1H, d, J = 8.0 Hz). (Method 2)
    [0472] To a suspension of methyl 4-cyano-2-(ethylamino)benzoate (10 g) inmethyl acetate (50 ml) was added dropwise trifluoromethanesulfonicacid (43.4 ml) at room temperature with stirring the suspension.Then, a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(25.89g) in methyl acetate (260ml) was added dropwise thereto with keeping the internaltemperature at 60 to 65°C. The mixture was stirred for 2 hours at60°C, and the reaction solution was concentrated under reducedpressure. To the residue were added diisopropyl ether (10 ml) andice water (50 ml), and added 25% ammonia water (50 ml) with ice-cooling.The layers were separated, and the aqueous layer wasextracted with diisopropyl ether (50 ml). The organic layer was collected and washed twice with water. The organic layer wasconcentrated, and re-concentrated with adding ethyl acetate (30ml). To the concentrated residue was added ethyl acetate (30 ml),and added dropwise a solution (12.3 ml) of 4M hydrogen chloride-ethylacetate. Heptane (15 ml) was added thereto and the mixturewas cooled with ice. The mixture was mixed with stirring for 2hours at less than 10°C, and the crystals were taken by filtrationto give the title compound as hydrochloride (15.3 g, yield 64%).1H NMR (CDCl3) δ 1.25-1.36 (9H, m), 1.51 (3H, t, J = 7.0 Hz), 1.61 (3H,br s), 1.79(3H, br s), 2.30-2.60(2H, m), 2. 80-3.20 (2H, m), 3.30(1H,br s), 3.88(3H, s), 3.50(1H, br s), 4.27(2H, q, J = 7.0 Hz), 6.50-6.61(1H,m), 6.70(1H, s), 7.10(1H, m), 7.77(1H, s), 7.97(1H, d, J= 8.2 Hz), 14.5(1H, s). Example 50 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoicacid (Method 1)
    [0473] The aqueous layer extracted with ethyl acetate in Method 1 ofExample 49 was neutralized with 5 M hydrochloric acid, andextracted three times with ethyl acetate. The combined organiclayer was washed with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, concentrated underreduced pressure, and crystallized from ethyl acetate-diisopropylether to give the title compound (327 mg, 24%).1H NMR (CDCl3) δ 1.14 (3H, t, J = 7.0 Hz), 1.31 (6H, s), 1.47 (6H,s), 1.47 (3H, t, J = 7.0 Hz), 2.37 (2H, s), 2.83 (2H, s), 3.09 (2H,q, J = 7.0 Hz), 4,21 (2H, q, J = 7.0 Hz), 6.45 (1H, dd, J = 8.1,1.5 Hz), 6.59 (1H, d, J = 1.5 Hz), 6.62 (1H, s), 7.84 (1H, d, J =8.1 Hz), 8.06 (1H, br s). (Method 2)
    [0474] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(2.98 g, 11.3 mmol) and methyl4-cyano-2-(ethylamino)benzoate (1.92 g, 9.40 mmol) in toluene (10ml) and acetic acid (6 ml) was added conc. sulfuric acid (1.25 ml,23.5 mmol) under ice-cooling, and the mixture was stirred for 2 hours at 80°C. Conc. sulfuric acid (0.25 ml, 4.7 mmol) wasfurther added thereto, and the mixture was stirred for 1 hour at80°C. Methanol (4.25 ml) was added dropwise thereto, and themixture was stirred for 30 minutes at 60°C. After cooling, thereaction mixture was combined with ice water, and washed withethyl acetate. The organic layer was extracted twice with 2 Mhydrochloric acid, the combined aqueous layer was adjusted at pH4.5 with sodium hydrogen carbonate, and extracted twice with ethylacetate. The combined organic layer was washed with a saturatedaqueous solution of sodium hydrogen carbonate, water and asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Tothe residue was added ethyl acetate, and the precipitated crystalswere removed. The filtrate was concentrated under reducedpressure, the residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate, 50:1 followed by 10:1), andcrystallized from pentane to give methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoate(1.54 g, yield 36%).
    [0475] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoate(1.54 g, 3.42 mmol) was suspended in methanol (7 ml) and 5 Maqueous solution (1.71 ml) of sodium hydroxide were added thereto,and the mixture was stirred at room temperature for 2 hours and at50°C for 1.5 hours. After cooling, methanol was distilled offunder reduced pressure, and the residue was combined with waterand washed with diisopropyl ether and ethyl acetate. The aqueouslayer was neutralized with 5 M hydrochloric acid, and extractedtwice with ethyl acetate. The combined organic layer was washedwith a saturated aqueous solution of sodium chloride, dried oversodium sulfate, filtered, concentrated under reduced pressure, andrecrystallized from ethyl acetate-hexane to give the titlecompound (1.30 g, yield 87%). (Method 3)
    [0476] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoate hydrochloride (2 g) in methanol (4 ml) wasadded dropwise 5 M aqueous solution (2.87 ml) of sodium hydroxideand the mixture was stirred at the internal temperature of 45 toat 55°C for 2 hours. The mixture was cooled, methanol wasdistilled off, and the residue was adjusted at pH about 8 with 6 Mhydrochloric acid. Ethyl acetate (8 ml) was added thereto, andthe mixture was further adjusted at pH 6.1 with 6M hydrochloricacid. The mixture was mixed by stirring at room temperature for 1hour and at less than 10°C for 2 hours. The precipitated crystalswere taken by filtration, and washed with water (6 ml) and cooledethyl acetate (6 ml) in this order to give the title compound(1.58 g, yield 88%). Example 51 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[ethyl(2-pyridinylcarbonyl)amino]benzoate
    [0477] With methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoateandpicolinic acid chloride hydrochloride, the title compound wasobtained by the method similar to that in Example 13. Yield 37%.1H NMR (CDCl3) δ 1.17 (3H, s), 1.21 (0.6H, t, J = 6.9 Hz), 1.29 (3H,s), 1.30 (3H, s), 1.31 (2.4H, t, J = 6.9 Hz), 1.36 (3H, s), 1.47(3H, t, J = 6.9 Hz), 2.29 (1H, d, J = 16.2 Hz), 2.35-2.65 (1H, br),2.62 (1H, d, J = 15.6 Hz), 2.70 (1H, d, J = 15.6 Hz), 3.40-3.56(0.4H, m), 3.78 (2.4H, s), 3.90 (0.6H, s), 3.94-4.10 (1.6H, m),4.18 (2H, q, J = 6.9 Hz), 6.91 (1H, s), 7.11 (0.8H, t, J = 6.3 Hz),7.30-7.36 (1H, m), 7.48 (0.8H, s), 7.56-7.83 (3.2H, m), 8.06-8.16(1H, m), 8.62 (0.2H, d, J = 5.1 Hz). Example 52 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[ethyl(2-pyridinylcarbonyl)amino]benzoicacid
    [0478] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[ethyl(2-pyridinylcarbonyl)amino]benzoate,the title compound was obtained by the method similar to that in Example 9. Yield 60%.1H NMR (DMSO-d6) δ 1.06-1.36 (18H, m), 2.20 (1H, t, J = 16.9 Hz),2.31 (1H, t, J = 16.9 Hz), 2.62 (2H, s), 3.67-3.84 (1H, m), 3.87-4.04(1H, m), 4.09 (2H, q, J = 6.8 Hz), 6.80 (1H, s), 7.24-7.30(2.6H, m), 7.45-8.15 (4.2H, m), 8.64 (0.2H, d, J = 5.0 Hz). Example 53 Methyl 2-(acetylethylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoatehydrochloride
    [0479] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoate,the title compound was obtained as free base by the method similarto that in Example 17. This was dissolved in ethyl acetate, and asolution of 4 M hydrogen chloride/ethyl acetate was added thereto.The mixture was concentrated under reduced pressure, and theresidue was crystallized from ethyl acetate-diisopropyl ether togive the title compound. Yield 88%.1H NMR (DMSO-d6) δ 0.92-1.05 (3H, m), 1.17 (6H, s), 1.37 (3H, t, J= 7.0 Hz), 1.48 (6H, s), 1.74 (2.25H, s), 2.12 (1H, d, J = 16.0Hz), 2.16 (0.75H, s), 2.22 (1H, d, J = 16.0 Hz), 3.16 (2H, s),3.30-3.55 (1.5H, br), 3.70-3.90 (0.5H, br), 3.82 (0.75H, s), 3.87(2.25H, s), 4.24 (2H, q, J = 7.0 Hz), 7.09 (1H, s), 7.58 (0.25H,s), 7.51 (0.25H, d, J = 7.8 Hz), 7.74 (0.75H, s), 7.76 (0.75H, d,J = 7.8 Hz), 8.06 (0.25H, d, J = 7.8 Hz), 8.14 (0.75H, d, J = 7.8Hz). Example 54 2-(Acetylethylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0480] From methyl 2-(acetylethylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate,the title compound was obtained by the method similar to that inExample 12. Yield 71%.1H NMR (CDCl3) δ 0.85-1.10 (3H, br), 1.31 (6H, s), 1.46-1.52 (12H,m), 2.19 (2H, s), 2.91 (2H, br s), 3.25-3.45 (1H, br), 3.65-4.10(1H, br), 4.24 (2H, q, J = 7.2 Hz), 5.20-6.40 (1H, br), 6.68 (1H, s), 7.26 (1H, s), 7.56 (1H, d, J = 7.8 Hz), 7.98 (1H, d, J = 7.8Hz). Example 55 2-Amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochloride
    [0481] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate,the title compound was obtainedas a free base by the method similar to that in Example 9. Thiswas dissolved in ethyl acetate, and a solution of 4 M hydrogenchloride/ethyl acetate was added thereto. The mixture wasconcentrated under reduced pressure to give the title compound.Yield 53%.Amorphous.1H NMR (DMSO-d6) δ 1.27 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.43 (6H,s), 2.40 (2H, s), 3.15 (2H, s), 4.24 (2H, q, J = 7.0 Hz), 6.66 (1H,dd, J = 8.1, 1.0 Hz), 6.92 (1H, d, J = 1.0 Hz), 7.08 (1H, s), 7.89(1H, d, J = 8.1 Hz). Example 56 2-Amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide
    [0482] To a suspension of 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacidhydrochloride (691 mg, 1.55 mmol) in 1,2-dimethoxyethane (5 ml)were added methylamine hydrochloride (145 mg, 2.15 mmol), diethylcyanophosphonate (0.24 ml, 1.58 mmol) and triethylamine (0.90 ml,6.48 mmol), and the mixture was stirred at 80°C for 7 hours.After cooling, the reaction mixture was combined with water, andextracted twice with ethyl acetate. The combined organic layerwas washed with a saturated aqueous solution of sodium chloride,dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified with a basic silicagel column chromatography (hexane/ethyl acetate, 1:1 followed by1:2) to give the title compound (254 mg, yield 39%).Amorphous. 1H NMR (CDCl3) δ 1.23 (6H, s), 1.33 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.35 (2H, s), 2.65 (2H, s), 2.97 (3H, d, J = 4.5 Hz), 4.17(2H, q, J = 7.0 Hz), 5.56 (2H, br s), 6.28-6.38 (1H, br), 6.58 (1H,dd, J = 8.1, 1.0 Hz), 6.59 (1H, s), 6.72 (1H, d, J = 1.0 Hz), 7.28(1H, d, J = 8.1 Hz). Example 57 2-(Benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide
    [0483] To a suspension of 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide(122 mg, 0.289 mmol) in tetrahydrofuran (1 ml) were addedtriethylamine (0.044 ml, 0.318 mmol) and benzoyl chloride (0.037ml, 0.318 mmol), and the mixture was stirred for 1 hour at roomtemperature. The reaction mixture was combined with ice water,neutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was purified with a basic silica gel column chromatography(hexane/ethyl acetate, 1:1 followed by 1:2), and the obtainedcrystals were washed with diisopropyl ether to give the titlecompound (77 mg, yield 51%).1H NMR (CDCl3) δ 1.29 (12H, s), 1.46 (3H, t, J = 7.0 Hz), 2.28 (2H,s), 2.69 (2H, s), 3.12 (3H, d, J = 4.6 Hz), 4.18 (2H, q, J = 7.0Hz), 6.59 (1H, s), 6.82 (1H, d, J = 7.8 Hz), 7.30-7.45 (4H, m),7.70-7.85 (1H, br), 7.88-7.92 (2H, m), 8.92 (1H, s), 12.26 (1H, s). Example 58 N-[5-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(methylamino)carbonyl]phenyl]-2-pyridinecarboxamide
    [0484] With 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamideandpicolinic acid chloride hydrochloride, the title compound wasobtained by the method similar to that in Example 13. Yield 64%.1H NMR (CDCl3) δ 1.28 (6H, s), 1.29 (6H, s), 1.46 (3H, t, J = 7.2 Hz), 2.29 (2H, br s), 2.68 (2H, s), 3.11 (3H, d, J = 4.8 Hz), 4.18(2H, q, J = 7.2 Hz), 6.59 (1H, s), 6.85-6.95 (1H, br), 7.03 (1H,dd, J = 8.0 Hz), 7.38 (1H, dd, J = 7.7, 4.6 Hz), 7.49 (1H, d, J =8.0 Hz), 7.78-7.87 (1H, m), 8.21 (1H, d, J = 7.7 Hz), 8.65 (1H, d,J = 4.6 Hz), 8.95 (1H, s). Example 59 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methyl-2-[(1-methylethylidene)amino]benzamidehydrochloride
    [0485] 2-Amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N-methylbenzamide(352 mg,0,835 mmol) was dissolved in ethyl acetate, a solution of 4 Mhydrogen chloride/ethyl acetate was added thereto, and the mixturewas concentrated under reduced pressure. The residue was combinedwith acetone, heated, and concentrated under reduced pressure togive the title compound (378 mg, yield 91%).Amorphous.1H NMR (DMSO-d6) δ 1.24 (3H, s), 1.27 (3H, s), 1.33-1.48 (15H, m),2.34 (2H, s), 2.96 (3H, s), 3.09 (1H, d, J = 16.4 Hz), 3.21 (1H, d,J = 16.4 Hz), 4.23 (2H, q, J = 7.0 Hz), 6.82 (1H, s), 6.85 (1H, d,J = 7.8 Hz), 7.07 (1H, s), 7.31 (1H, s), 7.83 (1H, d, J = 7.8 Hz). Example 60 N-[2-Amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester
    [0486] With glycine ethyl ester hydrochloride, the title compoundwas obtained by the method similar to that in Example 56. Yield59%.1H NMR (CDCl3) δ 1.23-1.36 (15H, m), 1.46 (3H, t, J = 6.9 Hz), 2.37(2H, s), 2.65 (2H, s), 4.12-4.26 (4H, m), 4.27 (2H, q, J = 6.9 Hz),5.60 (2H, br s), 6.58 (1H, s), 6.58 (1H, dd, J = 8.2, 1.4 Hz),6.76 (1H, d, J = 1.4 Hz), 6.86 (1H, t, J = 4.8 Hz), 7.37 (1H, d, J= 8.2 Hz). Example 61 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(4-pyridinylcarbonyl)amino]benzoyl]glycine ethyl ester
    [0487] With N-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl esterand isonicotinic acid chloride hydrochloride, the title compoundwas obtained by the method similar to that in Example 13. Yield74%.1H NMR (CDCl3) δ 1.28 (6H, s), 1.31 (6H, s), 1.35 (3H, t, J = 7.0Hz), 1.46 (3H, t, J = 7.0 Hz), 2.32 (2H, br s), 2.69 (2H, s), 4.18(2H, q, J = 7.0 Hz), 4.30 (2H, q, J = 7.0 Hz), 6.60 (1H, s), 7.04(1H, d, J = 8.0 Hz), 7.58 (1H, d, J = 8.0 Hz), 7.74-7.76 (3H, m),8.71-8.73 (2H, m), 8.84 (1H, d, J = 1.5 Hz). Example 62 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoyl]glycineethyl ester
    [0488] With N-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl esterand picolinic acid chloride hydrochloride, the title compound wasobtained by the method similar to that in Example 13. Yield 80%.1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 1.33 (3H, t, J = 7.0Hz), 1.47 (3H, t, J = 7.2 Hz), 2.36 (2H, s), 2.68 (2H, s), 4.19(2H, q, J = 7.0 Hz), 4.23-4.34 (4H, m), 6.60 (1H, s), 6.93 (1H, t,J = 5.0 Hz), 7.18 (1H, dd, J = 8.1, 1.8 Hz), 7.45 (1H, ddd, J =7.7, 4.8, 1.4 Hz), 7.65 (1H, d, J = 8.1), 7.87 (1H, td, J = 7.7,1.8 Hz), 8.23 (1H, d, J = 7.7 Hz), 8.73 (1H, d, J = 4.8), 8.97 (1H,d, J = 1.4 Hz). Example 63 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoyl]glycine
    [0489] From N-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoyl]glycineethyl ester, the titlecompound was obtained by the method similar to that in Example 12.Yield 82%.1H NMR (CDCl3) δ 1.30 (6H, s), 1.49 (6H, s), 1.49 (3H, t, J = 7.0 Hz), 2.14 (1H, d, J = 17.8 Hz), 2.52 (1H, d, J = 17.8 Hz), 2.75-3.10(2H, br), 3.95 (2H, d, J = 4.8 Hz), 4.25 (2H, q, J = 7.0 Hz),6.66 (1H, s), 7.34-7.41 (2H, m), 7.77-7.96 (3H, m), 8.14 (1H, d, J= 8.0 Hz), 8.66 (1H, d, J = 4.4 Hz), 8.95 (1H, s). Example 64 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-pyridinylcarbonyl)amino]benzoyl]glycineethyl ester
    [0490] With N-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl esterand nicotinic acid chloride hydrochloride, the title compound wasobtained by the method similar to that in Example 13. Yield 78%.1H NMR (CDCl3) δ 1.28 (6H, s), 1.33 (6H, s), 1.34 (3H, t, J = 6.9Hz), 1.47 (3H, t, J = 6.9 Hz), 2.35 (2H, br s), 2.69 (2H, s), 4.19(2H, q, J = 6.9 Hz), 4.26-4.33 (4H, m), 6.60 (1H, s), 7.14 (1H, d,J = 7.8 Hz), 7.28-7.35 (1H, br), 7.38 (1H, dd, J = 8.1, 4.8 Hz),7.63 (1H, d, J = 7.8 Hz), 8.21 (1H, dd, J = 8.1, 2.1 Hz), 8.73 (1H,d, J = 4.8 Hz), 8.87 (1H, s), 9.23 (1H, d, J = 2.1 Hz). Example 65 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-pyridinylcarbonyl)amino]benzoyl]glycine
    [0491] With N-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-pyridinylcarbonyl)amino]benzoyl]glycineethyl ester, the titlecompound was obtained by the method similar to that in Example 12.Yield 49%.1H NMR (CDCl3) δ 1.31 (6H, s), 1.49 (6H, s), 1.49 (3H, t, J = 7.0Hz), 2.22-2.53 (2H, br), 2.91 (2H, s), 3.78 (2H, s), 4.25 (2H, q,J = 7.0 Hz), 6.67 (1H, s), 6.95-7.35 (1H, br), 7.26-7.40 (2H, m),7.88 (2H, d, J = 8.0 Hz), 8.21-8.26 (1H, m), 8.70 (1H, d, J = 4.4Hz), 8.91 (1H, s), 9.24 (1H, s). Example 66 N-[2-(Benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester
    [0492] With N-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycine ethyl ester,the title compound was obtained by the method similar to that inExample 57. Yield 80%.1H NMR (CDCl3) δ 1.29-1.35 (15H, m), 1.47 (3H, t, J = 6.9 Hz), 2.34(2H, br s), 2.69 (2H, s), 4.19 (2H, q, J = 6.9 Hz), 4.28 (2H, q, J= 6.9 Hz), 6.59 (1H, s), 7.08 (1H, d, J = 7.8 Hz), 7.41-7.52 (4H,m), 7.63 (1H, d, J = 7.8 Hz), 7.95 (1H, d, J = 7.2 Hz), 8.91 (1H,s). Example 67 N-[2-(Benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycine
    [0493] With N-[2-(benzoylamino)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester, the title compound was obtained by the method similarto that in Example 12. Yield 91%.1H NMR (DMSO-d6) δ 1.16 (6H, s), 1.23 (6H, s), 1.34 (3H, t, J = 6.9Hz), 2.42 (2H, br s), 2.65 (2H, s), 4.00 (2H, d, J = 4.0 Hz), 4.10(2H, q, J = 6.9 Hz), 6.81 (1H, s), 7.24 (1H, d, J = 8.4 Hz), 7.56-7.64(3H, m), 7.89-7.95 (3H, m), 8.70 (1H, s), 9.37 (1H, t, J =4.0 Hz). Example 68 N-[2-[[(E)-(Dimethylamino)methylidene]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester
    [0494] With N-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl esterand 4-(acetamido)benzoic acid, the title compound was obtained bythe method similar to that in Example 15. Yield 43%.1H NMR (CDCl3) δ 1.21 (6H, s), 1.30 (6H, s), 1.30 (3H, t, J = 7.0Hz), 1.46 (3H, t, J = 7.0 Hz), 2.25 (2H, s), 2.67 (2H, s), 3.11(3H, s), 3.16 (3H, s), 4.18 (2H, q, J = 7.0 Hz), 4.24 (2H, q, J =7.0 Hz), 4.25-4.36 (2H, br), 6.60 (1H, s), 6.90 (1H, d, J = 1.8Hz), 7.08 (1H, dd, J = 8.1, 1.8 Hz), 7.69 (1H, s), 8.28 (1H, d, J= 8.1 Hz), 10.68 (1H, d, J = 4.6 Hz). Example 69 8-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-4-methyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione
