Novel imidazoline compounds

专利摘要:
Compounds represented by the general formula (I):wherein Ar1 and Ar2 are each aryl or heteroaryl; R1 is lowercycloalkyl, -Ar3, or a group of the general formula (a), (b)or (c):orand R2 and R3 are each hydrogen, lower cycloalkyl, lower alkenyl,or optionally substituted lower alkyl (with the proviso thatwhen R2 and R3 are simultaneously hydrogen, Ar1, Ar2 and R1 donot simultaneously represent unsubstituted phenyl). Thecompounds are useful as treating agents for various NPY-relateddiseases, for example, circulatory diseases includinghypertension, kidney diseases, cardiac diseases, vasospasm andarteriosclerosis; central nervous system diseases includinghyperphagia, depression, anxiety, convulsion, epilepsy,dementia, pain, alcohol dependence, and withdrawal symptoms dueto abstinence from drugs; metabolic diseases including obesity,diabetes, hormonal disorders, hypercholesterolemia, andhyperlipidemia; sexual dysfunction and reproductive functiondisorders; digestive diseases including enterokinetic disorders; respiratory diseases; inflammation; or glaucoma.
公开号:EP1264826A1
申请号:EP01906215
申请日:2001-02-22
公开日:2002-12-11
发明作者:Nagaaki c/o BANYU PHARMACEUTICAL CO. LTD. SATO；Osamu c/o BANYU PHARMACEUTICAL CO. LTD. OKAMOTO；Makoto c/o BANYU PHARMACEUTICAL CO. LTD JITSUOKA；Keita c/o BANYU PHARMACEUTICAL CO. LTD. NAGAI；Akio c/o BANYU PHARMACEUTICAL CO. LTD. KANATANI；Akane c/o BANYU PHARMACEUTICAL CO. LTD ISHIHARA；Yasuyuki c/o BANYU PHARMACEUTICAL CO. LTD ISHII；Takehiro c/o BANYU PHARMACEUTICAL CO. LTD FUKAMI
申请人:Banyu Phamaceutical Co Ltd；
IPC主号:C07D401-00

