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    • 专利摘要:
    The present invention provides an excellent squalenesynthesizing enzyme inhibitor. Specifically, it provides acompound (I) represented by the following formula, a saltthereof or a hydrate of them.In which R1 represents (1) hydrogen atom or (2) hydroxyl group;HAr represents an aromatic heterocycle which may be substitutedwith 1 to 3 groups; Ar represents an optionally substitutedaromatic ring; W represents a chain represented by (1) -CH2-CH2-which may be substituted, (2) -CH=CH- which may be substituted,(3) -C≡C-, (4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7) -CH2-NH-,(8) -CH2-CO-, (9) -CO-CH2- (10) -NH-S(O)1-, (11) -S(O)1-NH-,(12) -CH2-S(O)1- or (13) -S(O)1-CH2- (1 denotes 0, 1 or 2); andX represents a chain represented by (1) a single bond, (2) anoptionally substituted C1-6 alkylene chain, (3) an optionallysubstituted C2-6 alkenylene chain, (4) an optionally substitutedC2-6 alkynylene chain, (5) a formula -Q- (wherein Q representsoxygen atom, sulfur atom, CO or N(R2) (wherein R2 representsa C1-6 alkyl group or a C1-6 alkoxy group)), (6) -NH-CO-, (7)-CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-,(12) -NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (wherein m denotes 0, 1 or 2) or (16) -(CH2)n-O-(wherein n denotes an integer from 1 to 6).
    公开号:EP1217001A1
    申请号:EP00962889
    申请日:2000-09-27
    公开日:2002-06-26
    发明作者:Toshimi Okada；Nobuyuki Kurusu；Keigo Tanaka；Kazuki Miyazaki；Daisuke Shinmyo；Hiroyuki Sugumi；Hironori Ikuta；Hironobu Ruminasu Kannondaiichibank. 405 HIYOSHI；Takao Saeki；Mamoru Yanagimachi；Masashi Ito
    申请人:Eisai Co Ltd；
    IPC主号:C07D453-00
    专利说明:
    [0001] The present invention relates to a novel compound, amethod for producing the it, a squalene-synthesizing enzymeinhibitor, a cholesterol biosynthesis inhibitor and atriglyceride biosynthesis inhibitor containing such a novelcompound and also to a medicinal composition containing them.More specifically, the present invention relates topreventive and curative agents for hyper lipidemia includingarterial sclerosis diseases and ischemic heart diseases. Prior art
    [0002] Cholesterol is a sterol which is biosynthesized in allanimal cells except for a red blood cell and is a factor essentialfor maintaining a plasma membrane and for the creation of asteroid hormone. Cholesterol is liposoluble and exists ashypobaric lipoprotein (LDL), hyperbaric lipoprotein (HDL) andthe like in blood. LDL in blood is incorporated into cellsthrough an acceptor on the surface of the cells and regeneratesfree cholesterol after decomposed. This is a major route forincorporating cholesterol from the outside of cells. Also, ithas been known that a major enzyme which participates in thebiosynthesis of LDL acceptor protein and cholesterol undergoes feedback of the concentration of cholesterol which is theharvested product. In this manner, the level of cholesterolin cells is maintained and controlled exquisitely by thefeedback control mechanism of the LDL acceptor and biosynthetictype enzyme on the basis of a balance between the biosynthesisof a cell itself and the incorporation of LDL from the outsideof a cell.
    [0003] In recent years, cholesterol has been recognized as themain culprit of hyper lipidemia and also as the mostdangerous factor causing arterial sclerosis diseases (e.g.,coronary diseases, cerebrovascular diseases, aorticdiseases and peripheral arterial diseases) and ischemicheart diseases (e.g., angina pectoris and cardiacinfarction), giving rise to a serious problem. Hyperlipidemia is defined as one showing any one or two or moreof the followings: cholesterol in blood is 220 mg/dl or more,neutral lipid is 150 mg/dl or more and hyperbaric lipoprotein(HDL)-cholesterol is less than 35 mg/dl (Guideline of JapanSociety of Arterial Sclerosis) and is catastrophic diseasescausing arterial sclerosis and the like. One of the majorreasons is a rise in the level of LDL-cholesterol in blood(high cholesteremia) and the deposition of cholesterol onthe inner wall of a blood vessel. At present, treatmentperformed to reduce serum cholesterol has come to be thoughteffective to prevent the development and progress ofarterial sclerosis and the like. A cholesterolbiosynthesis inhibitor, especially, an inhibitor of 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reducing enzymesuch as pravastatin has obtained good results as a medicinefor reducing serum cholesterol in recent years instead ofconventional fibrate type drugs and nicotinic acidpreparations. The HMG-CoA reducing enzyme inhibitorcompetitively inhibits the HMG-CoA reducing enzyme which isan enzyme limiting the rate of biosynthesis of cholesterolin the liver to decrease the rate of biosynthesis ofcholesterol, whereby the liver is increased in the abilityto synthesize LDL acceptors, with the result that the serumLDL is decreased. However, the inhibition of the productionof mevalonic acid based on the inhibition of the HMG-CoAreducing enzyme affects the production of isoprene includingfarnecyl diphosphoric acid (FPP). Therefore, there is afear as to an influence on, for example, other metabolicsubstances, such as ubiquinone, dolichol, heme A,isopentenyl tRNA and prenyl protein, produced throughisoprene as a synthetic intermediate. Further, risks ofside effects such as cataract and myopathy have been pointedout.
    [0004] The squalene synthesizing enzyme is a membrane-boundenzyme of 47-kDa and reducibly catalyzes the head-to-headcondensation of two molecules of FPP to synthesize squalenewhich is an intermediate for the synthesis of cholesterol.In a cholesterol-biosynthesizing system, the squalenesynthesizing enzyme is positioned downstream of a systemgenerating the HMG-CoA reducing enzyme and isoprene and therefore the squalene synthesizing enzyme inhibitor isconsidered to have almost no effect on metabolic systemsother than cholesterol and is therefore expected to work asa new cholesterol depressor which will solve the problemsconcerning the HMG-CoA reducing enzyme inhibitor. Asqualene synthesizing enzyme inhibitor which was reportedfirst is analogous compounds of FPP and squalene. However,these analogous compounds has an activity inhibiting theformation of prenyl protein and the like in addition tosqualene synthesizing enzyme inhibitive action and it isdifficult to put these analogous compounds to practical use.In the meantime, it has been disclosed recently that acertain type substituted phenylethynylquinuclidinecompound and substituted pyridinylethynylquinuclidinecompound are useful as a squalene synthesizing enzymeinhibitor in JP-A 7-502283, 8-502731, 8-504803 (U.S. Patent5731323) and 8-509488. However, no squalene synthesizingenzyme inhibitor which can produce an effect as a medicinefor hyper lipidemia has been created so far.
    [0005] That is, an object of the present invention is to searchand to find a compound which has stronger squalenesynthesizing enzyme inhibitive activities and cholesteroldepressing action over those currently in use and is usefulas a remedy for hyper lipidemia. Disclosure of the Invention
    [0006] In view of the above situation, the inventors of the present invention have made earnest studies and as a result,found that a specific quinuclidine compound and its salt haveunprecedented strong squalene synthesizing inhibitiveactivities. The inventors have also found that thesecompounds and their salts have strong cholesterolbiosynthesizing inhibitive activities, triglyceridebiosynthesizing inhibitive activities and serum cholesteroldepressing action and serum triglyceride depressing actionbased on the squalene synthesizing inhibitive activities.The present invention has been thus completed. A compoundaccording to the present invention is useful as a remedy forhyper lipidemia.
    [0007] Accordingly, the present invention relates to: (1) a compound (I) represented by the following formula:
    [0008] In the specification of the present invention, there isthe case where the structural formula of a compoundrepresents a definite isomer. However, the presentinvention includes isomers such as geometrical isomers,optical isomers based on asymmetric carbon, stereoisomersand tautomers and is not limited by the description of theformula illustrated for the sake of convenience.
    [0009] The definitions of the terms used in the specificationof the present invention will be explained below.
    [0010] In the specification of the present invention, the grouprepresented by R1 in the above formula (I) means hydrogenatom or hydroxyl group and preferably hydroxyl group.
    [0011] In the specification of the present invention, the"aromatic heterocycle which may be substituted with 1 to 3groups" represented by HAr in the aforementioned formula (I)is preferably, for example, a 5- to 14-membered aromaticheterocycle which has 1 to 4 atoms selected optionally fromnitrogen atom, sulfur atom and oxygen atom and may besubstituted with 1, 2 or 3 substituents, and more preferably,an aromatic heterocycle which may be substituted with 1 to 3 groups selected from (1) halogen atom, (2) hydroxyl group, (3)thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6 chainhydrocarbon group which may be substituted, (7) a C3-8 cyclichydrocarbon group which may be substituted, (8) a C6-14 aromatichydrocarbon cyclic group which may be substituted, (9) a 5- to14-membered aromatic heterocyclic group which may besubstituted, (10) a 4- to 10-membered non-aromatic heterocyclicgroup which may be substituted, (11) a C1-6 alkoxy group whichmay be substituted, (12) a C3-8 cycloalkoxy group which may besubstituted, (13) a C1-6 chain hydrocarbon-thio group which maybe substituted, (14) a C3-8 cyclic hydrocarbon-thio group whichmay be substituted, (15) a C6-14 aromatic hydrocarbon-oxy groupwhich may be substituted, (16) a 5- to 14-memberedheterocycle-oxy group which may be substituted, (17) a C6-14aromatic hydrocarbon-thio group which may be substituted, (18)a 5- to 14-membered heterocycle-thio group which may besubstituted, (19) an amino group which may be substituted, (20)azide group, (21) guanidino group, (22) carbamide group, (23)formyl group, (24) a C1-6 imidoyl group which may be substituted,(25) a carbonyl group which is substituted, (26) a carbonyl-oxygroup which is substituted, (27) a carboxy group which may forma salt, (28) a carbamoyl group which may be substituted, (29)a C1-4 alkylenedioxy group which may be substituted, (30) asulfinyl group which may be substituted and (31) a sulfonylgroup which may be substituted.
    [0012] In the above-mentioned definition of HAr, the "aromaticheterocycle" means monocyclic type, dicyclic type or tricyclic type aromatic heterocycles. Examples thereofinclude 5- to 14-membered aromatic heterocyclic groupscontaining 1 to 4 atoms selected from nitrogen atom, sulfuratom and oxygen atom. Specifically, aromatic heterocyclescontaining two or more different atoms selected fromnitrogen atom, sulfur atom and oxygen atom, such asnitrogen-containing aromatic heterocycles, e.g., pyrrolering, pyridine ring, pyridone ring, pyridazine ring,pyrimidine ring, pyrazine ring, pyrazole ring, imidazolering, indole ring, isoindolyl ring, indolizine ring, purinering, indazole ring, quinoline ring, isoquinoline ring,quinolizine ring, phthalazine ring, naphthyridine ring,quinoxaline ring, quinazoline ring, cinnoline ring,pteridine ring, imidazotriazine ring, pyrazinopyridazinering, acridine ring, phenanthridine ring, carbazole ring,carbazoline ring, perimidine ring, phenanthroline ring andphenarsine ring; sulfur-containing aromatic heterocycles,e.g., a thiophene ring and benzothiophene ring; oxygen-containingaromatic heterocycles, e.g., a furan ring, pyranring, cyclopentapyran ring, benzofuran ring, isobenzofuranring; thiazole ring, isothiazole ring, benzthiazole ring,benzthiadiazole ring, phenothiazine ring, isoxazole ring,furazane ring, phenoxazine ring, pyrazoloxazole ring,imidazothiazole ring, thienofuran ring, furopyrrole ringand pyridoxazine ring. As preferable examples thereofpyrrole ring, pyridine ring, pyridone ring, pyrimidine ring,imidazole ring, indole ring, quinoline ring, isoquinoline ring, quinolizine ring, phthalazine ring, naphthyridinering, quinazoline ring, acridine ring, phenarsine ring,thiophene ring, benzothiophene ring, furan ring, pyran ring,benzofuran ring, thiazole ring, benzthiazole ring andphenothiazine ring are given. As more preferable examplesthereof, pyrrole ring, pyridine ring, thiophene ring,benzothiophene ring, thiazole ring and benzthiazole ring aregiven.
    [0013] In the above definition, the "halogen atom" meanshalogen atoms such as fluorine atom, chlorine atom, bromineatom and iodine atom and is preferably fluorine atom,chlorine atom and bromine atom.
    [0014] The "C1-6 chain hydrocarbon group" in the "C1-6 chainhydrocarbon group which may be substituted" given as thesubstituent of HAr means "a C1-6 alkyl group", "a C2-6 alkenylgroup" and "a C2-6 alkynyl group". As the " C1-6 alkyl group",for example, straight-chain or branched C1-6 alkyl groups suchas methyl group, ethyl group, n-propyl group, i-propyl group,sec-propyl group, n-butyl group, i-butyl group, sec-butylgroup, t-butyl group, n-pentyl group, i-pentyl group,sec-pentyl group, t-pentyl group, n-hexyl group, i-hexylgroup, 1,2-dimethylpropyl group, 2-ethylpropyl group, 1-methyl-2-ethylpropylgroup, 1-ethyl-2-methylpropyl group,1,1,2-trimethylpropyl group, 1,1,2-triethylpropyl group,1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 2-ethylbutylgroup, 1,3-dimethylbutyl group, 2-methylpentylgroup and 3-methylpentyl group are preferable. As the "C2-6 alkenyl group", straight-chain or branched C2-6 alkenylgroups such as vinyl group, allyl group, isopropenyl group,1-propene-2-yl group, 1-butene-1-yl group, 1-butene-2-ylgroup, 1-butene-3-yl group, 2-butene-1-yl group and 2-butene-2-ylgroup are preferable. As the "C2-6 alkynylgroup", ethynyl group, propynyl group, butynyl group,pentynyl group and hexynyl group are preferable. Also, theterm "may be substituted" implies that may be substitutedwith one or two groups selected from, for example, (1) ahydroxyl group which may be protected, (2) halogen atom, (3)nitrile group, (4) carboxyl group, (5) a C3-8 cycloalkyl group,C3-8 cycloalkenyl group or C3-8 cycloalkynyl group, which maybe hydroxylated or halogenated, (6) a C1-6 alkoxy group whichmay be substituted with a group selected from a halogen atom,hydroxyl group, a C6-14 aryl group, 5- to 14-memberedheteroaryl group and a C6-14 aryl-C1-6 alkoxy group, (7) a C3-8cycloalkyloxy group which may be halogenated or hydroxylated,(8) a C3-8 cycloalkenyloxy group which may be halogenated orhydroxylated, (9) a C1-6 alkoxy-carbonyl group, (10) a C1-4alkylenedioxy group which may be halogenated, (11) a C1-6alkanoyl group which may be substituted with a group selectedfrom hydroxyl group, a C1-6 alkoxy group and a C1-6 alkanoyloxygroup, (12) a C6-14 aryl group which may be substituted witha group selected from a halogen atom, a C1-6 alkyl group anda C1-6 alkoxy group, (13) a 5- to 14-membered aromaticheterocyclic group which may be substituted with a groupselected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (14) a4- to 10-membered non-aromatic heterocyclic group which maybe substituted with a group selected from a halogen atom,a C1-6 alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl groupand a C1-6 alkoxy group, (15) a group (EtO)2PO-, (16) acetylgroup, (17) a sulfonyl group which may be substituted witha group selected from a C1-6 hydrocarbon group, a mino-(C1-6hydrocarbon)-amino group and a di-(C1-6 hydrocarbon)-aminogroup, (18) an amino group which may be substituted with C1-6hydrocarbon group, (19) a C1-6 hydrocarbon group-thio groupwhich may be hydroxylated or halogenated and (20) a carbamoylgroup which may be substituted with a C1-6 hydrocarbon group.
    [0015] The "C1-6 chain hydrocarbon group which may be substituted"is preferably a C1-6 chain hydrocarbon groups which maysubstituted with one or two groups selected from (1) hydroxylgroup, (2) a halogen atom, (3) nitrile group, (4) a C1-6cycloalkyl group, (5) a C1-6 alkoxy group, (6) a C1-6 alkoxy-C1-6alkoxy group, (7) a C1-4 alkylenedioxy group, (8) a C1-6alkoxy-carbonyl group, (9) a C1-6 alkanoyl group, (10) a C1-6alkoxy-C1-6 alkanoyl group, (11) a C1-6 alkanoyl-oxy group, (12)a C1-6 alkanoyl -oxy-C1-6 alkanoyl group, (13) a 5- to 14-memberedheterocyclic group, (14) a 5- to 10-membered condensedheterocyclic group which may substituted with a C1-6 alkoxy group,(15) carboxyl group, (16) (EtO)2PO- and (17) a C1-6 alkyl -sulfonylgroup, and more preferably a substituted C1-6 chain hydrocarbongroup such as (1) unsubstituted C1-6 chain hydrocarbon groupssuch as ethyl group, propyl group and 2-propene-1-yl group, (2) C1-6 chain hydrocarbon groups substituted with a C6-14 aromatichydrocarbon group such as phenyl group, (3) C1-6 chainhydrocarbon groups substituted with a 5- to 14-memberedaromatic heterocyclic group such as pyridyl group and (4)substituted C1-6 chain hydrocarbon groups such as a C1-6 alkoxy-C1-6chain hydrocarbon group.
    [0016] In the above-mentioned definition, for example, the "C1-6chain hydrocarbon group which may be halogenated" means thatany one of the carbons of the "C1-6 chain hydrocarbon group" maybe substituted with a halogen atom. Specific examples thereofinclude trifluoromethyl group, 2-chloroethyl group, 1,2-dichloroethylgroup, 2-bromoethyl group, 3-bromopropyl group,3,3,3-trifluoropropyl group, 4-chlorobutyl group, 1,1-dimethyl-3-chloroethylgroup, 2,2-dimethyl-4-bromobutylgroup and 3-chloro-2-propenyl group. Also, the "C1-6 alkoxygroup which may be halogenated" means that any one of the carbonsof the "C1-6 alkoxy group" may be substituted with a halogen atom.Specific examples thereof include trifluoromethoxy group,2-chloroethoxy group, 1,2-dichloroethoxy group, 2-bromoethoxygroup, 3-bromopropyloxy group, 3,3,3-trifluoropropyloxy group,4-chlorobutyloxy group, 1,1-dimethyl-3-chloroethoxy group and2,2-dimethyl-4-bromobutyloxy group.
    [0017] The "C3-8 cyclic hydrocarbon group" in the "C3-8 cyclichydrocarbon group which may be substituted" which is given asthe substituent of HAr means a "C3-8 cycloalkyl group", a "C3-8cycloalkenyl group" and the like. As the "C3-8 cycloalkyl group",3- to 8-membered cycloalkyl groups such as cyclopropanyl group, cyclobutanyl group, cyclopentanyl group, cyclohexanyl groupand cycloheptanyl group are preferable. As the "C3-8cycloalkenyl group", 3- to 8-membered cycloalkenyl groups suchas cyclopropenyl group, cyclobutenyl group, cyclopentenylgroup, cyclohexenyl group and cycloheptenyl group arepreferable. Also, the term "may be substituted" implies thatthe above "C3-8 cyclic hydrocarbon group" may be substituted withone or two groups selected from, for example, (1) a hydroxylgroup which may be protected, (2) a halogen atom, (3) nitrilegroup, (4) carboxy group, (5) a C1-6 alkyl group which may besubstituted with a group selected from hydroxyl group, a halogenatom, a C1-6 alkoxy group which may be halogenated, a C1-6hydrocarbon-thio group which may be halogenated, an amino groupwhich may be substituted with a C1-6 hydrocarbon group and a C1-6alkanoyl group, (6) a C1-6 alkenyl group which may be substitutedwith a group selected from hydroxyl group, a halogen atom, aC1-6 alkoxy group which may be halogenated, a C1-6hydrocarbon-thio group which may be halogenated, an amino groupwhich may be substituted with a C1-6 hydrocarbon group and a C1-6alkanoyl group, (7) a C1-6 alkynyl group which may be substitutedwith a group selected from hydroxyl group, a halogen atom, aC1-6 alkoxy group which may be halogenated, a C1-6hydrocarbon-thio group which may be halogenated, an amino groupwhich may be substituted with a C1-6 hydrocarbon group and a C1-6alkanoyl group, (8) an amino group which may be substituted witha group selected from hydroxyl group, a halogen atom, a C1-6alkoxy group which may be halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, a C1-6 alkanoyl group and a C1-6hydrocarbon group, (9) a C1-6 alkoxy group which may besubstituted with a group selected from hydroxyl group, a halogenatom, a C1-6 alkyl group which may be halogenated, a C1-6 alkoxygroup which may be hydroxylated or halogenated, a C1-6hydrocarbon-thio group which may be halogenated, an amino groupwhich may be substituted with a C1-6 hydrocarbon group and a C1-6alkanoyl group, (10) a C1-6 hydrocarbon-thio group which may besubstituted with a group selected from hydroxyl group, a halogenatom, a C1-6 alkyl group which may be halogenated, a C1-6 alkenylgroup which may be halogenated, a C1-6 alkynyl group which maybe halogenated, a C1-6 alkoxy group which may be hydroxylatedand halogenated, a C1-6 hydrocarbon-thio group which may behalogenated, an amino group which may be substituted with a C1-6hydrocarbon group and a C1-6 alkanoyl group, (11) a C1-6 alkanoylgroup which may be substituted with a group selected fromhydroxyl group, a C1-6 alkoxy group and a C1-6 alkanoyloxy group,(12) a C6-14 aryl group which may be substituted with a groupselected from a halogen atom, a C1-6 alkyl group and a C1-6 alkoxygroup, (13) a 5- to 14-membered aromatic heterocyclic groupwhich may be substituted with a halogen group, a C1-6 alkyl group,a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group,(14) a non-aromatic heterocyclic group which may be substitutedwith a group selected from a halogen atom, a C1-6 alkyl group,a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group,(15) a C1-6 alkoxy-carbonyl group, (16) a C1-4 alkylenedioxy groupwhich may be halogenated, (17) the formula (EtO)2PO- and (18) acetyl group.
    [0018] It is to be noted that in the specification of the presentinvention, the "hydrocarbon group" shown in the formula (I)implies both of the "C1-6 chain hydrocarbon group" and the"C3-8 cyclic hydrocarbon group" which have the samedefinitions as above.
    [0019] Preferable examples of the "C6-14 aromatic hydrocarboncyclic group" in the "C6-14 aromatic hydrocarbon cyclic groupwhich may be substituted" which is given as the substituent ofHAr include phenyl group, pentalenyl group, indenyl group,naphthyl group, azulenyl group, heptalenyl group,benzocyclooctenyl group and phenanthrenyl group. Among thesegroups, a phenyl group and naphthyl group are more preferable.Also, the term "may be substituted" implies that the above "C6-14aromatic hydrocarbon cyclic group" may be substituted with oneor more groups selected from, for example, (1) hydroxyl group,(2) a halogen atom, (3) a C1-6 alkyl-sulfonyl group, a C1-6alkenyl-sulfonyl group or a C1-6 alkynyl-sulfonyl group whichmay be halogenated, (4) a C1-4 alkylenedioxy group which may behalogenated, (5) a C1-6 alkoxy group which may be halogenated,(6) a C1-6 hydrocarbon-thio group which may be halogenated, (7)a C1-6 alkoxy-carbonyl group, (8) a C6-14 aryl-C1-6 alkoxy group,(9) a C1-7 alkanoylamino group, (10) a C1-6 alkyl-carbamoyl group,(11) a C1-6 alkenyl-carbamoyl group, (12) a C1-6 alkynyl-carbamoylgroup and (13) an amino group which may be substituted with aC1-6 hydrocarbon group. Preferable examples of the "C6-14aromatic hydrocarbon cyclic group which is substituted" include phenyl groups converted into nitriles, halogenated phenyl group,phenyl group substituted with a C1-6 alkyl group such as an ethylgroup, phenyl group substituted with a C1-6 alkoxy group suchas methoxy group, phenyl group substituted with analkylenedioxy group such as 2,4-methylenedioxy group and phenylgroup substituted with a di-(C1-6 alkyl)-amino group such asdimethylamino group.
    [0020] It is to be noted that, in the present invention, the"C6-14 aryl group" shown in the formula (I) has the same meaningas the above-mentioned "C6-14 aromatic hydrocarbon cyclicgroup" and excludes aromatic heterocyclic groups.
    [0021] The "5- to 14-membered aromatic heterocyclic group" in the"5- to 14-membered aromatic heterocyclic group which may besubstituted" which is given as the substituent of HAr means anaromatic heterocycle having 1 to 4 atoms selected from nitrogenatom, oxygen atom and sulfur atom. Specific examples thereofinclude pyrrolyl group, pyridinyl group, pyridazinyl group,pyrimidinyl group, pirazinyl group, thiazolyl group andoxazolyl group. Also, the term "may be substituted" means thatthe above-mentioned "5- to 14-membered aromatic heterocyclicgroup" may be substituted with one or more groups selected from(1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4)a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group, whichmay be halogenated, (5) a C1-6 alkoxy group which may behalogenated, (6) a C1-6 alkyl-thio group, C1-6 alkenyl group orC1-6 alkynyl group, which may be halogenated, (7) a C1-6 alkoxy-C1-6alkyl group, (8) acetyl group, (9) a C1-6 alkanoyl group, (10) a mono-(C1-6 hydrocarbon) -amino group, (11) a di-(C1-6hydrocarbon)-amino group and (12) a tri-(C1-6 hydrocarbon)-aminogroup. Preferable examples of the "substituted 5- to14-membered aromatic heterocyclic group" include aromaticheterocycles converted to nitriles, aromatic heterocyclessubstituted with a C1-6 alkyl group, aromatic heterocyclessubstituted with a C1-6 alkoxy group, aromatic heterocyclessubstituted with a C1-6 alkoxy-C1-6 alkyl group, aromaticheterocycles substituted with a mono-(C1-6 alkyl)-amino groupand aromatic heterocycles substituted with a di-(C1-6alkyl)-amino group.
    [0022] In the specification of the present invention, the "C6-14aryl group" shown in the formula (I) has the same meaningas the above-mentioned "5- to 14-membered aromaticheterocyclic group".
    [0023] It is to be noted that in the specification of the presentinvention, the "aromatic ring" shown in the formula (I)implies all rings having the same meanings as the above-mentioned"C6-14 aromatic hydrocarbon ring" and "5- to14-membered aromatic heterocyclic group".
    [0024] The "4- to 10-membered non-aromatic heterocyclic group" inthe "4- to 10-membered aromatic heterocyclic group which maybe substituted" which is given as the substituent of HAr meansa ring which has the same meaning as the aforementioned "C3-8cyclic hydrocarbon group" and in which 1 to 4 carbon atoms aresubstituted with an atom selected from nitrogen atom, oxygenatom and sulfur atom and also means that it includes a unsaturated condensed ring. Preferable specific examplesthereof include pyrrolidinyl group, pyrrolinyl group,piperidinyl group, piperazinyl group, imidazolinyl group,pyrazolidinyl group, imidazolydinyl group, morpholinyl group,tetrahydropyranyl group, azetidinyl group, oxetanyl group,oxathiolanyl group, phthalimide and succinimide. Morepreferable examples include pyrrolidinyl group, piperidinylgroup and morpholinyl group. Also, the term "may besubstituted" means that the above-mentioned "4- to 10-memberedaromatic heterocyclic group" may be substituted with one or moregroups selected from (1) hydroxyl group, (2) a halogen atom,(3) nitrile group, (4) a C1-6 alkyl group, C1-6 alkenyl group orC1-6 alkynyl group which may be halogenated, (5) a C1-6 alkoxygroup which may be halogenated, (6) a C1-6 alkyl-thio group, C1-6alkenyl group or C1-6 alkynyl group which may be halogenated,(7) a C1-6 alkoxy-C1-6 alkyl group, (8) acetyl group, (9) a C1-6alkanoyl group, (10) a mono- (C1-6 hydrocarbon) -amino group, (11)a di-(C1-6 hydrocarbon)-amino group, (12) a tri- (C1-6 hydrocarbongroup-amino group and (13) an oxo group forming carbonyl group,N-oxide group, sulfoxide group or sulfonic group.
    [0025] It is to be noted that in the specification of the presentinvention, the "heterocycle" shown in the formula (I)implies both of the "5- to 14-membered heterocyclic group"and the "4- to 10-membered non-aromatic heterocyclic group"which have the same definitions as above.
    [0026] The "C1-6 alkoxy group" in the "C1-6 alkoxy group which maybe substituted" given as the substituent of HAr means the "alkoxy group" corresponding to the "C1-6 chain hydrocarbongroup" in the aforementioned definition. Preferable examplesthereof include C1-6 alkyl-oxy groups such as methoxy group,ethoxyl group, n-propoxy group, i-propoxy group, sec-propoxygroup, n-butoxy group, i-butoxy group, sec-butoxy group, t-butoxygroup, n-pentoxy group, i-pentoxy group, sec-pentoxygroup, t-pentoxy group, n-hexoxy group, i-hexoxy group,1,2-dimethylpropoxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxygroup, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxygroup, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxygroup, 2,2-dimethylbutoxy group, 2-ethylbutoxygroup, 1,3-dimethylbutoxy group, 2-methylpentoxy group and3-methylpentoxy group; C2-6 alkenyl-oxy groups such as vinyloxygroup, allyloxy group, isopropoxyl group, 1-propenyl-2-oxygroup, 1-butenyl-1-oxy group, 1-butenyl-2-oxy group, 1-butenyl-3-oxygroup, 2-butenyl-1-oxy group, 2-butenyl-1-oxygroup and 2-butenyl-2-oxy group; and C2-6 alkynyl-oxy groups suchas ethynyloxy group, propinyloxy group, butynyloxy group,pentynyloxy group and hexynyloxy group. The term "may besubstituted" means that may be substituted with one or moregroups selected from, for example, (1) hydroxyl group, (2) ahalogen atom, (3) a C1-6 alkyl group, C2-6 alkenyl group or C2-6alkynyl group, which may be substituted with a group selectedfrom hydroxyl group, a halogen atom, a 5- to 14-memberedaromatic heterocyclic group and a 4- to 10-membered non-aromaticheterocyclic group, (4) a C3-8 cycloalkyl group or C3-8cycloalkenyl group, which may be hydroxylated or halogenated, (5) a C1-6 alkoxy group which may be hydroxylated or halogenated,(6) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6alkynylthio group, which may be halogenated, (7) a C3-8cycloalkyloxy group, C3-8 cycloalkenyloxy group or C3-8cycloalkynyloxy group which may be halogenated, (8) a C3-8cycloalkylthio group, C3-8 cycloalkenylthio group or C3-8cycloalkynylthio group, which may be halogenated, (9) a C6-14aryl group, (10) a C1-6 alkanoyl group which may be halogenated,(11) a 5- to 14-membered aromatic heterocyclic group and (12)a 4- to 10-membered non-aromatic heterocycle. Preferableexamples of the "C1-6 alkoxy group which is substituted" includea C1-6 alkoxy group which is hydroxylated, a C1-6 alkoxy groupwhich is halogenated, a C1-6 alkoxy group substituted with ahydroxy-C3-8 cycloalkyl group, a C1-6 alkoxy group substitutedwith a non-aromatic heterocycle-oxy group, a C1-6 alkoxy-C1-6alkoxy group, a C1-6 alkoxy group substituted with a C1-6alkoxy-carbonyl group, a C1-6 alkoxy group substituted with anon-aromatic heterocyclic group and a C1-6 alkoxy group whichis formyl-aminated.
    [0027] The "C3-8 cycloalkoxy group" in the "C3-8 cycloalkoxy groupwhich may be substituted" given as the substituent of HAr meansthe "cycloalkoxy group" corresponding to the "C1-6 cyclichydrocarbon group" in the above definition. Preferableexamples thereof include C3-8 cycloalkyloxy groups such ascyclopropyloxy group, cyclobutyoxy group, cyclopentyloxy groupand cyclohexyloxy group and C3-8 cycloalkenyloxy groups such ascyclopropenyloxy group, cyclobutenyloxy group, cyclopentenyloxy group and cyclohexenyloxy group. Also, theterm "may be substituted" means that the above-mentioned C3-8alkoxy group may be substituted with one or two groups selectedfrom, for example, (1) hydroxyl group, (2) a halogen atom, (3)a C1-6 hydrocarbon group which may be substituted with a groupselected from hydroxyl group, a halogen atom, a C1-6 alkoxy groupand a C1-6 alkanoyl group, (4) a C1-6 alkoxy group which may besubstituted with a group selected from a halogen atom, a C1-6alkoxy group and a C1-6 alkanoyl group and (5) a C1-6hydrocarbon-thio group which may be substituted with a groupselected from a halogen atom, a C1-6 alkoxy group and a C1-6alkanoyl group. A C3-8 cycloalkoxy group which may besubstituted with a C1-6 alkoxy group and the like are preferable.
    [0028] The "C1-6 chain hydrocarbon-thio group" in the "C1-6 chainhydrocarbon-thio group which may be substituted" given as thesubstituent of HAr means the "C1-6 chain hydrocarbon-thio group"corresponding to the "C1-6 chain hydrocarbon group" in the abovedefinition, that is, a "C1-6 alkyl-thio group", "C1-6 alkenyl-thiogroup" and "C1-6 alkynyl-thio group". Specific examples thereofinclude methylthio group, ethylthio group, n-propylthio group,i-propylthio group, sec-propylthio group, n-butylthio group,i-butylthio group, sec-butylthio group, t-butylthio group,1,2-dimethylpropylthio group, 2-ethylpropylthio group, 1,1-dimethylbutylthiogroup, 2,2-dimethylbutylthio group, 2-tylbutylthiogroup, 1,3-dimethylbutylthio group,isopropenylthio group, ethynylthio group and propinylthiogroup. Also, the term "may be substituted" implies that may be substituted with one or two groups selected from, for example,(1) hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl group,C1-6 alkenyl group or C1-6 alkynyl group, which may be substitutedwith a group selected from hydroxyl group, a halogen atom, a5- to 14-membered aromatic heterocyclic group and a 4- to10-membered non-aromatic heterocyclic group, (4) a C3-8cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynylgroup, which may be hydroxylated or halogenated, (5) a C1-6 alkoxygroup which may be hydroxylated or halogenated, (6) a C1-6alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group,which may be halogenated, (7) a C3-8 cycloalkyloxy group, C3-8cycloalkenyloxy group or C3-8 cycloalkynyloxy group which maybe halogenated, (8) a C3-8 cycloalkylthio group, C3-8cycloalkenylthio group or C3-8 cycloalkynylthio group, which maybe halogenated, (9) a C6-14 aryl group, (10) a C1-6 alkanoyl groupwhich may be halogenated, (11) a 5- to 14-membered aromaticheterocyclic group and (12) a 4- to 10-membered non-aromaticheterocyclic group. The "C1-6 chain hydrocarbon-thio groupwhich may be substituted" is preferably a C1-6 chainhydrocarbon-thio group which may be hydroxylated, a C1-6 chainhydrocarbon-thio group which may be substituted with a C1-6alkoxy group and the like.
    [0029] The "C3-8 cyclic hydrocarbon-thio group" in the "C3-8 cyclichydrocarbon-thio group which may be substituted" given as thesubstituent of HAr means the "C1-6 cyclic hydrocarbon-thio group"corresponding to the "C1-6 cyclic hydrocarbon group" in the abovedefinition, that is, a "C1-6 cycloalkyl-thio group" and "C1-6 cyclic alkenyl-thio group". Specific examples thereof includecyclopropanylthio group, cyclobutanylthio group,cyclohexanylthio group, cyclopropenylthio group,cyclobutenylthio group, cyclopentenylthio group andcyclohexenylthio group. The "C3-8 cyclic hydrocarbon-thiogroup which may be substituted" is preferably a "C3-8 cyclichydrocarbon-thio group" substituted with one or two groupsselected from (1) hydroxyl group, (2) a halogen atom, (3) a C3-8alkyl group, C3-8 alkenyl group or C3-8 alkynyl group, which maybe halogenated, (4) a C1-6 alkoxy group which may be halogenated,(5) a C1-6 hydrocarbon-thio group which may be halogenated and(6) a C1-6 alkanoyl group which may be halogenated.
    [0030] The "C6-14 aromatic hydrocarbon-oxy group" in the "C6-14aromatic hydrocarbon-oxy group which may be substituted" givenas the substituent of HAr means the "C1-6 cyclic hydrocarbon-oxygroup" corresponding to the "C6-14 aromatic hydrocarbon group"in the above definition. For example, phenyloxy group,pentalenyloxy group and naphthyloxy group are preferable. Asthe "C6-14 aromatic hydrocarbon-oxy group which may besubstituted", a "C6-14 aromatic hydrocarbon-oxy group" which issubstituted with one or more groups selected from (1) hydroxylgroup, (2) a halogen atom, (3) a C1-6 alkyl-sulfonyl group, C1-6alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl group, which maybe halogenated, (4) a C1-4 alkylenedioxy group which may behalogenated, (5) a C1-6 alkoxy group which may be halogenated,(6) a C1-6 hydrocarbon-thio group which may be halogenated, (7)a C1-6 alkoxy-carbonyl group, (8) C6-14 aryl-C1-6 alkoxy group, (9) a C1-7 alkanoylamino group, (10) a C1-6 alkyl-carbamoyl group,(11) a C1-6 alkenyl-carbamoyl group, (12) a C1-6 alkynyl-carbamoylgroup and (13) an amino group which may be substituted with aC1-6 hydrocarbon group is preferable.
    [0031] It is to be noted that in the specification of the presentinvention, the "C6-14 aryloxy group" shown in the formula (I)has the same meaning as the "C6-14 aromatic hydrocarbon-oxygroup" in the above definition.
    [0032] The "5- to 14-membered heterocycle-oxy group" in the "5-to14-membered heterocycle-oxy group which may be substituted"which is given as the substituent of HAr means a "5- to 14-memberedheterocycle-oxy group" corresponding to a ring havingthe same meaning as the "5- to 14-membered heterocyclic group"and the "4- to 10-membered non-aromatic heterocyclic group" inthe aforementioned definition. Specific examples thereofinclude an "aromatic heterocycle-oxy group" such as pyrrolyloxygroup, pyridinyloxy group, pyridazinyloxy group,pyrimidinyloxy group, pirazinyloxy group and thiazolyloxygroup; and a "non-aromatic heterocycle-oxy group" such aspyrrolidinyloxy group, pyrrolinyloxy group, piperidinyloxygroup, piperazinyloxy group, imidazolinyloxy group,imidazolydinyloxy group, morpholinyloxy group andtetrahydropyranyloxy group. As the "5- to 14-memberedheterocycle-oxy group which may be substituted ", a "5- to14-membered heterocycle-oxy group" which may be substitutedwith one or more groups selected from (1) hydroxyl group, (2)a halogen atom, (3) nitrile group, (4) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group which may be halogenated,(5) a C1-6 alkoxy group which may be halogenated, (6) a C1-6alkyl-thio group, C1-6 alkenyl-thio group or C1-6 alkynyl-thiogroup which may be halogenated, (7) a C1-6 alkoxy-C1-6 alkyl group,(8) acetyl group, (9) a C1-6 alkanoyl group, (10) a mono-(C1-6hydrocarbon) -amino group, (11) a di- (C1-6 hydrocarbon) -aminogroup and (12) a tri- (C1-6 hydrocarbon)-amino group ispreferable.
    [0033] The "C6-14 aromatic hydrocarbon-thio group" in the "C6-14aromatic hydrocarbon-thio group which may be substituted" givenas the substituent of HAr means the "C1-6 cyclic hydrocarbon-thiogroup" corresponding to the "C6-14 aromatic hydrocarbon group"in the above definition. For example, phenylthio group,pentalenylthio group and naphthylthio group are preferable.As the "C6-14 aromatic hydrocarbon-thio group which may besubstituted", a C6-14 aromatic hydrocarbon-thio group" which maybe substituted with one or more groups selected from (1)hydroxyl group, (2) a halogen atom, (3) a C1-6 alkyl-sulfonylgroup, C1-6 alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl groupwhich may be halogenated, (4) a C1-4 alkylenedioxy group whichmay be halogenated, (5) a C1-6 alkoxy group which may behalogenated, (6) a C1-6 hydrocarbon-thio group which may behalogenated, (7) a C1-6 alkoxy-carbonyl group, (8) a C6-14 aryl-C1-6alkoxy group, (9) a C1-7 alkanoylamino group, (10) a C1-6alkyl-carbamoyl group, (11) a C1-6 alkenyl-carbamoyl group, (12)a C1-6 alkynyl-carbamoyl group and (13) an amino group which maybe substituted with a C1-6 hydrocarbon group is preferable.
    [0034] The "5- to 14-membered heterocycle-thio group" in the "5-to14-membered heterocycle-thio group which may be substituted"which is given as the substituent of HAr means a "5- to 14-memberedheterocycle-thio group" corresponding to a ring havingthe same meaning as the "5 - to 14 -membered aromatic heterocyclicgroup" and the "4- to 10-membered non-aromatic heterocyclicgroup" in the aforementioned definition. Specific examplesthereof include an "aromatic heterocycle-thio group" such aspyrrolylthio group, pyridinylthio group, pyridazinylthio group,pyrimidinylthio group, pirazinylthio group and thiazolylthiogroup; and an "non-aromatic heterocycle-thio group" such aspyrrolidinylthio group, pyrrolinylthio group, piperidinylthiogroup, piperazinylthio group, imidazolinylthio group,imidazolydinylthio group and morpholinylthio group. Also, asthe "5- to 14-membered heterocycle-thio group which may besubstituted", a "5- to 14-membered heterocycle-thio group"which may be substituted with one or more groups selected from(1) hydroxyl group, (2) a halogen atom, (3) nitrile group, (4)a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group whichmay be halogenated, (5) a C1-6 alkoxy group which may behalogenated, (6) a C1-6 alkyl-thio group, C1-6 alkenyl - thio groupor C1-6 alkynyl-thio group which may be halogenated, (7) a C1-6alkoxy-C1-6 alkyl group, (8) acetyl group, (9) a C1-6 alkanoylgroup, (10) a mono-(C1-6 hydrocarbon) -amino group, (11) a di-(C1-6hydrocarbon)-amino group and (12) a tri-(C1-6 hydrocarbon)-aminogroup and (3) an oxo group is preferable.
    [0035] The "amino group which may be substituted" given as the substituent of HAr means an amino group represented by theformula -N(R3)R4 (wherein R3 and R4 are the same as or differentfrom each other and each is a group selected from (1) an aromaticheterocyclic group, (2) a non-aromatic heterocyclic group, (3)a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynyl group whichmay be substituted with a halogen atom or a C1-6 alkoxy group,(4) a C3-8 cycloalkyl group, C3-8 cycloalkenyl group or C3-8cycloalkynyl group which may be halogenated, (5) a carbonylgroup which is substituted with a C1-6 alkyl group, C1-6 alkenylgroup or C1-6 alkynyl group which may be halogenated, a C3-8cycloalkyl group, C3-8 cycloalkenyl group or C3-8 cycloalkynylgroup which may be halogenated, a C1-6 alkoxy group which maybe halogenated, a C6-14 aryl group or an aromatic heterocyclicgroup, (6) a C1-6 alkanoyl group which may be substituted witha group selected from a C6-14 aryl group and an aromaticheterocyclic group, (7) a carbamoyl group which may besubstituted with a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6alkynyl group, a C6-14 aryl group or an aromatic heterocyclicgroup and (8) a sulfonyl group which is substituted with a C1-6alkyl group, a C1-6 alkenyl group or a C1-6 alkynyl group. Also,(9) R3 and R4 may be combined and united to form a 3- to 10-memberedring, and the cyclic amino group may be substituted with oneor more groups selected from hydroxyl group, a halogen atom,a C1-6 alkyl group, a C1-6 alkenyl group, a C1-6 alkynyl group,a C1-6 alkoxy group, a C1-6 hydrocarbon-thio group and a C1-4alkylenedioxy group). An amino group , R3 and R4 are the sameas or different from each other and each is a group selected from a C1-6 alkyl group, a C1-6 alkoxy-C1-6 alkyl group, a C1-6alkoxy-carbonyl group, a C1-6 alkanoyl group, a C6-14 arylcarbonylgroup, a heteroaryl-carbonyl group, a C1-6 alkyl-carbamoylgroup, a C6-14 alkyl-carbamoyl group, a C6-14 arylsulfonylgroup and a 5- to 14-membered heterocyclic group.
    [0036] Given as example of the "C1-6 imidoyl group" in the "C1-6imidoyl group which may be substituted" given as thesubstituent of HAr are formimidoyl, hexaneimidoyl andsuccinimidoyl. As the "C1-6 imidoyl group which may besubstituted", a C1-6 imidoyl group which may be substitutedwith a halogen atom is preferable.
    [0037] Examples of the "substituted carbonyl group" given asthe substituent of HAr include carbonyl groups substitutedwith a group selected from a C1-6 alkyl group, a C2-6 alkenylgroup, a C2-6 alkynyl group, a C1-6 alkoxy-C1-6 alkyl group,a C1-6 alkoxy group, a C6-14 aryl group and a 5- to 14-memberedaromatic heterocyclic group.
    [0038] The "substituted carbonyl group" in the "the "substitutedcarbonyl-oxy group" given as the substituent of HAr is acarbonyl having the same meaning as the "substituted carbonylgroup" in the aforementioned definition. Examples of the"substituted carbonyl-oxy group" include a C1-6 alkyl-carbonyl-oxygroup, a C2-6 alkenyl-carbonyl-oxy group, a C2-6alkynyl-carbonyl-oxy group, a C1-6 alkoxy-C1-6 alkyl-carbonyl-oxygroup, a C1-6 alkoxy-carbonyl-oxy group, a C6-14aryl-carbonyl-oxy group and 5- to 14-membered aromaticheterocycle-carbonyl-oxy group. Preferable examples are a C1-6 alkyl-carbonyl-oxy group, a C2-6 alkenyl-carbonyl-oxy group anda C2-6 alkynyl-carbonyl-oxy group.
    [0039] Examples of the "carboxyl group which may form a salt"given as the substituent of HAr include salts of alkalimetals such as lithium, sodium and potassium, salts of alkaliearth metals such as magnesium and calcium,tetramethylammonium salts, quaternary ammonium salts suchas a tetraethylammonium salt, amino acid salts such asalginates, aspartates, glutamate and a proline salt, andfurther betaines with amino groups in a molecule.
    [0040] The "carbamoyl group which may be substituted" given as thesubstituent of HAr is, specifically, carbamoyl groupsrepresented by the formula -CO-N(R5)R6 (wherein R5 and R6 arethe same as or different from each other and each representsa group selected from (1) hydrogen atom, (2) a C1-6 alkyl group,(3) a C1-6 alkenyl group, (4) a C1-6 alkynyl group, (5) a C3-8cycloalkyl group, (6) a C3-8 cycloalkenyl group, (7) a C3-8cycloalkynyl group, (8) a C6-14 aryl group and (9) an aromaticheterocyclic group or (10) R5 and R6 may be combined and unitedto form a 3- to 8-membered ring). A carbamoyl group, whereinR5 and R6 are the same as or different from each other and eachis a group selected from a C1-6 alkynyl group, a C3-8 cycloalkylgroup, a C6-14 aryl group which may be halogenated etc., ispreferable.
    [0041] Given as examples of the "C1-4 alkylenedioxy group" inthe "C1-4 alkylenedioxy group which may be substituted" givenas the substituent of HAr are a methylenedioxy group, ethylenedioxy group and propylenedioxy group. As the "C1-4alkylenedioxy group which may be substituted", a C3-4alkylenedioxy group which may be hydroxylated or halogenatedis preferable.
    [0042] As the "sulfinyl group which may be substituted" givenas the substituent of HAr, a sulfinyl group which may besubstituted with a group selected from (1) a C1-6 hydrocarbongroup which may be halogenated and (2) an amino group whichmay be mono- or di-substituted with a C1-6 hydrocarbon groupwhich may be halogenated is preferable.