    [0495] With sarcosine methyl ester hydrochloride, the title compoundwas obtained by the method similar to that in Example 56. Yield76%.1H NMR (CDCl3) δ 1.26 (6H, s), 1.34 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.28 (2H, s), 2.68 (2H, s), 3.29 (3H, s), 3.87 (2H, s), 4.19(2H, q, J = 7.0 Hz), 6.61 (1H, s), 7.12 (1H, s), 7.27 (1H, d, J =8.1 Hz), 7.97 (1H, d, J = 8.1 Hz), 7.98 (1H, s). Example 70 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoyl]glycineethylester
    [0496] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoicacid (810 mg, 1.62 mmol), glycineethyl ester hydrochloride (249 mg, 1.79 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (274 mg, 1.79 mmol) in N,N-dimethylformamide(6 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (404 mg, 2.11 mmol),and the mixture was stirred for 1 hour at room temperature. Thereaction mixture was combined with ice water, and extracted threetimes with ethyl acetate. The combined organic layer was washedwith a saturated aqueous solution of sodium chloride, dried oversodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate 2:1), and crystallized fromdiethyl ether-hexane to give the title compound (713 mg, yield75%).1H NMR (CDCl3) δ 1.22 (6H, s), 1.31 (6H, s), 1.32 (3H, t, J = 7.0Hz), 1.46 (3H, t, J = 7.0 Hz), 2.26 (2H, s), 2.65 (2H, s), 4.17(2H, q, J = 7.0 Hz), 4.26 (2H, q, J = 7.0 Hz), 4.38 (2H, d, J =5.4 Hz), 6.57 (1H, s), 6.60 (1H, d, J = 8.0 Hz), 6.71 (1H, s),7.19-7.35 (5H, m), 7.45 (1H, d, J = 8.0 Hz), 8.03 (1H, t, J = 5.4 Hz). Example 71 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoyl]glycine
    [0497] From N-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoyl]glycineethyl ester, the titlecompound was obtained by the method similar to that in Example 9.Yield 85%.1H NMR (CDCl3) δ 1.29 (6H, s), 1.46-1.53 (9H, m), 2.16 (1H, d, J =12.8 Hz), 2.31 (1H, d, J = 12.8 Hz), 2.91 (1H, d, J = 13.2 Hz),3.01 (1H, d, J = 13.2 Hz), 3.77 (2H, s), 4.24 (2H, q, J = 7.0 Hz),4.23 (2H, s), 6.59 (1H, d, J = 8.0 Hz), 6.66 (1H, s), 6.72 (1H, s),7.17-7.37 (5H, m), 7.57 (1H, d, J = 8.0 Hz), 8.27 (1H, br s). Example 72 N-(2-Amino-2-oxoethyl)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzamidehydrochloride
    [0498] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoicacid (301 mg, 0.604 mmol),glycinamide hydrochloride (73 mg, 0.664 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (102 mg, 0.664 mmol) and triethylamine(0.093 ml, 0.664 mmol) in N,N-dimethylformamide (3 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (151mg, 0.785 mmol) under ice-cooling, and the mixture was stirred atroom temperature for 3 hours. To the reaction mixture was pouredice water, and the mixture was extracted three times with a mixedsolution of ethyl acetate-tetrahydrofuran. The combined organiclayer was washed with a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was purified with a basicsilica gel column chromatography (ethyl acetate followed by ethylacetate/methanol 50:1) to give the title compound as free base.This was dissolved in ethyl acetate, a solution of 4 M hydrogen chloride/ethyl acetate was added thereto, and the mixture wasconcentrated under reduced pressure to give the title compound(237 mg, yield 66%).Amorphous.1H NMR (DMSO-d6) δ 1.21 (3H, s), 1.24 (3H, s), 1.37 (3H, t, J = 7.0Hz), 1.43 (6H, s), 2.20 (1H, d, J = 17.0 Hz), 2.34 (1H, d, J =17.0 Hz), 3.13 (2H, s), 3.80 (1H, d, J = 9.6 Hz), 3.82 (1H, d, J =9.6 Hz), 4.23 (2H, q, J = 7.0 Hz), 4.43 (2H, d, J = 5.4 Hz), 6.75(1H, dd, J = 8.0, 1.4 Hz), 6.91 (1H, d, J = 1.4 Hz), 7.06 (2H, s),7.25-7.35 (5H, m), 7.48 (1H, s), 7.89 (1H, d, J = 8.0 Hz), 8.86(1H, t, J = 5.4 Hz) . Example 73 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzamide
    [0499] From 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoicacid, the title compound was obtainedby the method similar to that in Example 10. Yield 74%.1H NMR (CDCl3) δ 1.22 (6H, s), 1.30 (6H, s), 1.46 (3H, t, J = 6.9Hz), 2.26 (2H, s), 2.65 (2H, s), 4.17 (2H, q, J = 6.9 Hz), 4.40(2H, d, J = 5.4 Hz), 5.45-6.10 (2H, br), 6.56 (1H, dd, J = 8.1,1.5 Hz), 6.57 (1H, s), 6.71 (1H, d, J = 1.5 Hz), 7.23-7.40 (6H, m),8.29 (1H, t, J = 5.4 Hz). Example 74 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzonitrile
    [0500] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzamide(2.97 g, 5.96 mmol) in chloroform(20 ml) was added phosphorus oxychloride (2.78 ml, 29.8 mmol), andthe mixture was stirred for 1 hour at 85°C. After cooling, thereaction mixture was poured into ice water, neutralized withsodium hydrogen carbonate, and extracted twice with ethyl acetate.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant crystalswere washed with hexane to give the title compound (2.57 g, yield90%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.26 (6H, s), 1.46 (3H, d, J = 7.0Hz), 2.21 (2H, s), 2.66 (2H, s), 4.17 (2H, q, J = 7.0 Hz), 4.43(2H, d, J = 5.6 Hz), 4.97 (1H, t, J = 5.6 Hz), 6.58 (1H, s), 6.70(1H, dd, J = 7.8, 1.2 Hz), 6.73 (1H, d, J = 1.2 Hz), 7.30-7.38 (5H,m), 7.43 (1H, d, J = 7.8 Hz). Example 75 N-[2-Amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalanineethyl ester
    [0501] With ethyl 2-aminoisobutyrate hydrochloride, the titlecompound was obtained by the method similar to that in Example 72.Yield 32%.1H NMR (CDCl3) δ 1.22 (6H, s), 1.28 (3H, t, J = 7.0 Hz), 1.35 (6H,s), 1.46 (3H, t, J = 7.0 Hz), 1.70 (6H, s), 2.39 (2H, s), 2.65 (2H,s), 4.18 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 5.53 (2H,s), 6.59 (1H, s), 6.62 (1H, dd, J = 8.0, 1.8 Hz), 6.73 (1H, d, J =1.8 Hz), 7.34 (1H, d, J = 8.0 Hz). Example 76 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoyl]-2-methylalanineethyl ester hydrochloride
    [0502] The free base of the title compound which was obtained at thesame time in Example 75, was dissolved in ethyl acetate, asolution of 4 M hydrogen chloride/ethyl acetate was added thereto,and the mixture was concentrated under reduced pressure to givethe title compound. Yield 11%.Amorphous.1H NMR (DMSO-d6) δ 1.08 (3H, t, J = 7.0 Hz), 1.19 (3H, s), 1.25 (3H,s), 1.37 (3H, t, J = 7.0 Hz), 1.42 (6H, s), 1.47 (6H, s), 2.07 (1H,d, J = 14.0 Hz), 2.27 (1H, d, J = 14.0 Hz), 3.13 (2H, s), 4.03 (2H,q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 4.43 (2H, s), 6.74 (1H,d, J = 7.8 Hz), 6.91 (1H, s), 7.06 (1H, s), 7.20-7.40 (5H, m), 7.87 (1H, d, J = 7.8 Hz), 8.24 (1H, br s), 8.76 (1H, s). Example 77 N-[2-Amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalanine
    [0503] To a solution of N-[[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalanineethyl ester (299 mg, 0.573 mmol) in methanol (2 ml)was added 5 M aqueous solution (0.5 ml) of sodium hydroxide, andthe mixture was stirred at room temperature for 5 hours. Thesolvent was distilled off under reduced pressure, and the residuewas combined with water, and neutralized with 5 M hydrochloricacid. The residue was combined with diethyl ether, andcrystallized to give the title compound (73 mg, yield 26%).1H NMR (CDCl3) δ 1.34 (6H, s), 1.48 (6H, s), 1.48 (3H, t, J = 7.0Hz), 1.60 (6H, s), 2.37 (2H, s), 2.90 (2H, br s), 4.24 (2H, q, J =7.0 Hz), 5.00-5.50 (2H, br s), 6.56 (1H, d, J = 8.0 Hz), 6.64 (1H,s), 6.71 (1H, s), 7.31 (1H, d, J = 8.0 Hz), 7.42 (1H, s). Example 78 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoyl]-2-methylalanineethyl ester
    [0504] With N-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]-2-methylalanineethyl ester and picolinic acid chloride hydrochloride, the titlecompound was obtained by the method similar to that in Example 13.Yield 71%.1H NMR (CDCl3) δ 1.22 (3H, t, J = 7.2 Hz), 1.25 (6H, s), 1.33 (6H,s), 1.47 (3H, t, J = 7.2 Hz), 1.74 (6H, s), 2.38 (2H, br s), 2.67(2H, s), 4.16-4.26 (4H, m), 6.60 (1H, s), 6.81 (1H, s), 7.20 (1H,d, J = 7.8 Hz), 7.43-7.47 (1H, m), 7.58 (1H, d, J = 7.8 Hz), 7.83-7.89(1H, m), 8.21 (1H, d, J = 7.8 Hz), 8.71 (1H, d, J = 4.8 Hz),8.89 (1H, s). Example 79 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoyl]-2-methylalanine hydrochloride
    [0505] With N-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzoyl]-2-methylalanineethyl ester, thetitle compound was obtained by the method similar to that inExample 12. Yield 49%.1H NMR (CDCl3) δ 1.30 (3H, s), 1.36 (3H, s), 1.48-1.55 (6H, m),1.68 (6H, s), 1.86 (3H, s), 2.26 (1H, d, J = 16.7 Hz), 2.71 (1H, d,J = 16.7 Hz), 2.82 (1H, d, J = 17.0 Hz), 3.27 (1H, d, J = 17.0 Hz),4.29 (2H, q, J = 7.0 Hz), 6.71 (1H, s), 7.42-7.52 (1H, m), 7.75-8.02(4H, m), 8.14 (1H, d, J = 7.6 Hz), 8.74 (1H, d, J = 4.4 Hz),8.89 (1H, s). Example 80 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoyl]-2-methylalaninehydrochloride
    [0506] From N-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoyl]-2-methylalanineethyl esterhydrochloride, the title compound was obtained as free base by themethod similar to that in Example 9. This was dissolved in ethylacetate, a solution of 4 M hydrogen chloride/ethyl acetate wasadded thereto, and the mixture was concentrated under reducedpressure to give the title compound. Yield 73%.Amorphous.1H NMR (DMSO-d6) δ 1.21 (3H, s), 1.25 (3H, s), 1.37 (3H, t, J = 7.0Hz), 1.43 (6H, s), 1.47 (6H, s), 2.21 (1H, d, J = 17.6 Hz), 2.36(1H, d, J = 17.6 Hz), 3.13 (2H, s), 4.23 (2H, q, J = 7.0 Hz), 4.43(2H, s), 6.74 (1H, d, J = 8.4 Hz), 6.91 (1H, s), 7.06 (1H, s),7.25-7.40 (6H, m), 7.90 (1H, d, J = 8.4 Hz), 8.36 (1H, br s), 8.61(1H, s). Example 81 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-hydroxybenzoatehydrochloride
    [0507] From methyl 4-cyano-2-hydroxybenzoate methyl, the title compound was obtained by the method similar to that in Example 2.Yield 38%.1H NMR (DMSO-d6) δ 1.25 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.44 (6H,s), 2.30 (2H, s), 3.14 (2H, s), 3.92 (3H, s), 4.24 (2H, q, J = 7.0Hz), 7.08 (1H, s), 7.11 (1H, dd, J = 8.0, 1.4 Hz), 7.30 (1H, d, J= 1.4 Hz), 7.95 (1H, d, J = 8.0 Hz), 10.86 (1H, s). Example 82 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethoxy)benzoatehydrochloride
    [0508] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-hydroxybenzoatehydrochloride (614 mg, 1.33 mmol) in N,N-dimethylformamide (5 ml)were added potassium tert-butoxide (313 mg, 2.79 mmol) and benzylbromide (0.17 ml, 1.47 mmol), and the mixture was stirred at roomtemperature for 2 hours and at 50°C for 2 hours. Potassium tert-butoxide(149 mg, 1.33 mmol) and benzyl bromide (0.16 ml, 1.33mmol) were further added thereto, and the mixture was stirred atroom temperature for 2 hours. The reaction mixture was combinedwith ice water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with 0.5 M aqueous solution ofsodium hydroxide, water and a saturated aqueous solution of sodiumchloride, dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified with a silica gelcolumn chromatography (hexane/ethyl acetate, 5:1 followed by 3:1)to give the title compound as free base. This was dissolved inethyl acetate, a solution of 4 M hydrogen chloride/ethyl acetatewas added thereto, and the mixture was concentrated under reducedpressure, and the residue was crystallized from ethyl acetate-diisopropylether to give the title compound (271 mg, yield 37%).1H NMR (DMSO-d6) δ 1.23 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.46 (6H,s), 2.24 (2H, s), 3.14 (2H, s), 3.87 (3H, s), 4.25 (2H, q, J = 7.0Hz), 5.23 (2H, s), 7.09 (1H, s), 7.26 (1H, d, J = 7.8 Hz), 7.34-7.52(5H, m), 7.60 (1H, s), 7.91 (1H, d, J = 7.8 Hz). Example 83 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethoxy)benzoic acid hydrochloride
    [0509] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethoxy)benzoatehydrochloride, the title compound was obtained as free base by themethod similar to that in Example 9. This was dissolved in ethylacetate, a solution of 4 M hydrogen chloride/ethyl acetate wasadded thereto, and the mixture was concentrated under reducedpressure to give the title compound. Yield 85%.Amorphous.1H NMR (DMSO-d6) δ 1.24 (6H, s), 1.38 (3H, t, J = 7.0 Hz), 1.45 (6H,s), 2.26 (2H, s), 3.15 (2H, s), 3.87 (3H, s), 4.24 (2H, q, J = 7.0Hz), 5.28 (2H, s), 7.09 (1H, s), 7.20-7.53 (7H, m), 7.86 (1H, d, J= 7.6 Hz). Example 84 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methoxyphenyl]-2-propenoate (Method 1)
    [0510] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(799 mg, 3.02 mmol) and methyl(E)-3-(4-cyano-2-methoxyphenyl)-2-propenoate (547 mg, 2.52 mmol)in toluene (3.5 ml) and acetic acid (2 ml) was added conc.sulfuric acid (0.34 ml, 6.30 mmol), and the mixture was stirredfor 2 hours at 70°C. After cooling, the reaction mixture wascombined with ice water, washed with diisopropyl ether,neutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was purified with a basic silica gel column chromatography(hexane/ethyl acetate, 10:1 followed by 5:1), and crystallizedfrom diisopropyl ether-hexane to give the title compound (376 mg,yield 32%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.33 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.29 (2H, s), 2.67 (2H, s), 3.81 (3H, s), 3.91 (3H, s), 4.19 (2H, q, J = 7.0 Hz), 6.57 (1H, d, J = 16.2 Hz), 6.61 (1H, s), 6.96(1H, s), 6.98 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz), 8.01(1H, d, J = 16.2 Hz). (Method 2)
    [0511] Methyl (E)-3-(4-cyano-2-methoxyphenyl)-2-propenoate (800 mg)was suspended in methyl acetate (8 ml), andtrifluoromethanesulfonic acid(3.25 ml) was added dropwise thereto.Then, a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1.95 g) in methyl acetate (22ml) was slowly added dropwise thereto at around 60°C. The mixturewas stirred for 1 hour at around 60°C. Ice-cooled 25% ammoniawater (6 ml) was added dropwise thereto. Toluene and water werefurther added thereto and the layers were separated. The organiclayer was washed with water. The organic layer was extractedthree times with 1 M hydrochloric acid. The organic layer wasfurther combined with diisopropyl ether and further extracted with1 M hydrochloric acid. The aqueous layer was combined, and washedwith diisopropyl ether. The aqueous layer was alkalified byadding sodium hydrogen carbonate. The mixture was extracted withethyl acetate. The extracts were washed with water, dried withanhydrous sodium sulfate, and concentrated under reduced pressure.The residue was subjected to a basic silica gel chromatography (20g), and eluted with hexane/ethyl acetate=5/1 to give the titlecompound (1.45 g, yield 85%). Example 85 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methoxyphenyl]-2-propenoicacid
    [0512] To a suspension of methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methoxyphenyl]-2-propenoate(277 mg, 0.598 mmol) in methanol (2ml) was added 5 M aqueous solution (0.5 ml) of sodium hydroxide,and the mixture was stirred at room temperature for 1 hour and at50°C for 30 minutes. After cooling, methanol was distilled offunder reduced pressure, and the residue was combined with waterand washed with diisopropyl ether. The aqueous layer was adjusted at pH 4.5 with 5 M hydrochloric acid, and extracted three timeswith a mixed solution of ethyl acetate-tetrahydrofuran. Thecombined organic layer was dried over sodium sulfate, filtered,concentrated under reduced pressure, and recrystallized fromacetone-diisopropyl ether to give the title compound (240 mg,yield 89%).1H NMR (CDCl3) δ 1.33 (6H, s), 1.38 (6H, s), 1.48 (3H, t, J = 7.0Hz), 2.30 (2H, s), 2.78 (2H, s), 3.94 (3H, s), 4.21 (2H, q, J =7.0 Hz), 6.48 (1H, d, J = 16.2 Hz), 6.64 (1H, s), 6.97 (1H, d, J =7.9 Hz), 7.08 (1H, s), 7.50 (1H, d, J = 7.9 Hz), 7.91 (1H, d, J =16.2 Hz). Example 86 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-hydroxyphenyl]-2-propenoate
    [0513] From methyl (E)-3-[4-cyano-2-(phenylmethoxy)phenyl]-2-propenoate,the title compound was obtained by the method similarto that in Example 84. Yield 22%.1H NMR (CDCl3) δ 1.28 (12H, s), 1.46 (3H, t, J = 7.0 Hz), 2.25 (2H,s), 2.78 (2H, br s), 3.77 (3H, s), 4.19 (2H, q, J = 7.0 Hz), 6.34(1H, d, J = 16.1 Hz), 6.58 (1H, dd, J = 8.0, 1.4 Hz), 6.60 (1H, s),6.82 (1H, d, J = 1.4 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.82 (1H, d, J= 16.1 Hz). Example 87 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethoxy)phenyl]-2-propenoatehydrochloride
    [0514] To a solution of methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-hydroxyphenyl]-2-propenoate (283 mg, 0.630 mmol) in N,N-dimethylformamide(2.5 ml) were added potassium carbonate (96 mg,0.692 mmol) and benzyl bromide (0.082 ml, 0.692 mmol), and themixture was stirred at 60°C for 4 hours. After cooling, water waspoured to the reaction mixture, and the mixture was extractedtwice with ethyl acetate. The combined organic layer was washed with water and a saturated aqueous solution of sodium chloride,dried over sodium sulfate, and concentrated under reduced pressure.The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate, 20:1 followed by 7:1) togive the title compound as free base. This was dissolved in ethylacetate, a solution of 4 M hydrogen chloride/ethyl acetate wasadded thereto, and the mixture was concentrated under reducedpressure to give the title compound (224 mg, yield 62%).1H NMR (DMSO-d6) δ 1.24 (6H, s), 1.46 (3H, t, J = 6.8 Hz), 1.45 (6H,s), 2.28 (2H, s), 3.14 (2H, s), 3.72 (3H, s), 4.25 (2H, q, J = 6.8Hz), 5,29 (2H, s), 6.84 (1H, d, J = 16.4 Hz), 7.09 (1H, s), 7.23(1H, d, J = 8.2 Hz), 7.30-7.56 (6H, m), 7.95 (1H, d, J = 16.4 Hz),8.04 (1H, d, J = 8.2 Hz). Example 88 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethoxy)phenyl]-2-propenoicacid