专利说明:
[0001] The present invention is useful in medical fields.In more detail, novel imidazoline compounds of this inventionare useful as neuropeptide Y receptor antagonists and as agentsfor the treatment of various kinds of cardiovascular disorders,central nervous system disorders, metabolic diseases, or thelike. Background Art
[0002] Neuropeptide Y (hereinafter referred to as NPY), a peptideconsisting of 36 amino acids, was first isolated from porcinebrain by Tatemoto et al. in 1982 (Nature, 296: 659(1982)). NPYis widely distributed in the central nervous system and theperipheral nervous system and plays various roles as one of themost abundant peptide in the nervous system. That is, NPY actsas an orexigenic substance in the central nervous system andmarkedly promotes fat accumulation via the secretion of varioushormones or the action of the nervous system. It is known thatthe continuous intracerebroventricular administration of NPYinduces obesity and insulin resistance based on these actions(International Journal of Obesity, vol.19:517(1995);Endocrinology, vol.133:1753(1993)). It is also known that NPYhas central effects, such as depression, anxiety, schizophrenia,pain, dementia, or the like (Drugs, vol.52: 371(1996)). Further,in the periphery, NPY coexistswithnorepinephrine in sympathetic nerve ending and is involved in the tonicity of the sympatheticnervous system. It is known that peripheral administration ofNPY causes vasoconstriction and enhances the effects of othervasoconstrictive substances such as norepinephrine (BritishJournal of Pharmacology, vol.95: 419(1988)). It is alsoreported that NPY is involved in the enhancement of cardiachypertrophy as a result of the acceleration of sympatheticnervous system (Proceeding National Academic Science USA, vol.97: 1595(2000)).
[0003] Further, it is reported that NPY is also involved in thesecretory function of sexual hormones and growth hormone, sexualand reproductive function, gastro-intestinal motility,bronchoconstriction, inflammation and alcohol preference (LifeScience, vol. 55: 551(1994); The Journal of Allergy andImmunology, vol. 101:S345(1998); Nature, vol.396: 366(1998)).
[0004] NPY has a variety of pharmacological effects which resultfrom its binding to some receptors to which peptide YY andpancreatic polypeptide, which are similar to NPY, also bind.It is known that these pharmacological effects are caused andmediatedby the action of, at least, five receptors with or withoutsynergistic interactions (Trends in Neuroscience, vol.20:294(1997)).
[0005] It is reported that the central action mediatedby NPY Y1 receptor includes the remarkable orexigeniceffect(Endocrinology, vol. 137: 3177(1996); Endocrinology,vol.141: 1011(2000)). Further, it is reported that NPY Y1receptor is involved in anxiety and pain (Nature, vol. 259:528(1993); Brain research, vol. 859: 361(2000)). In addition,the pressor effects mediated by the strong action of vasoconstriction in the periphery is also reported. (FEBSLetters, vol.362: 192(1995); Nature Medicine, vol. 4:722(1998)).
[0006] It is known that actions mediated by NPY Y2 receptor includethe inhibitory effect on the release of various neurotransmittersin the nerve endings (British Journal of Pharmacology, vol. 102:41(1991); Synapse, vol.2: 299(1988)). In the periphery, NPYcauses constriction of blood vessel or vas deferens directlyor by controlling these neurotransmitters (The Journal ofPharmacology and Experimental Therapeutics, vol.261:863(1992); British Journal of Pharmacology, vol. 100:190(1990)). In addition, inhibition of lipolysis in adiposetissues is known (Endocrinology, vol. 131: 1970(1992)). Further,the inhibition of ion secretion in the gastro-intestinal tractis reported (British Journal of Pharmacology, vol. 101:247(1990)).
[0007] On the other hand, the effect on the central nervous systemfunctions such as memory and anxiety are also reported (BrainResearch, vol. 503: 73(1989); Peptides, vol. 19: 359(1998)).
[0008] It is reported that NPY Y3 receptor is expressed mainlyin brain stem and in the heart and is related to regulation ofblood pressure and heart rate (The Journal of Pharmacology andExperimental Therapeutics, vol. 258: 633(1991); Peptides, vol.11: 545(1990)). Further, it is known that NPY Y3 receptor isinvolved in the control of catecholamine secretion in adrenalgland (The Journal of Pharmacology and Experimental Therapeutics,vol. 244: 468(1988); Life Science, vol. 50: PL7 (1992)).
[0009] NPY Y4 receptor has a high affinity especially forpancreatic polypeptide and has pharmacological effects on the inhibition of pancreatic exocrine secretion and thegastro-intestinal motility (Gastroenterology, vol.85:1411(1983)). Further, it is reported that NPY enhances thesecretion of the sexual hormone in the central nervous system(Endocrinology, vol. 140: 5171 (1999)).
[0010] The effects mediated by NPY Y5 receptor include theremarkable fat accumulating action including the orexigeniceffect (Nature, vol. 382: 168(1996)); American Journal ofPhysiology, vol. 277: R1428 (1999)). It is reported that theNPY Y5 receptor also mediates the central nervous system effects,such as seizure and epilepsy, or pain and the morphine withdrawalsymptoms (Nature Medicine, vol.3: 761(1997); ProceedingNational Academic Science USA, vol. 96: 13518(1999)); The Journalof Pharmacology and Experimental Therapeutics, vol. 284:633(1998)). It is reported that in the periphery, NPYY5 receptoris involved in diuretic action and hypoglycemic effect (BritishJournal of Pharmacology, vol. 120: 1335(1998); Endocrinology,vol. 139: 3018(1998)). It is also reported that NPY enhancescardiac hypertrophy as a result of the acceleration ofsympathetic nervous system (Proceeding National AcademicScience USA, vol. 97: 1595(2000)).
[0011] The function of NPY is caused by binding to the NPY receptorsexisting in the central or peripheral nervous system. Therefore,expression of the effect of NPY can be curbed by blocking thebinding of NPY to NPY receptors. Substances which antagonizeNPY binding to NPY receptors may be useful for the prophylaxisor treatment of various diseases which NPY relates to, such ascardiovascular disorders exemplified by hypertension,nephropathy, heart diseases and vasospasm, central nervous system disorders exemplified by bulimia, depression, anxiety,convulsion, epilepsy, dementia, pain, alcoholism and drugwithdrawal, metabolic diseases exemplified by obesity, diabetesand hormone abnormality, sexual and reproductive dysfunction,gastro-intestinal motility disorder, respiratory disorder,inflammation or glaucoma, or the like (Trends in PharmacologicalScience, 15: 153(1994); Life Science, 55: 551(1994); Drugs, vol.52: 371(1996); The Journal of Allergy and Immunology, vol. 101:S345(1998); Nature, vol.396: 366(1998); The Journal ofPharmacology and Experimental Therapeutics, vol. 284:633(1998); Trends in Pharmacological Science, vol.20:104(1999); Proceeding National Academic Science USA, vol. 97:1595(2000)).
[0012] Recently, the investigation of the present inventors hasrevealed that some kind of NPY receptor antagonist is usefulin the prophylaxis or treatment of hypercholesterolemia,hyperlipidemia and arteriosclerosis (International applicationpublication WO99/27965).
[0013] Imidazolone derivatives are disclosed in Internationalapplication publication W099/48888 and these compounds aredescribed to have NPY receptor antagonistic activities.However, the compounds of the present invention are neitherdisclosed nor suggested.
[0014] 2,4,4-triphenyl-2-imidazoline is described inCA 52:17240f of Chemical Abstracts, however, NPY receptorantagonistic activities of the compound are neither disclosednor suggested. Disclosure of Invention
[0015] The object of the present invention is to provide novelmedicines having NPY antagonistic activities.
[0016] The present inventors have discovered that the compoundsrepresented by the general formula (I):
[0017] The compounds of the present invention (I) are useful asagents for the treatment of various diseases which NPY relatesto, that is, for example, cardiovascular disorders exemplifiedby hypertension, nephropathy, heart diseases, vasospasm andarteriosclerosis, central nervous system disorders exemplifiedby bulimia, depression, anxiety, convulsion, epilepsy, dementia,pain, alcoholism and drug withdrawal, metabolic diseasesexemplified by obesity, diabetes, hormone abnormality,hypercholesterolemia and hyperlipidemia, sexual andreproductive dysfunction, gastro-intestinal disorder such asthe inhibition of gastro-intestinal motility, respiratorydisorder, inflammation, or glaucoma, or the like since they exhibit NPY antagonistic activities and are excellent ininternal kinetics such as intracerebral transition ortransition to cerebrospinal fluid.
[0018] More particularly, the compounds of the present invention(I) are useful as agents for the treatment of bulimia, obesity,diabetes, or the like.
[0019] The present invention relates to the compounds representedby the general formula (I), the salts or esters thereof, andthe process for production as well as the use thereof.
[0020] Further, the present invention relates to theintermediates for producing the compounds represented by thegeneral formula (I). That is, the present invention relatesto the compounds represented by the general formula (II'):
[0021] The means of terms used in the present specification aredefined and more detailed description of this invention is shown in the following.
[0022] "Halogen atom" means fluorine atom, chlorine atom, bromineatom or iodine atom.
[0023] "Lower alkyl" means a straight- or branched-chain alkylgroup of C1 to C6 and includes, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, hexyl, isohexyl, or the like.
[0024] "Halo(lower)alkyl" means the aforesaid lower alkylsubstituted with 1 or not less than 2, preferably 1 to 3aforesaid halogen atoms identically or differently at thesubstitutable, arbitrarypositions, andincludes, for example,fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,1,2-difluoroethyl, chloromethyl, 2-chloroethyl,1,2-dichloroethyl, bromomethyl, iodomethyl, or the like.
[0025] "Hydroxy(lower)alkyl" means the aforesaid lower alkylsubstituted with 1 or not less than 2, preferably 1 or 2 hydroxygroups at the substitutable, arbitrary positions and includes,for example, hydroxymethyl, 2-hydroxyethyl,1-hydroxy-1-methylethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl,or the like.
[0026] "Cyclo(lower)alkyl" means a cycloalkyl group of C3 to C6and includes cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl.
[0027] "Cyclo(lower)alkyl(lower)alkyl" means the aforesaidlower alkyl substituted with 1 or not less than 2cyclo(lower)alkyl groups, preferably 1 aforesaid cyclo (lower)alkyl group at the substitutable, arbitrary positions andincludes, for example, cyclopropylmethyl, 2-cyclopropylethyl,3-cyclopropylpropyl, cyclobutylmethyl, 2-cyclobutylethyl, 3-cyclobutylpropyl, cyclopentylmethyl, 2-cyclopentylethyl,3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl,3-cyclohexylpropyl, or the like.
[0028] "Lower alkenyl" means a straight- or branched-chainalkenyl group of C2 to C6 and includes, for example, vinyl,1-propenyl, 2-propenyl, isopropenyl, 3-butenyl, 2-butenyl,1-butenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl,1-ethyl-1-ethenyl, 2-methyl-2-propenyl, 2-methyl-1-propenyl,3-methyl-2-butenyl, 4-pentenyl, or the like.
[0029] "Lower alkylamino" means an amino group mono-substitutedwith the aforesaid lower alkyl group and includes, for example,methylamino, ethylamino, propylamino, isopropylamino,butylamino, sec-butylamino, tert-butylamino, or the like.
[0030] "Di-lower alkylamino" refers to an amino groupdi-substituted with identical or different aforesaidlower alkyl and includes, for example, dimethylamino,diethylamino, ethylmethylamino, dipropylamino,methylpropylamino, diisopropylamino, or the like.
[0031] "Lower alkanoyl" means an alkanoyl group containing theaforesaid lower alkyl, that is, an alkanoyl group of C2 to C7and includes, for example, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl, or the like.
[0032] "Lower alkanoyl amino" means an amino groupmono-substituted with the aforesaid lower alkanoyl and includes,for example, acetylamino, propionylamino, butyrylamino,isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino,or the like.
[0033] "Lower alkylsulfonyl" means a alkylsulfonyl groupcontaining the aforesaid lower alkyl and includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, or the like.
[0034] "Lower alkylsulfonylamino" means an amino groupmono-substituted with the aforesaid lower alkylsulfonyl andincludes, for example, methylsulfonylamino, ethylsulfonylamino,propylsulfonylamino, isopropylsulfonylamino,butylsulfonylamino, sec-butylsulfonylamino,tert-butylsulfonylamino, or the like.
[0035] "Aryl" includes, for example, phenyl, naphthyl or the like.
[0036] "Arylsulfonyl" means an arylsulfonyl group containing theaforesaid aryl and include, for example, phenylsulfonyl,1-naphthylsulfonyl, 2-naphtylsulfonyl, or the like.
[0037] "Arylsulfonylamino" means an amino group mono-substitutedwith the aforesaid arylsulfonyl and includes, forexample, phenylsulfonylamino, 1-naphthylsulfonylamino,2-naphtylsulfonylamino, or the like.
[0038] "Lower alkoxy" means a straight- or branched-chain alkoxygroup of C1 to C6 and include, for example, methoxy, ethoxy,propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy,tert-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy,or the like.
[0039] "Halo(lower)alkoxy" refers to the aforesaid lower alkoxysubstituted with 1 or not less than 2, preferably 1 to 3aforesaid halogen atoms identically or differently at thesubstitutable, arbitrary positions and includes, for example,fluoromethoxy, difluoromethoxy, trifluoromethoxy,2-fluoroethoxy, 1,2-difluoroethoxy, chloromethoxy,2-chloroethoxy, 1,2-dichloroethoxy, bromomethoxy, iodomethoxy, or the like.
[0040] "Aryloxy" means an aryloxy group containing the aforesaidaryl and includes, for example, phenoxy, 1-naphtoxy, 2-naphtoxy,or the like.
[0041] "Lower alkylthio" means a straight- or branched-chainalkylthio group of C1 to C6 and includes, for example, methylthio,ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio,isobutylthio, tert-butylthio, pentylthio, isopentylthio,hexylthio, isohexylthio, or the like.
[0042] "Lower alkoxycarbonyl" means an alkoxycarbonyl groupcontaining the aforesaid lower alkoxy group, that is, analkoxycarbonyl group of C2 to C7 and includes, for example,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, or the like.
[0043] "Lower alkylcarbamoyl" refers to a carbamoyl groupmono-substituted with the aforesaid lower alkyl and includes,for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl,tert-butylcarbamoyl, or the like.
[0044] "Di-lower alkylcarbamoyl" means a carbamoyl groupdi-substituted with the aforesaid lower alkyl and includes, forexample, dimethylcarbamoyl, diethylcarbamoyl,ethylmethylcarbamoyl, dipropylcarbamoyl,methylpropylcarbamoyl, diisopropylcarbamoyl, or the like.
[0045] "Heteroaryl" means a 5- or 6-membered monocyclicheteroaromatic group which contains 1 or not less than 2,preferably 1 to 3 hetero atoms identically or differentlyselected from the group of oxygen atom, nitrogen atom and sulfur atom, or "Heteroaryl" means a condensed cyclic heteroaromaticgroup, where the aforesaid monocyclic heteroaromatic group iscondensed with the aforesaid aryl group, or the identical ordifferent aforesaid monocyclic heteroaromatic group arecondensed each other and includes, for example, pyrrolyl, furyl,thienyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl1,3,4-thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl,purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,1,5-naththyridinyl, or the like.
[0046] "Heteroaryloxy" means a heteroaryloxy group whichcontains the aforesaid heteroaryl group and includes, for example,2-thienyloxy, 3-thienyloxy, 2-pyridyloxy, 3-pyridyloxy,4-pyridyloxy, 3-indolyloxy, 4-indolyloxy, 5-indolyloxy,6-indolyloxy, and the like.
[0047] The salts of compounds represented by the general formula(I) means the pharmaceutically acceptable and common salts andinclude, for example, base addition salt to carboxyl group whenthe compound has a carboxyl group, or acid addition salt to aminoor basic heterocyclyl when the compound has an amino or a basicheterocyclyl group.
[0048] The aforesaid base addition salts include saltswith alkali metals (for example, sodium, potassium, etc.);alkaline earth metals (for example, calcium, magnesium, etc.); ammonium; organic amines (for example trimethylamine,triethylamine, dicyclohexylamine, ethanolamine,diethanolamine, triethanolamine, procaine,N,N'-dibenzylethylenediamine, etc.); or the like.
[0049] The aforesaid acid addition salts include salts withinorganic acids (for example, hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid, perchloric acid, etc.); organicacids (for example, maleic acid, fumaric acid, tartaric acid,citric acid, ascorbic acid, trifluoroacetic acid, etc.);sulfonic acids (for example, methanesulfonic acid,isethionicacid, benzenesulfonic acid, p-toluenesulfonic acid, etc.); orthe like.
[0050] The esters of the compounds represented by the generalformula (I) refer to, for example, the pharmaceuticallyacceptable, common esters on the carboxyl group when the compoundhas a carboxyl group and include, for example, esters with loweralkyls (for example, methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl,cyclopropyl, cyclobutyl, cyclopentyl, etc.), aralkyls (forexample, benzyl, phenethyl, etc.), lower alkenyls (for example,allyl, 2-butenyl, etc.), lower alkoxy (lower)alkyls (for example,methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, etc.), loweralkanoyloxy(lower)alkyls (for example, acetoxymethyl,pivaloyloxymethyl, 1-pivaloyloxyethyl, etc.), loweralokoxycarbonyl(lower)alkyls (for example,methoxycarbonylmethyl, isopropoxycarbonylmethyl, etc.),carboxy(lower)alkyls(for example, carboxymethyl, etc.), loweralkoxycarbonyloxy(lower)alkyls (for example,1-(ethoxycarbonyloxy)ethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, etc.),carbamoyloxy(lower)alkyls (for example, carbamoyloxymethyl,etc.), phthalidyl, (5-substituted-2-oxo-1,3-dioxol-4-yl)methyl (for example, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl,etc.), or the like.
[0051] "An agent for treatment" means a medicament which isemployed for the treatment and/or prophylaxis of variousdiseases.
[0052] In order to disclose the aforesaid compounds representedby the general formula (I), the various symbols used in the formula(I) are explained in more detail by the use of preferredembodiments.
[0053] Ar¹, Ar² and Ar³ represent independently aryl orheteroaryl which may be substituted, the substituent beingselected from the group consisting of cyano, halogen atom, nitro,lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl(lower)alkyl, lower alkenyl, lower alkylamino,di-lower alkylamino, lower alkanoylamino, loweralkylsulfonylamino, arylsulfonylamino, hydroxy, lower alkoxy,halo(lower)alkoxy, aryloxy, heteroaryloxy, lower alkylthio,carboxyl, formyl, lower alkanoyl, lower alkoxycarbonyl,carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl,lower alkylsulfonyl, arylsulfonyl, aryl and heteroaryl.
[0054] The expression "Ar¹, Ar² and Ar³ represent independentlyaryl or heteroaryl which may be substituted, the substituentbeing selected from the group consisting of cyano, halogen atom,nitro, lower alkyl, halo(lower)alkyl, hydroxy(lower)alkyl,cyclo(lower)alkyl(lower)alkyl, lower alkenyl, lower alkylamino,di-lower alkylamino, lower alkanoylamino, lower alkylsulfonylamino, arylsulfonylamino, hydroxy, lower alkoxy,halo(lower)alkoxy, aryloxy, heteroaryloxy, lower alkylthio,carboxyl, formyl, lower alkanoyl, lower alkoxycarbonyl,carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl,lower alkylsulfonyl, arylsulfonyl, aryl and heteroaryl" refersto the unsubstituted aforesaid aryl or the unsubstitutedaforesaid heteroaryl, or the aforesaid aryl or the aforesaidheteroaryl which has substituent(s) at the substitutable,arbitrary position(s). The aforesaid substituent can be,identically or differently, 1 or not less than 2 substituents,preferably 1 or 2 substituents selected from the group consistingof cyano, halogen atom, nitro, lower alkyl, halo(lower)alkyl,hydroxy(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, loweralkenyl, lower alkylamino, di-lower alkylamino, loweralkanoylamino, lower alkylsulfonylamino, arylsulfonylamino,hydroxy, lower alkoxy, halo(lower)alkoxy, aryloxy,heteroaryloxy, lower alkylthio, carboxyl, formyl, loweralkanoyl, lower alkoxycarbonyl, carbamoyl, loweralkylcarbamoyl, di-lower alkylcarbamoyl, lower alkylsulfonyl,arylsulfonyl, aryl and heteroaryl.
[0055] Halogen atom as the aforesaid substituent preferablyincludes, for example, fluorine atom, chlorine atom, bromineatom, or the like.
[0056] Lower alkyl as the aforesaid substituent preferablyincludes, for example, methyl, ethyl, propyl, isopropyl, or thelike.
[0057] Halo(lower)alkyl as the aforesaid substituent preferablyincludes, for example, difluoromethyl, trifluoromethyl, or thelike.
[0058] Hydroxy(lower)alkyl as the aforesaid substituentpreferably includes, for example, hydroxymethyl,2-hydroxyethyl, 1-hydroxy-1-methylethyl, or the like.
[0059] Cyclo(lower)alkyl(lower)alkyl as the aforesaidsubstituent preferably includes, for example,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, or thelike.
[0060] Lower alkenyl as the aforesaid substituent preferablyincludes, for example, vinyl, 1-propenyl, 2-methyl-1-propenyl,or the like.
[0061] Lower alkylamino as the aforesaid substituent preferablyincludes, for example, methylamino, ethylamino, or the like.
[0062] Di-lower alkylamino as the aforesaid substituentpreferably includes, for example, dimethylamino, diethylamino.or the like.
[0063] Lower alkanoyl amino as the aforesaid substituentpreferably includes, for example, acetylamino, propionylamino,or the like.
[0064] Lower alkylsulfonylamino as the aforesaid substituentpreferably includes, for example, methylsulfonylamino,ethylsulfonylamino, or the like.
[0065] Arylsulfonylamino as the aforesaid substituentpreferably includes, for example, phenylsulfonylamino, or thelike.
[0066] Lower alkoxy as the aforesaid substituent preferablyincludes, for example, methoxy, ethoxy, or the like.
[0067] Halo(lower)alkoxy as the aforesaid substituentpreferably includes, for example, fluoromethoxy,difluoromethoxy, trifluoromethoxy, or the like.
[0068] Aryloxy as the aforesaid substituent preferably includes,for example, phenoxy, or the like.
[0069] Heteroaryloxy as the aforesaid substituent preferablyincludes, for example, 2-pyridyloxy, 3-pyridyloxy,4-pyridyloxy, or the like.
[0070] Lower alkylthio as the aforesaid substituent preferablyincludes, for example, methylthio, ethylthio, or the like.
[0071] Lower alkanoyl as the aforesaid substituent preferablyincludes, for example, formyl, acetyl, propionyl, or the like.
[0072] Lower alkoxycarbonyl as the aforesaid substituentpreferably includes, for example, methoxycarbonyl,ethoxycarbonyl, or the like.
[0073] Lower alkylcarbamoyl as the aforesaid substituentpreferably includes, for example, methylcarbamoyl,ethylcarbamoyl, or the like.
[0074] Di-lower alkylcarbamoyl as the aforesaid substituentpreferably includes, for example, dimethylcarbamoyl,diethylcarbamoyl, or the like.
[0075] Lower alkylsulfonyl as the aforesaid substituentpreferably includes, for example, methylsulfonyl,ethylsulfonyl, or the like.
[0076] Arylsulfonyl as the aforesaid substituent preferablyincludes, for example, phenylsulfonyl, or the like.
[0077] Aryl as the aforesaid substituent preferably includes,for example, phenyl, or the like.
[0078] Heteroaryl as the aforesaid substituent preferablyincludes, for example, thienyl, thiazolyl, isothiazolyl,pyridyl, pyrazinyl, or the like.
[0079] The substituent(s) of Ar¹ include, preferably, for example, halogen atom, lower alkyl, halo(lower)alkyl,hydroxy(lower)alkyl, lower alkoxy, halo(lower)alkoxy, loweralkanoyl or the like, more preferably, halogen atom,halo(lower)alkyl, halo(lower)alkoxy, or the like.
[0080] Aryl in Ar¹ includes, preferably, for example, phenyl orthe like, and heteroaryl in Ar¹ includes, preferably, for example,thienyl, pyridyl, or the like.