    [0043] As the "sulfonyl group which may be substituted" givenas the substituent of HAr, a sulfonyl group which may besubstituted with a group selected from (1) a C1-6 hydrocarbongroup which may be halogenated and (2) an amino group whichmay be mono- or di-substituted with a C1-6 hydrocarbon groupwhich may be halogenated is preferable.
    [0044] The definition of the "aromatic heterocycle which may besubstituted" represented by HAr in the formula (I) is asabove-mentioned. Preferable examples of the substituent ofthe "aromatic heterocycle" include (1) a C1-6 alkyl group, C1-6alkenyl group or C1-6 alkynyl group, which may be substitutedwith one or two groups selected from (a) hydroxyl group, (b)a halogen atom, (c) a 5- to 14-aromatic heterocyclic group, (d)a 4- to 10-membered non-aromatic heterocyclic group, (e) a 5-to10-membered condensed heterocyclic group which may besubstituted with a C1-6 alkoxy group and (f) a C1-6 alkyl-sulfonylgroup, (2) a C1-6 alkoxy group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogenatom, (c) a 4- to 10-membered non-aromatic heterocycle-oxygroup, (d) a C1-6 alkoxy group, (e) a C1-6 alkoxy-carbonyl groupand (f) a 4- to 10-membered non-aromatic heterocycle, (3) a C6-14aromatic hydrocarbon cyclic group which may be substituted withone or more groups selected from (a) a halogen atom, (b) a C1-6alkoxy group and (c) a C1-4 alkylenedioxy group, (4) a 5- to14-membered aromatic heterocyclic group which may besubstituted with one or more groups selected from (a) hydroxylgroup, (b) nitrile group, (c) a C1-6 alkyl group, (d) a C1-6 alkoxygroup, (e) a C1-6 alkoxy-C1-6 alkyl group, (f) a C1-6 alkanoyl group,(g) a C1-4 alkylenedioxy group, (h) a mono-(C1-6 alkyl)-aminogroup and (i) a di-(C1-6 alkyl)-amino group and (5) a 4- to10-membered non-aromatic heterocyclic group which may besubstituted with one or more groups selected from (a) hydroxylgroup, (b) nitrile group, (c) a C1-6 alkyl group, (d) a C1-6 alkoxygroup, (e) a C1-6 alkoxy-C1-6 alkyl group, (f) a C1-6 alkanoyl group,(g) a C1-4 alkylenedioxy group, (h) a mono-(C1-6 alkyl)-aminogroup and (i) a di-(C1-6 alkyl)-amino group. More preferableexamples include a C1-6 alkyl group which may be halogenated,a C2-6 alkenyl group which may be halogenated, a C1-6 alkoxy-C1-6alkyl group, a C1-6 alkyl group substituted with a C6-14aromatic hydrocarbon cyclic group, a C1-6 alkyl group substitutedwith 5- or 6-membered aromatic heterocycle, a C1-6 alkoxy groupwhich may be halogenated, a C1-6 alkoxy-C1-6 alkoxy group, a C6-14aromatic hydrocarbon group, a 5- or 6-membered aromaticheterocycle which may be substituted with a C1-6 alkyl group and a 4- to 10-membered non-aromatic heterocyclic group which maybe substituted with one or more groups selected from (a)hydroxyl group, (b) nitrile group and (c) a C1-6 alkoxy group.
    [0045] The terms "halogen atom", "C1-6 hydrocarbon group", "C1-6alkyl group", "C3-8 alkenyl group", "C3-8 alkynyl group", "C3-8cycloalkyl group", "C3-8 cycloalkenyl group", "C3-8cycloalkynyl group", "C6-14 aromatic hydrocarbon group","C6-14 aryl group", "5- to 14-membered aromatic heterocyclicgroup", "5- to 14-membered heteroaryl group", "4- to 10-memberednon-aromatic heterocyclic group", "C1-6 alkoxygroup", "C3-8 cycloalkoxy group", "C3-8 cycloalkyloxy group","C3-8 cycloalkenyloxy group", "C1-6 hydrocarbon-thio group","C1-6 alkylthio group", "C1-6 alkenylthio group", "C1-6alkynylthio group", "C3-8 cycloalkylthio group", "C3-8cycloalkenylthio group", "C1-6 alkoxy-carbonyl group", "C1-6alkanoyl group", "C1-6 alkanoyloxy group", "carbamoyl group","C1-6 imidoyl group", "carboxyl group which may form a salt","C1-4 alkylenedioxy group", "sulfonyl group" and "sulfinylgroup", which are all used in the above-mentioneddefinitions concerning the substituents of the aromaticheterocycle HAr have the same meanings as defined above.
    [0046] In the specification of the present invention, the"aromatic ring" in the "aromatic ring which may be substituted"represented by Ar in the formula (I) means a ring having thesame meaning as the "aromatic ring" in the above definition.For example, benzene ring, a pyridine ring and the like arepreferable. Examples of the "aromatic ring which may be substituted" include aromatic rings which may be substitutedwith one or more groups selected from (1) hydroxyl group, (2)a halogen atom, (3) a C1-6 chain hydrocarbon group which may besubstituted, (4) a C3-8 cyclic hydrocarbon group which may besubstituted, (5) a C1-6 alkoxy group which may be substituted,(6) a C3-8 cycloalkoxy group which may be substituted, (7) a C1-6chain hydrocarbon-thio group which may be substituted, (8) aC3-8 cyclic hydrocarbon-thio group, (9) a C6-14 aromatichydrocarbon cyclic group which may be substituted, (10) a 5-to14-membered heterocyclic group which may be substituted,(11) an amino group which may be substituted with a C1-6 alkylgroup and (12) a C1-4 alkylenedioxy group which may besubstituted.
    [0047] The "C1-6 chain hydrocarbon group which may besubstituted" given as the substituent of Ar means a grouphaving the same meaning as the "C1-6 chain hydrocarbon groupwhich may be substituted" shown in the definition of HAr.As the "C1-6 chain hydrocarbon group which may be substituted",a C1-6 alkyl group which may be halogenated, a C1-6 alkenylgroup which may be halogenated, a C1-6 alkynyl group whichmay be halogenated and the like are preferable.
    [0048] The "C3-8 cyclic hydrocarbon group which may besubstituted" given as the substituent of Ar means a grouphaving the same meaning as the "C3-8 cyclic hydrocarbon groupwhich may be substituted" shown in the definition of HAr.As the "C3-8 cyclic hydrocarbon group which may besubstituted", a C3-8 cycloalkyl group which may be halogenated, a C3-8 cycloalkenyl group which may be halogenated and thelike are preferable.
    [0049] The "C1-6 alkoxy group which may be substituted" givenas the substituent of Ar means a group having the same meaningas the "C1-6 alkoxy group which may be substituted" shown inthe definition of HAr. As the "C1-6 alkoxy group which maybe substituted", a C1-6 alkoxy group which may be halogenatedand the like are preferable.
    [0050] The "C3-8 cycloalkoxy group which may be substituted"given as the substituent of Ar means a group having the samemeaning as the "C3-8 cycloalkoxy group which may besubstituted" shown in the definition of HAr. As the "C3-8cycloalkoxy group which may be substituted", a C3-8cycloalkyloxy group which may be halogenated, a C3-8cycloalkenyloxy group which may be halogenated and the likeare preferable.
    [0051] The "C1-6 chain hydrocarbon-thio group which may besubstituted" given as the substituent of Ar means a grouphaving the same meaning as the "C1-6 chain hydrocarbon-thiogroup which may be substituted" shown in the definition ofHAr. As the "C1-6 chain hydrocarbon-thio group which may besubstituted", a C1-6 alkyl-thio group which may be halogenated,a C1-6 alkenyl-thio group which may be halogenated, a C1-6alkynyl-thio group which may be halogenated and the like arepreferable.
    [0052] The "C3-8 cyclic hydrocarbon-thio group" given as thesubstituent of Ar means a group having the same meaning as the "C3-8 cyclic hydrocarbon-thio group which may besubstituted" shown in the definition of HAr. As the "C3-8cyclic hydrocarbon-thio group which may be substituted", aC3-8 cycloalkylthio group which may be halogenated, a C3-8cycloalkenylthio group which may be halogenated and the likeare preferable.
    [0053] The "C6-14 aromatic hydrocarbon cyclic group which maybe substituted" and "5- to 14-membered heterocyclic groupwhich may be substituted" which are given as the substituentsof Ar mean groups having the same meanings as the "C6-14aromatic hydrocarbon cyclic group which may be substituted"and the "5- to 14-membered heterocyclic group which may besubstituted" shown in the definitions of HAr respectively.
    [0054] The "amino group which may be substituted with a C1-6 alkylgroup" given as the substituent of Ar means an amino groupmono-substituted with a C1-6 alkyl group such as methylaminogroup and ethylamino group and an amino group di-substitutedwith a C1-6 alkyl group such as dimethylamino group anddiethylamino group. Further, the nitrogen atom may betri-substituted with a C1-6 alkyl group to form an ammoniumsalt.
    [0055] The "C1-4 alkylenedioxy group which may be substituted"given as the substituent of Ar means a group having the samemeaning as the "C1-4 alkylenedioxy group which may besubstituted" shown in the definition of HAr. For example,a C1-4 alkylenedioxy group which may be substituted with ahalogen atom etc. is preferable.
    [0056] As above-mentioned, the "aromatic ring which may besubstituted" represented by Ar in the formula (I) is defined.Preferable examples of Ar include a benzene ring, pyridinering, pyrazine ring, thiophene ring and thiazole ring, whichmay be substituted with a group selected from hydroxyl group,a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group andthe like.
    [0057] In the specification of the present invention, W in theformula (I) means a connecting chain in which the primarychain is constituted of two or more atoms. Examples thereofinclude preferably a chain represented by (1) -CH2-CH2- whichmay be substituted, (2) -CH=CH- which may be substituted,(3) -C≡C-, (4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7)-CH2-NH-, (8) -CH2-CO-, (9) -CO-CH2-, (10) -NH-S(O)1-, (11)-S(O)1-NH-, (12) -CH2-S(O)1- and (13) -S(O)1-CH2- (l denotes0, 1 or 2), more preferably (1) -CH2-CH2-, (2) -CH=CH- and(3) -C≡C-, and further preferably -C≡C-.
    [0058] In the specification of the present invention, examplesof the connecting group X in the formula (I) include chainsrepresented by (1) a single bond, (2) a C1-6 alkylene chainwhich may be substituted, (3) a C2-6 alkenylene chain whichmay be substituted, (4) a C2-6 alkynylene chain which may besubstituted, (5) a formula -Q- (wherein Q represents oxygenatom, sulfur atom, CO or N(R2) (wherein R2 represents a C1-6alkyl group or a C1-6 alkoxy group)), (6) -NH-CO-, (7) -CO-NH-,(8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-, (12)-NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15) -S(O)m-CH2- (wherein m denotes 0, 1 or 2) or (16) -(CH2)n-O-(wherein n denotes an integer from 1 to 6). Here, the"C1-6 alkylene chain", the "C1-6 alkenylene chain" and the "C1-6alkynylene chain" mean chains corresponding to C1-6hydrocarbon groups having the same meanings as the "C1-6 alkylgroup", the "C1-6 alkenyl group" and the "C1-6 alkynyl group"in the above definitions. The connecting chain X representspreferably a single bond, a C1-6 alkylene chain, a C2-6alkynylene chain, -CO- or the like and more preferably asimple bond, methylene chain, ethylene chain or -CO-.
    [0059] The amino group in the "amino group which may besubstituted with a C1-6 alkyl group or an acyl group" meansan amino group which may be substituted with a C1-6 alkyl grouphaving the same meaning as the aforementioned definition oran acyl group having the same meaning as the above definition.Specific examples thereof include an N-formylamino group,N-acetylamino group, N-propionylamino group, N-pivaloylaminogroup, N-benzoylamino group, N-methyl-N-formylaminogroup, N-methyl-N-benzoylamino group, N-methylaminogroup, N,N-dimethylamino group, N-methyl-N-ethylaminogroup, N-(n-propyl)amino group, N-(i-propyl)aminogroup and N-(t-butyl)amino group.
    [0060] The "C1-6 alkoxycarbonyl group" is an alkoxycarbonylgroup corresponding to the C1-6 alkoxy group in the abovedefinition. Specific examples thereof includemethoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonylgroup, i-propoxycarbonyl group, sec-propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonylgroup, 1,2-dimethylpropoxycarbonyl groupand 2-ethylpropoxycarbonyl group.
    [0061] The definitions of R1, HAr, Ar, W and X to be used in theformula (I) have been described as above. To state morepreferable examples, as examples of -X-Ar, a benzyl group(X=methylene chain; Ar=benzene ring) which may be substitutedis given and as examples of HAr, besides a substituent -X-Ar,a pyridine ring, pyrimidine ring, pyridazine ring, pyrazinering, indole ring, quinoline ring, thiophene ring orbenzothiophene ring which may be substituted with one or twogroups selected from (1) a 5- or 6-membered aromatic heterocyclewhich may be substituted with a C1-6 alkyl group, (2) a 5- or6-membered non-aromatic heterocycle which may be substitutedone or more groups selected from (a) hydroxyl group, (b) a C1-6alkyl group and (c) a C1-6 alkoxy group, (3) a C6-10 aromatichydrocarbon ring which may be substituted with one or moregroups selected from (a) a halogen atom, (b) a C1-6 alkoxy group,(c) a C1-4 alkylenedioxy group and (d) a sulfonyl group whichmay be substituted with a C1-6 alkyl group, (4) a C1-6 alkyl groupwhich may be substituted with one or two groups selected from(a) hydroxyl group, (b) a halogen atom, (c) a 5- or 6-memberedaromatic heterocycle and (d) a C1-6 alkoxy group and (5) a C1-6alkoxy group which may be substituted with (a) a halogen atomand (b) a C1-6 alkoxy group. More preferable examples of HArinclude a pyridine ring, pyrimidine ring, pyridazine ring,pyrazine ring, indole ring, quinoline ring, thiophene ring or benzothiophene ring which may be substituted with one or twogroups selected from (1) a benzene ring which may be substitutedwith a C1-4 alkylenedioxy group, (2) pyridine ring, (3)pyrimidine ring, (4) pyridazine ring, (5) pyrazine ring, (6)thiophene ring, (7) a piperidine ring which may be substitutedwith a C1-6 alkoxy group, (8) a piperazine ring which may besubstituted with a C1-6 alkoxy group, (9) a pyrrolidine ring whichmay be substituted with a C1-6 alkoxy group, (10) a piperidinering substituted with hydroxyl group and a C1-6 alkoxy group,(11) a piperazine ring substituted with hydroxyl group and aC1-6 alkoxy group, (12) a pyrrolidine ring substituted withhydroxyl group and a C1-6 alkoxy group, (13) morpholine ring,(14) a C1-6 alkyl group which may be substituted with a C1-6 alkoxygroup and (15) a C1-6 alkoxy group which may be substituted withhydroxyl group or a C1-6 alkoxy group.
    [0062] The salts in the present invention means generallypharmacologically acceptable salts. Examples of these saltsinclude hydrohalides such as hydrofluorides, hydrochlorides,hydrobromides and hydroiodides; inorganic acid salts such assulfates, nitrates, perchlorates, phosphates, carbonates andbicarbonates; organic carboxylates such as acetates, maleates,tartrates and fumarates; organic sulfonates such asmethanesulfonates, trifluoromethanesulfonates,ethanesulfonates, benzene sulfonates and toluene sulfonates;aminates such as alginates, aspartates and glutamates; saltswith amines such as trimethylamine salts, triethylamine salts,procaine salts, pyridium salts and phenethylbenzylamine salts; alkali metal salts such as sodium salts and potassium salts;and alkali earth metal salts such as magnesium salts and calciumsalts. General production method
    [0063] Various methods are considered as a method for producingthe compound represented by the formula (I) according to thepresent invention and the compound can be produced by a usualorganic synthetic method. To state a typical method, forexample, the following method may be used to produce thecompound. Production method 1
    [0064]
    [0065] The above production method is a method of producing thecompound (IV) according to the invention of the patentapplication of this case by coupling the aromatic heterocycliccompounds (II) and (III) with each other. In the formula, A1,A2 and A3 are the same as or different form each other and eachmeans (1) a carbon atom which may be substituted or (2) aheteroatom such as nitrogen atom, sulfur atom or oxygen atom,wherein there is the case where A2 further means a single bond.When A2 means a single bond, the ring to which A1, A2 and A3 belongis a 5-membered ring. Here, in the case where A1, A2 and A3respectively represent the "carbon atom which may be substituted", the term "may be substituted" means that it maybe substituted with the substituent shown in HAr defined above.Specifically, the carbon atom may be substituted with a groupselected from (1) halogen atom, (2) hydroxyl group, (3) thiolgroup, (4) nitro group, (5) nitrile group, (6) a C1-6 chainhydrocarbon group which may be substituted, (7) a C3-8 cyclichydrocarbon group which may be substituted, (8) a C6-14 aromatichydrocarbon cyclic group which may be substituted, (9) a 5- to14-membered aromatic heterocyclic group which may besubstituted, (10) a 4- to 10-membered non-aromatic heterocyclicgroup which may be substituted, (11) a C1-6 alkoxy group whichmay be substituted, (12) a C3-8 cycloalkyloxy group which maybe substituted, (13) a C1-6 chain hydrocarbon-thio group whichmay be substituted, (14) a C3-8 cyclic hydrocarbon-thio groupwhich may be substituted, (15) a C6-14 aromatic hydrocarbon-oxygroup which may be substituted, (16) a 5- to 14-memberedheterocycle-oxy group which may be substituted, (17) a C6-14aromatic hydrocarbon-thio group which may be substituted, (18)a 5- to 14-membered heterocycle-thio group which may besubstituted, (19) an amino group which may be substituted, (20)azide group, (21) guanidino group, (22) carbamide group, (23)formyl group, (24) a C1-6 imidoyl group which may be substituted,(25) a carbonyl group which is substituted, (26) a carbonyl-oxygroup which is substituted, (27) a carboxyl group which may forma salt, (28) a carbamoyl group which may be substituted, (29)a C1-4 alkylenedioxy group which may be substituted, (30) asulfinyl group which may be substituted and (31) a sulfonyl group which may be substituted. * L means a leaving group andR1 means hydrogen atom or hydroxyl group. a and b respectivelymean a group -X-Ar (wherein X and Ar have the same meaning asdefined above) and the substituent of HAr of the formula (I)described in the aforementioned definition, or respectivelymean the substituent of HAr and group -X-Ar (wherein X and Arhave the same meaning as defined above) of the formula (I)described in the above definition. The leaving group L may beany group so long as it is known as a leaving group in organicsynthesis and no particular limitation is imposed. Examplesthereof include halogen atoms such as chlorine atom, bromineatom and iodine atom; substituted or unsubstituted acetoxygroups such as acetoxy group and trifluoroacetoxy group;substituted sulfonyloxy groups such as methanesulfonyloxygroup trifluoromethanesulfonyloxy group, benzenesulfonyloxygroup and p-toluenesulfonyloxy group; and substitutedphosphoryloxy groups such as diphenoxyphosphoryloxy. Amongthese groups, halogen atoms such as chlorine atom, bromine atomand iodine atom and trifluoromethanesulfonyloxy group arepreferable. As the palladium catalyst, for example,tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride may be used inan amount of 0.0001 to 0.1 mol equivalents. For example, 0.0001to 0.1 mol equivalents of cuprous iodide or cuprous chloridemay be used as the copper salt and for example, 1 to 5 equivalentsof triethyl amine or N,N-diisopropylethylamine may be used asthe base. As the solvent, N,N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, methanol or a mixture ofthese solvents is used. The reaction temperature is preferably0°C to 140°C. Production method 2
    [0066]
    [0067]
    [0068] The above production methods ensure that the compounds(VI) and (VIII) according to the present invention may beproduced. In the reaction formula, L and a have the samemeanings as those in the above definition. As L, for example,chlorine atom, bromine atom, iodine atom ortrifluoromethanesulfonyloxy group may be used. M means ametal atom which may have a substituent. For example,trinbutyltin or dihydroxyboron is preferable. As thepalladium catalyst, for example, tetrakistriphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium(II) chloride may be usedin an amount of 0.0001 to 0.1 mol equivalents. Examples ofthe solvent include toluene, xylene, N,N-dimethylformamideand N-methylpyrrolidone. A reaction temperature ranging from 50°C to 150°C is adopted. When the metal M is boron,an inorganic base such as sodium carbonate or an organic basesuch as triethylamine is used as the base. As the solvent,an organic solvent containing water is also used.
    [0069] No particular limitation is imposed on the dosage formof the compound according to the present invention and eitheroral administration or parenteral administration accordingto a method which is usually used is acceptable. Thecompound may be made into preparations of a tablet, powder,granule, capsule agent, syrup agent, troche, inhalant,suppository, injection, ointment, ophthalmic ointment,ophthalmic solution, collunarium, ear drop, cataplasm andlotion, and administered. In the preparation of these forms,fillers, binders, lubricants, colorants, flavoring agents,and if necessary, stabilizers, emulsifiers, absorbefacientagents, surfactants, pH regulators, antiseptics andantioxidants etc. may be used and components which areusually used as raw materials of medicinal preparations areformulated to prepare a medicine by a usual method. Examplesof these components include animal or vegetable oils suchas soybean oil, beef tallow and synthetic glyceride;hydrocarbons such as liquid paraffin, squalane and solidparaffin; ester oils such as octyldodecyl myristate andisopropyl myristate; higher alcohols such as cetostearylalcohol and behenyl alcohol; silicon resins; silicon oils;surfactants such as polyoxyethylene fatty acid ester,sorbitan fatty acid ester, glycerol fatty acid ester, polyoxyethylenesorbitan fatty acid ester, polyoxyethylenehydrogenated castor oil andpolyoxyethylene/polyoxypropylene block copolymers;water-soluble polymers such as hydroxyethyl cellulose,polyacrylic acid, carboxyvinyl polymers, polyethyleneglycol, polyvinylpyrrolidone and methyl cellulose; loweralcohols such as ethanol and isopropanol; polyhydricalcohols such as glycerol, propylene glycol, dipropyleneglycol and sorbitol; sugars such as glucose and cane sugar;inorganic powders such as silicic acid anhydride, aluminummagnesium silicate and aluminum silicate; and purifiedwater.
    [0070] The medicine according to the present invention isadministered to an adult patient at a dose of generally about30µg to 10 g, preferably 100µg to 5 g and more preferably100µg to 100 mg in the case of oral administration and about30µg to 1 g, preferably 100µg to 500 mg and more preferably100µg to 30 mg in the case of injection in one to severalparts a day although the dose differs depending on the degreeof a symptom, age, sex, weight, dosage form and type ofdisease.
    [0071] The biochemical activities of the compound according tothe present invention and the effects (squalene synthesizingenzyme activity, cholesterol biosynthesis inhibitiveactivity and cholesterol and triglyceride biosynthesisinhibitive activity) of the compound as a medicine may beevaluated by the following methods. Test Example 1 Measurement of squalene synthesizing enzyme inhibitiveactivity by using a rat liver microsome
    [0072] (I) The reaction was run on a scale of 500 µl. 200 µlof a solution containing 125 mM tris-hydrochloric acid (pH:7.3), 2.5 mM magnesium chloride, 5 mM potassium fluoride and10 mM reduction type nicotinamidoadenine dinucleotidephosphoric acid, 100 µl of the specimen solution with a 5-foldconcentration, 100 µl of distilled water and 50 µl of 0.4to 1 mg/ml rat liver microsome prepared by the followingmethod were mixed.(II) The above mixture was pre-incubated at 37°C for 10minutes and thereafter, 50 µl of 100 µM [3H]-farnesylpyrophosphoricacid (30 mCi/mmol, NEN) was added tothe mixture to start a reaction. The reaction was continuedat 37°C for 10 minutes. 1 ml of ethanol was added to theresulting mixture to terminate the reaction and then 1 mlof distilled water and 3 ml of petroleum ether were addedto the reaction solution, which was then shaken for 30minutes. The water phase was separated from the oil phase,the water phase was frozen at -70°C in dry ice/methanol andthe radiative activity of the organic phase was measuredusing a liquid scintillator. Or the organic phase wasevaporated to dryness using nitrogen gas and the residue wasdissolved as a marker in 25 µl of chloroform containingsqualene, farnesol and cholesterol. This sample wasspotted on a TCL plate (Merck) and developed using heptane for 15 to 20 minutes. A band of squalene was cut from theplate to measure the radiative activity by using a liquidscintillation counter. The data was expressed by aconcentration (IC50) at which 50% of the radiative activityof a control group was inhibited.
    [0073] The following operations were all carried out on ice andthe centrifugation was performed at 4°C. The liver wasexcised from a male Spraugue-Dawly rat (hereinafter referredto as SD rat) (8 to 9 weeks age) and perfused with 1.15%potassium chloride to remove the blood. Then, the liver wasminced using a forceps and the minced liver was homogenizedusing a Teflon homogenizer. The resulting sample wascentrifuged at 16000×g twice for 15 minutes. Thesupernatant was further centrifuged at 105000×g for 60minutes. The obtained deposit was determined as a microsomefraction, which was then suspended in a 25 mM tris-hydrochloricacid solution. The concentration of proteinwas measured quantitatively by a Bradford method and theconcentration of protein was adjusted to 20 mg/ml by usingthe same solution. The resulting solution was stored at70°C. Test Example 2 Measurement of cholesterol biosynthesis inhihitive activityin a rat
    [0074] (I) An SPF grade male SD rat (4 weeks age, SLC) was bredfor more than one week in a day-night-reversal room and subjected to an experiment made in the daytime. The compounddissolved in a 2% Tween 80 solution was administered (5ml/kg) to the rat using an oral sonde. After one hour, a[1-14C]Acetic acid, sodium salt (1.67-2.22 GBq/mmol, 37MBq/ml, NEN) prepared by diluting to 1.85 MBq/ml by usingphysiological saline was intraabdominally administered (300µl/animal). After one hour, the rat was anesthetized bydiethyl ether to carry out exsanguination from the aortaabdominalis. The collected blood was centrifuged at 3000rpm for 10 minutes to prepare blood plasma.(II) 1 ml of 4N KOH and 1 ml of ethanol were added to2 ml of the blood plasma, which was then incubated at 65°Cfor one hour and thereafter, 3 ml of petroleum ether was added.The plasma was shaken for 30 minutes. After the water phasewas separated from the organic phase by centrifugation, itwas frozen at -80°C and the radiative activity of the organicphase was measured using a liquid scintillation counter. Orthe organic phase was evaporated to dryness using nitrogengas and the residue was dissolved as a marker in 25 µl ofchloroform containing squalene, farnesol and cholesterol.This sample was applied to a TCL plate (Merck) and developedusing toluene and isopropyl ether (1:1) for 15 to 20 minutes.A band of cholesterol was cut from the plate to measure theradiative activity by using a liquid scintillation counter.The cholesterol biosynthesis inhibition activity wasexpressed by an inhibition rate (%) to a control group.
    [0075] A liver cell was isolated from a male SD rat accordingto a usual method (collagenase perfusion method) andsubjected to an experiment.
    [0076] The isolated liver cells were planted in an amount of500 µl every well on a Type collagen coated 24 well plate(cell density: 4×105 cell/ml). As the cell culture solution,a Williams'E medium (adjusted to pH 7.4) containing 10% FCS,1 µM insulin, 1 µM dexamethasone, 100 units/ml penicillinand 100µg/ml streptomycin was used. After the liver cellswere incubated in a CO2 incubator for 2 hours, unstuck cellswere removed and the liver cells were further incubatedovernight.
    [0077] After the culture medium was exchanged, the specimendiluted in a 10% DMSO-90% cell culture solution was addedto each well in an amount of 5 µl. DMSO (final concentration:0.1%) was added to a control group. A [1-14C]Acetic acid,sodium salt (5µCi/well) was added to the media 10 minutesand 4 hours after the specimen was added for the measurementof cholesterol synthesis inhibitive action and for themeasurement of triglyceride synthesis inhibitive actionrespectively, followed by culturing for further 2 hours.
    [0078] After the cultivation was finished, the supernatant wasremoved and the cells were washed using PBS(-) (Phosphatebuffered saline (Ca2+, Mg2+ free) twice. Hexane/isopropylalcohol (3:2, v/v) was added to the cells and the cells were then allowed to stand for 10 minutes to extract intracellularlipid. The extract was transferred to a glass tube andexsiccated under a nitrogen gas stream. Further, theexsiccated extract was washed with 25 mL of petroleum etherand then dissolved in petroleum ether containing thefollowing components: 0.01% squalene, 0.3% free cholesterol,0.3% cholesterol acetate, 0.1% triolein, 0.01% farnesol and0.3% lanosterol.
    [0079] The resulting solution was spotted on a TLC plate toperform an isolating operation. The spotted solution wasdeveloped for 10 minutes by using toluene/isopropyl ether(1:1, v/v) as the solvents and for further 15 minutes by usingheptane in place of the above solvent after it was dried usingair.
    [0080] After the development was finished, the TLC plate wassubjected to iodine color development. After each positionof free cholesterol and triolein which were used as standardswas confirmed, the image of the TLC plate was transferredto a BAS 2000 (Fuji Film) imaging plate by exposure performedfor 16 hours. This transferred image was analyzed using aBAS 2000 IP Reader and an Imaging analyzer II to measureradiative activities contained in the free cholesterol andtriglyceride fractions.
    [0081] The cholesterol biosynthesis inhibitive activity wasexpressed by a concentration (IC50) at which 50% of theradiative activity of the control group was inhibited andthe triceride biosynthesis inhibitive activity was expressed by an inhibition rate (%) to the control group.
    [0082] The test results based on Test Example 1 (Measurementof squalene synthesizing enzyme inhibitive activity by usinga rat liver microsome), Test Example 2 (Measurement ofcholesterol biosynthesis inhibitive activity in a rat) andTest Example 3 (Measurement of cholesterol and triglyceridebiosynthesis inhibitive activities in a rat liver cell) areshown below. Example Squalene synthesizing enzyme inhibitive activity IC50 (µM) 1 10 2 20 9 34 10 2 18 25 19 10 104 6.7 106 6.9 110 2.1 116 0.77 117 4.5 118 2.5 119 3.9 124 1.8 138 0.35 142 5 144 2.6 153 11 166 15 180 6.3 201 1.6 Example Dose (mg/kg) Cholesterol biosynthesis inhibitive activity inhibition(%) 6 3 7311 3 72 12 3 78 13 3 87 104 2 88 123 3 86 142 3 82 147 3 87 148 3 92 150 1 73 153 1 82 168 3 89 169 3 92 Example Cholesterol biosynthesis inhibitive activity IC50(µM) 116 0.072 117 0.079 118 0.075 120 0.075 124 0.081 138 0.014 148 0.16 149 0.59 153 0.055 179 0.13 186 0.069 Example Triglyceride biosynthesis inhibitive activity inhibition in 1 µM of the specimen 106 81 110 84 118 85 120 80 124 79 150 80 153 85 166 82 176 74 179 84 201 85
    [0083] The compound according to the present invention is veryuseful as a squalene synthesizing enzyme inhibitor (Table1) and also as a cholesterol biosynthesis inhibitor in actual(Table 2 and Table 3). Further, it is very useful also asan inhibitor of the synthesis of triglyceride as neutral fat(Table 4). Accordingly, the compound according to thepresent invention is useful as preventive and curativeagents for a disease on which squalene synthesizinginhibition, cholesterol biosynthesis inhibition ortriglyceride biosynthesis inhibition is effective. Fromthe above results, the compound according to the presentinvention is useful as a preventive and curative agent forhyper lipidemia and also as a preventive and curative agentfor arterial sclerosis diseases or ischemic heart diseases. Examples
    [0084] The present invention will be explained in more detailand concretely by way of the following Examples, however,the present invention is not limited by them. The structuralformulae of compounds in these Examples are listed in Tables5 to 10 shown below. Production Examples Production Example 1 4-Benzyl-5-bromo-2-pyridyltrifluoromethanesulfonate a) 4-Benzoyl-2-chloropyridine
    [0085] 102 g of 2-chloronicotinic acid was suspended in 250 ml ofbenzene. 50 ml of thionyl chloride was added thereto, followed by heating under reflux for 7 hours. After cooling as it was,the reaction solution was evaporated. The residue wasdissolved in 250 ml of benzene, followed by adding 200 g ofanhydrous aluminum chloride little by little under stirring ina water bath. After leaving the reaction solution as it wasovernight at room temperature, 2L of ice-water was added theretolittle by little and the mixture was extracted with ethylacetate. The organic phase was washed with dilute hydrochloricacid, an aqueous sodium bicarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was removed,to give 135 g of the target compound.1H-NMR(CDCl3) δ ppm=7.50-7.56(3H, m), 7.61(1H, dd, J=0.8,1.2Hz), 7.68(1H, t, J=8Hz), 7.81(2H, d, J=8Hz), 8.58(1H, dd,J=0.8, 5.2Hz) b) 4-Benzoyl-2-methoxypyridine
    [0086] While heating under reflux a 28% sodium methoxidemethanol solution mildly, a mixture of 135 g of 4-benzoyl-2-chloropyridineand 150 ml of methanol was addeddropwise thereinto over one hour, followed by heating underreflux for further 2 hours. After cooling as it was, thereaction solution was filtered to remove insoluble mattersand the solvent was removed. To the residue was added anaqueous sodium bicarbonate solution and the mixture wasextracted with ethyl acetate. The organic phase was washedwith brine, dried over anhydrous magnesium sulfate and thenthe solvent was removed, to give 130 g of the target compound.1H-NMR(CDCl3) δ ppm=4.00(3H, s), 7.00(1H, dd, J=0.8, 1.2Hz), 7.16(1H, dd, J=1.2, 5.2Hz), 7.50(2H, t, J=8Hz), 7.63(1H, t,J=8Hz), 7.83(2H, d, J=8Hz), 8.32(1H, dd, J=0.8, 5.2Hz) c) 4-(α-Hydroxybenzyl)-2-methoxypyridine
    [0087] 9.4 g of sodium borohydride was added little by little toa mixture of 130 g of 4-benzoyl-2-methoxypyridine and 300 mlof methanol under stirring in an ice bath. After the dropwiseaddition was completed, the mixture was stirred at roomtemperature overnight. The reaction solution was added to 1L of water and then extracted with ethyl acetate. The organicphase was washed with brine, dried over anhydrous magnesiumsulfate and then the solvent was removed, to give 104 g of thetarget compound.1H-NMR(CDCl3) δppm=2.39(1H, d, J=3Hz), 3.92(3H, s), 5.74(1H,d, J=3Hz), 6.82(1H, s), 6.86(1H, d, J=5Hz), 7.28-7.36(5H, m),8.08(1H, d, J=5Hz) d) 4-(α-Acetoxybenzyl)-2-methoxypyridine
    [0088] A mixture of 104 g of 4-(α-hydroxybenzyl)-2-methoxypyridine,100 ml of acetic acid anhydride and 100 mlof pyridine was heated under stirring for 5 hours in an oilbath kept at 110°C. After the reaction solution wasevaporated, water was added to the residue and the mixturewas extracted with ethyl acetate. The extract was washedwith an aqueous sodium bicarbonate solution and brine, driedover anhydrous magnesium sulfate and the solvent was removed.The residue was subjected to silica gel columnchromatography using 5-20% ethyl acetate/hexane, to give 112g of the target compound. 1H-NMR(CDCl3) δppm=2.18(3H, s), 3.92(3H, s), 6.73-6.76(2H, m),6.79(1H, d, J=5Hz), 7.28-7.38(5H, m), 8.10(1H, d, J=5Hz) e) 4-Benzyl-2-methoxypyridine
    [0089] 5 g of 10% palladium carbon and 500 ml of methanol wereadded to 112 g of 4-(α-acetoxybenzyl)-2-methoxypyridine,followed by conducting hydrocracking in a hydrogenatmosphere. The catalyst was filtered off and the filtratewas evaporated. Then, the residue was neutralized by anaqueous saturated sodium bicarbonate solution and themixture was extracted with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfateand the solvent was removed, to give 73 g of the targetcompound.1H-NMR(CDCl3) δppm=3.90(5H, s), 6.55(1H, s), 6.70(1H, d, J=5Hz),7.17(2H, d, J=8Hz), 7.22(1H, t, J=8Hz), 7.30(2H, t, J=8Hz),8.04(1H, d, J=5Hz) f) 4-Benzyl-5-bromo-2-methoxypyridine
    [0090] A mixed solution of 22 ml of bromine, 90 g of potassiumbromide and 500 ml of water was added dropwise into a mixtureof 73 g of 4-benzyl-2-methoxypyridine, 28 g of potassiumhydroxide, 1.7 g of tetraethylammonium chloride, 90 g ofpotassium bromide and 500 ml of water under stirring in anice bath. After stirring overnight, sodium sulfite wasadded thereto and the mixture was extracted with ethylacetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and the solvent was removed.The residue was subjected to silica gel column chromatography using 5-10% ethyl acetate/hexane, to give 62g of the target compound.1H-NMR(CDCl3) δ ppm=3.87 (3H, s), 4.00 (2H, s), 6.46(1H, s),7.19 (2H, d, J=7Hz), 7.25(1H, t, J=7Hz), 7.32(2H, t, J=7Hz),8.22(1H, s) g) 4-Benzyl-5-bromo-2-hydroxypyridine
    [0091] 250 ml of 47% hydrobromic acid was added to 62 g of4-benzyl-5-bromo-2-methoxypyridine, followed by heatingunder stirring for 3 hours in an oil bath kept at 100°C.After cooling as it was, the reaction solution was added toan aqueous potassium carbonate solution little by little andneutralized. The resulting precipitates were collected byfiltration, to give 59 g of the target compound.1H-NMR(DMSO-d6) δppm=3.87(2H, s), 6.20(1H, s), 7.21-7.36(5H,m), 7.72(1H, s) h) 4-Benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate
    [0092] 100 g of N-phenyltrifluoromethanesulfonimide was addedto a suspension of 200 ml of dichloromethane containing 59g of 4-benzyl-5-bromo-2-hydroxypyridine, 100 ml oftriethylamine and 8 g of 4-dimethylaminopyridine little bylittle. After stirring at room temperature for 7 hours, thereaction solution was evaporated. The residue wassubjected to silica gel column chromatography using 5-10%ethyl acetate/hexane, to give 82 g of the target compound.1H-NMR(CDCl3) δ ppm=4.11(2H, s), 6.82(1H, s), 7.18(2H, d, J=7Hz),7.32(1H, t, J=7Hz), 7.38(2H, t, J=7Hz), 8.46(1H, s) Production Example 2 2-Benzyl-6-pyridyl trifluoromethanesulfonate a) 2-Bromo-6-methoxypyridine
    [0093] 250 ml of 28% sodium methoxide methanol solution wasadded dropwise into a mixture of 200 g of 2,6-dibromopyridineand 150 ml of methanol while heating at 80°C stirring in anoil bath, followed by stirring under heating for 2 hours asit was. After cooling as it was, the mixture was extractedwith diethyl ether-water, and the organic phase was washedwith water and brine, dried over anhydrous magnesium sulfateand the solvent was removed, to give 150 g of the targetcompound.1H-NMR(CDCl3) δppm=3.94(3H, s), 6.68(1H, d, J=7Hz), 7.06(1H,d, J=8Hz), 7.40(1H, t, J=8Hz) b) 2-Benzyl-6-methoxypyridine
    [0094] A Grignard's reagent prepared from 123 ml of benzylbromide, 30 g of magnesium and 400 ml of diethylether wasslowly added dropwise into a mixture of 150 g of 2-bromo-6-methoxypyridine,4.3 g of 1,3-bis(diphenylphosphino)propanenickel(II)chloride and 500ml of tetrahydrofuran under stirring in an ice bath. Afterstirring overnight as it was, the mixture was extracted withan aqueous ammonium chloride solution and hexane. Theorganic phase was washed with water and then brine, driedover anhydrous magnesium sulfate and the solvent was removed.The residue was subjected to silica gel columnchromatography using 1% and 1.5% of ethyl acetate/hexane,to give 150 g of the target compound. 1H-NMR(CDCl3) δ ppm=3.92(3H, s), 4.03 (2H, s), 6.54(1H, d, J=8Hz),6.65(1H, d, J=7Hz), 7.18-7.32(5H, m), 7.44(1H, dd, J=7, 8Hz) c) 2-Benzyl-6-hydroxypyridine
    [0095] A mixture of 59 g of 2-benzyl-6-methoxypyridine and 200ml of 47% hydrobromic acid was heated under stirring for 7hours in an oil bath kept at 100°C. After cooling as it was,250 ml of water was added thereto, and the resulting crystalswere collected by filtration, washed with water andvacuum-dried, to give 38.9 g of the target compound.1H-NMR(DMSO-d6) δ ppm=3.78(2H, s), 5.96(1H, d, J=7Hz), 6.15(1H,d, J=9Hz), 7.20-7.36(6H, m) d) 2-Benzyl-6-pyridyl trifluoromethanesulfonate
    [0096] A mixture of 10 g of 2-benzyl-6-hydroxypyridine, 23 gof N-phenyltrifluoromethanesulfonimide, 0.66 g of 4-dimethylaminopyridine,23 ml of triethylamine and 100 ml ofdichloromethane was stirred at room temperature in a waterbath for one hour. The reaction solution was evaporated andthe residue was subjected to silica gel columnchromatography using 2-3% ethyl acetate/hexane and furtherfiltered through NH-silica gel (Fuji Silicia Kagaku) andeluted with 3% ethyl acetate/hexane. The eluate wasevaporated, to give 11.7 g of the target compound.1H-NMR(CDCl3) δppm=4.13(2H, s), 6.99(1H, d, J=8Hz), 7.16(1H,d, J=8Hz), 7.22-7.34(5H, m), 7.75(1H, t, J=8Hz) Production Example 3 2-Benzyl-3-bromo-6-pyridyltrifluoromethanesulfonate a) 2-Benzyl-3-bromo-6-methoxypyridine
    [0097] A mixed solution of 17 ml of bromine, 90 g of potassiumbromide and 450 ml of water was added dropwise into a mixtureof 60 g of 2-benzyl-6-methoxypyridine (Production Example2-b), 90 g of potassium bromide, 450 ml of water, 20 g ofpotassium hydroxide and 2.5 g of tetraammonium chloride over2 hours under stirring in an ice bath. After stirringovernight as it was, sodium sulfite was added thereto andthe mixture was extracted with hexane. The organic phasewas washed with water and brine, dried over anhydrousmagnesium sulfate and the solvent was removed. The residuewas subjected to silica gel column chromatography to elutewith 0.5-1.5% of ethyl acetate/hexane, to give 72.5 g of thetarget compound.1H-NMR(CDCl3) δ ppm=3.88(3H, s), 4.20(2H, s), 6.48(1H, d, J=8Hz),7.17-7.38(5H, m), 7.62(1H, d, J=8Hz) b) 2-Benzyl-3-bromo-6-hydroxypyridine
    [0098] A mixture of 72.5 g of 2-benzyl-3-bromo-6-methoxypyridineand 300 ml of 47% hydrobromic acid was heatedunder stirring for 4 hours in an oil bath kept at 100°C.After cooling as it was, 500 ml of water was added thereto.The resulting crystals were collected by filtration, washedwith water and diethyl ether, air-dried and then dried underheating under reduced pressure, to give 63.8 g of the targetcompound.1H-NMR(DMSO-d6) ppm=3.97(2H, s), 6.25(1H, d, J=9Hz), 7.20-7.35(5H,m), 7.58(1H, d, J=9Hz) c) 2-Benzyl-3-bromo-6-pyridyl trifluoromethanesulfonate
    [0099] A mixture of 1.2 g of 2-benzyl-3-bromo-6-hydroxypyridine,1.7 g of N-phenyltrifluoromethanesulfonimide,1.9 ml of triethylamine,28 mg of 4-dimethylaminopyridine and 15 ml ofdichloromethane was stirred at room temperature for 3 hours.Silica gel was added to the reaction solution and the solventwas removed. The residue was subjected to silica gel columnchromatography using 5% ethyl acetate/hexane, to give 1.6g of the target compound.1H-NMR(CDCl3) δ ppm=4.28(2H, s), 6.92(1H, d, J=8Hz), 7.22-7.33(5H,m), 7.97(1H, d, J=8Hz) Production Example 4 4-Benzyl-5-bromo-2-iodopyrimidine a) tert-Butyl 2-(dimethylaminomethylene)-3-oxo-4-phenylbutyrate