    [0515] From methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethoxy)phenyl]-2-propenoate,the title compound was obtained by the methodsimilar to that in Example 9. Yield 63%.1H NMR (CDCl3) δ 1.30 (12H, s), 1.47 (3H, t, J = 7.0 Hz), 2.21 (2H,s), 2.72 (2H, s), 4.19 (2H, q, J = 7.0 Hz), 5,16 (2H, s), 6.50 (1H,d, J = 16.2 Hz), 6.61 (1H, s), 6.96 (1H, d, J = 8.0 Hz), 7.08 (1H,s), 7.29-7.43 (5H, m), 7.52 (1H, d, J = 8.0 Hz), 8.03 (1H, d, J =16.2 Hz). Example 89 5-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(phenylmethyl)-1H-isoindol-1,3(2H)-dione
    [0516] A suspension of a solution of 4-bromophthalic anhydride (854mg, 1.72 mmol) in 28% sodium methoxide/methanol (8 ml) andtetrahydrofuran (8 ml) was heated under reflux for 10 minutes.After cooling, a 1:1 mixture of the precipitated 2-methyl 4-bromo-1,2-benzenedicarboxylate1-sodium salt and 1-methyl 4-bromo-1,2-benzenedicarboxylate2-sodium salt was taken by filtration, andwashed with diethyl ether. The filtrate was concentrated under reduced pressure, the residue was combined with ice water,acidified with 2 M hydrochloric acid, and extracted twice withethyl acetate. The combined organic layer was washed with waterand a saturated aqueous solution of sodium chloride, dried overmagnesium sulfate, filtered, concentrated under reduced pressure,and crystallized from diisopropyl ether-hexane to give 1:1 mixtureof 4-bromo-1,2-benzenedicarboxylic acid 1-methyl ester and 4-bromo-1,2-benzenedicarboxylicacid 2-methyl ester (1.16 g, yield20%). Furthermore, the mother liquor was concentrated to give thesame mixture (1.63 g, yield 29%) as an oily matter. The mixtureof the sodium salts was dissolved in water, acidified with 2 Mhydrochloric acid, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over magnesium sulfate,filtered, and concentrated under reduced pressure to give 1:1mixture of 4-bromo-1,2-benzenedicarboxylic acid 1-methyl ester and4-bromo-1,2-benzenedicarboxylic acid 2-methyl ester (1.41 g, yield25%). A suspension of the resultant mixture (210 mg, 0.811 mmol)of bromo forms, zinc cyanate (52 mg, 0.446 mmol) andtetrakis(triphenylphosphine)palladium(0) (19 mg, 0.0162 mmol) intoluene (1.6 ml) and N-methyl-2-pyrrolidone (0.4 ml) was stirredat 100°C for 8 hours. After cooling, the reaction mixture wascombined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wasdissolved in toluene (1.5 ml) and acetic acid (1 ml). 7-Ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(214 mg, 0.811 mmol) and conc. sulfuric acid (0.11 ml, 2.03 mmol)were added thereto, and the mixture was stirred for 2 hours at80°C. After cooling, the reaction mixture was combined with icewater, washed with diisopropyl ether, neutralized with sodiumhydrogen carbonate, and extracted twice with ethyl acetate. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product(130 mg) containing 1:1 mixture of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1,2-benzenedicarboxylicacid 1-methyl ester and 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1,2-benzenedicarboxylicacid 2-methyl ester. This product (120 mg)without purification was dissolved in N,N-dimethylformamide (2 ml).Benzylamine (43 mg, 0.399 mmol), 1-hydroxy-1H-benzotriazolemonohydrate (65 mg, 0.426 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (92 mg, 0.478 mmol)were added thereto, and the mixture was stirred at roomtemperature for 15 hours. The reaction mixture was combined withice water, and extracted twice with ethyl acetate. The combinedorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wassubjected to a silica gel column chromatography to give the titlecompound (26 mg, yield 1.8%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.16 (2H, s), 2.68 (2H, s), 4.19 (2H, q, J = 7.0 Hz), 4.87(2H, s), 6.62 (1H, s), 7.28-7.38 (3H, m), 7.46 (2H, dd, J = 7.6,1.6 Hz), 7.72 (1H, d, J = 7.6, 1.3 Hz), 7.84 (1H, d, J = 7.6 Hz),7.94 (1H, d, J = 1.3 Hz). Example 90 5-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1H-isoindol-1,3(2H)-dione
    [0517] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(17.4 g, 65.9 mmol) and 2,3-dihydro-1,3-dioxo-1H-isoindol-5-carbonitrile(6.30 g, 35.8 mmol)in toluene (40 ml) and acetic acid (25 ml) was added conc.sulfuric acid (9.46 ml, 55.0 mmol) under ice-cooling, and themixture was stirred for 30 minutes at 80°C. Ethanol was addeddropwise thereto, and the mixture was stirred for 30 minutes atthe same temperature. After cooling, the reaction mixture wascombined with ice water, washed with diisopropyl ether, neutralized with sodium hydrogen carbonate, and extracted threetimes with ethyl acetate. The combined organic layer wasextracted three times with 1 M hydrochloric acid. The combinedaqueous layer was neutralized with sodium hydrogen carbonate, andextracted twice with ethyl acetate. The combined organic layerwas washed with a saturated aqueous solution of sodium chloride,dried over sodium sulfate, filtered, and concentrated underreduced pressure. To the residue was added ethyl acetate, and theprecipitated crystals were taken and removed by filtration. Thefiltrate was concentrated under reduced pressure, the residue waspurified with a silica gel column chromatography (hexane/ethylacetate, 3:1 followed by 2:1), and the obtained crystals werewashed with hexane to give the title compound (3.60 g, yield 16%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 6.9Hz), 2.16 (2H, s), 2.70 (2H, s), 4.20 (2H, q, J = 6.9 Hz), 6.64(1H, s), 7.79 (1H, dd, J = 7.8, 1.5 Hz), 7.88 (1H, dd, J = 7.8,0.9 Hz), 7.95 (1H, dd, J = 1.5, 0.9 Hz), 7.98 (1H, s). Example 91 Diethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1,2-benzenedicarboxylatehydrochloride
    [0518] The washed solution of the title compound in Example 90 wasconcentrated under reduced pressure, and the residue was purifiedwith a basic silica gel column chromatography (hexane/ethylacetate, 10:1) to give the title compound as free base. This wasdissolved in ethyl acetate, and a solution of 4 M hydrogenchloride/ethyl acetate was added thereto. The mixture wasconcentrated under reduced pressure, and the residue wascrystallized from ethyl acetate-hexane to give a hydrochloride ofthe title compound (227 mg, yield 0.78%).1H NMR (DMSO-d6) δ 1.25-1.44 (21H, m), 2.17 (1H, d, J = 17.0 Hz),2.28 (1H, d, J = 17.0 Hz), 3.13 (2H, s), 4.19-4.40 (6H, m), 7.08(1H, s), 7.88-8.01 (3H, m). Example 92 5-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methyl-1H-isoindol-1,3(2H)-dione
    [0519] From 5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1H-isoindol-1,3(2H)-dioneand iodomethane, the title compound was obtained by the methodsimilar to that in Example 82. Yield 71%.1H NMR (CDCl3) δ 1.25 (6H, s), 1.31 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.16 (2H, s), 2.69 (2H, s), 3.21 (3H, s), 4.19 (2H, q, J =7.0 Hz), 6.63 (1H, s), 7.75 (1H, dd, J = 7.8, 1.4 Hz), 7.86 (1H,dd, J = 7.8, 0.8 Hz), 7.92 (1H, dd, J = 1.4, 0.8 Hz). Example 93 Methyl [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]acetate
    [0520] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(6.80 g, 25.7 mmol) and methyl[(4-cyanophenyl)methoxy]acetate (4.40 g, 21.4 mmol) in toluene (24ml) and acetic acid (14 ml) was added conc. sulfuric acid (2.85 ml,111 mmol), and the mixture was stirred for 1.5 hours at 80°C.Methanol (10.8 ml) was added dropwise thereto, and the mixture wasstirred for 30 minutes at 70°C. After cooling, the reactionmixture was combined with ice water, washed with diisopropyl ether,neutralized with sodium hydrogen carbonate, and extracted twicewith ethyl acetate. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was purified with a basic silica gel column chromatography(hexane/ethyl acetate, 5:1 followed by 1:1) to give the titlecompound (1.18 g, yield 12%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.21 (2H, s), 2.66 (2H, s), 3.78 (3H, s), 4.10 (2H, s), 4.18(2H, q, J = 7.0 Hz), 4.69 (2H, s), 6.60 (1H, s), 7.39 (4H, s). Alternative synthetic method
    [0521] A solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenemethanol(580 mg,1.53 mmol) in N,N-dimethylformamide (4 ml) was cooled with ice, sodium hydride (66% dispersion in oil) (61 mg, 1.68 mmol) wasadded thereto, and the mixture was stirred at room temperature for30 minutes. To this mixture was added methyl bromoacetate (0.16ml, 1.68 mmol), and the mixture was stirred at room temperaturefor 5 hours. The reaction mixture was combined with ice water,and extracted three times with ethyl acetate. The combinedorganic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (hexane/ethyl acetate, 5:1followed by 1:1) to give the title compound (179 mg, yield 26%). Example 94 Methyl [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]acetatehydrochloride
    [0522] Methyl [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]acetate(179mg, 0.396 mmol) was dissolved in ethyl acetate, a solution of 4 Mhydrogen chloride/ethyl acetate was added thereto, and the mixturewas concentrated under reduced pressure to give the title compound(123 mg, yield 64%) as amorphous.1H NMR (DMSO-d6) δ 1.23 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.44 (6H,s), 2.21 (2H, s), 3.14 (2H, s), 3.69 (3H, s), 4.24 (2H, q, J = 7.0Hz), 4.27 (2H, s), 4.71 (2H, s), 7.08 (1H, s), 7.58-7.65 (4H, m). Example 95 [[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]aceticacid hydrochloride
    [0523] To a solution of methyl [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]acetate(660 mg, 1.46 mmol) in methanol (8 ml)was added 5 M aqueous solution (1.5 ml) of sodium hydroxide, andthe mixture was stirred for 30 minutes at room temperature.Methanol was distilled off under reduced pressure, the residue wascombined with water washed with diisopropyl ether, and acidifiedwith 5 M hydrochloric acid. Acetone was added thereto, the insolubles were removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was crystallizedfrom acetone-diisopropyl ether to give the title compound (594 mg,yield 86%).1H NMR (DMSO-d6) δ 1.24 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.43 (6H,s), 2.22 (2H, s), 3.14 (2H, s), 4.15 (2H, s), 4.23 (2H, q, J = 7.0Hz), 4.70 (2H, s), 7.08 (1H, s), 7.61 (4H, s). Example 96 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester
    [0524] From 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid hydrochlorideand glycine ethyl ester hydrochloride, the title compound wasobtained by the method similar to that in Example 72. Yield 68%.1H NMR (CDCl3) δ 1.25 (6H, s), 1.31 (6H, s), 1.33 (3H, t, J = 7.2Hz), 1.46 (3H, t, J = 7.0 Hz), 2.18 (2H, s), 2.68 (2H, s), 4.19(2H, q, J = 7.0 Hz), 4.23-4.33 (4H, m), 6.61 (1H, s), 6.70 (1H, t,J = 5.0 Hz), 7.49 (2H, d, J = 8.5 Hz), 7.85 (2H, d, J = 8.5 Hz). Example 97 N-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycinehydrochloride
    [0525] From N-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoyl]glycineethyl ester,the title compound was obtained by the method similar to that inExample 95. Yield 94%.Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.37 (3H, t, J = 7.0 Hz), 1.45 (6H,s), 2.21 (2H, s), 3.16 (2H, s), 3.98 (2H, t, J = 5.8 Hz), 4.24 (2H,q, J = 7.0 Hz), 7.09 (1H, s), 7.76 (2H, d, J = 8.5 Hz), 8.13 (2H,d, J = 8.5 Hz), 9.24 (1H, t, J = 5.8 Hz). Example 98 Methyl 5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-((E)-3-methoxy-3-oxo-1-propenyl)benzoate
    [0526] From methyl 5-cyano-2-((E)-3-methoxy-3-oxo-1-propenyl)benzoate,the title compound was obtained by the method similar to that in Example 90. Yield 4%. Example 99 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(methoxycarbonyl)phenyl]-2-propenoicacid
    [0527] The title compound was obtained in Example 98 at the sametime. Yield 14%.1H NMR (CDCl3) δ 1.29 (6H, s), 1.33 (6H, s), 1.48 (3H, t, J = 7.0Hz), 2.23 (2H, s), 2.70 (2H, s), 3.91 (3H, s), 4.20 (2H, q, J =7.0 Hz), 6.35 (1H, d, J = 16.0 Hz), 6.63 (1H, s), 7.64 (1H, d, J =8.0 Hz), 7.69 (1H, d, J = 8.0 Hz), 8.01 (1H, s), 8.49 (1H, d, J =16.0 Hz). Example 100 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate
    [0528] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-a-(1-methylethyl)-5-benzofuranmethanol(0.780 g, 2.94 mmol) and methyl(E)-3-(4-cyanophenyl)-2-propenoate (0.500 g, 2.67 mmol) in aceticacid (4.4 ml)-toluene (5 ml) was added dropwise conc. sulfuricacid (0.37 ml), and the mixture was stirred for 1 hour at 80°C.The reaction solution, which was cooled to room temperature, wascombined with water, and washed with diisopropyl ether. Theaqueous layer was cooled with ice, alkalified with conc. ammoniawater, and extracted with ethyl acetate. The extracts were washedwith water, and concentrated under reduced pressure. The residuewas purified with a silica gel column chromatography (hexane/ethylacetate 1:1) to give the title compound (0.480 g, yield 41%).Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J = 7.0Hz), 2.23 (2H, s), 2.67 (2H, s), 3.82 (3H, s), 4.18 (2H, q, J =7.0 Hz), 6.49 (1H, d, J = 15.8 Hz), 6.61 (1H, s), 7.43 (2H, d, J =8.0 Hz), 7.56 (2H, d, J = 8.0 Hz), 7.73 (1H, d, J = 15.8 Hz). Example 101 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoicacid
    [0529] To a solution of methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate in methanol (5 ml) was added a 2 M aqueous solution(5 ml) of sodium hydroxide, and the mixture was stirred at roomtemperature for 4 hours. The reaction solution was combined with2 M hydrochloric acid (5 ml), and the precipitated crystals weretaken by filtration. This was washed with water and diisopropylether, dried, and recrystallized from methanol-ethyl acetate togive the title compound (0.610 g, yield 70%).1H NMR (DMSO-d6) δ 1.13 (6H, s), 1.22 (6H, s), 1.33 (3H, t, J = 6.8Hz), 2.25 (2H, s), 2.61 (2H, s), 4.09 (2H, q, J = 6.8 Hz), 6.54(1H, d, J = 16.0 Hz), 6.78 (1H, s), 7.31-7.42 (3H, m), 7.61 (2H, d,J = 8.0 Hz). Example 102 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methylphenyl]-2-propenoate
    [0530] To a suspension of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(635 mg, 2.40 mmol) and methyl(E)-3-(4-cyano-2-methylphenyl)-2-propenoate (403 mg, 2.00 mmol) intoluene (3 ml) and acetic acid (1.5 ml) was added dropwise conc.sulfuric acid (0.29 ml, 5.4 mmol), and the mixture was stirred at85°C for 1.5 hours. The reaction mixture was cooled to 65°C,methanol (1.2 ml) was added dropwise thereto, and the mixture wasstirred for 1 hour at the same temperature. After cooling, themixture was added dropwise to sodium hydrogen carbonate (1.4 g, 17mmol), combined with water, and extracted twice with ethyl acetate.The combined organic layer was washed twice with water, andconcentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (hexane/ethyl acetate 2:1)to give the title compound (385 mg, yield 43%).Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.32 (6H, s), 1.47 (3H, t, J = 7.0Hz), 2.25 (2H, s), 2.46 (3H, s), 2.66 (2H, s), 3.82 (3H, s), 4.19(2H, q, J = 7.0 Hz), 6.41 (1H, d, J = 15.9 Hz), 6.61 (1H, s),7.21-7.29 (2H, m), 7.57 (1H, d, J = 8.1 Hz), 8.00 (1H, d, J = 15.9 Hz). Example 103 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methylphenyl]-2-propenoicacid
    [0531] To a solution of methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methylphenyl]-2-propenoate(279 mg, 0.623 mmol) in methanol (1 ml)was added a 5 M aqueous solution of sodium hydroxide (0.24 ml, 1.2mmol), and the mixture was stirred at room temperature for 1.5hours and at 50°C for 1 hour. The reaction mixture was combinedwith 1 M hydrochloric acid (1.2 ml, 1.2 mmol), and extracted twicewith chloroform. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, concentrated under reduced pressure to give thetitle compound (257 mg, yield 95%).Amorphous.1H NMR (DMSO-d6) δ 1.14 (6H, s), 1.23 (6H, s), 1.33 (3H, t, J = 7.0Hz), 2.27 (2H, s), 2.42 (3H, s), 2.62 (2H, s), 4.09 (2H, q, J =7.0 Hz), 6.49 (1H, d, J = 15.9 Hz), 6.79 (1H, s), 7.21 (1H, d, J =7.8 Hz), 7.26 (1H, s), 7.76 (1H, d, J = 7.8 Hz), 7.84 (1H, d, J =15.9 Hz). Example 104 Ethyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-methyl-2-propenoate
    [0532] To a solution of triethyl 2-phosphonopropionate (4.05 g, 17.0mmol) in tetrahydrofuran (15 ml) was added sodium hydride (66%dispersion in oil) (0.62 g, 17 mmol) under ice-cooling, and themixture was stirred at the same temperature for 15 minutes. Tothis mixture was added 4-cyanobenzaldehyde (1.86 g, 14.2 mmol),and the mixture was stirred at room temperature for 30 minutes.The obtained mixture was combined with a solution which had beenseparately prepared from triethyl 2-phosphonopropionate (0.81 g,3.4 mmol), sodium hydride (66% dispersion in oil) (0.12 g, 3.3mmol) and tetrahydrofuran (3 ml) in the same manner, and stirred at room temperature for 30 minutes. The reaction mixture waspoured into a saturated aqueous solution of ammonium chloride, andextracted twice with ethyl acetate. The combined organic layerwas washed twice with water, and concentrated under reducedpressure. The residue was purified with a silica gel columnchromatography (hexane/ethyl acetate, 100:1 followed by 5:1) togive a semi-solid containing ethyl (E)-3-(4-cyanophenyl)-2-methyl-2-propenoate(3.09 g).1H NMR (CDCl3) δ 1.36 (3H, t, J = 7.2 Hz), 2.10 (3H, d, J = 1.2 Hz),4.29 (2H, q, J = 7.2 Hz), 7.47 (2H, d, J = 8.1 Hz), 7.64-7.66 (1H,m), 7.69 (2H, d, J = 8.1 Hz).