[0081] Ar¹ is preferably exemplified by phenyl which hassubstituent(s) selected from the group consisting of halogenatom, halo(lower)alkyl and halo(lower)alkoxy, or by thienyl orpyridyl which may have substituent(s) selected from the groupconsisting of halogen atom, halo(lower)alkyl andhalo(lower)alkoxy. More concretely, Ar¹ is for example, phenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl,3-bromophenyl,4-bromophenyl,2-methylphenyl,3-methylphenyl,4-methylphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-hydroxymethylphenyl, 3-hydroxymethylphenyl,4-hydroxymethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-difluoromethoxyphenyl,3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-formylphenyl, 3-formylphenyl,4-formylphenyl, 2-thienyl, 4-chloro-2-thienyl,5-chloro-2-thienyl 4-bromo-2-thienyl, 5-bromo-2-thienyl,4-methyl-2-thienyl, 5-methyl-2-thienyl, 4-methoxy-2-thienyl,5-methoxy-2-thienyl, 3-thienyl, 5-chloro-3-thienyl,5-methyl-3-thienyl, 5-methoxy-3-thienyl 2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 4-methoxy-2-pyridyl,5-methoxy-2-pyridyl, 4-chloro-2-pyridyl, 5-chloro-2-pyridyl,3-pyridyl, 4-methyl-3-pyridyl, 5-methyl-3-pyridyl,4-methoxy-3-pyridyl, 5-methoxy-3-pyridyl, 6-fluoro-3-pyridyl,4-chloro-3-pyridyl, 5-chloro-3-pyridyl, 4-pyridyl,2-fluoro-4-pyridyl, 2-chloro-4-pyridyl, 3-chloro-4-pyridyl,2-methyl-4-pyridyl, 3-methyl-4-pyridyl, 2-methoxy-4-pyridyl,3-methoxy-4-pyridyl, and the like, preferably, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,3-chlorophenyl,4-chlorophenyl,3-bromophenyl, 4-bromophenyl,3-methylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl3-difluoromethoxyphenyl, 4-difluoromethoxyphenyl, 2-thienyl,4-chloro-2-thienyl, 5-chloro-2-thienyl, 4-bromo-2-thienyl,5-bromo-2-thienyl, 3-pyridyl, 4-methoxy-3-pyridyl,5-methoxy-3-pyridyl, 6-fluoro-3-pyridyl, 4-chloro-3-pyridyl,5-chloro-3-pyridyl, 2-fluoro-4-pyridyl, and the like,particularly, 4-fluorophenyl, 6-fluoro-3-pyridyl,2-fluoro-4-pyridyl or the like, more preferably, 4-fluorophenyl,or the like.
[0082] The substituent of Ar² includes, preferably, for example,cyano, halogen atom, nitro, lower alkyl, halo(lower)alkyl, loweralkoxy, halo(lower)alkoxy, formyl, lower alkanoyl, loweralkoxycarbonyl, lower alkylsulfonyl, or the like, morepreferably, cyano, or the like.
[0083] Aryl in Ar² includes, for example, phenyl or the like,and heteroaryl in Ar² includes, for example, a 5- or6-membered monocyclic heteroaromatic group containing 1 or not less than 2, preferably 1 to 3 hetero atoms identically ordifferently selected from the group consisting of oxygen atom,nitrogen atom and sulfur atom, more concretely, for example,thienyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, pyridyl,pyrazinyl, pyrimidinyl, or the like preferably.
[0084] Ar² includes, for example, phenyl which containssubstituent(s) selected from the group consisting of cyano,halogen atom, nitro, lower alkyl, halo(lower)alkyl, lower alkoxy,halo(lower)alkoxy, formyl, lower alkanoyl, loweralkoxycarbonyl and lower alkylsulfonyl, or a 5- or 6-memberedmonocyclic heteroaromatic group containing 1 or not less than2, preferably 1 to 3 hetero atoms identically or differentlyselected from the group consisting of oxygen atom, nitrogen atomand sulfur atom, which may have substituent(s) selected fromthe group consisting of cyano, halogen atom, nitro, lower alkyl,halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, formyl,lower alkanoyl, lower alkoxycarbonyl and lower alkylsulfonyl.5- or 6-membered monocyclic heteroaromatic group includes,preferably, thienyl, thiazolyl, isothiazolyl,1,2,5-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinylor the like.More concretely, Ar² includes, for example, phenyl,3-cyanophenyl,4-cyanophenyl,3-fluorophenyl,4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl,3-nitrophenyl,4-nitrophenyl, 3-methylphenyl,4-methylphenyl,3,5-dimethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-hydroxymethylphenyl,4-hydroxymethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,3-formylphenyl, 4-formylphenyl, 3-acetylphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl,3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 2-thienyl,4-cyano-2-thienyl, 5-cyano-2-thienyl, 4-chloro-2-thienyl,5-chloro-2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 3-isothiazolyl, 4-isothiazolyl,1,2,5-thiadiazol-3-yl, 2-pyridyl, 4-cyano-2-pyridyl,6-cyano-2-pyridyl, 4-chloro-2-pyridyl, 6-chloro-2-pyridyl,4-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl,6-hydroxy-2-pyridyl, 4-methoxy-2-pyridyl,4-methoxycarbonyl-2-pyridyl, 3-pyridyl, 5-cyano-3-pyridyl,5-bromo-3-pyridyl, 4-pyridyl, 2-cyano-4-pyridyl,2-chloro-4-pyridyl, pyrazinyl, 2-pyrimidinyl,4-cyano-2-pyrimidinyl, 4-chloro-2-pyrimidinyl,4-trifluoromethyl-2-pyrimidinyl, 4-carbamoyl-2-pyrimidinyl,4-pyrimidinyl, 6-cyano-4-pyrimidinyl, 6-chloro-4-pyrimidinyl,5-pyrimidinyl, 3-pyridazinyl or the like, preferably,3-cyanophenyl, 3-fluorophenyl, 3-chlorophenyl,3-bromophenyl, 3-nitrophenyl, 3-methylphenyl,3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,3-formylphenyl, 3-methylsulfonylphenyl, 5-thiazolyl,4-isothiazolyl, 1,2,5-thiadiazol-3-yl, 4-cyano-2-pyridyl,6-cyano-2-pyridyl, 3-pyridyl, 5-cyano-3-pyridyl,2-cyano-4-pyridyl, 2-chloro-4-pyridyl, pyrazinyl,4-cyano-2-pyrimidinyl, 6-cyano-4-pyrimidinyl, and the like,more preferably, 3-cyanophenyl, 3-methylsulfonylphenyl,4-cyano-2-pyridyl, 6-cyano-2-pyridyl, 5-cyano-3-pyridyl,2-chloro-4-pyridyl, 4-cyano-2-pyrimidinyl, or the like.
[0085] The substituent(s) of Ar³ include, preferably, for example,halogen atom, lower alkyl, hydroxy(lower)alkyl, lower alkenyl, di-lower alkylamino, lower alkoxy, halo(lower)alkoxy, loweralkanoyl, aryl, or the like.
[0086] Aryl in Ar³ includes, preferably, for example, phenyl,naphthyl, or the like, and heteroaryl in Ar³ includes, preferably,for example, thienyl, pyridyl, quinolyl, 1,5-naphthyridinyl,or the like.
[0087] Ar³ is preferably, phenyl, naphthyl, thienyl, pyridyl,quinolyl, 1,5-naphthyridinyl or the like which may havesubstituent(s) selected from the group consisting of, forexample,halogen atom, lower alkyl, hydroxy(lower)alkyl, lower alkenyl,di-lower alkylamino, lower alkoxy, halo(lower)alkoxy, loweralkanoyl, aryl, and the like, more concretely, for example,phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 3,4-dimethylphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-hydroxymethylphenyl, 4-hydroxymethylphenyl, 3-vinylphenyl,4-vinylphenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,2-difluoromethoxyphenyl, 3-difluoromethoxyphenyl,4-difluoromethoxyphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,3-formylphenyl,4-formylphenyl, 4-biphenylyl, 1-naphthyl,2-naphthyl,2-thienyl,4-chloro-2-thienyl, 5-chloro-2-thienyl,4-bromo-2-thienyl, 5-bromo-2-thienyl, 4-methyl-2-thienyl,5-methyl-2-thienyl, 4-methoxy-2-thienyl, 5-methoxy-2-thienyl,3-thienyl, 5-chloro-3-thienyl, 5-methyl-3-thienyl,5-methoxy-3-thienyl, 2-pyridyl, 5-fluoro-2-pyridyl, 4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 4-methyl-2-pyridyl,5-methyl-2-pyridyl, 4-methoxy-2-pyridyl,5-methoxy-2-pyridyl,3-pyridyl, 6-fluoro-3-pyridyl, 4-chloro-3-pyridyl,5-chloro-3-pyridyl, 6-chloro-3-pyridyl,4-methyl-3-pyridyl,5-methyl-3-pyridyl, 4-methoxy-3-pyridyl,5-methoxy-3-pyridyl, 6-methoxy-3-pyridyl,6-difluoromethoxy-3-pyridyl, 4-pyridyl, 2-fluoro-4-pyridyl,2-chloro-4-pyridyl, 3-chloro-4-pyridyl, 2-methyl-4-pyridyl,3-methyl-4-pyridyl, 2-methoxy-4-pyridyl, 3-methoxy-4-pyridyl,3-quinolyl, 6-quinolyl, 1,5-naphthyridin-3-yl, and the like,preferably, phenyl, 3-fluorophenyl, 4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-methylphenyl,4-methylphenyl, 3,4-dimethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,3-vinylphenyl, 4-vinylphenyl, 4-dimethylaminophenyl,2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3 -difluoromethoxyphenyl, 4-difluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl,4-formylphenyl, 4-biphenylyl, 2-naphthyl, 2-thienyl,5-chloro-2-thienyl, 5-methyl-2-thienyl, 5-methoxy-2-thienyl,2-pyridyl, 5-fluoro-2-pyridyl, 3-pyridyl, 6-fluoro-3-pyridyl,6-chloro-3-pyridyl, 6-methoxy-3-pyridyl,6-difluoromethoxy-3-pyridyl, 4-pyridyl, 2-fluoro-4-pyridyl,3-quinolyl, 6-quinolyl, 1,5-naphthyridin-3-yl, and the like,particularly, 6-fluoro-3-pyridyl, 2-fluoro-4-pyridyl, and thelike, more preferably, 6-fluoro-3-pyridyl, or the like.
[0088] R¹ represents cyclo(lower)alkyl or a group representedby the formula of -Ar³;
[0089] Cyclo(lower)alkyl in R¹ includes, for example, cyclobutyl,cyclopentyl or cyclohexyl, or the like preferably.
[0090] The definition and preferred examples of Ar³ are aforesaid.
[0091] In the group represented by the formula of (a), (b) or(c), n means 0, 1 or 2; both R¹⁰ and R¹¹ represent hydrogen atomor they combine to represent oxo; X and Y represent independentlymethylene, ethenylene, a group represented by the formula of-NR¹²-, oxygen atom or sulfur atom; Z represents methine ornitrogen atom; and R¹² represents hydrogen atom or lower alkyl.
[0092] With regards to the group represented by the formula of(a), (b) or (c), it is preferred that n represents 0 or 1; bothR¹⁰ and R¹¹ combine to represent oxo; X and Y representindependently methylene, ethenylene, the group represented bythe formula of -NR¹²- or oxygen atom; Z represents methine; andR¹² represents hydrogen atom. That is, a group represented bythe formula of (a₀) or (b₀) when n is 0, or the like is preferable.
[0093] And a group represented by the formula of (a₁), (b₁) or(c₁) when n is 1, or the like is preferable.
[0094] Further, in case n is 0, it is preferred that the combinationof X and Y is, for example, oxygen atom and methylene, oxygenatom and ethenylene, oxygen atom and imino, or the like. Incase n is 1, it is preferred that the combination of X and Yis, for example, imino and oxygen atom, oxygen atom and oxygenatom, and the like.
[0095] Therefore, more concretely, with regards to a grouprepresented by the formula of (a), (b) or (c), a group representedby the formula of (aa), or the like is preferable.
[0096] With regard to R¹, a group represented by the formula of-Ar³ is preferable.
[0097] R² and R³ represent independently hydrogen atom,cyclo(lower)alkyl, lower alkenyl or lower alkyl which may besubstituted, the substituent being selected from the groupconsisting of halogen atom, lower alkylamino, di-loweralkylamino, lower alkanoylamino, hydroxy, loweralkoxy, formyl,lower alkoxycarbonyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl.
[0098] Cyclo(lower)alkyl represented by R² or R³ includes, forexample, cyclopentyl, cyclohexyl, or the like preferably.
[0099] Lower alkenyl represented by R² or R³ includes, for example,vinyl, 1-propenyl, 2-propenyl, or the like preferably.
[0100] "Lower alkyl which may be substituted, the substituentbeing selected from the group consisting of halogen atom, loweralkylamino, di-lower alkylamino, lower alkanoylamino, hydroxy,lower alkoxy, formyl, lower alkoxycarbonyl, loweralkylcarbamoyl and di-lower alkylcarbamoyl" represents theunsubstituted aforesaid lower alkyl or the aforesaid lower alkylcontaining 1 or not less than 2, preferably 1 or 2 substituentsat the substitutable, arbitrary position(s) identically ordifferently, the substituent being selected from the groupconsisting of halogen atom, lower alkylamino, di-loweralkylamino, lower alkanoylamino, hydroxy, lower alkoxy, formyl,lower alkoxycarbonyl, lower alkylcarbamoyl and di-loweralkylcarbamoyl.
[0101] With regard to halogen atom as the substituent, for example,fluorine atom, and the like are preferred.
[0102] With regard to lower alkylamino as the substituent, forexample, methylamino, ethylamino, and the like are preferred.
[0103] With regard to di-lower alkylamino as the substituent,for example, dimethylamino, diethylamino, and the like arepreferred.
[0104] With regard to lower alkanoyl amino as the substituent,for example, acetylamino, propionylamino, and the like arepreferred.
[0105] With regard to lower alkoxy as the substituent, for example, methoxy, ethoxy, and the like are prefereed.
[0106] With regards to lower alkoxycarbonyl as the substituent,for example, methoxycarbonyl, ethoxycarbonyl, and the like arepreferred.
[0107] With regard to lower alkylcarbamoyl as the substituent,for example, methylcarbamoyl, ethylcarbamoyl, and the like arepreferred.
[0108] With regard to di-lower alkylcarbamoyl as the substituent,for example, dimethylcarbamoyl, diethylcarbamoyl, and the likeare preferred.
[0109] With regard to the substituent of lower alkyl in R² orR³, for example, halogen atom, lower alkylamino, di-loweralkylamino, hydroxyl, lower alkoxy, and the like are preferred.
[0110] With regards to lower alkyl in R² or R³, for example, methyl,ethyl, propyl, isopropyl, isobutyl, and the like are preferred,and methyl, and the like are more preferred.
[0111] More concretely, lower alkyl which may have the aforesaidsubstituent(s) and which is represented by R² or R³ includes,for example, methyl, ethyl, propyl, isopropyl, isobutyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,methylaminomethyl, 2-methylaminoethyl, dimethylaminomethyl,2-dimethylaminoethyl, 2-diethylaminoethyl,(acetylamino)methyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl,methoxymethyl,2-methoxyethyl, formylmethyl,methoxycarbonylmethyl, ethoxycarbonylmethyl,(methylcarbamoyl)methyl, (ethylcarbamoyl)methyl,(dimethylcarbamoyl)methyl, (diethylcarbamoyl)methyl, and thelike, particularly, methyl, ethyl, propyl, hydroxymethyl, andthe like, more preferably, methyl, and the like.
[0112] With regard to R² and R³, it is preferred when both arehydrogen atom; or either of them is hydrogen atom and the otheris lower alkyl which may have the aforesaid substituent(s).
[0113] The compounds of the present invention include preferably,for example, (a) compounds, wherein R¹ is the group representedby the formula of -Ar³, and Ar² is phenyl containing substituent(s)selected from the group consisting of cyano, halogen atom, nitro,lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy,formyl, lower alkanoyl, lower alkoxycarbonyl and loweralkylsulfonyl; or R¹ is a group represented by the formula of-Ar³, and Ar² is a 5- or 6-membered monocyclic heteroaromaticgroup which may have substituent(s) selected from the groupconsisting of cyano, halogen atom, nitro, lower alkyl,halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, formyl,lower alkanoyl, lower alkoxycarbonyl and lower alkylsulfonyl,the 5- or 6-membered monocyclic heteroaromatic group containing1 or not less than 2 , preferably 1 to 3 hetero atoms identicallyor differently selected from the group consisting of oxygen atom,nitrogen atom and sulfur atom. The 5- or 6-membered monocyclicheteroaromatic group is more preferably, thienyl, thiazolyl,isothiazolyl, 1,2,5-thiadiazolyl, pyridyl, pyrimidinyl,pyrazinyl; or the like.
[0114] The aforesaid (a) compounds include preferably (b)compounds, wherein Ar¹ is phenyl containing the substituent(s)selected from the group consisting of halogen atom,halo(lower)alkyl and halo(lower)alkoxy or Ar¹ is thienyl orpyridyl which may have substituent(s) selected from the groupconsisting of halogen atom, halo(lower)alkyl andhalo(lower)alkoxy, and the like and include more preferably, (c) compounds, wherein both R² and R³ are hydrogen; or eitherR² or R³ is hydrogen atom and the other is lower alkyl which mayhave substituent(s) selected from the group consisting of halogenatom, lower alkylamino, di-lower alkylamino, loweralkanoylamino, hydoroxy, lower alkoxy, formyl, loweralkoxycarbonyl, lower alkylcarbamoyl and di-loweralkylcarbamoyl, and the like.
[0115] The aforesaid (c) compounds include more preferably, (d)compounds, wherein Ar³ is phenyl, naphthyl, thienyl, pyridyl,quinolyl or 1,5-napththyridinyl, which may have substituent(s)selected from the group consisting of halogen atom, lower alkyl,hydroxy(lower)alkyl, lower alkenyl, di-lower alkylamino, loweralkoxy, halo(lower)alkoxy, lower alkanoyl and aryl.
[0116] Further, the aforesaid (a) compounds preferably include(e) compounds, respectively, wherein Ar¹ is 4-fluorophenyl,6-fluoro-3-pyridyl or 2-fluoro-4-pyridyl, Ar³ is6-fluoro-3-pyridyl or 2-fluoro-4-pyridyl, and either R² or R³is hydrogen atom and the other is methyl, and more preferably,particularly, the compounds, wherein Ar¹ is 4-fluorophenyl, andAr³ is 6-fluoro-3-pyridyl; Ar¹ is 4-fluorophenyl, and Ar³ is2-fluoro-4-pyridyl; both Ar¹ and Ar³ are 6-fluoro-3-pyridyl;or both Ar¹ and Ar³ are 2-fluoro-4-pyridyl; or the like.
[0117] However, the compounds, wherein both R² and R³ are hydrogenatom simultaneously, and Ar¹, Ar² and R¹ are unsubstituted phenylsimultaneously, are deleted from the present invention.
[0118] The compounds of the present invention may includestereoisomers such as optical isomers, diastereoisomers andgeometrical isomers, or tautomers depending upon the mode ofsubstituents. Thus, the compounds of the present invention includes all the stereoisomers, tautomers and a mixture thereof.
[0119] Also the polymorphs, hydrates and solvates of the compoundsof the present invention are included within the scope of theinvention.
[0120] The present invention includes prodrugs of the compoundsof the present invention within its scope. In general, suchprodrugs will be functional derivatives of the compounds of thepresent invention which are readily convertible in vivo intothe compounds which are required in vivo or for the living body.Thus, in the treatment methods of various diseases related tothe present invention, the term "administering" shall encompassadministering of a compound which may not be specificallydisclosed, but which converts to the specifically disclosedcompound in vivo after administration to the patient, in additionto administering of the compound specifically disclosed.Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in"Design of Prodrugs" ed. H. Bundgaard, Elsevier, 1985 or thelike which is incorporated by reference herein in its entirety.Metabolites of these compounds include the active compoundsproduced upon introduction of the compounds of the presentinvention into biological milieu and belong to the category ofthe present invention.
[0121] The specific example of the compound represented by thegeneral formula (I) is, for example, 2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,4,4-bis(4-fluorophenyl)-2-pyradinyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(1,5-naphthyridin-3-yl)-2-imidazoline, 2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-methyl-2-imidazoline, 2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline, 2-(3-cyanophenyl)-4,4-bis(3-fluorophenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(3-quinolyl)-4-(2-thienyl)-2-imidazoline, 4-(4-bromophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline, 4,4-bis(4-chlorophenyl)-2-(3-cyanophenyl)-2-imidazoline, 4-(4-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-quinolyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-phenyl-4-(4-vinylphenyl)-2-imidazoline, 4-(6-chloro-3-pyridyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline, 4-(5-chloro-2-thienyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-methylphenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(3-methylphenyl)-4-phenyl-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-nitrophenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-phenyl-4-(3-quinolyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-methoxyphenyl)-4-phenyl-2-imidazoline, 4-(3-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline. 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(5-methyl-2-thienyl)-2-imidazoline, 2-(3-cyanophenyl)-4-phenyl-4-(4-trifluoromethylphenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(3-methoxyphenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(3,4-dimethylphenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-vinylphenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(2-naphthyl)-4-(3-pyridyl)-2-imidazoline, 4-(3-bromophenyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline, 4-(2-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-quinolyl)-2-imidazoline, 2-(3-cyanophenyl)-4-phenyl-4-(2-thienyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-dimethylaminophenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-pyridyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-formylphenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-thienyl)-2-imidazoline, 4,4-diphenyl-2-pyrazinyl-2-imidazoline, 2-(3-cyanophenyl)-4,4-bis(4-methoxyphenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-formylphenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-methylsulfonylphenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-formylphenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(2-methylphenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-hydroxymethylphenyl)-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(1,2,3,4-tetrahydro-1,5-naphthyridin-7-yl)-2-imidazoline, 2-(3-cyanophenyl)-4-(2-fluorophenyl)-4-(3-pyridyl)-2-imidazoline, 4-(4-biphenylyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(2-methoxyphenyl)-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-cyclohexyl-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(4-pyridyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(5-pyrimidinyl)-2-imidazoline, 2-(3-cyanophenyl)-4-cyclopentyl-4-phenyl-2-imidazoline, 2-(3-cyanophenyl)-4-cyclobutyl-4-phenyl-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-pyridazinyl)-2-imidazoline, 4-(4-fluorophenyl)-5-methyl-2-pyrazinyl-4-(3-quinolyl)-2-imidazoline, (4S,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(3-methylsulfonylphenyl)-5-methyl-2-imidazoline, (4R,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(3-methylsulfonylphenyl)-5-methyl-2-imidazoline, (4S,5S)-2-(5-cyano-3-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(5-cyano-3-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (5R)-2-(2-cyano-4-pyridyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline, (5S)-2-(2-cyano-4-pyridyl)-4,4-bis(4-fluorophenyl)-5-methyl-2-imidazoline, (4S,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline, (5S)-2-(2-cyano-4-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, 4,4-bis(4-fluorophenyl)-5-methyl-2-pyrazinyl-2-imidazoline, 4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-pyrazinyl-2-imidazoline, 5-ethyl-4,4-bis(4-fluorophenyl)-2-pyrazinyl-2-imidazoline, 4,4-bis(4-fluorophenyl)-5-propyl-2-pyrazinyl-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(4-isothiazolyl)-2-imidazoline, 2-(3-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline, 2-(3-chlorophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-trifluoromethylphenyl)-2-imidazoline, 2-(3-fluorophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-trifluoromethoxyphenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(5-thiazolyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-methylphenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(2-thienyl)-2-imidazoline, 2-(5-bromo-3-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline, 2-(3-bromophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline, 4,4-bis(4-fluorophenyl)-2-(3-thienyl)-2-imidazoline, 2-(4-cyano-2-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline, (4S,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, 2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-(1-hydroxyethyl)-2-imidazoline, (4S,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-(1,2,5-thiadiazol-3-yl)-2-imidazoline, (4R,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-(1,2,5-thiadiazol-3-yl)-2-imidazoline, (5R)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-(6-hydroxy-2-pyridyl)-2-imidazoline, (5S)-4,4-bis(4-fluorophenyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-2-(2-chloro-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(2-chloro-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline, (5S)-2-(3-cyanophenyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4S,5R)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline, (4R,5R)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline, (4S,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-5-methyl-4-(1,5-naphthyridin-3-yl)-2-imidazoline, (4R,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-5-methyl-4-(1,5-naphthyridin-3-yl)-2-imidazoline, (4S,5S)-2-(3-cyanophenyl)-4-(6-fluoro-3-pyridyl)-4-(4-fluorophenyl)-5-methyl-2-imidazoline, (4R,5S)-2-(3-cyanophenyl)-4-(6-fluoro-3-pyridyl)-4-(4-fluorophenyl)-5-methyl-2-imidazoline, (5S)-2-(5-cyano-3-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (5R)-2-(4-cyano-2-pyridyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline, 2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-imidazoline, 2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-2-imidazoline, (4S,5R)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline, (4R,5R)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline, (4S,5S)-2-(6-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(6-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline, (4R,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline, (5S)-2-(4-cyano-2-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, (4S,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-5-methyl-4-(3-pyridyl)-2-imidazoline, (4R,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-5-methyl-4-(3-pyridyl)-2-imidazoline, (5R)-2-(4-cyano-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline, (4S,5S)-2-(4-cyano-2-pyrimidyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline, or (4R,5S)-2-(4-cyano-2-pyrimidyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazolineor the like.