    [0100] Phenylacetyl chloride was slowly added dropwise into amixture of 110 g of mel drum acid, 120 ml of pyridine and500 ml of dichloromethane under stirring in an ice bath.After stirring overnight as it was, 650 ml of an aqueous 1.2N hydrochloric acid solution was added thereto. the mixture.The organic phase was washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was removed. Tothe residue was added 600 ml of tert-butanol, followed byheating under reflux for 3 hours. After cooling as it was,the solvent was removed while ethanol was added. To theresidue were added 600 ml of toluene and 110 ml of N,N-dimethylformamidodimethylacetal,followed by heating understirring for 2 hours in an oil bath kept at 100°C while removing methanol by using Dean-Stark apparatus. Thereaction solution was evaporated, and the residue wassubjected to silica gel column chromatography using 50-70%ethyl acetate/hexane, to give 93 g of the target compound.1H-NMR(CDCl3) δppm=1.51(9H, s), 4.03 (2H, s), 7.18-7.30(5H, m),7.56(1H, s) b) 4-Benzyl-2-aminopyrimidine
    [0101] Trifluoroacetic acid was slowly added dropwise into amixture of 93 g of tert-butyl 2-(dimethylaminomethylene)-3-oxo-4-phenylbutyrateand 400ml of dichloromethane under stirring in an ice bath. Afterstirring overnight as it was, the solvent was removed andthe residue was extracted with an aqueous sodium bicarbonatesolution, ethyl acetate and tetrahydrofuran. The organicphase was washed with water and brine, dried over anhydrousmagnesium sulfate and the solvent was removed. To theresidue were added 500 ml of ethanol, 110 g of guanidinehydrochloride and 96 g of sodium ethoxide, followed byheating under reflux vigorously for 20 hours. After coolingas it was, 800 ml of water, 150 ml of hexane and 30 ml ofdiethyl ether were added thereto. After stirring at roomtemperature for 30 minutes, the resulting crystals werecollected by filtration, washed with water, air-dried andthen vacuum-dried under heating, to give 26 g of the targetcompound.1H-NMR(CDCl3) δ ppm=3.91(2H, s), 5.01(2H, s), 6.41(1H, d,J=5Hz), 7.23-7.35(5H, m), 8.15(1H, d, J=5Hz) c) 4-Benzyl-5-bromo-2-iodopyrimidine
    [0102] A solution of 60 ml of a methanol containing 7.3 ml ofbromine was slowly added dropwise into a mixture of 26 g of4-benzyl-2-aminopyrimidine, 24 g of sodium bicarbonate and150 ml of N,N-dimethylformamide while stirring in an ice bath.After stirring for 10 minutes in an ice bath, an aqueoussodium thiosulfate solution was added thereto. Afterstirring at room temperature for 30 minutes, insolublematters were filtered and vacuum-dried under heating. Amixture of the resulting crude compound, 51 ml of isoamylnitrite, 51 ml of diiodomethane, 24 g of cuprous iodide and400 ml of tetrahydrofuran was heated under stirring for 2hours in a 65°C oil bath. After cooling as it was, 400 mlof ethyl acetate was added thereto and insoluble matters werefiltered through Celite. The filtrate was partitioned byadding an aqueous sodium thiosulfate solution and an aqueousammonium chloride solution thereto. The organic phase waswashed with brine and the solvent was removed. The residuewas subjected to silica gel column chromatography and elutedwith 6% ethyl acetate/hexane, to give 20 g of the targetcompound.1H-NMR(CDCl3) δ ppm=4.20(2H, s), 7.23-7.35(5H, m), 8.42(1H, s) Production Example 5 3-Benzyl-5-bromo-2-pyridyltrifluoromethane sulfonate a) 3-Benzyl-2-methoxypyridine
    [0103] 16 g of aluminum chloride was added to a mixture of 8.6g of 2-chloronicotinic acid and 120 ml of benzene in an ice bath under stirring. After stirring at room temperature for2 hours, water and ethyl acetate were added thereto.Insoluble matters were filtered off using Celite, and theorganic phase was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was removed. To theresidue were added 100 ml of methanol and 30 ml of 28% sodiummethoxide methanol solution, followed by heating underreflux overnight. After cooling as it was, the solvent wasremoved and the mixture was partitioned by adding water andethyl acetate thereto. The organic phase was washed withwater and brine, dried over anhydrous magnesium sulfate andthe solvent was removed. To the residue were added 90 mlof diethylene glycol, 6.8 g of potassium carbonate and 4.3ml of hydrazine mono hydrate. The mixture was heated understirring for one hour in a 100°C oil bath and then for 3 hoursin a 170°C oil bath. After cooling as it was, the mixturewas partitioned by adding water and ethyl acetate thereto.The organic phase was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was removed. The residuewas subjected to silica gel column chromatography and elutedwith 10% ethyl acetate/hexane, to give 4.2 g of the targetcompound.1H-NMR(CDCl3) δ ppm=3.91(2H, s), 3.97(3H, s), 6.79(1H, dd, J=5,7Hz), 7.18-7.32(6H, m), 8.03(1H, dd, J=2, 5Hz) b) 3-Benzyl-5-bromo-2-methoxypyridine
    [0104] 0.12 ml of bromine was added to a mixture of 430 mg of3-benzyl-2-methoxypyridine, 460 mg of sodium bicarbonate and 10 ml of methanol under stirring in an ice bath, followedby stirring at room temperature for 8 hours. The mixturewas partitioned by adding an aqueous sodium thiosulfatesolution and ethyl acetate thereto. The organic phase waswashed with saturated brine, dried over anhydrous magnesiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography and elutedwith 5% ethyl acetate/hexane, to give 140 mg of the targetcompound.1H-NMR(CDCl3) δppm=3.87(2H, s), 3.92(3H, s), 7.17-7.34(6H, m),8.05(1H, d, J=2Hz) c) 3-Benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate
    [0105] A mixture of 190 mg of 3-benzyl-5-bromo-2-methoxypyridineand 2 ml of 47% hydrobromic acid was stirred under heating inan oil bath kept at 70°C for 2 hours. After cooling as it was,the mixture was partitioned by adding an aqueous potassiumcarbonate solution and ethyl acetate were added thereto. Theorganic phase was washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was removed. Tothe residue were added 300 mg of N-phenyltrifluoromethanesulfonimide,8.4 mg of 4-dimethylaminopyridine,0.29 mg of triethylamine and 2 ml ofdichloromethane, followed by stirring at room temperature forone hour. Silica gel was added to the reaction solution andthe solvent was removed. The residue was subjected to silicagel column chromatography using 5% ethyl acetate/hexane, togive 220 mg of the target compound. 1H-NMR(CDCl3) δppm=4.01(2H, s), 7.17-7.20(2H, m), 7.28-7.39(3H,m), 7.65-7.67(1H, m), 8.27(1H, d, J=2Hz) Production Example 6 (3-Pyridyl)tributyltin
    [0106] 1.45 ml of a hexane solution containing 1.54 M normalbutyl lithium was added dropwise into 200 ml of diethylsolution containing 10.0 g of 3-bromopyridine at -78°C ina nitrogen atmosphere over 10 minutes. After the dropwiseaddition, the mixture was stirred for 10 minutes and then20 ml of tributyltin chloride was added dropwise thereintoover 10 minutes. Then, after stirring for 30 minutes, waterwas added to the reaction mixture and then extracted withethyl acetate. The extract was washed with brine and thesolvent was removed. The residue was subjected to silicacolumn chromatography and eluted with hexane and then withhexane/ethyl acetate (7:1), to give 21.9 g of the targetcompound.1H-NMR(CDCl3) δ ppm=0.87-0.94 (9H, m), 1.07-1.11(6H, m),1.26-1.38(6H, m), 1.50-1.58(6H, m), 7.22(1H, m), 7.73(1H, m),8.50(1H, m), 8.59(1H, s) Production Example 7 (2-Pyridyl)tributyltin
    [0107] The title compound was synthesized in the same manneras in Production Example 6.1H-NMR(CDCl3) δppm=0.87-0.94(9H, m), 1.09-1.14(6H, m),1.28-1.37(6H, m), 1.52-1.58(6H, m), 7.10(1H, m), 7.40(1H, m),7.48(1H, m) , 8.73(1H, m) Production Example 8 (3,4-Methylenedioxyphenyl)tributyltin
    [0108] The title compound was synthesized in the same manneras in Production Example 6 except that the reaction solvent(diethyl ether) was altered to tetrahydrofuran.1H-NMR(CDCl3) δ ppm=0.87-0.90(9H, m), 1.00-1.04(6H, m),1.30-1.37(6H, m), 1.49-1.56(6H, m), 5.61(2H, s), 6.83-6.93(3H,m) Production Example 9 (4-Pyridyl)tributyltin
    [0109] 9.0 ml of a hexane solution of 2.52 M of normalbutyllithium was added dropwise into 20 ml of atetrahydrofuran solution of 3.2 ml of diisopropylamine underice-cooling over 10 minutes in a nitrogen atmosphere. Afterstirring under ice-cooling for 20 minutes, 6.3 ml ofhydrogenated tributyltin was added dropwise thereinto over10 minutes, followed by stirring under ice-cooling forfurther 20 minutes. Then, under cooling to -78'C, asuspension of 2.0 g of 4-bromopyridine hydrochloride and 30ml of tetrahydrofuran was added dropwise thereto over 10minutes. After stirring for 2 hours, water was added to thereaction mixture and the mixture was extracted with ethylacetate. The extract was washed with brine and the solventwas removed. Then, the residue was subjected to NH-silicagel column chromatography to elute with hexane/ethyl acetate(7:1) and further subjected to silica column chromatographyand eluted with hexane/ethyl acetate (2:1), to give 580 mg(15%) of the target compound.1H-NMR(CDCl3) δ ppm=0.87-0.91(9H, m), 1.07-1.11(6H, m) ,1.30-1.35(6H, m), 1.49-1.60(6H, m), 7.35-7.37(2H, m), 8.47-8.48(2H, m) Production Example 10 Pyrazyltributyltin
    [0110] 5.0 g of tetrakistriphenylphosphinepalladium(0) wasadded to 50 ml of a xylene solution containing 8.0 g ofchloropyrazine and 200 g of bis(tributylthin), followed byheating under stirring at 140°C for one hour in a nitrogenatmosphere. After cooling the reaction mixture to roomtemperature, the solvent was removed. The residue wassubjected to silica column chromatography and eluted withhexane and then with hexane/ethyl acetate (10:1), to give9.5 g of pyrazyltributyltin.1H-NMR(CDCl3) δppm=0.87-0.94(9H, m), 1.15-1.19(6H, m),1.26-1.38(6H, m), 1.53-1.60(6H, m), 8.36(1H, m), 8.54(1H, m),8.71(1H, m) Production Example 11 2-Benzyl-3-methoxymethyloxypyridine-6-carboxyaldehyde a) 3-Benzyloxy-2-hydroxymethyl-6-methylpyridine
    [0111] 100 g of 3-hydroxy-6-methyl-2-pyridine methanol and 150g of potassium carbonate were suspended in 400 ml ofN,N-dimethylformamide. Under heating under stirring 60°Cin an oil bath, 85 ml of benzyl bromide was added dropwisethereinto. Further, after heating under stirring for 30minutes, insoluble matters were filtered off. Water wasadded to the filtrate, and the mixture was extracted withethyl acetate. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was recrystallized from ethanol/hexane, to give 145 g of the target compound.1H-NMR(CDCl3) δ =2.49(3H, s), 4.48(1H, t, J=4Hz), 4.77(2H, d,J=4Hz), 5.09(2H, s), 6.98(1H, d, J=8Hz), 7.08(1H, d, J=8Hz),7.28-7.45(5H, m) b) 3-Benzyloxy-6-methylpyridine-2-carboxyaldehyde
    [0112] 145 g of 3-benzyloxy-2-hydroxymethyl-6-methylpyridinewas dissolved in 500 ml of chloroform. 400 g of manganesedioxide was added thereto under heating under stirring at60°C in an oil bath, followed by heating under stirring asit was for one hour. After cooling as it was, the reactionsolution was filtered to remove insoluble matters, and thesolvent was removed. The resulting crystals werevacuum-dried, to give 139 g of the target compound.1H-NMR(CDCl3) δ=2.57(3H, s), 5.22(2H, s), 7.25-7.46(7H, m),10.41(1H, s) c) 3-Benzyloxy-2-(α-hydroxybenzyl)-6-methylpyridine
    [0113] 139 g of 3-benzyloxy-6-methylpyridine-2-carboxyaldehydewas dissolved in 700 ml of tetrahydrofuran,followed by cooling to -60°C or less. Under stirring usinga mechanical stirrer, 400 ml of a cyclohexane/ether solutioncontaining 1.8 mol of phenyllithium was added dropwisethereinto. After stirring for 30 minutes under cooling asit was, an aqueous saturated ammonium chloride solution wasadded thereto and the temperature was returned to roomtemperature. Further, water was added thereto and themixture was extracted with ethyl acetate. The resultingorganic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed.The residue was recrystallized from ethanol under cooling,to give 116 g of the target compound.1H-NMR(CDCl3) δ=2.53(3H, s), 4.92(1H, d, J=12Hz), 4.98(1H, d,J=12Hz), 5.80(1H, d, J=7Hz), 5.91(1H, d, J=7Hz), 6.99(1H, d,J=8Hz), 7.04(1H, d, J=8Hz), 7.07-7.14(2H, m), 7.20-7.36(8H, m) d) 2-Benzoyl-3-benzyloxy-6-methylpyridine
    [0114] 116 g of 3-benzyloxy-2-(α-hydroxybenzyl)-6-methylpyridinewas dissolved in 500 ml of chloroform. 400g of manganese dioxide was added under stirring, followedby heating under stirring at 60°C for one hour in an oil bath.After cooling as it was, the reaction solution was filteredto remove insoluble matters, and the solvent was removed.The resulting crystals were vacuum-dried, to give 113 g ofthe target compound.1H-NMR(CDCl3) δ=2.53(3H, s), 5.06(2H, s), 7.13-7.30(7H, m),7.45(2H, t, J=8Hz), 7.58(1H, t, J=8Hz), 7.87(2H, d, J=8Hz) e) 6-Hydroxymethyl-2-benzoyl-3-benzyloxypyridine
    [0115] 113 g of 2-benzoyl-3-benzyloxy-6-methylpyridine wasdissolved in 600 ml of dichloromethane. 96 g of 3-chloroperbenzoicacid was added thereto, followed bystirring under heating at 50°C in an oil bath. After coolingin a water bath, an aqueous sodium sulfite solution andfurther an aqueous saturated sodium bicarbonate solutionwere added to the reaction solution. The organic phase wasseparated, further washed with an aqueous saturated sodiumbicarbonate solution and brine. Then, it was dried over anhydrous magnesium sulfate and the solvent was removed.The resulting residue was dissolved in 200 ml of acetic acidanhydride, followed by heating under stirring at 150°C for3 hours in an oil bath. Then, the solvent was removed and400 ml of methanol and 200 ml of an aqueous 2N sodium hydroxidesolution were further added thereto, followed by heatingunder stirring at 60°C for 3 hours in an oil bath. Activatedcarbon was added to the reaction solution. After stirringfor a while, it was filtered off. Water was added to thefiltrate to precipitate crystals. The resulting crystalswere collected by filtration and vacuum-dried, to give 116g of the target compound.1H-NMR(CDCl3) δ =3.18(1H, t, J=5Hz), 4.74(2H, d, J=5Hz), 5.12(2H,s), 7.17-7.30(5H, m), 7.32(1H, d, J=9Hz), 7.39(1H, d, J=9Hz),7.46(2H, t, J=8Hz), 7.60(1H, t, J=8Hz), 7.85(2H, d, J=8Hz) f) 2-Benzoyl-6-(tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridine
    [0116] 116 g of 6-hydroxymethyl-2-benzoyl-3-benzyloxypyridinewas dissolved in 450 ml of N,N-dimethylformamide.100 g of imidazole and 85 g of tertbutyldimethylsilylchloride was added thereto, followed bystirring at room temperature overnight. The solvent wasremoved, water was added thereto and the mixture wasextracted with ethyl acetate. Further, the organic phasewas washed with dilute hydrochloric acid, water, an aqueoussaturated sodium bicarbonate solution and brine, dried overanhydrous magnesium sulfate and evaporated. The residue was dried, to give 141 g of the target compound.1H-NMR(CDCl3) δ=0.11(6H, s), 0.95(9H, s), 4.80(2H, s), 5.10(2H,s), 7.15-7.32(5H, m), 7.39(1H, d, J=9Hz), 7.44(2H, t, J=8Hz),7.53-7.61(2H, m), 7.85(2H, d, J=8Hz) g) 2-(α-Acetoxybenzyl)-6-(tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridine
    [0117] 141 g of 2-benzoyl-6-(tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridinewasdissolved in 500 ml of methanol. Under ice-cooling, 4.9 g ofhydrogenated boron sodium thereto, followed by stirring for 2hours. After returning to room temperature, water was addedthereto and the mixture was extracted with ethyl acetate.Further, the organic phase was washed with brine; dried overanhydrous magnesium sulfate and evaporated. The resultingresidue was dissolved in 200 ml of pyridine and 100 ml of aceticacid anhydride was added thereto, followed by heating understirring for one hour at 150°C in an oil bath. The Solvent wasremoved, water was added thereto and the mixture was extractedwith ethyl acetate. Further, the organic phase was washed withdilute hydrochloric acid, water, an aqueous saturated sodiumbicarbonate solution and brine, dried over anhydrous magnesiumsulfate and evaporated. The residue was dried, to give 160 gof the target compound.1H-NMR(CDCl3) δ=0.10(6H, s), 0.94(9H, s), 2.17(3H, s), 4.79(2H,s), 5.04(1H, d, J=12Hz), 5.09(1H, d, J=12Hz), 7.14-7.46(13H,m) h) 2-Benzyl-6-(tert-butyldimethylsilyl)oxymethyl-3- hydroxypyridine
    [0118] 160 g of 2-(α-acetoxybenzyl)-6-tert-butyldimethylsilyl)oxymethyl-3-benzyloxypyridinewasdissolved in a mixed solvent of 200 ml of tetrahydrofuranand 200 ml of methanol. 8 g of 10% palladium carbon was addedthereto to conduct hydrocracking. After the atmosphere inthe reaction system was replaced by nitrogen, the catalystwas filtered off and the filtrate was evaporated. Theresidue was dissolved in ethyl acetate, washed with anaqueous saturated sodium bicarbonate solution and brine,dried over anhydrous magnesium sulfate and evaporated, togive 100 g of the target compound.1H-NMR(CDCl3) δ=0.11(6H, s), 0.95(9H, s), 4.19(2H, s), 4.79(2H,s), 7.09(1H, d, J=8Hz), 7.10-7.34(6H, m) i) 2-Benzyl-6-hydroxymethyl-3-methoxymethyloxypyridine
    [0119] 63 g of potassium carbonate and 300 ml of N,N-dimethylformamidewere added to 100 g of 2-benzyl-6-(tert-butyldimethylsilyl)oxymethyl-3-hydroxypyridineand23 ml of chloromethyl methyl ether was added dropwise intothe mixture at room temperature under stirring using amechanical stirrer. After heating under stirring at 50°Cfor 2 hours in an oil bath, water was added thereto and themixture was extracted with ethyl acetate. Further, theorganic phase was washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was removed.The resulting residue was dissolved by adding 400 ml oftetrahydrofuran and 300 ml of a tetrahydrofuran solution containing 1 mol of tetra-n-butylammonium fluoride was addedthereto under ice-cooling. After stirring under ice-cooling,water was added thereto and the mixture wasextracted with ethyl acetate. Further, the organic phasewas washed with water and brine, dried over anhydrousmagnesium sulfate and evaporated. The residue wasdissolved in 50% ethyl acetate/hexane and filtered throughsilica gel. The filtrate was evaporated and dried, to give73 g of the target compound.1H-NMR(CDCl3) δ=3.29(3H, s), 4.17(2H, s), 4.79(2H, s), 5.12(2H,s), 7.14(1H, t, J=7Hz), 7.18-7.32(5H, m), 7.37(1H, d, J=8Hz) j) 2-Benzyl-3-methoxymethyloxypyridine-6-carboxyaldehyde
    [0120] 73 g of 2-benzyl-6-hydroxymethyl-3-methoxymethyloxypyridinewas dissolved in 300 ml ofchloroform, followed by adding 220 g of manganese dioxideunder stirring. Then, the mixture was heated under stirringat 50°C for 1.5 hours in an oil bath. After cooling as itwas, the reaction solution was filtered to remove insolublematters and the solvent was removed. The resulting crystalswere recrystallized from ether/hexane, to give 30 g of thetarget compound. The filtrate obtained duringrecrystallization was concentrated. The residue wassubjected to silica gel column chromatography using 5-10%ethyl acetate/hexane as an eluent for separation andpurification and recrystallized from ether/hexane, to give11 g of the target compound.1H-NMR(CDCl3) δ =3.29(3H, s), 4.27(2H, s), 5.25(2H, s), 7.18(1H, t, J=7Hz), 7.26(2H, t, J=7Hz), 7.31(2H, d, J=7Hz), 7.45(1H, d,J=8Hz), 7.85(1H, d, J=8Hz), 10.00(1H, s) Production Example 12 2-Benzyl-3-methoxymethyloxy-6-iodopyridine a) 2-Bromo-3-methoxymethyloxypyridine
    [0121] 50 g of 2-bromo-3-hydroxypyridine was suspended in 200ml of tetrahydrofuran, followed by adding 33 ml ofchloromethyl methyl ether. While cooling to -20°C andstirring, 17 g of 60% oily sodium hydride was added theretolittle by little. After adding sodium hydride, the coolingmedium was removed, followed by stirring at room temperaturefor 3.5 hours. Under cooling, ice water was added theretolittle by little and the mixture was extracted with ethylacetate. The organic phase was further washed with brine,dried over anhydrous sodium sulfate and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using 10-15% ethyl acetate/hexane as aneluent for separation and purification, to give 35 g of thetarget compound.1H-NMR(CDCl3) δ=3.53(3H, s), 5.28(2H, s), 7.21(1H, dd, J=4.6,8.2Hz), 7.43(1H, dd, J=1.6, 8.2Hz), 8.05(1H, dd, J=1.6, 4.6Hz) b) 2-Benzyl-3-methoxymethyloxypyridine
    [0122] A diethyl ether solution of magnesium benzyl bromideprepared from 38 ml of benzyl bromide, 8 g of magnesium and 250ml of diethyl ether anhydride was slowly added dropwise intoa mixture of 35 g of 2-bromo-3-methoxymethyloxypyridine, 5 gof 1,3-bis(diphenylphosphino)propanenickel (II) chloride and 200 ml of tetrahydrofuran under stirring under ice-cooling ina nitrogen atmosphere. After stirring for 4.5 hours, an aqueoussaturated ammonium chloride solution was added thereto and themixture was extracted with ethyl acetate. The organic phasewas further washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The residue was subjectedto silica gel column chromatography using 8-20% ethylacetate/hexane as an eluent for separation and purification,to give 27 g of the target compound.1H-NMR(CDCl3) δ=3.34(3H, s), 4.21(2H, s), 5.17(2H, s),7.11-7.38(7H, m), 8.20(1H, dd, J=1.3, 4.8Hz) c) 2-Benzyl-3-hydroxy-6-iodopyridine
    [0123] 60 ml of trifluoroacetic acid was added to 27 g of 2-benzyl-3-methoxymethyloxypyridine,followed by stirring atroom temperature for 2 hours and then heating under stirringfor one hour at 50°C in an oil bath. The reaction solution wasadded to an aqueous potassium carbonate solution which wasice-cooled, and the resulting crystals were collected byfiltration. The filtrate was evaporated, and to the resultingcrystals were added 19 g of sodium iodide, 5 g of sodium hydroxideand 200 ml of methanol. Under stirring under ice-cooling, 158ml of an aqueous 5% sodium hypochlorite solution was addeddropwise thereinto over 30 minutes. After stirring overnightas it was, 60 ml of 5N hydrochloric acid was added thereto andan aqueous saturated sodium thiosulfate solution was furtheradded thereto, followed by extracting with ethyl acetate. Theorganic phase was washed further with brine, dried over anhydrous sodium sulfate and the solvent was removed. Theresulting crystals were collected by filtration and vacuum-dried,to give 17 g of the target compound. d) 2-Benzyl-3-methoxymethyloxy-6-iodopyridine
    [0124] 12 g of 2-benzyl-3-hydroxy-6-iodopyridine was dissolvedin 50 ml of tetrahydrofuran, followed by adding 3.8 ml ofchloromethyl methyl ether. 2 g of 60% oily sodium hydridewas added little by little thereto to under stirring underice-cooling. After adding sodium hydride, the coolingmedium was removed and the mixture was stirred at roomtemperature for 2.5 hours. Then, ice water was added theretolittle by little under cooling, followed by extracting withethyl acetate. The organic phase was further washed brine,dried over anhydrous sodium sulfate and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using 15% ethyl acetate/hexane as an eluentfor separation and purification, to give 13 g of the targetcompound.1H-NMR(CDCl3) δ =3.28 (3H, s), 4.14 (2H, s), 5.11 (2H, s), 7.04(1H,d, J=8.4Hz), 7.14-7.30(5H, m), 7.48(1H, d, J=8.4Hz) Production Example 13 2-(4-Fluorobenzyl)-3-bromo-6-hydroxypyridine
    [0125] Benzyl bromide in Production Example 2-b) was alteredto 4-fluorobenzyl chloride and in succession, the sameprocedures as in Production Examples 3-a) and 3-b) wereconducted to synthesize the title compound.1H-NMR(CDCl3) δ=4.15(2H, s), 6.36(1H, d, J=9Hz), 6.99-7.03(2H, m), 7.33-7.37(2H, m), 7.51(1H, d, J=9Hz) Production Example 14 2-(3-Fluorobenzyl)-3-bromo-6-hydroxypyridine
    [0126] Benzyl bromide in Production Example 2-b) was alertedto 3-fluorobenzyl chloride and then the same procedures asin Production Examples 3-a) and 3-b) were conducted, tosynthesize the title compound.1H-NMR(CDCl3) δ=4.18(2H, s), 6.37(1H, d, J=9Hz), 6.92-6.97(1H,m), 7.06-7.17(2H, m), 7.26-7.31(1H, m), 7.52(1H, d, J=9Hz) Production Example 15 4-Benzyl-5-bromo-2-chloropyrimidine
    [0127] The title compound was synthesized in the same manneras in Production Example 4 except that isoamyl nitrite wasaltered to tert-butyl nitrite, diiodomethane and cuprousiodide were altered to copper chloride and tetrahydrofuranas the solvent was altered to acetonitrile.1H-NMR(CDCl3) δ=4.75(2H, s), 7.25-7.35(5H, m), 7.70(1H, s) Production Example 16 2-Benzyl-3-bromo-6-hydroxy-5-iodopyridine
    [0128] 1.19 g of N-iodosuccinimide was added to a mixture of1.16 g of 2-benzyl-3-bromo-6-hydroxypyridine (ProductionExample 3-b) and 10 ml of N,N-dimethylformamide at roomtemperature, followed by stirring at the same temperatureovernight. 50 ml of water was added to the reaction solutionand the resulting crystals were collected by filtration,washed with water and then vacuum-dried, to give 1.47 g ofthe target compound.1H-NMR(CDCl3) δ =4.02(2H, s), 7.30-7.37(5H, m), 8.11(1H, s) Production Example 17 2-Bromo-6-iodo-3-pyridyltrifluoromethanesulfonate a) 2-Bromo-3-hydroxy-6-iodopyridine
    [0129] 17.6 g of Chloramine T was added to a mixture of 10.9g of 2-bromo-3-hydroxypyridine, 9.35 g of sodium iodide and110 ml of N,N-dimethylformamide under stirring in an ice bath,followed by stirring at the same temperature for 30 minutesand then at room temperature for 10 minutes. Water, ethylacetate and 11 ml of an aqueous 6N hydrochloric acid solutionwere added thereto, and the organic phase was washed withbrine and the solvent was removed. The residue was subjectedto silica gel column chromatography and eluted with 30% ethylacetate/hexane, to give 16.5 g of the target compound.1H-NMR(CDCl3) δ=5.58(1H, br s), 6.98-7.01(1H, m), 7.55-7.58(1H,m) b) 2-Bromo-6-iodo-3-pyridyl trifluoromethanesulfonate
    [0130] 19.7 g of N-phenyltrifluoromethanesulfonimide, 336 mgof 4-dimethylaminopyridine and 23.0 ml of triethylamine wereadded to a mixture of 16.5 g of 2-bromo-3-hydroxy-6-iodopyridineand 150 ml of dichloromethane at roomtemperature, followed by stirring at room temperature for1.5 hours. Silica gel was added to the reaction solutionand the solvent was removed. The residue was subjected tosilica gel column chromatography using 5% ethylacetate/hexane, to give 19.9 g of the target compound.1H-NMR(CDCl3) δ=7.30(1H, d, J=9Hz), 7.78(1H, d, J=9Hz) Production Example 18 (2-Benzyl-3-methoxymethyloxy-6- pyridyl)tributyltin
    [0131] The title compound was synthesized in the same manneras in Production Example 6 except that 3-bromopyridine wasaltered to 2-benzyl-6-iodo-3-methoxymethyloxypyridine(Production Example 12).1H-NMR(CDCl3) δ=0.84.0.89(9H, m), 1.03-1.08(6H, m), 1.28-1.38(6H,m), 1.51-1.59(6H, m), 3.32(3H, s), 4.20(2H, s),5.12(1H, s), 7.10-7.36(7H,m) Production Example 19 Pyrazylacetylene a) Pyrazyltrimethylsilylacetylene
    [0132] 10.1 g of trimethylsilylacetylene and 28.6 ml oftriethylamine were added to a mixture of 6.11 ml ofchloropyrazine, 653 mg of cuprous iodide, 3.96 g oftetrakis(triphenylphosphine)palladium(0) and 100 ml of N,N-dimethylformamide,followed by stirring at 50°C for 3.5 hours.After cooling as it was at room temperature, Celite and hexanewere added thereto, followed by filtering off insoluble mattersthrough Celite. After evaporating the solvent, the residue wassubjected to silica gel column chromatography and eluted with10% ethyl acetate/hexane, to give 9.58 g of the target compound.1H-NMR(CDCl3) d=0.31(9H, s), 8.47(1H, s), 8.53(1H, s), 8.68(1H,s) b) Pyrazylacetylene
    [0133] 7.51 g of potassium carbonate was added to a mixture of9.58 g of pyrazyltrimethylsilylacetylene and 70 ml ofmethanol at 0°C, followed by stirring at room temperaturefor 30 minutes. Water and diethyl ether were added thereto, and the organic layer was washed with brine, dried overanhydrous magnesium sulfate and the solvent was evaporated,to give 2.50 g of the title compound.1H-NMR(CDCl3) d=3.20(1H, s), 8.38(1H, s), 8.41(1H, s), 8.57(1H,s) Production Examples 20 2-Methoxymethyloxy-1-iodobenzene
    [0134] 216 mg of 60% oily sodium hydride was added to a mixtureof 1.65 of 2-iodophenol and 20 ml of N,N-dimethylformamideunder ice-cooling followed by stirring at room temperaturefor 30 minutes. Under ice-cooling, 570 µl of chloromethylmethyl ether was added thereto, followed by stirring for 30minutes at room temperature. Water and ethyl acetate wereadded thereto. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and thesolvent was removed, to give 2.12 g of the target compound.1H-NMR(CDCl3) d=3.52(3H, s), 5.24 (2H, s), 6.76(1H, dt, J=1, 8Hz),7.07(1H, dd, J=1, 8Hz), 7.26-7.30(1H, m), 7.78(1H, dd, J=1, 8Hz) Production Example 21 2-Methyl-2-propenyltributyltin
    [0135] 1,2-dibromomethan 140 µl and 0.400 ml of 1-chloro-2-methyl-2-propenewas added to a mixture of 505 mg ofmagnesium and 2 ml of tetrahydrofuran, followed by heating.After initiating, the heating was stopped. The reactionsolution was diluted with 5 ml of tetrahydrofuran, followedby adding dropwise 8 ml of a tetrahydrofuran solution of 1.18ml of 1-chloro-2-methyl-2-propene thereinto. Afterstirring at room temperature for 30 minutes, tributyltinchloride was added to the reaction solution, followed by stirring at room temperature for 4 hours. An aqueousammonium chloride solution and ethyl acetate were addedthereto, and the organic phase was washed with an aqueoussaturated sodium bicarbonate and brine, dried over anhydrousmagnesium sulfate and the solvent was removed, to give 5.29g of the target compound.1H-NMR(CDCl3) δ=0.85-0.98(9H, m), 1.25-1.78(23H, m), 4.43-4.48(2H,m) Production Example 22 2-Iodo-1,3,4-thiadiazole
    [0136] A mixture of 19.2 g of 2-amino-1,3,4-thiadiazole, 35.0g of cuprous iodide, 74.0 ml of diiodomethane, 74.0 ml ofisopentyl nitrite and 500 ml of tetrahydrofuran was heatedunder reflux for 5 hours. After cooling as it was, 200 mlof ethyl acetate was added to the reaction solution. Afterfiltering off the insoluble matters, the filtrate wassubjected to silica gel column chromatography and elutedwith hexane/ethyl acetate (10:1) and then with hexane/ethylacetate (1:2). Then the eluate was crystallized from ethylacetate/methanol/hexane, to give 15.7 g of the targetcompound.1H-NMR(CDCl3) δ=9.13(1H, s) Production Example 23 (2-Pyrimidyl)tri-n-butyltin
    [0137] 3.2 ml of a hexane solution containing 1.57 mol ofn-butyllithium was slowly added dropwise into a solution of20 ml of tetrahydrofuran containing 707 µl ofdiisopropylamine under ice-cooling. After stirring at 0°Cfor 30 minutes, 1.4 ml of tri-n-butyltin hydride was slowly added dropwise thereinto. After stirring at 0°C for 30minutes, the mixture cooled to -78°C and a suspension of 30ml of tetrahydrofuran containing 2-chloropyrimidine wasslowly added drowise thereinto. After stirring at -78°C forone hour as it was and then at 0°C for 2 hours, water wasadded to the reaction solution. The mixture was extractedwith ethyl acetate, and the organic phase was washed withbrine and the solvent was removed. Then, the residue wassubjected to silica gel column chromatography and elutedwith hexane/ethyl acetate (10:1) and then with hexane/ethylacetate (7:1), to give 654 mg of the target compound.1H-NMR(CDCl3) δ=0.86-0.90(9H, m), 1.15-1.20(6H, m), 1.30-1.36(6H,m), 1.54-1.61(6H, m) , 7.12(1H, t, J=5Hz), 8.68(2H, d,J=5Hz) Production Example 24 (5-Pyrimidyl)tri-n-butyltin
    [0138] The title compound was synthesized in the same manneras in the synthesis of (2-pyrimidyl)tri-n-butyltin.1H-NMR(CDCl3) δ =0.87-0.91(9H, m), 1.12-1.16(6H, m), 1.30-1.38(6H,m), 1.50-1.59(6H, m), 8.67-8.71(2H, m), 9.12(1H, s) Production Example 25 (4-Pyrimidyl)tri-n-butyltin
    [0139] 5.8 ml of a hexane solution containing 2.52 mol of n-butyllithiumwas slowly added dropwise into a solution of 20ml of tetrahydrofuran containing 2.5 ml of 2,2,6,6-tetramethylpiperidine.After stirring at 0°C for 30 minutes,a mixture of 0.98 ml of pyrimidine, 4.6 ml of tri-n-butyltinchloride and 20 ml of tetrahydrofuran was slowly added dropwisethereinto. After stirring at -78°C for 4 hours, water was added to the reaction solution and then extracted with ethyl acetate.The organic phase was washed with brine and the solvent wasremoved. Then, the residue was subjected to silica gel columnchromatography to elute with hexane/ethyl acetate (10:1), togive 474 mg of the target compound.1H-NMR(CDCl3) δ=0.86-0.91(9H, m), 1.14-1.18(6H, m), 1.30-1.38(6H,m), 1.52-1.60(6H, m), 7.44(1H, dd, J=4.8Hz, 1.6Hz),8.47(1H, d, J=4.8Hz), 9.23(1H, d, J=1.6Hz) Production Example 26 (3-Pyridazyl)tri-n-butyltin
    [0140] 11.2 ml of a hexane solution containing 2.52 mol ofn-butyllithium was slowly added to a solution of 30 ml oftetrahydrofuran containing 4.8 ml of 2,2,6,6-tetramethylpiperidineat -30°C, followed by stirring at 0°Cfor 30 minutes. Thereafter, 7.3 ml of N,N,N',N'-tetramethylethylenediaminewas added and then a mixture of1.74 ml of pyridazine, 10.3 ml of tri-n-butyltin chlorideand 10 ml of tetrahydrofuran was slowly added to the mixtureat -78°C, followed by stirring at -78°C for 3 hours, Then,water was added to the reaction solution, and then extractedwith ethyl acetate. The organic phase was washed with brineand the solvent was removed. Then, the residue was subjectedto NH-silica gel (Fuji Silicia) column chromatography andeluted with hexane/ethyl acetate (10:1), and then subjectedto silica gel chromatography and eluted with hexane/ethylacetate (10:1) and then with hexane/ethyl acetate (1:1), togive 660 mg of the target compound.1H-NMR(CDCl3) δ=0.86-0.91(9H, m), 1.14-1.22(6H, m), 1.24-1.38(6H, m), 1.54-1.61(6H, m), 7.24-7.28(1H, m), 7.48-7.50(1H,m), 9.03-9.04(1H, m) Production Example 27 (4-Pyridazyl)tri-n-butyltin
    [0141] 58.0 ml of a hexane solution containing 2.52 mol of n-butyllithiumwas slowly added dropwise into a solution of 200ml of tetrahydrofuran containing 25.0 mol of 2,2,6,6-tetramethylpiperidineat -30°C. After stirring at 0°C for 30minutes, a mixture of 9.1 ml of pyridazine, 46.0 ml of tri-n-butyltinchloride and 100 ml of tetrahydrofuran was slowlyadded dropwise thereinto at -78°C. After stirring at -78°C for4 hours, water was added to the reaction solution and thenextracted with ethyl acetate. The organic phase was washed withbrine and the solvent was removed. Then, the residue wassubjected to NH-silica gel (Fuji Silicia) column chromatographyand eluted with hexane/ethyl acetate (10:1). Then, it wassubjected to silica gel chromatography and eluted withhexane/ethyl acetate (10:1) and then with hexane/ethyl acetate(1:1), to give 6.6 g of the target compound.1H-NMR(CDCl3) δ=0.87-0.91(9H, m), 1.13-1.18(6H, m),1.31-1.36(6H, m), 1.50-1.58(6H, m), 7.53(1H, d, J=5Hz),9.02(1H, d, J=5Hz), 9.17(1H, s) Production Example 28 (1,4-Dioxene-2-yl)tri-n-butyltin
    [0142] 5.8 ml of a pentane solution containing 1.51 mol oftert-biutyllithium was slowly added to 30 ml of atetrahydrofuran solution containing 1.0 g of 1,4-dioxene at- 40°C. After stirring at -40°C for one hour, 1.7 ml oftri-n-butyltin chloride was slowly added dropwise thereinto at -78°C. After stirring at -78°C for 3 hours, water wasadded to the reaction solution and then extracted with ethylacetate. The organic phase was washed with brine and thesolvent was removed. Then, the residue was filtered throughsilica gel and the solvent was removed, to give 1.5 g of thetarget compound.1H-NMR(CDCl3) δ=0.87-1.56(27H, m), 4.00-4.11(4H, m), 5.69(1H,s) Production Example 29 (3R)-3-Ethynyl-3-quinuclidinol a) (3R)-3-Ethynyl-3-quinuclidinol L-(+)-tartaric acid
    [0143] 15.1 g of 3-ethynyl-3-quinuclidinol and 15 g of L-(+)-tartaricacid were dissolved under heating in 300 ml ofmethanol. After cooling as it was, the resulting crystalswere collected by filtration and recrystallized frommethanol three times, to give 2.07 g of the title compound.1H-NMR(DMSO-d6) δppm=1.45-1.54(1H, m), 1.68-1.78(1H, m),1.83-2.03(3H, m), 2.83-3.01(5H, m), 3.21(1H, dd, J=2,14Hz),3.50(1H, s), 4.05(2H, s) b) (3R)-3-Ethynyl-3-quinuclidinol
    [0144] 15.6 g of (3R)-3-ethynyl-3-quinuclidinol L-(+)-tartratewas dissolved in 150 ml of water and 20 g of anhydrouspotassium carbonate was added little by little understirring. The resulting crystal were collected byfiltration, washed with water and then dried, to give 6.88g of the title compound.1H-NMR(DMSO-d6) δ ppm=1.20-1.30(1H, m), 1.47-1.55 (1H, m),1.70-1.90(3.H, m), 2.54-2.70(4H, m), 2.72(1H, dd, J=2,14Hz), 2.93(1H, d, J=14Hz), 3.29(1H, s), 5.47(1H, s)[α]24 589=+58.3 (c=1.02, MeOH)(literature; [α]20 589=+54.5 (c=0.99, MeOH); Tetrahedron :Asymmetry, 6 (6), 1393, 1995) Production Example 30 (3S)-3-Ethynyl-3-quinuclidinol
    [0145] The title compound was synthesized from 3-ethynyl-3-quinuclidinolin the same manner as in Production Example29 using D-(-)-tartaric acid was used as an opticalresolution agent.1H-NMR(DMSO-d6) δ=1.20-1.30(1H, m), 1.47-1.55(1H, m), 1.70-1.90(3.H,m), 2.54-2.70(4H, m), 2.72(1H, dd, J=2,14Hz), 2.93(1H,d, J=14Hz), 3.29(1H, s), 5.47(1H, s)[α]22.5 589 = -56.9 (c = 1.00, MeOH)(literature; [α]20 589=-56.1 (c=1.02, MeOH); Tetrahedron :Asymmetry, 6 (6), 1393, 1995) Examples Example 1 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)pyridine
    [0146] A mixture of 400 mg of 4-benzyl-5-bromo-2-pyridyltrifluoromethanesulfonate, 410 mg of (3,4-methylenedioxyphenyl)tributyltin,300 mg oftetrabutylammonium chloride, 20 mg oftetrakis(triphenylphsphine)palladium (0) and 2 ml of xylenewas stirred under heating for 3 hours in an oil bath keptat 140°C in a nitrogen atmosphere. The reaction solution was subjected to silica gel column chromatography using5-10% ethyl acetate/hexane, to give 140 mg of the titlecompound.1H-NMR (CDCl3) δ ppm=4.12(2H, s), 6.00(2H, s), 6.85(1H, d,J=8Hz), 7.23(2H, d, J=8Hz), 7.27(1H, t, J=7Hz), 7.32-7.41(5H,m), 8.68(1H,s) b) 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0147] A mixture of 140 mg of 4-benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)pyridine,70 mg of 3-ethynyl-3-quinucllidinol,10 mg oftetrakis(triphenylphosphine)palladium(0), 1 mg of cuprousiodide, 0.5 ml of triethylamine and 1 ml of N,N-dimethylformamidewas stirred under heating for 2hr in anoil bath kept at 100°C in a nitrogen atmosphere. Aftercooling as it was, aqueous dilute ammonia was added thereto,followed by extracting with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfateand the solvent was evaporated. The residue was subjectedto NH-silica gel column chromatography using 50% ethylacetate/hexane and then ethyl acetate, to give 40 mg of thetitle compound.1H-NMR (CDCl3) δppm=1.30-1.95(3H, m), 2.00-2.15 (2H, m),2.65-2.95(4H, m), 3.03(1H, d, J=14Hz), 3.23(1H, d, J=14Hz),4.15(2H, s), 6.01(2H, s), 6.87(1H, d, J=8Hz), 7.19(2H, d, J=8Hz),7.22-7.28(1H, m), 7.32(2H, t, J=7Hz), 7.40(1H, s), 7.42-7.46(2H,m), 8.65(1H, s) Example 2 3-[4-Benzyl-2-(2-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0148] The title compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ ppm=1.35-1.90(3H, m), 2.00-2.15(2H, m),2.70-2.95(4H,m), 3.03(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),4.21(2H, s), 7.20-7.32(6H,m), 7.81(1H, dt, J=2, 8Hz), 8.29(1H,s), 8.38(1H, d, J=8Hz), 8.64-8.67(1H,m), 8.68(1H, s) Example 3 3-[4-Benzyl-2-(3-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0149] The title compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ ppm=1.38-1.92(3H, m), 2.00-2.11(2H, m),2.70-3.00(4H, m), 3.06(1H, d, J=14Hz), 3.25(1H, dd, J=2, 14Hz),4.18(2H, s), 7.20(2H, d, J=7Hz), 7.22-7.29(1H, m), 7.32(2H, t,J=7Hz), 7.39(1H, dd, J=5, 7Hz), 7.49(1H, s), 8.22-8.27(1H, m),8.63(1H, dd, J=2, 5Hz), 8.74(1H, s), 9.13(1H, dd, J=1, 2Hz) Example 4 3-[4-Benzyl-2-pyrazyl-5-pyridyl]ethynyl-3-quinuclidinol
    [0150] The title compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ ppm=1.37-1.90(3H, m), 2.00-2.11(2H, m),2.70-2.96(4H, m), 3.05(1H, d, J=14Hz), 3.24(1H, dd, J=2, 14Hz),4.20(2H, s), 7.18-7.33(5H, m), 8.20(1H, s), 8.56-8.60(2H, m),8.73 (1H, s), 9.61(1H, d, J=2Hz) Example 5 3-[4-Benzyl-2-(4-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0151] The title compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ ppm=1.41-1.43(1H, m), 1.61-1.67(1H, m),1.84-1.87(1H, m), 2.04-2.06(2H, m), 2.77-2.85(4H, m), 3.05(1H,dd, J=2, 14Hz), 3.25(1H, dd, J=2, 14Hz), 4.20(2H, s), 7.19-7.35(5H,m) , 7.55(1H, s), 7.80-7.82(2H, m), 8.69-8.70(2H, m),8.74(1H, s) Example 6 3-[4-Benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethynyl-3-quinuclidinol a) 4-(a-Hydroxybenzyl)-2-(2-methoxyethoxy)pyridine
    [0152] 3 g of sodium was added to 50 ml of methoxy ethanol andthe mixture was stirred under heating in an oil bath keptat 100°C in a nitrogen atmosphere for lhr. After sodium wasdissolved, a mixture of 5.6 g of 4-benzoyl-2-chloropyridine(Production Example 1-a) and 10 ml of methoxy ethanol wasadded dropwise thereinto, followed by stirring under heatingin an oil bath kept at 100°C in a nitrogen atmosphere for3 hours. The reaction solution was evaporated and an aqueoussodium hydrogencarbonate solution was added thereto. Themixture was extracted with ethyl aceate, and the organiclayer was washed with brine and subjected to silica gelcolumn chromatography using 10-50% ethyl acetate/hexane, togive 5.9 g of the title compound.1H-NMR (CDCl3) δ ppm=2.55(1H, brs), 3.42(3H, s), 3.70-3.75(2H,m), 4.40-4.45(2H, m), 5.96(1H, brs), 7.18(1H, s), 7.24-7.40(6H,m), 8.12(1H,s) b) 4-Benzyl-5-bromo-2-(2-methoxyethoxy)pyridine
    [0153] 7.32 g of the title compound was obtained from 11.8 gof 4-(a-hydroxybenzyl)-2-(2-methoxyethoxy)pyridine in thesame manner as in Production Examples (1-d, e and f).1H-NMR (CDCl3) δ ppm=3.40(3H, s) , 3.66-3.70(2H, m), 3.98(2H, s),4.37-4.42(2H, m), 6.50(1H, s), 7.15-7.35(5H, m), 8.18(1H, s) (c) 3-[4-Benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethynyl-3-quinuclidinol
    [0154] 310 mg of the title compound was obtained from 1.38 gof 4-benzyl-5-bromo-2-(2-methoxyethoxy)pyridine in thesame manner as in Example 12.1H-NMR (CDCl3) δ ppm=1.35.1.90(3H, m), 1.98-2.08(2H, m),2.70-2.96(4H, m), 3.02(1H, d, J=14Hz), 3.24(1H, dd, J=2, 14Hz),3.42(3H, s), 3.69-3.73(2H, m), 4.04(2H, s), 4.42-4.46(2H, m),6.55(1H, s), 7.16(2H, d, J=7Hz), 7.23(1H, t, J=7Hz), 7.30(2H,t, J=7Hz), 8.18(1H, s) Example 7 3-[2-Benzyl-6-(4-ethoxycarbonylpiperidino)-3-pyridyl]ethynl-3-quinuclidinol a) 2-Benzyl-6-(4-ethoxycarbonylpiperidino)pyridine
    [0155] A mixture of 5 g of 2-benzyl-6-pyridyltrifluoromethanesulfonate, 3.6 ml of ethyl isonipecotinate,3.3 g of potassium carbonate and 15 ml of N-methylpyrrolidonewas heated under stirring in an oil bath kept at 100°C ina nitrogen atmosphere. After cooling as it was, the mixturewas extracted with ethyl acetate/water. The organic phasewas washed with water and brine, dried over anhydrousmagnesium sulfate and evaporated. The residue wassubjected to silica gel column chromatography and eluted with 1-5% ethyl acetate/hexane, to give 4.7 g of the targetcompound.1H-NMR(CDCl3) δ ppm=1.26(3H, t, J=7Hz), 1.70-1.82(2H, m),1.94-2.01(2H, m), 2.51(1H, tt, J=4, 11Hz), 2.88-2.97(2H, m),3.97(2H, s), 4.15(2H, q, J=7Hz), 4.22-4.29(2H, m), 6.38(1H, d,J=7Hz), 6.46(1H, d, J=9Hz), 7.16-7.22(1H, m), 7.26-7.31(4H, m),7.34(1H, dd, J=7, 9Hz) b) 2-Benzyl-3-iodo-6-(4- ethoxycarbonylpiperidino)pyridine