    [0533] This product (972 mg) and 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1.43 g, 5.41 mmol) weresuspended in toluene (7 ml) and acetic acid (3.5 ml), and conc.sulfuric acid (0.66 ml, 12 mmol) was added dropwise thereto. Theresultant mixture was stirred at 85°C for 1.5 hours. To thereaction mixture was added dropwise ethanol (5 ml), and themixture was stirred for 1 hour at the same temperature. Aftercooling, the mixture was added dropwise to sodium hydrogencarbonate (3.12 g, 37.1 mmol), combined with water, and extractedtwice with ethyl acetate. The combined organic layer was washedwith water and a saturated aqueous solution of sodium chloride,dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified with a silica gelcolumn chromatography (hexane/ethyl acetate, 20:1 followed by 5:1),and crystallized from hexane to give the title compound (734 mg,yield 35%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.32 (6H, s), 1.36 (3H, t, J = 7.1Hz), 1.47 (3H, t, J = 6.9 Hz), 2.13 (3H, d, J = 1.5 Hz), 2.22 (2H,s), 2.67 (2H, s), 4.19 (2H, q, J = 7.0 Hz), 4.28 (2H, q, J = 7.1Hz), 6.61 (1H, s), 7.43 (4H, s), 7.72 (1H, q, J = 1.5 Hz). Example 105 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-methyl-2-propenoicacid
    [0534] To a suspension of ethyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-methyl-2-propenoate (300 mg, 0.65 mmol) in ethanol (1.5 ml) wasadded a 5 M aqueous solution of sodium hydroxide (0.26 ml, 1.3mmol), and the mixture was stirred at 50°C for 1.5 hours. Thereaction mixture was combined with 1 M hydrochloric acid (1.3 ml,1.3 mmol) under ice-cooling, and extracted twice with chloroform.The combined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue wasrecrystallized from ethyl acetate-diethyl ether to give the titlecompound (190 mg, yield 67%).1H NMR (DMSO-d6) δ 1.14 (6H, s), 1.23 (6H, s), 1.33 (3H, t, J = 6.8Hz), 2.07 (3H, s), 2.24 (2H, s), 2.62 (2H, s), 4.09 (2H, q, J =6.8 Hz), 6.79 (1H, s), 7.40 (2H, d, J = 7.4 Hz), 7.51 (2H, d, J =7.4 Hz), 7.64 (1H, s), 12.57 (1H, br s). Example 106 Ethyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-butenoate
    [0535] 7-Ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(793 mg, 3.00 mmol) and ethyl (E)-3-(4-cyanophenyl)-2-butenoate(538 mg, 2.50 mmol) were suspended intoluene (4 ml) and acetic acid (2 ml), conc. sulfuric acid (0.37ml, 6.9 mmol) was added dropwise thereto, and the mixture wasstirred at 85°C for 1.5 hours. To the reaction mixture was addeddropwise ethanol (3 ml), and the mixture was stirred for 2 hoursat the same temperature. After cooling, the mixture was addeddropwise to sodium hydrogen carbonate (1.75 g, 20.8 mmol),combined with water, and extracted twice with ethyl acetate. Thecombined organic layer was washed with water and a saturatedaqueous solution of sodium chloride, and concentrated underreduced pressure. The residue was purified with a silica gelcolumn chromatography (hexane/ethyl acetate, 5:1 followed by 2:1)to give the title compound (413 mg, yield 36%).Amorphous.1H NMR (CDCl3) δ 1.24 (6H, s), 1.32 (6H, s), 1.33 (3H, t, J = 7.2 Hz), 1.47 (3H, t, J = 7.1 Hz), 2.23 (2H, s), 2.59 (3H, d, J = 1.4Hz), 2.67 (2H, s), 4.14-4.23 (2H, m), 4.23 (2H, q, J = 7.1 Hz),6.19 (1H, q, J = 1.4 Hz), 6.61 (1H, s), 7.41 (2H, d, J = 8.6 Hz),7.51 (2H, d, J = 8.6 Hz). Example 107 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-butenoicacid
    [0536] To a solution of ethyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-butenoate(206 mg, 0.446 mmol) in ethanol (1.5 ml) was added a 5 M aqueoussolution of sodium hydroxide (0.18 ml, 0.90 mmol), and the mixturewas stirred at room temperature for 4 hours and at 50°C for 4hours. The reaction mixture was cooled, combined with 1 Mhydrochloric acid (0.90 ml, 0.90 mmol), and extracted twice withchloroform. The combined organic layer was washed with asaturated aqueous solution of sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. Theresidue was crystallized from ethyl acetate-diethyl ether-hexaneto give the title compound (40 mg, yield 21%).1H NMR (DMSO-d6) δ 1.13 (6H, s), 1.23 (6H, s), 1.33 (3H, t, J = 7.1Hz), 2.25 (2H, s), 2.50-2.53 (3H, m), 2.61 (2H, s), 4.09 (2H, q, J= 7.1 Hz), 6.18-6.21 (1H, m), 6.79 (1H, s), 7.38 (2H, d, J = 8.4Hz), 7.61 (2H, d, J = 8.4 Hz), 12.20-12.40 (1H, br). Example 108 Ethyl (Z)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-butenoate
    [0537] With ethyl (Z)-3-(4-cyanophenyl)-2-butenoate, the titlecompound was obtained by the method similar to that in Example 106.Yield 29%.1H NMR (CDCl3) δ 1.18 (3H, t, J = 7.1 Hz), 1.24 (6H, s), 1.33 (6H,s), 1.46 (3H, t, J = 7.1 Hz), 2.16 (3H, d, J = 1.3 Hz), 2.28 (2H,s), 2.67 (2H, s), 4.02 (2H, q, J = 7.1 Hz), 4.18 (2H, q, J = 7.0Hz), 5.92 (1H, q, J = 1.3 Hz), 6.59 (1H, s), 7.22 (2H, d, J = 8.4Hz), 7.36 (2H, q, J = 8.4 Hz). Example 109 Ethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenepropanoate
    [0538] To a solution of ethyl (E)-3-(4-cyanophenyl)-2-propenoate(8.04 g, 40.0 mmol) in ethyl acetate (40 ml) was added 10%palladium/carbon (50% water-containing product) (0.80 g), and themixture was stirred under hydrogen atmosphere at room temperaturefor 80 minutes. The catalyst was filtered, and the filtrate wasconcentrated under reduced pressure to give oil matter (8.36 g)containing ethyl 4-cyanobenzenepropanoate.
    [0539] This substance and 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(10.6 g, 40.1 mmol) weredissolved in toluene (40 ml) and acetic acid (20 ml), and conc.sulfuric acid (5.9 ml, 0.11 mol) was added dropwise thereto. Theresultant mixture was stirred at 85°C for 1.5 hours. To thereaction mixture was added dropwise ethanol (20 ml), and themixture was stirred for 1 hour at the same temperature. Aftercooling, the mixture was added dropwise to sodium hydrogencarbonate (24.5 g, 0.292 mol), and ethyl acetate and water wereadded thereto. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined organiclayer was washed with water and a saturated aqueous solution ofsodium chloride, dried through sodium sulfate-basic silica gel(eluting with ethyl acetate), and concentrated under reducedpressure. The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate, 10:1 followed by 3:1) togive the title compound (3.42 g, yield 19%).Oily matter.1H NMR (CDCl3) δ 1.23 (6H, s), 1.25 (3H, t, J = 7.2 Hz), 1.31 (6H,s), 1.46 (3H, t, J = 7.1 Hz), 2.19 (2H, s), 2.61 (2H, t, J = 7.7Hz), 2.65 (2H, s), 2.98 (2H, t, J = 7.7 Hz), 4.13 (2H, q, J = 7.1Hz), 4.18 (2H, q, J = 7.1 Hz), 6.59 (1H, s), 7.21 (2H, d, J = 8.4Hz), 7.31 (2H, d, J = 8.4 Hz). Example 110 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenepropanoicacid
    [0540] To a solution of ethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzenepropanoate(450 mg, 1.00 mmol) in ethanol (1 ml) was added 5 M aqueoussolution of sodium hydroxide (0.40 ml, 2.0 mmol), and the mixturewas stirred at room temperature for 4.5 hours. The reactionmixture was combined with 1 M hydrochloric acid (2.0 ml, 2.0 mmol)under ice-cooling, and extracted twice with chloroform. Thecombined organic layer was washed with a saturated aqueoussolution of sodium chloride, dried over sodium sulfate, filtered,concentrated under reduced pressure to give the title compound(418 mg, yield 99%).Amorphous.1H NMR (DMSO-d6) δ 1.12 (6H, s), 1.21 (6H, s), 1.32 (3H, t, J = 6.9Hz), 2.18 (2H, s), 2.55 (2H, t, J = 7.5 Hz), 2.61 (2H, s), 2.87(2H, t, J = 7.5 Hz), 4.08 (2H, q, J = 6.9 Hz), 6.78 (1H, s), 7.25(4H, s), 12.15 (1H, br s). Example 111 6-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2H-1,4-benzoxazin-3(4H)-one
    [0541] To a suspension of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1.03 g, 3.90 mmol) and methyl(2-amino-4-cyanophenoxy)acetate (730 mg, 3.54 mmol) in toluene (4ml), a solution of conc. sulfuric acid (0.71 ml, 13 mmol) inacetic acid (2 ml) was added dropwise under ice-cooling, and themixture was stirred for 1 hour at 85°C. The reaction mixture wascombined with water, washed with diisopropyl ether, neutralizedwith sodium hydrogen carbonate, and extracted twice with ethylacetate. The combined organic layer was washed with water (twice)and a saturated aqueous solution of sodium chloride, dried throughsodium sulfate-basic silica gel (eluting with ethyl acetate), andconcentrated under reduced pressure. The residue was crystallizedfrom ethyl acetate-diethyl ether to give the title compound (775mg, yield 52%).1H NMR (CDCl3) δ 1.23 (6H, br s), 1.35 (6H, s), 1.47 (3H, t, J =6.9 Hz), 3.32 (2H, s), 2.66 (2H, s), 4.18 (2H, q, J = 6.9 Hz), 4.62 (2H, s), 6.60 (1H, s), 6.91-6.98 (3H, m), 8.46 (1H, br s) . Example 112 6-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-4-(phenylmethyl)-2H-1,4-benzoxazin-3(4H)-one
    [0542] To a suspension of 6-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2H-1,4-benzoxazin-3(4H)-one(631 mg, 1.50 mmol) in N,N-dimethylformamide (3 ml) was addedsodium hydride (66% dispersion in oil) (66 mg, 1.8 mmol), and themixture was stirred at room temperature for 40 minutes. Theobtained mixture was combined with benzyl bromide (0.23 ml, 1.9mmol), and stirred at room temperature for 40 minutes. Thereaction mixture was combined with water, and extracted twice withethyl acetate. The combined organic layer was washed twice withwater, and concentrated under reduced pressure. The residue wascrystallized from ethyl acetate-diethyl ether to give the titlecompound (502 mg, yield 66%).1H NMR (CDCl3) δ 1.19 (6H, br s), 1.22 (6H, s), 1.45 (3H, t, J =7.1 Hz), 1.95 (2H, br s), 2.62 (2H, s), 4.17 (2H, q, J = 7.1 Hz),4.72 (2H, s), 5.00-5.20 (2H, br), 6.57 (1H, s), 6.94 (1H, dd, J =8.3, 1.4 Hz), 6.98 (1H, d, J = 8.3 Hz), 7.02 (1H, d, J = 1.4 Hz),7.13-7.28 (5H, m). Example 113 Sodium [4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]phenoxy]acetate
    [0543] To a suspension of 6-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-4-(phenylmethyl)-2H-1,4-benzoxazin-3(4H)-one(409 mg, 0.801 mmol) in ethanol (1 ml) wasadded a 5 M aqueous solution of sodium hydroxide (160 µl, 0.800mmol), and the mixture was heated under reflux for 20 hours. Tothe obtained mixture was further added 5 M aqueous solution ofsodium hydroxide (160 µl, 0.800 mmol), and the mixture was heatedunder reflux for 7 hours. After cooling, the reaction mixture wascombined with ethanol and diethyl ether, and crystallized to givethe title compound. 1H NMR (CDCl3) δ 1.06 (6H, s), 1.19 (6H, s), 1.31 (3H, t, J = 6.7Hz), 2.25 (2H, s), 2.53 (2H, s), 4.05 (2H, q, J = 6.7 Hz), 4.11(2H, s), 4.26 (2H, d, J = 4.8 Hz), 6.12-6.24 (1H, m), 6.40 (1H, s),6.45 (1H, d, J = 8.4 Hz), 6.66-6.72 (2H, m), 7.16-7.37 (5H, m). Example 114 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetate
    [0544] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1067 mg, 4.04 mmol) and methyl4-cyanobenzeneacetate (701 mg, 4.00 mmol) in toluene (4 ml) andacetic acid (2 ml) was cooled with ice, and conc. sulfuric acid(0.64 ml) was added dropwise thereto. The resultant mixture wasstirred for 2 hours at 80°C. The reaction mixture was combinedwith methanol (2 ml), and the mixture was stirred at 60°C for 45minutes. The resultant mixture was cooled, the aqueous layer wasseparated by adding water, and the organic layer was extractedwith water. The combined aqueous layer was combined with anaqueous solution of 10% potassium carbonate, alkalified, andextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The residue was subjected toa basic alumina column chromatography (hexane/ethyl acetate, 10:1followed by 2:1), and crystallized from diisopropyl ether-hexaneto give the title compound (285 mg, yield 17%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.46 (3H, t), 2.21 (2H,s), 2.66 (2H, s), 3.66 (2H, s), 3.68 (3H, s), 4.18 (2H, q), 6.60(1H, s), 7.29 (2H, d), 7.35 (2H, d). Example 115 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneaceticacid
    [0545] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzeneacetate(285mg, 0.676 mmol) in methanol (3 ml) was added a 1 M aqueoussolution (2 ml) of sodium hydroxide, and the mixture was stirredat room temperature for 6 hours. The reaction solution was combined with 1 M hydrochloric acid, and further with 1 Mhydrochloric acid until the pH become 4, and extracted withchloroform. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure. The resultant crude crystals were crystallized fromethyl acetate-hexane to give the title compound (251 mg, yield91%).1H NMR (CDCl3) δ 1.30 (6H, br s), 1.45 (6H, s), 1.47 (3H, t), 2.14(2H, s), 2.81 (2H, s), 3.58 (2H, s), 4.21 (2H, q), 6.63 (1H, s),7.26 (2H, d), 7.37 (2H, d). Example 116 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneacetate
    [0546] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1462 mg, 5.52 mmol) and methyl4-cyano-α,α-dimethylbenzeneacetate (1121 mg, 5.53 mmol) in toluene(4 ml) and acetic acid (2 ml) was cooled with ice, and conc.sulfuric acid (0.80 ml) was added dropwise thereto. The resultantmixture was stirred for 2 hours at 80°C. To the reaction mixturewas added dropwise methanol (2 ml), and the mixture was stirred at60°C for 45 minutes. The resultant mixture was cooled, theaqueous layer was separated by adding water, and the organic layerwas extracted with water. The combined aqueous layer was combinedwith an aqueous solution of 10% potassium carbonate, alkalified,and extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The residue was subjected toa basic alumina column chromatography (hexane/ethyl acetate, 10:1followed by 2:1) and purified with a silica gel columnchromatography (hexane/ethyl acetate 1:1), and recrystallized fromethyl acetate-hexane to give the title compound (799 mg, yield32%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.30 (6H, s), 1.46 (3H, t), 1.59 (6H,s), 2.18 (2H, s), 2.66 (2H, s), 3.63 (3H, s), 4.18 (2H, q), 6.60(1H, s), 7.33 (4H, s). Example 117 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneaceticacid
    [0547] The separated fractions obtained by eluting withmethanol/ethyl acetate (1:1) in basic alumina columnchromatography in Example 116 were recrystallized from acetone-hexaneto give the title compound (348 mg, yield 14%).1H NMR (DMSO-d6) δ 1.13 (6H, br s), 1.21 (6H, s), 1.34 (3H, t),1.51 (6H, s), 2.17 (2H, s), 2.59 (2H, s), 4.09 (2H, q), 6.75 (1H,s), 7.29 (2H, d), 7.37 (2H, d). Example 118 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneaceticacid hydrochloridehydrate
    [0548] To a mixed solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneacetate(507 mg, 1.13 mmol) in methanol (6 ml) andtetrahydrofuran (6 ml) was added a 1 M aqueous solution (4 ml) ofsodium hydroxide, and the mixture was stirred at room temperaturefor 6 hours. The reaction solution was combined with 1 Mhydrochloric acid, and further with 1 M hydrochloric acid untilthe pH 4, and extracted with ethyl acetate. The organic layer waswashed with a saturated aqueous solution of sodium chloride, dried,and concentrated under reduced pressure. The resultant crudecrystals were recrystallized from ethanol-diisopropyl ether togive the title compound (366 mg, yield 66%).1H NMR (DMSO-d6) δ 1.23 (6H, br s), 1.40 (3H, t), 1.44 (6H, s),1.56 (6H, s), 2.15 (2H, s), 3.13 (2H, s), 4.24 (2H, q), 7.05 (1H,s), 7.55 (2H, d), 7.61 (2H, d). Example 119 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-N,α,α-trimethylbenzeneacetamide hydrochloride
    [0549] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (311 mg, 0.635 mmol), methylamine hydrochloride (65 mg, 0.963 mmol) and 1-hydroxy-1H-benzotriazolemonohydrate (115 mg, 0.751 mmol) in N,N-dimethylformamide (3 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (150 mg, 0.782 mmol) and triethylamine (0.42 ml),and the mixture was stirred at room temperature for 24 hours. Thereaction mixture was combined with a saturated aqueous solution ofsodium hydrogen carbonate, and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried, and concentrated under reduced pressure.The residue was subjected to a silica gel column chromatography(hexane/ethyl acetate 1:2) to prepare hydrochloride. Thehydrochloride was recrystallized from ethanol-diisopropyl ether togive the title compound (290 mg, yield 94%).1H NMR (Free form, CDCl3) δ 1.24 (6H, s), 1.31 (6H, s), 1.46 (3H,t), 1.60 (6H, s), 2.18 (2H, s), 2.66 (2H, s), 2.68 (3H, d), 4.18(2H, q), 5.09 (1H, br s), 6.60 (1H, s), 7.37 (4H, s). Example 120 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneacetamide
    [0550] To a solution of 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneaceticacid hydrochloride hydrate (306 mg, 0.624 mmol) and 1-hydroxy-1H-benzotriazoleammonium salt (119 mg, 0.782 mmol) in acetonitrile(10 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (146 mg, 0.762 mmol) and triethylamine (0.22 ml),and the mixture was stirred at room temperature for 14 hours. Thereaction mixture was combined with a saturated aqueous solution ofsodium hydrogen carbonate, and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried, and concentrated under reduced pressure.The residue was purified with a silica gel column chromatography(hexane/ethyl acetate 1:3). The resultant crude crystals wererecrystallized from ethyl acetate-hexane to give the titlecompound (242 mg, yield 89%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.30 (6H, s), 1.46 (3H, t), 1.61 (6H, s), 2.18 (2H, s), 2.66 (2H, s), 4.17 (2H, q), 5.13 (1H, br s),5.18 (1H, br s), 6.59 (1H, s), 7.36-7.43 (4H, m). Example 121 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-nitrobenzeneacetate
    [0551] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1463 mg, 5.53 mmol) and methyl4-cyano-2-nitrobenzeneacetate (1103 mg, 5.00 mmol) in toluene (6ml) and acetic acid (3 ml) was cooled with ice, and conc. sulfuricacid (0.8 ml) was added dropwise thereto. The resultant mixturewas stirred for 2 hours at 80°C. To the reaction mixture wasadded methanol (3 ml), and the mixture was stirred for 1 hour at60°C. The resultant mixture was cooled, the aqueous layer wasseparated by adding water, and the organic layer was extractedwith water. The combined aqueous layer was combined with anaqueous solution of 10% potassium carbonate, alkalified, andextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (hexane/ethyl acetate 1:2).The resultant crude crystals were recrystallized from ethylacetate-hexane to give the title compound (898 mg, yield 38%).1H NMR (CDCl3) δ 1.25 (6H, s), 1.34 (6H, s), 1.47 (3H, t), 2.25 (2H,s), 2.68 (2H, s), 3.71 (3H, s), 4.07 (2H, s), 4.20 (2H, q), 6.63(1H, s), 7.38 (1H, d), 7.66 (1H, dd), 8.19 (1H, d). Example 122 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-nitrobenzeneaceticacid
    [0552] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-nitrobenzeneacetate(618 mg, 1.32 mmol) in methanol (6 ml) wasadded 1 M aqueous solution (3 ml) of sodium hydroxide, and themixture was stirred at room temperature for 5 hours. The reactionsolution was combined with 1 M hydrochloric acid (3 ml) andextracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The resultant crude crystalswere recrystallized from ethanol-diisopropyl ether to give thetitle compound (570 mg, yield 95%).1H NMR (DMSO-d6) δ 1.21 (6H, br s), 1.26 (6H, br s), 1.35 (3H, t),2.28 (2H, s), 2.60 (2H, s), 3.35 (2H, s), 4.05-4.21 (2H, m), 6.86(1H, br s), 7.48-7.80 (2H, m), 7.91-8.20 (1H, m). Example 123 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzeneacetate
    [0553] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(992 mg, 3.75 mmol), methyl 4-cyano-2-[(2-pyridinylcarbonyl)amino]benzeneacetate(1001 mg, 3.34mmol) in toluene (4 ml) and acetic acid (2 ml) was cooled with ice,and conc. sulfuric acid (0.54 ml) was added dropwise thereto. Theresultant mixture was stirred for 2 hours at 80°C. The reactionmixture was combined with methanol (2 ml), and stirred for 2 hoursat 60°C. The resultant mixture was cooled, the aqueous layer wasseparated by adding water, and the organic layer was extractedwith water. The combined aqueous layer was combined with anaqueous solution of 10% potassium carbonate, alkalified, andextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The residue was purifiedwith a basic silica gel column chromatography (hexane/ethylacetate 1:1) to give the title compound (356 mg, yield 19%).Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.35 (6H, s), 1.46 (3H, t), 2.48 (2H,br s), 2.65 (2H, s), 3.68-3.81 (2H, m), 3.73 (3H, s), 4.18 (2H, q),6.59 (1H, s), 7.28-7.34 (2H, m), 7.44-7.52 (1H, m), 7.89 (1H, dt),8.07 (1H, d), 8.26 (1H, d), 8.62-8.69 (1H, m), 10.55 (1H, s). Example 124 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzeneaceticacid
    [0554] To a solution of methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzeneacetate(135 mg, 0.25 mmol) inmethanol (1 ml) was added 1 M aqueous solution (0.5 ml) of sodiumhydroxide, and the mixture was stirred at room temperature for 14hours. The reaction solution was combined with 1 M hydrochloricacid (0.5 ml) and extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium chloride,dried, and concentrated under reduced pressure. The resultantcrude crystals were recrystallized from ethanol-diisopropyl etherto give the title compound (66 mg, yield 50%).1H NMR (DMSO-d6) δ 1.14 (6H, br s), 1.25 (6H, br s), 1.34 (3H, t),2.50 (2H, br s), 2.62 (2H, s), 3.73 (2H, s), 4.10 (2H, q), 6.75(1H, s), 7.20 (1H, d), 7.37 (1H, d), 7.61-7.68 (1H, m), 7.76 (1H,s), 8.04 (1H, t), 8.12 (1H, d), 8.68 (1H, d), 10.54 (1H, s). Example 125 6-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1,3-dihydro-2H-indol-2-one
    [0555] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(2114 mg, 8.00 mmol) and methyl4-cyano-2-(trifluoroacetylamino)benzeneacetate (2065 mg, 7.21mmol) in toluene (8 ml) and acetic acid (4 ml) was cooled with ice,and conc. sulfuric acid (1.2 ml) was added dropwise thereto. Theresultant mixture was stirred for 1 hour at 80°C. The reactionmixture was combined with methanol (5 ml), and stirred for 1 hourat 60°C. The resultant mixture was cooled, the aqueous layer wasseparated by adding water, and the organic layer was extractedwith water. The combined aqueous layer was combined with anaqueous solution of 10% potassium carbonate, alkalified, andextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The residue was subjected toa basic alumina column chromatography (ethyl acetate/methanol10:1) and purified with a silica gel column chromatography (ethylacetate). The resultant crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (542 mg, yield19%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.34 (6H, s), 1.46 (3H, t), 2.30 (2H,s), 2.66 (2H, s), 3.56 (2H, s), 4.19 (2H, q), 6.60 (1H, s), 6.97-7.04(2H, m), 7.20 (1H, d), 8.05 (1H, br s). Example 126 6-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1,3-dihydro-3,3-dimethyl-2H-indol-2-one
    [0556] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(1500 mg, 5.67 mmol) and 6-cyano-1,3-dihydro-3,3-dimethyl-2H-indol-2-one(955 mg, 5.13 mmol)in toluene (5 ml) and acetic acid (2.5 ml) was cooled with ice,and conc. sulfuric acid (0.82 ml) was added dropwise thereto. Theresultant mixture was stirred at 80°C for 85 minutes. Theresultant mixture was cooled, the aqueous layer was separated byadding water, and the organic layer was extracted with water. Thecombined aqueous layer was combined with an aqueous solution of10% potassium carbonate, alkalified, and extracted with ethylacetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure. The residue was purified with a basic silica gel columnchromatography (ethyl acetate). The resultant crude crystals werewashed with diisopropyl ether to give the title compound (66 mg,yield 3%).1H NMR (CDCl3) δ 1.24 (6H, br s), 1.33 (6H, s), 1.40 (6H, s), 1.47(3H, t), 2.28 (2H, s), 2.66 (2H, s), 4.19 (2H, q), 6.60 (1H, s),6.99-7.05 (2H, m), 7.16 (1H, d), 7.82 (1H, s). Example 127 Methyl (E)-3-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate
    [0557] A solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(2550 mg, 9.65 mmol) and methyl3-(2-amino-4-cyanophenyl)-2-propenoate (1771 mg, 8.76 mmol) intoluene (5 ml) and acetic acid (2.5 ml) was cooled with ice, andconc. sulfuric acid (0.82 ml) was added dropwise thereto. The resultant mixture was stirred at 80°C for 85 minutes. Theresultant mixture was cooled, the aqueous layer was separated byadding water, and the organic layer was extracted with water. Thecombined aqueous layer was combined with an aqueous solution of10% potassium carbonate, alkalified, and extracted with ethylacetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure. The residue was purified with a silica gel columnchromatography (ethyl acetate) and basic alumina columnchromatography (hexane/ethyl acetate 4:1). The resultant crudecrystals were washed with diisopropyl ether to give the titlecompound (895 mg, yield 23%).1H NMR (CDCl3) δ 1.22 (6H, br s), 1.34 (6H, s), 1.46 (3H, t), 2.36(2H, s), 2.65 (2H, s), 3.81 (3H, s), 4.00 (2H, s), 4.18 (2H, q),6.39 (1H, d), 6.59 (1H, s), 6.72-6.82 (2H, m), 7.39 (1H, d), 7.84(1H, d). Example 128 7-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-quinolinol
    [0558] The separated fractions obtained by eluting with methanol inbasic alumina column chromatography in Example 127 wererecrystallized from ethanol-diisopropyl ether to give the titlecompound (43 mg, yield 1%).1H NMR (CDCl3) δ 1.26 (6H, br s), 1.30 (6H, s), 1.47 (3H, t), 2.22(2H, s), 2.69 (2H, s), 4.19 (2H, q), 6.63 (1H, s), 6.71 (1H, d),7.22 (1H, dd), 7.40 (1H, s), 7.57 (1H, d), 7.82 (1H, d), 11.13 (1H,br s). Example 129 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]phenyl]-2-propenoate
    [0559] To a solution of methyl (E)-3-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate(711 mg, 1.59 mmol) and 4-(dimethylamino)pyridine(596 mg, 4.88 mmol) in N,N-dimethylformamide (5 ml) was added picolinic acid chloride hydrochloride (481 mg, 2.70 mmol), and themixture was stirred at room temperature for 20 minutes. Theobtained mixture was alkalified by adding an aqueous solution of10% potassium carbonate, and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried, and concentrated under reduced pressure.The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate 1:1). The resultant crudecrystals were recrystallized from ethyl acetate-hexane to give thetitle compound (570 mg, yield 65%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.34 (6H, s), 1.46 (3H, t), 2.45 (2H,s), 2.66 (2H, s), 3.83 (3H, s), 4.19 (2H, q), 6.54 (1H, d), 6.60(1H, d), 7.24-7.33 (1H, m), 7.46-7.55 (1H, m), 7.64 (1H, d), 7.86-7.95(1H, m), 8.00 (1H, d), 8.18 (1H, d), 8.26 (1H, d), 8.66 (1H,d), 10.23 (1H, s). Example 130 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]phenyl]-2-propenoicacid
    [0560] To a solution of methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]phenyl]-2-propenoate(417 mg, 0.753 mmol)in methanol (5 ml) was added 1 M aqueous solution (1.6 ml) ofsodium hydroxide, and the mixture was stirred at room temperaturefor 5 hours. The reaction solution was combined with 1 Mhydrochloric acid (1.6 ml) and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried, and concentrated under reduced pressure.The resultant crude crystals were suspended in methanol to givethe title compound (362 mg, yield 89%).1H NMR (CDCl3) δ 1.29 (6H, br s), 1.31 (6H, br s), 1.46 (3H, t),2.41 (2H, br s), 2.69 (2H, s), 4.19 (2H, q), 6.41 (1H, d), 6.60(1H, s), 7.18-7.26 (1H, m), 7.32-7.41 (1H, m), 7.54 (1H, d), 7.70-7.82(2H, m), 8.10-8.20 (2H, m), 8.55 (1H, d), 10.21 (1H, s). Example 131 Methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(1H-indol-2-ylcarbonyl)amino]phenyl]-2-propenoate
    [0561] To a solution of indole-2-carboxylic acid (110 mg, 0.683mmol) in tetrahydrofuran (2 ml) were added oxalyl chloride (0.07ml) and N,N-dimethylformamide (1 drop) at 0°C, and the mixture wasstirred at room temperature for 30 minutes. The solvent wasdistilled off under reduced pressure, and the residue wasdissolved again in tetrahydrofuran (2 ml), and added to a solutionof methyl (E)-3-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate(254mg, 0.549 mmol) and triethylamine (0.09 ml) in tetrahydrofuran (3ml). The reaction mixture was stirred at room temperature for 1hour. The obtained mixture was combined with an aqueous solutionof 10% potassium carbonate, and extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried, and concentrated under reduced pressure.The residue was purified with a silica gel column chromatography(hexane/ethyl acetate 1:1) to give the title compound (305 mg,yield 94%).Amorphous.1H NMR (CDCl3) δ 1.33 (6H, s), 1.35 (6H, s), 1.48 (3H, t), 2.14 (2H,s), 2.75 (2H, s), 3.78 (3H, s), 4.20 (2H, q), 6.44 (1H, d), 6.61(1H, s), 7.10-7.20 (3H, m), 7.26-7.35 (1H, m), 7.43 (1H, d), 7.59-7.68(2H, m), 7.77 (1H, s), 7.84 (1H, d), 8.85 (1H, br s), 9.65(1H, br s). Example 132 (E)-3-[4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(1H-indol-2-ylcarbonyl)amino]phenyl]-2-propenoicacid
    [0562] To a mixed solution of methyl (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(1H-indol-2-ylcarbonyl)amino]phenyl]-2-propenoate(300 mg, 0.507 mmol)in methanol (2 ml) and tetrahydrofuran (2 ml) was added in 1 Maqueous solution (2.5 ml) of sodium hydroxide, and the mixture was stirred at room temperature for 14 hours. The reaction solutionwas combined with 1 M hydrochloric acid (2.5 ml) and extractedwith ethyl acetate. The organic layer was washed with a saturatedaqueous solution of sodium chloride, dried, and concentrated underreduced pressure. The resultant crude crystals wererecrystallized from ethanol-diisopropyl ether to give the titlecompound (171 mg, yield 58%).1H NMR (CD3OD) δ 1.34 (6H, s), 1.45 (6H, s), 1.45 (3H, t), 2.2-2.8(2H, m), 3.06 (2H, s), 4.26 (2H, q), 6.67 (1H, d), 6.93 (1H, s),7.09 (1H, t), 7.26 (1H, t), 7.37 (1H, s), 7.47 (2H, d), 7.66 (1H,d), 7.74 (1H, d), 7.90 (1H, d), 8.02 (1H, d). Example 133 Ethyl (E)-3-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate
    [0563] With ethyl (E)-3-(2-amino-4-cyanophenyl)-2-propenoate, thetitle compound was obtained by the method similar to that inExample 90. Yield 22%.Oily matter.1H NMR (CDCl3) δ 1.23 (6H, s), 1.34 (6H, s), 1.34 (3H, t, J = 7.0Hz), 1.46 (3H, t, J = 7.0 Hz), 2.36 (2H, s), 2.65 (2H, s), 4.01(2H, s), 4.22 (2H, q, J = 7.0 Hz), 4.27 (2H, q, J = 7.0 Hz), 6.39(1H, d, J = 15.8 Hz), 6.59 (1H, s), 6.74-6.80 (2H, m), 7.39 (1H, d,J = 8.0 Hz), 7.83 (1H, d, J = 15.8 Hz). Example 134 Ethyl (E)-3-[2-[[[(2-ethoxy-2-oxoethyl)amino]carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate
    [0564] From ethyl (E)-3-[2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate,the title compound was obtained by the method similarto that in Example 35. Yield 84%.1H NMR (CDCl3) δ 1.26-1.34 (18H, m), 1.46 (3H, t, J = 6.9 Hz), 2.27(2H, s), 2.69 (2H, br s), 3.99-4.06 (2H, m), 4.16-4.28 (6H, m),5.92 (1H, br s), 6.29 (1H, d, J = 15.8 Hz), 6.57 (1H, s), 6.94 (1H,d, J = 8.0 Hz), 7.38 (1H, d, J = 8.0 Hz), 7.53 (1H, s), 7.76 (1H, br s), 7.79 (1H, d, J = 15.8 Hz). Example 135 Methyl (E)-3-[2-(2,5-dioxo-1-imidazolidinyl)-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate
    [0565] From ethyl (E)-3-[2-[[[(2-ethoxy-2-oxoethyl)amino]carbonyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-propenoate,the title compound was obtained by the method similarto that in Example 36. Yield 17%.1H NMR (CDCl3) δ 1.20 (6H, s), 1.29 (6H, s), 1.39 (3H, t, J = 6.9Hz), 2.40 (2H, br s), 2.56 (1H, d, J = 15.3 Hz), 2.61 (1H, d, J =15.3 Hz), 3.72 (3H, s), 4.04 (1H, d, J = 21.3 Hz), 4.10-4.21 (3H,m), 6.44 (1H, d, J = 15.9 Hz), 6.52 (1H, s), 7.18 (1H, s), 7.28(1H, br s), 7.49 (1H, d, J = 15.9 Hz), 7.51 (1H, d, J = 8.1 Hz),7.72 (1H, d, J = 8.1 Hz). Example 136 Dimethyl 7-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-1,4-dihydro-2-oxo-3,4(2H)-quinazolinediacetatehydrochloride
    [0566] The free base of the title compound was obtained in Example135 at the same time. This was dissolved in ethyl acetate, asolution of 4 M hydrogen chloride/ethyl acetate was added thereto,and the mixture was concentrated under reduced pressure to givethe title compound. Yield 10%.Amorphous.1H NMR (DMSO-d6) δ 1.25 (3H, s), 1.28 (3H, s), 1.37 (3H, t, J = 7.0Hz), 1.41 (3H, s), 1.45 (3H, s), 2.10-3.25 (6H, m), 3.35 (3H, s),3.64 (3H, s), 4.05-4.42 (4H, m), 5.00-5.15 (1H, m), 6.94 (0.6H, s),7.00 (0.4H, s), 7.08 (1H, s), 7.12 (1H, d, J = 8.1 Hz), 7.37 (1H,d, J = 8.1 Hz), 9.89 (1H, s). Example 137 Methyl 2-[(3-chlorophenylmethyl)(trifluoroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0567] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(519 mg, 1 mmol), m-chlorobenzylbromide (300 mg, 1.46 mmol), potassium carbonate (600 mg, 4.35mmol) and sodium iodide (100 mg, 0.66 mmol) were stirred in N,N-dimethylformamide(4 ml) at the bath temperature of 50 to 55°C for0.5 hour. The reaction solution was cooled to room temperature,and thioglycolic acid (0.1 ml) was added thereto, and the mixturewas stirred for 15 minutes. The reaction solution was combinedwith water/a saturated aqueous solution of sodium chloride (2:1)and ethyl acetate/hexane (2:1), and mixed with stirring toseparate the layers. The upper layer was washed with water andconcentrated under reduced pressure. The residue was dissolvedagain in methanol and concentrated under reduced pressure to givethe title compound (638 mg, yield 99%).Amorphous.1H NMR (CDCl3) δ 1.20 (3H, s), 1.25 (3H, s), 1.28 (3H, s), 1.30 (3H,s), 1.45 (3H, t), 2.14 (2H, dd), 2.65 (2H, dd), 3.75 (3H, s), 4.17(2H, q), 4.56 (1H, d), 5.07 (1H, d), 6.59 (1H, d), 7.08-7.28 (5H,m), 7.50 (1H, dd), 8.06 (1H, dd). Example 138 Methyl 2-[(3-chlorophenyl)methylamino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0568] Methyl 2-[(3-chlorophenylmethyl)(trifluoroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(630 mg, 0.98 mmol) was dissolved inmethanol (10 ml), potassium carbonate (500 mg, 3.62 mmol) wasadded thereto, and the mixture was stirred at room temperature for17 hours. The mixture was further stirred at the bath temperatureof 50-55°C for 0.5 hour and concentrated under reduced pressure.The residue was dissolved by adding water, adjusted at pH 4 to 5with 2 M hydrochloric acid, combined with ethyl acetate, and mixedwith stirring to separate the layers. The upper layer was washedwith saline and concentrated under reduced pressure. The residuewas purified with a silica gel column chromatography (hexane/ethyl acetate, 2:1, 1:1 followed by hexane/ethyl acetate/methanol 3:3:1)to give the title compound (400 mg, yield 75%).Amorphous.1H NMR (CDCl3) δ 1.22 (6H, s), 1.29 (6H, s), 1.45 (3H, t), 2.22 (2H,s), 2.65 (2H, s), 3.88 (3H, s), 4.17 (2H, q), 4.42 (2H, d), 6.57(1H, s), 6.60 (1H, dd), 6.67 (1H, d), 7.22-7.23 (3H, m), 7.32 (1H,s), 7.92 (1H, d), 8.18 (1H, t). Example 139 2-[(3-Chlorophenyl)methylamino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0569] Methyl 2-[(3-chlorophenyl)methylamino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(217 mg, 0.397 mmol) was dissolved in a mixed solvent ofmethanol/tetrahydrofuran (1:1, 5 ml), 4 M aqueous solution (0.4ml) of lithium hydroxide was added thereto, and the mixture wasstirred at room temperature for 60 hours. The reaction solutionwas concentrated under reduced pressure, the residue was dissolvedby adding water, and adjusted at pH 4 to 5 with 2 M hydrochloricacid. The produced precipitate was extracted with ethyl acetate,and the ethyl acetate layer was washed with water and concentratedunder reduced pressure. The residue was washed with diisopropylether and dried to give the title compound (159 mg, yield 75%).Amorphous.1H NMR (CDCl3) δ 1.25 (6H, s), 1.47 (3H, t), 1.48 (6H, br), 2.31(2H, br), 2.86 (2H, s), 4.20 (2H, q), 4.26 (2H, br), 6.41 (1H, d),6.49 (1H, s), 6.61 (1H, s), 6.90-7.17 (3H, m), 7.23 (1H, s), 7.79(1H, d), 8.75 (1H, br). Example 140 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylmethyl)(trifluoroacetyl)amino]benzoate
    [0570] With stirring methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(519 mg, 1 mmol), potassiumcarbonate (1.38g, 10 mmol) and sodium iodide (300 mg, 1.99 mmol) in N,N-dimethylformamide (4 ml), 2-chloromethylquinolinehydrochloride (278 mg, 1.3 mmol) was added thereto, and themixture was stirred at room temperature for 15 hours. Thereaction solution was combined with thioglycolic acid (0.1 ml),and the mixture was stirred for 15 minutes. The reaction solutionwas combined with water/a saturated aqueous solution of sodiumchloride (2:1) and ethyl acetate/hexane (2:1), and the mixture wasmixed with stirring to separate the layers. The upper layer waswashed with water and concentrated under reduced pressure. Theresidue was washed with methanol and dried to give the titlecompound (639 mg, yield 97%).Melting point: 185 to 186°C.1H NMR (CDCl3) δ 1.12 (3H, s), 1.26 (9H, br), 1.47 (3H, t), 2.23(2H, br), 2.57 (1H, d), 2.70 (1H, d), 3.71 (3H, s), 4.19 (2H, q),4.76 (1H, d), 5.48 (1H, d), 6.60 (1H, s), 7.25-7.29 (1H, m), 7.48-7.54(3H, m), 7.61 (1H, br), 7.77 (1H, d), 7.86 (1H, br), 8.08 (1H,d), 8.12 (1H, d). Example 141 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylmethyl)amino]benzoate
    [0571] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylmethyl)(trifluoroacetyl)amino]benzoate(550 mg, 0.863mmol) was dissolved in methanol (20 ml), and potassium carbonate(480 mg, 3.48 mmol) was added thereto. The mixture was heatedunder reflux for 1 hour and concentrated under reduced pressure.The residue was dissolved by adding water, adjusted at pH 4 to 5with 2 M hydrochloric acid, combined with ethyl acetate, and mixedwith stirring to separate the layers. The upper layer was washedwith a saturated aqueous solution of sodium chloride andconcentrated under reduced pressure. The residue was purifiedwith a silica gel column chromatography (hexane/ethyl acetate, 2:1,1:1 followed by hexane/ethyl acetate/methanol 3:3:1) to give thetitle compound (422 mg, yield 90%).Amorphous. 1H NMR (CDCl3) δ 1.21 (6H, s), 1.25 (6H, s), 1.45 (3H, t), 2.24 (2H,s), 2.65 (2H, s), 3.95 (3H, s), 4.17 (2H, q), 4.75 (2H, d), 6.57(1H, s), 6.62 (1H, dd), 6.80 (1H, d), 7.44 (1H, dd), 7.52 (1H, t),7.69-7.73 (1H, m), 7.79 (1H, d), 7.96 (1H, d), 8.10-8.13 (2H, m),8.88 (1H, br). Example 142 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylmethyl)amino]benzoicacid
    [0572] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylmethyl)amino]benzoate(250 mg, 0.444 mmol) was dissolvedin methanol (4 ml), and 4 M aqueous solution (0.3 ml) of lithiumhydroxide was added thereto. The mixture was heated under refluxfor 4 hours, and concentrated under reduced pressure. The residuewas dissolved by adding water, and adjusted at pH 4 to 5 with 2 Mhydrochloric acid. The produced precipitate was extracted withethyl acetate, and the ethyl acetate layer was washed with waterand concentrated under reduced pressure. The residue was washedwith diisopropyl ether and dried to give the title compound (190mg, yield 79 %).1H NMR (CDCl3) δ 1.15 (6H, br), 1.44 (6H, s), 1.46 (3H, t), 2.16(2H, br), 2.81 (2H, s), 4.18 (2H, q), 4.66 (2H, s), 6.48 (1H, dd),6.58 (1H, s), 6.67 (1H, s), 7.36 (1H, d), 7.43-7.47 (1H, m), 7.60-7.70(1H, m), 7.69 (1H, d), 7.82 (1H, d), 7.94 (1H, d), 7.97 (1H,d). Example 143 Methyl 2-[[(4-cyanophenyl)methyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0573] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(520 mg, 1 mmol) and p-cyanobenzylbromide (200 mg, 1.72 mmol) were dissolved in N,N-dimethylformamide(10 ml). To this mixture were added potassiumiodide (100 mg) and potassium carbonate (500 mg, 3.61 mmol), andthe mixture was stirred at room temperature overnight. The mixture was extracted with diisopropyl ether, washed with water,dried, and concentrated to give methyl 2-[[(4-cyanophenyl)methyl](trifluoroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(730 mg) as a syrup.