[0122] The process for producing the compounds of the presentinvention is illustrated as follows.
[0123] The compounds of the present invention (I) can besynthesized, for example, by the following processes forproduction or the processes shown in Examples, but theseembodiments are not intended to restrict the process forproducing the compounds of the present invention (I). Production Process 1
[0124] A compound represented by the general formula (II):
[0125] When a reactant has an amino, imino, hydroxy, carboxyl,oxo, carbonyl, or the like group which does not participate inthe above reaction, the reaction may be carried out afterprotecting the amino, imino, hydroxy, carboxyl, oxo, carbonyl,or the like group with an protecting group for amino or imino,a protecting group for hydroxyl, a protecting group for carboxyl,or a protecting group for oxo or carbonyl, followed by eliminationof the protecting group after completion of the reaction.
[0126] "Protecting group for amino or imino" preferably includesaralkyl (for example, benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl, trityl, etc.); lower alkanoyl (for example, formyl, acetyl,propionyl, butyryl, pivaloyl, etc.); benzoyl; arylalkanoyl (forexample, phenylacetyl, phenoxyacetyl, etc.); loweralkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl,propyloxycarbonyl, tert-butoxycarbonyl, etc.);aralkyloxycarbonyl (for example, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, phenethyloxycarbonyl, etc.); loweralkylsilyl (for example, trimethylsilyl,tert-butyldimethylsilyl, etc.); or the like, especially, acetyl.pivaloyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, or thelike.
[0127] "Protecting group for hydroxy" preferably includes loweralkylsilyl (for example, trimethylsilyl,tert-butyldimethylsilyl, etc.); lower alkoxymethyl (forexample, methoxymethyl, 2-methoxyethoxymethyl, etc.);tetrahydropyranyl; trimethylsilylethoxymethyl; aralkyl (forexample, benzyl, p-methoxybenzyl, 2,3-dimethoxybenzyl,o-nitrobenzyl, p-nitrobenzyl, trityl, etc.); acyl (for example,formyl, acetyl, etc.), and the like, especially methoxymethyl,tetrahydropyranyl, trityl, trimethylsilylethoxymethyl,tert-butyldimethylsilyl, acetyl, or the like.
[0128] "Protecting group for carboxyl" preferably includes loweralkyl (for example, methyl, ethyl, propyl, isopropyl,tert-butyl, etc.); halo(lower)alkyl (for example,2,2,2-trichloroethyl, etc.); lower alkenyl (for example,2-propenyl, etc.); aralkyl (for example, benzyl,p-methoxybenzyl, p-nitrobenzyl, benzhydryl, trityl, etc.); orthe like, especially, methyl, ethyl, tert-butyl, 2-propenyl,benzyl, p-methoxybenzyl, benzhydryl, or the like.
[0129] "Protecting group for oxo or carbonyl" includes acetalor ketal (for example, ethylene ketal, trimethylene ketal,dimethyl ketal, etc.), or the like.
[0130] The reaction between a compound represented by the generalformula (II) and an acid addition salt of a compound representedby the general formula (III) is usually carried out by employing1 to excessive moles, preferably 1 to 5 moles of the acid additionsalt of the compound (III) per mole of the compound (II).
[0131] The acid addition salt of the compound (III) includespreferably, for example, hydrochloride, or the like.
[0132] The reaction is usually carried out in an inert solvent,and the inert solvent preferably includes, for example, alcohol(for example, methanol, ethanol, etc.), dimethylformamide,dimethyl sulfoxide, or a mixture thereof or the like.
[0133] Reaction temperature is usually -30°C to 200°C, preferably0°C to 150°C.
[0134] Reaction time is usually 30 minutes to 7 days, preferably2 hours to 5 days.
[0135] At the termination of the reaction, a crude product ofa compound represented by the general formula (IV) can be obtainedby usual treatment. Thus obtained compound represented by thegeneral formula (IV) is purified by the conventional method,or not purified, optionally followed by cleavage of theprotecting groups for amino, imino, hydroxyl, carboxyl, oxo,and carbonyl to give the compound represented by the generalformula (I).
[0136] The cleavage of protecting groups may be carried out, forexample, by the manner described in the literature (ConferProtective Groups in Organic Synthesis, T. W. Greene, John Wiley & Sons, (1981)) or by its similar manner, for example, solvolysisusing, for example, 0.01 mole to a large excess of acid, preferablytrifluoroaceticacid, formicacid, hydrochloric acid or the like,or 1 mole to a large excess of base, preferably potassium hydroxide.calcium hydroxide or the like; chemical reduction using metalliccomplex hydride, or the like; or catalytic reduction usingpalladium-carbon catalyst, Raney nickel catalyst or the like,depending upon the kinds of the aforesaid protecting groups,the stability of the desired compound (I) and so on. Production Process 2
[0137] A compound represented by the general formula (II):
[0138] The reaction in the presence of tri(lower)alkylaluminumbetween a compound represented by the general formula (II) anda compound represented by the general formula (V) is usuallycarried out by employing 0.5 to 5 moles, preferably 0.7 to 3moles of the compound (V) and 1 to excessive moles, preferably1 to 5 moles of tri(lower)alkylaluminum per mole of the compound(II).
[0139] Tri(lower)alkylaluminum used for the reaction includes,for example, trimethylaluminum, triethylaluminum,tripropylaluminum, tributylaluminum, and the like.
[0140] The reaction is usually carried out in an inert solvent,and the inert solvent preferably includes, for example, benzene,toluene, xylene, methylene chloride, chloroform, hexane or amixture thereof, or the like.
[0141] Reaction temperature is usually -20°C to a boiling pointof a solvent used for the reaction, preferably 0°C to 110°C.
[0142] Reaction time is usually 30 minutes to 3 days, preferably3 to 24 hours.
[0143] A compound represented by the general formula (I) can beproduced by treating a reaction mixture in the usual way after elimination of a protecting group if the product has a protectinggroup after termination of the reaction, or by treating themixture as it is in the usual way if the protecting group isabsent in the reaction product.
[0144] Cleavage of the protecting groups and post-treatment, andthe like can be carried out according to the method as describedin the aforesaid production process 1. Production Process 3
[0145] A compound represented by the general formula (II):
[0146] Then the product (VII) is subjected intramolecularcyclo-condensation reaction to provide a compound representedby the general formula (IV):
[0147] The reaction between a compound represented by the generalformula (II) and a compound represented by the general formula(VI) is usually carried out by employing 0.5 to excessive moles,preferably 1 to 2 moles of the compound (VI) per mole of thecompound (II).
[0148] The reaction is usually carried out in an inert solvent,and the inert solvent preferably includes, for example, methylenechloride, chloroform, tetrahydrofuran, dimethylformamide,pyridine or a mixture thereof, or the like.
[0149] The aforesaid reaction is preferably carried out in thepresence of a condensing agents, for example, N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate, diphenylphosphoryl azide, 1,1-carbonyldiimidazole, or the like.
[0150] The aforesaid condensing agent is usually employed at 1mole to excessive mole, preferably 1 mole to 3 moles per moleof the compound represented by the general formula (II).
[0151] Reaction temperature is usually -20°C to the boiling pointof a solvent used for the reaction, preferably 0°C to 60°C.
[0152] Reaction time is usually 30 minutes to 3 days, preferably1 to 24 hours.
[0153] A crude compound represented by the general formula (VII)can be produced by treating the reaction mixture in the usualway after termination of the reaction. Thus obtained crudecompound represented by the general formula (VII) is purifiedby the conventional method, or not purified, followed by thenext intramolecular cyclo-condensation reaction.
[0154] The intramolecular cyclo-condensation reaction by whichthe compound (IV) is produced from the compound (VII) is usuallycarried out in an inert solvent or without solvent.
[0155] The inert solvent preferably includes, for example,ethanol, propanol, butanol, pentanol, 1,4-dioxane,dimethoxyethane, dimethylformamide, dimethyl sulfoxide,benzene, toluene, xylene, or a mixture thereof, or the like.
[0156] Reaction temperature is usually room temperature to theboiling point of a solvent used for the reaction, preferably80°C to 190°C.
[0157] Reaction time is usually 5 hours to 7 days, preferably12 hours to 3 days.
[0158] The cyclization reaction described above may be carriedout in the presence of a dehydrating agent or a catalytic amountof Lewis acid. The dehydrating agent includes, for example,phosphorus oxychloride, phosphorus pentachloride,polyphosphoric acid, thionyl chloride or the like. The Lewisacid includes, for example, scandium trifluoromethanesulfonate,yttrium trifluoromethanesulfonate, lanthanumtrifluoromethanesulfonate, trifluoromethanesulphonic acidlanthanide, or the like. The reaction is carried out preferably,without solvent or in a solvent, for example, methylene chloride,chloroform, benzene, toluene, xylene or a mixture thereof, orthe like.
[0159] The aforesaid dehydrating agent is usually employed at1 to excessive moles, preferably 2 to 10 moles per mole of thecompound represented by the general formula (VII). The amountof Lewis acid is 1 to 50 molar %, preferably, 5 to 30 molar %.
[0160] Reaction temperature is usually room temperature to theboiling point of a solvent used for the reaction preferably.
[0161] Reaction time is usually 1 hour to 7 days, preferably 5hours to 3 days.
[0162] A compound represented by the general formula (I) can beproduced by treating a reaction mixture in the usual way aftercleavage of a protecting group if the product has a protectinggroup or by treating the mixture as it is in the usual way ifthe protecting group is absent.
[0163] Cleavage of the protecting groups, post-treatment, andthe like may be carried out according to the method as describedin the aforesaid production process 1.
[0164] The compounds represented by the general formula (I) may readily be isolated and purified by the conventional separationtechnique, for example, solvent extraction, recrystallization,column chromatography, preparative thin layer chromatography,or/and the like.
[0165] These compounds may be converted into the pharmaceuticalacceptable salts or esters by the conventional method, on thecontrary, the conversion of the salts or esters into freecompounds may also be carried out according to the conventionalmethod.
[0166] The compounds represented by the general formula (II),(III), (V) or (VI) are, for example, commercially available,or are prepared according to the known methods, the methods asshown below or in Examples and Reference Examples, analogousmethods hereto, or optionally in combination of those methods.
[0167] This process refers to a process for producing a compoundrepresented by the general formula (II). According to thepresent invention, the compound (II) may be prepared bysubjecting process that a compound represented by the generalformula (1) to olefination to give a compound represented bythe general formula (2), subjecting the compound (2) toiodoazidation to give a compound represented by the generalformula (3), subjecting the compound (3) to reduction to givea compound represented by the general formula (4), and subjectingthe compound (4) to azidation, followed by reduction.
[0168] Regarding the olefination reaction in the step forproducing the compound (2) from the compound (1), olefinationreaction for oxo well-known per se in the field of organicchemistry, for example, the so-called Horner Emmons reaction,Wittig reaction, Peterson olefination, and the like can beapplied.
[0169] In the step for producing the compound (3) from the compound(2), iodomonochloride and iodoazide generated from metal azide,for example, silver azide, potassium azide, sodium azide or thelike may be reacted with the compound (2).
[0170] The reaction is usually carried out in an inert solvent,for example, methylene chloride, chloroform, acetonitrile,benzene, toluene, or a mixture thereof, or the like using 1 toexcessive moles, preferably 1 to 2 moles of iodoazide per moleof the compound (2).
[0171] Reaction temperature is usually 0°C to the boiling pointof a solvent used for the reaction, preferably room temperatureto 80°C. Reaction time is usually 30 minutes to 7 days, preferably2 hours to 5 days.
[0172] In the step for producing the compound (4) from the compound(3), reduction reaction of azide known per se in the field oforganic chemistry may be applied. More concretely, chemicalreduction using, for example, metal, metallic complex hydride,triphenylphosphine, or the like, or catalytic reduction usingpalladium-carbon catalyst, Raney nickel catalyst, or the likemay be applied.
[0173] In the process for producing the compound (II) from thecompound (4), usually the reaction is made with azide compound(for example, tetraalkylammonium azide, potassium azide, sodiumazide or the like) in the presence of acid (for example, aceticacid, ammonium chloride), followed by reduction of the azidegroup of the obtained compound according to the method well-knownper se in the field of organic chemistry.
[0174] The solvent used in the step for reacting azide compound,includes, for example, alcohol (for example, methanol, ethanolor the like), dimethyl sulfoxide, dimethylformamide,tetrahydrofuran, water or the like, or a mixture thereof or thelike preferably.
[0175] Reaction temperature is usually 0°C to the boiling pointof a solvent used for the reaction, preferably room temperatureto 100°C. Reaction time is usually 3 hours to 1 day preferably.
[0176] In the step for reduction of azide, more concretely,reduction can be carried out by chemical reduction using, forexample, metal, metallic complex hydride, triphenylphosphine,or the like, or catalytic reduction using palladium-carboncatalyst, Raney nickel catalyst, or the like.
[0177] The compounds represented by the general formula (1) andraw materials used for the olefination reaction may be commercially available, or can be prepared according to the knownmethods, or in Examples and Reference Examples, or analogousmethods hereto, optionally in combination.
[0178] This process is the alternative process for producing acompound represented by the general formula (II). Accordingto this method, the compound (II) may be prepared by subjectinga compound represented by the general formula (5) is successivelysubjected to alkylation or arylation in this order on theactivated carbonyl groups thereof to give a compound representedby the general formula (6), subjecting the compound (6) tocleavage of a protecting group for the amino group to producethe hydroxylamine compound, followed by aziridination withintramolecular dehydration of the generated hydroxyamine compound to give a compound represented by the general formula(4), and subjecting the compound (4) to azidation, followed byreduction.
[0179] A leaving group for L¹ preferably includes, for example,halogen atom, alkoxy, amide or the like.
[0180] A protecting group for amino represented by P includesa protecting group for amino as described in Production process1 and with regard to the method for cleavage of a protectinggroup, and the method as described in Production process 1 canbe applied.
[0181] The step for producing the compound (6) from the compound(5) may be carried out usually by subjecting the compound (5)to reaction with an organometallic compound, for example, alkyllithium, aryl lithium, alkyl magnesium, aryl magnesium, alkylzinc, aryl zinc, alkyl copper, aryl copper, or the like, whichhas a group represented by Ar^1p or R^1p as alkyl or aryl.
[0182] The reaction is carried out by the use of 1 to excessivemoles, preferably, 2 to 5 moles of the aforesaid organometalliccompound per mole of the compound (5) in an inert solvent, forexample, an ether solvent (for example, diethyl ether,tetrahydrofuran, 1,2-dimethoxyethane), or a mixture thereof orthe like.
[0183] Reaction temperature is usually -130°C to the boiling pointof a solvent used for the reaction, preferably, -100°C to roomtemperature, and reaction time is usually 30 minutes to 2 days,preferably 1 hour to 1 day.
[0184] In case when L¹ is hydrogen atom, the compound (6) canbe prepared by oxidation of an alcohol compound obtained byalkylation or arylation to give the corresponding ketone compound by the oxidation being well-known per se in the field of organicchemistry and then by alkylation or arylation of the obtainedketone compound again.
[0185] The step for producing the compound (4) from the compound(6) may so be carried out by reacting the hydroxyamino compoundobtained after elimination of the protecting group P with halideof trialkyl or triaryl phosphine (for example, dichlorotriethylphosphorane, dichlorotributyl phosphorane, dichlorotriphenylphosphorane, dibromotriethyl phosphorane, dibromotributylphosphorane, dibromotriphenyl phosphorane or the like) usuallyin the presence of base (for example,triethylamine,diisopropylamine, N,N-diisopropylethylamine,pyridine or the like)
[0186] The reaction is usually carried out by employing 1 toexcessive moles, preferably 2 to 7 moles of a base and 0.5 toexcessive moles, preferably 1 to 5 moles of halide of trialkylor triaryl phosphine relative to 1 mole of the compound (6) inan inert solvent, for example, diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, toluene, benzene, dichloromethane,1,2-dichloroethane, chloroform, acetonitrile or a mixturethereof, and the like.
[0187] Reaction temperature is usually -50°C to the boiling pointof a solvent used for the reaction, preferably, 0°C to 70°C andreaction time is usually 30 minutes to 3 days, preferably 1 hourto 24 hours.
[0188] The method as described in Production process A-1 can beapplied to the step for preparing the compound (II) from thecompound (4).
[0189] Throughout a series of steps for preparing the compound (II) from the compound (5) as described above, configurationon carbon atoms bonding to R^2p and R^3p remains unchanged. Therefore,in case Ar^1p and R^1p of the desired compound are identical,optically active compound (II) can be prepared by employingan optically active amino acid derivative as the compoundrepresented by the general formula (5) of the raw material. Onthe contrary, in case Ar^1p and R^1p of the desired compound aredifferent, an optically active compound (II) can be preparedby reacting an optically active amino acid derivative as thecompound represented by the general formula (5) of the rawmaterial, followed by separating the mixture of usually generateddiastereoisomers based on configuration on carbon atoms bondingto Ar^1p and R^1p at an appropriate stage using the known methodper se and then followed by reacting respectively correspondingoptically active compound in the step hereafter.
[0190] Further, the compounds represented by the general formula(5) and organic metal compounds for alkylation or arylation arecommercially available, or are prepared according to the methodsdescribed in the known methods, or in Examples and ReferenceExamples, or analogous methods hereto, or optional combinationof those methods.
[0191] This process refers to the process for producing a compound represented by the general formula (II-1). The compound (II-1)may be prepared by the present process in which a compoundrepresented by the general formula (1) is subjected toaminocyanation of oxo group of the compound represented by thegeneral formula (1) to give the compound represented by thegeneral formula (7), followed by reduction of the cyano groupof the compound (7).
[0192] In the steps for preparing the compound (7) from thecompound (1), the so-called Strecker's synthetic methodwell-known per se in the field of organic chemistry, or an improvedmethod thereof can be applied,
[0193] In the step for preparing the compound (II-1) from thecompound (7), reduction reaction of a cyano group well-knownper se in the field of organic chemistry, that is, for example,chemical reduction using metal, or metallic complex hydride,or the like, or catalytic reduction or the like can be applied.
[0194] Further, the raw materials for the reaction ofaminocyanation are commercially available, or are preparedaccording to the methods described in the known methods, or inExamples and Reference Examples, analogous methods hereto, oroptional combination of those methods.
[0195] The specific example of the compound represented by thegeneral formula (II) or (II') is, for example, 1,1-bis(4-fluorophenyl)-1,2-ethanediamine, 1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-ethanediamine, 1,1-bis(4-fluorophenyl)-1,2-propanediamine, (2R)-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1,2-propanediamine, (2S)-1,1-bis(4-fluorophenyl)-1,2-propanediamine, (2S)-1,1-bis(6-fluoro-3-pyridyl)-1,2-propanediamine, (2S)-1,1-bis(2-fluoro-4-pyridyl)-1,2-propanediamine, (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine, (1S,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine, (1R,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine, (2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine, (1S,2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine, (1R,2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine, (1S,2S)-1-(4-fluorophenyl)-1-(2-fluoro-4-pyridyl)-1,2-propanediamine, (1R,2S)-1-(4-fluorophenyl)-1-(2-fluoro-4-pyridyl)-1,2-propanediamine, (1S,2S)-1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-propanediamine, (1R,2S)-1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-propanediamine, (1S,2S)-1-(4-fluorophenyl)-1-(3-pyridyl)-1,2-propanediamine, (1R,2S)-1-(4-fluorophenyl)-1-(3-pyridyl)-1,2-propanediamine,or the like.
[0196] The utility of compounds of the present invention as amedicament is proved by showing NPY antagonistic activity, for example, in the following pharmacological tests. Pharmacological Test 1 (NPY binding inhibition test)
[0197] cDNA sequence encoding human NPY Y5 receptor (Conferdescription of International patent publication numberWO96/16542)was cloned into expression vectors pcDNA3, pRc/RSV(made by Invitrogen Inc.) and pCI-neo(made by Promega Inc.).These obtained expression vectors were transfected to host cellsCOS-7, CHO and LM(tk-)(American Type Culture Collection)bycationic lipidmethod (ConferProceedings of the National Academyof Sciences of the United States of America, vol. 84:7413(1987))to give recombinant cells which express NPY Y5 receptor.
[0198] A membrane sample prepared from the cells which expressedNPY Y5 receptor was incubated together with a test compound and(¹²⁵I)peptideYY(made by NEN) (20,000cpm) in an assay buffer (25mMTris buffer, pH7.4, containing 10mM magnesium chloride, 1mMphenylmethylsulfonyl fluoride, 0.1% bacitracin and 0.5% bovineserum albumin) at 25°C for 2 hours, then filtered through a glassfilter GF/C and washed with 5mM Tris buffer (pH7.4) containing0.3% BSA. The radioactivity on the glass filter was measured.Nonspecific binding was measured in the presence of 1µM peptideYYand a 50% Inhibitory Concentration(IC₅₀) of the test compoundagainst specific peptide YY binding was determined (ConferEndocrinology, vol. 131: 2090(1992)). The results aresummarized in Table 1. Inhibitory activities on NPY receptor bindingCompounds IC₅₀ (nM) Example 5-1 2.3 Example 7 3.4 Example 13 1.7