    [0156] Under stirring in an ice bathe, 1.25 g of N-iodosuccinimidewas added little by little to a mixture of1.2 g of 2-benzyl-6-(4-ethoxycarbonylpiperidino)pyridineand 10 ml of N,N-dimethylformamide, followed by stirring asit was overnight. Sodium sulfite was added thereto, and themixture was extracted with ethyl acetate-water. Theorganic phase was washed with water and brine, dried overanhydrous magnesium sulfate and evaporated. The residuewas subjected to silica gel column chromatography and elutedwith 1-5% ethyl acetate/hexane, to give 1.42 g of the targetcompound.1H-NMR (CDCl3) δ ppm=1.26(3H, t, J=7Hz), 1.64-1.76(2H, m),1.90-1.98(2H, m), 2.50(1H, tt, J=11Hz, 4Hz), 2.87-2.96(2H, m),4.10-4.20(6H, m), 6.27(1H, d, J=9Hz), 7.18(1H, t, J=7Hz),7.26(2H, t, J=7Hz), 7.32(2H, d, J=7Hz), 7.70(1H, d, J=9Hz) c) 3-[2-Benzyl-6-(4-ethoxycarbonylpiperidino)-3-pyridyl]ethynyl-3-quinuclidinol
    [0157] A mixture of 1.42 g of 2-benzyl-3-iodo-6-(4-ethoxycarbonylpiperidino)pyridine, 520 mg of 3-ethynyl-3-quinuclidinol,110 mg oftetrakis(triphenylphosphine)palladium(0), 3 mg of cuprousiodide, 1.3 ml of triethylamine and 6 ml of N,N-dimethylformamidewas heated under stirring in an oil bath keptat 80°C for 3 hours in a nitrogen atmosphere. After coolingas it was, the mixture was extracted with ethyl acetate-diluteaqueous ammonia. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and evaporated.The residue was subjected to NH-silica gel columnchromatography and eluted with 20-100% ethyl acetate/hexane andthen with 2.5% methanol/ethyl acetate, to give 700 mg of thetarget compound.1H-NMR (CDCl3) δ ppm=1.26(3H, t, J=7Hz), 1.34-1.45(1H, m),1.53-1.78(3H, m), 1.83-2.08(5H, m), 2.53(1H, tt, J=4, 11Hz),2.69-3.04(7H, m), 3.23(1H, dd, J=2, 14Hz), 4.10-4.18(4H, m),4.22-4.30(2H, m), 6.43(1H, d, J=9Hz), 7.16(1H, t, J=7Hz),7.25(2H, t, J=7Hz), 7.30(2H, d, J=7Hz), 7.43(1H, d, J=9Hz) Example 8 3-(2-Benzyl-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol
    [0158] The title compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ ppm=1.35-1.45(1H, m), 1.54-1.64(1H, m),1.83-1.93(1H, m), 1.98-2.08(2H, m), 2.68-2.94(4H, m), 3.02(1H,d, J=14Hz), 3,24(1H, dd, J=2, 14Hz), 3.52(4H, t, J=5Hz), 3.79(4H,t, J=5Hz), 4.16(2H, s), 6.40(1H, d, J=8Hz), 7.14-7.31(5H, m),7.47(1H, d, J=8Hz) Example 9 3-[2-Benzyl-6-(4-methoxypiperidino)-3-pyridyl)ethynyl-3-quinuclidinol
    [0159] The title compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ ppm=1.35-1.45(1H, m), 1.52-1.65(3H, m),1.83-1.96 (3H, m), 1.98-2.08(2H, m), 2.70-2.93(4H, m), 3.02(1H,d, J=14Hz), 3.19-3.27(3H, m), 3.38(3H, s), 3.39-3.46(1H, m),3.96-4.04(2H, m), 4.15(2H, s), 6.44(1H, d, J=9Hz), 7.16(1H, t,J=7Hz), 7.25(2H, t, J=7Hz), 7.30(2H, d, J=7Hz), 7.42(1H, d,J=9Hz) Example 10 (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl)ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine
    [0160] 11 ml of 1,8-diazabicyclo[5.4.0] -7- undecene was addeddropwise into a mixture of 11.3 g of 2-benzyl-6-pyridyltrifluoromethanesulfonate, 11.3 g of (3R,4R)-3,4-dihydroxypyrrolidineacetate (synthesized from D-tartaricacid as starting material, Angew. Chem. Int. Ed. Engl., 23(6), 435, 1984) and 10 ml of N-methylpyrrolidone in an oilbath kept at 100°C in a nitrogen atmosphere, followed bystirring for 6 hours. After cooling as it was, the mixturewas extracted with ethyl acetate-water. The organic phasewas washed with water and brine, dried over anhydrousmagnesium sulfate and evaporated. The residue wassubjected to silica gel column chromatography and eluted with ethyl acetate, to give 5.35 g of the target compound.1H-NMR (CDCl3) δ ppm=3.47(2H, dd, J=2,11Hz), 3.79(2H, dd,J=4,11Hz), 3.97(2H, s), 4.26-4.30(2H, m), 6.17(1H, d, J=8Hz),6.38(1H, d, J=8Hz), 7.19(1H, t, J=7Hz), 7.26-7.36(5H, m) b) 2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine
    [0161] 800 mg of oily (60%) sodium hydride was added little bylittle to a mixture of 5.35 g of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridineand 40 ml oftetrahydrofuran while stirring, followed by stirring as itwas for one hour. Then 1.24 ml of methyl iodide was addedthereto, followed by stirring as it was overnight. Themixture was extracted with ethyl acetate-water, and theorganic phase was washed with water and brine, dried overanhydrous magnesium sulfate and evaporated. The residuewas subjected to silica gel column chromatography and elutedwith 30% ethyl acetate/hexane, to give 2.18 g of the targetcompound.1H-NMR (CDCl3) δ ppm=3.42(3H, s), 3.47-3.55(2H, m), 3.69-3.78(2H,m), 3.85-3.89(1H, m), 3.97(2H, s), 4.38-4.42(1H, m),6.17(1H, d, J=8Hz), 6.35(1H, d, J=7Hz), 7.19(1H, t, J=7Hz),7.26-7.35(5H, m) c) 2-Benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine
    [0162] Under stirring in an ice bath, 2.5 g of N-iodosuccinimidewas added little by little to a mixture of 3.11 g of 2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine and 10 ml of N,N-dimethylformamide, followed bystirring as it was overnight. Sodium sulfite was addedthereto and the mixture was extracted with ethylacetate-water. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and evaporated.The residue was subjected to silica gel columnchromatography and eluted with 30% ethyl acetate/hexane, togive 4.19 g of the target compound.1H-NMR (CDCl3) δ ppm=3.41(3H, s), 3.42-3.51(2H, m), 3.64-3.71(2H,m), 3.84-3.87(1H, m), 4.19(2H, s), 4.38-4.42(1H, m),5.98(1H, d, J=8Hz), 7.18(1H, t, J=7Hz), 7.26(2H, t, J=7Hz),7.37(2H, d, J=7Hz), 7.69(1H, d, J=8Hz) d) (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl)ethynyl-3-quinuclidinol
    [0163] A mixture of 4.19 g of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine,1.7 g of (3R)-3-ethynyl-3-quinuclidinol,500 mg oftetrakis(triphenylphosphine)palladium (0), 10 mg of cuprousiodide, 4.2 ml of triethylamine and 13 ml of N,N-dimethylformamidewas heated under stirring in an oil bath keptat 70°C for 3 hours in a nitrogen atmosphere. After coolingas it was, the mixture was extracted with ethyl acetate-diluteaqueous ammonia. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and evaporated.The residue was subjected to NH-silica gel columnchromatography and eluted with 20-100% ethyl acetate/hexane and then with 5% methanol/ethyl acetate, to give 1.54 g of the targetcompound.1H-NMR (CDCl3) δ ppm=1.34-1.44(1H, m), 1.50-1.60(1H, m),1.80-1.90(1H, m), 1.97-2.08(2H, m), 2.60-2.90(4H, m), 2.97(1H,d, J=14Hz), 3.19(1H, dd, J=2, 14Hz), 3.40(3H, s), 3.41-3.54(2H,m), 3.62-3.73(2H, m), 3.82-3.85(1H, m), 4.13(2H, s), 4.34-4.37(1H,m), 6.09(1H, d, J=9Hz), 7.14(1H, t, J=7Hz), 7.23(2H,t, J=7Hz), 7.29(2H, d, J=7Hz), 7.39(1H, d, J=9Hz) Example 11 3-[2-Benzyl-6-(3-methoxypropylamino)-3-pyridyl)ethynyl-3-quinuclidinol
    [0164] The title compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ ppm=1.34-1.44(1H, m), 1.52-1.66(1H, m),1.81-1.91(3H, m), 1.97-2.07(2H, m), 2.67-2.93(4H, m), 3.01(1H,dd, J=2, 14Hz), 3.21(1H, dd, J=2,14Hz), 3.34(3H, s), 3.36(2H,q, J=6Hz), 3.48(2H, t, J=6Hz), 4.93(1H, t, J=6Hz), 6.20(1H, d,J=8Hz), 7.16(1H, t, J=7Hz), 7.22-7.31(4H, m), 7.42(1H, d,J=8Hz) Example 12 3-[2-Benzyl-6-(2-methoxyethyloxy)-3-pyridyl)ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-(2-methoxyethyloxy)pyridine
    [0165] A mixture of 5 g of 2-benzyl-3-bromo-6-hydroxypyridine,3.9 g of potassium carbonate anhydride, 2.7 ml of 2-bromoethylmethyl ether and 20 ml of N,N-dimethylformamidewas heated under stirring in an oil bath kept at 80°C forone hour. After cooling as it was, the mixture was extractedwith ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate andevaporated. The residue was subjected to silica gel columnchromatography and eluted with 1-3% ethyl acetate/hexane,to give 4.2 g of the target compound.1H-NMR(CDCl3) δ ppm=3.41(3H, s), 3.68(2H, t, J=5Hz), 4.19(2H,s), 4.41(2H, t, J=5Hz), 6.54(1H, d, J=9Hz), 7.20(1H, t, J=7Hz),7.27(2H, t, J=7Hz), 7.32(2H, d, J=7Hz), 7.63(1H, d, J=9Hz) b) 3-[2-Benzyl-6-(2-methoxyethyloxy)-3-pyridyl)ethynyl-3-quinuclidinol
    [0166] A mixture of 720 mg of 2-benzyl-3-bromo-6-(2-methoxyethyloxy)pyridine,340 mg of 3-ethynyl-3-quinuclidinol,130 mg of tetrakis(triphenylphosphine)palladium (0), 42 mg ofcuprous iodide, 0.93 ml of triethylamine and 3 ml of N,N-dimethylformamidewas heated under stirring in an oil bath keptat 80°C for 2 hours in a nitrogen atmosphere. After coolingas it was, the mixture was extracted with ethyl acetate-diluteaqueous ammonia. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and evaporated.The residue was subjected to NH-silica gel columnchromatography and eluted with 20-100% ethyl acetate/hexane andthen with 2.5% methanol/ethyl acetate, to give 500 mg of thetarget compound.1H-NMR(CDCl3) δppm=1.35-1.45(1H, m), 1.55-1.65(1H, m), 1.83-1.93(1H,m), 1.98-2.08(2H, m), 2.7-2.93(4H, m), 3.02(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.41(3H, s), 3.69(2H, t,J=5Hz), 4.19(2H, s), 4.45(2H, t, J=5Hz), 6.59(1H, d, J=8Hz),7.14-7.3(5H, m), 7.53(1H, d, J=8Hz) Example 13 3-[2-Benzyl-6-(3-methoxypropyloxy)-3-pyridyl]ethynyl-3-quinuclidinol
    [0167] The title compound was synthesized in the same manneras in Example 12.1H-NMR(CDCl3) δ ppm=1.38-1.48(1H, m), 1.58-1.69(1H, m),1.82-1.93(1H, m), 2.00(2H, quint, J=6.4Hz), 2.72-2.94(6H, m),3.03(1H, dd, J=1.2, 14Hz), 3.24(1H, dd, J=2.0, 14Hz), 3.34(3H,s), 3.51(2H, t, J=6.4Hz), 4.20(2H, s), 4.37(2H, t, J=6.4Hz),6.53(1H, d, J=8.4Hz), 7.18-7.31(5H, m), 7.54(1H, d, J=8.4Hz) Example 14 3-[2-Benzyl-6-(4-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-(4-pyridyl)pyridine
    [0168] A mixture of 298 mg of 2-benzyl-3-bromo-6-pyridyltrifluoromethanesulfonate, 277 mg of (4-pyridyl)tributyltin,87 mg oftetrakis(triphenylphosphine)palladium(0), 209 mg oftetrabutylammonium chloride and 5.0 ml of xylene was heatedunder stirring in an oil bath kept at 140°C for one hour ina nitrogen atmosphere. After cooling as it was, the solventwas removed, and the residue was subjected to NH-silica gelcolumn chromatography and eluted with hexane/ethyl acetate(5:1) and then with hexane/ethyl acetate (3:1), to give 196mg of the target compound.1H-NMR (CDCl3) δ ppm=4.42(2H, s), 7.23-7.39(5H, m), 7.54(1H, d,J=8Hz), 7.88-7.90(2H, m), 7.93(1H, d, J=8Hz), 8.71-8.72(2H, m) b) 3-[2-Benzyl-6-(4-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0169] A mixture of 196 mg of 2-benzyl-3-bromo-6-(4-pyridyl)pyridine,100 mg of 3-ethynyl-3-quinuclidinol, 70mg of tetrakis(triphenylphosphine)palladium(0), 11 mg ofcuprous iodide, 0.25 ml of triethylamine and 3.0 ml ofN,N-dimethylformamide was heated under stirring in an oilbath kept at 85°C for one hour in a nitrogen atmosphere.After cooling as it was, the mixture was extracted with ethylacetate-dilute aqueous ammonia. The organic phase waswashed with brine and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography andeluted with hexane/ethyl acetate (1:1) and then withmethanol/ethyl acetate (20:1). After removing the solvent,the residue was recrystallized from hexane/ethyl acetate,to give 178 mg of the target compound.1H-NMR (CDCl3) δ ppm=1.39-1.45(1H, m), 1.62-1.67(1H, m),1.83-1.88(1H, m), 2.02-2.75(2H, m), 2.78-2.89(4H, m), 3.03(1H,d, J=14Hz), 3.25(1H, dd, J=2, 14Hz), 4.41(2H, s), 7.19-7.33(5H,m), 7.63(1H, d, J=8Hz), 7.78(1H, d, J=8Hz), 7.90-7.92(2H, m),8.70-8.72(2H, m) Example 15 3-[2-Benzyl-6-(3-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0170] The title compound was synthesized in the same manneras in Example 14.1H-NMR(CDCl3) δ ppm=1.43-1.47(1H, m), 1.57-1.62(1H, m),1.80-1.94(1H, m), 2.05-2.07(2H, m), 2.77-2.90(4H, m), 3.05(1H,d, J=14Hz), 3.25(1H, d, J=14Hz), 4.40(2H, s), 7.18-7.34(5H, m),7.39-7.42(1H, m), 7.56(1H, d, J=8Hz), 7.75(1H, d, J=8Hz), 8.34-8.37(1H, m), 8.63(1H, dd, J=2, 5Hz), 9.21(1H, d, J=2Hz) Example 16 3-(2-Benzyl-6-pyrazyl-3-pyridyl)ethynyl-3-quinuclidinol
    [0171] The title compound was synthesized in the same manneras in Example 14.1H-NMR(DMSO-d6) δppm=1.27-1.36(1H, m), 1.52-1.60(1H, m),1.72-1.82(1H, m), 1.87-1.96(1H, m), 1.99-2.03(1H, m), 2.56-2.72(4H,m), 2.87(1H, d, J=14Hz), 3.07(1H, d, J=14Hz), 4.39(2H,s), 5.80(1H, s) , 7.18-7.41(5H, m), 7.99(1H, d, J=8Hz), 8.20(1H,d, J=8Hz), 8.72(1H, d, J=3Hz), 8.75(1H, m), 9.51(1H, s) Example 17 3-[2-Benzyl-6-(2-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0172] The title compound was synthesized in the same manneras in Example 14.1H-NMR(CDCl3) δppm=1.40-1.93(3H, m), 2.00-2.11(2H, m),2.70-2.95(4H, m), 3.02(1H, d, J=14Hz), 3.22(1H, dd, J=2, 14Hz),4.42(2H, s), 7.18-7.34 (6H, m) , 7.81(1H, d, J=8Hz), 7.81(1H, dt,J=2, 8Hz), 8.27(1H, d, J=8Hz), 8.46(1H, d, J=8Hz), 8.65-8.68(1H,m) Example 18 3-[4-Benzyl-2-(3-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-(3-pyridyl)pyrimidine
    [0173] A mixture of 440 mg of 4-benzyl-5-bromo-2-iodopyrimidine,430 mg of (3-pyridyl)tributyltin, 68 mg oftetrakis(triphenylphosphine)palladium(0) and 5 ml of xylenewas heated under reflux for one hour in a nitrogen atmosphere.After cooling as it was, silica gel was added to the reaction solution and the solvent was removed. The residue wassubjected to silica gel column chromatography using 30%ethyl acetate/hexane, to give 110 mg of the target compound.1H-NMR(CDCl3) δppm=4.33(2H, s), 7.21-7.42(6H, m), 8.66(1H, td,J=2, 8Hz), 8.71(1H, dd, J=2, 5Hz), 8.80(1H, s), 9.62(1H, d,J=2Hz) b) 3-[4-Benzyl-2-(3-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0174] A mixture of 110 mg of 4-benzyl-5-bromo-2-(3-pyridyl)pyrimidine,59 mg of 3-ethynyl-3-quinuclidinol, 19mg of tetrakis(triphenylphosphine)palladium(0), 10 mg ofcuprous iodide, 0.14 ml of triethylamine and 1.5 ml ofN,N-dimethylformamide was heated under stirring in an oilbath kept at 100°C for 2 hours in a nitrogen atmosphere.After cooling as it was, NH-silica gel was added to thereaction solution and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using2.5% methanol/ethyl acetate, to give 62 mg of the targetcompound.1H-NMR(CDCl3) δ ppm=1.42-1.92(3H, m), 2.05-2.12(2H, m),2.76-2.99(4H, m), 3.10(1H, d, J=14Hz), 3.28(1H, dd, J=2, 14Hz),4.32(2H, s), 7.21-7.35(5H, m), 7.40-7.43(1H, m), 8.68-8.70(2H,m), 8.74(1H, s), 9.65-9.66(1H, m) Example 19 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyrimidyl)ethynyl-3-quinuclidinol
    [0175] The title compound was synthesized in the same manneras in Example 18. 1H-NMR(CDCl3) δ ppm=1.40-1.70(2H, m), 1.84-1.92(1H, m),2.04-2.12(2H, m), 2.74-2.91(4H, m), 3.05(1H, d, J=14Hz),3.25(1H, dd, J=2, 14Hz), 4.29(2H, s), 6.04(2H, s), 6.91(1H, d,J=8Hz), 7.21-7.34(5H, m), 7.94(1H, d, J=2Hz), 8.08(1H, dd, J=2,8Hz), 8.66(1H, s) Example 20 3-(4-Benzyl-2-phenyl-5-pyrimidyl)ethynyl-3-quinuclidinol
    [0176] The title compound was synthesized in the same manneras in Example 18.1H-NMR(CDCl3) δppm=1.43-1.70(2H, m), 1.84-1.92(1H, m),2.02-2.11(2H, m), 2.75-2.92(4H, m), 3.06(1H, d, J=14Hz),3.26(1H, dd, J=2, 14Hz), 4.33(2H, s), 7.21-7.36(5H, m),7.48-7.50(3H, m), 8.45-8.48(2H, m), 8.73(1H, s) Example 21 3-[4-Benzyl-2-(2-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0177] The title compound was synthesized in the same manneras in Example 18.1H-NMR(CDCl3) δppm=1.40-1.48(1H, m), 1.61-1.88(2H, m),2.00-2.08(2H, m), 2.76-2.95(4H, m), 3.06(1H, d, J=14Hz),3.25(1H, dd, J=2, 14Hz), 4.40(2H, s), 7.21-7.33(5H, m),7.39-7.42(1H, m), 7.86(1H, td, J=2, 8Hz), 8.54(1H, d, J=8Hz),8.85-8.87(2H, m) Example 22 3-[3-Benzyl-5-(2-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol a) 3-(3-Benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol
    [0178] A mixture of 2.2 g of 3-benzyl-5-bromo-2-pyridyltrifluoromethanesulfonate, 840 mg of 3-ethynyl-3-quinuclidinol, 920 mg oftetrakis (triphenylphosphine)palladiuin(0), 170 mg ofcuprous iodide, 2.3 ml of triethylamine and 25 ml ofN,N-dimethylformamide was stirred at room temperature forone hour in a nitrogen atmosphere. NH-silica gel was addedto the reaction solution and the solvent was removed. Theresidue was subjected to NH-silica gel column chromatographyusing 3.5% methanol/ethyl acetate, to give 940 mg of thetarget compound.1H-NMR(CDCl3) δppm=1.35-1.44(1H, m), 1.56-1.65(1H, m),1.80-1.90(1H, m), 1.98-2.09(2H, m), 2.70-2.92(4H, m), 3.04(1H,d, J=14Hz), 3.25(1H, dd, J=2, 14Hz), 4.11(2H, s), 7.14-7.17(2H,m), 7.23-7.34(3H, m), 7.57(1H, d, J=2Hz), 8.50(1H, d, J=2Hz) b) 3-[3-Benzyl-5-(2-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0179] A mixture of 150 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol,150 mg of (2-pyridyl)tributyltin,86 mg oftetrakis(triphenylphosphine)palladium(0) and 3.5 ml oftoluene was heated under stirring in an oil bath kept at 110°Cfor 2 hours in a nitrogen atmosphere. After cooling as itwas, NH-silica gel was added to the reaction solution andthe solvent was removed. The residue was subjected toNH-silica gel column chromatography using 2.5%methanol/ethyl acetate, to give 100 mg of the targetcompound.1H-NMR(CDCl3) δppm=1.35-1.43(1H, m), 1.54-1.63(1H, m), 1.83-1.92(1H, m), 1.99-2.10(2H, m), 2.71-2.94(4H, m), 3.07(1H,d, J=14Hz), 3.26(1H, dd, J=2, 14Hz), 4.21(2H, s), 7.19-7.30(6H,m), 7.70(1H, d, J=8Hz), 7.76(1H, td, J=2, 8Hz), 8.16(1H, d,J=2Hz), 8.68-8.70(1H, m), 9.02(1H, d, J=2Hz) Example 23 3 3-(3-Benzyl-5-phenyl-2-pyridyl)ethynyl-3-quinuclidinol
    [0180] The title compound was synthesized in the same manneras in Example 22.1H-NMR(CDCl3) δppm=1.36-1.44(1H, m), 1.56-1.64(1H, m),1.86-1.95(1H, m), 1.98-2.11(2H, m), 2.71-2.95(4H, m), 3.08(1H,d, J=14Hz), 3.28(1H, dd, J=2, 14Hz), 4.21(2H, s), 7.19-7.53(10H,m), 7.64(1H, d, J=2Hz), 8.69(1H, d, J=2Hz) Example 24 3-[3-Benzyl-5-(3-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0181] The title compound was synthesized in the same manneras in Example 22.1H-NMR(CDCl3) δppm=1.37-1.45(1H, m), 1.56-1.64(1H, m),1.84-1.92(1H, m), 2.04-2.12(2H, m), 2.73-2.94(4H, m), 3.09(1H,d, J=14Hz), 3.28(1H, dd, J=2, 14Hz), 4.21(2H, s), 7.18-7.31(5H,m), 7.38(1H, ddd, J=1, 5, 8Hz), 7.61(1H, d, J=2Hz), 7.82(1H,td, J=2, 8Hz), 8.62(1H, dd, J=2, 5Hz), 8.64(1H, d, J=2Hz),8.87(1H, dd, J=1, 2Hz) Example 25 3-[3-Benzyl-5-(4-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0182] The title compound was synthesized in the same manneras in Example 22.1H-NMR(CDCl3) δ ppm=1.37-1.45(1H, m), 1.57-1.65(1H, m), 1.85-1.92(1H, m), 2.00-2.11(2H, m), 2.73-2.93 (4H, m), 3.08(1H,d, J=14Hz), 3.28(1H, dd, J=2, 14Hz), 4.22(2H, s), 7.18-7.34(5H,m), 7.42-7.44(2H, m), 7.67(1H, d, J=2Hz), 8.67-8.69(2H, m),8.70(1H, d, J=2Hz) Example 26 3-(3-Benzyl-5-pyrazyl-2-pyridyl)ethynyl-3-quinuclidinol
    [0183] The title compound was synthesized in the same manneras in Example 22.1H-NMR(CDCl3) δppm=1.36-1.44(1H, m), 1.56-1.64(1H, m),1.85-1.93(1H, m), 2.01-2.11(2H, m), 2.73-2.95(4H, m), 3.08(1H,d, J=14Hz), 3.27(1H, dd, J=2, 14Hz), 4.23(2H, s), 7.19-7.32(5H,m), 8.13(1H, d, J=2Hz), 8.54(1H, d, J=2Hz), 8.64(1H, dd, J=1,2Hz), 9.04(1H, d, J=1Hz), 9.08(1H, d, J=2Hz) Example 27 3-[3-Benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethynyl-3-quinuclidinol a) 3-Benzyl-5-formyl-2-methoxypryridine
    [0184] 4.6 ml of a hexane solution of 1.6 M normal butyllithiumwas added dropwise into a mixture of 1.0 g of 3-benzyl-5-bromo-2-methoxypyridine(Production Example 5-b) and 10ml of diethyl ether at -78°C. After stirring at the sametemperature for one hour, 0.56 ml of N,N-dimethylformamidewas added thereto, followed by heating gradually to roomtemperature. The reaction mixture was partitioned byadding water and ethyl acetate thereto. The organic phasewas washed with water and brine, dried over anhydrousmagnesium sulfate and the solvent was removed.1H-NMR(CDCl3) δ ppm=3.94(2H, s), 4.03(3H, s), 4.00(3H, s), 7.19-7.33(5H, m), 7.77-7.78(1H, m), 8.49(1H, d, J=4Hz), 9.90(1H,s) b) 3-Benzyl-5-(2-ethoxycarbonylethenyl)-2-methoxypyridine
    [0185] To 3-benzyl-5-formyl-2-methoxypryridine were added0.92 ml of triethylphosphono acetate, 11 ml of methanol and2.9 ml of a 21% sodium ethoxide ethanol solution, followedby stirring at room temperature for one hour. The mixturewas partitioned by adding water and ethyl acetate thereto,and the organic phase was washed with water and brine, driedover anhydrous magnesium sulfate and the solvent was removed.The residue was subjected to silica gel columnchromatography and eluted with 5% ethyl acetate/hexane, togive 950 mg of the target compound.1H-NMR(CDCl3) δppm=1.32(3H, t, J=7Hz), 3.92(2H, s), 4.00(3H,s), 4.23(2H, q, J=7Hz), 6.23(1H, d, J=16Hz), 7.19-7.34(5H, m),7.45(1H, d, J=2Hz), 7.57(1H, d, J=16Hz), 8.14(1H, d, J=2Hz) c) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine
    [0186] A mixture of 950 mg of 3-benzyl-5-(2-ethoxycarbonylethenyl)-2-methoxypyridine,90 mg of 10%palladium carbon and 10 ml of ethanol was stirred at roomtemperature for one hour in a hydrogen atmosphere. Afterthe atmosphere in the system was replaced by nitrogen, themixture was filtered through Celite. The solvent wasremoved, to give 950 mg of the target compound.1H-NMR(CDCl3) δppm=1.21(3H, t, J=7Hz), 2.52(2H, t, J=7Hz),2.80(2H, t, J=7Hz), 3.88(2H, s), 3.93(3H, s), 4.09(2H, q, J=7Hz), 7.12(1H, s), 7.18-7.30(5H, m), 7.86(1H, s) d) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-hydroxypyridine
    [0187] A mixture of 240 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-methoxypyridine,2.5 ml of 1,2-dichloroethaneand a solution of 1.0 M boron tribromide in0.39 ml of dichloromethane was stirred at 50°C for 8 hours.Water and silica gel were added to the reaction solution,and the solvent was removed. The residue was subjected tosilica gel column chromatography using 75% ethylacetate/hexane, to give 86 mg of the target compound.1H-NMR(CDCl3) δ ppm=1.21(3H, t, J=7Hz), 2.45(2H, t, J=7Hz),2.66(2H, br s), 3.89 (2H, br s), 4.08(2H, q, J=7Hz), 6.99-7.34 (7H,m) e) 3-Benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyltrifluoromethanesulfonate
    [0188] A mixture of 86 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-hydroxypyridine,130 mg of N-phenyltrifluoromethanesulfonimide,0.13 ml oftriethylamine, 3.7 mg of 4-dimethylaminopyridine and 1.5 mlof dichloromethane was stirred at room temperature for onehour. Silica gel was added to the reaction solution and thesolvent was removed. The residue was subjected to silicagel column chromatography using 15% ethyl acetate/hexane,to give 130 mg of the target compound.1H-NMR(CDCl3) δppm=1.21(3H, t, J=7Hz), 2.58(2H, t, J=7Hz),2.92(2H, t, J=7Hz), 4.00(2H, s), 4.09(2H, q, J=7Hz), 7.15-7.19(2H,m) , 7.24-7.36(3H, m), 7.42(1H, d, J=2Hz), 8.06(1H, d, J=2Hz) f) 3-[3-Benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0189] A mixture of 180 mg of 3-benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyltrifluoromethanesulfonate,66 mg of 3-ethynyl-3-quinuclidinol, 100 mg oftetrakis(triphenylphosphine)palladium(0), 17 mg of cuprousiodide, 0.18 ml of triethylamine and 2 ml of N,N-dimethylformamidewas heated under stirring at 70°C in anoil bath for one hour in a nitrogen atmosphere. Aftercooling as it was, NH-silica gel was added thereto and thesolvent was removed. The residue was subjected to NH-silicagel column chromatography using 2.5% methanol/ethyl acetate,to give 120 mg of the target compound.1H-NMR(CDCl3) δppm=1.20(3H, t, J=7Hz), 1.33-1.42(1H, m),1.53-1.61(1H, m), 1.82-1.91(1H, m), 1.98-2.08(2H, m), 2.57(2H,t, J=7Hz), 2.68-2.92(6H, m), 3.05(1H, d, J=14Hz), 3.23(1H, dd,J=2, 14Hz), 4.08(2H, q, J=7Hz), 7.12-7.16(2H, m), 7.19-7.31(4H,m), 8.31(1H, d, J=2Hz) Example 28 3-[3-Benzyl-5-(3-oxobutyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0190] The title compound was synthesized in the same manneras in Example 27.1H-NMR(CDCl3) δ ppm=1.36-1.47(1H, m), 1.55-1.63(1H, m) ,1.80-1.92(1H, m), 2.00-2.10(2H, m), 2.12(3H, s), 2.68-3.05(8H,m), 3.08(1H, dd, J=1.6, 14Hz), 3.25(1H, dd, J=2.0, 14Hz),4.11(2H, s), 7.12-7.16(2H, m), 4.20-7.32(4H, m), 8.30(1H, d, J=2.2Hz) Example 29 3-[3-Benzyl-5-(3-hydroxybutyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0191] A mixture of 314 mg of 3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethynyl-3-quinuclidinolhydrochloride, 129 mg ofpotassium carbonate, 35 mg of sodium borohydride and 10 mlof methanol was stirred at room temperature for one hour.A small amount of water was added thereto, and the mixturewas evaporated. The residue was subjected to NH-silica gelcolumn chromatography using chloroform and thenchloroform/methanol/aqueous concentrated ammonia(46:1:0.1), to give 340 mg of the target compound.1H-NMR(CDCl3) δ ppm=1.21(3H, d, J=6.0Hz), 1.33-1.41(1H, m),1.52-1.61(1H, m), 1.65-1.80(2H, m), 1.80-1.91(1H, m), 2.00-2.10(2H,m), 2.58-2.94(6H, m), 3.06(1H, dd, J=1.2, 14Hz),3.24(1H, dd, J=2.0, 14Hz), 3.72-3.81(1H, m), 4.11(2H, s),7.13-7.30(6H, m), 8.30(1H, d, J=2.2Hz) Example 30 3-[3-(2-Thienylmethyl)-2-pyridyl]ethynyl-3-quinuclidinol a) 2-Chloro-3-(2-thienylcarbonyl)pyridine
    [0192] 10 g of 2-chloronicotinic acid chloride was added to amixture of 7.2 g of aluminum chloride and 100 ml of carbondisulfide under ice-cooling, followed by adding 8.8 ml ofthiophene was slowly added dropwise thereinto. Afterstirring at room temperature for two nights, the reactionsolution was slowly poured into ice water. The mixture wasextracted with ethyl acetate, and the organic phase was successively washed with aqueous saturated sodiumbicarbonate and brine. After removing the solvent, theresidue was subjected to silica gel column chromatographyand eluted with hexane/ethyl acetate (3:1) and then withhexane/ethyl acetate (2:1), to give 1.64 g of the targetcompound.1H-NMR(CDCl3) δ=7.15-7.17(1H, m), 7.37-7.40(1H, m), 7.42-7.44(1H,m), 7.78-7.83(2H, m), 8.54-8.57(1H, m) b) 2-Methoxy-3-(2-thienylcarbonyl)pyridine
    [0193] A mixture of 1.64 g of 2-chloro-3-(2-thienylcarbonyl)pyridine,4.5 ml of a methanol solution of28% sodium methoxide and 2.0 ml of methanol was heated understirring for 30 minutes. After cooling as it was, water wasadded to the reaction solution and the mixture was extractedwith ethyl acetate. The organic phase was washed with brineand the solvent was removed, to give 1.46 g of the targetcompound.1H-NMR(CDCl3) δ=3.96(3H, s), 6.90-7.05(1H, m), 7.11-7.14(1H,m), 7.48-7.50(1H, m), 7.72-7.76(2H, m), 8.30-8.33(1H, m) c) 2-Methoxy-3-[2-thienyl(hydroxy)methyl]pyridine
    [0194] 303 mg of sodium borohydride was added little by littleto a solution containing 1.46 g of 2-methoxy-3-(2-thienylcarbonyl)pyridineand 10 ml of ethanol under ice-cooling.After stirring at room temperature for 2 hours,water was slowly added thereto and the mixture was extractedwith ethyl acetate. The organic phase was washed with brineand the solvent was removed, to give 1.47 g of the target compound.1H-NMR(CDCl3) δ=3.99(3H, s), 6.26(1H, d), 6.88-6.96(3H, m),7.25(1H, m), 7.64(1H, dd), 8.12(1H, dd) d) 2-Methoxy-3-[2-thienylmethyl]pyridine
    [0195] A mixture of 1.47 g of 2-methoxy-3-[2-thienyl(hydroxy)methyl]pyridine,3.2 g of zinc iodide, 3.4g of sodium cyanoborohydride and 30 ml of 1,2-dichloroethanewas stirred at room temperature for two nights. Insolublematters were filtered off, and to the filtrate was added anaqueous sodium hydroxide solution. The mixture wasextracted with ethyl acetate, and the organic phase waswashed with brine and the solvent was evaporated. Then, theresidue was subjected to silica gel column chromatographyand eluted with hexane and then with hexane/ethyl acetate(40:1), to give 734 mg of the target compound.1H-NMR(CDCl3) δ=3.99(3H, s), 4.10(2H, s), 6.79-6.84(2H, m),6.92-6.95(1H, m), 7.13-7.16(1H, m), 7.35-7.36(1H, m), 8.04(1H,dd) e) 3-(2-Thienylmethyl)-2-pyridyltrifluoromethanesulfonate
    [0196] 10 ml of 47% hydrobromic acid was added to 216 mg of2-methoxy-3-(2-thienylmethyl)pyridine, followed byheating under stirring for 4 hours in an oil bath kept at80°C. After cooling as it was, the reaction mixture wasneutralized by adding potassium carbonate thereto carefully.Water was added thereto, and the mixture was extracted withethyl acetate/tetrahydrofuran. The organic phase was washed with brine, dried over anhydrous magnesium sulfateand the solvent was removed, to give 140 mg of a crude product.A mixture of 140 mg of the crude product, 314 mg of N-phenyltrifluoromethanesulfonimide,153 µl of triethylamine,27 mg of 4-dimethylaminopyridine and 5.0 ml ofdichloromethane was stirred at room temperature for 3 hours.Water was added to the reaction solution and extracted withethyl acetate. The organic phase was washed with brine andthe solvent was removed. The residue was subjected toNH-silica gel (Fuji Silicia) column chromatography andeluted with hexane and then with hexane/ethyl acetate (40:1),to give 89 mg of the target compound.1H-NMR(CDCl3) δ=4.23(2H, s), 6.86-6.89(1H, m) , 6.96-6.99(1H,m), 7.21-7.24(1H, m), 7.29-7.33(1H, m), 7.66-7.69(1H, m),8.25(1H, dd) f) 3-[3-(2-Thienylmethyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0197] A mixture of 89 mg of 3-(2-thienylmethyl)-2-pyridyltrifluoromethanesulfonate, 50 mg of 3-ethynyl-3-quinuclidinol,64 mg oftetrakis(triphenylphosphine)palladium (0), 11 mg of cuprousiodide, 105 µl of triethylamine and 3.0 ml of N,N-dimethylformamidewas heated under stirring at 70°C for 1.5hours in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia, followed by extractingwith ethyl acetate. Then, the organic phase was washed withbrine and the solvent was removed, and the residue was subjected to NH-silica gel (Fuji silicia) columnchromatography and eluted with hexane/ethyl acetate (1:1)and then with ethyl acetate/methanol (15:1), to give 88 mgof the target compound.1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.56-1.68(1H, m),1.86-1.99(1H, m), 2.02-2.13(2H, m), 2.73-2.94(4H, m),3.05-3.10(1H, m), 3.29-3.33(1H, m), 4.32(2H, s), 6.76-6.79(1H,m), 6.92-6.95(1H, m), 7.15-7.23(2H, m), 7.55(1H,d), 8.46(1H, d) Example 31 3-[6-Pyrazyl-3-benzyl-2-pyridyl]ethynyl-3-quinuclidinol a) 6-Chloro-3-(α-hydroxybenzyl)-2-methoxypyridine
    [0198] 100 ml of a pentane solution containing 1.56 mol oftert-butyllithium was slowly added dropwise into a solutionof 200 ml of tetrahydrofuran containing 11.9 ml of 2-bromomesityleneat -78°C under cooling. After stirring atthe same temperature for one hour, 7.2 ml of 2-chloro-6-methoxypyridinewas slowly added dropwise thereinto. Afterstirring under ice-cooling for one hour and then at roomtemperature for one hour, 8.5 ml of benzaldehyde was addedthereto under ice-cooling, followed by stirring at roomtemperature for further one hour. Water was added to thereaction solution, followed by extracting with ethyl acetate.The organic phase was washed with brine and the solvent wasremoved. The residue was subjected to silica gel columnchromatography and eluted with hexane and then withhexane/ethyl acetate (7:1), to give 15.0 g of the target compound.1H-NMR(CDCl3) δ =3.95(3H, s), 5.96(1H, d, J=4Hz), 6.90-6.92(1H,m), 7.25-7.37(5H, m), 7.54-7.57(1H, m) b) 6-Chloro-3-benzoyl-2-methoxypyridine
    [0199] 36.0 g of manganese(IV) oxide was added to a solutionof 3.7 g of 6-chloro-3-(α-hydroxybenzyl)-2-methoxypyridinein 80 ml of tetrahydrofuran, followed by stirring at roomtemperature for 2 hours. Insoluble matters were filteredoff and then the solvent was evaporated, to give 3.6 g ofthe title compound.1H-NMR(CDCl3) δ=3.90(3H, s), 7.04(1H, dd, J=0.4Hz, 8Hz),7.44-7.48(2H, m), 7.56-7.62(1H, m), 7.70(1H, dd, J=0.4Hz, 8Hz),7.76-7.81(2H, m) c) (3-Benzoyl-2-methoxy-6-pyridyl)tributyltin
    [0200] A mixture of 3.6 g of 6-chloro-3-benzoyl-2-methoxypyridine,42.1 g of bis(tributyltin), 1.7 g oftetrakis(triphenylphosphine)palladium(0) and 20 ml oftoluene was heated under reflux for 2 hours. After coolingas it was, the solvent was removed, and the residue wassubjected to silica gel column chromatography and elutedwith hexane and then with hexane/ethyl acetate (2:1), to give5.1 g of the target compound.1H-NMR(CDCl3) δ=0.85-1.65(27H, m), 3.90(3H, s), 7.12-7.14(1H,m), 7.28-7.59(4H, m), 7.79-7.82(2H, m) d) 6-Pyrazyl-3-benzoyl-2-methoxypyridine
    [0201] A mixture of 5.1 g of (3-benzoyl-2-methoxy-6-pyridyl)tributyltin,5.4 ml of chloropyrazine, 1.8 g of tetrakis(triphenylphosphine)palladium(0) and 30 ml ofxylene was heated under reflux for 2 hours. After coolingas it was, the solvent was removed, and the residue wassubjected to silica gel column chromatography and elutedwith hexane and then with hexane/ethyl acetate (1:1), to give1.3 g of the target compound.1H-NMR(CDCl3) δ =4.02(3H, s), 7.45-7.50(2H, m), 7.59-7.63(1H,m), 7.83-7.91(3H, m), 8.10-8.13(1H, m), 8.63-8.66(2H, m),9.66(1H, d, J=1.4Hz) e) 6-Pyrazyl-3-benzyl-2-methoxypyridine
    [0202] A mixture of 806 mg of 6-pyrazyl-3-benzoyl-2-methoxypyridine,177 µl of hydrazine, 421 mg of potassiumcarbonate and 35 ml of diethylene glycol was heated understirring at 100°C for one hour and then at 170°C for 3 hours.After cooling as it was, water was added to the reactionsolution, followed by extracting with ethyl acetate. Theorganic phase was washed with brine and the solvent wasremoved, and the residue was subjected to silica gel columnchromatography and eluted with hexane/ethyl acetate (5:1)and then with hexane/ethyl acetate (4:1), to give 234 mg ofthe target compound.1H-NMR(CDCl3) δ=3.98(2H, s), 4.08(3H, s), 7.21-7.33(5H, m),7.44(1H, d, J=8Hz), 7.89(1H, d, J=8Hz), 8.53-8.57(2H, m),9.60(1H, d, J=1.5Hz) f) 6-Pyrazyl-3-benzyl-2-hydroxypyridine
    [0203] 5.0 ml of 47% hydrobromic acid was added to 234 mg of6-pyrazyl-3-benzyl-2-methoxypyridine, followed by heating under stirring for one hour in an oil bath kept at 80°C.After cooling as it was, the reaction solution was slowlyadded to an aqueous potassium carbonate solution. Theresulting crystals were collected by filtration and dried,to give 222 mg of the target compound.1H-NMR(CDCl3) δ=3.95(2H, s), 6.83(1H, d, J=7Hz), 7.12-7.15(1H,m), 7.21-7.36(5H, m), 8.59-8.61(2H, m), 9.07(1H, d, J=1.3Hz) g) 6-Pyrazyl-3-benzyl-2-pyridyl trifluoromethanesulfonate
    [0204] 222 mg of 6-pyrazyl-3-benzyl-2-hydroxypyridine, 365 mgof N-phenyltrifluoromethanesulfonimide, 178 µl oftriethylamine, 31 mg of 4-dimethylaminopyridine, 10 ml ofdichloromethane and 3.0 ml of N,N-dimethylformamide wereadded, followed by stirring at room temperature for 3 hours.Water was added to the reaction solution, followed byextracting with ethyl acetate. The extract was washed withbrine and the solvent was removed. The residue was subjectedto silica gel column chromatography and eluted with hexaneand then with hexane/ethyl acetate (4:1), to give 336 mg ofthe target compound.1H-NMR(CDCl3) δ=4.11(2H, s), 7.22-7.42(5H, m), 7.75(1H, d,J=8Hz), 8.36(1H, d, J=8Hz), 8.59-8.63(2H, m), 9.50(1H, d,J=1.3Hz) h) 3-[6-Pyrazyl-3-benzyl-2-pyridyl]ethynyl-3-quinuclidinol
    [0205] A mixture of 336 mg of 6-pyrazyl-3-benzyl-2-pyridyltrifluoromethanesulfonate, 161 mg of 3-ethynyl-3-quinuclidinol,205 mg of tetrakis(triphenylphosphine)palladium (0), 34 mg of cuprousiodide, 370 µl of triethylamine and 5.0 ml of N,N-dimethylformamidewas heated under stirring at 80°C for 3hours in a nitrogen atmosphere. After cooling as it was,the solvent was removed, and the residue was subjected toNH-silica gel (Fuji silicia) column chromatography andeluted with ethyl acetate/methanol (20:1), to give 204 mgof the target compound.1H-NMR(CDCl3) δ=1.39-1.79(2H, m), 1.89-1.96(1H, m), 2.06-2.14(2H,m), 2.75-2.94(4H, m), 3.07(1H, d, J=14Hz), 3.29(1H,d, J=14Hz), 4.23(2H, s), 7.18-7.34(5H, m), 7.62(1H, d, J=8Hz),8.25(1H, d, J=8Hz), 8.59(2H, s), 9.64(1H, s) Example 32 3-[3-Benzyl-5-(3-thienyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0206] A mixture of 127 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol(Example 22-a), 61.4 mg of3-thiopheneboronic acid, 55.4 mg oftetrakis(triphenylphosphine)palladium (0), 2 ml of toluene,0.5 ml of methanol and 1 ml of aqueous 2 mol sodium carbonatesolution was stirred at 80°C for 2 hours in a nitrogenatmosphere. NH-silica gel was added to the reactionsolution and the solvent was removed. The residue wassubjected to NH-silica gel column chromatography using 3%methanol/ethyl acetate, to give 83.9 mg of the targetcompound.1H-NMR(CDCl3) δ=1.35-1.42(1H, m), 1.54-1.62(1H, m), 1.84-1.92(1H,m), 2.00-2.10(2H, m), 2.68-2.83(3H, m), 2.87-2.94(1H, m), 3.09(1H, d, J=14Hz), 3.26(1H, dd, J=2, 14Hz), 4.18(2H, s),7.17-7.33(6H, m), 7.39-7.42(1H, m), 7.47-7.49(1H, m), 7.61(1H,s), 8.70(1H, d, J=2Hz) Example 33 3-[6-(Methylamino)-3-benzyl-5-pyrazyl-2-pyridyl]ethynyl-3-quinuclidinol a) 6-(Acetoxymethyl)-3-benzoyl-2-methoxypyridine
    [0207] A mixture of 5 g of 6-methyl-3-benzoyl-2-methoxypyridinesynthesized in the same manner as inProduction Example-1b, 4.3 g of N-bromosuccinimide and 100ml of benzene was irradiated with light of 200 W tungstenlamp for 30 minutes and refluxed. After cooling, insolublematters were filtered off, and the filtrate was concentrated.To the residue were added 30 ml of acetic acid and 5 g ofsodium acetate, followed by heating in an oil bath kept at100°C overnight. After concentrating the reaction solution,it was extracted with ethyl acetate-aqueous saturated sodiumbicarbonate. The organic phase was washed with brine, driedover anhydrous magnesium sulfate and evaporated. Theresidue was subjected to silica gel column chromatographyusing 5-10% ethyl acetate/hexane, to give 3.69 g of thetarget compound.1H-NMR(CDCl3) δ=2.21(3H, s), 3.87(3H, s), 5.20(2H, s), 7.02(1H,d, J=8Hz), 7.45(2H, t, J=8Hz), 7.58(1H, t, J=8Hz), 7.73(1H, d,J=8Hz), 7.79(2H, d, J=8Hz) b) 6-(Acetoxymethyl)-3-benzyl-2-methoxy-5-pyrazylpyridine
    [0208] A mixture of 3.93 g of 6-(acetoxymethyl)-3-benzoyl-2-methoxypyridine, 8.81 ml of triethylsilane and 30 ml oftrifluoroacetic acid was stirred at 60°C for one hour. Aftercooling as it was, the mixture was neutralized by adding anaqueous potassium carbonate thereto. Ethyl acetate was addedthereto, and the organic phase was washed with water and brine,dried over anhydrous magnesium sulfate and the solvent wasremoved. After adding 20 ml of methanol and 3.48 g of sodiumbicarbonate to the residue, 1.07 ml of bromine was added theretounder ice-cooling, followed by stirring at room temperature for30 minutes. An aqueous sodium thiosulfate solution and ethylacetate were added to the reaction solution. The organic phasewas washed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. To the residue were added3.10 g of pyrazyltrubutyltin, 1.46 g oftetrakis(triphenylphosphine)palladium(0) and 40 ml of xylene,followed by heating under reflux for 2.5 hours. Silica gel wasadded to the reaction solution and the solvent was removed. Theresidue was subjected to silica gel column chromatography using30% ethyl acetate/hexane, to give 2.18 g of the target compound.1H-NMR(CDCl3) δ=2.02(3H, s), 3.96(2H, s), 4.01(3H, s), 5.29(2H,s), 7.21-7.33(5H, m), 7.46(1H, s), 8.50(1H, d, J=2Hz),8.59-8.60(1H, m), 8.66(1H, d, J=1Hz) c) 3-Benzyl-6-(tert-butoxycarbonylamino)-2-methoxy-5-pyrazylpyridine
    [0209] 6.24 ml of an aqueous 1N sodium hydroxide solution was addedto a mixture of 2.18 g of 6-(acetoxymethyl)-3-benzyl-2-methoxy-5-pyrazylpyridineand 20 ml of methanol at ambient temperature, followed by stirring at the same temperature.Water and ethyl acetate were added to the reaction solution,and the organic phase was washed with water and brine, driedover anhydrous magnesium sulfate and the solvent was removed.14.1 ml of a Jone's reagent was added to a solution of the residuein 20 ml of acetone, followed by stirring at room temperatureovernight. 6 ml of 2-propanol was added to the reaction mixture,followed by extracting with ethyl acetate. The organic phasewas washed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. A mixture of the residue,25 ml of tert-butanol, 733 µl of triethylamine and 1.13 g ofdiphenyl phosphorylazide was stirred at room temperature for3 hours. After evaporating the solvent, the residue wassubjected to silica gel column chromatography using 25% ethylacetate/hexane, to give 212 mg of the target compound.1H-NMR(CDCl3) δ=1.51(9H, s), 3.93(2H, s), 4.08(3H, s),7.19-7.31(5H, m), 7.65(1H, s), 8.42(1H, d, J=2Hz), 8.52-8.54(1H,m), 8.80(1H, d, J=1Hz) d) 3-[6-(Methylamino)-3-benzyl-5-pyrazyl-2-pyridyl]ethynyl-3-quinuclidinol
    [0210] 11.8 mg of 60% oily sodium hydride was added to a mixtureof 77.2 mg of 3-benzyl-6-(tert-butoxycarbonylamino)-2-methoxy-5-pyrazylpyridineand 1 ml of N,N-dimethylformamideunder ice-cooling. After stirring at the same temperature for5 minutes, 14.7 µl of methyl iodide was added thereto. Afterstirring at room temperature for 2 hours, water and ethylacetate were added thereto. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and thesolvent was removed. A mixture of the residue and 2 ml of 48%hydrobromic acid was stirred at 80°C for 2 hours. After coolingas it was, it was neutralized using an aqueous potassiumcarbonate solution. The resulting crystals were collected byfiltration and vacuum-dried. Then, 3 ml of N,N-dimethylformamide,40.4 mg of N-phenyltrifluoromethanesulfonimide,47.2 µl of triethylamineand 1.4 mg of 4-dimethylaminopyridine were added thereto,followed by stirring at room temperature for 13 hours. Thereaction solution was filtered through silica gel, and thesolvent was evaporated. A mixture of the residue, 12.1 mg of3-ethynyl-3-quinuclidinol, 16.9 mg oftetrakis(triphenylphosphine)palladium(0), 2.8 mg of cuprousiodide, 30.5 µl of triethylamine and 1ml of N,N-dimethylformamidewas stirred at 70°C for one hour in a nitrogenatmosphere. To the reaction mixture was added NH-silica gel,followed by removing the solvent. The residue was subjectedto NH-silica gel column chromatography using 3% methanol/ethylacetate, to give 15.9 mg of the target compound.1H-NMR(CDCl3) δ=1.34-1.42(1H, m), 1.52-1.60(1H, m), 1.83-1.92(1H,m), 1.98-2.07(2H, m), 2.70-2.82(4H, m), 3.02(1H, d,J=14Hz), 3.11(3H, d, J=5Hz), 3.25(1H, dd, J=2, 14Hz), 4.09(2H,s), 7.18-7.22(3H, m), 7.26-7.31(2H, m), 7.68(1H, s), 8.44(1H,d, J=2Hz), 8.50-8.51(1H, m), 8.53-8.55(1H, m), 8.92(1H, d,J=1Hz) Example 34 3-[3-Benzyl-5-(1-hydroxycyclopentyl)ethynyl 2-pyridyl]ethynyl-3-quinuclidinol
    [0211] 100 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol(Example 22-a), 55 mg of 1-ethynylcyclopentanol,50 mg oftetrakis(triphenylphosphine)palladium(0), 10 mg of cuprousiodide and 1 ml of triethylamine were mixed in 5 ml ofN,N-dimethylformamide, followed by stirring in an oil bathkept at 80°C for one hour. An aqueous sodium carbonatesolution was added thereto, followed by extracting withethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and evaporated. The residuewas subjected to NH-silica gel column chromatography andeluted with 10% methanol/ethyl acetate, to give 93 mg of thetarget compound.1H-NMR (CDCl3) δ=1.33-1.43(1H, m), 1.52-1.62(1H, m), 1.70-1.92(5H,m), 1.95-2.10(6H, m), 2.69-2.94(4H, m), 3.07(1H, d,J=14Hz), 3.26(1H, dd, J=2,14Hz), 4.03(2H, s), 7.12(2H, d,J=7Hz), 7.22(1H, t, J=7Hz), 7.29(2H, t, J=7Hz), 7.43(1H, d,J=2Hz), 8.50(1H, d, J=2Hz) Example 35 3-[3-Benzyl-5-(N-phenylcarbamoyl)-2-pyridyl]ethynyl-3-quinuclidinol a) 3-Benzyl-2-methoxypyridine-5-carboxylic acid