    [0574] The product was dissolved in methanol (10 ml), and potassiumcarbonate (300 mg) was added thereto. The mixture was stirred atroom temperature overnight and concentrated. The residue wasextracted with diisopropyl ether, washed with water, dried, andpurified with a silica gel column chromatography (hexane/ethylacetate, 5:1, 4:1, 1:1 followed by ethyl acetate) to give thetitle compound (410 mg, yield 76%).Amorphous.1H NMR (CDCl3) δ 1.20 (6H, s), 1.30 (6H, s), 1.45 (3H, t, J = 6.8Hz), 2.35 (2H, s), 2.63 (2H, s), 3.89 (3H, s), 4.17 (2H, q, J =6.8 Hz), 4.52 (2H, d, J = 5.6 Hz), 6.57 (1H, s), 6.61-6.66 (2H, m),7.45 (2H, d, J = 8.4 Hz), 7.60 (2H, d, J = 8.4 Hz), 7.94 (1H, d, J= 8.0 Hz), 8.25 (1H, t, J = 5.6 Hz). Example 144 2-[[(4-Cyanophenyl)methyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0575] Methyl 2-[[(4-cyanophenyl)methyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(210 mg, 0.39 mmol) was dissolved in methanol (10 ml), and 2 Maqueous solution (6 ml) of sodium hydroxide was added thereto.The mixture was stirred at room temperature for 4 hours,neutralized with hydrochloric acid, and concentrated. The residuewas purified with a silica gel column chromatography (chloroformfollowed by chloroform/methanol 4:1) to give the title compound(177 mg, yield 87%).Amorphous.1H NMR (CDCl3) δ 1.15-1.35 (9H, br), 1.47 (3H, t, J = 6.8 Hz),1.35-1.55 (3H, br), 2.00-2.40 (2H, br), 2.70-3.00 (2H, br), 4.21(2H, q, J = 6.8 Hz), 4.28 (2H, s), 6.42 (1H, d, J = 6.8 Hz), 6.61(2H, s), 7.21 (2H, d, J = 8.0 Hz), 7.49 (2H, d, J = 8.0 Hz), 7.77 (1H, d, J = 6.8 Hz), 8.67 (1H, br). Example 145 Ethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylmethyl)amino]benzoate
    [0576] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(520 mg, 1.00 mmol) and 2-(chloromethyl)pyridinehydrochloride (215 mg, 1.31 mmol) weredissolved in N,N-dimethylformamide (5 ml). To this mixture wereadded potassium carbonate (550 mg, 3.97 mmol) and potassium iodide(100 mg), and the mixture was stirred at room temperatureovernight. The mixture was neutralized with hydrochloric acid,extracted with diisopropyl ether, washed with water, dried, andpurified with a silica gel column chromatography (hexane/ethylacetate 5:1 followed by ethyl acetate) to give ethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylmethyl)(trifluoroacetyl)amino]benzoate as asyrup (726 mg).
    [0577] The product was dissolved in methanol (10 ml), and potassiumcarbonate (300 mg) was added thereto. The mixture was stirred atroom temperature overnight and concentrated. The residue wascombined with ethyl acetate and stirred, and the ethyl acetatesolution was purified with silica gel layer to give the titlecompound (510 mg, yield 96%).Amorphous.1H NMR (CDCl3) δ 1.22 (6H, s), 1.29 (6H, s), 1.42 (3H, t, J = 7.2Hz), 1.45 (3H, t, J = 7.2 Hz), 2.27 (2H, s), 2.65 (2H, s), 4.17(2H, q, J = 7.2 Hz), 4.37 (2H, q, J = 7.2 Hz), 4.57 (2H, d, J =5.2 Hz), 6.57 (1H, s), 6.60 (1H, dd, J = 8.4, 1.2 Hz), 6.68 (1H, d,J = 1.2 Hz), 7.16-7.20 (1H, m), 7.31 (1H, d, J = 7.6 Hz), 7.63 (1H,td, J = 7.6, 2.0 Hz), 7.95 (1H, d, J = 8.4 Hz), 8.60 (2H, m). Example 146 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylmethyl)amino]benzoicacid
    [0578] Ethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylmethyl)amino]benzoate (340 mg) was dissolved in methanol(6 ml), and 2 M aqueous solution (6 ml) of sodium hydroxide wasadded thereto. The mixture was stirred at room temperature for 2hours, and methanol was distilled off. The residual aqueoussolution was adjusted at pH 7 with hydrochloric acid, extractedwith ethyl acetate, dried, and concentrated to give a crudeproduct. The crude product was purified with a silica gel columnchromatography (chloroform), and further purified with MCI CHP-20Presin column (water followed by methanol) to give the titlecompound (296 mg, yield 92%).Amorphous.1H NMR (CD3OD) δ 1.20 (6H, s), 1.26 (6H, s), 1.40 (3H, t, J = 6.8Hz), 2.17 (2H, s), 2.82 (2H, s), 4.17 (2H, q, J = 6.8 Hz), 4.54(2H, s), 6.52 (1H, s), 6.55 (1H, dd, J = 8.0, 1.2 Hz), 6.77 (1H,s), 7.25 (1H, m), 7.51 (1H, d, J = 8.0 Hz), 7.76 (1H, m), 8.00 (1H,d, J = 7.6 Hz), 8.41 (1H, m). Example 147 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[[4-(methoxycarbonyl)phenyl]methyl]amino]benzoate
    [0579] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(520 mg, 1.00 mmol) and methyl 4-(bromomethyl)benzoate(344 mg, 1.50 mmol) were dissolved in N,N-dimethylformamide(10 ml). To this mixture were added potassiumiodide (200 mg, 1.20 mmol) and potassium carbonate (450 mg, 3.25mmol), and the mixture was stirred at room temperature for 15hours. The reaction solution was combined with diisopropyl etherand an aqueous solution of sodium chloride, and the layers wereseparated, dried with sodium sulfate and concentrated to givemethyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[[4-(methoxycarbonyl)phenyl]methyl](trifluoroacetyl)amino]benzoate.
    [0580] The product was dissolved in methanol (10 ml), potassium carbonate (300 mg) was added thereto, and the mixture was stirredat room temperature for 5 hours. The mixture was concentrated,and the residue was extracted with diisopropyl ether, dried, andconcentrated to give a crude product. The crude product waspurified with a silica gel column chromatography (hexane/ethylacetate 4:1 followed by ethyl acetate) to give the title compound(393 mg, yield 68%).Amorphous.1H NMR (CDCl3) δ 1.21 (6H, s), 1.28 (6H, s), 1.44 (3H, t, J = 7.2Hz), 2.20 (2H, s), 2.63 (2H, s), 3.88 (3H, s), 3.89 (3H, s), 4.16(2H, q, J = 7.2 Hz), 4.51 (2H, d, J = 5.6 Hz), 6.56 (1H, s), 6.57(1H, dd, J = 8.0, 1.6 Hz), 6.65 (1H, d, J = 1.6 Hz), 7.41 (2H, d,J = 8.4 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.98 (2H, d, J = 8.4 Hz),8.23 (1H, t, J = 5.6 Hz). Example 148 2-[[(4-Carboxylphenyl)methyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0581] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[[4-(methoxycarbonyl)phenyl]methyl]amino]benzoate(233 mg) wasdissolved in methanol(10 ml), and 2 M aqueous solution (6 ml) ofsodium hydroxide was added thereto. The mixture was stirred atroom temperature for 4 hours, and methanol was distilled off. Theresidual aqueous solution was adjusted at pH 4 with 1 Mhydrochloric acid, and the precipitated crystals were taken byfiltration, washed with water, and dried to give the titlecompound (174 mg, yield 78%).1H NMR (DMSO-d6) δ 1.16 (6H, s), 1.20-1.45 (6H, m), 1.34 (3H, t, J= 6.9 Hz), 2.00-2.20 (2H, m), 2.60-3.30 (2H, br), 4.07-4.25 (2H,m), 4.60 (2H, s), 6.50-7.10 (3H, m), 7.43 (2H, d, J = 8.3 Hz),7.83-8.02 (1H, m), 7.89 (2H, d, J = 8.3 Hz), 8.42-8.70 (1H, br),12.50-13.30 (2H, m). Example 149 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[(2-methoxyphenyl)methyl]amino]benzoate
    [0582] With 2-methoxybenzyl chloride, the title compound wasobtained by the method similar to that in Example 147. Yield 90%.Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.27 (6H, s), 1.44 (3H, t, J = 6.8Hz), 2.23 (2H, s), 2.65 (2H, s), 3.77 (3H, s), 3.85 (3H, s), 4.17(2H, q, J = 6.8 Hz), 4.40 (2H, d, J = 5.2 Hz), 6.54 (1H, d, J =7.6 Hz), 6.57 (1H, s), 6.74 (1H, s), 6.80-6.92 (2H, m), 7.21 (1H,t, J = 7.2 Hz), 7.27 (1H, s), 7.89 (1H, d, J = 8.0 Hz), 8.12 (1H,t, J = 5.2 Hz). Example 150 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[(2-methoxyphenyl)methyl]amino]benzoicacid
    [0583] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[(2-methoxyphenyl)methyl]amino]benzoate,the title compound wasobtained by the method similar to that in Example 148. Yield 99%.1H NMR (CDCl3) δ 1.24 (6H, s), 1.36 (6H, s), 1.45 (3H, t, J = 7.2Hz), 2.20 (2H, s), 2.75 (2H, s), 3.72 (3H, s), 4.18 (2H, q, J =7.2 Hz), 4.36 (2H, s), 6.45 (1H, dd, J = 7.6, 1.2 Hz), 6.55 (1H, d,J = 1.2 Hz), 6.58 (1H, s), 6.77 (1H, d, J = 8.0 Hz), 6.81 (1H, t,J = 7.6 Hz), 7.12-7.18 (1H, m), 7.22-7.30 (1H, m), 7.83 (1H, d, J= 8.0 Hz). Example 151 Methyl 2-[([1,1'-biphenyl]-4-ylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0584] With 4-(chloromethyl)biphenyl, the title compound wasobtained by the method similar to that in Example 147. Yield 76%.Amorphous.1H NMR (CDCl3) δ 1.23 (6H, s), 1.29 (6H, s), 1.44 (3H, t, J = 6.8Hz), 2.28 (2H, s), 2.65 (2H, s), 3.87 (3H, s), 4.16 (2H, q, J =6.8 Hz), 4.47 (2H, d, J = 5.2 Hz), 6.57 (1H, s), 6.61 (1H, dd, J =8.0, 1.2 Hz), 6.76 (1H, d, J = 1.2 Hz), 7.30-7.35 (1H, m), 7.38-7.45(4H, m), 7.52-7.58 (4H, m), 7.93 (1H, d, J = 8.0 Hz), 8.15(1H, t, J = 5.2 Hz). Example 152 2-[([1,1'-Biphenyl]-4-ylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0585] From methyl 2-[([1,1'-biphenyl]-4-ylmethyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate,the title compound was obtained bythe method similar to that in Example 152. Yield 99%.Amorphous.1H NMR (CDCl3) δ 1.22 (6H, s), 1.42-1.48 (9H, m), 2.24 (2H, s),2.81 (2H, s), 4.17 (2H, q, J = 6.8 Hz), 4.31 (2H, s), 6.42 (1H, d,J = 6.4 Hz), 6.58 (2H, s), 7.25-7.55 (9H, m), 7.83 (1H, d, J = 8.0Hz). Example 153 2-[[(4-Chlorophenyl)methyl]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0586] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(520 mg, 1.00 mmol) was dissolvedin N,N-dimethylformamide (6 ml), and tert-butoxy potassium (150 mg,1.33 mmol) was added thereto. Then, p-chlorobenzyl bromide (229mg, 1.11 mmol) was added thereto, and the mixture was stirred atroom temperature for 5 hours. The reaction solution was combinedwith diisopropyl ether and an aqueous solution of potassiumdihydrogen phosphate, and stirred. The layers were separated, thediisopropyl ether layer was dried, and concentrated to give acrude product, which was purified with a silica gel columnchromatography (hexane/ethyl acetate, 9:1 followed by 4:1) to givemethyl 2-[[(4-chlorophenyl)methyl](trifluoroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(250 mg) as a syrup.
    [0587] The product was dissolved in methanol, hydrolyzed by adding 2M aqueous solution of sodium hydroxide, neutralized with 2 Mhydrochloric acid, and extracted with ethyl acetate to give acrude product, which was purified with a silica gel column chromatography (chloroform followed by chloroform/methanol 5:1) togive the title compound (yield 27%).Amorphous.1H NMR (CDCl3) δ 1.25 (6H, s), 1.46 (3H, t, J = 6.8 Hz), 1.47-1.53(6H, m), 2.10-2.30 (2H, m), 2.85 (2H, s), 4.13-4.25 (2H, m), 4.20(2H, q, J = 6.8 Hz), 6.39 (1H, d, J = 7.6 Hz), 6.52 (1H, s), 6.60(1H, s), 7.11 (2H, d, J = 8.8 Hz), 7.17 (2H, d, J = 8.8 Hz), 7.78(1H, d, J = 8.0 Hz), 8.61 (1H, br). Example 154 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[(4-methoxyphenyl)methyl]amino]benzoicacid
    [0588] Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate(520 mg, 1.00 mmol) was dissolvedin N,N-dimethylformamide (10 ml). To this mixture were added p-methoxybenzylchloride (210 mg, 1.34 mmol), potassium iodide (230mg, 1.38 mmol) and potassium carbonate (450 mg, 3.25 mmol), andthe mixture was stirred at room temperature overnight. Thereaction solution was extracted with diisopropyl ether, washedwith water, dried, and concentrated to methyl give 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[(4-methoxyphenyl)methyl](trifluoroacetyl)amino]benzoate.
    [0589] The product was dissolved in methanol (10 ml), 2 M aqueoussolution (6 ml) of sodium hydroxide was added thereto, and themixture was stirred at room temperature for 4 hours. The mixturewas concentrated, and the residue was adjusted at pH 4 withhydrochloric acid. The precipitate was taken by filtration,washed with water, and dried to give the title compound (287 mg,yield 54%).1H NMR (CDCl3) δ 1.29 (6H, s), 1.37 (6H, s), 1.45 (3H, t, J = 6.8Hz), 2.19 (2H, s), 2.75 (2H, s), 3.70 (3H, s), 4.19 (2H, s), 4.19(2H, q, J = 6.8 Hz), 6.40 (1H, d, J = 7.2 Hz), 6.53 (1H, s), 6.57(1H, s), 6.71 (2H, d, J = 7.6 Hz), 7.12 (2H, d, J = 7.6 Hz), 7.78-7.90(1H, br). Example 155 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(3-phenoxypropyl)amino]benzoicacid
    [0590] With 3-phenoxypropyl bromide, the title compound was obtainedby the method similar to that in Example 154. Yield 75%.Amorphous.1H NMR (CDCl3) δ 1.29 (6H, s), 1.45 (6H, s), 1.47 (3H, t, J = 7.2Hz), 1.97 (2H, t, J = 6.4 Hz), 2.36 (2H, s), 2.80 (2H, s), 3.24(1H, s), 3.91 (2H, t, J = 6.0 Hz), 4.20 (2H, q, J = 7.2 Hz), 6.44-6.52(1H, m), 6.61 (2H, d, J = 6.4 Hz), 6.66 (1H, s), 6.80-6.90(3H, m), 7.19 (2H, t, J = 8.0 Hz), 7.82-7.88 (1H, m). Example 156 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-methoxybenzoyl)amino]benzoate
    [0591] Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(211 mg, 0.5 mmol)was dissolved in N,N-dimethylacetamide (3 ml), 2-methoxybenzoylchloride (0.1 ml, 0.74 mmol) was added thereto, and the mixturewas stirred at room temperature for 1 hour. Then, the mixture wasextracted with ethyl acetate, washed with water, dried, andconcentrated to give a crude product. The crude product wastreated with hexane, and the precipitated crystals were taken byfiltration to give the title compound (259 mg, yield 93%).1H NMR (CDCl3) δ 1.24 (6H, s), 1.32 (6H, s), 1.46 (3H, t, J = 6.8Hz), 2.40 (2H, br), 2.66 (2H, s), 3.95 (3H, s), 4.09 (3H, s), 4.18(2H, q, J = 6.8 Hz), 6.51 (1H, s), 7.00-7.10 (2H, m), 7.14-7.16(1H, m), 7.48 (1H, m), 8.05 (1H, d, J = 8.0 Hz), 8.14 (1H, dd, J =8.0, 1.6 Hz), 9.00 (1H, s), 12.10 (1H, s). Example 157 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-methoxybenzoyl)amino]benzoicacid
    [0592] From methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-methoxybenzoyl)amino]benzoate,the title compound was obtained bythe method similar to that in Example 9. Yield 89%.1H NMR (CDCl3) δ 1.29 (6H, s), 1.50 (3H, t, J = 6.8 Hz), 1.63 (6H, s), 2.22 (1H, d, J = 16.0 Hz), 2.58 (1H, d, J = 16.0 Hz), 2.98 (2H,s), 3.96 (3H, s), 4.25 (2H, q, J = 6.8 Hz), 6.66 (1H, s), 6.83-6.90(3H, m), 7.25-7.36 (1H, m), 7.72 (1H, d, J = 8.2 Hz), 7.87 (2H, d,J = 8.2 Hz), 8.30 (1H, br s), 8.37 (1H, s). Example 158 Methyl 2-[(chloroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0593] Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(2.03 g, 4.80mmol) were dissolved in N,N-dimethylacetamide (10 ml). To thismixture was added chloroacetyl chloride (0.5 ml, 6.28 mmol), andthe mixture was stirred at room temperature for 3 hours. Thereaction solution was concentrated, the residue was combined withethyl acetate, and the precipitated crystals were taken byfiltration to give the title compound (2.37 g, yield 99%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.45 (3H, t, J = 7.2Hz), 2.29 (2H, s), 2.66 (2H, s), 3.98 (3H, s), 4.17 (2H, q, J =7.2 Hz), 4.18 (2H, s), 6.59 (1H, s), 7.19 (1H, dd, J = 8.0, 1.2Hz), 8.08 (1H, d, J = 8.0 Hz), 8.73 (1H, s). Example 159 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[[[(2-methoxy-2-oxoethyl)sulfanyl]acetyl]amino]benzoate
    [0594] Methyl 2-[(chloroacetyl)amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(500 mg, 1.0 mmol) was dissolved in methanol (20 ml). To thissolution were added ethyl thioglycolate (0.13 ml, 1.18 mmol) andpotassium carbonate (170 mg, 1.23 mmol), and the mixture wasstirred for 1 hour at room temperature. The reaction solution wasconcentrated, and the residue was extracted with diisopropyl ether,washed with water, and dried, and the solvent was distilled off togive the title compound (524 mg, yield 92%).1H NMR (CDCl3) δ 1.23 (6H, s), 1.31 (6H, s), 1.45 (3H, t, J = 7.2Hz), 2.35 (2H, s), 2.65 (2H, s), 3.39 (2H, s), 3.52 (2H, s), 3.71(3H, s), 3.97 (3H, s), 4.18 (2H, q, J = 7.2 Hz), 6.58 (1H, s), 7.16 (1H, dd, J = 8.0, 1.2 Hz), 8.06 (1H, d, J = 8.0 Hz), 8.74 (1H,s), 11.5 (1H, s). Example 160 Methyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-thienylacetyl)amino]benzoate