[0199] As shown above, compounds of this invention potentlyinhibited peptideYY (NPY homoloque) binding to NPY Y5 receptors. Pharmacological Test 2 (Antagonistic effect on feeding behaviorinduced by D-Trp³⁴NPY)
[0200] An chronic guide cannula (26 gauge, length 11mm) wasinserted by stereotactic surgery into the third ventricle ofmale SD rats (7-8 weeks old, 200-300g) anesthetized withKetamine.Xylazine (single intraperitoneal administration of 74and 11 mg/kg) and fixed by dental resin. The top of the cannulawas located 2.2mm behind bregma, on the median line and 8 mmdepth from the surface of cranial bone. After about 1-weekrecovery period, D-Trp³⁴ NPY (1µg/0.4µL/head, artificialcerebrospinal fluid containing 0.05% bovine serum albumin) wasinjected into the third ventricle. A test compound suspendedin aqueous 0.5% methylcellulose solution was administered orally2 hours before the administration of D-Trp³⁴ NPY and the foodconsumption was measured for 2 hours after administration ofD-Trp³⁴ NPY.
[0201] Compounds of the present invention significantlyinhibited the increase in food consumption induced by D-Trp³⁴NPY (homologue of NPY) which was administered to the thirdventricle. Pharmacological Test 3 (Test for pharmacokinetics)
[0202] The tested compound was administered orally orintravenously to male SD rats (7-10 weeks old, 200-400g) underovernight fasting condition, and about 100µL of blood was takenfrom tail vein using a heparinized capillary at predefined timepoints. The blood samples were separated by centrifuge (4°C,6,000rpm, for 10 minutes) to obtain plasma. To the plasma, 3-foldvolume of ethanol containing the internal standard substanceswas added and the mixture was stirred, then left at -20°C for20 minutes, followed by centrifugation (4°C, 10,000rpm for 10minutes). The supernatant was analyzed by LC/MS/MS and thenthe concentration of the test compound in plasma was measuredby the relative calibration curve method.
[0203] Consequently, for example, the compound of Example 7 wasfound to be biological availability ratio: 35% and half-lifein blood: 5.1 hours. Pharmacological Test 4 (Brain and cerebrospinal fluidpenetration test)
[0204] The tested compound was administered orally orintravenously to male SD rats (7-10 weeks old, 200-400g). Therats anesthetized with ether, and the all blood were taken atpredefined time points with a heparinized syringe from theabdominal aorta. Further, the rats were cut the skin of occipitalregion of head and inserted a 30G dental needle between cervicalvertebrae, into subarachnoid cavity. And then, 50-100µL ofcerebrospinal fluid was collected in a 1mL syringe through atube connected with the 30G dental needle, followed by takingout the brain. To the plasma obtained from the centrifuged bloodsample (4°C, 6,000rpm, for 10 minutes), 3-fold volume of ethanolincluding the internal standard substances was added and the mixture was stirred. To the brain sample, 2mL of water was addedand the mixture was homogenized. To an aliquot of the homogenizedmixture, 3-fold volume of ethanol including the internal standardsubstances was added, followed by stirring. ' To thecerebrospinal fluid, 3-fold volume of ethanol containing theinternal standard substances was added, followed by stirring.The above samples were left at -20°C for 20 minutes and separatedby centrifuge (4°C, 12,000g, for 10 minutes). The supernatantwas analyzed by LC/MS/MS and then each concentration in plasma,brain and cerebrospinal fluid was measured by the relativecalibration curve method.
[0205] Consequently, for example, the compound of Example 7 showedcerebral concentration: 2.95nM/g, cerebrospinalconcentration: 0.032µM and plasma concentration: 0.73µM in2 hours after oral administration (10mg/kg)
[0206] Compounds of the general formula (I) can be administeredorally or parenterally and may be formulated in the form suitablefor administration to provide an agent for treatment of, forexample, cardiovascular disorders (for example, hypertension,nephropathy, heart disease, vasospasm, arteriosclerosis)central nervous system disorders (for example, bulimia,depression, anxiety, seizure, epilepsy, dementia, pain,alcoholism, drug withdrawal), metabolic diseases (for example,obesity, diabetes, hormone abnormality, hypercholesterolemia,hyperlipidemia), sexual and reproductive dysfunction,gastric-intestinal disorder such as the inhibition ofgastro-intestinal motility, respiratory disorder, inflammationor glaucoma or the like. In clinical use, compounds of thepresent invention can be administered after being formulated, together with pharmaceutically acceptable additives, into anappropriate preparation according to the mode of administration.For said additives, those which are usually used in the fieldof pharmaceutical formulation may be used, for example, gelatin,lactose, sucrose, titanium oxide, starch, crystalline cellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, cornstarch, microcrystalline wax, white petrolatum, magnesiumaluminomethasilicate, anhydrous calcium phosphate, citric acid,trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitanfatty acid ester, polysorbate, sucrose fatty acid ester,polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone,magnesium stearate, light anhydrous silicic acid, talc,vegetable oil, benzyl alcohol, gum arabic, propylene glycol,polyalkylene glycol, cyclodextrin or hydroxypropylcyclodextrin.
[0207] A mixture with said additives may be formulated in theform of solid preparations (for example, tablets, capsules,granules, powder, suppositories); or liquid preparations (forexample, syrups, elixirs, injections). Such preparations maybe formulated according to techniques well-known in the art ofpharmaceutical formulation. Liquid preparations may be in theform of preparations which are dissolved or suspended in wateror other appropriate media when used and especially injectablepreparations may be dissolved or suspended in physiologicalsaline or glucose solution if necessary, optionally togetherwith a buffer and preservative.
[0208] Such preparations may contain 1.0 to 100 wt.%, preferably1.0 to 60 wt. % of compounds of this invention and may also containtherapeutically effective other compounds.
[0209] The compounds of the present invention can be used incombination with other agents useful for treating metabolicand/or feeding disorders. The individual components of suchcombinations can be administered separately at different timesduring the course of therapy or concurrently in divided or singledosage forms. The present invention is therefore to beunderstood as embracing all such regimes of simultaneous oralternating treatment and the term "administering" is to beinterpreted accordingly. It will be understood that the scopeof combinations of the compounds of the present invention withother agents useful for treating metabolic and/or feedingdisorders includes in principle any combination with anypharmaceutical compositions useful for treating metabolicand/or feeding disorders.
[0210] When compounds of the present invention are used clinically,the dose and frequency of dosage may be varied depending uponthe sex, age. body weight, the degree of symptoms and the kindand range of the desired treatment effects. A daily dose foran adult is 0.01 to 100mg/kg, preferably 0.03 to 1mg/kg orallyin a single or divided doses per day or 0.001 to 10mg/kg, preferably0.001 to 0.1mg/kg parenterally, preferably in a single ordivided doses per day.
[0211] An ordinarily skilled physician, veterinarian orclinician can readily determine and prescribe the effectiveamount of the drug required to inhibit, control or arrest theprogress of the condition. Best mode for carrying out the invention
[0212] The present invention will be explained more concretelyby the use of Examples and Reference Examples, but the inventionis not to be limited to those examples.
[0213] The compound having the symbol "*" in structural formula,means the compound of a substantially single configuration atasymmetric carbon atom, to which the symbol is attached.
[0214] Melting point was determined by using Model MP-S3(produced by Yanagimoto Co. Ltd.,) and its result was statedwithout correcting. Also, the mass spectrum was determined byelectrospray ionization method (ESI) using QuattroII(Micromass Ltd.,). Example 1 Production of2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline
[0215]
[0216] To a solution of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine(500mg) in methanol (10mL) was added3-cyanobenzeneimidic acid methyl ester (792mg), and the mixturewas stirred at room temperature for 18 hrs. After concentratingthe reaction mixture, the residue was dissolved in ethyl acetate(30mL), washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodium chloride aqueous solution in thisorder, and dried over anhydrous sodium sulfate. Sodium sulfatewas removed by filtration, and the organic solvent wasevaporated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=3:1 → 2:1) to give the objective compound (370mg).Mass spectrum (ESI): 360.2¹HNMR(300MHz,CDCl₃,δppm): 4.15(1.4H,brs), 4.57(0.7H,brs),5.10(0.7H,brs), 5.38(0.3H,brs), 6.94-7.08(4H,m),7.22-7.43(4H,m), 7.54(1H,t,J=7.8Hz), 7.74(1H,d,J=7.8Hz),8.11(1H,d,J=7.6Hz), 8.19(1H,s) Example 2 Production of4,4-bis(4-fluorophenyl)-2-pyrazinyl-2-imidazoline
[0217]
[0218] To a solution of1,1-bis(4-fluorophenyl)-1,2-ethanediamine(500mg) inmethanol(10mL) was added pyrazineimidic acid methyl ester(385mg), and the mixture was stirred at room temperature for18 hrs. After concentrating the reaction mixture, the residuewas dissolved in ethyl acetate (50ml), washed with saturatedsodium hydrogen carbonate aqueous solution and saturated sodiumchloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed byfiltration, and the organic solvent was evaporated in vacuo.The obtained residue was purified by silica gel columnchromatography (C-300; hexane: ethyl acetate =1:1) to give theobjective compound (446mg).Melting point 144-146°C¹HNMR(300MHz,CDCl₃,δppm): 4.17(1.4H,brs), 4.65(0.6H,brs),6.08(0.7H,brs), 6.51(0.3H,brs), 6.96-7.04(4H,m),7.26-7.50(4H,m), 8.54(1H,s) 8.66(1H,d,J=2.4Hz),9.45(0.3H,brs), 9.56(0.7H,brs) Example 3 Production of2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(1,5-naphthyridin-3-yl)-2-imidazoline
[0219]
[0220] To a solution of1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-ethanediamine(17mg) in methanol (1mL was added3-cyanobenzeneimidic acid methyl ester (23mg), and the mixturewas stirred at room temperature for 19 hrs. To the reactionmixture was added chloroform and insolubles were removed byfiltration, followed by concentration of the filtrate in vacuo.The residue was purified by preparative thin-layerchromatography (100% ethyl acetate) to give the objective compound (8.0mg).Mass spectrum (ESI): 394.0¹HNMR(300MHz, CDCl₃, δppm): 4.21-4.26(1H,m), 4.39-4.44(1H,m),5.15(1H,brs), 7.02-7.09(2H,m), 7.45-7.51(1H,m),7.58(2H,t,J=7.8Hz), 7.60-7.65(1H,m),7.78(1H,dt,J=1.4Hz,7.7Hz), 8.13-8.17(1H,m), 8.22(1H,brs),8.36-8.41(2H,m), 8.95-8.97(1H,m), 9.06(1H,brs) Example 4 Production of2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-methyl-2-imidazoline
[0221]
[0222] 1,1-bis(4-fluorophenyl)- 1,2-propanediamine(50mg) wasdissolved in methanol(1mL), and to the solution was added3-cyanobenzeneimidic acid methyl ester (75mg). The mixturewas stirred at room temperature for 24 hrs. After chloroform(5ml) was added to the reaction mixture, insolubles were removedby filtration. After concentrating the filtrate in vacuo, theobtained residue was purified by silica gel columnchromatography (C-300; hexane: ethyl acetate =3:1 → 1:1) togive the objective compound (10mg).Mass spectrum (ESI): 374.1¹HNMR(300MHz,CDCl₃,δppm): 0.92(3H,d,J=6.6Hz), 4.60-5.40(2H,m), 7.40-7.50(2H,m), 7.52-7.57(1H,m), 7.72-7.76(1H,m),8.10(1H,d,J=8.0Hz), 8.17(1H,s) Example 5 Production of2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline
[0223]
[0224] 1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine(218mg)was dissolved in methanol(3mL), and tothe solution was added 3-cyanobenzeneimidic acid methyl ester(266mg), and the mixture was stirred at room temperature for17 hrs. To the reaction mixture was added an additional amountof 3-cyanobenzeneimidic acid methyl ester (266mg), and thereaction mixture was stirred at room temperature for 6 hrs. Tothe reaction mixture was added ethyl acetate (50ml), and theorganic layer was washed with saturated sodium hydrogencarbonate aqueous solution and saturated sodium chlorideaqueous solution in this order, and dried over anhydrous sodiumsulfate. Sodium sulfate was removed by filtration, and thenthe organic solvent was evaporated in vacuo. The obtainedresidue was purified by silica gel column chromatography(C-300; hexane: ethyl acetate =2:1) to give2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline (146mg) as colorlessoil. The protected compound (115mg) was dissolved in themixture solution of 2N hydrochloric acid (1.5mL) andtetrahydrofuran (1.5ml), and the solution was stirred at 50°Cfor 3 days. After cooling the mixture to the room temperatureby standing it at room temperature and neutralizing withsaturated sodium hydrogen carbonate aqueous solution, themixture was extracted with ethyl acetate. The organic layerwas washed with saturated sodium chloride aqueous solution, anddried over anhydrous sodium sulfate. Sodium sulfate wasremoved by filtration, and the organic solvent was evaporatedin vacuo to give the title compound (105mg).Mass spectrum(ESI):390.0¹NMR(300MHz,CDCl₃, δppm): 3.09, 3.30[2H(3.09,brs),(3.30,dd,J=4.5Hz,10.5Hz)],4.68(1H,brs),5.59(1H,brs),7.01(4H,m),7.23(2H,m),7.48(2H,brs),7.56(1H,t,J=7.8Hz),7.76(1H,d,J=7.8Hz),8.11(1H,d,J=7.8Hz),8.21(1H,s)
[0225] According to any one of the methods described inabove-mentioned Example 1 to 5, corresponding diamine andimidic acid methyl ester were reacted to give the followingcompounds. Example 5-1 2-(3-cyanophenyl)-4.4-bis(3-fluorophenyl)-2-imidazoline
[0226] Mass spectrum(ESI):360.1 Example 5-2 2-(3-cyanophenyl)-4-(3-quinolyl)-4-(2-thienyl)-2-imidazoline
[0227] Mass spectrum(ESI):381.0 Example 5-3 4-(4-bromophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline
[0228] Mass spectrum(ESI):402.0 Example 5-4 4,4-bis(4-chlorophenyl)-2-(3-cyanophenyl)-2-imidazoline
[0229] Mass spectrum(ESI):392.0 Example 5-5 4-(4-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline
[0230] Mass spectrum(ESI):358.1 Example 5-6 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-quinolyl)-2-imidazoline
[0231] Mass spectrum(ESI):393.1 Example 5-7 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-phenyl-2-imidazoline
[0232] Mass spectrum(ESI):342.2 Example 5-8 2-(3-cyanophenyl)-4-phenyl-4-(4-vinylphenyl)-2-imidazoline
[0233] Mass spectrum(ESI):350.1 Example 5-9 4-(6-chloro-3-pyridyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline
[0234] Mass spectrum(ESI):377.0 Example 5-10 4-(5-chloro-2-thienyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline
[0235] Mass spectrum(ESI):382.1 Example 5-11 2-(3-cyanophenyl)-4-(4-methylphenyl)-4-phenyl-2-imidazoline
[0236] Melting point:179-180°C Example 5-12 2-(3-cyanophenyl)-4-(3-methylphenyl)-4-phenyl-2-imidazoline
[0237] Mass spectrum(ESI):338.1 Example 5-13 4,4-bis(4-fluorophenyl)-2-(3-nitrophenyl)-2-imidazoline
[0238] Melting point:156-158°C Example 5-14 2-(3-cyanophenyl)-4-phenyl-4-(3-quinolyl)-2-imidazoline
[0239] Mass spectrum(ESI):375.2 Example 5-15 2-(3-cyanophenyl)-4-(4-methoxyphenyl)-4-phenyl-2-imidazoline
[0240] Mass spectrum(ESI):354.0 Example 5-16 4-(3-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazolinehydrochloride
[0241] Mass spectrum(ESI):358.1 Example 5-17 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(5-methyl-2-thienyl)-2-imidazoline
[0242] Mass spectrum(ESI):362.1 Example 5-18 2-(3-cyanophenyl)-4-phenyl-4-(4-trifluoromethylphenyl)-2-imidazoline
[0243] Mass spectrum(ESI):392.1 Example 5-19 2-(3-cyanophenyl)-4-(3-methoxyphenyl)-4-phenyl-2-imidazoline
[0244] Mass spectrum(ESI):354.1 Example 5-20 2-(3-cyanophenyl)-4-(3,4-dimethylphenyl)-4-phenyl-2-imidazoline
[0245] Mass spectrum(ESI):352.1 Example 5-21 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-vinylphenyl)-2-imidazoline
[0246] Mass spectrum(ESI):368.1 Example 5-22 2-(3-cyanophenyl)-4-(2-naphthyl)-4-(3-pyridyl)-2-imidazoline
[0247] Mass spectrum(ESI):375.1 Example 5-23 4-(3-bromophenyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline
[0248] Mass spectrum(ESI):420.1 Example 5-24 4-(2-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline
[0249] Mass spectrum(ESI):358.1 Example 5-25 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-quinolyl)-2-imidazoline
[0250] Mass spectrum(ESI):393.1 Example 5-26 2-(3-cyanophenyl)-4-phenyl-4-(2-thienyl)-2-imidazoline
[0251] Mass spectrum(ESI):330.3 Example 5-27 2-(3-cyanophenyl)-4-(4-dimethylaminophenyl)-4-phenyl-2-imidazoline
[0252] Melting point:210-213°C Example 5-28 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-pyridyl)-2-imidazoline
[0253] Mass spectrum(ESI):343.0 Example 5-29 2-(3-cyanophenyl)-4-(4-formylphenyl)-4-phenyl-2-imidazoline
[0254] Mass spectrum(ESI):352.2 Example 5-30 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-thienyl)-2-imidazoline
[0255] Mass spectrum(ESI):348.1 Example 5-31 4,4-diphenyl-2-pyrazinyl-2-imidazoline
[0256] Melting point:183-184°C Example 5-32 2-(3-cyanophenyl)-4,4-bis(4-methoxyphenyl)-2-imidazoline
[0257] Mass spectrum(ESI):384.1 Example 5-33 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-formylphenyl)-2-imidazoline
[0258] Mass spectrum(ESI):370.1 Example 5-34 4,4-bis(4-fluorophenyl)-2-(3-methylsulfonylphenyl)-2-imidazoline
[0259] Melting point:209-212°C Example 5-35 4,4-bis(4-fluorophenyl)-2-(3-formylphenyl)-2-imidazoline
[0260] Mass spectrum(ESI):363.1 Example 5-36 2-(3-cyanophenyl)-4-(2-methylphenyl)-4-phenyl-2-imidazoline
[0261] Mass spectrum(ESI):338.1 Example 5-37 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-hydroxymethylphenyl)-2-imidazoline
[0262] Mass spectrum(ESI):372.1 Example 5-38 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(1,2,3,4-tetrahydro-1,5-naphthyridin-7-yl)-2-imidazoline
[0263] Mass spectrum(ESI):398.1 Example 5-39 2-(3-cyanophenyl)-4-(2-fluorophenyl)-4-(3-pyridyl)-2-imidazoline
[0264] Mass spectrum(ESI):343.0 Example 5-40 4-(4-biphenylyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline
[0265] Mass spectrum(ESI):400.3 Example 5-41 2-(3-cyanophenyl)-4-(2-methoxyphenyl)-4-phenyl-2-imidazoline
[0266] Mass spectrum(ESI):354.0 Example 5-42 2-(3-cyanophenyl)-4-cyclohexyl-4-phenyl-2-imidazolineMelting point:151-152°C Example 5-43 2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(4-pyridyl)-2-imidazoline
[0267] Mass spectrum(ESI):343.0 Example 5-44 4,4-bis(4-fluorophenyl)-2-(5-pyrimidinyl)-2-imidazoline
[0268] Mass spectrum(ESI):337.0 Example 5-45 2-(3-cyanophenyl)-4-cyclopentyl-4-phenyl-2-imidazoline
[0269] Mass spectrum(ESI):316.2 Example 5-46 2-(3-cyanophenyl)-4-cyclobutyl-4-phenyl-2-imidazoline
[0270] Melting point:117-118°C Example 5-47 4,4-bis(4-fluorophenyl)-2-(3-pyridazinyl)-2-imidazoline
[0271] Mass spectrum(ESI):337.0 Example 5-48 4-(4-fluorophenyl)-5-methvl-2-pyrazinyl-4-(3-quinolyl)-2-imidazoline
[0272] ¹HNMR(400MHz,CD₃OD,δppm): 0.90(3H,d,J=6.4Hz), 4.97-5.08(1H,m),7.06-7.16(2H,m), 7.32-7.38 and 7.57-7.66(3H,m),7.72-7.80(1H,m), 7.86-8.04(2H,m), 8.31(0.8H,s), 8.51(0.2H,s), 8.64(0.8H,s), 8.66-8.76(2H,m), 8.88(0.2H,s), 9.34(0.2H,s),9.39(0.8H,s) Example 5-49 The optical active(5 S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(3-methylsulfonylphenyl)-5-methyl-2-imidazoline,wherein thestarting material is the diamine described in Reference Example5-1
[0273] ¹HNMR(300MHz,CDCl₃,δppm): 0.90(3H,d,J=6.3Hz), 3.10(3H,s),4.72-4.74(1H,m), 5.10-5.40(1H,brs), 7.00-8.37(11H,m)[α]_D ²⁵:-263.3°(c0.9,CHCl₃) Example 5-50 The optical active(5 S)-2-(5-cyano-3-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 5-1
[0274] ¹HNMR(300MHz,CDCl₃,δppm): 0.90(3H,d,J=6.3Hz),4.75(1H,q,J=6.3), 5.38(1H,s), 6.89(1H,dd,J=2.9Hz,8.6Hz),7.03(2H,t,J=8.6Hz), 7.20-7.30(2H,m),7.89(1H,dt,J=2.2Hz,7.9Hz), 8.34(1H,s), 8.50-8.60(1H,m),8.96(1H,d,J=2.0Hz), 9.23(1H,d,J=2.0Hz)[α]_D ²⁵: -307.6°(c1.0,MeOH) Example 6 Production of the optical active(5 S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazolinehydrochloride
[0275]
[0276] To a solution of 4-cyanopyridine N-oxide (100mg) inmethanol (4mL) were added sodium methoxide (13.5mg), and themixture was stirred at room temperature for 24 hrs. To thereaction mixture was added methanesulfonic acid (104mg), andthe reaction mixture was stirred at room temperature for anadditional 10 minutes. To the 3.5ml of this solution was addedto the solution (2mL) of(2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediaminedescribed in Reference Example 5-1, and themixture was stirred at room temperature for 15 hrs. Afterconcentrating the reaction mixture in vacuo, the obtainedresidue was dissolved in ethyl acetate, washed with saturatedsodium hydrogen carbonate aqueous solution and saturated sodiumchloride aqueous solution in this order, and dried overanhydrous sodium sulfate. Sodium sulfate was removed byfiltration, and the organic solvent was evaporated in vacuo.The obtained residue was purified by silica gel columnchromatography (C-300; chloroform: methanol =9:1) to give2-(1-oxido-pyridin-4-yl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline(172mg) as colorless oil.To the solution (5ml) of the obtained N-oxide compound inacetonitrile was added trimethylsilylcyanide (140mg) andtriethylamine (142mg), and the mixture was stirred at 90°C for 17 hrs. To the mixture was added trimethylsilylcyanide (140mg)and triethylamine (142mg), and the mixture was stirred at 90°Cfor 2 hrs, and concentrated in vacuo. The obtained residue wasdissolved in chloroform, washed with saturated sodium hydrogencarbonate aqueous solution, water and saturated sodium chlorideaqueous solution in this order, and dried over anhydrous sodiumsulfate. Sodium sulfate was removed by filtration, and theorganic solvent was evaporated in vacuo. The obtained residuewas purified by silica gel column chromatography (C-300;hexane: ethyl acetate =1:1) and treated with 4N hydrogenchloride - ethyl acetate solution to give the title compound(108mg).¹HNMR(300MHz,DMSO-d₆,δppm): 0.95(3H,d,J=6.6Hz), 5.40(1H,brs),7.23-7.36(5H,m), 8.22-8.28(1H,m), 8.47(1H,d,J=4.8Hz),8.58(1H,s), 8.83(1H,s), 9.12(1H,d,J=5.1Hz)[α]_D ²⁵: -309.7°(c1.0,MeOH)
[0277] By applying the method described in Example 6,corresponding diamine and 4-cyanopyridine N-oxide weresubjected to the ring condensation reaction, followed byreacting with trimethylsilylcyanide, optionally theprotecting group was removed by the method similar to the methoddescribed in Example 5 to give the following compounds. Example 6-1(5R)-2-(2-cyano-4-pvridyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline
[0278] ¹HNMR(300MHz,CDCl₃,δppm): 3.09(1H,br),3.29(1H,dd,J=4.4Hz,10.6Hz), 4.74(0.9H,brs), 5.02(0.1H,d,J=5.1Hz), 5.74(1H,brs), 6.97-7.05(4H,m),7.19-7.23(2H,m), 7.42-7.47(2H,m), 7.92(1H,d,J=4.1Hz),8.21(1H,s), 8.81(1H,d,J=5.5Hz) Example 6-2 (5S)-2-(2-cyano-4-pyridyl)-4,4-bis(4-fluorophenyl)-5-methyl-2-imidazoline
[0279] ¹HNMR(300MHz,CDCl₃,δppm): 0.85-0.97(3H,m), 4.70-4.78(1H formajor,m), 4.92-5.00(1H for minor,m), 5.02(1H for major,brs),5.32(1H for minor,brs), 6.92-7.07(4H,m), 7.10-7.53(4H,m),7.87-7.92(1H,m), 8.10-8.20(1H,m), 8.77-8.83(1H,m)[α]_D ²⁵: -300.0°(C1.0,CHCl₃) Example 6-3 The optical active (5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 7
[0280] ¹HNMR(300MHz,CDCl₃,δppm): 0.93(3H,d,J=6.6Hz),4.71(1H,q,J=6.6Hz), 5.30(1H,brs), 6.98-7.12(3H,m),7.15-7.24(3H,m), 7.94(1H,dd,J=5.0Hz,1.6Hz), 8.15-8.22(2H,m),8.83(1H,d,J=5.0Hz)[α]_D ²⁵: -260.0°(c1.0,CHCl₃) Example 6-4 (5S)-2-(2-cyano-4-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline hydrochloride
[0281] ¹HNMR(400MHz,CD₃OD,δppm): 1.15(3H,d,J=6.4Hz),5.51(1H,q,J=6.4Hz), 7.19(1H,dd,J=8.8Hz,2.8Hz), 7.24(1H,dd,J=8.8Hz,2.8Hz), 7.84-7.89(1H,m), 8.09-8.12(1H,m),8.17(1H,dd,J=5.2Hz,1.6Hz), 8.23(1H,d,J=2.4Hz),8.40(1H,d,J=1.6Hz), 8.45(1H,d,J=2.4Hz), 9.07(1H,d,J=5.2Hz)[α]_D ²⁵: -239.5°(c0.8,MeOH) Example 7 Production of4,4-bis(4-fluorophenyl)-5-methyl-2-pyrazinyl-2-imidazoline