    [0212] 11.1 g of 3-benzyl-5-bromo-2-methoxypyridine (ProductionExample 5-b) was dissolved in 70 ml of diethyl ether. 30 mlof a hexane solution containing 1.6 mol of n-butyllithium wasadded dropwise thereinto in a dry ice-acetone bath. After onehour, carbon dioxide was blown into the reaction solution, followed by adding water. After washing the aqueous phase withdiethyl ether, 50 ml of 1N hydrochloric acid was added thereto,followed by extracting with ethyl acetate. The extract waswashed with brine, dried over anhydrous magnesium sulfateanhydride and evaporated. The residue was crystallized fromhexane-ethyl acetate, to give 7.76 g of the target compound.1H-NMR (CDCl3) δ=3.93(2H, s), 4.04(3H, s), 7.18-7.33(5H, m) ,7.92(1H, d, J=2Hz), 8.77(1H, d, J=2Hz) b) 3-Benzyl-5-(N-phenylcarbamoyl)-2-methoxypyridine
    [0213] 200 mg of 3-benzyl-2-methoxypyridine-5-carboxylic acidand 0.25 ml of pyridine were dissolved in 5 ml ofdichloromethane. Under ice-cooling, 0.073 ml of thionylchloride was added dropwise thereinto. After stirring for30 minutes, 0.1 ml of aniline was added thereto. Thetemperature was raised to room temperature and the mixturewas stirred for 30 minutes. After adding water, the mixturewas extracted with ethyl acetate. The extract was washedwith 1N hydrochloric acid and brine, dried over anhydrousmagnesium sulfate and evaporated, to give 275 mg of thetarget compound.1H-NMR (CDCl3) δ=3.97(2H, s), 4.04(3H, s), 7.15(1H, t, J=7Hz),7.20-7.40(7H, m), 7.58(2H, d, J=7Hz), 7.81(1H, d, J=2Hz),8.55(1H, d, J=2Hz) c) 3-Benzyl-5-(N-phenylcarbamoyl)-2-pyridyltrifluoromethanesulfonate
    [0214] 275 mg of 3-benzyl-5-(N-phenylcarbamoyl)-2-methoxypyridinewas dissolved in 5 ml of 1,2-dichloroethane. 0.5 ml of dichloromethane solution containing 1 mol of borontribromide was added thereto, follwed by stirring at 50°Cfor 3 hours. Aqueous ammonium chloride was added theretoand the mixture was extracted with ethyl acetate. Theextract was washed with brine and then evaporated. To theresidue were added 360 mg of N-phenyltrifluoromethanesulfonimide,10 mg of 4-dimethylaminopyridine,0.4 ml of triethylamine and 5 ml ofdichloromethane, followed by stirring at room temperatureovernight. The reaction solution was subjected to silicagel column chromatography and eluted with 30% ethylacetate/hexane, to give 150 mg of the target compound.1H-NMR (CDCl3) δ=4.09(2H, s), 7.17-7.42(8H, m), 7.57(2H, d,J=8Hz), 7.69(1H, brs), 8.10(1H, d, J=2Hz), 8.65(1H, d, J=2Hz) d) 3-[3-Benzyl-5-(N-phenylcarbamoyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0215] 150 mg of 3-benzyl-5-(N-phenylcarbamoyl)-2-pyridyltrifluoromethanesulfonate, 60 mg of 3-ethynyl-3-quinuclidinol,50 mg oftetrakis(triphenylphosphine)palladium(0), 10 mg of cuprousiodide and 0.15 ml of triethylamine were added to 2 ml ofN,N-dimethylformamide, followed by stirring for 3 hours inan oil bath kept at 50°C. After cooling as it was, aqueousammonia was added thereto and the mixture was extracted withethyl acetate. The extract was washed with brine, dried overanhydrous magnesium sulfate and evaporated. The residuewas subjected to NH-silica gel column chromatography, to synthesize 90 mg of the target compound.1H-NMR (CDCl3) δ=1.35-1.92 (3H, m), 1.98-2.10(2H, m), 2.70-2.95(4H,m), 3.07(1H, d, J=14Hz), 3.27(1H, dd, J=2,14Hz),4.20(2H, s), 7.14-7.19(3H, m), 7.24 (1H, t, J=7Hz), 7.31(2H, t,J=7Hz), 7.36(2H, t, J=8Hz), 7.58(2H, d, J=8Hz), 7.98(1H, d,J=2Hz), 8.00(1H, brs), 8.87(1H, d, J=2Hz) Example 36 3-[3-Benzyl-5-[N-(4-fluorophenyl)carbamoyl]-2-pyridyl)ethynyl-3-quinuclidinol
    [0216] The title compound was synthesized in the same manneras in Example 35.1H-MMR (CDCl3) δ=1.34-1.44(1H, m), 1.54-1.64(1H, m), 1.78-1.89(1H,m), 1.99-2.09(2H, m), 2.66-2.95(4H, m), 3.08(1H, d,J=14Hz), 3.25(1H, dd, J=2,14Hz), 4.15(2H, s), 7.00(2H, t,J=8Hz), 7.13(2H, d, J=7Hz), 7.22(1H, t, J=7Hz), 7.28(2H, t,J=7Hz), 7.48-7.56(2H, m), 7.93(1H, d, J=2Hz), 8.48(1H, brs),8.80(1H, d, J=2Hz) Example 37 3-[3-Benzyl-5-(N-cyclohexylcarbamoyl)-2-pyridy]ethnyl-3-quinuclidinol
    [0217] The target compound was synthesized in the same manneras in Example 35.1H-NMR (CDCl3) δ=1.24-1.90(11H, m), 1.97-2.10(4H, m), 2.65-2.95(4H,m), 3.06(1H, dd, J=2,14Hz), 3.24(1H, dd, J=2,14Hz),3.88-4.00(1H, m), 4.16(2H, s), 6.10(1H, d, J=8Hz), 7.14(2H, d,J=7Hz), 7.22(1H, t, J=7Hz), 7.28(2H, t, J=7Hz), 7.89(1H, d,J=2Hz), 8.72(1H, d, J=2Hz) Example 38 3-[3-Benzyl-5-(1-pyrrolidinylcarbamoyl)-2-pyridyl]ethynyl-3-quinuclidinol
    [0218] The target compound was synthesized in the same manneras in Example 35.1H-NMR (CDCl3) δ=1.35-1.65 (2H, m), 1.83-2.10(7H, m), 2.70-2.95(4H,m), 3.04(1H, d, J=14Hz), 3.27(1H, dd, J=2,14Hz),3.38(2H, t, J=7Hz), 3.62(2H, t, J=7Hz), 4.18(2H, s), 7.17(2H,d, J=7Hz), 7.24(1H, t, J=7Hz), 7.31(2H, t, J=7Hz), 7.63(1H, d,J=2Hz), 8.62(1H, d, J=2Hz) Example 39 3-[3-Benzyl-5-methoxycarbonyl-2-pyridyl)ethynyl-3-quinuclidinol a) 3-Benzyl-2-methoxy-5-methoxycarbonylpyridine
    [0219] A mixture of 2.1 g of 3-benzyl-2-methoxypyridine-5-carboxylicacid and 2.9 g of potassium carbonate wassuspended in 40 ml of N,N-dimethylformamide. 1.1 ml ofmethyl iodide was added thereto at room temperature understirring. After stirring for 40 minutes, water was addedthereto and extracted with ethyl acetate. The organic phasewas further washed with brine, dried over anhydrous sodiumsulfate and the solvent was evaporated. The residue wassubjected to silica gel column chromatography using 11-14%ethyl acetate/hexane as an eluent for separation andpurification, to give 2.2 g of the target compound.1H-NMR(CDCl3) δ=3.87(3H, s), 3.92(2H, s), 4.02(3H, s),7.18-7.32(5H, m), 7.90(1H, dd, J=2.3Hz, 0.7Hz), 8.70(1H, d,J=2.3Hz) b) 3-Benzyl-2-hydroxy-5-methoxycarbonylpyridine
    [0220] 2.2 g of 3-benzyl-2-methoxy-5-methoxycarbonylpyridinewas dissolved in 40 ml of 1,2-dichloroethane. 8.5 ml of a dichloromethane solution containing 1.0 mol of borontribromide was added thereto in a nitrogen atmosphere,followed by heating under stirring at 50°C in an oil bathovernight. After cooling as it was, water was added theretoand the solvent was removed at a low temperature. Theresidue was subjected to silica gel column chromatographyusing 50-60% ethyl acetate/hexane as an eluent forseparation and purification to give 1.2 g of the targetcompound.1H-NMR(CDCl3) δ=3.83(3H, s), 3.87(2H, s), 7.20-7.34(5H, m),7.73(1H, d, J=2.4Hz), 8.11(1H, d, J=2.4Hz) c) 3-Benzyl-5-methoxycarbonyl-2-pyridyltrifluoromethanesulfonate
    [0221] 1.2 g of 3-benzyl-2-hydroxy-5-methoxycarbonylpyridinewas dissolved in 40 ml of 1,2-dichloroethane. 2.3 g ofN-phenyltrifluoromethanesulfonimide, 202 mg of 4-dimethylaminopyridineand 0.9 ml of triethylamine were addedthereto, followed by stirring at room temperature for 3 hours.Then, the solvent was removed, and the residue was subjectedto silica gel column chromatography using 11% ethylacetate/hexane as an eluent for separation and purification,to give 2.0 g of the target compound.1H-NMR(CDCl3) δ=3.93(3H, s), 4.05(2H, s), 7.16-7.43(5H, m),8.20(1H, d, J=2.3Hz), 8.82(1H, d, J=2.3Hz) d) 3-[3-Benzyl-5-methoxycarbonyl-2-pyridyl)]ethynyl-3-quinuclidinol
    [0222] 50 ml of N,N-dimethylformamide was added to a mixture of 2.0 g of 3-benzyl-5-methoxycarbonyl-2-pyridyltrifluoromethanesulfonate, 742 mg of 3-ethynyl-3-quinuclidinol,1.5 g oftetrakis(triphenylphosphine)palladium(0), 374 mg of cuprousiodide and 2.7 ml of triethylamine, followed by heating understirring for one hour in an oil bath kept at 60°C in a nitrogenatmosphere. After cooling as it was, ethyl acetate and aqueousammonia were added thereto and the mixture was extracted withethyl acetate. The organic phase was further washed with brine,dried over anhydrous magnesium sulfate and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using chloroform/methanol/aqueous 36% ammonia(46:3:0.3) as an eluent for separation and purification, to give1.1 g of the target compound.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.58-1.68(1H, m), 1.82-1.92(1H,m), 2.00-2.14(2H, m), 2.70-2.98(4H, m), 3.09(1H, dd,J=14Hz, 1.8Hz), 3.27(1H, dd, J=14Hz, 2.0Hz), 3.92(3H, s),4.19(2H, s) , 7.12-7.74(5H, m), 8.09(1H, d, J=2.0Hz), 9.04(1H,d, J=2.0Hz) Example 40 3-[3-Benzyl-5-(N-methylbenzoylamino)-2-pyridyl]ethynyl-3-quinuclidinol a) 3-Benzyl-5-tert-butoxycarbonylamino-2-methoxypyridine
    [0223] 7.34 g of 3-benzyl-2-methoxypyridine-5-carboxylic acid(Example 35-a), 6.5 ml of diphenylphosphorylazide and 4.2ml of triethylamine were mixed in 100 ml of tert-butanol,followed by heating under reflux overnight. Afterevaporating the reaction solution, it was partitioned by adding water and ethyl acetate thereto, washed with brine,dried over anhydrous magnesium sulfate and then evaporated.The residue was subjected to silica gel columnchromatography, to synthesize 9.37 g of the target compound.1H-NMR (CDCl3) δ=1.48(9H, s), 3.89(2H, s), 3.92(3H, s), 6.25(1H,brs), 7.17-7.31(5H, m), 7.48(1H, brs), 7.92(1H, brs) b) 3-Benzyl-5-(N-methyl-tert-butoxycarbonylamino)-2-methoxypyridine
    [0224] 970 mg of 3-benzyl-5-tert-butoxycarbonylamino-2-methoxypyridinewas dissolved in 10 ml of N,N-dimethylformamide,followed by adding 200 mg of 60% oilysodium hydride thereto. After stirring at room temperature,0.192 ml of methyl iodide was added thereto in an ice bath.After the returned to room temperature, water was added andthe mixture was extracted with ethyl acetate. The extractwas washed with brine, dried over anhydrous magnesiumsulfate and evaporated, to give 920 mg of the targetcompound.1H-NMR (CDCl3) δ=1.37(9H, brs), 3.17(3H, s), 3.89(2H, s),3.96(3H, s), 7.13(1H, brs), 7.18-7.25(3H, m), 7.30(2H, d,J=7Hz), 7.88(1H, d, J=2Hz) c) 3-Benzyl-5-(N-methylbenzoylamino)-2-methoxypyridine
    [0225] 920 mg of 3-benzyl-5-(N-methyl-tert-butoxycarbonylamino)-2-methoxypyridinewas dissolved in 5 mlof ethyl acetate, followed by adding 10 ml of 4N hydrochloricacid/ethyl acetate thereto. The resulting solid (640 mg) wascollected by filtration. To the solid (230 mg) were added 10 ml of ethyl acetate, 150 mg of benzoyl chloride and 0.5 ml ofpyridine in an ice bath, followed by stirring. After addingwater thereto, the mixture was extracted with ethyl acetate.The extract was washed with 1N hydrochloric acid, aqueoussaturated sodium hydrogencarbonate and brine, dried overanhydrous magnesium sulfate and then evaporated, to give 270mg of the target compound.1H-NMR (CDCl3) δ =3.42(3H, s), 3.75(2H, s), 3.89(3H, s),6.80-6.95(3H, m), 7.15-7.30(8H, m), 7.80(1H, brs) d) 3-[3-Benzyl-5-(N-methylbenzoylamino)-2-pyridyl]ethynyl-3-quinuclidinol
    [0226] The target compound was synthesized in the same manneras in Example 35-c.1H-NMR (CDCl3) δ =1.35-1.46 (1H, m), 1.54-1.64(1H, m), 1.75-1.85(1H, m), 2.01-2.12(2H, m), 2.60-2.90(4H, m), 2.98 (1H, dd,J=2,14Hz), 3.15(1H, dd, J=2,14Hz), 3.47(3H, s), 4.00(2H, s),6.85 - 6.89 (2H, m), 7.04(1H, d, J=2Hz), 7.18-7.27(7H, m),7.31-7.35(1H, m), 8.19(1H, d, J=2Hz) Example 41 3-(3-Benzyl-5-(N-methylbenzenesulfonylamino)-2-pyridyl)ethynyl-3-quinuclidinol
    [0227] The target compound was synthesized in the same manneras in Example 40.1H-NMR (CDCl3) δ=1.35-1.95(3H, m), 1.98-2.08(2H, m), 2.70-2.95(4H,m), 3.03(1H, d, J=14Hz), 3.15(3H, s), 3.25(1H, dd,J=2,14Hz), 4.11(2H, s), 7.11(2H, d, J=7Hz), 7.22-7.33(4H, m),7.42(2H, t, J=7Hz), 7.50(2H, dd, J=2,8Hz), 7.57(1H, t, J=7Hz),8.16(1H, d, J=3Hz) Example 42 3-(2-Allyl-6-pyrazyl-3-pyridyl)ethynyl-3-quinuclidinol a) 2-Allyl-6-pyrazyl-3-pyridyl trifluoromethane sulfonate
    [0228] A mixture of 1.22 g of 2-bromo-6-iodo-3-pyridyltrifluoromethanesulfonate (Production Example 17), 1.04 gof pyrazyltributyltin, 326 g oftetrakis(triphenylphosphine)palladium(0) and 10 ml ofxylene was stirred at 140°C for 2 hours. After cooling toroom temperature as it was, the mixture was filtered usingsilica gel and the solvent was evaporated. A mixture of theresidue, 868 µl of allyltributyltin, 324 mg oftetrakis(triphenylphosphine)palladium(0) and 10 ml oftoluene was heated under reflux for 1.5 hours. After coolingto room temperature as it was, silica gel was added to themixture and the solvent was evaporated. The residue wassubjected to silica gel column chromatography and elutedwith 20% ethyl acetate/hexane, to give 500 mg of the targetcompound.1H-NMR(CDCl3) δ=3.79(2H, d, J=6Hz), 5.20-5.26(2H, m), 6.11-6.21(1H,m), 7.75(1H, d, J=12Hz), 8.37(1H, d, J=12Hz),8.60-8.63(2H, m), 9.68(1H, s) b) 3-(2-Allyl-6-pyrazyl-3-pyridyl)ethynyl-3-quinuclidinol
    [0229] A mixture of 500 mg of 2-allyl-6-pyrazyl-3-pyridyltrifluoromethanesulfonate, 203 mg of 3-ethynyl-3-quinuclidinol,155 mg oftetrakis(triphenylphosphine)palladium(0), 25.5 mg of cuprous iodide, 0.560 ml of triethylamine and 5 ml ofN,N-dimethylformamide was stirred at 65°C for 20 minutes ina nitrogen atmosphere. After cooling as it was, NH-silicagel was added to the reaction mixture and the solvent wasremoved. The residue was subjected to NH-silica gel columnchromatography using 2.5% methanol/ethyl acetate, to give428 mg of the target compound.1H-NMR(CDCl3) δ=1.42-1.50(1H, m), 1.66-1.75(1H, m), 1.97-2.14(3H,m), 2.82-2.98(4H, m), 3.11(1H, d, J=14Hz), 3.36(1H,dd, J=2, 14Hz), 3.84(2H, d, J=6Hz), 5.14-5.20(2H, m), 6.13-6.22(1H,m), 7.83(1H, d, J=12Hz), 8.19(1H, d, J=12Hz),8.57-8.60(2H, m), 9.68(1H, s) Example 43 3-(2-Allyl-6-phenyl-3-pyridyl)ethynyl-3-quinuclidinol
    [0230] The title compound was synthesized in the same manneras in Example 42.1H-NMR(CDCl3) δ=1.42-2.16(5H, m), 2.82-2.96(4H, m), 3.10(1H,d, J=14Hz), 3.34(1H, dd, J=2, 14Hz), 3.83(2H, d, J=6Hz),5.14-5.18(2H, m), 6.13-6.23(1H, m), 7.39-7.57(5H, m), 7.73(1H,d, J=8Hz), 8.03(1H, d, J=8Hz) Example 44 3-[2-Allyl-6-(3-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0231] The title compound was synthesized in the same manneras in Example 42.1H-NMR(CDCl3) δ=1.42-1.50(1H, m), 1.65-1.74(1H, m), 1.96-2.13(3H,m), 2.81-2.95(4H, m), 3.10(1H, d, J=14Hz), 3.34(1H,dd, J=2, 14Hz), 3.79-3.80(2H, m), 5.11-5.19(2H, m), 6.11-6.21 (1H, m), 7.39-7.42(1H, m), 7.52-7.56(1H, m), 7.72-7.76(1H,m), 8.35-8.37(1H, m), 8.63-8.64(1H, m), 9.21(1H, s) Example 45 3-[2-(2-Methyl-2-propenyl)-6-pyrazyl-3-pyridyl]ethynyl-3-quinuclidinol a) 2-(2-Methyl-2-propenyl)-6-pyrazyl-3-pyridyltrifluoromethanesulfonate
    [0232] A mixture of 220 mg of 2-bromo-6-iodo-3-pyridyltrifluoromethane sulfonate, 187 mg of pyrazyltributyltin,58.7 mg of tetrakis(triphenylphosphine)palladium(0) and 2mlof xylene was stirred at 140°C for 2 hours. After coolingto room temperature as it was, the mixture was filteredthrough silica gel and the solvent was evaporated. To theresidue were added 1.20 ml of 2-methyl-2-propenyltributyltin(Production Example 21), 60.2 mg oftetrakis(triphenylphosphine)palladium(0) and 3 ml of xylene,followed by heating under reflux for 2 hours. After coolingto room temperature as it was, silica gel was added theretoand the solvent was evaporated. The residue was subjectedto silica gel column chromatography and eluted with 20% ethylacetate/hexane, to give 83.1 mg of the target compound.1H-NMR(CDCl3) δ=1.83(3H, s), 3.71(2H, s), 4.73(1H, s), 4.92(1H,s), 7,75(1H, d, J=8Hz), 8.36(1H, d, J=8Hz), 8.60-8.62(2H, m),9.66(1H, s) b) 3-[2-(2-Methyl-2-propenyl)-6-pyrazyl-3-pyridyl]ethynyl-3-quinuclidinol
    [0233] A mixture of 83.1 mg of 2-(2-methyl-2-propenyl)-6-pyrazyl-3-pyridyltrifluoromethane sulfonate, 35.0 mg of 3-ethynyl-3-quinuclidinol, 13.3 mg oftetrakis(triphenylphosphine)palladium(0), 2.2 mg ofcuprous iodide, 96.6 µl of triethylamine and 1 ml ofN,N-dimethylformamide was stirred at room temperature forone hour in a nitrogen atmosphere. NH-silica gel was addedto the reaction solution, and the solvent was removed. Theresidue was subjected to NH-silica gel column chromatographyusing 2.5% methanol/ethyl acetate, to give 71.2 mg of thetarget compound.1H-NMR(CDCl3) δ=1.42-1.49(1H, m), 1.65-1.74(1H, m), 1.85(3H,s), 1.97-2.12(3H, m), 2.78-2.95(4H, m), 3.10(1H, d, J=14Hz),3.34(1H, dd, J=2, 14Hz), 3.78(2H, s), 4.70(1H, s), 4.88(1H, s),7.83(1H, d, J=8Hz), 8.19(1H, d, J=8Hz), 8.58-8.60(2H, m),9.67(1H, d, J=2Hz) Example 46 3-[2-Benzyl-6-(4-pyridazyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0234] The target compound was synthesized in the same manneras in Example 14.1H-NMR(CDCl3) δ=1.41-1.48(1H, m), 1.63-1.91(2H, m), 2.04-2.09(2H,m), 2.76-2.92(4H, m), 3.07(1H, d, J=14Hz), 3.26(1H,d, J=14Hz), 4.41(2H, s), 7.19-7.33(5H, m), 7.65(1H, d, J=8Hz),7.80(1H, d, J=8Hz), 8.04-8.06(1H, m), 9.27-9.29(1H, m),9.78-9.79(1H, m) Example 47 (3R)-3-[2-Benzyl-6-(3-pyridazyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0235] The target compound was synthesized in the same manner as in Example 14.1H-NMR(CDCl3) δ=1.43-1.47(1H, m), 1.60-1.87(2H, m), 2.05-2.08(2H,m), 2.71-2.99(4H, m), 3.05(1H, d, J=14Hz), 3.25(1H,dd, J=2, 14Hz), 4.42(2H, s), 7.21-7.30(5H, m), 7.52-7.60(1H,m), 7.87(1H, d, J=8Hz), 8.54-8.58(2H, m), 9.17-9.19(1H, m) Example 483-[2-Benzyl-6-(1,4-dioxene-2-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0236] The target compound was synthesized in the same manneras in Example 14.1H-NMR(CDCl3) δ=1.39-1.41(1H, m), 1.59-1.61(1H, m), 1.80-1.87(1H,m), 2.01-2.05(2H, m), 2.72-2.87(4H, m), 3.00(1H, d,J=14Hz), 3.20(1H, dd, J=2, 14Hz), 4.16-4.27(6H, m), 7.16-7.27(6H,m), 7.34(1H, s), 7.61(1H, d, J=8Hz) Example 49 3-[2-Benzyl-6-(3-oxo-1-cyclohexenyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0237] The target compound was synthesized in the same manneras in Example 14 by using (3-oxo-1-cyclohexenyl)tributyltinsynthesized according to literature (Tetrahedron Letters,Vol. 31, No. 13, 1837 (1990)).1H-NMR(CDCl3) δ=1.42-1.44(1H, m), 1.63-1.99(2H, m), 2.00-2.17(4H,m), 2.49-2.52(2H, m), 2.77-2.91(6H, m), 3.04(1H, d,J=14Hz), 3.24(1H, dd, J=2, 14Hz), 4.34(2H, s), 6.81 (1H, t,J=1Hz), 7.19-7.32(5H, m), 7.44(1H, d, J=8Hz), 7.71(1H, d,J=8Hz) Example 50 3-[2-Benzyl-6-(3,4-dihydro-2 H-6-pyranyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0238] The target compound was synthesized in the same manneras in Example 14 by using (3,4-dihydro-2H-6-pyranyl)tributyltinsynthesized with reference to aliterature (Synlett 152 (1994)).1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.66-1.82(2H, m), 1.89-2.04(4H,m), 2.52-2.30(2H, m), 2.74-2.94(4H, m), 3.00(1H, d,J=14Hz), 3.20(1H, dd, J=2, 14Hz), 4.17-4.20(2H, m), 4.32(2H,s), 6.15-6.17(1H, m), 7.17-7.26(5H, m), 7.38(1H, d, J=8Hz),7.65(1H, d, J=8Hz) Example 513-[2-Benzyl-6-(2-hydroxyphenyl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-hydroxy-6-(2-hydroxyphenyl)pyridine
    [0239] A mixture of 641 mg of (2-benzyl-3-methoxymethyloxy-6-pyridyl)tributyltin(Production Example 18), 327 mg of2-methoxymethyloxyiodobenzene (Production Example 20),71.6 mg of tetrakis(triphenylphosphine)palladium(0) and 7ml of xylene was heated under refluxed for one hour innitrogen atmosphere. After cooling as it was, the mixturewas filtered through silica gel and the solvent was removed.To the residue was added 2 ml of trifluoroacetic acid,followed by stirring at room temperature overnight. Thereaction solution was neutralized by aqueous potassiumcarbonate. Ethyl acetate was added thereto, and the organicphase was washed with water and brine, dried over anhydrousmagnesium sulfate and the solvent was removed. The residuewas subjected to silica gel column chromatography using 30% ethyl acetate/hexane, to give 54.5 mg of the target compound.1H-NMR(CDCl3) δ=4.24(2H, s), 6.85-6.90(1H, m), 6.96-6.99(1H,m), 7.21-7.27(3H, m), 7.33-7.34(4H, m), 7.68-7.70(2H, m) b) 2-Benzyl-6-(2-hydroxyphenyl)-3-pyridyltrifluoromethane sulfonate
    [0240] A mixture of 54.5 mg of 2-benzyl-3-hydroxy-6-(2-hydroxyphenyl)pyridine,70.2 mg of N-phenyltrifluoromethanesulfonimide,824 µl of triethylamine,1.2 mg of 4-dimethylaminopyridine and 1.5 ml ofdichloromethane was stirred at room temperature for 2.5hours. Silica gel was added to the reaction solution, andthe solvent was removed. The residue was subjected to silicagel column chromatography using 12% ethyl acetate/hexane,to give 68.5 mg of the target compound.1H-NMR(CDCl3) δ=4.29(2H, s), 6.88-6.92(1H, m), 6.95-6.98(1H,m), 7.28-7.32(4H, m), 7.35-7.39(2H, m), 7.70-7.76(2H, m),7.83(1H, d, J=8Hz), 12.81(1H, s) c) 3-[2-Benzyl-6-(2-hydroxyphenyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0241] A mixture of 67.0 mg of 2-benzyl-6- (2-hydroxyphenyl)-3-pyridyltrifluoromethane sulfonate, 24.7mg of 3-ethynyl-3-quinuclidinol, 19.0 mg oftetrakis(triphenylphosphine)palladium(0), 0.1 mg ofcuprous iodide, 68.6 µl of triethylamine and 1.5 ml ofN,N-dimethylformamide was heated under stirring at 100°C for2 hours in a nitrogen atmosphere. NH-silica gel was addedto the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatographyusing 3% methanol/ethyl acetate, to give 56.8 mg of thetarget compound.1H-NMR(CDCl3) δ=1.40-1.48(1H, m), 1.52-1.60(1H, m), 1.88-2.10(3H,m), 2.80-2.90(4H, m), 3.08(1H, d, J=14Hz), 3.28(1H,dd, J=2, 14Hz), 4.36(2H, s), 6.85-6.89(1H, m), 6.96(1H, d,J=8Hz), 7.24-7.34(6H, m), 7.67-7.72(2H, m), 7.78(1H, d, J=8Hz),13.81(1H, s) Example 52 (3R)-3-[2-Benzyl-6-(1,3,4-thiadiazole-2-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0242] The target compound was synthesized in the same manneras in Example 51 by using 2-iodo-1,3,4-thiadiazole(Production Example 22).1H-NMR(CDCl3) δ=1.41-1.44(1H, m), 1.62-1.98 (2H, m), 2.01-2.07(2H,m), 2.50-2.95(4H, m), 3.05(1H, d, J=14Hz), 3.24(1H,dd, J=2, 14Hz), 4.37(2H, s), 7.19-7.29(5H, m), 7.82(1H, d,J=8Hz), 8.18(1H, d, J=8Hz), 9.16(1H,s) Example 53 3-[2-(4-Methoxybenzyl)-6-methyl-3-pyridyl]ethynyl-3-quinuclidinol a) 3-Benzyloxy-2-[(4-methoxyphenyl)hydroxymethyl]-6-methylpyridine
    [0243] A 1.6 mol solution of n-butyllithium in hexane was addeddropwise to a mixture of 2.43 g of 4-bromoanisole and 20 mlof diethyl ether at -50°C, followed by stirring at -20°C for30 minutes. Further, a mixture of 2.27 g of 3-benzyloxy-6-methylpyridine-2-carboxyaldehyde(ProductionExample 11-b) and 50 ml of diethyl ether was added thereto at -60°C over 15 minutes. After stirring at the sametemperature for 30 minutes, aqueous saturated ammoniumchloride was added to the reaction solution. The mixturewas extracted with ethyl acetate, and the organic phase waswashed with brine, dried over anhydrous magnesium sulfateand concentrated. The residue was subjected to silica gelcolumn chromatography using 5-20% ethyl acetate/hexane, togive 1.16 g of the target compound.1H-NMR(CDCl3) δ=2.52(3H, s), 3.77(3H, s), 4.92(1H, d, J=12Hz),4.98(1H, d, J=12Hz), 5.75(1H, d, J=6Hz), 5.87(1H, d, J=6Hz),6.79(2H, d, J=9Hz), 6.98(1H, d, J=8Hz), 7.03(1H, d, J=8Hz),7.10-7.15(2H, m), 7.23(2H, d, J=9Hz), 7.27-7.34(3H, m) b) 3-Hydroxy-2-(4-methoxybenzyl)-6-methylpyridine
    [0244] A mixture of 0.87 g of 3-benzyloxy-2-[(4-methoxyphenyl)hydroxymethyl]-6-methylpyridine,2.5 ml ofacetic acid anhydride and 20 ml of pyridine was heated understirring for 4 hours in an oil bath kept at 120°C. Afterthe reaction solution was evaporated, water was addedthereto. The mixture was extracted with ethyl acetate, andthe organic phase was washed with brine, dried over anhydrousmagnesium sulfate and concentrated. To the residue wereadded 20 ml of methanol, 10 ml of tetrahydrofuran and acatalytic amount of 10% palladium/carbon, followed bystirring for 10 hours in a hydrogen atmosphere. After thecatalyst was filtered off, the filtrate was concentrated.Then, the crystals were washed with diethyl ether, to give320 mg of the target compound. 1H-NMR(d6-DMSO) δ=2.32(3H, s), 3.69(3H, s), 3.92(2H, s),6.80(2H, d, J=8Hz), 6.92(1H, d, J=7Hz), 7.07(1H, d, J=7Hz),7.14(2H, d, J=8Hz) c) 2-(4-Methoxybenzyl)-6-methyl-3-pyridyltrifluoromethanesulfonate
    [0245] A mixture of 160 mg of 3-hydroxy-2-(4-methoxybenzyl)-6-methylpyridine,300 mg of N-phenyltrifluoromethanesulfonimide,146 µl of triethylamine,26 mg of 4-dimethylaminopyridine and 5.0 ml ofdichloromethane was stirred at room temperature for 2 hours.Water was added to the reaction solution, and the mixturewas extracted with ethyl acetate. The organic phase waswashed with brine and the solvent was removed. The residuewas subjected to NH-silica gel (Fuji silicia) columnchromatography to elute with hexane and then withhexane/ethyl acetate (2:1), to give 230 mg of the targetcompound.1H-NMR(CDCl3) δ=2.57(3H, s), 3.77(3H, s), 4.15(2H, s),6.80-6.82(2H, m), 7.08(1H, d, J=8Hz), 7.19-7.21(2H, m), 7.44(1H,d, J=8Hz) d) 3-[2-(4-Methoxybenzyl-6-methyl-3-pyridyl]ethynyl-3-quinuclidinol
    [0246] A mixture of 230 mg of 2-(4-methoxybenzyl)-6-methyl-3-pyridyltrifluoromethane sulfonate, 116 mg of 3-ethynyl-3-quinuclidinol,147 mg oftetrakis(triphenylphosphine)palladium(0), 24 mg of cuprousiodide, 266 µl of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 80°C for 3hours in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia, and the mixture wasextracted with ethyl acetate. Then; the organic phase waswashed with brine and the solvent was removed. The residuewas subjected to NH-silica gel (Fuji Silicia) columnchromatography and eluted with hexane/ethyl acetate (1:1)and then with ethyl acetate/methanol (20:1), to give 192 mgof the target compound.1H-NMR(CDCl3) δ=1.35-1.44(1H, m), 1.54-1.65(1H, m), 1.77-1.89(1H,m), 2.02-2.04(2H, m), 2.54(3H, s), 2.75-2.95(4H, m),3.02(1H, dd, J=2, 14Hz), 3.23(1H, dd, J=2, 14Hz), 3.75(3H, s),4.23(2H, s), 6.77-6.80(2H, m), 6.97(1H, d, J=8Hz), 7.16-7.19(2H,m), 7.55(1H, d, J=8Hz) Example 54 3-[6-Methyl-2-(2-pyridylmethyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0247] The target compound was synthesized in the same manneras in Example 53.1H-NMR(CDCl3) δ=1.38-1.44(1H, m), 1.53-1.84(2H, m), 1.96-2.14(2H,m), 2.58(3H, s), 2.75-2.95(4H, m), 3.05(1H, d, J=14Hz),3.16(1H, dd, J=2, 14Hz), 4.49(2H, s), 7.00(1H, d, J=8Hz),7.11-7.15(1H, m), 7.25-7.30(1H, m), 7.49(1H, d, J=8Hz),7.55-7.60(1H, m), 7.44-8.47(1H, m) Example 55 3-[6-Methyl-2-(3-pyridylmethyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0248] The target compound was synthesized in the same manneras in Example 53. 1H-NMR(CDCl3) δ=1.31-1.39(1H, m), 1.52-1.78(2H, m), 1.93-2.00(2H,m), 2.47(3H, s), 2.63-2.89(4H, m), 2.98(1H, dd, J=2,14Hz), 3.15(1H, dd, J=2, 14Hz), 4.21(2H, s), 6.93(1H, d, J=8Hz),7.09-7.19(1H, m), 7.51(1H, d, J=8Hz), 7.53-7.63(1H, m),8.34-8.36(1H, m), 8.50(1H, d, J=2Hz) Example 563-[6-Methyl-2-(4-pyridylmethyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0249] The target compound was synthesized in the same manneras in Example 53.1H-NMR(CDCl3) δ=1.36-1.45(1H, m), 1.54-1.80(2H, m), 1.97-2.06(2H,m), 2.55(3H, s), 2.66-2.95(4H, m), 3.03(1H, dd, J=2,14Hz), 3.19(1H, dd, J=2, 14Hz), 4.28(2H, s), 7.04(1H, d, J=6Hz) ,7.13-7.15(2H, m), 7.61(1H, d, J=8Hz), 8.40-8.42(2H, m) Example 57 3-[2-(2-Phenylethyl)-6-methyl-3-pyridyl]ethynyl-3-quinuclidinol a) 3-Benzyloxy-6-methyl-2-styrylpyridine
    [0250] 1.5 g of diethyl benzylphosphonate was dissolved in 20ml of tetrahydrofuran, followed by adding 810 mg of potassiumtert-butoxide at room temperature. After stirring for 15minutes, a solution of 10 ml of tetrahydrofuran containing1,2 g of 3-benzyloxy-6-methylpyridine-2-carboxyaldehyde(Production Example 11-b) was added thereto, followed bystirring for further 1.5 hours. Then, water was addedthereto, and the mixture was extracted with ethyl acetate.The organic phase was washed with brine, dried over anhydroussodium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 10%ethyl acetate/hexane as an eluent, to give 1.2 g of the targetcompound.1H-NMR(CDCl3) δ=2.53(3H, s), 5.13(2H, s), 6.95(1H, d, J=8.4Hz),7.12(1H, d, J=8.4Hz), 7.24-7.48(8H, m), 7.59(2H, d, J=8.4Hz),7.61(1H, d, J=16Hz), 7.80(1H, d, J=16Hz) b) 3-Hydroxy-6-methyl-2-(2-phenylethyl)pyridine
    [0251] 1.2 g of 3-benzyloxy-6-methyl-2-styrylpyridine wasdissolved in 20 ml of methanol. 684 mg of 10% palladiumcarbon was added thereto, and the mixture was to hydrogenated.The atmosphere in the reaction.system was replaced bynitrogen and the catalyst was filtered off. The filtratewas evaporated, to give 695 mg of the target compound. c) 6-Methyl-2-(2-phenylethyl)pyridyltrifluoromethanesulfonate
    [0252] A mixture of 695 mg of 3-hydroxy-6-methyl-2-(2-phenylethyl)pyridine,1.5 g of N-phenyltrifluoromethanesulfonimide,121 mg of 4-dimethylaminopyridineand 0.6 ml of triethylamine wasdissolved in 20 ml of dichloromethane, followed by stirringat room temperature for 5 hours. Then, the solvent wasremoved and the residue was subjected to silica gel columnchromatography using 10% ethyl acetate/hexane as an eluentfor separation and purification, to give 1.2 g of the targetcompound.1H-NMR(CDCl3) δ=2.59(3H, s), 3.02-3.09(2H, m), 3.12-3.19(2H,m), 7.08(1H, d, J=8.4Hz), 7.20-7.31(5H, m), 7.44(1H, d, J=8.4Hz) d) 3-[2-(2-Phenylethyl)-6-methyl-3-pyridyl]ethynyl-3-quinuclidinol
    [0253] 10 ml of N,N-dimethylformamide was added to a mixtureof 1.2 g of 6-methyl-2-(2-phenylethyl)pyridyltrifluoromethane sulfonate, 522 mg of 3-ethynyl-3-quinuclidinol,400 mg oftetrakis(triphenylphosphine)palladium(0), 217 mg ofcuprous iodide and 1.7 ml of triethylamine, followed byheating under stirring at 50°C in an oil bath for one hourin a nitrogen atmosphere. After cooling as it was, thereaction solution was sprinkled over silica gel andsubjected to silica gel column chromatography usingchloroform/methanol/aqueous 36% ammonia (46:5:0.5) as aneluent for separation and purification, to give 490 mg ofthe target compound.1H-NMR(CDCl3) δ=1.42-1.52(1H, m), 1.61-1.72(1H, m), 1.89-2.02(1H,m), 2.04-2.16(2H, m), 2.56(3H, s), 2.80-2.95(4H, m),3.02-3.11(3H,m), 3.20-3.32(3H, m), 6.97(1H, d, J=8.0Hz),7.18-7.28(5H, m), 7.54(1H, d, J=8.0Hz) Example 58 3-(2-Styryl-6-methyl-3-pyridyl)ethynyl-3-quinuclidinol a) 3-Hydroxy-6-methyl-2-styrylpyridine
    [0254] 875 mg of 3-benzyloxy-6-methyl-2-styrylpyridine(Example 57a) was dissolved in 15 ml of 1,2-dichloroethaneand 1.2 ml of a dichloromethane solution containing 1.0 molof boron tribromide was added thereto in a nitrogen atmosphere, followed by heating under stirring at 50°C inan oil bath over night. After cooling as it was, an aqueoussaturated sodium bicarbonate solution was added thereto, andthe mixture was extracted with 5% methanol/dichloromethane.The organic phase was further washed with brine, dried overanhydrous magnesium sulfate and the solvent was removed.The residue was vacuum-dried, to give 200 mg of the targetcompound. b) 3-(2-Styryl-6-methyl-3-pyridyl)ethynyl-3-quinuclidinol
    [0255] The target compound was synthesized in the same manneras in Example 57.1H-NMR(CDCl3) δ=1.40-1.50(1H, m), 1.66-1.80(1H, m), 2.00-2.18(3H,m), 2.59(3H, s), 2.80-3.00(4H, m), 3.12(1H, d, J=14Hz),3.38(1H, dd, J=2, 14Hz), 6.96(1H, d, J=7.9Hz), 7.30(1H, d,J=7.3Hz), 7.37(2H, dd, J=7.5Hz, 7.3Hz), 7.565(1H, d, J=7.9Hz),7.572 (1H, d, J=7.5Hz), 7.60(1H, d, J=16Hz), 7.97(1H, d, 16Hz) Example 59 3-[2-Benzyl-6-(3-methoxypropyl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-(2-ethoxycarbonylethenyl)-3-methoxymethyloxypyridine
    [0256] 1.3 g of ethyl diethylphosphonoacetate was dissolved in20 ml of tetrahydrofuran, followed by adding 657 mg ofpotassium tert-butoxide thereto at room temperature. Afterstirring for 15 minutes, a solution of 10 ml oftetrahydrofuran containing 1.0 g of 2-benzyl-3-methoxymethyloxypyridine-6-carboxyaldehyde(Production Example 11) was added thereto, followed by stirring forfurther one hour. Then, water was added thereto, and themixture was extracted with ethyl acetate. The organic phasewas washed with brine, dried over anhydrous sodium sulfateand the solvent was removed. The residue was subjected tosilica gel column chromatography using 17% ethylacetate/hexane as an eluent for separation and purification,to give 1.4 g of the target compound. b) 2-Benzyl-6-(2-ethoxycarbonylethyl)-3-methoxymethyloxypyridine
    [0257] 1.4 g of 2-benzyl-6-(2-ethoxycarbonylethenyl)-3-methoxymethyloxypyridinewas dissolved in 20 ml of ethylacetate. 457 mg of 10% palladium carbon was added thereto,and the mixture was hydrogenated. After the atmosphere inthe reaction system was replaced by nitrogen, the catalystwas filtered off. The filtrate was further filtered throughsilica gel, and the filtrate was evaporated, to give 1.3 gof the target compound.1H-NMR(CDCl3) δ=1.22(3H, t, J=7.1Hz), 2.76(2H, t, J=7.6Hz),3.05(2H, t, J=7.6Hz), 3.30(3H, s), 4.13(2H, q, J=7.1Hz),4.15(2H, s), 5.09(2H, s), 6.97(1H, d, J=8.4Hz), 7.14-7.29(6H,m) c) 2-Benzyl-6-(3-hydroxypropyl)-3-methoxymethyloxypyridine
    [0258] 205 mg of aluminum lithium hydride was suspended in 20ml of anhydrous ether. A solution of 10 ml of anhydrous ethercontaining 1.3 g of 2-benzyl-6-(2-ethoxycarbonylethyl)-3-methoxymethyloxypyridine was added dropwise under ice-cooling.After stirring for one hour as it was, 0.2 ml ofwater, then 0.2 ml of an aqueous 5N sodium hydroxide solutionand then 0.6 ml of water were added thereto under ice-cooling.The reaction solution was filtered through filter paper toremove insoluble matters. After washing with ether, theorganic phase was evaporated. The residue was subjected tosilica gel column chromatography using 40% ethylacetate/hexane as an eluent for separation and purification,to give 1.0 g of the target compound.1H-NMR(CDCl3) δ=1.94(2H, tt, J=6.5Hz, 5.7Hz), 2.91(2H, t,J=6.5Hz), 3.34(3H, s), 3.70(2H, t, J=5.7Hz), 4.15(2H, s),5.13(2H, s), 6.97(1H, d, J=8.4Hz), 7.15-7.31(6H, m) d) 2-Benzyl-6-(3-methoxypropyl)-3-methoxymethyloxypyridine
    [0259] 527 mg of 2-benzyl-6-(3-hydroxypropyl)-3-methoxymethyloxypyridinewas dissolved in 5 ml of N,N-dimethylformamide,and 108 mg of 60% oily sodium hydride wasadded thereto at room temperature under stirring. After 10minutes, 0.16 ml of methyl iodide was added thereto, followedby stirring for one hour at room temperature. Then, waterwas added thereto, and the mixture was extracted with ethylacetate. The organic phase was further washed with brine,dried over anhydrous sodium sulfate and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using 20% ethyl acetate/hexane as an eluentfor separation and purification, to give 389 mg of the target compound.1H-NMR(CDCl3) δ=1.98(2H, tt, J=7.8Hz, 6.6Hz), 2.79(2H, t,J=7.8Hz), 3.31(3H, s), 3.34(3H, s), 3.41(2H, t, J=6.6Hz),4.17(2H, s), 5.09(2H, s), 6.95(1H, d, J=8.4Hz), 7.14-7.30(6H,m) e) 3-[2-Benzyl-6-(3-methoxypropyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0260] The compound obtained above was deprotected usingtrifluoroacetic acid and in succession, the same proceduresas in Example 57 were carried out to synthesize the targetcompound.1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.53-1.63(1H, m), 1.75-1.88(1H,m), 1.98-2.05(4H, m), 2.67-2.92(4H, m), 2.85(2H, t,J=7.5Hz), 3.00(1H, dd, J=2, 14Hz), 3.20(1H, dd, J=2, 14Hz),3.32(3H, s), 3.40(2H, t, J=6.4Hz), 4.31(2H, s), 6.99(1H, d,J=7.9Hz), 7.15-7.26(5H, m), 7.58(1H, d, J=7.9Hz) Example 60 3-[2-Benzyl-6-(5,6-dihydro-2 H-pyran-4-yl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-(4-hydroxytetrahydro-4 H-pyran-4-yl)-3-methoxymethyloxypyridine
    [0261] A solution of 10 ml of diethyl ether containing 1.79 gof 2-benzyl-6-iodo-3-methoxymethyloxypyridine (ProductionExample 12) was added dropwise to a mixture of a 4.25 ml hexanesolution of 1.54 mol of n-butyllithium and 10 ml of diethylether at -78°C. After stirring at the same temperature for20 minutes, tetrahydro-4H-pyran-4-one was added dropwisethereinto. The temperature of the resulting mixture was raised to room temperature and water and diethyl ether wereadded thereto. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 30% ethyl acetate/hexane,to give 1.39 g of the target compound.1H-NMR(CDCl3) δ=1.47-1.56(2H, m), 2.05-2.12(2H, m), 3.38(3H,s), 3.90-4.01(4H, m), 4.19(2H, s), 5.18(2H, s), 7.14-7.30(6H,m), 7.41(1H, d, J=8Hz) b) 2-Benzyl-3-hydroxy-6-(4-hydroxytetrahydro-4 H-pyran-4-yl)pyridine
    [0262] A mixed solution of 377 mg of 2-benzyl-6-(4-hydroxytetrahydro-4H-pyran-4-yl)-3-methoxymethyloxypyridine,2 ml of dichloromethane and 2 mlof trifluoroacetic acid was stirred at room temperatureovernight. The reaction solution was neutralized by anaqueous sodium bicarbonate solution, and ethyl acetate wasadded thereto. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 60% ethyl acetate/hexane,to give 241 mg of the target compound.1H-NMR(CDCl3) δ=1.51-1.57(2H, m), 2.05-2.12(2H, m), 3.90-4.01(4H,m), 4.21(2H, s), 5.00(1H, s), 5.39(1H, s), 7.12(2H,s), 7.21-7.30(5H, m) c) 2-Benzyl-6-(4-hydroxytetrahydro-4 H-pyran-4-yl)-3-pyridyltrifluoromethanesulfonate
    [0263] A mixture of 241 mg of 2-benzyl-3-hydroxy-6-(4-hydroxytetrahydro-4H-pyran-4-yl)pyridine,302 mg of N-phenyltrifluoromethanesulfonimide,353 µl of triethylamine,5.2 mg of 4-dimethylaminopyridine and 3 ml ofdichloromethane was stirred at room temperature for 2 hours.Silica gel was added to the reaction solution, and thesolvent was removed. The residue was subjected to silicagel column chromatography using 30% ethyl acetate/hexane,to give 332 mg of the target compound.1H-NMR(CDCl3) δ=1.53-1.56(2H, m), 2.08-2.17(2H, m), 3.92-3.97(4H,m), 4.26(2H, s), 4.60(1H, s), 7.23-7.36(6H, m),7.65(1H, d, J=8Hz) d) 2-Benzyl-6-(5,6-dihydro-2 H-pyran-4-yl)-3-pyridyltrifluoromethanesulfonate
    [0264] 57.9 µl of methanesulfonyl chloride was added dropwiseto a mixture of 104 mg of 2-benzyl-6-(4-hydroxytetrahydro-4H-pyran-4-yl)-3-pyridyltrifluoromethane sulfonate, 139 µl of triethylamine and 2ml of dichloromethane under ice-cooling. After stirring atroom temperature for 3 hours, water and ethyl acetate wereadded thereto. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 15% ethyl acetate/hexane,to give 60.7 mg of the target compound.1H-NMR(CDCl3) δ=2.60(2H, br.s), 3.92(2H, t, J=5Hz), 4.23(2H,s), 4.37(2H, s), 6.74(1H, s), 7.21-7.31(6H, m), 7.53(1H, d, J=8Hz) e) 3-[2-Benzyl-6-(5,6-dihydro-2 H-pyran-4-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0265] A mixture of 60.7 g of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-pyridyltrifluoromethane sulfonate, 23.0 mgof 3-ethynyl-3-quinuclidinol, 17.6 mg oftetrakis(triphenylphosphine)palladium(0), 2.9 mg ofcuprous iodide, 63.6 µl of triethylamine and 1 ml ofN,N-dimethylformamide was stirred at 60°C for 1.5 hours ina nitrogen atmosphere. NH-silica gel was added to thereaction solution, and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using3% methanol/ethyl acetate, to give 40.7 mg of the targetcompound.1H-NMR(CDCl3) δ=1.33-1.44(1H, m), 1.56-1.64(1H, m), 1.80-1.88(1H,m), 2.00-2.07(2H, m), 2.60(1H, br s), 2.73-2.88(4H,m), 3.02(1H, d, J=14Hz), 3.22(1H, dd, J=2, 14Hz), 3.93(1H, t,J=5Hz), 4.31(2H, s), 4.36-4.38(2H, m), 6.75-6.77(1H, m),7.12-7.29(6H, m), 7.61(1H, d, J=8Hz) Example 61 3-[2-Benzyl-6-(4-hydroxy-1-cyclohexenyl)-3-pyridyl]ethynyl-3-quinuclidinola) 2-Benzyl-3-hydroxy-6-(4-oxo-1-hydroxycyclohexyl)pyridine
    [0266] The target compound was synthesized in the same manneras in Example 60-a and b except that tetrahydro-4H-pyran-4-onewas altered to 1,4-cyclohexanedionemonoethyleneketal. 1H-NMR(CDCl3) δ=2.00-2.06(2H, m), 2.14-2.22(2H, m), 2.35-2.41(4H,m), 2.95-3.04(2H, m), 4.21(2H, s), 7.05-7.31(7H, m) b) 2-Benzyl-6-(1,4-dihydroxycyclohexyl)-3-hydroxypyridine
    [0267] 67. 4 mg of sodium borohydride was added to a mixtureof 353 mg of 2-benzyl-3-hydroxy-6-(4-oxo-1-hydroxycyclohexyl)pyridineand 4 ml of methanol underice-cooling, followed by stirring at the same temperaturefor one hour. Acetone was added thereto, and the solventwas removed. Then, the residue was subjected to silica gelcolumn chromatography using 20% hexane/ethyl acetate, togive 193 mg of the target compound.1H-NMR(CDCl3) δ=1.30-1.95(8H, m), 3.70-3.75(1H, m), 4.20(2H,s), 7.06-7.31(7H, m) c) 3-[2-Benzyl-6-(4-hydroxy-1-cyclohexynyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0268] The target compound was synthesized in the same manneras in Example 60-c,d and e except that 2-benzyl-3-hydroxy-6-(4-hydroxytetrahydro-4H-pyran-4-yl)pyridinewas altered to 2-benzyl-6-(1,4-dihydroxycyclohexyl)-3-hydroxypyridine.1H-NMR(CDCl3) δ=1.37-1.44(1H, m), 1.56-1.64(1H, m), 1.77-1.88(2H,m), 2.00-2.06(3H, m), 2.24-2.31(1H, m), 2.51-2.91(7H,m), 3.01(1H, d, J=14Hz), 3.22(1H, dd, J=2, 14Hz), 4.04-4.10(1H,m), 4.31(2H, s), 6.69(1H, s), 7.16-7.28(6H, m), 7.60(1H, d,J=8Hz) Example 62 3-[2-Benzyl-6-(tetrahydro-4 H-pyran-4-yl)-3- pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-(5,6-dihydro-2 H-pyran-4-yl)-3-methoxymethyloxypyridine
    [0269] 716 µl of methanesulfonyl chloride was added dropwiseinto a mixture of 1.02 g of 2-benzyl-6-(4-hydroxytetrahydro-4H-pyran-4-yl)-3-methoxymethyloxypyridine(Example 60a), 1.72 ml oftriethylamine and 10 ml of dichloromethaneunderice-cooling.After stirring at room temperature overnight, water andethyl acetate were added thereto. The organic phase waswashed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 20%ethyl acetate/hexane, to give 355 mg of the target compound.1H-NMR(CDCl3) δ =2.59-2.63(2H, m), 3.33(3H, s) , 3.94(2H, t,J=5Hz), 4.19(2H, s), 4.35-4.38(2H, m), 5.15(2H, s), 6.59-6.62(1H,m), 7.13-7.33(7H, m) b) 2-Benzyl-3-methoxymethyloxy-6-(tetrahydro-4 H-pyran-4-yl)pyridine
    [0270] 20 mg of 10% palladium carbon was added to a mixture of197 mg of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-methoxymethyloxypyridineand 3 ml of ethanol, followed bystirring at room temperature overnight in a hydrogenatmosphere. After the atmosphere in the reaction system wasreplaced by nitrogen, the reaction solution was filteredthrough Celite. The solvent was removed, and then theresidue was subjected to silica gel column chromatography using 20% ethyl acetate/hexane, to give 83.7 mg of the targetcompound.1H-NMR(CDCl3) δ=1.83-1.88(4H, m), 2.88-2.96(1H, m), 3.32(3H,s), 3.52-3.58(2H, m), 4.06-4.17(4H, m), 5.10(2H, s), 6.96(1H,d, J=8Hz), 7.12-7.16(1H, m), 7.21-7.31(5H, m) c) 3-[2-Benzyl-6-(tetrahydro-4 H-pyran-4-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0271] The target compound was synthesized in the same manneras in Example 60-b, c and e.1H-NMR(CDCl3) δ=1.36-1.44(1H, m), 1.55-1.63(1H, m), 1.79-1.90(5H,m), 1.98-2.04(2H, m), 2.68-2.87(5H, m), 3.01(1H, d,J=14Hz), 3.22(1H, dd, J=2, 14Hz), 3.41-3.58(2H, m), 4.07-4.11(2H,m), 4.30(2H, s), 6.99(1H, d, J=8Hz), 7.15-7.27(5H, m),7.62(1H, d, J=8Hz) Example 63 3-[2-Benzyl-6-(3-methoxy-1-propinyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0272] A mixture of 500 mg of 2-benzyl-3-bromo-6-pyridyltrifluoromethanesulfonate obtained in Production Example 3,0.12 ml of methyl propargyl ether, 40 mg oftetrakis(triphenylphosphine)palladium(0), 1.2 mg ofcuprous iodide, 0.53 ml of triethylamine and 1 ml ofN,N-dimethylformamide was stirred at room temperatureovernight in a nitrogen atmosphere. Ethyl acetate andaqueous dilute ammonia were added to the reaction solutionto separate. The organic phase was washed with water andbrine, dried over anhydrous magnesium sulfate and thenconcentrated. The residue was subjected to silica gel column chromatography using 1-10% ethyl acetate/hexane, togive 170 mg of 2-benzyl-3-bromo-6-(3-methoxy-1-propinyl)pyridine.