    [0595] Methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(211 mg, 0.5 mmol)was dissolved in N,N-dimethylacetamide (10 ml). To this solutionwas added thiophene-2-acetyl chloride (0.1 ml, 0.81 mmol) and themixture was stirred for 3 hours at room temperature. The reactionsolution was extracted with ethyl acetate, washed with water, anddried, concentrated, and the residue was treated with hexane togive the title compound (255 mg, yield 93%).Amorphous.1H NMR (CDCl3) δ 1.22 (6H, s), 1.29 (6H, s), 1.45 (3H, t, J = 7.2Hz), 2.28 (2H, s), 2.64 (2H, s), 3.90 (3H, s), 3.95 (2H, s), 4.17(2H, q, J = 7.2 Hz), 6.57 (1H, s), 6.99-7.05 (2H, m), 7.12 (1H, dd,J = 8.4, 1.6 Hz), 7.22-7.28 (1H, m), 8.01 (1H, d, J = 8.0 Hz),8.75 (1H, d, J = 1.6 Hz), 11.1 (1H, s). Example 161 Methyl 2-[[(E)-(dimethylamino)methylidene]amino]-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0596] To methyl 2-amino-4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(250 mg, 0.6 mmol)was added N,N-dimethylformamide dimethylacetal (2 ml), and themixture was stirred at 130°C for 3 hours, and concentrated. Theresidue was purified with a silica gel column chromatography(diisopropyl ether) to give the title compound (210 mg, yield 74%).1H NMR (CDCl3) δ 1.21 (6H, s), 1.30 (6H, s), 1.45 (3H, t, J = 7.2Hz), 2.29 (2H, s), 2.66 (2H, s), 3.01 (6H, s), 3.86 (3H, s), 4.17(2H, q, J = 7.2 Hz), 6.58 (1H, s), 6.90 (1H, d, J = 1.6 Hz), 7.00(1H, dd, J = 8.0, 1.6 Hz), 7.41 (1H, s), 7.79 (1H, d, J = 8.0 Hz). Example 162 Methyl 2-amino-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0597] To a mixture of methyl 2-amino-4-cyanobenzoate (2.62 g, 14.9mmol) and 2,3-dihydro-7-methoxy-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(4.12 g, 16.8 mmol) in acetic acid (9.10 ml)and toluene (14.5 ml) was added conc. sulfuric acid (2.15 ml, 40.3mmol) at room temperature, and the mixture was stirred at 80°C for2 hours and at 65°C for 13 hours. To the reaction mixture wasadded methanol (26.0 ml), and the mixture was heated under refluxfor 2 hours and 30 minutes. After cooling, the reaction solutionwas concentrated under reduced pressure. The resultant residuewas distributed to ethyl acetate and a saturated aqueous solutionof sodium hydrogen carbonate, and further the organic substanceswere extracted with ethyl acetate from the aqueous layer. Theethyl acetate solution was collected, washed with a saturatedaqueous solution of sodium chloride, dried with sodium sulfate,and concentrated under reduced pressure. The resultant residuewas purified with a silica gel column chromatography(chloroform/methanol, 50:1 followed by 20:1). The resultant crudeproduct was purified with a basic silica gel column chromatography(hexane/ethyl acetate, 5:1 followed by 3:1), and crystallized fromdiisopropyl ether to give the title compound (1.23 g, yield 18%).Melting point: 161.0 to 162.0°C.1H NMR (CDCl3) δ 1.23 (6H, br s), 1.34 (6H, s), 2.37 (2H, s), 2.67(2H, s), 3.89 (3H, s), 3.92 (3H, s), 5.76 (2H, s), 6.60 (1H, s),6.62 (1H, dd, J = 8.4, 1.2 Hz), 6.74 (1H, d, J = 1.2 Hz), 7.85 (1H,d, J = 8.4 Hz). Example 163 Methyl 4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(trifluoroacetyl)amino]benzoate
    [0598] To a solution of methyl 2-amino-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(1.34 g, 3.28 mmol) and triethylamine (0.55 ml, 3.9 mmol) intetrahydrofuran (13 ml) was added trifluoroacetic anhydride (0.51ml, 3.6 mmol) at 0°C, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 2 hours and10 minutes. The reaction solution was distributed to ethylacetate and water, and the organic substances were extracted withethyl acetate from the aqueous layer. The ethyl acetate solutionwas collected, washed with a saturated aqueous solution of sodiumhydrogen carbonate and a saturated aqueous solution of sodiumchloride, dried with sodium sulfate, and concentrated underreduced pressure. The resultant residue was washed withdiisopropyl ether to give the title compound (0.435 g, yield 26%).Melting point: 146.0 to 147.0°C.1H NMR (CDCl3) δ 1.25 (6H, s), 1.33 (6H, s), 2.29 (2H, s), 2.69 (2H,s), 3.82 (3H, s), 4.00 (3H, s), 6.62 (1H, s), 7.28 (1H, dd, J =8.2, 1.6 Hz), 8.12 (1H, d, J = 8.0 Hz), 8.71 (1H, d, J = 1.6 Hz),12.27 (1H, s). Example 164 Methyl 2-[[3-(acetylamino)benzoyl]amino]-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate
    [0599] To a suspension of 3-(acetamido)benzoic acid (215 mg, 1.20mmol) in 1,2-dichloroethane (1.5 ml) were added thionyl chloride(0.18 ml, 2.5 mmol) and N,N-dimethylformamide (1 drop), and themixture was stirred for 2 hours at 75°C. The reaction mixture wasconcentrated under reduced pressure, and the residue was dissolvedin 1,2-dichloroethane (0.5 ml). This was added dropwise to asolution of methyl 2-amino-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(337 mg,0.825 mmol) and triethylamine (0.18 ml, 1.3 mmol) in 1,2-dichloroethane(1 ml), and the mixture was stirred at roomtemperature for 25 minutes. The reaction mixture was combinedwith water and ethyl acetate, and weakly alkalified with asaturated aqueous solution of sodium hydrogen carbonate. Theorganic layer was separated, and the aqueous layer was extractedwith ethyl acetate. The combined organic layer was washed withwater and a saturated aqueous solution of sodium chloride, driedthrough sodium sulfate-basic silica gel (eluting with ethylacetate), and concentrated under reduced pressure. The residue was purified with a basic silica gel column chromatography(hexane/ethyl acetate 1:3), and crystallized from ethyl acetate-diethylether to give the title compound (160 mg, yield 34%).1H NMR (CDCl3) δ 1.26 (6H, s), 1.32 (6H, s), 2.22 (3H, s), 2.37 (2H,br s), 2.70 (2H, s), 3.93 (3H, s), 4.01 (3H, s), 6.17 (1H, s),7.17 (1H, dd, J = 8.2, 1.4 Hz), 7.40 (1H, br s), 7.49 (1H, t, J =7.7 Hz), 7.75 (1H, d, J = 7.7 Hz), 7.89-7.92 (1H, m), 7.98-8.03(1H, m), 8.11 (1H, d, J = 8.2 Hz), 8.96 (1H, d, J = 1.4 Hz), 12.04(1H, s). Example 165 2-[[3-(Acetylamino)benzoyl]amino]-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoicacid
    [0600] To a suspension of methyl 2-[[3-(acetylamino)benzoyl]amino]-4-(3,4,8,9-tetrahydro-6-methoxy-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)benzoate(85 mg, 0.15 mmol) in methanol (0.4ml) was added 5 M aqueous solution (76 µl, 0.38 mmol) of sodiumhydroxide, and the mixture was stirred at 75°C for 15 minutes.The reaction mixture was combined with 1 M hydrochloric acid (0.38ml, 0.38 mmol), and extracted twice with chloroform. The combinedorganic layer was washed with a saturated aqueous solution ofsodium chloride, dried through sodium sulfate, concentrated underreduced pressure to give the title compound (81 mg, yield 97%).Amorphous.1H NMR (DMSO-d6) δ 1.22 (6H, s), 1.25 (6H, br s), 2.08 (3H, s),2.39 (2H, br s), 2.81 (2H, br s), 3.86 (3H, s), 6.92 (1H, s), 7.22(1H, dd, J = 8.1, 1.5 Hz), 7.50 (1H, t, J = 7.8 Hz), 7.59-7.64 (1H,m), 7.77 (1H, m), 8.13 (1H, d, J = 8.1 Hz), 8.24 (1H, s), 8.75 (1H,d, J = 1.5 Hz), 10.21 (1H, s). Example 166 Butyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(1-pyrrolidinyl)benzeneacetate
    [0601] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(343 mg, 1.30 mmol) and methyl4-cyano-2-pyrrolidinylbenzeneacetate (279 mg, 1.12 mmol) in butylacetate (3 ml) was added methanesulfonic acid (0.5 ml). The resultant mixture was stirred at 90°C for 5 hours. The resultantmixture was cooled, the aqueous layer was separated by addingwater, and the organic layer was extracted with water. Thecombined aqueous layer was combined with an aqueous solution of10% potassium carbonate, alkalified, and extracted with ethylacetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure. The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate 1:1) to give the titlecompound (173 mg, yield 28%).Oily matter.1H NMR (CDCl3) δ 0.91 (3H, t), 1.23 (6H, br s), 1.28-1.41 (2H, m),1.31 (6H, s), 1.46 (3H, t), 1.52-1.63 (2H, m), 1.85-1.90 (4H, m),2.27 (2H, s), 2.66 (2H, s), 3.08 (4H, br s), 3.71 (2H, s), 4.08(2H, t), 4.18 (2H, q), 6.59 (1H, s), 6.97-7.02 (2H, m), 7.20 (1H,d). Example 167 Butyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzeneacetate
    [0602] To a solution of 7-ethoxy-2,3-dihydro-2,2-dimethyl-α-(1-methylethyl)-5-benzofuranmethanol(668 mg, 2.53 mmol), methyl 4-cyano-2-[(2-pyridinylcarbonyl)amino]benzeneacetate(668 mg, 2.26mmol) in butyl acetate (5 ml) was added methanesulfonic acid (0.85ml). The resultant mixture was stirred for 2 hours at 90°C. Theresultant mixture was cooled, the aqueous layer was separated byadding water, and the organic layer was extracted with water. Thecombined aqueous layer was combined with an aqueous solution of10% potassium carbonate, alkalified, and extracted with ethylacetate. The organic layer was washed with a saturated aqueoussolution of sodium chloride, dried, and concentrated under reducedpressure. The residue was purified with a basic silica gel columnchromatography (hexane/ethyl acetate 1:1) to give the titlecompound (465 mg, yield 35%).Amorphous.1H NMR (CDCl3) δ 0.89 (3H, t), 1.23 (6H, s), 1.30-1.40 (2H, m), 1.35 (6H, s), 1.46 (3H, t), 1.57-1.68 (2H, m), 2.47 (2H, br s),2.65 (2H, s), 3.75 (2H, br s), 4.11 (2H, t), 4.18 (2H, q), 6.58(1H, s), 7.21 (1H, dd), 7.31 (1H, d), 7.44-7.49 (1H, m), 7.88 (1H,dt), 8.07 (1H, d), 8.22-8.27 (1H, m), 8.60-8.64 (1H, m), 10.54 (1H,s). Example 168 4-(6-Ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(1-pyrrolidinyl)benzeneaceticacid
    [0603] To a solution of butyl 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(1-pyrrolidinyl)benzeneacetate(140 mg, 0.263 mmol) in ethanol (2 ml)was added 1 M aqueous solution (0.5 ml) of sodium hydroxide, andthe mixture was stirred for 2 hours at room temperature. Thereaction solution was combined with 1 M hydrochloric acid (0.5 ml)and extracted with ethyl acetate. The organic layer was washedwith a saturated aqueous solution of sodium chloride, dried, andconcentrated under reduced pressure. The resultant residue wasmade as amorphous powders from ethyl acetate-hexane to give thetitle compound (101 mg, yield 81%).1H NMR (DMSO-d6) δ 1.12 (6H, br s), 1.22 (6H, s), 1.34 (3H, t),1.83 (4H, br s), 2.27 (2H, s), 2.59 (2H, s), 3.05 (4H, br s), 3.59(2H, s), 4.08 (2H, q), 6.74 (1H, s), 6.84-6.93 (2H, m), 7.18 (1H,d).
    [0604] In the following, the compounds prepared in Examples 1 to 168are shown in Tables 1 to 10.
    [0605] (1) Compound of Example 6 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg
    [0606] A mixture of 10.0 mg of the compound obtained in Example 6,60.0 mg of lactose and 35.0 mg of a corn starch was granulatedusing 0.03 ml of 10% aqueous solution of gelatin (3.0 mg asgelatin) through a 1 mm mesh sieve, dried at 40°C and then sievedagain. The resultant granule was combined with 2.0 mg ofmagnesium stearate and then compressed. The resultant core wascoated with a sugar coating comprising sucrose, titanium dioxide,talc and gum arabic in an aqueous suspension. The resultantcoated tablet was imparted by polishing with beeswax to obtain acoated tablet. Formulation Example 2
    [0607] (1) Compound of Example 6 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg
    [0608] 10.0 mg of the compound obtained in Example 6 and 3.0 mg ofmagnesium stearate were granulated using 0.07 ml of an aqueoussolution of a soluble starch (7.0 mg as soluble starch), dried,and then combined with 70.0 mg of lactose and 50.0 mg of a cornstarch. The mixture was compressed into a tablet. Formulation Example 3
    [0609] (1) Compound of Example 1 5.0 mg (2) Sodium chloride 20.0 mg (3) Distilled water to 2 ml
    [0610] 5.0 mg of the compound obtained in Example 6 and 20.0 mg ofsodium chloride were dissolved in distilled water and water wasthen added to make the entire volume 2.0 ml. The solution wasfiltered, and filled aseptically in a 2 ml ampoule. The ampoule was sterilized, sealed, whereby obtaining an injection solution.Formulation Example 4
    [0611] In a fluidized bed granulating drier (FD-5S, manufactured byPOWREX Corporation), 1500 g of the compound obtained in Example 6,2025 g of lactose and 556.5 g of corn starch were mixedhomogeneously, and then an aqueous solution in which 126 g ofhydroxypropylcellulose was dissolved was sprayed in the drier toconduct a granulation, after which the mixture was dried in thefluidized bed granulating drier. The resultant granule was groundusing a power mill and sieved through a 1.5 mm punching screen toobtain sized granules. 3927 g of these sized granules werecombined with 210 g of croscarmellose sodium and 63 g of magnesiumstearate, and mixed in a tumbler mixer to obtain granules to becompacted into tablets. These granules were compacted into 300 mgcore tablets using a 6.5 mm frame in a tablet-compacting machine.The resultant core tablets were coated with a solution containinghydroxypropylmethyl cellulose 2910 (TC-5) and macrogol 6000dissolved therein in a Doria coater coating machine and titaniumoxide and iron(III) oxide dispersed therein to obtain about 13500film-coated tablets each containing 100 mg whose composition isshown below. Tablet formulation: Composition Content (mg) (1) Compound of Example 6 100.0 (2) Lactose 135.0 (3) Corn starch 37.1 (4) Sodium croscarmellose 15.0 (5) Hydroxypropylcellulose 8.4 (6) Magnesium stearate 4.5 Total (core tablet) 300.0 Film-coated tablet composition: (1) Core tablet 300.0 (Film component) (2) Hydroxypropylmethyl cellulose 2910 7.485 (3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0 Formulation Example 5
    [0612] According to the method described in Formulation Example 4,about 13500 film-coated tablets having the formulation shown beloweach containing 25 mg of the compound obtained in Example 6 wereobtained. Tablet formulation: Composition Content (mg) (1) Compound of Example 6 25.0 (2) Lactose 210.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxypropylcellulose 8.4 (6) Magnesium stearate 4.5 Total (core tablet) 300.0 Film-coated formulation: (1) Core tablet 300.0 (Film ingredients) (2) Hydroxypropylcellulose 2910 7.485 (3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0 Formulation Example 6
    [0613] According to the method described in Formulation Example 4,about 13500 film-coated tablets having the formulation shown beloweach containing 5 mg of the compound obtained in Example 6 wereobtained. Tablet formulation: Composition Content (mg) (1) Compound of Example 6 5.0 (2) Lactose 230.0 (3) Corn starch 37.1 (4) Croscarmellose sodium 15.0 (5) Hydroxypropylcellulose 8.4 (6) Magnesium stearate 4.5 Total (core tablet) 300.0 Film-coated formulation: (1) Core tablet 300.0 (Film ingredients) (2) Hydroxypropylcellulose 2910 7.485 (3) Macrogol 6000 1.5 (4) Titanium oxide 1.0 (5) Iron sesquioxide 0.015 Total 310.0 Formulation Example 7
    [0614] According to the method described in Formulation Example 4,about 13500 film-coated tablets having the formulation shown beloweach containing 1 mg of the compound obtained in Example 6 wereobtained. Tablet formulation: Composition Content (mg) Compound of Example 6 1.0 Lactose 234.0 Corn starch 37.1 Croscarmellose sodium 15.0 Hydroxypropylcellulose 8.4 Magnesium stearate 4.5 Total (core tablet) 300.0 Film-coated formulation: Core tablet 300.0 (Film ingredients) Hydroxypropylcellulose 2910 7.485 Macrogol 6000 1.5 Titanium oxide 1.0 Iron sesquioxide 0.015 Total 310.0 Formulation Example 8
    [0615] White vaseline 40 g Cetanol 10 g Bleached beeswax 5 g Sorbitan sesquioleate 5 g Lauromocrogold 0.5 g Methyl p-oxybenzoate 0.1 g Propyl p-oxybenzoate 0.1 g Purified water adequate amount
    [0616] An official absorption ointment (100 g) having thecomposition shown above was heated preliminarily at 70°C, and thesolution was combined with a solution which was obtained bydissolving 1 g of the compound obtained in Example 6 in 20 ml ofmethanol with heating. At the same temperature, the mixture wasstirred with heating for 10 minutes to remove residual methanol,and then cooled to room temperature to obtain a wettable ointment. Experimental Example 1 Assay of phosphodiesterase IV-inhibiting action (1) Expression of recombinant human brain-derivedphosphodiesterase 4D3 in Escherichia coli and purification thereof
    [0617] Using the Escherichia coli BL21/pPDE4D3 (FERM BP-7075)producing recombinant human brain-derived phosphodiesterase 4D3, arecombinant human brain-derived phosphodiesterase 4D3 was obtained.The expression and purification of E. coli were in accordance withthe protocol attached to GST Gene Fusion System (Pharmacia). (2) Assay of phosphodiesterase IV-inhibiting action
    [0618] To a 96-well plate (OPTI plate, Packard), 10 µl of a buffersolution [0.5 M Tris-HCl (pH 7.5), 83 mM MgCl2, 17 mM EGTA], 10 µlof the recombinant human brain-derived phosphodiesterase 4D3(0.0034 mg/ml) obtained in Section (1) described above, 65 µl ofUltrapure water, 5 µl of an inhibitor sample and 10 µl of [3H]CAMP were added and reacted for 30 minutes at 30°C. Aftercompleting the reaction, 50 µl of SPA beads solution [18 mg/mlYttrium silicate beads, 18 mM ZnSO4] was added thereto, and themixture was allowed to stand at room temperature for about 20minutes. The radioactivity was counted using a scintillation counter (Topcount, Packard). Inhibiting activity of the compoundagainst recombinant human brain-derived phosphodiesterase 4D3 wascalculated, based on that enzymatic activity under absence of thecompound was 100%. The inhibiting activities of the compounds ofthe present invention were shown in Table 11 as IC50 value. Example No. Phosphodiesterase 4D inhibiting action (IC50, nM) 6 0.566 17 4.01 21 1.89 23 0.756 30 0.761 50 8.40 57 1.63 74 1.71 85 5.50 94 3.27 95 10.9 118 11.5 120 3.50 124 0.637 INDUSTRIAL APPLICABILITY
    [0619] The furoisoquinoline derivative of the present invention hasan excellent phosphodiesterase IV-inhibiting action, and is usefulas a prophylactic and/or therapeutic agent against inflammatorydiseases, atopic dermatitis, allergic rhinitis, asthma, chronicobstructive pulmonary diseases, chronic rheumatoid arthritis,autoimmune diseases, depression, Alzheimer's dementia,osteoporosis, memory disorders, diabetes, atherosclerosis and thelike.