[0282]
[0283] 1,1-bis(4-fluorophenyl)-1,2-propanediamine (94mg) andpyrazinecarboxylic acid (53mg) was dissolved in pyridine (1mL),and to the solution was added1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(103mg). Themixture was stirred at room temperature for 24 hrs. Thereaction mixture was concentrated, and the obtained residue wasdissolved in chloroform, followed by washing with saturatedsodium hydrogen carbonate aqueous solution. The aqueous layerwas extracted with chloroform twice, and the combinedchloroform layers were dried over magnesium sulfate. Afterevaporating the solvent in vacuo, the obtained residue waspurified by silica gel column chromatography (C-300; hexane:ethyl acetate =1:1 → 1:3) to giveN-[2-amino-2,2-bis(4-fluorophenyl)-1-methylethyl]-2-pyrazinecarboxamide(112mg)as the mixture with pyrazinecarboxylic acid methyl ester. The mixture wasdissolved in methanol (1mL), and to the solution was added 2Nsodium hydroxide aqueous solution (0.5mL), and the solution wasstirred at room temperature for one hr. The reaction mixturewas diluted with chloroform, followed by washing with water.The aqueous layer was extracted with chloroform twice, and thecombined chloroform layers were dried over anhydrous magnesiumsulfate. The solvent was evaporated in vacuo to give the pureamide compound (95mg).
[0284] To a solution of the above-mentioned amide compound(157mg) in benzene (4mL) was added phosphorus pentachloride(266mg), and the mixture was stirred at 50°C for 3 days. Aftercooling to room temperature, to the reaction mixture was added2N sodium hydroxide aqueous solution (4ml), and the reactionmixture was stirred for an additional 30 minutes. The obtainedmixture was extracted with chloroform thrice, and dried overanhydrous magnesium sulfate. The solvent was evaporated invacuo, and the obtained residue was purified by silica gelcolumn chromatography (C-300; hexane: ethyl acetate =1:1 → 1:2)to give the objective compound (100mg).Mass spectrum(ESI):351.2¹HNMR(300MHz,CDCl₃,δppm): 0.90(2.1H,d,J=6.4Hz),0.99(0.9H,d,J=6.9Hz), 4.70(0.7H,q,J=6.4Hz),5.03(0.3H,q,J=6.9Hz), 5.97-6.00(0.7H,m), 6.43-6.45(0.3H,m),6.95-7.08(4H,m), 7.25-7.37(2.6H,m), 7.51-7.56(1.4H,m),8.53-8.55(1H,m), 8.66(1H,d,J=2.5Hz), 9.42(0.3H,d,J=1.7Hz),9.54(0.7H,d,J=1.5Hz)
[0285] By applying the method described in Example 7, corresponding diamine and carboxylic acid were cyclized andcondensed, followed by optionally deprotecting by the methodsimilar to the method described in Example 5 to give thefollowing compounds. Example 7-1 4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-pyrazinyl-2-imidazoline
[0286] Mass spectrum(ESI):367.1¹HNMR(300MHz,CDCl₃,δppm): 3.12,3.30[2H(3.12,t,J=9.6Hz),(3.30,m)], 4.66,5.08[1H(4.66,dd,J=3.9,8.7Hz),(5.08,m)], 6.55,6.60[1H(6.55,s),(6.60,s)], 7.00(4H,m), 7.14(2H,m), 7.35,7.54[2H(7.35,dd,J=4.5Hz,5.7Hz),(3.30,dd,J=5.4Hz,8.1Hz)],8.54(1H,d,J=2.0Hz), 8.66(1H,d,J=2.0Hz),9.43,9.52[1H(9.43,s),(9.52,s)] Example 7-2 5-ethyl-4,4-bis(4-fluorophenyl)-2-pyrazinyl-2-imidazoline
[0287] ¹HNMR(300MHz,CDCl₃, δppm): 0.95-1.35(3H,m), 4.36-4.45(1H formajor,m), 4.73-4.79(1H for minor,m), 6.21-6.29(1H formajor,br), 6.42-6.44(1H for minor,br), 6.90-7.18(4H,m),7.12-7.21(2H,m), 7.29-7.60(2H,m), 8.50-8.58(1H,m),8.61-8.68(1H,m), 9.44(1H,d,J=1.5Hz for minor),9.55(1H,d,J=1.5Hz for major) Example 7-3 4,4-bis(4-fluorophenyl)-5-propyl-2-pyrazinyl-2-imidazoline hydrochloride
[0288] ¹HNMR(300MHz,CD₃OD,δppm): 0.87(3H,t,J=7.0Hz), 1.14-1.66(4H,m),5.10-5.20(1H,m), 7.10-7.30(6H,m), 7.54-7.65(2H,m),8.87-8.94(1H,m), 8.95-9.00(1H,m), 9.36-9.40(1H,br) Example 8 Production of4,4-bis(4-fluorophenyl)-2-(4-isothiazolyl)-2-imidazoline
[0289]
[0290] While stirring a solution of1,1-(4-fluorophenyl)-1,2-ethanediamine (330mg) in anhydroustoluene(8mL) at 0°C, 0.98M trimethylaluminum hexane solution(1.36mL) was dropwise added to the solution under nitrogen, andthe mixture was stirred at 0°C for 5 minutes.4-Isothiazolecarboxylic acid methyl ester(120mg) wasdissolved in toluene(1mL), and the solution was added to theabove reaction mixture. Then the mixture was heated at 110°Cfor 3 hours. After the reaction mixture was cooled, sodiumsulfate decahydrate was added to the reaction mixture, and thenthe mixture was stirred at room temperature for 15 minutes.Anhydrous sodium sulfate was added to the reaction mixture, andthe mixture was stirred for an additional 20 minutes. Theobtained mixture was filtered through celite, and the filtrate was concentrated in vacuo. The obtained residue was purifiedby silica gel column chromatography (C-300; hexane: ethylacetate =1:1) to give the objective compound(116mg).   Mass spectrum(ESI):342.0   ¹HNMR(300MHz,CDCl₃,δppm):4.26(2H,brs),6.97-7.07(4H,m),7.32-7.37(4H,m),8.93(1H,s),9.03(1H,s) Example 9 Production of2-(3-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazolinehydrochloride
[0291]
[0292] While stirring a solution of1,1-bis(4-fluorophenyl)-1,2-ethanediamine (300mg) inanhydrous toluene(3mL) at 0°C, a solution of 0.98Mtrimethylaluminum in hexane (1.23mL) was dropwise added to thesolution under nitrogen, and the mixture was stirred at roomtemperature for 15 minutes. Methyl nicotinate (103mg) wasdissolved in toluene 1mL, and the solution was added to the abovereaction mixture. Then the mixture was heated at 80°C for 5hours. After the reaction mixture was cooled, sodium sulfatedecahydrate was added to the reaction mixture, and the mixturewas stirred at room temperature for 15 minutes. Anhydrous sodium sulfate was added to the reaction mixture, and themixture was stirred for an additional 20 minutes. The obtainedmixture was filtered through celite, and the filtrate wasconcentrated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=1:2), treated with 4N hydrogen chloride - ethyl acetatesolution and dried in vacuo to give the objectivecompound(111mg).   Melting point : 172-176°C   ¹HNMR(300MHz,DMSO-d₆,δppm):4.70(2H,s),7.24-7.33(4H,m),7.53-7.60(4H,m),7.72-7.76(1H,m),8.60-8.65(1H,m),8.93-8.95(1H,m),9.36(1H,s),11.61(1H,s),12.29(1H,s)
[0293] By applying the methods described in above-mentionedExample 8 and 9, corresponding diamine and ester were reactedto give the following compounds. Example 9-1 2-(3-chlorophenyl)-4,4-bis(4-fluorophenyl)-2-imidazolinehydrochloride
[0294] Mass spectrum(ESI):369.0 Example 9-2 4,4-bis(4-fluorophenyl)-2-(3-trifluoromethylphenyl)-2-imidazoline
[0295] Mass spectrum(ESI):403.1 Example 9-3 2-(3-fluorophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline
[0296] Mass spectrum(ESI):353.1 Example 9-4 4,4-bis(4-fluorophenyl)-2-(3-trifluoromethoxyphenyl)-2-imidazoline
[0297] Melting point : 114-117°C Example 9-5 4,4-bis(4-fluorophenyl)-2-(5-thiazolyl)-2-imidazoline
[0298] Mass spectrum(ESI):342.0 Example 9-6 4,4-bis(4-fluorophenyl)-2-(3-methylphenyl)-2-imidazoline
[0299] Melting point : 148-149°C Example 9-7 4,4-bis(4-fluorophenyl)-2-(2-thienyl)-2-imidazoline
[0300] Melting point : 156-160°C Example 9-8 2-(5-bromo-3-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline
[0301] Mass spectrum(ESI):414.0/416.0 Example 9-9 2-(3-bromophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline
[0302] Mass spectrum(ESI):412.9/415.0 Example 9-10 4,4-bis(4-fluorophenyl)-2-(3-thienyl)-2-imidazoline
[0303] Melting point : 160-163°C Example 10 Production of2-(4-cyano-2-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline
[0304]
[0305] The mixture of1,1-bis(4-fluorophenyl)-1,2-ethanediamine(153mg) and4-cyano-2-ethoxycarbonylpyridine(95mg) was stirred at 180°Cfor 2 hours. The obtained oily compound was purified by silicagel column chromatography (C-300; hexane: ethyl acetate =3:2)to give the objective compound (103mg).   Melting point : 206-208°C Example 11 Production of the optical active (5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline
[0306]
[0307] 3-Cyanobenzoic acid (84mg), triethylamine (159µL) and2-chloro-1,3-dimethylimidazolinium chloridedichloromethane 25% solution (212µL) were added to a solutionof (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine(100mg)described in Reference Example 5-1 inchloroform(3mL) in this order at 0°C. Then temperature of themixture was raised to room temperature, and the mixture wasstirred for 15 minutes. Saturated sodium hydrogen carbonateaqueous solution was added to the reaction mixture, and thenthe mixture was extracted with ethyl acetate. The organiclayer was washed with saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate. Sodiumsulfate was removed by filtration, and the organic solvent wasevaporated in vacua. The obtained crude product was stirredat 130°C for 15 hours. The obtained oil was purified by silicagel column chromatography (C-300; hexane: ethyl acetate =1:1)to give the objective compound (140mg).   ¹HNMR(300MHz,CDCl₃,δppm):0.89(3H,d,J=6.5Hz),4.66-4.74(1H,m),5.10(1H,brs),6.85-6.90(1H,m),7.02(2H,t,J=8.4Hz),7.20-7.30(2H,m),7.57(1H,t,J=7.9Hz),7.74-7.79(1H,m),7.85-7.95(1H,m),8.07-8.12(1H,m),8.19(1H,s),8.37-8.42(1H,m)   [α]_D ²⁵:-295.6°(c1.0,CHCl₃)
[0308] By applying the method described in above-mentionedExample 11, corresponding diamine and carboxylic acid werecyclized, and the reactant was optionally deprotected by themethod similar to the method described in Example 7 to give thefollowing compounds. Example 11-1 2-(3-cyanophenyl)-4.4-bis(4-fluorophenyl)-5-(1-hydroxyethyl)-2-imidazoline
[0309] ¹HNMR(300MHz,CDCl₃,δppm):1.08(3H,d,J=6.3Hz),3.54-3.72(1H,m),4.47-4.55(1H for major,m),4.85-4.90(1H forminor,m),5.17(1H for major,brs),5.48(1H forminor,brs),6.93-7.10(4H,m),7.15-7.28(2H,m),7.22-7.60(2H,m),7.65-7.80(2H,m),8.07-8.25(2H,m) Example 11-2 The optical active (5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,wherein the starting material is the diamine described in Reference Example 7
[0310] ¹HNMR(300MHz,CDCl₃,δppm):0.92(3H formajor,d,J=6.6Hz),1.02(3H for minor,dJ=6.9Hz,),4.66(1H formajor,q,J=6.6Hz),4.87(1H for minor,q,J=6.9Hz),5.22(1H formajor,brs),5.68(1H forminor,brs),6.97-7.09(3H,m),7.12(1H,s),7.15-7.35(3H,m),7.54-7.61(1H,m),7.75-7.80(1H,m),8.08-8.23(3H,m)   [α]_D ²⁵:-291.6°(c1.0,CHCl₃) Example 11-3 The optical active (5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 8
[0311] ¹HNMR(300MHz,CDCl₃,δppm):0.98(3H,d,J=6.6Hz),4.74(1H,q,J=6.6Hz),4.98-5.08(1H,m),5.07(1H for major,brs),5.30(1H forminor,brs),6.91-7.12(4H,m),7.47-7.63(3H,m),7.78(1H,d,J=7.8Hz),8.08-8.21(3H,m)   [α]_D ²⁵:-258.97°(c0.16,CHCl₃) Example 12 Production of the optical active (5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-(1,2,5-thiadiazol-3-yl)-2-imidazoline
[0312]
[0313] Triethylamine(23mg) and1,1'-carbonyldiimidazole(37mg) were added to a solution of1,2,5-thiadiazole-3-carboxylic acid(30mg) intetrahydrofuran(3mL) in this order, and the mixture was stirredat room temperature for one hour. A solution of(2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine(50mg) described in Reference Example 5-1 in tetrahydrofuran (1mL) was added to the above reaction mixture,and the resultant mixture was stirred at room temperature for17 hours. The reaction mixture was concentrated in vacuo, andthen the obtained residue was dissolved in ethyl acetate. Thenthe solution was washed with water and saturated sodium chlorideaqueous solution in this order, and dried over anhydrous sodiumsulfate. Sodium sulfate was removed by filtration, and theorganic solvent was evaporated in vacuo. The obtained crudeproduct was dissolved in toluene (0.5mL). Ytterbiumtriflomethanesulfonate (12mg) was added to the solution, andthen the mixture was stirred at 100°C for 10 hours. The reactionmixture was diluted with ethyl acetate, and the dilution waswashed with saturated sodium hydrogen carbonate aqueoussolution, water and saturated sodium chloride aqueous solutionin this order. The mixture was dried over anhydrous sodiumsulfate. Sodium sulfate was removed by filtration, and theorganic solvent was evaporated in vacuo. The obtained residuewas purified by silica gel column chromatography (C-300;hexane: ethyl acetate =2:3) to give the objective compound(37mg) as colorless oil.   ¹HNMR(300MHz,CDCl₃,δppm):0.88,0.98(3.0H,d,J=6.6Hz),4.70,4.98(1.0H,q,J=6.6Hz),5.74,6.06(1H,brs),6.88(1H,dd,J=3.0Hz,8.7Hz),6.99-7.05(2H,m),7.24-7.29(2H,m),7.74-7.93(2H,m),8.26,8.40(1H,d,J=1.8Hz),9.15,9.19(1H,s)   [α]_D ²⁵:-369.2°(c1.0,MeOH)
[0314] By applying the method described in above-mentionedExample 12, corresponding diamine and carboxylic acid werecyclized and condensed, and then the reactant was optionally deprotected by the method similar to the method described inExample 7 to give the following compounds. Example 12-1 (5R)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-(6-hydroxy-2-pyridyl)-2-imidazoline
[0315] ¹HNMR(300MHz,CDCl₃,δppm):3.13(2H,ds,J=6.6Hz),4.75(1H,br),6.68(1H,d,J=8.1Hz),6.85(1H,d,J=6.0Ha),6.95-7.00(4H,m),7.21-7.25(4H,m),7.39-7.53(3H,m)   [α]_D ²⁵:-269.6°(c0.5,MeOH) Example 12-2 (5S)-4,4-bis(4-fluorophenyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline
[0316] ¹HNMR(300MHz,CDCl₃,δppm):0.85-0.95(3H,m),4.68-4.95(1H,m),5.61(1H,brs),6.63-6.75(2H,m),6.90-7.07(4H,m),7.10-7.20(2H,m),7.30-7.51(3H,m)   [α]_D ²⁵:-305.4°(c0.7,CHCl₃) Example 12-3 The optical active (5S)-2-(2-chloro-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 5-1
[0317] ¹HNMR(300MHz,CDCl₃,δppm):0.88(3H,d,J=6.6Hz),4.72-4.84(1H,m),5.05-5.15(1H,brs),6.90-6.98(1H,m),7.05-7.15(2H,m),7.25-7.30(2H,m),7.65-7.72(1H,m),7.82-7.88(1H,m),7.90-7.98(1H,m),8.41-8.45(1H,m),8.48-8.51(1H,m)   [α]_D ²⁵:-294.0°(c0.5,MeOH) Example 12-4 The optical active(5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline, wherein the startingmaterial is the diamine described in Reference Example 5-1
[0318] ¹HNMR(300MHz,CDCl₃,δppm):0.87(3H,d.J=6.5Hz),4.70-4.80(1H,m),5.65-5.85(1H,br),6.65-6.80(2H,m),6.86-6.92(1H,m),6.98-7.06(2H,m),7.15-7.24(2H,m),7.45-7.52(1H,m),7.80-7.88(1H,m),8.33(1H,s)   [α]_D ²⁵:-258.8°(c0.7,MeOH) Example 12-5 (5S)-2-(3-cyanophenyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline
[0319] ¹HNMR(300MHz,CDCl₃,δppm):0.96(3H,d,J=6.6Hz),4.75(1H,q,J=6.6Hz),5.16(1H,s),6.89-6.93(2H,m),7.55-7.95(4H,m),8.08-8.20(3H,m),8.41(1H,s)   [α]_D ²⁵:-256.1°(c0.4,MeOH) Example 12-6 The optical active(5R)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 6-1
[0320] ¹HNMR(300MHz,CDCl₃,δppm):3.10(1H,br),3.24(1H,d,J=4.2Hz,10.5Hz),4.67(1H,br),5.34,5.83(1H,br),6.88(1H,dd,J=3.3Hz,9.0Hz),7.02(2H,t,J=8.7Hz),7.28(2H,t,J=8.7Hz),7.57(1H,t,J=8.1Hz),7.77(1H,d,J=7.8Hz),7.88(1H,td,J=2.7Hz,8.3Hz),8.10(1H,d, J=8.1Hz),8.22(1H,s),8.39(1H,d,J=0.9Hz)   [α]_D ²⁵:-268.6°(c1.0,CHCl₃) Example 12-7 The optical active(5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-5-methyl-4-(1,5-naphtyridin-3-yl)-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 7-1
[0321] ¹HNMR(300MHz,CDCl₃,δppm):0.96(3H,d,J=5.9Hz),4.80-5.00(1H,m),5.42(1H,brs),7.03(2H,t,J=8.6Hz),7.20-7.40(2H,m),7.53(1H,t,J=8.6Hz),7.63(1H,dd,J=4.2Hz,8.6Hz),7.70-7.80(1H,m),8.10-8.20(1H,m),8.20(1H,s),8.38(1H,d,J=8.6Hz),8.50(1H,d,J=1.6Hz),8.97(1H,dd,J=1.6Hz,4.2Hz),9.08(1H,s)   [α]_D ²⁵: -363.6°(c0.5,CHCl₃) Example 12-8 The optical active(5S)-2-(3-cyanophenyl)-4-(6-fluoro-3-pyridyl)-4-(4-fluorophenyl)-5-methyl-2-imidazolinehydrochloride, whereinthe starting material is the diamine described in ReferenceExample 5-2
[0322] ¹HNMR(300MHz,CD₃OD,δppm):1.24(3H,d,J=7.1Hz),5.42(1H,q,J=7.1Hz),7.15(1H,dd,J=8.5Hz,2.6Hz),7.27(2H,dd,J=8.9Hz,8.5Hz),7.60(2H,dd,J=8.9Hz,4.9Hz),7.78-7.92(2H,m),8.13-8.29(3H,m),8.39-8.40(1H,m)   [α]_D ²⁵:-283.6°(c0.5,MeOH) Example 12-9 The optical active(5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-5-methyl-4-(1,5-naphtyridin-3-yl)-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 8-1
[0323] ¹HNMR(300MHz,CDCl₃,δppm):1.02(3H,d,J=6.6Hz),4.82-4.91(1H,m),5.09-5.12(1H,br),7.03-7.13(2H,m),7.55-7.70(4H,m),7.79(1H,dt,J=7.8Hz,1.3Hz),8.19(1H,d,J=7.9Hz),8.25(1H,s),8.34-8.41(2H, m),8.78(1H,d,J=2.5Hz),8.96(1H,dd,J=4.2Hz,1.6Hz) Example 12-10 (5S)-2-(5-cyano-3-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazolinehydrochloride
[0324] ¹HNMR(400MHz,CD₃OD,δppm):1.15(3H,d,J=6.4Hz),5.49(1H,q,J=6.4Hz),7.19(1H,dd,J=8.8Hz,2.8Hz),7.24(1H,dd,J=8.8Hz,2.8Hz),7.85-7.90(1H,m),8.09-8.14(1H,m),8.24(1H,d,J=2.8Hz),8.45(1H,d,J=2.8Hz),8.77-8.78(1H,m),9.29(1H,d,J=2.0Hz),9.35(1H,d,J=2.0Hz)   [α]_D ²⁵:-252.0°(c0.1,MeOH) Example 13 Production of the optical active (5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline
[0325]
[0326] 2,4-Dicyanopyridine(46.5mg) and ytterbiumtrifluoromethanesulfonate (24mg) were added to a solution ofthe optical active (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine(100mg)described in ReferenceExample 5-1 in toluene(0.25mL), and the mixture was stirred at100°C for 5 hours. The reaction mixture was diluted with ethylacetate, washed with saturated sodium hydrogen carbonateaqueous solution, water and saturated sodium chloride aqueoussolution in this order, and dried over anhydrous sodium sulfate.Sodium sulfate was removed by filtration, and the organicsolvent was evaporated in vacuo. The obtained residue waspurified by silica gel column chromatography (C-300; hexane:ethyl acetate =2:3) to give the objective compound (106mg) asa white solid.   Melting point : 177-179°C   ¹HNMR(300MHz,CDCl₃,δppm):0.87,0.98(3.0H,d,J=6.7Hz),4.73,4.98(1.0H,q,J=6.6Hz),6.85-6.98(1.0H,m),6.99-7.06(2H,m),7.18-7.29(2H,m),7.61(1H,d,J=4.4Hz),7.77-7.93(1H,m),8.25,8,39(1.0H,d,J=2.6Hz),8.45,8.48(1H,s),8.76(1H,dd,J=0.9Hz,5.1Hz)   [α]_D ²⁵:-416.9°(c1.0,CHCl₃) Example 14 Production of(5R)-2-(4-cyano-2-pyridyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline
[0327]
[0328] 2,4-Dicyanopyridine (601mg) and ytterbiumtrifluoromethanesulfonate (289mg) were added to a solution of(2R)-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1,2-propanediamine(1.50g)in toluene(30mL), and the mixture wasrefluxed under stirring for 2 days. The reaction mixture wasconcentrated in vacuo, and then the residue was dissolved intetrahydrofuran (20mL). 6N Hydrochloric acid (10mL) was addedto the solution, and then the mixture was stirred at roomtemperature for 24 hours. The reaction mixture wasconcentrated in vacuo, and then the residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=2:1) to give the objective compound (385mg).   ¹HNMR(200MHz,CD₃OD,δppm):3.15(2H,brs),4.71(1H,brs),7.02(2H,m),7.08(2H,m),7.23(2H,m),7.57(2H,m),7.83(1H,dd,J=3.0Hz,10.0Hz),8.46(1H,s),8.87(1H,d,J=10.0Hz)   [α]_D ²⁵:-312.8°(c1.0,CHCl₃)
[0329] By applying the methods described in Example 13 and 14,corresponding diamine and cyanopyridine were cyclized,optionally followed by cleavage the protecting groups to givethe following compounds. Example 14-1 2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-imidazoline
[0330] ¹HNMR(300MHz,CDCl₃,δppm):4.16-4.26(2H,m),4.54-4.71(1H,m),6.20(0.8H,s),6.58(0.2H,s),6.86-8.78(10H,m) Example 14-2 2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-2-imidazoline
[0331] Melting point: 169-171°C Example 14-3 The optical active(5R)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline,wherein thestarting material is the diamine described in Reference Example6-1
[0332] ¹HNMR(400MHz,CD₃OD,δppm):3.17(2H,d,J=6.2Hz),4.76(1H,t,J=6.2Hz),7.06(3H,m),7.28(2H,m),7.85(1H,d,J=4.8Hz),8.12(1H,ddd,J=2.8Hz,7.6Hz,7.6Hz),8.43(1H,d,J=2.8Hz),8.47(1H,s),8.88(1H,d,J=4.8Hz)   [α]_D ²⁵:-304.7° (c0.6,CHCl₃) Example 14-4 The optical active(5S)-2-(6-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 5-1
[0333] ¹HNMR(300MHz,CDCl₃,δppm):0.88(2.5H,d,J=6.5Hz),0.98(0.5 H,d,J=6.8Hz),4.68-4.78(0.8H,m),4.92-5.05(0.2H,m),6.16(0.8H,brs),6.52(0.2H,brs),6.85-7.09(3H,m),7.20-7.25(2H,m),7.72-8.00(3H,m),8.30-8.55(2H,m)   [α]_D ²⁵:-335.35° (c0.2,MeOH) Example 14-5 The optical active(5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline(epimer in 4th position ofExample 13 compound), wherein the starting material is thediamine described in Reference Example 5-2
[0334] ¹HNMR(300MHz,CDCl₃,δppm):0.96(2.4H,d,J=6.5Hz),1.01(0.6H,d,J=6.9Hz),4.76(0.8H,q,J=6.5Hz),5.07(0.2H,q,J=6.9Hz),6.14(0.8H,brs),6.54(0.2H,brs),6.84-6.91(1H,m),7.00-7.10(2H,m),7.30-7.37(0.4H,m),7.48-7.56(1.6H,m),7.60-7.71(2H,m),8.08(0.8H,d,J=2.6Hz),8.15(0.2H,d,J=2.6Hz),8.45(0.2H,s),8.57(0.8H,s),8.74-8.78(1H,m)   [α]_D ²⁵:-291.0° (c0.8,MeOH) Example 14-6 The optical active (5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 7
[0335] ¹HNMR(300MHz,CD₃OD,δppm)0.90(3H,d,J=6.3Hz),4.80-4.90(1H,m)7.05-7.34(4H,m),7.23(1H,d,J=1.5Hz),7.44-7.47(1H,m),7.82-7.84(1H,m),8.15(1H,d,J=5.1Hz),8.44(1H,s),8.86(1H,m)   [α]_D ²⁵:-332.3° (c1.1,CHCl₃) Example 14-7 (5S)-2-(4-cyano-2-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline
[0336] Melting point:160-162°C   [α]_D ²⁵:-332.8° (c0.5,MeOH) Example 14-8 The optical active(5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-5-methyl-4-(3-pyridyl)-2-imidazolinehydrochloride, wherein the startingmaterial is the diamine described in Reference Example 7-2
[0337] ¹HNMR(300MHz,CD₃OD,δppm):1.15(3H,d,J=6.7Hz),5.54(1H,q,J=6.7Hz),7.16-7.33(2H,m),7.33-7.45(2H,m),8.08(1H,dd,J=5.5Hz,8.3Hz),8.16(1H,dd,J=1.4Hz,4.9Hz),8.56(1H,brs),8.65(1H,ddd,J=1.1Hz,2.3Hz,8.3Hz),8.90(1H,dd,J=1.1Hz,5.5Hz),9.07(1H,dd,J=1.1Hz,2.3Hz),9.10(1H,dd,J=1.0Hz,4.9Hz)   [α]_D ²⁵:-292.0° (c0.1,MeOH) Example 14-9 The optical active(5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methvl-2-imidazoline,wherein the startingmaterial is the diamine described in Reference Example 8
[0338] ¹HNMR(300MHz,CDCl₃,δppm):0.97(3H,d,J=6.6Hz),4.74-4.90(1H,m),6.13(1H,brs),6.96(1H,s),6.99-7.10(3H,m),7.40-7.57(2H,m),7.62(1H,dd,J=5.0Hz,1.6Hz),8.14(1H,d,J=5.3Hz),8.52-8.61(1H,m),8.76(1H.d,J=4.2Hz)   [α]_D ²⁵:-278.8° (c0.5,CHCl₃) Example 15 Production of(5R)-2-(4-cyano-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline
[0339]
[0340] 2-Cyano-4-ethoxycarbonylpyrimidine (207.3mg) andscandium trifluoromethanesulfonate (48.8mg) were added to asolution of (2R)-1,1-bis(4-fluorophenyl)-3-methoxymethoxy-1,2-propanediamine(303.5mg) in toluene (2.0mL), and themixture was stirred at 110°C for 4 hours. The reaction mixturewas concentrated in vacuo, and then the residue was purifiedby silica gel column chromatography (C-300; hexane: ethylacetate =1:1 → 1:2) to give(5R)-2-(4-ethoxycarbonyl-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-[(methoxymethoxy)methyl]-2-imidazoline(279mg). The obtained ester compound was dissolved in methanol(2mL), and ammonia gas was passed through the solution at -78°Cfor 20 minutes. Then the solution was stirred at roomtemperature for 20 hours. The reaction mixture wasconcentrated in vacuo, and then the residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=1:1 → chloroform: methanol= 9:1) to give the correspondingamide compound (273mg). Triethylamine (0.75mL) and trifluoroacetic anhydride (0.26mL) were added at -78°C to asolution of the obtained amide compound in tetrahydrofuran(2mL), and the temperature of the mixture was raised up to roomtemperature, followed by stirring for 7 hours. Water was addedto the reaction mixture, and the mixture was extracted by ethylacetate. The organic layer was dried over anhydrous sodiumsulfate, and then sodium sulfate was removed by filtration.Then the organic solvent was evaporated in vacuo. The residuewas purified by silica gel column chromatography (C-300;hexane: ethyl acetate =1:1 → 1:2) to give the correspondingcyano compound (178mg). The obtained cyano compound wasdissolved in tetrahydrofuran (6mL), and 6N hydrochloricacid(6mL) was added to the solution. Then the mixture wasstirred at room temperature for 5 hours. Saturated sodiumhydrogen carbonate aqueous solution was added to the reactionmixture carefully, and the mixture was extracted by ethylacetate. The organic layer was dried over anhydrous sodiumsulfate, and then sodium sulfate was removed by filtration. Theorganic solvent was evaporated in vacuo. The residue waspurified by silica gel column chromatography (C-300;chloroform: ethyl acetate =2:1) to give the title compound(74.7mg).   ¹HNMR(300MHz,CDCl₃,δppm):3.10-3.40(2H,br),4.62-4.90(1H,br),6.50-6.80(1H,br),6.95-7.08(4H,m),7.21-7.32(2H,m),7.39-7.57(2H,br),7.32(1H,d,J=4.8Hz),9.13(1H,d,J=4.9Hz)   [α]_D ²⁵:-295.1° (c0.49,MeOH)
[0341] By applying the method described in Example 15, thecorresponding diamine and 2-cyano-4-ethoxycarbonylpyrimidine were cyclized and condensed, and ester group of the product wasconverted into a cyano group to give the following compounds. Example 15-1 The optical active (5S)-2-(4-cyano-2-pyrimidyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,wherein the starting material is the diamine described inReference Example 5-1