    [0273] Next, a mixture of 170 mg of 2-benzyl-3-bromo-6-(3-methoxy-1-propinyl)pyridine,90 mg of 3-ethynyl-3-quinuclidinol,30 mg oftetrakis(triphenylphosphine)palladium(0), 1 mg of cuprousiodide, 0.22 ml of triethylamine and 1 ml of N,N-dimethylformamidewas stirred for 2 hours in an oil bath keptat 85°C in a nitrogen atmosphere. Ethyl acetate and aqueousdilute ammonia were added to the reaction solution toseparate. The organic phase was washed with water and brine,dried over anhydrous magnesium sulfate and then concentrated.The residue was subjected to silica gel columnchromatography using NH-silica gel to elute with 20-100%ethyl acetate/hexane and then with 2.5% methanol/ethylacetate, to give 120 mg of the target compound.1H-NMR (CDCl3) δ=1.35-1.84(3H, m), 1.96-2.06(2H, m), 2.64-2.92(4H,m), 2.99(1H, dd, J=2, 14Hz), 3.17(1H, dd, J=2, 14Hz),3.47(3H, s), 4.33(2H, s), 4.36(2H, s), 7.15-7.28(5H, m),7.30(1H, d, J=8Hz), 7.64(1H, d, J=8Hz) Example 64 3-[2-Benzyl-6-(4-hydroxy-1-butynyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0274] The target compound was synthesized in the same manneras in Example 63.1H-NMR (CDCl3) δ=1.34-1.84(3H, m), 1.96-2.06(2H, m), 2.64-2.92(4H,m), 2.73(2H, t, J=6Hz), 2.99(1H, dd, J=2, 14Hz), 3.16(1H, dd, J=2, 14Hz), 3.85(2H, t, J=6Hz), 4.31(2H, s),7.14-7.28(6H, m), 7.60(1H, d, J=8Hz) Example 65 3-[2-(4-Fluorobenzyl)-6-(3-hydroxy-1-butynyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0275] The target compound was synthesized in the same manneras in Example 63.1H-NMR (CDCl3) δ=1.35-1.85(6H, m), 1.95-2.08(2H, m), 2.68-2.93(4H,m), 3.03(1H, d, J=14Hz), 3.21(1H, dd, J=2,14Hz),4.28(2H, s), 4.79(1H, q, J=7Hz), 6.94(2H, t, J=8Hz), 7.20(2H,dd, J=6,8Hz), 7.28(1H, d, J=8Hz), 7.65(1H, d, J=8Hz) Example 66 3-[2-Benzyl-6-(pyrazylethynyl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-(pyrazylethynyl)pyridine
    [0276] A mixture of 788 mg of 2-benzyl-3-bromo-6-pyridyltrifluoromethane sulfonate (Production Example 3), 207 mgof pyrazylacetylene (Production Example 19), 230 mg oftetrakis(triphenylphosphine)palladium(0), 37.9 mg ofcuprous iodide, 832 µl of triethylamine and 6 ml of N,N-dimethylformamidewas stirred at 80°C for one hour in anitrogen atmosphere. Silica gel was added to the reactionsolution, and the solvent was removed. The residue wassubjected to silica gel column chromatography using 25%ethyl acetate/hexane, to give 443 mg of the target compound.1H-NMR(CDCl3) δ=4.39(2H, s), 7.19-7.39(6H, m), 7.87(1H, d,J=8Hz), 8.54-8.56(1H, m), 8.61-8.62(1H, m), 8.86(1H, s) b) 3-[2-Benzyl-6-(pyrazylethynyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0277] A mixture of 109 mg of 2-benzyl-3-bromo-6-(pyrazylethynyl)pyridine,47.1 mg of 3-ethynyl-3-quinuclidinol,35.9 mg oftetrakis (triphenylphosphine)palladium(0), 5.9 mg ofcuprous iodide, 130 µl of triethylamine and 1.5 ml ofN,N-dimethylformamide was stirred for 5 hours at 70°C in anitrogen atmosphere. NH-silica gel was added to thereaction solution, and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using3% methanol/ethyl acetate, to give 61.0 mg of the targetcompound.1H-NMR(CDCl3) δ=1.37-1.43 (1H, m), 1.56-1.64(1H, m), 1.75-1.83(1H,m), 1.98-2.04(2H, m), 2.67-2.88(4H, m), 3.01(1H, d,J=14Hz), 3.19(1H, dd, J=2, 14Hz), 4.38(2H, s), 7.17-7.28(5H,m) , 7.48(1H, d, J=8Hz), 7.70(1H, d, J=8Hz), 8.53-8.54(1H, m),8.61-8.62(1H, m), 8.85-8.86(1H, m) Example 67 3-[2-Benzyl-6-(2-pyrazylethyl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-(2-pyrazylethyl)pyridine
    [0278] 12 mg of platinum oxide was added to a mixture of 230mg of 2-benzyl-3-bromo-6-pyrazylethynyl)pyridine(Production Example 66-a), 2.5 ml of ethyl acetate and 2 mlof methanol, followed by stirring at room temperatureovernight in a hydrogen atmosphere. After the atmospherein the reaction system was replaced by nitrogen, it wasfiltered through Celite. After removing the solvent, theresidue was subjected to silica gel column chromatography using 50% ethyl acetate/hexane, to give 85.4 mg of the targetcompound.1H-NMR(CDCl3) δ=3.20-3.30(4H, m), 4.30(2H, s), 6.84(1H, d,J=8Hz), 7.17-7.28(5H, m), 7,66(1H, d, J=8Hz), 8.34(1H, s),8.38(1H, d, J=2Hz), 8.47-8.48(1H, m) b) 3-[2-Benzyl-6-(2-pyrazylethyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0279] A mixture of 85.4 mg of 2-benzyl-3-bromo-6-(2-pyrazylethyl)pyridine,36.4 mg of 3-ethynyl-3-quinuclidinol,27.8 mg oftetrakis(triphenylphosphine)palladium(0), 4.6 mg ofcuprous iodide, 101 µl of triethylamine and 1.5 ml ofN,N-dimethylformamide was stirred for 7 hours at 80°C in anitrogen atmosphere. NH-silica gel was added to thereaction solution, and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using3% methanol/ethyl acetate, to give 45.4 mg of the targetcompound.1H-NMR(CDCl3) δ=1.36-1.44(1H, m), 1.54-1.63 (1H, m), 1.78-1.86(1H,m), 1.98-2.05(2H, m), 2.67-2.91(4H, m), 3.01(1H, d,J=14Hz), 3.20(1H, dd, J=2, 14Hz), 3.25-3.27(4H, m), 4.30(2H,s), 6.92(1H, d, J=8Hz), 7.16-7.28(5H, m), 7.54(1H, d, J=8Hz),8.32(1H, s), 8.36(1H, d, J=2Hz), 8.47-8.48(1H, m) Example 68 3-[2-Benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyl]ethynyl-3-quinuclidinol a) Dimethyl 3-methoxy-2-oxopropyl phosphonate
    [0280] 108 ml of a hexane solution containing 1.58 mol of n-butyllithium was dissolved in 100 ml of tetrahydrofurananhydride. To the mixture was added dropwise a mixture of15 ml of dimethyl methylphosphonate and 50 ml oftetrahydrofuran anhydride over 45 minutes in a nitrogenatmosphere while the mixture was kept at -60°C. Further,after 15 minutes, a mixture of 16.5 ml of methylmethoxyacetate and 50 ml of tetrahydrofuran anhydride wasadded dropwise to the reaction solution over 30 minutes. Thesolution was stirred for 1.5 hours under ice-cooling.Further, a cooling medium was removed and the reactionsolution was stirred overnight at room temperature. Then,acetic acid and water were added to the reaction solution,the solvent was removed, and extracted with dichloromethane.The organic phase was washed with brine, dried over anhydroussodium sulfate and subjected to silica gel columnchromatography using 2% methanol/ethyl acetate as an eluent,to give 17 g of the target compound.1H-NMR(CDCl3) δ=3.18(2H, d, J=23Hz), 3.44(3H, s), 3.79(3H, s),3.82(3H, s), 4.14(2H, s) b) 2-Benzyl-3-methoxymethyloxy-6-(4-methoxy-3-oxo-1-butenyl)pyridine
    [0281] 6 g of dimethyl 3-methoxy-2-oxopropyl phosphonate wasdissolved in 200 ml of tetrahydrofuran, to which was thenadded 3.2 g of potassium tert-butoxide. After stirring for15 minutes, a solution of 50 ml of tetrahydrofuran containing6 g of 2-benzyl-3-methoxymethyloxypyridine-6-carboxyaldehyde(Production Example 11) was added thereto, followed by stirring for further one hour. Then, water wasadded thereto, the solvent was removed and the mixture wasextracted with ethyl acetate. Further, the organic phasewas washed with brine, dried over anhydrous sodium sulfateand the solvent was removed. The residue was subjected tosilica gel column chromatography using 17-33% ethylacetate/hexane as an eluent for separation and purification,to give 4.6 g of the target compound.1H-NMR(CDCl3) δ=3.30(3H, s), 3.49(3H, s), 4.21(2H, s), 4.32(2H,s), 5.19(2H, s), 7.15-7.35(8H, m), 7.64(1H, d, J=16Hz) c) 2-Benzyl-3-methoxymethyloxy-6-(4-methoxy-3-oxobutyl)pyridine
    [0282] 4.6 g of 2-benzyl-3-methoxymethyloxy-6-(4-methoxy-3-oxo-1-butenyl)pyridinewas dissolved in 100 ml of ethylacetate, 976 mg of 10% palladium carbon was added thereto,and then hydrogenated. After the atmosphere in the reactionsystem was replaced by nitrogen, the catalyst was filteredoff, and the filtrate was evaporated. The resulting residuewas subjected to silica gel column chromatography using 33%ethyl acetate/hexane as an eluent for separation andpurification, to give 1.8 g of the target compound.1H-NMR(CDCl3) δ=2.86(2H, t, J=7.0Hz), 3.05(2H, t, J=7.0Hz),3.31(3H, s), 3.37(3H, s), 4.01(2H, s), 4.14(2H, s), 5.10(2H,s), 6.97(1H, d, J=8.4Hz), 7.15-7.27(6H, m) d) 2-Benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyltrifluoromethane sulfonate
    [0283] 1.8 g of 2-benzyl-3-methoxymethyloxy-6-(4-methoxy-3-oxobutyl)pyridine was dissolved in 50 ml of methanol, and2 ml of concentrated hydrochloric acid was added thereto,followed by heating under reflux for 1.5 hours. Aftercooling as it was, it was neutralized by an aqueous saturatedsodium bicarbonate solution and extracted with ethyl acetate.Further, the organic phase was washed with brine, dried overanhydrous sodium sulfate and the solvent was removed. Theresulting residue was dissolved in 50 ml of dichloromethane.2.7 g of N-phenyltrifluoromethanesulfonimide, 209 mg of4-dimethylaminopyridine and 1 ml of triethylamine were addedthereto, followed by stirring at room temperature for 1.5hours. The solvent was removed, and the residue wassubjected to silica gel column chromatography using 25%ethyl acetate/hexane as an eluent for separation andpurification, to give 2.3 g of the target compound.1H-NMR(CDCl3) δ=2.91(2H, t, J=6.8Hz), 3.13(2H, t, J=6.8Hz),3.37(3H, s), 3.96(2H, s), 4.19(2H, s), 7.14(1H, d, J=8.4Hz),7.20-7.29(5H, m), 7.46(1H, d, J=8.4Hz) e) 3-[2-Benzyl-6- (4-methoxy-3-oxobutyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0284] 10 ml of N,N-dimethylformamide was added to a mixtureof 1.9 g of 2-benzyl-6-(4-methoxy-3-oxobutyl)-3-pyridyltrifluoromethanesulfonate, 773 mg of 3-ethynyl-3-quinuclidinol,525 mg oftetrakis(triphenylphosphine)palladium(0), 267 mg ofcuprous iodide and 2.2 ml of triethylamine, followed bystirring for one hour at 50°C in an oil bath in a nitrogen atmosphere. After cooling as it was, ethyl acetate was addedthereto. The mixture was filtered through Celite, followedby washing with water. The organic phase was washed withbrine, dried over anhydrous sodium sulfate and the solventwas removed. The residue was subjected to silica gel columnchromatography using chloroform/methanol/36% aqueousammonia (46:5:0.5) as an eluent for separation andpurification, to give 1.3 g of the target compound.1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.54-1.64(1H, m), 1.75-1.86(1H,m), 1.95-2.05(2H, m), 2.67-2.90(4H, m), 2.89(2H, t,J=7.0Hz), 3.00(1H, dd, J=2, 14Hz), 3.11(2H, t, J=7.0Hz),3.20(1H, dd, J=2, 14Hz), 3.37(3H, s), 4.00(2H, s), 4.27(2H, s),7.01(1H, d, J=7.9Hz), 7.17-7.26(5H, m), 7.57(1H, d, J=7.9Hz) Example 69 3-[2-Benzyl-6-(2-ethoxycarbonylethenyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0285] The target compound was synthesized in the same manneras in Example 68.1H-NMR(CDCl3) δ=1.34(3H, t, J=7.1Hz), 1.44-1.53(1H, m),1.62-1.72(1H, m), 1.80-1.89(1H, m), 2.08-2.17(2H, m), 2.75-3.05(4H,m), 3.11(1H, dd, J=2, 14Hz), 3.25(1H, dd, J=2, 14Hz),4.28(2H, q, J=7.1Hz), 4.33(2H, s), 6.94(1H, d, J=16Hz),7.18-7.30(6H, m), 7.63(1H, d, J=16Hz), 7.66(1H, d, J=7.9Hz) Example 70 3-[2-Benzyl-6-(2-cyanoethyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0286] The target compound was synthesized in the same manneras in Example 68.1H-NMR(CDCl3) δ=1.36-1.46(1H, m), 1.56-1.66(1H, m), 1.76-1.89(1H, m), 1.98-2.08(2H, m), 2.69-2.95(4H, m), 2.84(2H, t,J=7.3Hz), 3.02(1H, dd, J=2, 14Hz), 3.10(2H, t, J=7.3Hz),3.21(1H, dd, J=2, 14Hz), 4.31(2H, s), 7.04(1H, d, J=7.9Hz),7.18-7.28(5H, m), 7.64(1H, d, J=7.9Hz) Example 71 3-[2-Benzyl-6-(3-oxobutyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0287] The target compound was synthesized in the same manneras in Example 68.1H-NMR(CDCl3) δ=1.35-1.44(1H, m), 1.52-1.62(1H, m), 1.75-1.87(1H,m), 1.98-2.08(2H, m), 2.13(3H, s), 2.68-2.95(4H, m),2.88(2H, t, J=6.9Hz), 3.00(1H, dd, J=2, 14Hz), 3.03(2H, t,J=6.9Hz), 3.19(1H, dd, J=2, 14Hz), 4.27(2H, s), 6.99(1H, d,J=7.9Hz), 7.16-7.28(5H, m), 7.55(1H, d, J=7.9Hz) Example 72 3-(2-Phenyl-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol a) 2-Bromo-6-morpholinopyridine
    [0288] A mixture of 10 g of 2,6-dibromopyridine, 7.4 ml ofmorpholine, 11.7 g of potassium carbonate anhydride and 30ml of N-methyl-2-pyrrolidinonewas heated under stirring for5 hours in an oil bath kept at 100°C in a nitrogen atmosphere.The mixture was extracted by adding ethyl acetate and waterthereto. The extract was washed with water and brine, driedover anhydrous magnesium sulfate and then concentrated.The residue was subjected to silica gel columnchromatography using 2-10% ethyl acetate/hexane, to give 9.8g of the target compound.1H-NMR (CDCl3) δ=3.50(4H, t, J=5Hz), 3.80(4H, t, J=5Hz), 6.50(1H, d, J=8Hz), 6.79(1H, d, J=8Hz), 7.31(1H, t, J=8Hz) b) 2-Phenyl-6-morpholinopyridine
    [0289] A mixture of 1 g of 2-bromo-6-morpholinopyridine, 110mg of 1,3-bis(diphenylphosphino)propanenickel (II)chloride and 4 ml of tetrahydrofuran was stirred in an icebath in a nitrogen atmosphere. A tetrahydrofuran solutionof phenylmagnesium bromide which was prepared from 0.65 mlof bromobenzene, 200 mg of magnesium and 5 ml oftetrahydrofuran was added dropwise into the mixture,followed by stirring at room temperature overnight as it was.The reaction solution was extracted with an aqueoussaturated ammonium chloride and ethyl acetate, and theorganic phase was washed with water and brine, dried overanhydrous magnesium sulfate and then concentrated. Theresidue was subjected to silica gel column chromatographyusing 2-10% ethyl acetate/hexane, to give 750 mg of thetarget compound.1H-NMR (CDCl3) δ=3.62(4H, t, J=5Hz), 3.86(4H, t, J=5Hz), 6.60(1H,d, J=8Hz), 7.15(1H, d, J=8Hz), 7.37(1H, t, J=7Hz), 7.44(2H, t,J=7Hz), 7.58(1H, t, J=8Hz), 8.01(2H, d, J=7Hz) c) 2-Phenyl-6-morpholino-3-iodopyridine
    [0290] A solution of 750 mg of 2-phenyl-6-morpholinopyridineand 5 ml of N,N-dimethylformamide was stirred in an ice bath,and to the mixture was added 740 mg of N-iodosuccinimide,followed by stirring at room temperature overnight.Further, 70 mg of N-iodosuccinimide was added thereto,followed by stirring at room temperature for 5 hours. The reaction mixture was extracted by adding ethyl acetate,water and sodium sulfite thereto, and the organic phase waswashed with water and brine, dried over anhydrous magnesiumsulfate and then concentrated. The residue was subjectedto silica gel column chromatography using 5-10% ethylacetate/hexane, to give 1.1 g of the target compound.1H-NMR (CDCl3) δ=3.52(4H, t, J=5Hz), 3.80(4H, t, J=5Hz), 6.37(1H,d, J=9Hz), 7.36-7.45(3H, m), 7.60-7.65(2H, m), 7.93(1H, d,J=9Hz) d) 3-(2-Phenyl-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol
    [0291] A mixture of 500 mg of 2-phenyl-6-morpholino-3iodopyridine,230 mg of 3-ethynyl-3-quinuclidinol, 79 mg oftetrakis(triphenylphosphine)palladium(0), 1.3 mg ofcuprous iodide, 0.57 ml of triethylamine and 1 ml ofN,N-dimethylformamide was heated under stirring for 4 hoursin an oil bath kept at 75°C in a nitrogen atmosphere. Themixture was extracted by adding aqueous dilute ammonia andethyl acetate thereto, and the organic phase was washed withwater and brine, dried over anhydrous magnesium sulfate andthen concentrated. The residue was subjected to NH-silicagel column chromatography, and eluted with 50% ethylacetate/hexane, ethyl acetate and then 2.5% methanol/ethylacetate, and crystallized from ethyl acetate, to give 296mg of the target compound.1H-NMR (CDCl3) δ=1.32-1.82(3H, m), 1.94-2.03(2H, m), 2.65-2.91(4H,m), 2.95(1H, d, J=14Hz), 3.19(1H, dd, J=2, 14Hz), 3.62(4H, t, J=5Hz), 3.82(4H, t, J=5Hz), 6.54(1H, d, J=8Hz),7.34-7.44(3H, m), 7.62(1H, d, J=8Hz), 7.92(2H, d, J=8Hz) Example 73 3-(2-Phenyloxy-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol a) 2-Phenyloxy-6-morpholino-3-pyridine
    [0292] 250 mg of 60% oil sodium hydride was added to a mixtureof 1 g of 2-bromo-6-morpholinopyridine obtained in Example72a, 580 mg of phenol, 80 mg of cuprous iodide, 26 mg of acopper powder and 3 ml of N-methylpyrrolidine. Afterfoaming stopped, the mixture was heated under stirring inan oil bath kept at 150°C for 3 hours in a nitrogen atmosphere.Aqueous dilute ammonia and ethyl acetate were added thereto,and the mixture was extracted. The organic phase was washedwith water and brine, dried over anhydrous magnesium sulfateand then concentrated. The residue was subjected to silicagel chromatography using 5 to 7% ethyl acetate/hexane, togive 1.1 g of the target compound.1H-NMR (CDCl3) δ=3.40(4H,t,J=5Hz), 3.76(4H, t, J=5Hz)., 6.11(1H,d, J=8Hz), 6.28(1H, d, J=8Hz), 7.15-7.19(3H, m),7.36(2H,t,J=8Hz), 7.47(1H,t,J=8Hz) b) 3-(2-Phenyloxy-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol
    [0293] The target compound was synthesized in the same manneras in Examples 72 c and d.1H-NMR (CDCl3) δ=1.34-2.06(5H, m), 2.74-2.94(4H, m), 3.00(1H,d, J=14Hz), 3.27(1H, dd, J=2, 14Hz), 3.34(4H, t, J=5Hz), 3.69(4H,t, J=5Hz), 6.24(1H, d, J=8Hz), 7.09-7.17(3H, m), 7.34(2H, t, J=4Hz), 7.56(1H, d, J=8Hz) Example 74 3-[2-Benzyl-6-(4-piperidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0294] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.36-1.96(3H, m), 2.00-2.10(2H, m), 2.46(4H,t, J=6Hz), 2.72-2.96(4H, m), 3.04(1H, d, J=14Hz), 3.26(1H, dd,J=2, 14Hz), 3.92(4H, t, J=6Hz), 4.18(2H, s), 6.54(1H, d, J=8Hz),7.14-7.32(5H, m), 7.52(1H, d, J=8Hz) Example 75 3-[2-Benzyl-6-(2-methoxyethyl)amino-3-pyridyl]ethynyl-3-quinuclidinol
    [0295] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.34-1.92(3H, m), 1.98-2.07(2H, m), 2.68-2.92(4H,m), 3.01(1H, d, J=14Hz), 3.22(1H, dd, J=2, 14Hz),3.37(3H, s), 3.49(2H, q, J=5Hz), 3.55(2H, t, J=5Hz), 4.14(2H,s), 4.93(1H, br.t, J=5Hz), 6.21(1H, d, J=8Hz), 7.13-7.31(5H,m), 7.40(1H, d, J=8Hz) Example 76 3-[2-Benzyl-6-(4-acetylpiperidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0296] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.34-1.44(1H, m), 1.53-1.67(3H, m), 1.83-2.08(5H,m), 2.17(3H, s), 2.55(1H, tt, J=4, 11Hz), 2.68-2.96(6H,m), 3.02(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz), 4.15(2H, s),4.35(2H, d, J=13Hz), 6.43(1H, d, J=8Hz), 7.17(1H, t, J=7Hz),7.22-7.32(4H, m), 7.43(1H, d, J=8Hz) Example 77 3-[2-Benzyl-6-[(2R)-2-methoxymethylpyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0297] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.36-2.10(9H, m), 2.74-2.95(4H, m), 3.04(1H,d, J=14Hz), 3.20-3.30(3H, m), 3.32(3H, s), 3.40-3.49(1H, m),3.53(1H, dd, J=3, 9Hz), 4.06-4.30(3H, m), 6.18(1H, d, J=9Hz),7.16(1H, t, J=7Hz), 7.25(2H, t, J=7Hz), 7.33(2H, d, J=7Hz),7.40(1H, d, J=9Hz) Example 78 3-[2-Benzyl-6-(thiomorpholino)-3-pyridyl]ethynyl-3-quinuclidinol
    [0298] The target compound was synthesized in the same manneras in Example 191 using 2-benzyl-3-bromo-6-pyridyltrifluoromethanesulfonate (Production Example 3) asstarting material.1H-NMR (CDCl3) δ=1.36-1.95(3H, m), 1.97-2.08(2H, m), 2.58-2.63(4H,m), 2.70-2.95(4H, m), 3.03(1H, d, J=14Hz), 3.25(1H,d, J=14Hz), 3.94-3.99(4H, m), 4.15(2H, s), 6.40(1H, d, J=9Hz),7.14-7.32(5H, m), 7.45(1H, d, J=9Hz) Example 79 3-[2-Benzyl-6-(3-hydroxypiperidino)-3-pyridyl]ethynyl-3-quinuclidinol
    [0299] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.36-1.98(7H, m), 1.98-2.08(2H, m), 2.70-2.95(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, d, J=14Hz),3.40-3.90(5H, m), 4.14(2H, s), 6.47(1H, d, J=9Hz), 7.12-7.32(5H, m), 7.42(1H, d, J=9Hz) Example 80 3-[2-Benzyl-6-(4-cyanopiperidino)-3-pyridyl]ethynyl-3-quinuclidinol
    [0300] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.36-2.10(9H, m), 2.70-2.95(5H, m), 3.03(1H,d, J=14Hz), 3.24(1H, dd, J=2,14Hz), 3.47-3.55(2H, m), 3.81-3.89(2H,m), 4.16(2H, s), 6.45(1H, d, J=9Hz), 7.15-7.31(5H, m),7.47(1H, d, J=9Hz) Example 81 3-(2-Benzyl-6-piperidino-3-pyridyl]ethynyl-3-quinuclidinol
    [0301] The target compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.52-1.82 (7H, m), 1.85-1.95(1H,m), 2.00-2.07(2H, m), 2.72-2.96(4H, m), 3.02(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.56(4H, dd, J=5.6Hz, 4.8Hz),4.15(2H, s), 6.41(1H, d, J=8.8Hz), 7.14-7.33(5H, m), 7.41(1H,d, J=8.8Hz) Example 82 3-[2-Benzyl-6-(N-morpholinoamino)-3-pyridyl]ethynyl-3-quinuclidinol
    [0302] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ = 1.35-1.95(3H, m), 1.98-2.08(2H, m), 2.70-2.93(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),3.53(4H, t, J=5Hz), 3.79(4H, t, J=5Hz), 4.17(2H, s), 6.41(1H,d, J=9Hz), 7.14-7.32(5H, m), 7.47(1H, d, J=9Hz) Example 83 3-[2-Benzyl-6-(4-tetrahydropyranyl)amino-3- pyridyl]ethynyl-3-quinuclidinol
    [0303] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.35-1.95(5H, m), 1.96-2.08(4H, m), 2.70-2.93(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),3.50(2H, dt, J=2, 12Hz), 3.75-3.85(1H, m), 3.98(2H, td, J=4,12Hz), 4.14(2H, s), 4.53(1H, d, J=8Hz), 6.18(1H, d, J=8Hz),7.14-7.32(5H, m), 7.41(1H, d, J=8Hz) Example 84 3-[2-Benzyl-6-(1-pyrrolidinyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0304] The target compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.57-1.67(1H, m), 1.89-1.95(1H,m), 1.98(4H, t, J=6.2Hz), 2.01-2.10(2H, m), 2.72-2.98(4H,m), 3.05(1H, d, J=14Hz), 3.25(1H, d, J=14Hz), 3.45(4H,t, J=6.2Hz), 4.16(2H, s), 6.14(1H, d, J=8.6Hz), 7.16-7.35(5H,m), 7.40(1H, d, J=8.6Hz) Example 85 3-[2-Benzyl-6-(3-hydroxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0305] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.35-1.95(3H, m), 1.98-2.20(4H, m), 2.70-2.95(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, d, J=14Hz),3.50-3.65(4H, m), 4.16(2H, s), 4.57-4.61(1H, m), 6.16(1H, d,J=9Hz), 7.16(1H, t, J=7Hz), 7.24(2H, t, J=7Hz), 7.32(2H, d,J=7Hz), 7.42(1H, d, J=9Hz) Example 86 (3R)-3-[2-Benzyl-6-[(3R)-3- hydroxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0306] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.35-1.95(3H, m), 1.98-2.20(4H, m), 2.70-2.95(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, d, J=14Hz),3.50-3.65(4H, m), 4.16(2H, s), 4.57-4.61(1H, m), 6.16(1H, d,J=9Hz), 7.16(1H, t, J=7Hz), 7.24(2H, t, J=7Hz), 7.32(2H, d,J=7Hz), 7.42(1H, d, J=9Hz) Example 87 (3R)-3-[2-Benzyl-6-[(3S)-3-hydroxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0307] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.35-1.95(3H, m), 1.98-2.20(4H, m), 2.70-2.95(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, d, J=14Hz),3.50-3.65(4H, m), 4.16(2H, s), 4.57-4.61(1H, m), 6.16(1H, d,J=9Hz), 7.16(1H, t, J=7Hz), 7.24(2H, t, J=7Hz), 7.32(2H, d,J=7Hz), 7.42(1H, d, J=9Hz) Example 88 3-[2-Benzyl-6-(1-azetidinyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0308] The target compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ=1.37-1.42(1H, m), 1.52-1.62(1H, m), 1.78-1.86(1H,m), 1.98-2.07(2H, m), 2.37(2H, quint, J=7.4Hz),2.70-2.92(4H, m), 3.00(1H, d, J=14Hz), 3.21(1H, dd, J=2, 14Hz),4.03(4H, t, J=7.4Hz), 4.16(2H, s), 6.05(1H, d, J=8.5Hz), 7.14-7.32(5H, m), 7.40(1H, d, J=8.5Hz) Example 89 (3R)-3-[2-Benzyl-6-(1-azetidinyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0309] The target compound was synthesized in the same manneras in Example 7.1H-NMR(CDCl3) δ =1.37-1.42(1H, m), 1.52-1.62(1H, m), 1.78-1.86(1H,m), 1.98-2.07(2H, m), 2.37(2H, quint, J=7.4Hz),2.70-2.92(4H, m), 3.00(1H, d, J=14Hz), 3.21(1H, dd, J=2, 14Hz),4.03(4H, t, J=7.4Hz), 4.16(2H, s), 6.05(1H, d, J=8.5Hz),7.14-7.32(5H, m), 7.40(1H, d, J=8.5Hz) Example 90 (3R)-3-[2-Benzyl-6-(3-hydroxyazetidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0310] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.40-1.95(3H, m), 2.05-2.15(2H, m), 2.65-2.95(4H,m), 2.98-3.22(2H, m), 3.88(2H, dd, J=5, 10Hz), 4.17(2H,s), 4.26(2H, dd, J=6, 10Hz), 4.65-4.75(1H, m), 6.13(1H, d,J=9Hz), 7.10-7.20(1H, m), 7.20-7.30(4H, m), 7.44(1H, d, J=9Hz) Example 91 3-[2-Benzyl-6-(3-methoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0311] The target compound was synthesized in the same manneras in Example 10.1H-NMR(CDCl3) δ=1.37-1.42(1H, m), 1.52-1.62(1H, m), 1.84-1.94(1H,m), 1.98-2.20(4H, m), 2.72-2.94(4H, m), 3.01(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.36(3H, s), 3.46-3.64(4H,m), 4.02-4.08(1H, m), 4.15(2H, s), 6.13(1H, d, J=8.6Hz),7.13-7.34(5H, m), 7.40(1H, d, J=8.6Hz) Example 92(3R)-3-[2-benzyl-6-[(3S)-3-methoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0312] The target compound was synthesized in the same manneras in Example 10.1H-NMR(CDCl3) δ=1.37-1.42(1H, m), 1.52-1.62(1H, m), 1.84-1.94(1H,m), 1.98-2.20(4H, m), 2.72-2.94(4H, m), 3.01(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.36(3H, s), 3.46-3.64(4H,m), 4.02-4.08(1H, m), 4.15(2H, s), 6.13(1H, d, J=8.6Hz),7.13-7.34(5H, m), 7.40(1H, d, J=8.6Hz) Example 93 (3R)-3-[2-Benzyl-6-[(3R)-3-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0313] The target compound was synthesized in the same manneras in Example 10.1H-NMR(CDCl3) δ=1.37-1.42(1H, m), 1.52-1.62(1H, m), 1.84-1.94(1H,m), 1.98-2.20(4H, m), 2.72-2.94(4H, m), 3.01(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.36(3H, s), 3.46-3.64(4H,m), 4.02-4.08(1H, m), 4.15(2H, s), 6.13(1H, d, J=8.6Hz),7.13-7.34(5H, m), 7.40(1H, d, J=8.6Hz) Example 94 3-[2-Benzyl-6-(3-ethoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0314] The target compound was synthesized in the same manneras in Example 10.1H-NMR(CDCl3) δ=1.21(3H, t, J=7.0Hz), 1.35-1.45(1H, m),1.54-1.62(1H, m), 1.85-1.95(1H, m), 1.98-2.15(4H, m), 2.72-2.94(4H,m), 3.01(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.48-3.62(6H, m), 4.12-4.20(3H, m), 6.13(1H, d, J=8.6Hz),7.13-7.34(5H, m), 7.40(1H, d, J=8.6Hz) Example 95 (3R)-3-[2-Benzyl-6-[(3R)-3-ethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0315] The target compound was synthesized in the same manneras in Example 10.1H-NMR(CDCl3) δ=1.21(3H, t, J=7.0Hz), 1.35-1.45(1H, m),1.54-1.62(1H, m), 1.85-1.95(1H, m), 1.98-2.15(4H, m), 2.72-2.94(4H,m), 3.01(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),3.48-3.62(6H, m), 4.12-4.20(3H, m), 6.13(1H, d, J=8.6Hz),7.13-7.34(5H, m), 7.40(1H, d, J=8.6Hz) Example 96(3R)-3-[2-Benzyl-6-[(3S)-3-ethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0316] The target compound was synthesized in the same manneras in Example 10.1H-NMR(CDCl3) δ =1.21 (3H, t, J=7.0Hz), 1.35-1.45(1H, m),1.54-1.62(1H, m), 1.85-1.95(1H, m), 1.98-2.15(4H, m), 2.72-2.94(4H,m), 3.01(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),3.48-3.62(6H, m), 4.12-4.20(3H, m), 6.13(1H, d, J=8.6Hz),7.13-7.34(5H, m), 7.40(1H, d, J=8.6Hz) Example 97 (3R)-3-[2-Benzyl-6-(4-ethoxypiperidino)-3-pyridyl]ethynyl-3-quinuclidinol
    [0317] The target compound was synthesized in the same manneras in Example 7 by using (3R)-3-ethynyl-3-quinuclidinol.1H-NMR (CDCl3) δ=1.22(3H, t, J=7Hz), 1.35-1.44(1H, m),1.51-1.62(3H, m), 1.73-1.96(3H, m), 1.97-2.08(2H, m), 2.70-2.95(4H, m), 3.01(1H, d, J=14Hz), 3.14-3.26(3H, m), 3.48-3.58(3H,m), 4.00-4.09(2H, m), 4.15(2H, s), 6.43(1H, d, J=9Hz),7.16(1H, t, J=7Hz), 7.24(2H, t, J=7Hz), 7.30(2H, d, J=7H.2),7.42(1H, d, J=9Hz) Example 98 3-[2-Benzyl-6-(3-methoxyazetidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0318] The target compound was synthesized in the same manneras in Example 10.1H-NMR (CDCl3) δ=1.35-1.90(3H, m), 1.97-2.08(2H, m), 2.70-2.95(4H,m), 3.01(1H, d, J=14Hz), 3.21(1H, dd, J=2, 14Hz),3.34(3H, s), 3.90(2H, dd, J=4, 10Hz), 4.16(2H, s), 4.21(2H, dd,J=6, 10Hz), 4.30-4.35(1H, m), 6.10(1H, d, J=9Hz), 7.16( 1H, t,J=7Hz), 7.22-7.32(4H, m), 7.42(1H, d, J=9Hz) Example 99 (3R)-3-[2-Benzyl-6-(3-methoxyazetidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0319] The target compound was synthesized in the same manneras in Example 10 by using (3R)-3-ethynyl-3-quinuclidinol.1H-NMR (CDCl3) δ=1.35-1.90(3H, m), 1.97-2.08(2H, m), 2.70-2.95(4H,m), 3.01(1H, d, J=14Hz), 3.21(1H, dd, J=2, 14Hz),3.34(3H, s), 3.90(2H, dd, J=5, 10Hz), 4.16(2H, s), 4.21(2H, dd,J=6, 10Hz), 4.30-4.35(1H, m), 6.10(1H, d, J=9Hz), 7.16( 1H, t,J=7Hz), 7.22-7.32(4H, m), 7.42(1H, d, J=9Hz) Example 100 (3R)-3-[2-Benzyl-6-(3-ethoxyazetidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0320] The target compound was synthesized in the same manneras in Example 10 by using (3R)-3-ethynyl-3-quinuclidinol.1H-NMR (CDCl3) δ=1.24(3H, t, J=7Hz), 1.34-1.43(1H, m), 1.51-1.64(1H, m), 1.80-1.90(1H, m), 1.97-2.08(2H, m), 2.66-2.93(4H,m), 3.00(1H, d, J=14Hz), 3.21(1H, dd, J=2, 14Hz),3.49(2H, q, J=7Hz), 3.90(2H, dd, J=4, 10Hz), 4.16(2H, s),4.21(2H, dd, J=6, 10Hz), 4.37-4.44(1H, m), 6.09(1H, d, J=8Hz),7.16(1H, t, J=7Hz), 7.24(2H, t, J=7Hz), 7.29(2H, d, J=7Hz),7.41(1H, d, J=8Hz) Example 101 (3R)-3-[2-Benzyl-6-(3-methoxymethyloxyazetidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0321] The target compound was synthesized in the same manneras in Example 7.1H-NMR (CDCl3) δ=1.35-1.90(3H, m), 1.97-2.08(2H, m), 2.68-2.93(4H,m), 3.00(1H, d, J=14Hz), 3.21(1H, dd, J=2, 14Hz),3.41(3H, s), 3.94(2H, dd, J=5, 10Hz), 4.16(2H, s), 4.26(2H, dd,J=7, 10Hz), 4.55-4.61(1H, m), 4.67(2H, s), 6.10(1H, d, J=8Hz),7.16( 1H, t, J=7Hz), 7.22-7.32(4H,m), 7.42(1H, d, J=9Hz) Example 102 3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-ethyloxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0322] The target compound was synthesized in the same manneras in Example 10 except that methyl iodide was altered toethyl iodide.1H-NMR(CDCl3) δ=1.26(3H, t, J=7Hz), 1.38-1.63(2H, m), 1.84-1.93(1H,m), 2.00-2.07(2H, m), 2.74-2.93(4H, m), 3.00-3.04(1H,m), 3.21-3.25(1H, m), 3.48-3.52(2H, m), 3.61(2H, q, J=7Hz),3.71-3.77(2H, m), 3.94-3.96(1H, m), 4.15(2H, s), 4.37-4.40(1H,m), 6.15(1H, d, J=8Hz), 7.16-7.33(5H, m), 7.42(1H, d, J=8Hz) Example 103 (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0323] The target compound was synthesized in the same manneras in Example 10.1H-NMR(DMSO-d6) δ=1.30-1.32(1H, m), 1.52(1H, m), 1.77-1.99(3H,m), 2.56-2.72(4H, m), 2.82(1H, d, J=14Hz), 3.01(1H,d, J=14Hz), 3.50-3.53(2H, m), 4.01-4.11(4H, m), 5.10-5.11(2H,m), 6.26(1H, d, J=8Hz), 7.14-7.34(5H, m), 7.42(1H,d, J=8Hz) Example 104 (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidine-1-yl]pyridine
    [0324] 700 mg of 60% oily sodium hydride and 1 ml of methyl iodidewere added to a mixture of 1.78 g of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine(Example10a), 10 ml of tetrahydrofuran and 10 ml of N,N-dimethylformamide.The mixture was extracted with ethylacetate-water. The organic layer was washed with water andbrine, dried over anhydrous magnesium sulfate and evaporated.The residue was subjected to silica gel chromatography andeluted with 15% ethyl acetate/hexane, to give 1.0 g of thetarget compound.1H-NMR (CDCl3) δ=3.42(6H, s), 3.55(2H, dd, J=2, 11Hz), 3.67(2H,dd, J=4, 11Hz), 3.92-3.96(2H, m), 3.97(2H, s), 6.16(1H, d, J=9Hz), 6.33(1H, d, J=7Hz), 7.18(1H, t, J=7Hz), 7.24-7.34(5H,m) (b) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0325] The target compound was synthesized in the same manneras in Example 10.1H-NMR (CDCl3) δ =1.34-1.44(1H, m), 1.52-1.62(1H, m), 1.82-1.92(1H,m), 1.97-2.08(2H, m), 2.70-2.95(4H, m), 3.01(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.41(6H, s), 3.53-3.67(4H,m) , 3.92-3.96(2H, m), 4.16(2H, s), 6.14(1H, d, J=9Hz), 7.15(1H,t, J=7Hz), 7.24(2H, t, J=7Hz), 7.31(2H, d, J=7Hz), 7.40(1H, d,J=9Hz) Example 105 (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-diethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0326] The target compound was synthesized in the same manneras in Example 104 by using (3R)-3-ethynyl-3-quinuclidinol.1H-NMR (CDCl3) δ=1.20(6H, t, J=7Hz), 1.35-1.95(3H, m),1.98-2.09(2H, m), 2.70-2.95(4H, m), 3.03(1H, d, J=14Hz),3.24(1H, dd, J=2, 14Hz), 3.50-3.56(2H, m), 3.59(4H, q, J=7Hz),3.67(2H, dd, J=4, 12Hz), 4.02(2H, dd, J=2, 4Hz), 4.15(2H, s),6.14(1H, d, J=9Hz), 7.15(1H, t, J=7Hz), 7.24(2H, t, J=7Hz),7.32(2H, d, J=7Hz), 7.40(1H, d, J=9Hz) Example 106(3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]pyridine
    [0327] 300 mg of 4-dimethylaminopyridine, 10 ml oftriethylamine and 9.7 g of 3-nitrobenzenesulfonyl chloridewere added to a solution of 10.0 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridineobtained in the same manner as in Example 10-c in 150 ml ofethyl acetate, followed by stirring at room temperature for3 days. The reaction solution was first filtered through50 g of silica gel, and washed with ethyl acetate. Further,the filtrate was filtered through 50 g of NH-silica gel andwashed with ethyl acetate. The filtrate was concentrated,to give 14.6 g of the target compound.1H-NMR (CDCl3) δ=3.38(3H, s), 3.48(1H, d, J=12Hz), 3.58-3.73(3H,m), 4.08-4.20(3H, m), 5.10-5.14(1H, m), 5.92(1H, d, J=8Hz),7.18(1H, t, J=7Hz), 7.25(2H, t, J=7Hz), 7.32(2H, d, J=7Hz),7.69(1H, d, J=8Hz), 7.73(1H, t, J=8Hz), 8.21(1H, d, J=8Hz),8.49(1H, d, J=8Hz), 8.75(1H, s) b) 2-Benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidine-1-yl]pyridine
    [0328] 4.2 ml of acetic acid was added to a mixture of 7.9 gof cesium carbonate and 15 ml of dimethyl sulfoxide. Afterfoaming stopped, a mixture of 14.4 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]pyridineand 35 ml of dimethylsulfoxide was added thereto, followed by heating under stirring for 6 hours in an oil bath kept at 70°C in a nitrogenatmosphere. The reaction solution was cooled and thensubjected to extraction with ethyl acetate-water. Theorganic phase was washed with water and brine brine, driedover anhydrous magnesium sulfate and then concentrated.The residue was subjected to silica gel columnchromatography using 10-15% ethyl acetate/hexane, to give7.5 g of the target compound.1H-NMR (CDCl3) δ=2.12(3H, s), 3.42(3H, s), 3.37-3.73(4H, m),4.04(1H, dt, J=4, 6Hz), 4.19(2H, s), 5.42-5.47(1H, m), 5.96(1H,d, J=8Hz), 7.19(1H, t, J=7Hz), 7.27(2H, t, J=7Hz), 7.38(2H, d,J=7Hz), 7.70(1H, d, J=8Hz) c) 2-Benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine
    [0329] A 28% solution of sodium methoxide in 0.33 ml of methanolwas added to a mixture of 7.5 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-acetoxy-4-methoxypyrrolidine-1-yl]pyridineand 30 ml of methanol, followed by stirring at roomtemperature for 30 minutes in a nitrogen atmosphere. Waterwas added thereto, and the mixture was extracted with ethylacetate. The organic phase was washed with brine, dried overanhydrous magnesium sulfate and then concentrated. Theresidue was subjected to silica gel column chromatographyusing 20-50% ethyl acetate, to give 6.7 g of the targetcompound.1H-NMR (CDCl3) δ=2.63(1H, d, J=5Hz), 3.38-3.67(4H, m), 3.47(3H,s), 3.93(1H, q, J=5Hz), 4.18(2H, s), 4.41(1H, quint., J=5Hz), 5.96(1H, d, J=9Hz), 7.18(1H, t, J=7Hz), 7.26(2H, t, J=7Hz),7.37(2H, d, J=7Hz), 7.69(1H, d, J=9Hz) d) (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0330] A mixture of 4.6 g of 2-benzyl-3-iodo-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine,1.7 g of(3R)-3-ethynyl-3-quinuclidinol, 130 mg oftetrakis(triphenylphosphine)palladium(0), 110 mg ofcuprous iodide and 3.1 ml of triethylamine was stirred for5 hours at room temperature in a nitrogen atmosphere. Thereaction solution was extracted with aqueous diluteammonia-ethyl acetate, and the organic phase was washed withwater and brine, dried over anhydrous magnesium sulfate andthen concentrated. The residue was subjected to NH-silicagel column chromatography using 0-5% methanol/ethyl acetate,to give 4.0 g of the target compound.1H-NMR (CDCl3) δ=1.34-1.93(3H, m), 1.97-2.07(2H, m), 2.63-2.94(5H,m), 3.02 (1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),3.41-3.57(2H, m), 3.48(3H, s), 3.60-3.73(2H, m), 3.94(1H, q,J=5Hz), 4.41(1H, q, J=5Hz), 6.12(1H, d, J=9Hz), 7.16(1H, t,J=7Hz), 7.24(2H, t, J=7Hz), 7.31(2H, d, J=7Hz), 7.41(1H, d,J=9Hz) Example 107 (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1- yl]pyridine
    [0331] 3.0 ml of a dichloromethane solution containing 481 mgof 2-benzyl-6-[(3S,4S)-3,4-dihydroxypyrrolidine-1-yl]pyridinewas slowly added dropwise into 5.0 ml of adichloromethane solution containing 235 µl ofdiethylaminosulfur trifluoride at -78°C. After stirringunder heating for 30 minutes at room temperature, it wasfurther stirred for one hour at 40°C. After cooling as itwas, water was added to the reaction solution and the mixturewas then extracted with ethyl acetate. The organic phasewas washed with brine and the solvent was removed. Theresidue was subjected to silica gel column chromatographyand eluted with hexane/ethyl acetate (5:1) and then withhexane/ethyl acetate (2:1), to give 104 mg of the targetcompound.1H-NMR(CDCl3) δ =3.71-3.93(4H, m), 3.99(2H, s), 5.19-5.34(2H,m), 6.19(1H, d, J=8Hz), 6.42(1H, d, J=7Hz), 7.21-7.38(6H, m) b) 2-Benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-iodopyridine
    [0332] 94 mg of N-iodosuccinic acid imide was added little bylittle to 5.0 ml of an N,N-dimethylformamide solutioncontaining 104 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]pyridineunder ice-cooling,followed by stirring overnight as it was. Water was addedto the reaction solution and the mixture was extracted withethyl acetate. The organic phase was washed with an aqueoussodium thiosulfate solution, water and brine, and the solvent was removed. The residue was subjected to NH-silicagel (Fuji Silicia) column chromatography and eluted withhexane/ethyl acetate (10:1), to give 152 mg of the targetcompound.1H-NMR(CDCl3) δ=3.66-3.86(4H, m), 4.20(2H, s), 5.18-5.33(2H,m), 6.01(1H, d, J=9Hz), 7.18-7.38(5H, m), 7.74(1H, d, J=9Hz) c) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0333] A mixture of 152 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-iodopyridine,60 mg of (3R)-3-ethynyl-3-quinuclidinol,22 mg oftetrakis(triphenylphosphine)palladium(0), 7 mg of cuprousiodide, 106 µl of triethylamine and 1.5 ml of methanol washeated under stirring for 3 hours at 75°C in a nitrogenatmosphere. The reaction solution was poured into anaqueous dilute ammonia and then extracted with ethyl acetate.The extract was washed with brine and the solvent was removed.The residue was subjected to NH-silica gel (Fuji Silicia)column chromatography, eluted with hexane/ethyl acetate(1:1) and then with ethyl acetate/methanol (15:1) andcrystallized from hexane/ethyl acetate, to give 65 mg of thetarget compound.1H-NMR(CDCl3) δ=1.37-1.44(1H, m), 1.58(1H, m), 1.88-1.89(1H,m), 2.02-2.05(2H, m), 2.75-2.88(4H, m), 3.03(1H, d, J=14Hz),3.24(1H, dd, J=2, 14Hz), 3.75-3.93(4H, m), 4.18(2H, s),5.19-5.34(2H, m), 6.19(1H, d, J=9Hz), 7.16-7.33(5H, m), 7.47(1H,d, J=9Hz) Example 108 (3R)-3-[2-Benzyl-6-[(3R)-3-fluoropyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0334] The target compound was synthesized from (3S)-1-benzyl-3-pyrrolidinolin the same manner as in Example 107.1H-NMR(CDCl3) δ=1.37-1.61(2H, m), 1.86-1.94(1H, m), 2.00-2.19(3H,m), 2.33-2.42(1H, m), 2.75-2.90 (4H, m), 3.03(1H, d,J=14Hz), 3.25(1H, dd, J=2, 14Hz), 3.52-3.90(4H, m), 4.17(2H,s), 5.29-5.43(1H, m), 6.18(1H, d, J=8Hz), 7.15-7.34(5H, m),7.44(1H, d, J=8Hz) Example 109 (3R)-3-[2-Benzyl-6-[(3S)-3-fluoropyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0335] The target compound was synthesized from (3R)-1-benzyl-3-pyrrolidinolin the same manner as in Example 107.1H-NMR(CDCl3) δ=1.37-1.60(2H, m), 1.86-1.93(1H, m), 1.99-2.19(3H,m), 2.32-2.42(1H, m), 2.75-2.90(4H, m), 3.03(1H, d,J=14Hz), 3.25(1H, dd, J=2, 14Hz), 3.52-3.90(4H, m), 4.17(2H,s), 5.29-5.43(1H, m), 6.18(1H, d, J=8Hz), 7.15-7.34(5H, m),7.44(1H, d, J=8Hz) Example 110 (3R)-3-[2-Benzyl-6-[(3S,4R)-3-fluoro-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0336] The target compound was synthesized using 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine(Production Example 10c) in the same manner asin Example 107. 1H-NMR(CDCl3) δ=1.39-1.44(1H, m), 1.57-1.63(1H, m), 1.87-1.93(1H,m), 2.02-2.06(2H, m), 2.75-2.89(4H, m), 3.03(1H, d,J=14Hz), 3.24(1H, dd, J=2, 14Hz), 3.43(3H, s), 3.66-3.80(4H,m), 4.06-4.09(1H, m), 4.16(2H,s), 5.08-5.21(1H, m), 6.16(1H,d, J=9Hz), 7.14-7.32(5H, m), 7.43(1H, d, J=9Hz) Example 111 (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Bromo-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine
    [0337] A mixture of 12.8 g of 2,6-dibromopyridine, 8.87 g of(3R,4R)-3,4-dihydroxypyrrolidine acetate, 10 ml of 1,8-diazabicyclo[5,4,0]-7-undeceneand 20 ml of 1-methyl-2-pyrrolidinonewas heated under stirring for 2 hours in a 70°Coil bath. After cooling, water was added thereto and themixture was extracted with ethyl acetate five times. Theorganic layers were combined, washed with water and brine,dried over anhydrous magnesium sulfate and concentrated.The residue was subjected to silica gel columnchromatography using 10-100% ethyl acetate/hexane, to give10.1 g of the target compound.1H-NMR (CDCl3) δ=1.86 (2H, br.s), 3.49(2H, d, J=11Hz),3.80(2H,dd,J=4,11Hz), 4.34(2H, br.s), 6.26(1H, d, J=8Hz),6.71(1H, d, J=8Hz), 7.26(1H, t, J=8Hz) b) 2-Bromo-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridine
    [0338] 1.54 g of 60% oily sodium hydride and then 3.0 ml of chloromethyl methyl ether were added to a mixture of 10 gof 2-bromo-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridineand 100 ml of tetrahydrofuran at roomtemperature under stirring, followed by stirring at the sametemperature for one hour. The reaction solution wasextracted with ethyl acetate-water, and the organic phasewas washed with brine, dried over anhydrous magnesiumsulfate and then concentrated. The residue was subjectedto silica gel column chromatography using 10-100% ethylacetate/hexane, to give7.6 g of the target compound.1H-NMR (CDCl3) δ=2.95(1H, d, J=4Hz), 3.36-3.50(2H, m), 3.44(3H,s), 3.78-3.88(2H, m), 4.06-4.12(1H, m), 4.32-4.38(1H, m),4.72(1H, d, J=7Hz), 4.76(1H, d, J=7Hz), 6.24(1H; d, J=8Hz),6.70(1H, d, J=8Hz), 7.25(1H, t, J=8Hz) c) 2-Benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridine
    [0339] 46.7 ml of a tetrahydrofuran solution containing 1.07mol of magnesium benzyl chloride was added dropwise into asolution of 50 ml of tetrahydrofuran containing 5.1 g of2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridineand 451 mg of 1,3-bis(diphenylphosphino)propanenickel(II)chloride over 10minutes in an ice bath. After cooling as it was overnight,the reaction solution was poured into aqueous saturatedammonium chloride and extracted with ethyl acetate. Theorganic phase was washed with brine and the solvent wasremoved. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethylacetate (10:1) and then with hexane/ethyl acetate (1:1), togive 5.2 g of the target compound.1H-NMR(CDCl3) δ=3.45(3H, s), 3.36-3.47(2H, m), 3.85-3.91(2H,m), 3.97(2H, s), 4.05-4.11(1H, m), 4.32-4.35(1H, m), 4.73-4.79(2H,m), 6.16(1H, d, J=8Hz), 6.37(1H, d, J=8Hz), 7.17-7.38(6H,m) d) 2-Benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]pyridineand 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine
    [0340] 5.0 ml of a dichloromethane solution of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridinewas added dropwise into a solution of 10 ml ofdichloromethane containing 278 µl of diethylaminosulfurtrifluoride at -78°C over 10 minutes. After stirring at roomtemperature for one hour, it was heated under stirring at 40°Cfor one hour. After cooling as it was, the reaction solutionwas poured into water. The mixture was extracted with ethylacetate, and the organic phase was washed with brine and thesolvent was removed. Then, the residue was subjected to silicagel column chromatography and eluted with hexane/ethyl acetate(10:1) and then with hexane/ethyl acetate (2:1), to give 56.7mg of 2-benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]pyridine (1H-NMR(CDCl3) δ=3.38(3H, s),3.65-3.82(4H, m), 3.97(2H, s), 4.41-4.43(1H, m), 4.69-4.75(2H,m), 5.18(1H, br.d, J=49Hz), 6.18(1H, d, J=8Hz), 6.38(1H, d,J=7Hz), 7.01-7.36(6H, m) ) and 294 mg of a crude refined product of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine.This crude purifiedproduct was purified by a thin layer chromatography (developedthree timed using hexane/ethyl acetate (5/1) and three timesusing hexane/ethyl acetate (4/1)), to give 47.8 g of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridine(1H-NMR(CDCl3) δ = 3.48(3H, s), 3.54-3.73(4H, m),3.97(2H, s), 4.00-4.04(1H, m), 4.41-4.46(1H, m), 5.41(2H, d,J=56Hz), 6.15(1H, d, J=8Hz), 6.37(1H, d, J=7Hz), 7,17-7.35(6H,m)). e) 2-Benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]-3-iodopyridine
    [0341] 44.4 mg of N-iodosuccinic acid imide was added littleby little to a solution containing 56.7 mg of 2-benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]pyridineand 3.0 ml of N,N-dimethylformamide understirring under ice-cooling, followed by stirring overnightas it was. Water was added to the reaction solution,followed by extracting with ethyl acetate. The organicphase was successively washed with an aqueous sodiumthiosulfate solution, water and brine, and the solvent wasremoved. The residue was eluted with ethyl acetate throughNH-silica gel (Fuji Silicia), to give 73.4 mg of the targetcompound.1H-NMR(CDCl3) δ=3.36(3H, s), 3.58-3.76(4H, m), 4.19(2H, s),4.37-4.41(1H, m), 4.70(2H, s), 5.09-5.22(1H, m), 6.00(1H, d,J=9Hz), 7.16-7.38(5H, m), 7.70(1H, d, J=9Hz) f) 2-Benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-iodopyridine
    [0342] A mixture of 73.4 mg of 2-benzyl-6-[(3R,4S)-3-methoxymethyloxy-4-fluoropyrrolidine-1-yl]-3-iodopyridineand 5.0 ml of trifluoroacetic acid was heatedunder stirring for 2 hours at 45°C. After cooling as it was,it was poured into an aqueous potassium carbonate solutionand extracted with ethyl acetate. The organic phase waswashed with brine and the solvent was removed. Then, theresidue was subjected to silica gel column chromatographyand eluted with hexane/ethyl acetate (5:1) and then withhexane/ethyl acetate (1:1), to give 50 mg of the targetcompound.1H-NMR(CDCl3) δ=3.46-3.82(4H, m), 4.19(2H, s), 4.48-4.51(1H,m), 5.04(1H, br.d, J=52Hz), 6.00(1H, d, J=9Hz), 7.16-7.38(5H,m), 7.71(1H, d, J=9Hz) g) (3R)-3-[2-Benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0343] A mixture of 50 mg of 2-benzyl-6-[(3R,4S)-3-hydroxy-4-fluoropyrrolidine-1-yl]-3-iodopyridine,21 mg of (3R)-3-ethynyl-3-quinuclidinol,15 mg oftetrakis(triphenylphosphine)palladium(0), 1 mg of cuprousiodide, 53 µl of triethylamine and 3.0 ml of N,N-dimethylformamidewas heated under stirring for 3 hours at75°C in a nitrogen atmosphere. The reaction solution waspoured into an aqueous dilute ammonia, was then extracted with ethyl acetate. Then, the organic phase was washed withbrine and the solvent was removed. The residue was subjectedto NH-silica gel (Fuji Silicia) column chromatography andeluted with hexane/ethyl acetate (1:1) and then with ethylacetate/methanol (15:1), to give 37 mg of the targetcompound.1H-NMR(CDCl3) δ =1.35-1.43(1H, m), 1.56-1.58(1H, m), 1.85-1.90(1H,m), 2.01-2.16(2H, m), 2.73-2.86(4H, m), 2.97-3.00(1H,m), 3.15-3.21(1H, m), 3.57-3.86(4H, m), 4.15(2H, s), 4.47-4.49(1H,m), 5.04(1H, br.d, J=52Hz), 6.14(1H, d, J=9Hz),7.15-7.32 (5H, m), 7.42(1H, d, J=9Hz) Example 112 (3R)-3-[2-Benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-iodopyridine
    [0344] 37.4 mg of N-iodosuccinimide was added little by littleto a solution containing 47.8 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]pyridineobtained in Example 111 and 4.0 ml of N,N-dimethylformamideunder stirring in an ice-bath, followed by stirringovernight as it was. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate.The organic phase was successively washed with an aqueoussodium thiosulfate solution, water and brine, and thesolvent was removed. The residue was subjected to NH-silicagel (Fuji Silicia) chromatography and eluted with hexane/ethyl acetate (5:1) and then with hexane/ethylacetate (3:1), to give 43.9 mg of the target compound.1H-NMR(CDCl3) δ=3.47(3H, s), 3.48-3.64(4H, m), 3.97-4.03(1H,m), 4.19(2H, s), 4.41-4.42(1H, m), 5.40(2H, d, J=56Hz), 5.97(1H,d, J=9Hz), 7.17-7.38(5H, m), 7.70(1H, d, J=9Hz) b) (3R)-3-[2-Benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0345] A mixture of 43.9 mg of 2-benzyl-6-[(3R,4S)-3-(fluoromethoxy)-4-methoxypyrrolidine-1-yl]-3-iodopyridine,16.5 mg of (3R)-3-ethynyl-3-quinuclidinol,11.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.9 mgof cuprous iodide, 42 µl of triethylamine and 3.0 ml ofN,N-dimethylformamide was heated under stirring for 1 hoursat 75°C in a nitrogen atmosphere. The reaction solution waspoured into an aqueous dilute ammonia, and then the mixturewas extracted with ethyl acetate. The organic phase waswashed with brine and the solvent was removed. The residuewas subjected to NH-silica gel (Fuji Silicia) columnchromatography and eluted with hexane/ethyl acetate (1:1)and then with ethyl acetate/methanol (15:1), to give 33 mgof the target compound.1H-NMR(CDCl3) δ=1.34-1.42(1H, m), 1.54-1.62(1H, m), 1.85-1.90(1H,m), 1.99-2.07(2H, m), 2.73-2.91(4H, m), 3.01(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.48(3H, s), 3.54-3.58(1H,m), 3.65-3.69(3H, m), 3.99-4.03(1H, m), 4.15(2H, s), 4.41-4.45(1H,m), 5.40(2H, d, J=56Hz), 6.13(1H, d, J=9Hz), 7.13-7.40(5H, m), 7.42(1H, d, J=9Hz) Example 113 (3R)-3-[2-Benzyl-6-[(3S,4R)-3-chloro-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(3R,4R)-3-(3-nitribenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]-3-iodopyridine
    [0346] A mixture of 1.0 g of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine(Example 10c),1.0 g of 3-nitrobenzenesulfonyl chloride, 0.1 g of 4-dimethylaminopyridineand 5 ml of pyridine was stirred atroom temperature overnight. Water was added to the reactionsolution, and the mixture was extracted with ethyl acetate.The organic phase was washed with water and brine and thesolvent was removed. The residue was subjected to NH-silicagel (Fuji Silicia) column chromatography and eluted withhexane/ethyl acetate (5:1) and then with hexane/ethylacetate (2:1), to give 1.23 g of the target compound.1H-NMR(CDCl3) δ=3.38(3H, s), 3.47-3.51(1H, m), 3.61-3.73(3H,m), 4.11-4.16(3H, m), 5.11-5.12(1H, m), 5.94(1H, d, J=9Hz),7.18-7.33(5H, m), 7.68-7.76(2H, m), 8.20-8.22(1H, m), 8.48-8.51(1H,m) , 8.75(1H, s) b) 2-Benzyl-6-[(3S,4R)-3-chloro-4-methoxypyrrolidine-1-yl]-3-iodopyridine
    [0347] A mixture of 553 g of 2-benzyl-6-[(3R,4R)-3-(3-nitrobenzenesulfonyl)oxy-4-methoxypyrrolidine-1-yl]-3-iodopyridine,79 mg of lithium chloride and 5.0 ml ofN,N-dimethylformamide was heated under stirring at 75°C for 9 hours. After cooling as it was, water was added to thereaction mixture and the mixture was extracted with ethylacetate. The organic phase was washed with water and brine,and the solvent was removed. The residue was subjected toNH-silica gel (Fuji Silicia) column chromatography andeluted with hexane/ethyl acetate (10:1) and then withhexane/ethyl acetate (5:1), to give 391 mg of the targetcompound.1H-NMR(CDCl3) δ=3.48(3H, s), 3.48-3.51(1H, m), 3.65-3.69(1H,m), 3.83-3.85(2H, m), 4.05-4.09(1H, m), 4.19(2H, s), 4.55-4.58(1H,m), 5.97(1H, d, J=9Hz), 7.18-7.38(5H, m), 7.72(1H, d,J=9Hz) c) (3R)-3-[2-Benzyl-6-[(3S,4R)-3-chloro-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0348] A mixture of 391 mg of 2-benzyl-6-[(3S,4R)-3-chloro-4-methoxypyrrolidine-1-yl)-3-iodopyridine,152 mg of(3R)-3-ethynyl-3-quinuclidinol, 105 mg oftetrakis(triphenylphosphine)palladium(0), 9 mg of cuprousiodide, 0.38 ml of triethylamine and 5.0 ml of N,N-dimethylformamidewas heated under stirring for 4 hours at75°C in a nitrogen atmosphere, followed by removing thesolvent. The residue was subjected to NH-silica gel (FujiSilicia) column chromatography and eluted with hexane/ethylacetate (1:1) and then with ethyl acetate/methanol (20:1)and then crystallized from hexane/ethyl acetate, to give 150mg of the target compound. 1H-NMR(CDCl3) δ=1.46-1.53(1H, m), 1.64-1.92(2H, m), 2.04-2.12(2H,m), 2.82-2.97(4H, m), 3.11(1H, d, J=14Hz), 3.29(1H,dd, J=2, 14Hz), 3.49(3H, s), 3.52-3.56(1H, m), 3.70-3.75(1H,m), 3.85-3.91(2H, m), 4.06-4.11(1H, m), 4.15(2H, s), 4.57-4.60(1H,m), 6.15(1H, d, J=9Hz), 7.17-7.30(5H, m), 7.44(1H, d,J=9Hz) Example 114 (3R)-3-[2-Benzyl-6[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Bromo-6-[(3R,4R)-3-methoxymethyloxy-4-[2-(tetrahydro-2 H-2-pyranyloxy)ethyl]oxypyrrolidine-1-yl]pyridine
    [0349] 3.88 g of 60% oily sodium hydride was added little by littleto a solution of 50 ml of N,N-dimethylformamide containing 14.7g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-hydroxypyrrolidine-1-yl]pyridine(Example 111b) understirring in an ice bath. The mixture was stirred for 10 minutesin an ice bath and then for 20 minutes at room temperature. Then,14.7 ml of 2-(2-bromoethyl)oxytetrahydro-2H-pyran was addeddropwise little by little thereinto in an ice bath. Thereaction solution was stirred at room temperature for 20 minutesand then at 60°C for 20 minutes. 7.4 ml of 2-(2-bromoethyl)oxytetrahydro-2H-pyranwas further added thereto atroom temperature, followed by heating under stirring at 60°Cfor 30 minutes. After cooling as it was, the reaction solutionwas poured into water and the mixture was extracted with ethylacetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gelchromatography and eluted with hexane/ethyl acetate (3:1) andthen with hexane/ethyl acetate (2:1), to give 17.58 g of thetarget compound.1H-NMR(CDCl3) δ=1.50-1.59(4H, m), 1.67-1.83(2H, m), 3.39(3H,s), 3.48-3.61(4H, m), 3.67-3.75(4H, m), 3.82-3.88(2H, m),4.13-4.14(1H, m), 4.31-4.34(1H, m), 4.61-4.63(1H, m), 4.70-4.74(2H,m), 6.25(1H, d, J=8Hz), 6.69(1H, d, J=7Hz), 7.22-7.27(1H,m) b) 2-Bromo-6-[(3R,4R)-3-methoxymethyloxy-4-(2-hydroxyethyl)oxypyrrolidine-1-yl]pyridine
    [0350] 2.26 g p-toluenesulfonic acid monohydrate was addeddropwise little by little into a solution of 60 ml of methanolcontaining 17.09 g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]oxypyrrolidine-1-yl]pyridinein an icebath. After stirring for 30 minutes under ice-cooling, itwas stirred at room temperature for 2 hours. 377 mg ofp-toluenesulfonic acid monohydrate was further addedthereto, followed by stirring for 2 hours. Then, thereaction solution was poured into aqueous saturated sodiumbicarbonate and extracted twice with ethyl acetate. Theorganic phase was washed with brine and the solvent wasremoved. The residue was filtered through silica gel, togive 13.14 g of the target compound.1H-NMR(CDCl3) δ=3.39(3H, s), 3.53-3.56(2H, m), 3.66-3.75(6H,m), 4.10-4.13(1H, m), 4.30-4.31(1H, m), 4.70-4.74(2H, m), 6.25(1H, d, J=8Hz), 6.70(1H, d, J=8Hz), 7.24-7.28(1H, m) c) 2-Bromo-6-[(3R,4R)-3-methoxymethyloxy-4-[2-(methanesulfonyloxy)ethyl]oxypyrrolidine-1-yl]pyridine
    [0351] 7.9 ml of triethylamine was slowly added to a solutionof 70 ml of dichloromethane containing 13.14 g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-(2-hydroxyethyl)oxypyrrolidine-1-yl]pyridinein an ice bath.Then, 3.2 ml of methanesulfonyl chloride was slowly addedthereto, followed by stirring for 15 minutes. Then, thereaction solution was poured into water and extracted twicewith dichloromethane. The organic phase was washed withbrine and the solvent was removed. The residue was filteredthrough NH-silica gel, to give 15.66 g of the targetcompound.1H-NMR(CDCl3) δ=3.00(3H, s), 3.38(3H, s), 3.52-3.59(2H, m) ,3.66-3.72(2H, m), 3.82-3.84(2H, m), 4.10-4.15(1H, m), 4.28-4.30(1H,m), 4.33-4.35(2H, m), 4.71(2H, s), 6.25(1H, d, J=8Hz),6.71(1H, d, J=8Hz), 7.24-7.28(1H, m) d) 2-Bromo-6-[(3R,4R)-3-hydroxy-4-[2-(methanesulfonyloxyethyl)oxypyrrolidine-1-yl]pyridine
    [0352] 2.0 ml of concentrated sulfuric acid was slowly addeddropwise into a solution of 160 ml of methanol containing15.66 g of 2-bromo-6-[(3R,4R)-3-methoxymethyloxy-4-(2-methanesulfonyloxyethyl)oxypyrrolidine-1-yl]pyridineunder stirring in an ice bath. The reaction solution wasstirred at room temperature for 10 minutes and then at 50°Cfor 45 minutes. Further, after adding dropwise 1.0 ml of concentrated sulfuric acid thereinto, the mixture wasstirred at 50°C for one hour. After cooling as it was, thereaction mixture was poured into an aqueous potassiumcarbonate solution and extracted twice with ethyl acetate.The organic phase was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was removed. The residuewas filtered through silica gel, to give 11.82 g of the targetcompound.1H-NMR(CDCl3) δ=3.01(3H, s), 3.44-3.56(2H, m), 3.69-3.87(4H,m), 4.01-4.04(1H, m), 4.34-4.37(2H, m), 4.44-4.45(1H, m),6.25(1H, d, J=8Hz), 6.72(1H, d, J=7Hz), 7.24-7.28(1H, m) e) 2-Bromo-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]pyridine
    [0353] 1.49 g of 60% oily sodium hydride was added little bylittle to a solution of 150 ml of N,N-dimethylformamidecontaining 11.82 g of 2-bromo-6-[(3R,4R)-3-hydroxy-4-(2-methanesulfonyloxyethyl)oxypyrrolidine-1-yl]pyridineunder stirring in an ice bath. Then, after stirring at roomtemperature for one hour, 372 mg of 60% oily sodium hydridewas added thereto. After stirred for further 45 minutes,the reaction mixture was poured into water and extractedtwice with ethyl acetate. The organic phase was washed withwater and brine, and the solvent was removed. The residuewas crystallized from ethyl acetate/hexane, to give 5.35 gof the target compound.1H-NMR(CDCl3) δ=3.20-3.25(2H, m), 3.73-3.92(8H, m), 6.23(1H,d, J=8Hz), 6.73(1H, d, J=8Hz), 7.25-7.29(1H, m) f) 2-Benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]pyridine
    [0354] 26.6 mol of a tetrahydrofuran solution containing 1.06mol of benzylmagnesium chloride was added dropwise into asolution of 100 ml of tetrahydrofuran containing 5.3 g of2-bromo-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]pyridineand 509 mg of 1,3-bis(diphenylphosphino)propanenickel(II) chloride over 10minutes under ice-cooling. After stirring at roomtemperature overnight, the reaction solution was poured intoaqueous saturated ammonium chloride and extracted with ethylacetate. The organic phase was washed with brine and thesolvent was removed. The residue was subjected to silicagel column chromatography and eluted with hexane/ethylacetate (10:1) and then with hexane/ethyl acetate (1:2).The resulting crude product was crystallized fromhexane/ethyl acetate, to give 4.84 g of the target compound.1H-NMR(CDCl3) δ=3.20-3.25(2H, m), 3.72-3.91(8H, m), 3.96(2H,s), 6.13(1H, d, J=8Hz), 6.39(1H, d, J=7Hz), 7.17-7.36(6H, m) g) 2-Benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]-3-iodopyridine
    [0355] 4.04 g of N-iodosuccinimide was added little by littleto a solution of 40 ml of N,N-dimethylformamide containing4.84 g of 2-benzyl-6- [(3R,4R) -3,4-ethylenedioxypyrrolidine-1-yl]pyridineunder stirring inan ice bath, followed by stirring overnight as it was. Thereaction solution was poured into water, and extracted with ethyl acetate. The organic phase was successively washedwith an aqueous sodium sulfite solution, water and brine,dried over anhydrous magnesium sulfate and the solvent wasremoved. The residue was subjected to filtration usingsilica gel and crystallized from hexane/ethyl acetate, togive 5.12 g of the target compound.1H-NMR(CDCl3) δ=3.15-3.18(2H, m), 3.71-3.91(8H, m), 4.14-4.22(2H,m), 5.95(1H, d, J=9Hz), 7.18-7.39(5H, m), 7.70(1H, d,J=9Hz) h) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0356] A mixture of 5.12 g of 2-benzyl-6-[(3R,4R)-3,4-ethylenedioxypyrrolidine-1-yl]-3-iodopyridine,1.83 g of(3R)-3-ethynyl-3-quinuclidinol, 140 mg oftetrakis(triphenylphosphine)palladium(0), 115 mg ofcuprous iodide, 3.4 ml of triethylamine and 12 ml of methanolwas stirred at room temperature overnight in a nitrogenatmosphere. The reaction solution was poured into aqueousdilute ammonia, and the mixture was extracted with ethylacetate/tetrahydrofuran (1:1). Then, the organic phase waswashed with brine and the solvent was removed. The residuewas crystallized from tetrahydrofuran/methanol/ethylacetate, to give 3.59 g of the target compound.1H-NMR(CDCl3) δ=1.37-1.44(1H, m), 1.55-1.64(1H, m), 1.87-1.91(1H,m), 2.04-2.05(2H, m), 2.75-2.89(4H, m), 3.04(1H, d,J=14Hz), 3.18-3.28(3H, m), 3.73-3.91(8H, m), 4.11-4.21(2H, m), 6.12(1H, d, J=9Hz), 7.14-7.34(5H, m), 7.44(1H, d, J=9Hz) Example 115 (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-cyclopropyloxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-vinyloxypyrrolidine-1-yl]pyridine
    [0357] 145 mg of 60% oily sodium hydride was added to a mixtureof 906 mg of 2-benzyl-6-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine(Example 10a) and 10 mlof tetrahydrofuran under ice cooling, followed by stirringfor one hour at the same temperature. 0.252 ml ofchloromethyl methyl ether was added thereto, followed bystirring at room temperature for 1.5 hours. Water and ethylacetate were added to the reaction solution, and the organicphase was washed with water and brine, dried over anhydrousmagnesium sulfate anhydride and the solvent was removed. Tothe residue was added 4 ml of ethyl vinyl ether and 238 mgof mercury acetate, followed by stirring two nights at roomtemperature. To the reaction solution were added an aqueoussaturated sodium bicarbonate solution and diethyl ether.The organic phase was washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was removed.The residue was subjected to silica gel columnchromatography using 15% ethyl acetate/hexane, to give 229mg of the target compound.1H-NMR(CDCl3) δ=3.39(3H, s), 3.51-3.61(4H, m), 3.97(2H, s),4.12(1H, dd, J=2, 7Hz), 4.42-4.46(2H, m), 4.54-4.55(1H, m), 4.71-4.76(2H, m), 6.17(1H, d, J=8Hz), 6.34-6.42(2H, m),7.16-7.34(6H, m) b) 2-Benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-cyclopropyloxypyrrolidine-1-yl]pyridine
    [0358] A mixture of 229 mg of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-vinyloxypyrrolidine-1-yl]pyridine,217 µl of diiodomethane, 1,35 ml of hexane solutioncontaining 1.0 mol of diethylzinc and 3 ml of toluene wasstirred at 80°C for 3 hours. Ammonium chloride was addedto the reaction solution, and the mixture was washed withbrine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 15% ethyl acetate/hexane,to give 47.8 mg of the target compound.1H-NMR(CDCl3) δ=0.50-0.63(4H, m), 3.38-3.42(4H, m), 3.52-3.60(2H,m), 3.69-3.75(2H, m), 3.97(2H, s), 4.18-4.21(1H, m),4.30-4.33(1H, m), 4.70-4.74(2H, m), 6.16(1H, d, J=8Hz), 6.33(1H,d, J=8Hz), 7.17-7.33(6H,m) c) (3R)-3-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-cyclopropyloxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0359] A mixture of 47.8 mg of 2-benzyl-6-[(3R,4R)-3-methoxymethyloxy-4-cyclopropyloxypyrrolidine-1-yl]pyridine,1.5 ml of dichloromethane and 0.156 ml oftrifluoroacetic acid was stirred overnight at roomtemperature. To the reaction solution were added an aqueoussaturated sodium bicarbonate solution and ethyl acetate, and the organic phase was washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was removed.The residue was subjected to the same reaction as in Example10, to synthesize the target compound.1H-NMR(CDCl3) δ=0.50-0.62(4H, m), 1.35-1.43(1H, m), 1.53-1.61(1H,m), 1.82-1.90(1H, m), 1.99-2.06(2H, m), 2.71-2.91(4H,m), 2.98(1H, d, J=14Hz), 3.20(1H, dd, J=2, 14Hz), 3.36-3.41(1H,m), 3.43-3.47(1H, m), 3.55-3.58(1H, m), 3.68(1H, dd, J=5, 11Hz),3.75(1H, dd, J=5, 12Hz), 4.06-4.15(3H, m), 4.39-4.42(1H, m),6.12(1H, d, J=8Hz), 7.13-7.32(5H, m), 7.40(1H, d, J=8Hz) Example 116 (3R)-3-[2-Benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-5-chloro-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine
    [0360] 100 mg of N-chlorosuccinimide was added little by littleto a mixture of 256 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine(Example 10c)and 3 ml of N,N-dimethylformamide, followed by stirring at70°C for 2 hours. After cooling as it was, water and ethylacetate were added thereto, and the mixture was extracted.The organic phase was washed with water and brine, dried overanhydrous magnesium sulfate and the solvent was removed.The residue was subjected to silica gel columnchromatography using 25% ethyl acetate/hexane, to give 132mg of the target compound.1H-NMR(CDCl3) δ=3.39(3H, s), 3.64-3.69(2H, m), 3.76-3.79(1H, m), 3.86-3.90(1H, m), 3.94-3.97(1H, m), 4.14(2H, s), 4.30-4.33(1H,m), 7.18-7.33(5H, m), 7.74(1H, s) b) (3R)-3-[2-Benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0361] A mixture of 132 mg of 2-benzyl-5-chloro-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine,49.4 mg of (3R)-3-ethynyl-3-quinuclidinol, 17.2 mg oftetrakis(triphenylphosphine)palladium(0), 11.3 mg ofcuprous iodide, 124 µl of triethylamine and 1.5 ml of methanolwas heated under reflux for one hour in a nitrogen atmosphere.After cooling as it was, water and ethyl acetate were addedto the reaction mixture. The organic phase was washed withwater and brine, dried over anhydrous magnesium sulfate andthe solvent was removed. The residue was subjected toNH-silica gel column chromatography using 3% methanol/ethylacetate, to give 125 mg of the target compound.1H-NMR(CDCl3) δ=1.36-1.44(1H, m), 1.56-1.63(1H, m), 1.82-1.89(1H,m), 1.99-2.05(2H, m), 2.50-2.88(4H, m), 3.00(1H, d,J=14Hz), 3.20(1H, dd, J=2, 14Hz), 3.40(3H, s), 3.71-3.78(3H,m), 3.92-3.97(1H, m), 4.00-4.04(1H, m), 4.09(2H, s), 4.30-4.32(1H,m), 7.17-7.29(5H, m), 7.45(1H, s) Example 117 (3R)-3-[2-Benzyl-5-bromo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0362] The target compound was synthesized in the same manneras in Example 116 except that N-chlorosuccinimide was altered to N-bromosuccinimide.1H-NMR(CDCl3) δ=1.36-1.44(1H, m), 1.58-1.64(1H, m), 1.82-1.91(1H,m), 1.99-2.06(2H, m), 2.72-2.93(4H, m), 3.02(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.40(3H, s), 3.72-3.80(3H,m), 3.92-3.97(1H, m), 4.01-4.06(1H, m), 4.09(2H, s), 4.30-4.32(1H,m), 7.16-7.30(5H, m), 7.67(1H, s) Example 118 (3R)-3-[2-Benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Bromo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine
    [0363] A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of3-hydroxypyrrolidine, 3.6 ml of 1,8-diazbicyclo[5.4.0]-7-undecene(DBU) and 20 ml of tetrahydrofuran was heatedunder stirring for 11 hours in an oil bath kept at 70°C. Themixture was partitioned between ethyl acetate-water, and theorganic layer was washed with water and brine, dried overanhydrous magnesium sulfate anhydride and then concentrated.The residue was subjected to silica gel columnchromatography using 10-30% ethyl acetate/hexane, to give5.9 g of 2-bromo-6-(3-hydroxypyrrolidine-1-yl)pyridine.