    权利要求:
    Claims (22)
    [1]
    A compound represented by the formula
    [2]
    The compound according to claim 1, wherein R1 is (i) acyano group, (ii) a carboxyl group, (iii) a C1-6 alkoxy-carbonylgroup which may have 1 to 5 substituents selected from a groupconsisting of (1) a halogen atom, (2) a C1-3 alkylenedioxy group,(3) a nitro group, (4) a cyano group, (5) an optionallyhalogenated C1-6 alkyl group, (6) an optionally halogenated C2-6alkenyl group, (7) an optionally halogenated C2-6 alkynyl group,(8) a C3-8 cycloalkyl group, (9) a C6-14 aryl group, (10) anoptionally halogenated C1-6 alkoxy group, (11) an optionallyhalogenated C1-6 alkylthio group, (12) a hydroxy group, (13) anamino group, (14) a mono-C1-6 alkylamino group, (15) a mono-C6-14arylamino group, (16) a di-C1-6 alkylamino group, (17) a di-C6-14arylamino group, (18) an acyl group selected from formyl, carboxyl,carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, sulfino, sulfo, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, (19) an acylamino group selected from formylamino,C1-6 alkyl-carboxamide, C6-14 aryl-carboxamide, C1-6 alkoxy-carboxamide,C1-6 alkylsulfonylamino and C6-14 arylsulfonylamino,(20) an acyloxy group selected from C1-6 alkyl-carbonyloxy, C6-14aryl-carbonyloxy, C1-6 alkoxy-carbonyloxy, mono-C1-6 alkyl-carbamoyloxy,di-C1-6 alkyl-carbamoyloxy, mono-C6-14 aryl-carbamoyloxy,di-C6-14 aryl-carbamoyloxy and nicotinoyloxy, (21) a5- to 14-membered heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, (22) a phosphono group, (23) aC6-14 aryloxy group, (24) a di-C1-6 alkoxy-phosphoryl group, (25) aC6-14 arylthio group, (26) a hydrazino group, (27) an imino group,(28) an oxo group, (29) an ureido group, (30) a C1-6 alkyl-ureido group, (31) a di-C1-6 alkyl-ureido group, (32) an oxide group and(33) a group formed by binding of 2 or 3 groups selected from (1)to (32) listed above and the like (hereinafter, abbreviated asSubstituent group A), (iv) a C3-8 cycloalkyloxy-carbonyl groupwhich may have 1 to 5 substituents selected from Substituent groupA described above, (v) a C7-16 aralkyloxy-carbonyl group which mayhave 1 to 5 substituents selected from Substituent group Adescribed above, (vi) a C6-14 aryloxy-carbonyl group which may have1 to 5 substituents selected from Substituent group A describedabove, (vii) a carbamoyl group, (viii) a mono-C1-6 alkyl-carbamoylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above, (ix) a di-C1-6 alkyl-carbamoyl group whichmay have 1 to 5 substituents selected from Substituent group Adescribed above, (x) a mono-C6-14 aryl-carbamoyl group which mayhave 1 to 5 substituents selected from Substituent group Adescribed above or (xi) a di-C6-14 aryl-carbamoyl group which mayhave 1 to 5 substituents selected from Substituent group Adescribed above,   R2 is (i) a hydrogen atom, (ii) a group represented by theformula -OR12 (R12 represents (a) a hydrogen atom, (b) a C1-6 alkylgroup, C2-6 alkenyl group, C2-6 alkynyl group, C3-8 cycloalkyl group,C3-8 cycloalkenyl group, C6-14 aryl group or C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above, or (c) an acyl group selected from formyl,carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, C1-6 alkoxysulfinyl, C6-14aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14 aryloxysulfonyl,which may have 1 to 5 substituents selected from Substituent groupA described above), (iii) a group represented by the formula-NR13R14(R13 and R14 are each (i') a hydrogen atom, (ii') a C1-6 alkylgroup, C2-6 alkenyl group, C2-6 alkynyl group, C3-8 cycloalkyl group,C3-8 cycloalkenyl group, C6-14 aryl group or C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above, (iii') an acyl group selected from formyl,carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, C1-6 alkoxysulfinyl, C6-14aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14 aryloxysulfonyl,which may have 1 to 5 substituents selected from Substituent groupA described above or (iv') a 5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, whichmay have 1 to 5 substituents selected from Substituent group Adescribed above, or R13 and R14 may be taken together with theadjacent a nitrogen atom to form a 5- to 14-membered ring), (iv) aC1-6 alkylideneamino group which may have 1 to 5 substituentsselected from Substituent group A described above, (v) a C1-6 alkylgroup which may have 1 to 5 substituents selected from Substituentgroup A described above, (vi) a carboxyl group, (vii) a C1-6alkoxy-carbonyl group which may have 1 to 5 substituents selectedfrom Substituent group A described above, (viii) a C3-8cycloalkyloxy-carbonyl group which may have 1 to 5 substituentsselected from Substituent group A described above, (ix) a C7-16aralkyloxy-carbonyl group which may have 1 to 5 substituentsselected from Substituent group A described above, (x) a C6-14aryloxy-carbonyl group which may have 1 to 5 substituents selectedfrom Substituent group A described above, (xi) a carbamoyl group,(xii) a mono-C1-6 alkyl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above,(xiii) a di-C1-6 alkyl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above,(xiv) a mono-C6-14 aryl-carbamoyl group which may have 1 to 5substituents selected from Substituent group A described above,(xv) a di-C6-14 aryl-carbamoyl group which may have 1 to 5 substituents selected from Substituent group A described above or(xvi) a nitro group, or R2 and A or R1 may be taken together toform a 5- to 14-membered ring containing 1 to 4 hetero atomsselected from a nitrogen atom and an oxygen atom in addition tocarbon atoms, which may have 1 to 5 substituents selected fromSubstituent group A described above;   each of R3 and R4 is any of the following (i) to (iii):
    (i) a hydrogen atom,
    (ii) a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group,C3-8 cycloalkyl group, C3-8 cycloalkenyl group, C6-14 aryl group orC7-16 aralkyl group, each of which may have 1 to 5 substituentsselected from Substituent group A described above,
    (iii) an acyl group selected from formyl, carboxyl, carbamoyl,C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl,C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl,C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, sulfino, sulfo, C1-6 alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl andC6-14 aryloxysulfonyl, which may have 1 to 5 substituents selectedfrom Substituent group A described above; or    R3 and R4 may be taken together with the adjacent carbon atomto form C3-8 cycloalkane or a 3- to 8-membered heterocycle, whichmay have respectively 1 to 3 substituents selected from C1-6 alkyl,C6-14 aryl, C7-16 aralkyl, amino, mono-C1-6 alkylamino, mono-C6-14arylamino, di-C1-6 alkylamino, di-C6-14 arylamino and a 4- to 10-memberedaromatic heterocyclic group,   R5 is (i) a hydrogen atom, (ii) a cyano group, (iii) a C1-6alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-8 cycloalkylgroup, C3-8 cycloalkenyl group, C6-14 aryl group or C7-16 aralkylgroup, each of which may have 1 to 5 substituents selected fromSubstituent group A described above, (iv) an acyl group selectedfrom formyl, carboxyl, carbamoyl, C1-6 alkyl-carbonyl, C3-8cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl,5- or 6-membered heterocyclic carbonyl containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl,5- or 6-membered heterocyclic carbamoyl containing 1 to 3 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl,C7-16 aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl,C7-16 aralkyloxy-thiocarbonyl, 5- or 6-membered heterocyclicthiocarbonyl containing 1 to 3 hetero atoms selected from anitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, sulfino, sulfo, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, which may have 1 to 5 substituents selected fromSubstituent group A described above, or (v) a group represented bythe formula -OR15 (R15 represents (a) a hydrogen atom, (b) a C1-6alkyl group, C2-6 alkenyl group, C2-6 alkynyl group, C3-8 cycloalkylgroup, C3-8 cycloalkenyl group, C6-14 aryl group or C7-16 aralkylgroup, each of which may have 1 to 5 substituents selected fromSubstituent group A described above, or (c) an acyl group selectedfrom formyl, carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl,C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl,C6-14 aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or6-membered heterocyclic carbamoyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl,mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, C1-6 alkoxysulfinyl, C6-14aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14 aryloxysulfonyl,which may have 1 to 5 substituents selected from Substituent group A described above),   R6 is any of the following (i) to (x):
    (i) a hydrogen atom,
    (ii) a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynyl group,C3-8 cycloalkyl group, C3-8 cycloalkenyl group, C6-14 aryl group orC7-16 aralkyl group, each of which may have 1 to 5 substituentsselected from Substituent group A described above,
    (iii) an acyl group selected from formyl, carboxyl, carbamoyl,C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl,C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl,C7-16 aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, sulfino, sulfo,C1-6 alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl andC6-14 aryloxysulfonyl, which may have 1 to 5 substituents selectedfrom Substituent group A described above,
    (iv) a 5- to 14-membered heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atoms, which may have 1 to 5substituents selected from Substituent group A described above,
    (v) a halogen atom,
    (vi) a group represented by the formula -OR16 (R16 represents(i') a hydrogen atom, (ii') a C1-6 alkyl group, C2-6 alkenyl group,C2-6 alkynyl group, C3-8 cycloalkyl group, C3-8 cycloalkenyl group,C6-14 aryl group or C7-16 aralkyl group, each of which may have 1 to5 substituents selected from Substituent group A described above,(iii') an acyl group selected from formyl, carbamoyl, C1-6 alkyl-carbonyl,C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl,C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, which may have 1 to 5 substituents selected fromSubstituent group A described above, or (iv') a 5- to 14-memberedheterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, which may have 1 to 5 substituents selected fromSubstituent group A described above),
    (vii) a group represented by the formula -SR17 (R17 represents(i') a hydrogen atom, (ii') a C1-6 alkyl group, C2-6 alkenyl group,C2-6 alkynyl group, C3-8 cycloalkyl group, C3-8 cycloalkenyl group,C6-14 aryl group or C7-16 aralkyl group, each of which may have 1 to5 substituents selected from Substituent group A described above,(iii') an acyl group selected from formyl, carbamoyl, C1-6 alkyl-carbonyl,C3-8 cycloalkyl-carbonyl, C1-6 alkoxy-carbonyl, C6-14 aryl-carbonyl,C7-16 aralkyl-carbonyl, C6-14 aryloxy-carbonyl, C7-16aralkyloxy-carbonyl, 5- or 6-membered heterocyclic carbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, mono-C1-6alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl, mono-C6-14 aryl-carbamoyl,di-C6-14 aryl-carbamoyl, 5- or 6-membered heterocycliccarbamoyl containing 1 to 3 hetero atoms selected from a nitrogenatom, a sulfur atom and an oxygen atom in addition to carbon atoms,C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl, C1-6 alkoxy-thiocarbonyl,C6-14 aryl-thiocarbonyl, C7-16 aralkyl-thiocarbonyl,C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl, 5- or 6-memberedheterocyclic thiocarbonyl containing 1 to 3 hetero atomsselected from a nitrogen atom, a sulfur atom and an oxygen atom inaddition to carbon atoms, thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl,di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl,di-C6-14 aryl-thiocarbamoyl, 5- or 6-memberedheterocyclic thiocarbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6alkylsulfamoyl, C6-14 arylsulfamoyl, C1-6 alkylsulfonyl, C6-14arylsulfonyl, C1-6 alkylsulfinyl, C6-14 arylsulfinyl, C1-6alkoxysulfinyl, C6-14 aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14aryloxysulfonyl, which may have 1 to 5 substituents selected fromSubstituent group A described above or (iv') a 5- to 14-memberedheterocycle containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, which may have 1 to 5 substituents selected fromSubstituent group A described above),
    (viii) a group represented by the formula -S(O)rR11 (R11represents (i') a C1-6 alkyl group, C2-6 alkenyl group, C2-6 alkynylgroup, C3-8 cycloalkyl group, C3-8 cycloalkenyl group, C6-14 arylgroup or C7-16 aralkyl group, each of which may have 1 to 5substituents selected from Substituent group A described above or(ii') a 5- to 14-membered heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygenatom in addition to carbon atoms, which may have 1 to 5substituents selected from Substituent group A described above andr is 1 or 2) or
    (ix) a group represented by the formula -NR18R19 (R18 and R19each represent (i') a hydrogen atom, (ii') a C1-6 alkyl group, C2-6alkenyl group, C2-6 alkynyl group, C3-8 cycloalkyl group, C3-8cycloalkenyl group, C6-14 aryl group or C7-16 aralkyl group, each ofwhich may have 1 to 5 substituents selected from Substituent groupA described above, (iii') an acyl group selected from formyl,carbamoyl, C1-6 alkyl-carbonyl, C3-8 cycloalkyl-carbonyl, C1-6alkoxy-carbonyl, C6-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, C6-14aryloxy-carbonyl, C7-16 aralkyloxy-carbonyl, 5- or 6-memberedheterocyclic carbonyl containing 1 to 3 hetero atoms selected froma nitrogen atom, a sulfur atom and an oxygen atom in addition tocarbon atoms, mono-C1-6 alkyl-carbamoyl, di-C1-6 alkyl-carbamoyl,mono-C6-14 aryl-carbamoyl, di-C6-14 aryl-carbamoyl, 5- or 6-memberedheterocyclic carbamoyl containing 1 to 3 hetero atoms selectedfrom a nitrogen atom, a sulfur atom and an oxygen atom in additionto carbon atoms, C1-6 alkyl-thiocarbonyl, C3-8 cycloalkyl-thiocarbonyl,C1-6 alkoxy-thiocarbonyl, C6-14 aryl-thiocarbonyl, C7-16aralkyl-thiocarbonyl, C6-14 aryloxy-thiocarbonyl, C7-16 aralkyloxy-thiocarbonyl,5- or 6-membered heterocyclic thiocarbonylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,thiocarbamoyl, mono-C1-6 alkyl-thiocarbamoyl, di-C1-6 alkyl-thiocarbamoyl, mono-C6-14 aryl-thiocarbamoyl, di-C6-14 aryl-thiocarbamoyl,5- or 6-membered heterocyclic thiocarbamoylcontaining 1 to 3 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms,sulfamoyl, mono-C1-6 alkylsulfamoyl, di-C1-6 alkylsulfamoyl, C6-14arylsulfamoyl, C1-6 alkylsulfonyl, C6-14 arylsulfonyl, C1-6alkylsulfinyl, C6-14 arylsulfinyl, C1-6 alkoxysulfinyl, C6-14aryloxysulfinyl, C1-6 alkoxysulfonyl and C6-14 aryloxysulfonyl,which may have 1 to 5 substituents selected from Substituent groupA described above or (iv') a 5- to 14-membered heterocyclecontaining 1 to 4 hetero atoms selected from a nitrogen atom, asulfur atom and an oxygen atom in addition to carbon atoms, whichmay have 1 to 5 substituents selected from Substituent group Adescribed above),    R7 and R8 are each (i) a hydrogen atom or (ii) a C1-6 alkylgroup, C2-6 alkenyl group, C2-6 alkynyl group, C3-8 cycloalkyl group,C3-8 cycloalkenyl group, C6-14 aryl group or C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above, or R7 and R8 may be taken together withthe adjacent carbon atom to form C3-8 cycloalkane or a 3- to 8-memberedheterocycle, which may have respectively 1 to 3substituents selected from C1-6 alkyl, C6-14 aryl, C7-16 aralkyl,amino, mono-C1-6 alkylamino, mono-C6-14 arylamino, di-C1-6 alkylamino,di-C6-14 arylamino and a 4- to 10-membered aromatic heterocyclicgroup;   R9 and R10 are each (i) a hydrogen atom or (ii) a C1-6 alkylgroup, C2-6 alkenyl group, C2-6 alkynyl group, C3-8 cycloalkyl group,C3-8 cycloalkenyl group, C6-14 aryl group or C7-16 aralkyl group, eachof which may have 1 to 5 substituents selected from Substituentgroup A described above, and   Y is a methylene group which may have 1 or 2 substituentsselected from Substituent group A described above.
    [3]
    The compound according to claim 1, wherein A is (1) abond, (2) a group represented by the formula -CRa=CRb- (Ra and Rb each represent a hydrogen atom or a C1-6 alkyl group), (3) a grouprepresented by the formula -(CONH)p-(C(Rc) (Rd))q- (Rc and Rd eachrepresent a hydrogen atom or a C1-6 alkyl group, p represents 0 or1 and q represent s 1 or 2), (4) a group represented by theformula -CH2OCH2- or (5) a group represented by the formula -OCH2-,   R1 is (1) a cyano group, (2) a carboxyl group, (3) a C1-6alkoxycarbonyl group, (4) a carbamoyl group or (5) an N-mono-C1-6alkylcarbamoyl group,   R2 is (1) a hydrogen atom, (2) a hydroxy group, (3) a C1-6alkoxy group, (4) a C7-16 aralkyloxy group, (5) an amino group, (6)a mono-C1-6 alkylamino group which may have one substituentselected from carboxyl, carbamoyl, quinolyl, phenoxy and pyridyl,(7) a mono-C7-16 aralkylamino group which may have one substituentselected from a halogen atom, cyano, C1-6 alkoxy, carboxyl and C1-6alkoxycarbonyl, (8) a mono-C6-14 arylamino group, (9) a mono-C1-6alkylcarbonylamino group which may have 1 to 3 substituentsselected from a halogen atom, thienyl and C1-6 alkoxycarbonyl-C1-6alkylthio, (10) a mono-C1-6 alkylsulfonylamino group, (11) a mono-C6-14arylcarbonylamino group which may have one substituentselected from C1-6 alkoxy and C1-6 alkylcarbonylamino, (12) aquinolylcarbonylamino group, (13) a pyridylcarbonylamino groupwhich may have 1 or 2 halogen atoms, (14) an indolylcarbonylaminogroup, (15) a N-C1-6 alkyl-N-C1-6 alkylcarbonylamino group which mayhave 1 to 4 substituents selected from a halogen atom, C1-6alkoxycarbonyl and quinolyl, (16) a N-C1-6 alkylcarbonyl-N-C7-16aralkylamino group which may have 1 to 3 halogens, (17) a N-C1-6alkyl-N-pyridylcarbonylamino group, (18) a C1-6 alkylideneaminogroup which may have one di-C1-6 alkylamino, (19) a mono-C1-6alkylureido group which may have one C1-6 alkoxycarbonyl, (20) adi-C1-6 alkylureido, (21) a mono-C6-14 arylureido group, (22) a 1-imidazolidinylgroup which may have 1 to 3 substituents selectedfrom C1-6 alkyl and oxo, (23) a C1-6 alkyl group, (24) a C1-6alkoxycarbonyl group, (25) a nitro group or (26) a 1-pyrrolidinylgroup, orR2 and A or R1 may be taken together with the adjacent carbon atom to form a nitrogen-containing 5- to 7-membered ring which may have1 to 3 substituents selected from (1) a hydroxy group, (2) C1-6alkyl which may have one C1-6 alkoxy-carbonyl, (3) C7-16 aralkyl,(4) C6-14 aryl and (5) oxo,   R3 and R4 are each a C1-6 alkyl group,   R5 is a hydrogen atom,   R6 is a C1-6 alkoxy group,   R7 and R8 are each a C1-6 alkyl group,   R9 and R10 are each a hydrogen atom,   Y is a methylene group and   n is 0.
    [4]
    A compound represented by the formula
    [5]
    A compound represented by the formula
    [6]
    The compound according to claim 4, wherein A is (1) abond or (2) a group represented by the formula -CH=CH-.
    [7]
    The compound according to claim 5, wherein A is (1) agroup represented by the formula -CH=CH-, (2) a group representedby the formula -(C(Rc) (Rd))- (Rc and Rd each represent a hydrogenatom or a C1-6 alkyl group) or (3) a group represented by theformula -CH2OCH2-.
    [8]
    The compound according to claim 4, wherein R1 is acarboxyl group or a carbamoyl group.
    [9]
    The compound according to claim 5, wherein R1 is acarboxyl group.
    [10]
    The compound according to claim 4, wherein R2 is (1) aC1-6 alkoxy group, (2) a mono-C1-6 alkylamino group, (3) a mono-C7-16aralkylamino group, (4) a quinolylcarbonylamino group or (5) apyridylcarbonylamino group.
    [11]
    The compound according to claim 4 or 5, wherein R3 andR4 are each methyl.
    [12]
    The compound according to claim 4 or 5, wherein R6 isethoxy.
    [13]
    The compound according to claim 4 or 5, wherein R7 andR8 are each methyl.
    [14]
    The compound according to claim 4, which is 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(phenylmethyl)amino]benzoicacid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-(ethylamino)benzoicacid, (E)-3-[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-methoxyphenyl]-2-propenoicacid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-quinolinylcarbonyl)amino]benzoicacid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-2-[(2-pyridinylcarbonyl)amino]benzeneacetic acid, N-[2-(aminocarbonyl)-5-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]-2-pyridinecarboxamideor a salt thereof.
    [15]
    The compound according to claim 5, which is [[4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)phenyl]methoxy]acetic acid, 4-(6-ethoxy-3,4,8,9-tetrahydro-3,3,8,8-tetramethylfuro[2,3-h]isoquinolin-1-yl)-α,α-dimethylbenzeneacetic acid or a salt thereof.
    [16]
    The pharmaceutical composition comprising the compoundaccording to claim 1 or a prodrug thereof.
    [17]
    The pharmaceutical composition according to claim 16,which is a phosphodiesterase IV inhibitor.
    [18]
    The pharmaceutical composition according to claim 16,which is a prophylactic and/or therapeutic agent againstinflammatory diseases, atopic dermatitis, allergic rhinitis,asthma, chronic obstructive pulmonary diseases, chronic rheumatoidarthritis, autoimmune diseases, depression, Alzheimer's dementia,memory disorders, osteoporosis, diabetes or atherosclerosis.
    [19]
    A method of inhibiting phosphodiesterase IV, whichcomprises administering to a mammal an effective amount of thecompound according to claim 1 or a prodrug thereof.
    [20]
    A method of preventing and/or treating inflammatorydiseases, atopic dermatitis, allergic rhinitis, asthma, chronicobstructive pulmonary diseases, chronic rheumatoid arthritis,autoimmune diseases, depression, Alzheimer's dementia, memorydisorders, osteoporosis, diabetes or atherosclerosis, whichcomprises administering to a mammal an effective amount of thecompound according to claim 1 or a prodrug thereof.
    [21]
    Use of the compound according to claim 1 or a prodrugthereof for manufacturing a phosphodiesterase IV inhibitor.
    [22]
    Use of the compound according to claim 1 or a prodrugthereof for manufacturing a prophylactic and/or therapeutic agent against inflammatory diseases, atopic dermatitis, allergicrhinitis, asthma, chronic obstructive pulmonary diseases, chronicrheumatoid arthritis, autoimmune diseases, depression, Alzheimer'sdementia, memory disorders, osteoporosis, diabetes oratherosclerosis.
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    CN1681823A|2005-10-12|
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    优先权:
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    PCT/JP2003/009386|WO2004011470A1|2002-07-26|2003-07-24|Furoisoquinoline derivative and use thereof|
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