[0342] ¹HNMR(300MHz,CD₃OD,δppm):0.85(3H,d,J=6.5Hz),4.80-4.93(1H,m),6.95-7.13(3H,m),7.26-7.35(2H,m),7.88-8.10(1H,m),8.0(1H,d,J=4.9Hz),8.13-8.40(1H,d,J=2.0Hz),9.18(1H,d,J=4.9Hz)   [α]_D ²⁵:-351.3° (c1.0,MeOH) Reference Example 1 Production of 1,1-bis(4-fluorophenyl)-1,2-ethanediamine
[0343]
[0344] 4,4'-difluorobenzophenone (25g) was dissolved inanhydrous toluene (800mL), and the solution was cooled at -30°C.Titanium tetrachloride (21.4mL) was dropwise added to thesolution under nitrogen, and ammonia gas was passed through themixture for about 20 minutes. Then the mixture was warmed upto room temperature and stirred over night. Saturatedpotassium carbonate aqueous solution (400mL) was added to thereaction mixture, and the mixture was stirred for an additional1 hour. The organic layer was separated and washed with waterand saturated saline once respectively. The organic layer was dried over anhydrous sodium sulfate, and then the solvent wasevaporated in vacuo to give crude product of1,1-bis(4-fluorophenyl)methanimine (31.7g). The crudeproduct was dissolved in anhydrous toluene (80mL), andtrimethylsilylcyanide (171.86mL) and zinc iodide (1.83g) wereadded to the solution. Then the mixture was stirred at roomtemperature over night. The reaction mixture was washed withsaturated sodium hydrogen carbonate aqueous solution andsaturated saline in this order, and dried over anhydrous sodiumsulfate. Then solvent was evaporated in vacuo to obtained crudeproduct of 2-amino-2,2-bis(4-fluorophenyl)acetonitrile(30.84g). The crude product was dissolved in anhydrous toluene(100mL), and then 1M diisobutylaluminum hydride - toluenesolution (500mL) was dropwise added to the solution at -78°C.Then temperature of the mixture was raised by standing to roomtemperature, and the mixture was stirred over night. Sodiumsulfate decahydrate was added to the reaction mixture, and theresultant mixture was stirred for one hour. Moreover,anhydrous magnesium sulfate was added to the reaction mixture,and the mixture was stirred for one hour. Then insolubles wereremoved by filtration. The filtrate was concentrated in vacuo,and then the obtained residue was purified by silica gel columnchromatography (C-300; 100% ethyl acetate → 100% methanol) togive the title compound (8.55g).   ¹HNMR(300MHz,CDCl₃,δppm):3.32(2H,s),6.96-7.00(4H,m),7.26-7.33(4H,m) Reference Example 2 Production of1-(4-fluorophenyl)-1-(1,5-naphtyridin-3-yl)-1,2-ethanediamine
[0345]
[0346] 4-fluorophenyl 1,5-naphtyridin-3-yl ketone (108mg) wasdissolved in anhydrous toluene (5mL), and the solution wascooled at -30°C. Titanium chloride (0.08mL) was dropwise addedto the solution under nitrogen, and ammonia gas was passedthrough the mixture for about 20 minutes. Then the mixture waswarmed up to room temperature and stirred over night. Saturatedpotassium carbonate aqueous solution (1mL) was added to thereaction mixture, and the mixture was stirred for an additional1 hour. The organic layer was separated, washed with water andsaturated saline once respectively and dried over anhydroussodium sulfate. Then the solvent was evaporated in vacuo togive crude product of(4-fluorophenyl)(1,5-naphtyridin-3-yl)-methanimine (103mg).The crude product was dissolved in anhydrous toluene (2mL), andtrimethylsilylcyanide (0.21mL) and 1M tetrabutylammoniumfluoride - tetrahydrofuran solution (0.01mL) were added to thesolution. The mixture was stirred at room temperature for 6days. The reaction mixture was washed with saturated sodiumhydrogen carbonate aqueous solution and saturated saline oncerespectively and then dried over anhydrous sodium surfacte. Thesolvent was evaporated in vacuo to give crude product of2-amino-2-(4-fluorophenyl)-2-(1,5-naphtyridin-3-yl)-acetonitrile. The crude product was dissolved in anhydroustoluene (2mL). 1M Diisobutylalumium hydride - toluenesolution (1.85mL) was dropwise added to the solution at -78°C,and mixture was warmed up to 0°C for 30 minutes. Sodium sulfatedecahydrate was added to the reaction mixture, and the mixturewas stirred for one hour. Moreover, anhydrous magnesiumsulfate was added to the reaction mixture, and the mixture wasstirred for one hour. Then insolubles were removed byfiltration. The filtrate was concentrated in vacuo, and thenthe obtained residue was purified by silica gel columnchromatography (C-300; chloroform: methanol= 20:1 → 10:1 →2:1) to give the title compound (17mg).   ¹HNMR(200MHz,CD₃OD,δppm):3.52(2H,s),6.99-7.10(2H,m),7.34-7.44(2H,m),7.63(1H,dd,J=4.4Hz,8.5Hz),8.35-8.40(1H,m),8.41-8.43(1H,m),8.92(1H,d,J=2.3Hz),8.98(1H,dd,J=1.7Hz,4.4Hz) Reference Example 3 Production of1,1-bis(4-fluorophenyl)-1,2-propanediamine
[0347]
[0348] Iodine monochloride (0.40g) was added to the suspensionof sodium azide (1.01g) in acetonitrile (6mL) at 0°C. Afterthe suspension was stirred for 10 minutes, the solution of1,1-bis(4-fluorophenyl)-1-propene(1.43g) in acetonitrile(6mL) was added to the suspension, and the mixture was warmed up to room temperature and stirred for 38 hours. The reactionmixture was poured into water, and the mixture was extractedwith diethyl ether. The extract was washed with 10% sodiumthiosulfate aqueous solution, water and saturated sodiumchloride aqueous solution in this order and dried over anhydrousmagnesium sulfate. The solvent was evaporated in vacuo, andthen the residue was purified by silica gel columnchromatography (C-300; hexane: ethyl acetate =10:1) to give thedesired compound.1,1-bis(4-fluorophenyl)-2-iodopropylazide(2.16g).
[0349] The above-mentioned iodoazide compound (40mg) wasdissolved in diethyl ether (1mL), and lithium aluminum hydride(8mg) was added to the solution at room temperature. Then themixture was stirred at room temperature for 2 hours. Sodiumsulfate decahydrate was added to the reaction mixture. Themixture was stirred for 30 minutes. Moreover, anhydrousmagnesium sulfate was added to the reaction mixture, and themixture was stirred for 30 minutes. Insolubles were removedby filtration, and then the filtrate was concentrated in vacuo.The obtained residue was purified by silica gel columnchromatography (C-300; hexane: ethyl acetate =2:1) to give thedesired compound, 2,2-bis(4-fluorophenyl)-3-methylaziridine(9mg).
[0350] The above-mentioned aziridine compound (342mg) wasdissolved in mixture of methanol (10mL) and water (2mL), andsodium azide (439mg) and ammonium chloride (155mg) were addedto the solution. The mixture was stirred at 60°C for 40 hours.After the reaction mixture was cooled by standing, the reactionmixture was diluted with ethyl acetate, and the dilution was washed with saturated sodium hydrogen carbonate aqueoussolution, water and saturated sodium chloride aqueous solutionin this order, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=2:1→ 1:1) to give the desired compound,1-azido-1,1-bis(4-fluorophenyl)-2-propaneamine (251mg).The above-mentioned azide compound (8mg) was reduced in thepresence of 10% palladium carbon catalyst (5mg) in methanolunder 1 atm hydrogen at room temperature. The catalyst wasremoved by filtration, and then the filtrate was concentratedin vacuo to give the title compound (7mg).   ¹HNMR(200MHz,CD₃OD,δppm):1.14(3H,d,J=6.5Hz),4.17(1H,q,J=6.5Hz),7.00-7.13(4H,m),7.42-7.55(4H,m) Reference Example 4 Production of(2R)-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1,2-propanediamine
[0351]
[0352] While stirring a solution of methyl(2S)-2-{[(benzyloxy)carbonyl]amino}-3-(methoxymethoxy)-propanoate(35.70g) in tetrahydrofuran (500mL) under nitrogenat 0°C, 1.0M 4-fluorophenylmagnesium bromide-tetrahydrofuransolution was added to the solution dropwise. Temperature of the mixture was raised to room temperature, and then the mixturewas stirred for 4 hours. Saturated ammonium chloride aqueoussolution (100mL) was added to the reaction mixture, and thenthe reaction mixture was concentrated in vacuo. Saturatedammonium chloride aqueous solution was added to the residue,and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated sodium hydrogen carbonateaqueous solution and saturated sodium chloride aqueous solutionin this order and dried over anhydrous sodium sulfate. Sodiumsulfate was removed by filtration, and then the organic solventwas evaporated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=9:1 → 5:1 → 3:1) to give benzylN-{(1S)-2,2-bis(4-fluorophenyl)-2-hydroxy-1-[(methoxymethoxy)methyl]ethyl)carbamate(49.97g) ascolorless oil. The product (49.80g) was stirred in the presenceof 10% palladium carbon catalyst (2.00g) in methanol solvent(500mL) under latm hydrogen for two days, and reaction mixturewas heated up to 50°C and stirred for 24 hours. The reactionmixture was filtered through celite, and then the obtainedfiltrate was concentrated in vacuo. The residue was purifiedby silica gel column chromatography (C-300; hexane: ethylacetate =2:1 → chloroform: methanol= 5:1) to give(2S)-2-amino-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1-propanol(33.30g)as yellow oil. While stirring a solution oftriphenylphosphine (40.56g) in toluene (400mL) at 0°C, 1.0Mbromine-benzene solution was added to the solution dropwise,and the mixture was stirred for 30 minutes. A solution of theabove-mentioned hydroxyamine compound (20.00g) in toluene (50mL) and triethylamine (43.11g) were dropwise added at 0°Cin this order. Thereafter the reaction mixture was stirred at0°C for 20 hours, and saturated sodium hydrogen carbonateaqueous solution was added to the reaction mixture. Theresultant mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated sodium chloride aqueoussolution and dried over anhydrous sodium sulfate. Sodiumsulfate was removed by filtration, and then the organic solventwas evaporated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; hexane: ethylacetate =4:1 → 2:1) to give (3R)-2,2-bis(4-fluorophenyl)-3-[(methoxymethoxy)methyl]aziridine(7.72g) as yellow oil.Water (40mL), sodium azide (7.45g) and ammonium chloride(2.70g) were added in this order to a solution of the aziridinecompound (7.70g) in N,N-dimethylformamide (80mL), and themixture was stirred at 100°C for 16 hours. Moreover, sodiumazide (7.45g) was added to the reaction mixture, and the mixturewas stirred at 120°C for 24 hours. Thereafter water was addedto the reaction mixture, and the mixture was extracted withdiethyl ether. The organic layer was washed with saturatedsodium hydrogen carbonate aqueous solution and saturated sodiumchloride aqueous solution in this order and dried over anhydroussodium sulfate. Sodium sulfate was removed by filtration, andthen the organic solvent was evaporated in vacuo. The obtainedresidue was purified by silica gel column chromatography(C-300; hexane: ethyl acetate =3:1) to give(2R)-1-azido-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-2-propanamine(7.68g) as yellow oil. The obtained azide compound(7.62g) was stirred in the presence of 5% palladium carbon catalyst (0.80g) in methanol solvent (80mL) under latm hydrogenfor 17 hours. The reaction mixture was filtered through celiteand washed with ethyl acetate. The obtained filtrate was washedwith saturated sodium hydrogen carbonate aqueous solution andsaturated sodium chloride aqueous solution in this order anddried over anhydrous sodium sulfate. Sodium sulfate wasremoved by filtration, and then the organic solvent wasevaporated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; ethyl acetate →chloroform: methanol= 5:1) to give the title diamine (5.70g)as pale yellow oil.   ¹HNMR(300MHz,CDCl₃,δppm):3.26-3.33(1H,m),3.32(3H,s),3.59(1H,dd,J=9.7Hz,2.6Hz),4.03(1H,dd,J=7.9Hz,2.6Hz),4.57(2H,dd,J=7.8Hz,6.5Hz),6.92-7.04(4H,m),7.38-7.53(4H,m)   [α]_D ²⁵:-44.3° (c1.0,CHCl₃)
[0353] The following compounds were produced by the methodsimilar to the method described in the above-mentionedReference Example 4. Reference Example 4-1 (2S)-1,1-bis(4-fluorophenyl)-1,2-propanediamine
[0354] ¹HNMR(300MHz,CDCl₃,δppm):0.99(3H,d,J=6.4Hz),4.01(1H,q,J=6.4Hz),6.92-7.03(4H,m ),7.38-7.52(4H,m) Reference Example 4-2 (2S)-1,1-bis(6-fluoro-3-pyridyl)-1,2-propanediamine
[0355] ¹HNMR(300MHz,CDCl₃,δppm):1.04(3H,d,J=6.3Hz),4.09(1H,q,J=6.3Hz),6.88(2H,dd,J=8.5Hz,3.1Hz),7.88(1H,ddd,J=8.5Hz,8.0H z,2.5Hz),7.96(1H,ddd,J=8.5Hz,8.GHz,2.5Hz),8.35(1H,d,J=2.5Hz),8.40(1H,d,J=2.5Hz) Reference Example 4-3 (2S)-1,1-bis(2-fluoro-4-pyridyl)-1,2-propanediamine
[0356] ¹HNMR(300MHz,CDCl₃,δppm):1.02(3H,d,J=6.3Hz),4.10(1H,q,J=6.3Hz),7.12(1H,s),7.23(1H,s),7.27(1H,d,J=5.4Hz),7.35(1H,d,J=5.7Hz),8.16(1H,d,J=5.7Hz),8.17(1H,d,J=5.4Hz) Reference Example 5 Production of(2 S)-1-(4-fluorophenyl)-l-(6-fluoro-3-pyridyl)-1,2-propanediamine
[0357]
[0358] The solution of t-buthylN-{(1S)-2-(methoxy(methyl)amino]-1-methyl-2-oxoethyl)-carbamate(50g) in tetrahydrofuran (700mL) was dropwise addedslowly at 0°C to 2.5M 4-fluorophenylmagnesium bromidetetrahydrofuran solution (300mL) prepared separately, and thenthe reaction mixture was stirred at room temperature for 14hours. After the reaction mixture was cooled to 0°C, saturatedsodium hydrogen carbonate aqueous solution was added to thereaction mixture, and then the mixture was extracted with ethertwice. The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution and saturated sodiumchloride aqueous solution in this order and dried over anhydroussodium sulfate. Sodium sulfate was removed by filtration, andthen the organic solvent was evaporated in vacuo. The obtainedresidue was purified by silica gel column chromatography(C-300; hexane: ethyl acetate =4:1) to give t-butylN-[(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]carbamate(57.75g) as pale yellow solid. The solution of the obtainedketone compound (61.20g) in ethylene glycol dimethyl ether(500mL) solution was dropwise added to the solution of6-fluoro-3-pyridyllithium in diethyl ether (prepared by thereaction of 5-bromo-2-fluoropyridine (59mL) and 1.6Mbutyllithium - hexane solution (358mL) in diethyl ether (1.5L)solvent at-78°C) at -78°C. Thereafter the reaction mixture wasstirred at-78°C for 30 minutes, and temperature of the reactionmixture was raised to 0°C. Saturated ammonium chloride aqueoussolution was added to the reaction mixture, and the mixture wasstirred at room temperature for an additional 15 minutes. Afteraqueous layer was removed, the organic layer was washed withwater and saturated sodium chloride aqueous solution in thisorder and dried over anhydrous sodium sulfate. Sodium sulfatewas removed by filtration, and then the organic solvent wasevaporated in vacuo. The residue was dissolved in a littleethyl acetate, and excess diisopropyl ether was added to thesolution to precipitate t-butylN-[(1S)-2-(4-fluorophenyl)-2-(6-fluoro-3-pyridyl)-2-hydroxy-1-methylethyl]carbamate.The precipitate wasfiltered (yield 74.35g). The precipitate was treated with 4Nhydrogen chloride-ethyl acetate solution to give (2S)-2-amino-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1-propanol(32.8g). The obtained hydroxyamino compound wasconverted into aziridine by the method similar to the methoddescribed in Reference Example 4 to give2-fluoro-5-[(3S)-2-(4-fluorophenyl)-3-methyl-2-aziridinyl]-pyridine.The obtained aziridine compound was converted intoazide by the method similar to the method described in ReferenceExample 4, and then the azide compound was reduced by theaddition of hydrogen to give the title diamine. Besides, theratio of diastereomers in 2nd position of aziridine ring isabout 3:2, and the diastereomers can be separated by silica gelcolumn chromatography (C-300; hexane: ethyl acetate =6:4 →4:6). Reference Example 5-1 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridvl)-1,2-propanediamine
[0359]
[0360] The mixture of diastereomers of2-fluoro-5-[(3S)-2-(4-fluorophenyl)-3-methyl-2-aziridinyl]pyridineobtained in Reference Example 5 wereseparated by silica gel column chromatography. The aziridinecompound eluted first was treated by the method similar to themethod described in Reference Example 4 to give the optical active title diamine.   ¹HNMR(300MHz,CDCl₃,δppm):1.00(3H,d,J=6.3Hz),4.65(1H,q,J=6.3Hz),6.85(1H,dd,J=3.0Hz,8.7Hz),7.00(2H,t,J=8.4Hz),7.43(2H,dd,J=5.4Hz,9.0Hz),7.97(1H,t,J=8.4Hz),8.40(1H,d,J=2.7Hz) Reference Example 5-2 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine(epimerin 1st position of Reference Example5-1)
[0361]
[0362] The mixture of diastereomers of2-fluoro-5-[(3S)-2-(4-fluorophenyl)-3-methyl-2-aziridinyl]pyridineobtained in Reference Example 5 wasseparated by silica gel column chromatography. The aziridinecompound eluted secondly was treated by the method similar tothe method described in Reference Example 4 to give the opticalactive title diamine.   ¹HNNR(300MHz,CDCl₃,δppm):1.02(3H,d,J=6.3Hz),4.05(1H,q,J=6.3Hz),6.84(1H,dd,J=8.5Hz,3.1Hz),7.01(2H,dd,J=8.9Hz,8.5Hz),7.49(2H,dd,J=8.9Hz,5.2Hz),7.87(1H,ddd,J=8.5Hz,8.0Hz,2.6Hz),8.34(1H,d,J=2.6Hz) Reference Example 6 Production of(2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine
[0363]
[0364] The title compound was produced by the method similar tothe method described in Reference Example 5 via2-fluoro-5-{(3R)-2-(4-fluorophenyl)-3-[(methoxymethoxy)methyl]-2-aziridinyl)pyridine.Saidintermediate, aziridine can be separated by silica gel columnchromatography. Reference Example 6-1 Production of the optical active(2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine
[0365]
[0366] The mixture of diastereomers of2-fluoro-5-{(3R)-2-(4-fluorophenyl)-3-[(methoxymethoxy)methyl]-2-aziridinyl)pyridineobtained inReference Example 6 were separated by silica gel columnchromatography (eluted with mixed solvent of hexane and ethylacetate). The aziridine compound eluted first was treated by the method similar to the method described in Reference Example4 to give the optical active title diamine.   ¹HNMR(300MHz,CDCl₃,δppm):3.31(4H,m),3.56(1H,dd,J=2.3Hz,9.8Hz),4.03(1H,dd,J=2.5Hz,7.9Hz),4.56(2H,s),6.85(1H,dd,J=3.0Hz,6.5Hz),7.00(2H,m),7.39(2H,m),7.94(1H,dt,J=2.7Hz,7.8Hz),8.39(1H,s) Reference Example 7 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(2-fluoro-4-pyridyl)-1,2-propanediamine
[0367]
[0368] The intermediate in Reference Example 5, t-butylN-[(1S)-2-(4-fluorophenyl)-1-methyl-2-oxoethyl]carbamateand 2-methyl-2-propanesulfinamide were condensed in thepresence of a dehydrating agent to give t-butylN-[(1S)-2-[(t-butylsulfinyl)imino]-2-(4-fluorophenyl)-1-methylethyl]carbamate.1.0M trimethylaluminum - hexanesolution (0.43mL) was added to the solution of saidsulfinylimine compound (80mg) in toluene (2mL) at -78°C, andthe mixture was stirred for 5 minutes. The obtained solutionwas dropwise added slowly to 2-fluoro-4-pyridyllithiumsolution (prepared by the reaction of 4-fluoro-2-bromopyridine(114mg) and 1.56M butyllithium - hexane solution (0.46mL) in diethyl ether solvent (3mL) at -78°C) at -78°C. Thereaftertetrahydrofuran (3mL) was added to the reaction mixture, andthen the reaction mixture was stirred at -78°C for 2.5 hours.Saturated sodium chloride aqueous solution was added to thereaction mixture, and temperature of the reaction mixture wasraised to room temperature. The obtained reaction mixture wasfiltered through celite, and then the organic layer of filtratewas dried over anhydrous magnesium sulfate. Magnesium sulfatewas removed by filtration, and then the organic solvent wasevaporated in vacuo. The obtained residue was purified bysilica gel column chromatography (C-300; hexane: ethyl acetate=2:1) to give the optical active t-butylN-[(1S)-2-[(t-butylsulfinyl)amino]-2-(4-fluorophenyl)-2-(2-fluoro-4-pyridyl)-1-methylethyl]carbamate(49mg). Theproduct was treated with 4N hydrogen chloride - dioxane solutionto give the optical active title diamine (31mg).   ¹HNMR(300MHz,CDCl₃,δppm):1.03(3H,d,J=6.3Hz),1.91(4H,brs),4.10(1H,q,J=6.3Hz),6.98-7.48(6H,m),8.12(1H,d,J=5.1Hz) Reference Example 7-1 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(1,5-naphtyridin-3-yl)-1,2-propanediamine
[0369]
[0370] 1,5-naphtyridin-3-yllithium was reacted with t-butyl N-[(1S)-2-[(t-butylsulfinyl)imino]-2-(4-fluorophenyl)-1-methylethyl]carbamateby the method similar to the methoddescribed in Reference Example 7, and the protecting groups ofthe product were removed under acidic condition to give theoptical active title diamine.   ¹HNMR(300MHz,CDCl₃,δppm):1.06(3H,d,J=6.3Hz),4.25(1H,q,J=6.3Hz),7.00(2H,t,J=8.6Hz),7.45-7.55(2H,m),7.60(1H,dd,J=4.2Hz,8.5Hz),8.35(1H,d,J=8.6Hz),8.57(1H,d,J=1.4Hz),8.95(1H,dd,J=1.4Hz,4.2Hz),9.13(1H,d,J=2.2Hz) Reference Example 7-2 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(3-pyridyl)-1,2-propanediamine
[0371]
[0372] 3-pridyllithium was reacted with t-butylN-[(1S)-2-[(t-butylsulfinyl)imino]-2-(4-fluorophenyl)-1-methylethyl]carbamateby the method similar to the methoddescribed in Reference Example 7, and the protecting groups ofthe product were removed under acidic condition to give theoptical active title diamine.   ¹HNMR(300MHz,CDCl₃,δppm):1.01(3H,d,J=6.3Hz),4.08(1H,q,J=6.3Hz),6.99(2H,dd,J=8.6Hz,9.OHz),7.23(1H,dd,J=4.7Hz,8.1Hz),7.45(2H,dd,J=5.3Hz,9.0Hz),7.86(1H,ddd,J=1.6Hz,2.5Hz,8.1Hz),8.44(1H,dd,J=1.6Hz,4.7Hz),8.79(1H,d,J=2.5Hz) Reference Example 8 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(2-fluoro-4-pyridyl)-1,2-propanediamine(epimer in 1st position of the compounddescribed in Reference Example 7)
[0373]
[0374] 4-fluorophenyllithium was reacted with t-butylN-[(1S)-2-[(t-butylsulfinyl)imino]-2-(2-fluoro-4-pyridyl)-1-methylethyl]carbamateby the method similar to the methoddescribed in Reference Example 7, and the protecting groups ofthe product were removed under acidic condition to give theoptical active title diamine.   ¹HNMR(300MHz,CDCl₃,δppm):0.98(3H,d,J=6.4Hz),4.07(1H,q,J=6.4Hz),6.98-7.07(2H,m),7.10(1H,s),7.24(1H,dt,J=5.4Hz,1.7Hz),7.48-7.58(2H,m),8.11(1H,d,J=5.3Hz) Reference Example 8-1 Production of the optical active(2S)-1-(4-fluorophenyl)-1-(1,5-naphtyridin-3-yl)-1,2-propanediamine(epimer in 1st position of the compounddescribed in Reference Example 7-1)
[0375]
[0376] 4-fluorophenyllithium was reacted with t-butylN-[(1S)-2-[(t-butylsulfinyl)imino]-2-(1,5-naphtyridin-3-yl)-1-methylethyl]carbamateby the method similar to the methoddescribed in Reference Example 7, and the protecting groups ofthe product were removed under acidic condition to give theoptical active title diamine.   ¹HNMR(300MHz,CDCl₃,δppm):1.09(1H,d,J=6.3Hz),1.85-2.45(4H,br),4.26(1H,q,J=6.3Hz),7.01(2H,t,J=8.6Hz),7.46-7.65(3H,m),8.35(1H,d,J=8.6Hz),8.52(1H,d,J=1.8Hz),8.96(1H,dd,J=4.1Hz,1.5Hz),9.07(1H,d,J=2.2Hz) Preparation Example 1
[0377] The compound of Example 1 20.0g, lactose 417g,crystalline cellulose 80g and partly pregelatinized starch 80gwere mixed by using V-type mixer, and magnesium stearate 3.0gwas added to the mixture. The resultant mixture was furthermixed. The mixture was compressed in a usual manner to give3000 tablets, diameter of each tablet being 7.0mm and weightof each tablet being 150mg. Content per a tablet(150mg) Compound of Example 1 5.0 mg Lactose 104.25mgCrystalline cellulose 20.0 mg Partly pregelatinized starch 20.0 mg Magnesium stearate 0.75mg Preparation Example 2
[0378] Hydroxypropylcellulose 2910 10.8g and polyethyleneglycol 6000 2.1g were dissolved in purified water 172.5g, andtitanium dioxide 2.1g was dispersed in the solution to preparecoating solution. 2500 tablets prepared separately inPreparation Example 1 were spray-coated with the coatingsolution by using HYCOATERMINI to give film-coated tablets, theweight of each tablet being 155mg. Content per a tablet(155mg) Compound of Example 1 150 mg Hydroxypropylcellulose 2910 3.6mg Polyethylene glycol 6000 0.7mg Titanium dioxide 0.7mg Industrial Applicability
[0379] The compounds of the present invention are useful asagents for the treatment of various diseases which NPY relatesto, that is, for example, cardiovascular disorders exemplifiedby hypertension, nephropathy, heart diseases, vasospasm andarteriosclerosis, central nervous system disordersexemplified by bulimia, depression, anxiety, seizure, epilepsy,dementia, pain, alcoholism and drug withdrawal, metabolicdiseases exemplified by obesity, diabetes, hormone abnormality,hypercholesterolemia and hyperlipidemia, sexual and reproductive dysfunction, gastro-intestinal disorder such asthe inhibition of gastro-intestinal motility, respiratorydisorder, inflammation, or glaucoma, and the like since theyexhibit NPY antagonistic activities and are excellent inpharmacokinetics such as penetration to brain and cerebrospinalfluid.

权利要求:
Claims (23)
[1]
A compound represented by the general formula (I):
[2]
The compound as claimed in Claim 1, wherein R¹ is a grouprepresented by the formula of -Ar³;
[3]
The compound as claimed in Claim 2, wherein Ar² is phenylwhich contains substituent(s) selected from the groupconsisting of cyano, halogen atom, nitro, lower alkyl,halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, formyl,lower alkanoyl, lower alkoxycarbonyl and lower alkylsulfonyl.
[4]
The compound as claimed in Claim 2, wherein Ar² is 5- or6-membered monocyclic heteroaromatic group containing 1 or notless than 2 hetero atoms identically or differently selectedfrom the group consisting of oxygen atom, nitrogen atom and sulfuratom, which may have substituent(s) selected from the groupconsisting of cyano, halogen atom, nitro, lower alkyl, halo(lower)alkyl, lower alkoxy, halo(lower)alkoxy, formyl,lower alkanoyl, lower alkoxycarbonyl and lower alkylsulfonyl.
[5]
The compound as claimed in Claim 4, wherein 5- or 6-memberedmonocyclic heteroaromatic group containing 1 or not less than2 hetero atoms identically or differently selected from the groupconsisting of oxygen atom, nitrogen atom and sulfur atom isthienyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, pyridyl,pyrimidinyl or pyrazinyl.
[6]
The compound as claimed in any one of Claims 3 to 5,wherein Ar¹ is phenyl which has substituent(s) selected fromthe group consisting of halogen atom, halo(lower)alkyl andhalo(lower)alkoxy.
[7]
The compound as claimed in any one of Claims 3 to 5,wherein Ar¹ is thienyl or pyridyl which may have substituent(s)selected from the group consisting of halogen atom,halo(lower)alkyl and halo(lower)alkoxy.
[8]
The compound as claimed in any one of Claims 6 and 7,wherein both R² and R³ are hydrogen atom.
[9]
The compound as claimed in any one of Claims 6 and 7,wherein either R² or R³ is hydrogen atom and the other is loweralkyl which may have substituent(s) selected from the groupconsisting of halogen atom, lower alkylamino, di-loweralkylamino, lower alkanoylamino, hydroxy, lower alkoxy, formyl,lower alkoxycarbonyl, lower alkylcarbamoyl and di-lower alkylcarbamoyl.
[10]
The compound as claimed in any one of Claims 8 and9, wherein Ar³ is phenyl, naphthyl, thienyl, pyridyl, quinolylor 1,5-naphthyridinyl which may have substituent(s) selcted fromthe group consisting of halogen atom, lower alkyl,hydroxy(lower)alkyl, lower alkenyl, di-lower alkylamino, loweralkoxy, halo(lower)alkoxy, lower alkanoyl and aryl.
[11]
The compound as claimed in any one of Claims 3 to 5,wherein Ar¹ is 4-fluorophenyl, 6-fluoro-3-pyridyl or2-fluoro-4-pyridyl and Ar³ is 6-fluoro-3-pyridyl or2-fluoro-4-pyridyl, and either R² or R³ is hydrogen atom andthe other is methyl.
[12]
The compound as claimed in Claim 11, wherein Ar¹ is4-fluorophenyl and Ar³ is 6-fluoro-3-pyridyl.
[13]
The compound as claimed in Claim 11, wherein Ar¹ is4-fluorophenyl and Ar³ is 2-fluoro-4-pyridyl.
[14]
The compound as claimed in Claim 11, wherein both Ar¹and Ar³ are 6-fluoro-3-pyridyl.
[15]
The compound as claimed in Claim 11, wherein both Ar¹and Ar³ are 2-fluoro-4-pyridyl.
[16]
The compound as claimed in Claim 1, which is
2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-pyradinyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(1,5-naphthyridin-3-yl)-2-imidazoline,
2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-methyl-2-imidazoline,
2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline,
2-(3-cyanophenyl)-4,4-bis(3-fluorophenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(3-quinolyl)-4-(2-thienyl)-2-imidazoline,
4-(4-bromophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline,
4,4-bis(4-chlorophenyl)-2-(3-cyanophenyl)-2-imidazoline,
4-(4-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-quinolyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-phenyl-4-(4-vinylphenyl)-2-imidazoline,
4-(6-chloro-3-pyridyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline,
4-(5-chloro-2-thienyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-methylphenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(3-methylphenyl)-4-phenyl-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-nitrophenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-phenyl-4-(3-quinolyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-methoxyphenyl)-4-phenyl-2-imidazoline,
4-(3-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(5-methyl-2-thienyl)-2-imidazoline,
2-(3-cyanophenyl)-4-phenyl-4-(4-trifluoromethylphenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(3-methoxyphenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(3,4-dimethylphenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-vinylphenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(2-naphthyl)-4-(3-pyridyl)-2-imidazoline,
4-(3-bromophenyl)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-2-imidazoline,
4-(2-chlorophenyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-quinolyl)-2-imidazoline,
2-(3-cyanophenyl)-4-phenyl-4-(2-thienyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-dimethylaminophenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-pyridyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-formylphenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-thienyl)-2-imidazoline,
4,4-diphenyl-2-pyrazinyl-2-imidazoline.
2-(3-cyanophenyl)-4,4-bis(4-methoxyphenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-formylphenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-methylsulfonylphenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-formylphenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(2-methylphenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(3-hydroxymethylphenyl)-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(1,2,3,4-tetrahydro-1,5-naphthyridin-7-yl)-2-imidazoline.
2-(3-cyanophenyl)-4-(2-fluorophenyl)-4-(3-pyridyl)-2-imidazoline,
4-(4-biphenylyl)-2-(3-cyanophenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(2-methoxyphenyl)-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-cyclohexyl-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(4-pyridyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(5-pyrimidinyl)-2-imidazoline,
2-(3-cyanophenyl)-4-cyclopentyl-4-phenyl-2-imidazoline,
2-(3-cyanophenyl)-4-cyclobutyl-4-phenyl-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-pyridazinyl)-2-imidazoline,
4-(4-fluorophenyl)-5-methyl-2-pyrazinyl-4-(3-quinolyl)-2-imidazoline,
(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(3-methylsulfonylphenyl)-5-methyl-2-imidazoline,
(4R,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(3-methylsulfonylphenyl)-5-methyl-2-imidazoline,
(4S,5S)-2-(5-cyano-3-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(5-cyano-3-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4S,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(5R)-2-(2-cyano-4-pyridyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline,
(5S)-2-(2-cyano-4-pyridyl)-4,4-bis(4-fluorophenyl)-5-methyl-2-imidazoline,
(4S,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(2-cyano-4-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,
(5S)-2-(2-cyano-4-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
4,4-bis(4-fluorophenyl)-5-methyl-2-pyrazinyl-2-imidazoline,
4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-pyrazinyl-2-imidazoline,
5-ethyl-4,4-bis(4-fluorophenyl)-2-pyrazinyl-2-imidazoline,
4,4-bis(4-fluorophenyl)-5-propyl-2-pyrazinyl-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(4-isothiazolyl)-2-imidazoline,
2-(3-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
2-(3-chlorophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-trifluoromethylphenyl)-2-imidazoline,
2-(3-fluorophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-trifluoromethoxyphenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(5-thiazolyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-methylphenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(2-thienyl)-2-imidazoline,
2-(5-bromo-3-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
2-(3-bromophenyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
4,4-bis(4-fluorophenyl)-2-(3-thienyl)-2-imidazoline,
2-(4-cyano-2-pyridyl)-4,4-bis(4-fluorophenyl)-2-imidazoline,
(4S,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
2-(3-cyanophenyl)-4,4-bis(4-fluorophenyl)-5-(1-hydroxyethyl)-2-imidazoline,
(4S,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,
(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-(1,2,5-thiadiazol-3-yl)-2-imidazoline,
(4R,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-(1,2,5-thiadiazol-3-yl)-2-imidazoline,
(5R)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-(6-hydroxy-2-pyridyl)-2-imidazoline,
(5S)-4,4-bis(4-fluorophenyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline,
(4S,5S)-2-(2-chloro-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(2-chloro-4-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-(6-hydroxy-2-pyridyl)-5-methyl-2-imidazoline,
(5S)-2-(3-cyanophenyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4S,5R)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline,
(4R,5R)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline,
(4S,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-5-methyl-4-(1,5-naphthyridin-3-yl)-2-imidazoline,
(4R,5S)-2-(3-cyanophenyl)-4-(4-fluorophenyl)-5-methyl-4-(1,5-naphthyridin-3-yl)-2-imidazoline,
(4S,5S)-2-(3-cyanophenyl)-4-(6-fluoro-3-pyridyl)-4-(4-fluorophenyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(3-cyanophenyl)-4-(6-fluoro-3-pyridyl)-4-(4-fluorophenyl)-5-methyl-2-imidazoline,
(5S)-2-(5-cyano-3-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4S,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(5R)-2-(4-cyano-2-pyridyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline,
2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-2-imidazoline,
2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-2-imidazoline,
(4S,5R)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline,
(4R,5R)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-hydroxymethyl-2-imidazoline,
(4S,5S)-2-(6-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(6-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,
(4S,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,
(4R,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-5-methyl-2-imidazoline,
(5S)-2-(4-cyano-2-pyridyl)-4,4-bis(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline.
(4S,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-5-methyl-4-(3-pyridyl)-2-imidazoline,
(4R,5S)-2-(4-cyano-2-pyridyl)-4-(4-fluorophenyl)-5-methyl-4-(3-pyridyl)-2-imidazoline,
(5R)-2-(4-cyano-2-pyrimidyl)-4,4-bis(4-fluorophenyl)-5-hydroxymethyl-2-imidazoline,
(4S,5S)-2-(4-cyano-2-pyrimidyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline,or
(4R,5S)-2-(4-cyano-2-pyrimidyl)-4-(4-fluorophenyl)-4-(6-fluoro-3-pyridyl)-5-methyl-2-imidazoline.
[17]
A process for producing a compound of the generalformula (I):
[18]
A process for producing a compound of the generalformula (I):
[19]
A process for producing a compound of the generalformula (I):
[20]
Neuropeptide Y receptor antagonist which containsa compound of the general formula (I):
[21]
An agent for the treatment of bulimia, obesityor diabetes which contains a compound of the general formula(I):
[22]
A compound represented by the general formula (II')
[23]
The compound as claimed in Claim 22, which is
1,1-bis(4-fluorophenyl)-1,2-ethanediamine,
1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-ethanediamine,
1,1-bis(4-fluorophenyl)-1,2-propanediamine,
(2R)-1,1-bis(4-fluorophenyl)-3-(methoxymethoxy)-1,2-propanediamine.
(2S)-1,1-bis(4-fluorophenyl)-1,2-propanediamine,
(2S)-1,1-bis(6-fluoro-3-pyridyl)-1,2-propanediamine,
(2S)-1,1-bis(2-fluoro-4-pyridyl)-1,2-propanediamine,
(2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine,
(1S,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine,
(1R,2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine,
(2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine,
(1S,2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine,
(1R,2R)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-3-(methoxymethoxy)-1,2-propanediamine,
(1S,2S)-1-(4-fluorophenyl)-1-(2-fluoro-4-pyridyl)-1,2-propanediamine,
(1R,2S)-1-(4-fluorophenyl)-1-(2-fluoro-4-pyridyl)-1,2-propanediamine,
(1S,2S)-1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-propanediamine,
(1R,2S)-1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-propanediamine,
(1S,2S)-1-(4-fluorophenyl)-1-(3-pyridyl)-1,2-propanediamine,or
(1R,2S)-1-(4-fluorophenyl)-1-(3-pyridyl)-1,2-propanediamine.

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同族专利:

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公开号 | 公开日

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AU2001234128B2|2004-11-11|

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US7064142B2|2006-06-20|

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DE60109756T2|2005-08-25|

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US20030158418A1|2003-08-21|

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DE60109756D1|2005-05-04|

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US20060135559A1|2006-06-22|

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CA2400659A1|2001-08-30|

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WO2001062738A1|2001-08-30|

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EP1264826B1|2005-03-30|

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AU3412801A|2001-09-03|

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EP1264826A4|2003-03-19|

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US7482358B2|2009-01-27|

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ES2236178T3|2005-07-16|

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AT292119T|2005-04-15|

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申请号 | 申请日 | 专利标题

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JP2000045042||2000-02-22||

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JP2000045042||2000-02-22||

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PCT/JP2001/001312|WO2001062738A1|2000-02-22|2001-02-22|Novel imidazoline compounds|

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