    [0364] Next, 4.6 ml of dimethylsulfoxide was added dropwise intoa solution of 100 ml of dichloromethane containing 2.8 ml ofoxalyl chloride under stirring in a dry ice-acetone bath. Then,a solution of 50 ml of dichloromethane containing 5.9 g of theresulting 2-bromo-6-(3-hydroxypyrrolidine-1-yl)pyridine wasadded dropwise thereinto. Finally, 17 ml of triethylamine wasadded dropwise thereinto and the temperature of the mixture was returned to room temperature over one hour. The reactionsolution was washed with water and brine, dried over anhydrousmagnesium sulfate and then concentrated. To the residue wereadded 50 ml of toluene, 7 ml of ethylene glycol and a catalyticamount of p-toluenesulfonic acid monohydrate, followed byheating under reflux for 3 hours while draining water. Aftercooling, the mixture was washed with an aqueous saturated sodiumbicarbonate solution and brine, dried over anhydrous magnesiumsulfate and then concentrated. The residue was subjected tosilica gel column chromatography using 5-7% ethylacetate/hexane, to give 6.3 g of the target compound.1H-NMR (CDCl3) δ=2.30(2H, t, J=7Hz), 3.54(2H, s), 3.58(2H, t,J=7Hz), 3.96-4.04(4H, m), 6.22(1H, d, J=8Hz), 6.70(1H, d,J=8Hz), 7.24(1H, t, J=8Hz) b) 2-Benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine
    [0365] A mixture of 6.3 g of 2-bromo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine,240 mg of 1,3-bis(diphenylphosphino)propanenickel(II)chloride and 20 mlof tetrahydrofuran was stirred in an ice bath in a nitrogenatmosphere. Into the mixture were added dropwise a diethylether solution of benzyl magnesium bromide prepared from 3.4ml of benzyl bromide, 0.8 g of magnesium and 15 ml of diethylether, followed by stirring at room temperature overnightas it was. The reaction solution was partitioned betweenan aqueous saturated ammonium chloride solution and ethylacetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and then concentrated. Theresidue was subjected to silica gel column chromatographyusing 5-10% ethyl acetate/hexane, to give 6.6 g of the targetcompound.1H-NMR (CDCl3) δ=2.19(2H, t, J=7Hz), 3.57(2H, s), 3.59(2H, t,J=7Hz), 3.97(2H, s), 4.01(4H, s) , 6.14(1H, d, J=8Hz), 6.34(1H,d, J=7Hz), 7.16-7.35(6H, m) c) 2-Benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine
    [0366] A mixture of 6.6 g of 2-benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridineand 60 ml of N,N-dimethylformamidewas stirred in an ice bath. Into themixture were added dropwise 5.5 g of N-iodosuccinimide,followed by stirring at room temperature overnight as it was.10 ml of an aqueous solution containing one mol of sodiumthiosulfate was added thereto, and the mixture waspartitioned between ethyl acetate and water. The organicphase was washed with water and brine, dried over anhydrousmagnesium sulfate and then concentrated. The residue wassubjected to silica gel column chromatography using 5-10%ethyl acetate/hexane, to give 6.7 g of the target compound.1H-NMR (CDCl3) δ=2.17(2H, t, J=7Hz), 3.50(2H, s), 3.54(2H, t,J=7Hz), 4.00(4H, s), 4.18(2H, s), 5.95(1H, d, J=8Hz), 7.18(1H,t, J=7Hz), 7.26(2H, t, J=7Hz), 7.37(2H, d, J=7Hz), 7.68(1H, d,J=8Hz) d) (3R)-3-[2-Benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0367] A mixture of 3.0 g of 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine,1.07 g of (3R)-3-ethynyl-3-quinuclidinol,82 mg oftetrakis (triphenylphosphine)palladium (0), 68 mg of cuprousiodide, 2.0 ml of triethylamine and 7 ml of methanol wasstirred at room temperature overnight in a nitrogenatmosphere. The reaction solution was partitioned betweenaqueous dilute ammonia-ethyl acetate, washed with washedwith water, dried over anhydrous magnesium sulfate and thenconcentrated. 10 ml of tetrahydrofuran was added to theresidue to dissolve under heating, and to the mixture wasadded 15 ml of ethyl acetate. The mixture was filteredthrough 10 g of NH-silica gel, washed with ethyl acetate,and concentrated. The residue was crystallized from ethylacetate, to give 2.79 g of the target compound.1H-NMR (CDCl3) δ=1.34-1.94(3H, m), 1.98-2.06(2H, m), 2.18(2H,t, J=8Hz), 2.70-2.94(4H, m), 3.02(1H, d, J=14Hz), 3.23(1H, dd,J=2, 14Hz), 3.55(2H, s), 3.60(2H, t, J=8Hz), 4.01(4H, s),4.15(2H, s), 6.12(1H, d, J=8Hz), 7.12-7.34(5H, m), 7.41(1H, d,J=8Hz) Example 119 (3R)-3-[2-Benzyl-5-chloro-6-(3,3-ethylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0368] A mixture of 500 mg of 2-benzyl-3-iodo-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridineobtained inExample 118c, 174 mg of N-chlorosuccinimide and 5 ml ofN,N-dimethylformamide was stirred under heating for 5 hours in an oil bath kept at 60°C. 1 ml of aqueous solutioncontaining 1 mol of sodium thiosulfate was added to thereaction solution, the mixture was partitioned between ethylacetate and water. The organic phase was washed with waterand brine, dried over anhydrous magnesium sulfate and thenconcentrated. The residue was subjected to silica gelcolumn chromatography using 5-10% ethyl acetate/hexane, togive 320 mg of 2-benzyl-3-iodo-5-chloro-6-(3,3-ethylenedioxypyrrolidine-1-yl)pyridine,and then the titlecompound was obtained in the same procedures as in Example118d. ..1H-NMR (CDCl3) δ=1.35-1.92 (3H, m), 1.98-2.05(2H, m), 2.09(2H,t, J=7Hz), 2.70-2.94(4H, m), 3.03 (1H, d, J=14Hz), 3.23 (1H, dd,J=2, 14Hz), 3.80(2H, s), 3.84(2H, t, J=7Hz), 4.00(4H, s),4.10(2H, s), 7.14-7.32(5H, m), 7.44(1H, s) Example 120 (3R)-3-[2-Benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Bromo-6-(3-pyrroline-1-yl)pyridine
    [0369] A mixture of 12.4 g of 2,6-dibromopyridine, 7.2 g of3-pyrroline (purity: 65%, Aldrich), 14.5 g of potassiumcarbonate and 100 ml of 1-methyl-2-pyrrolidinone was heatedunder stirring at 125°C for 4 hours. After cooling as itwas, the reaction mixture was poured into water and extractedwith ethyl acetate. The organic phase was washed with waterand brine, and the solvent was removed. The residue wassubjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (10:1), togive 11.6 g of a mixture of the target compound and 2-bromo-6-(pyrrolidine-1-yl)pyridine. b) 2-Benzyl-6-(3-pyrroline-1-yl)pyridine
    [0370] 72.3 ml of a tetrahydrofuran solution containing 1.07mol of benzylmagnesium chloride was added dropwise into amixture of 11.6 g of a mixture of 2-bromo-6-(3-pyrroline-1-yl)pyridineand 2-bromo-6-(pyrrolidine-1-yl)pyridineand 20 ml of tetrahydrofuran containing 1.4 gof 1,3-bis(diphenylphosphino)propanenickel (II) chlorideover 10 minutes in an ice bath. After cooling at roomtemperature overnight, the reaction solution was poured intoaqueous saturated ammonium chloride and extracted with ethylacetate. The organic phase was washed with aqueoussaturated sodium chloride and the solvent was removed. Theresidue was subjected to NH-silica gel (Fuji Silicia) columnchromatography and eluted with hexane and then withhexane/ethyl acetate (20:1), to give 11.8 g of the titlecompound as a mixture with 2-benzyl-6-(pyrrolidine-1-yl)pyridine. c) 2-Benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine
    [0371] 2.3 ml of a 2-methyl-2-propanol solution containing 2.5%osmium tetraoxide was added dropwise little by little intoa mixture of 11.8 g of a mixture of 2-benzyl-6-(3-pyrroline-1-yl)pyridineand 2-benzyl-6-(pyrrolidine-1-yl)pyridine,23.5 g of aqueous 50% N-methylmorpholine-N-oxide solution, 50 ml of acetone and 10 ml of water in anice bath. After stirring for 2 hours in an ice bath, it wasfurther stirred at room temperature overnight. A aqueoussodium thiosulfate solution was added to the reactionsolution, followed by stirring at room temperature for 30minutes. Then, the mixture was extracted with ethyl acetate,and the organic phase was washed with water and brine, andthe solvent was removed. Then, the residue was subjectedto silica gel column chromatography and eluted withhexane/ethyl acetate (5:1) and then with ethyl acetate, togive 4.2 g of the target compound.1H-NMR(CDCl3) δ=3.47-3.50(2H, m), 3.71-3.75(2H, m), 3.97(2H,s), 4.37-4.39(2H, m), 6.15(1H, d, J=8Hz), 6.37(1H, d, J=7Hz),7.17-7.35(6H, m) d) 2-Benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)pyridine
    [0372] 347 mg of 60% oily sodium hydride was added little bylittle to a mixture of 781 mg of 2-benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine,536 µl of methyl iodideand 6.0 ml of N,N-dimethylformamide in an ice bath. Afterstirring at room temperature for 2 hours, water was addedlittle by little to the reaction solution and the mixturewas extracted with ethyl acetate. The organic phase waswashed with water and brine, and the solvent was removed.Then, the residue was subjected to silica gel columnchromatography and eluted with hexane/ethyl acetate (5:1)and then with hexane/ethyl acetate (1:1), to give 783 mg of the target compound.1H-NMR(CDCl3) δ=3.47(6H, s), 3.60-3.65(4H, m), 3.97-4.02(4H,m), 6.16(1H, d, J=8Hz), 6.34(1H, d, J=7Hz), 7.18-7.34(6H, m) e) 2-Benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-iodopyridine
    [0373] 708 mg of N-iodosuccinimide was added little by littleto a mixture of 783 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)pyridineand 7.0 ml of N,N-dimethylformamideunder ice-cooling, followed by stirringovernight as it was. The reaction solution was poured intowater and extracted with ethyl acetate. The organic phasewas washed with sodium thiosulfate, water and brine, and thesolvent was removed. Then, the residue was subjected toNH-silica gel (Fuji Silicia) column chromatography andeluted with hexane/ethyl acetate (5:1) and then withhexane/ethyl acetate (3:1), to give 995 mg of the targetcompound.1H-NMR(CDCl3) δ=3.46(6H, s), 3.54-3.55(4H, m), 3.97-4.01(2H,m), 4.19(2H, s), 5.97(1H, d, J=9Hz), 7.16-7.38(5H, m), 7.69(1H,d, J=9Hz) f) (3R)-3-[2-Benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0374] A mixture of 510 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-iodopyridine,200 mg of(3R)-3-ethynyl-3-quinuclidinol, 139 mg oftetrakis (triphenylphosphine) palladium (0), 11 mg of cuprousiodide, 0.50 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75°C for 2hours in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia and extracted with ethylacetate. The extract was washed with brine and the solventwas removed. The residue was subjected to NH-silica gel(Fuji Silicia) column chromatography and eluted withhexane/ethyl acetate (1:1) and then with ethylacetate/methanol (15:1), to give 281 mg of the targetcompound.1H-NMR(CDCl3) δ =1.38-1.40(1H, m), 1.57-1.68(1H, m), 1.87-1.92(1H,m), 2.02-2.04(2H, m), 2.74-2.87(4H, m), 3.02(1H, d,J=14Hz), 3.23(1H, d, J=14Hz), 3.47(6H, s), 3.60(4H, m), 3.99(2H,m), 4.16(2H, s), 6.13-6.15(1H, m), 7.14-7.33(5H, m), 7.42(1H,d, J=9Hz) Example 121(3R)-3-[2-Benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)pyridine
    [0375] A mixture of 300 mg of 2-benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine,376 mg ofparaformaldehyde, 0.7 ml of concentrated sulfuric acid and5.0 ml of acetic acid was heated under stirring at 90°C for2 hours. After cooling as it was, the reaction solution wasslowly added to an aqueous potassium carbonate solution.The mixture was extracted with ethyl acetate, and the organicphase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatographyand eluted with hexane/ethyl acetate (5:1) and then withhexane/ethyl acetate (3:1), to give 221 mg of the targetcompound.1H-NMR(CDCl3) δ = 3.37-3.41 (2H, m), 3.90-3.93(2H, m), 3.97(2H,s), 4.81-4.82(2H, m), 4.97(1H, s), 5.11(1H, s), 6.26(1H, d,J=8Hz), 6.43(1H, d, J=7Hz), 7.17-7.37(6H, m) b) 2-Benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-iodopyridine
    [0376] 143 mg of N-iodosuccinic acid imide was added little bylittle to a mixture of 150 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)pyridineand 5.0 ml ofN,N-dimethylformamide under ice-cooling, followed bystirring overnight as it was. The reaction solution waspoured into water, and then extracted with ethyl acetate.The organic phase was washed with sodium thiosulfate, waterand brine, and the solvent was removed. The residue wassubjected to silica gel column chromatography and elutedwith hexane and then with hexane/ethyl acetate (4:1), to give116 mg of the target compound.1H-NMR(CDCl3) δ=3.34-3.38(2H, m), 3.82-3.86(2H, m ), 4.19(2H,s), 4.79-4.89(2H, m), 4.95(1H, s), 5.09(1H, s), 6.06(1H, d,J=9Hz), 7.07-7.38(5H, m), 7.72(1H, d, J=9Hz) c) (3R)-3-[2-Benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0377] A mixture of 116 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-iodopyridine, 47 mg of(3R)-3-ethynyl-3-quinuclidinol, 33 mg oftetrakis(triphenylphosphine)palladium (0), 3 mg of cuprousiodide, 0.12 ml of triethylamine and 3.0 ml of N,N-dimethylformamidewas heated under stirring at 75°C for 4hours in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia, and then extracted withethyl acetate. The extract was washed with brine and thesolvent was removed. The residue was subjected to NH-silicagel (Fuji Silicia) column chromatography and eluted withhexane/ethyl acetate (1:1) and then with ethylacetate/methanol (20:1), to give 38 mg of the targetcompound.1H-NMR(CDCl3) δ=1.40-1.43(1H, m), 1.63(1H, m), 1.80-1.88(1H,m), 2.00-2.12(2H, m), 2.72-2.85(4H, m), 3.03(1H, d, J=14Hz),3.11-3.23(1H, m), 3.41-3.44(2H, m), 3.88-3.91(2H, m), 4.16(2H,s), 4.81-4.82(2H, m), 4.96(1H, s), 5.10(1H, s), 6.23(1H, d,J=9Hz), 7.17-7.32(5H, m), 7.45(1H, d, J=9Hz) Example 122 (3R)-3-[2-Benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[cis-3,4-(dimethylmethylenedioxy)pyrrolidine-1-yl]pyridine
    [0378] A mixture of 2.5 g of 2-benzyl-6-(cis-3,4-dihydroxypyrrolidine-1-yl)pyridine,2.3 g of dl-10-camphorsulfonicacid, 20 ml of 2,2-dimethoxypropane and 5.0ml of N,N-dimethylformamide was stirred at room temperature overnight. Aqueous saturated sodium bicarbonate was addedto the reaction solution, and the mixture was extracted withethyl acetate. The organic phase was washed with water andbrine, and the solvent was removed. Then, the residue wassubjected to filtration through silica gel and eluted withethyl acetate, to give 2.87 g of the target compound.1H-NMR(CDCl3) δ=1.37(3H, s), 1.48(3H, s), 3.33-3.40(2H, m),3.85-3.88(2H, m), 3.97(2H, s), 4.86-4.87(2H, m), 6.24(1H, d,J=8Hz), 6.39(1H, d, J=7Hz), 7.17-7.35(6H, m) b) 2-Benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)pyridine
    [0379] A hexane solution containing 1.5 mol ofdiisobutylaluminum hydride was added little by little to asolution of 5.0 ml of diethyl ether containing 460 mg of2-benzyl-6- [cis-3,4-(dimethylmethylenedioxy)pyrrolidine-1-yl]pyridineat -20°C. After stirring at room temperatureovernight, the reaction solution was poured into an aqueousammonium chloride solution, and the mixture was filteredthrough Celite and extracted with ethyl acetate. Theorganic phase was washed with brine and the solvent wasremoved. Then, the residue was subjected to filtrationthrough silica gel and eluted with ethyl acetate, to give369 mg of the target compound.1H-NMR(CDCl3) δ=1.22-1.27 (6H, m), 3.44-3.50(2H, m) , 3.63-3.84(3H,m), 3.97 (2H, s), 4.09 - 4.15 (1H, m), 4.33-4.37 (1H, m),6.13-6.15(1H, m), 6.34 (1H, d, J=7Hz), 7.17-7.32(6H, m) c) 2-Benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine- 1-yl)-3-iodopyridine
    [0380] 342 mg of N-iodosuccinimide was added little by littleto a mixture of 396 mg of 2-benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)pyridineand 5.0ml of N,N-dimethylformamide under ice-cooling, followed bystirring overnight as it was. The reaction solution waspoured into water, and then extracted with ethyl acetate.The organic phase was washed with sodium thiosulfate, waterand brine, and the solvent was removed. The residue wassubjected to silica gel column chromatography and elutedwith hexane and then with hexane/ethyl acetate (3:1), to give464 mg of the target compound.1H-NMR(CDCl3) δ=1.21-1.27(6H, m), 3.40-3.46(2H, m), 3.56-3.82(3H,m), 4.09-4.19(3H, m), 4.31-4.34(1H, m), 5.96(1H, d,J=8Hz), 7.16-7.38(5H, m), 7.68(1H, d, J=8Hz) d) (3R)-3-[2-Benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0381] A mixture of 464 mg of 2-benzyl-6-(cis-3-isopropyloxy-4-hydroxypyrrolidine-1-yl)-3-iodopyridine,176 mg of (3R)-3-ethynyl-3-quinuclidinol, 122 mg oftetrakis(triphenylphosphine)palladium (0), 10 mg of cuprousiodide, 0.44 ml of triethylamine and 5.0 ml of N,N-dimethylformamidewas heated under stirring at 75°C for 2hours in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia, and then extracted withethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silicagel (Fuji Silicia) column chromatography and eluted withhexane/ethyl acetate (1:1) and then with ethylacetate/methanol (20:1), to give 168 mg of the targetcompound.1H-NMR(CDCl3) δ=1.21-1.27(6H, m), 1.50-1.97(3H, m), 2.04-2.17(2H,m), 2.75-2.98(4H, m), 3.12(1H, d, J=14Hz), 3.28-3.31(1H,m), 3.41-3.64(3H, m), 3.73-3.81(2H, m), 4.11-4.14(3H,m), 4.36(1H, br.s), 6.14(1H, d, J=9Hz), 7.16-7.29(5H, m),7.41(1H, d, J=9Hz) Example 123 (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-methoxymethyloxy-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidipone-1-yl]pyridine
    [0382] 3.6 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine(Production Example 12), 1.5 g of (3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinonesynthesized by amethod known in literature (J. Org. Chem., 1969, 34, 675),1.1 g of cuprous iodide and 3.3 g of potassium carbonate weresuspended in 20 ml of 1-methyl-2-pyrrolidinone, followed byheating stirring at 140°C for 20 minutes in an oil bath ina nitrogen atmosphere. After cooling as it was, ethylacetate and aqueous ammonia were added thereto, and themixture was extracted with ethyl acetate. The organic phasewas further washed with brine, dried over anhydrous sodiumsulfate anhydride and the solvent was removed. The residuewas subjected to silica gel column chromatography using 20-50% ethyl acetate/hexane as an eluent for separation andpurification, to give 2 g of the target compound.1H-NMR(CDCl3) δ=1.42(3H, s), 1.46(3H, s) , 3.37(3H, s),4.08-4,13(3H, m), 4.26(1H, d, J=13Hz), 4.80(2H, s), 5.14(2H,dd, J=6.8, 10Hz), 7.17-7.31(5H, m), 7.42(1H, d, J=9.0Hz),8.22(1H, d, J=9.0Hz) b) 2-Benzyl-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone-1-yl]-3-pyridyltrifluoromethanesulfonate
    [0383] 5 ml of trifluoroacetic acid was added to 2 g of 2-benzyl-3-methoxymethyloxy-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone-1-yl]pyridine,followed by stirring at room temperature for 6 hours. Then,the mixture was neutralized by an aqueous potassiumcarbonate solution and extracted with ethyl acetate.Further, the organic phase was washed with brine, dried overanhydrous sodium sulfate and the solvent was removed. Afterdissolving the resulting residue in 30 ml of dichloromethane,2.1 g of N-phenyltrifluoromethanesulfonimide, 192 mg of4-dimethylaminopyridine and 0.8 ml of triethylamine wereadded thereto. After stirring at room temperature for onehour, the solvent was removed, and the residue was subjectedto silica gel column chromatography using 25% ethylacetate/hexane as an eluent for separation and purification,to give 2.2 g of the target compound.1H-NMR(CDCl3) δ=1.42(3H, s), 1.46(3H, s), 4.03(1H, dd, J=4.0,13Hz), 4.18(2H, s), 4.23(1H, d, J=13Hz), 4.79-4.83(2H, m),7.20-7.42(5H, m), 7.60(1H, d, J=9.2Hz), 8.44(1H, d, J=9.2Hz) c) 2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyltrifluoromethanesulfonate (A) and 2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyltrifluoromethanesulfonate (B)
    [0384] 2.2 g of 2-benzyl-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone-1-yl]-3-pyridyltrifluoromethanesulfonate was dissolved in 20 ml of methanoland 5 ml of 5N hydrochloric acid was added thereto, followedby stirring at room temperature for 1.5 hours and at 50°Cin an oil bath for 2 hours. After cooling as it was, themixture was neutralized by an aqueous potassium carbonatesolution and extracted with ethyl acetate. Further, theorganic phase was washed with brine, dried over anhydroussodium sulfate and the solvent was removed. The resultingresidue was dissolved in 20 ml of acetonirile, and 1.5 mlof methyl iodide and 5.6 g of silver (I) oxide were addedthereto, followed by heating under stirring at 60°C in anoil bath for 1.5 hours. Insoluble matters were filtered offthrough Celite, and the filtrate was evaporated. Theresidue was subjected to silica gel column chromatographyusing 33-50% ethyl acetate/hexane as an eluent forseparation and purification, to give 685 mg of the targetcompound (A) and 599 mg of the target compound (B).Compound (A) : 1H-NMR(CDCl3) δ=3.47(3H, s), 3.69(3H, s), 3.80(1H,dd, J=3.8, 12Hz), 4.07-4.21(5H, m), 7.22-7.29(5H, m), 7.58(1H,d, J=9.2Hz), 8.38(1H, d, J=9.2Hz)Compound (B): 1H-NMR(CDCl3) δ=3.48(1H, d, J=4.6Hz), 3.74(3H, s), 3.86(1H, dd, J=13Hz, 4.0Hz), 4.06-4.18(4H, m), 4.54-4.57(1H,m), 7.24-7.30(5H, m), 7.59(1H, d, J=9.0Hz), 8.37(1H, d,J=9.0Hz) d) (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0385] 5 ml of N,N-dimethylformamide was added to a mixture of685 mg of 2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyltrifluoromethanesulfonate,293 mg of (3R)-3-ethynyl-3-quinuclidinol, 107 mg oftetrakis (triphenylphosphine)palladium (0), 22 mg of cuprousiodide and 0.7 ml of triethylamine, followed by heating understirring at 60°C in an oil bath for 1.3 hours in a nitrogenatmosphere. After cooling as it was, ethyl acetate andaqueous ammonia were added thereto, and extracted with ethylacetate. The organic phase was further washed with brine,dried over anhydrous sodium sulfate and the solvent wasremoved. The residue was subjected to NH-silica gel columnchromatography using 66% ethyl acetate/hexane and 2%methanol/ethyl acetate as eluents for separation andpurification, to give 361 mg of the target compound.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.57-1.67(1H, m), 1.68-1.92(1H,m), 2.00-2.19(2H, m), 2.70-2.95(4H, m), 3.03(1H, d,J=14Hz), 3.24(1H, dd, J=1.6, 14Hz), 3.48(3H, s), 3.70(3H, s),3.84(1H, dd, J=2.0, 13Hz), 4.09(1H, d, J=2.8Hz), 4.15-4.17(1H,m), 4.23-4.25(3H, m), 7.09-7.29(5H, m) , 7.67(1H, d, J=8.8Hz),8.24(1H, d, J=8.8Hz) Example 124 (3R)-3-[2-Benzyl-6-[(3R,4R)-4-hydroxy-3- methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0386] The target compound was synthesized in the same manneras in Example 123 by using 2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyltrifluoromethanesulfonate (Example 123c).1H-NMR(CDCl3) δ=1.36-1.47(1H, m), 1.58-1.68(1H, m), 1.82-1.93(1H,m), 2.00-2.09(2H, m), 2.70-2.95(4H, m), 3.03(1H, d,J=14Hz), 3.25(1H, dd, J=2.0, 14Hz), 3.74(3H, s), 3.90(1H, dd,J=4.0, 13Hz), 4.07(1H, d, J=3.6Hz), 4.21(1H, d, J=13Hz),4.24(2H, s), 4.55(1H, dd, J=3.6, 4.0Hz), 7.08-7.28(5H, m),7.66(1H, d, J=8.4Hz), 8.21(1H, d, J=8.4Hz) Example 125 (3R)-3-[2-Benzyl-6-[(3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0387] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.42 (3H, s), 1.47 (3H, s),1.58-1.72 (1H, m), 1.82-1.92(1H, m), 2.00-2.08(2H, m), 2.71-2.95(4H,m), 3.05(1H, d, J=14Hz), 3.26(1H, dd, J=1.8, 14Hz),4.07(1H, dd, J=4.0, 13Hz), 4.25(2H, s), 4.29(1H, d, J=13Hz),4.78-4.83(2H, m), 7.18-7.28(5H, m), 7.69(1H, d, J=8.6Hz),8.29(1H, d, J=8.6Hz) Example 126 3-[2-Benzyl-6-(2-oxo-1,3-oxazolidine-3-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0388] The target compound was synthesized in the same manneras in Example 123. 1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.60-1.70(1H, m), 1.85-1.95(1H,m), 2.00-2.13(2H, m), 2.74-2.98(4H, m), 3.04(1H, d,J=14Hz), 3.25(1H, d, J=14Hz), 4.23(2H, t, J=8.1Hz), 4.24(2H,s), 4.47(2H, t, J=8.1Hz), 7.17-7.28(5H, m), 7.66(1H, d,J=8.7Hz), 8.02(1H, d, J=8.7Hz) Example 127 3-[2-Benzyl-6-(2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0389] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.38-1.47(1H, m), 1.58-1.70(1H, m), 1.85-1.95(1H,m), 2.03-2.15(2H, m), 2.09(2H, tt, J=7.2, 8.1Hz),2.65(2H, t, J=8.1Hz), 2.73-2.95(4H, m), 3.03(1H, d, J=14Hz),3.24(1H, dd, J=2.0, 14Hz), 4.07(2H, t, J=7.2Hz), 4.24(2H, s),7.18-7.27(5H, m), 7.66(1H, d, J=8.7Hz), 8.24(1H, d, J=8.7Hz) Example 128 (3R)-3-[2-Benzyl-6-(2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0390] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.38-1.47(1H, m), 1.58-1.70(1H, m), 1.85-1.95(1H,m), 2.03-2.15(2H, m), 2.09(2H, tt, J=7.2, 8.1Hz),2.65(2H, t, J=8.1Hz), 2.73-2.95(4H, m), 3.03(1H, d, J=14Hz),3.24(1H, dd, J=2.0, 14Hz), 4.07(2H, t, J=7.2Hz), 4.24(2H, s),7.18-7.27(5H, m), 7.66(1H, d, J=8.7Hz), 8.24(1H, d, J=8.7Hz) Example 129 3-[2-Benzyl-6-(2-piperidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0391] The target compound was synthesized in the same manneras in Example 123. 1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.58-1.65(1H, m), 1.70-1.97(5H,m), 1.98-2.08(2H, m), 2.59(2H, t, J=6.4Hz), 2.69-2.94(4H,m), 3.02(1H, dd, J=1.5, 14Hz), 3.22(1H, dd, J=2.0,14Hz), 3.93(2H, t, J=5.7Hz), 4.25(2H, s), 7.17-7.27(5H, m),7.63(1H, d, J=8.5Hz), 7.74(1H, d, J=8.5Hz) Example 130 (3R)-3-[2-Benzyl-6-(2-piperidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0392] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.58-1.65(1H, m), 1.70-1.97(5H,m), 1.98-2.08(2H, m), 2.59(2H, t, J=6.4Hz), 2.69-2.94(4H,m), 3.02(1H, dd, J=1.5, 14Hz), 3.22(1H, dd, J=2.0,14Hz), 3.93(2H, t, J=5.7Hz), 4.25(2H, s), 7.17-7.27(5H, m),7.63(1H, d, J=8.5Hz), 7.74(1H, d, J=8.5Hz) Example 131 (3R)-3-[2-Benzyl-6-[(4R)-4-hydroxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0393] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.35-1.47(1H, m), 1.53-1.63 (1H, m), 1.78-1.89(1H,m), 2.00-2.09(2H, m), 2.63(1H, dd, J=2.0, 18Hz),2.68-2.94(4H, m), 2.93(1H, dd, J=6.2, 18Hz), 2.99(1H, dd, J=1.6,14Hz), 3.20(1H, dd, J=2.0, 14Hz), 4.09-4.18(2H, m), 4.20(2H,s), 4.50-4.56(1H, m), 7.15-7.28(5H, m), 7.53(1H, d, J=8.6Hz),8.12(1H, d, J=8.6Hz) Example 132 (3R)-3-[2-Benzyl]-6-[(4S)-4-hydroxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0394] The target compound was synthesized in the same manner as in Example 123.1H-NMR(CDCl3) δ=1.35-1.47 (1H, m), 1.53-1.63 (1H, m), 1.78-1.89(1H,m), 2.00-2.09(2H, m), 2.63(1H, dd, J=2.0, 18Hz),2.68-2.94 (4H, m), 2.93 (1H, dd, J=6.2, 18Hz), 2.99 (1H, dd, J=1.6,14Hz), 3.20 (1H, dd, J=2.0, 14Hz), 4.09-4.18 (2H, m), 4.20(2H,s), 4.50-4.56 (1H, m), 7.15-7.28 (5H, m), 7.53(1H, d, J=8.6Hz),8.12 (1H, d, J=8.6Hz) Example 133 3-[2-Benzyl-6-(2-oxo-2,5-dihydropyrrole-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0395] The target compound was synthesized in the same manneras in Example 123 by using 2-benzyl-6-(2-oxo-2,5-dihydropyrrole-1-yl)-3-pyridiyltrifluoromethanesulfonate which was by-produced when thecompound of Example 131 was synthesized.1H-NMR(CDCl3) δ=1.35-1.47(1H, m), 1.56-1.67(1H, m), 1.83-2.10(3H,m), 2.72-2.95(4H, m), 3.04(1H, d, J=14Hz), 3.25(1H,dd, J=14Hz, 2.1Hz), 4.24(2H, s), 4.64(2H, t, J=1.8Hz), 6.23(2H,dt, J=6.0Hz, 1.8Hz), 7.18-7.29(6H, m), 7.67(1H, d, J=8.6Hz),8.26(1H, d, J=8.6Hz) Example 134 (3R)-3-[2-Benzyl-6-[(4S)-4-methoxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0396] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.35-1.49(1H, m), 1.57-1.68(1H, m), 1.78-1.92(1H,m), 1.98-2.10(2H, m), 2.70-2.98(5H, m), 3.04(1H, d,J=14Hz), 3.25(1H, d, J=14Hz), 3.38(3H, s), 4.07-4.22(4H, m),4.25(2H, s), 7.08-7.29(5H, m), 7.67(1H, d, J=8.6Hz), 8.23(1H, d, J=8.6Hz) Example 135 3-[2-Benzyl-6-(1-imidazolyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0397] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.39-1.49(1H, m), 1.58-1.72(1H, m), 1.82-1.92(1H,m), 2.00-2.10(2H, m), 2.75-2.98(4H, m), 3.07(1H, d,J=14Hz), 3.27(1H, dd, J=1.9, 14Hz), 4.32(2H, s), 7.14(1H, d,J=8.2Hz), 7.18-7.30(7H, m), 7.78(1H, d, J=8.2Hz), 8.34(1H, s) Example 136 3-[2-Benzyl-6-(2-oxo-1,2-dihydropyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0398] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.58-1.68(1H, m), 1.75-1.90(1H,m), 2.00-2.09(2H, m), 2.69-2.95(4H, m), 3.04(1H, d,J=14Hz), 3.25(1H, dd, J=1.8, 14Hz), 4.34(2H, s), 6.29(1H, dd,J=6.5, 7.2Hz), 6.63(1H, d, J=9.2Hz), 7.16-7.34(5H, m), 7.37(1H,ddd, J=2.1, 6.5, 9.2Hz), 7.79(1H, d, J=8.4), 7.89(1H, d,J=8.4Hz), 7.92(1H, dd, J=2.1, 7.2Hz) Example 137 3-[2-Benzyl-6-(1-pyrazolyl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0399] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.58-1.68(1H, m), 1.79-1.93(1H,m), 2.00-2.10(2H, m), 2.70-2.95(4H, m), 3.04(1H, d,J=14Hz), 3.25(1H, dd, J=2.0, 14Hz), 4.31(2H, s), 6.44(1H, dd,J=1.0, 1.6Hz), 7.19-7.32(5H, m), 7.72-7.81(3H, m), 8.54(1H, dd, J=1.0, 2.7Hz) Example 138 (3R)-3-[2-Benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine
    [0400] 14.3 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine(Production Example 12) and 4.1 g of (3S)-3-hydroxy-2-pyrrolidinonesynthesized according to a method well-knownin a literature (Synthesis, 1978, 614), 4.6 g of cuprousiodide and 13.7 g of potassium carbonate were suspended in30 ml of 1-methyl-2-pyrrolidinone, followed by heating understirring at 140°C in an oil bath for 20 minutes in a nitrogenatmosphere. After cooling as it was, ethyl acetate andaqueous ammonia were added thereto. The mixture wasextracted with ethyl acetate, and the organic phase wasfurther washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 50-60%ethyl acetate as an eluent for separation and purification,to give 9.7 g of the target compound.1H-NMR(CDCl3) δ=1.95-2.08(1H, m), 2.53-2.58(1H, m), 3.09(1H,br.s), 3.37(3H, s), 3.76(1H, td, J=10Hz, 6.6Hz), 4.12(2H, s),4.19(1H, t, J=9.2Hz), 4.48(1H, t, J=10Hz), 5.14(2H, s),7.17-7.30(5H, m), 7.42(1H, d, J=9.0Hz), 8.14(1H, d, J=9.0Hz) b) 2-Benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-hydroxypyridine
    [0401] 1.1 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine was dissolved in 20ml of acetone, and 1 ml of a Jone's reagent was added thereto,followed by stirring at room temperature for 1.5 hours.2-Propanol and water were added thereto, followed byextracting with ethyl acetate. The organic phase wasfurther washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The resulting residuewas dissolved in 20 ml of toluene. 1 ml of ethylene glycoland 198 mg of p-toluenesulfonic acid were added thereto,followed by heating under reflux for 2 hours while removingwater by use of Dean Stark apparatus. After cooling as itwas, water was added thereto and the mixture was extractedwith ethyl acetate. The organic phase was further washedwith brine, dried over anhydrous sodium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 30-40% ethyl acetate/hexaneas an eluent for separation and purification, to give 398mg of the target compound.1H-NMR(CDCl3) δ=2.34(2H, t, J=6.9Hz), 4.01(2H, t, J=6.9Hz),4.12(4H, s), 4.39(2H, s), 5.28(1H, br.s), 7.13(1H, d, J=8.6Hz),7.18-7.30(5H, m), 8.11(1H, d, J=8.6Hz) c) 2-Benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyltrifluoromethanesulfonate
    [0402] 505 mg of 2-benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-hydroxypyridinewas dissolved in 10ml of dichloromethane, and 757 mg of N-phenyltrifluoromethanesulfonimide,61 mg of 4-dimethylaminopyridine and 0.3 ml of triethylamine were addedthereto, followed by stirring at room temperature overnight.Thereafter, the solvent was removed, and the residue wassubjected to silica gel column chromatography using 17%ethyl acetate/hexane as an eluent for separation andpurification, to give 1.1 g of the target compound.1H-NMR(CDCl3) δ=2.34(2H, t, J=7.0Hz), 3.96(2H, t, J=7.0Hz),4.10-4.21(4H, m), 4.34-4.42(2H, m), 7.20-7.42(5H, m), 7.59(1H,d, J=9.2Hz), 8.34(1H, d, J=9.2Hz) d) (3R)-3-[2-Benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol
    [0403] 7 ml of N,N-dimethylformamide was added to a mixture of1.1 g of 2-benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyltrifluoromethanesulfonate, 437 mg of(3R)-3-ethynyl-3-quinuclidinol, 168 mg oftetrakis(triphenylphosphine)palladium (0), 24 mg of cuprousiodide and 1.1 ml of triethylamine, followed by heating understirring at 60°C in an oil bath for 1.3 hours in a nitrogenatmosphere. After cooling as it was, ethyl acetate andaqueous ammonia were added thereto and the mixture wasextracted with ethyl acetate. The organic phase was furtherwashed with brine, dried over anhydrous sodium sulfate andthe solvent was removed. The residue was subjected toNH-silica gel column chromatography using 66% ethylacetate/hexane and 2% methanol/ethyl acetate as eluents forseparation and purification, to give 669 mg of the targetcompound. 1H-NMR(CDCl3) δ =1.35-1.45 (1H, m), 1.58-1.66(1H, m), 1.82-1.92(1H,m), 1.95-2.09(2H, m), 2.34(2H, t, J=6.8Hz), 2.71-2.95(4H,m), 3.03(1H, d, J=14Hz), 3.26(1H, dd, J=2.0, 14Hz),4.00(2H, t, J=6.8Hz), 4.09-4.18(2H, m), 4.24(2H, s), 4.34-4.42(2H,m), 7.08-7.28 (5H, m), 7.67(1H, d, J=8.4Hz), 8.22(1H,d, J=8.4Hz) Example 139 (3R)-3-[2-Benzyl-6-[(3S)-3-fluoro-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-methoxymethyloxy-6-[(3S)-3-(3-nitrobenzenesulfonyloxy)-2-pyrrolidinone-1-yl]pyridine
    [0404] 2.2 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine(Example 138a) wasdissolved in 20 ml of ethyl acetate, and 2.3 g of 3-nitrobenzenesulfonylchloride, 183 mg of 4-dimethylaminopyridineand 3 ml of triethylamine were addedthereto, followed by stirring at room temperature overnight.Then, water was added thereto, and the mixture was extractedwith ethyl acetate. The organic phase was further washedwith brine, dried over anhydrous sodium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 25-33% ethyl acetate/hexaneas an eluent, to give 3.5 g of the target compound.1H-NMR(CDCl3) δ=2.30-2.42(1H, m), 2.68-2.76(1H, m), 3.35(3H,s), 3.87-3.94(1H, m), 4.10(2H, s), 4.21(1H, ddd, J=2.4, 9.2,12Hz), 5.14(2H, s), 5.32(1H, t, J=8.2Hz), 7.15-7.27(5H, m),7.38(1H, d, J=9.0Hz), 7.81(1H, t, J=7.9Hz), 7.97(1H, d,J=9.0Hz), 8.38(1H, d, J=7.9Hz), 8.53(1H, d, J=7.9Hz), 8.88(1H, s) b) 2-Benzyl-3-methoxymethyloxy-6-[(3R)-3-acetoxy-2-pyrrolidinone-1-yl]pyridine
    [0405] 2.7 g of cesium carbonate was suspended in 20 ml ofdimethylsulfoxide, followed by adding 1.2 ml of acetic acidthereto. A solution of 20 ml of dimethylsulfoxidecontaining 3.5 g of 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-(3-nitrobenzenesulfonyloxy)-2-pyrrolidinone-1-yl]pyridinewas added thereto under stirring at roomtemperature, followed by heating under stirring at 70°C inan oil bath for 3 hours in a nitrogen atmosphere. Aftercooling as it was, water was added thereto and the mixturewas extracted with ethyl acetate. The organic phase wasfurther washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The residue wassubjected to separation and purification using silica gelcolumn chromatography using 33% ethyl acetate/hexane as aneluent, to give 2.2 g of the target compound.1H-NMR(CDCl3) δ=2.00-2.18(1H, m), 2.18(3H, s), 2.60-2.68(1H,m), 3.37(3H, s), 3.84-3.91(1H, m), 4.11(2H, s), 4.20(1H, ddd,J=2.4, 9.2, 12Hz), 5.15(2H, s), 5.51(1H, t, J=8.7Hz), 7.18-7.29(5H,m), 7.43(1H, d, J=9.0Hz), 8.17(1H, d, J=9.0Hz) c) 2-Benzyl-3-methoxymethyloxy-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine
    [0406] 453 mg of 2-benzyl-3-methoxymethyloxy-6-[(3R)-3-acetoxy-2-pyrrolidinone-1-yl]pyridinewas dissolved in 5 mlof methanol, and two droplets of a 28% methanol solution of sodium methoxide was added thereto under stirring at roomtemperature, followed by stirring for 30 minutes. Then,water was added thereto, and the mixture was extracted withethyl acetate. The organic phase was further washed withbrine, dried over anhydrous sodium sulfate and the solventwas removed. The residue was subjected to separation andpurification using silica gel column chromatography using66% ethyl acetate/hexane as an eluent, to give 371 mg of thetarget compound.1H-NMR(CDCl3) δ=1.95-2.08(1H, m), 2.53-2.58(1H, m), 3.09(1H,br.s), 3.37(3H, s), 3.76(1H, td, J=10Hz, 6.6Hz), 4.12(2H, s),4.19(1H, t, J=9.2Hz), 4.48(1H, t, J=10Hz). 5.14(2H, s),7.17-7.30(5H, m), 7.42(1H, d, J=9.0Hz), 8.14(1H, d, J=9.0Hz) d) 2-Benzyl-3-methoxymethyloxy-6-[(3S)-3-fluoro-2-pyrrolidinone-1-yl]pyridine
    [0407] 3 ml of dichloromethane was added to 0.18 ml ofdiethylaminosulfur trifluoride. Into the mixture was addeddropwise a solution of 3 ml of dichloromethane containing371 mg of 2-benzyl-3-methoxymethyloxy-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]pyridineunder cooling in anethanol/dry ice bath. The mixture was returned to roomtemperature and stirred for 2 hours. Then, water was addedthereto, and the mixture was extracted with ethyl acetate.The organic phase was further washed with brine, dried overanhydrous sodium sulfate and the solvents was removed. Theresidue was subjected to silica gel column chromatographyusing 17-20% ethyl acetate/hexane as an eluent for separation and purification, to give 116 mg of the targetcompound.1H-NMR(CDCl3) δ=2.20-2.36 (1H, m), 2.52-2.64(1H, m), 3.37 (3H,s), 3.87-3.95 (1H, m), 4.12(2H, s), 4.17-4.22(1H, m), 5.15(2H,s), 5.23(1H, dt, J=53, 7.2Hz), 7,17-7.29(5H, m), 7.44(1H, d,J=9.0Hz), 8.19(1H, d, J=9.0Hz) e) (3R)-3-[2-Benzyl-6-[(3S)-3-fluoro-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0408] The target compound was synthesized in the same manneras in Example 138.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.56-1.75(1H, m), 1.82-1.92(1H,m), 2.00-2.08(2H, m), 2.21-2.38(1H, m), 2.55-2.68(1H,m), 2.72-2.95(4H, m), 3.05(1H, d, J=14Hz), 3.26(1H, dd, J=2.0,14Hz), 3.85-3.93(1H, m), 4.19-4.28(1H, m), 4.26(2H, s), 5.23(1H,dt, J=7.9, 7.6Hz), 7.08-7.28(5H, m), 7.71(1H, d, J=8.6Hz),8.27(1H, d, J=8.6Hz) Example 140 (3R)-3-[2-Benzyl-6-[(3R)-3-fluoro-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0409] The target compound was synthesized in the same manneras in Example 139c by using 2-benzyl-3-methoxymethyloxy-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]pyridine(Example138a).1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.56-1.75(1H, m), 1.82-1.92(1H, m), 2.00-2.08 (2H, m), 2.21-2.38 (1H, m), 2.55-2.68 (1H,m), 2.72-2.95(4H, m), 3.05(1H, d, J=14Hz), 3.26(1H, dd, J=2.0,14Hz), 3.85-3.93(1H, m), 4.19-4.28(1H, m), 4.26 (2H, s), 5.23 (1H,dt, J=7.9, 7.6Hz), 7.08-7.28(5H, m), 7.71(1H, d, J=8.6Hz) 8.27(1H, d, J=8.6Hz) Example 141 (3R)-3-[2-Benzyl-6-[(3S)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0410] The target compound was synthesized in the same manneras in Example 123.1H-NMR(CDCl3) δ=1.39-1.49(1H, m), 1.50-1.78(1H, m), 1.82-1.92(1H,m), 1.98-2.09(2H, m), 2.52-2.61(1H, m), 2.73-2.94(4H,m), 3.05(1H, d, J=14Hz), 3.26(1H, dd, J=2.0, 14Hz), 3.72-3.79(1H,m), 4.12(1H, dd, J=7.2, 14Hz), 4.20-4.25(1H, m),4.25(2H, s), 4..49(1H, dd, J=8.0, 10Hz), 7.08-7.28(5H, m),7.69(1H, d, J=8.8Hz), 8.22(1H, d, J=8.8Hz) Example 142 (3R)-3-[2-Benzyl-6-[(3R)-3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0411] The target compound was synthesized in the same manneras in Example 123 except that the hydroxyl group was reversedaccording to the method of Example 139.1H-NMR(CDCl3) δ=1.39-1.49(1H, m), 1.50-1.78(1H, m), 1.82-1.92(1H,m), 1.98-2.09(2H, m), 2.52-2.61(1H, m), 2.73-2.94(4H,m), 3.05(1H, d, J=14Hz), 3.26(1H, dd, J=2.0, 14Hz), 3.72-3.79(1H,m), 4.12(1H, dd, J=7.2, 14Hz), 4.20-4.25(1H, m),4.25(2H, s), 4..49(1H, dd, J=8.0, 10Hz), 7.08-7.28(5H, m),7.69(1H, d, J=8.8Hz), 8.22(1H, d, J=8.8Hz) Example 143(3R)-3-[2-Benzyl-6-[(3S)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0412] The target compound was synthesized in the same manneras in Example 123. 1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.58-1.68(1H, m), 1.85-2.10(4H,m), 2.41-2.52(1H, m), 2.70-2.92(4H, m), 3.04(1H, dd,J=2.0, 14Hz), 3.25(1H, dd, J=2.0, 14Hz), 3.61(3H, s), 3.80-3.87(1H,m), 4.10-4.18(2H, m), 4.24(2H, s), 7.08-7.27(5H, m),7.68(1H, d, J=8.8Hz), 8.26(1H, d, J=8.8Hz) Example 144 (3R)-3-[2-Benzyl-6-[(3R)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol
    [0413] The target compound was synthesized in the same manneras in Example 123 except that the hydroxyl group was reversedaccording to the method of Example 139.1H-NMR(CDCl3) δ =1.38-1.48 (1H, m), 1.58-1.68(1H, m), 1.85-2.10(4H,m), 2.41-2.52(1H, m), 2.70-2.92(4H, m), 3.04(1H, dd,J=2.0, 14Hz), 3.25(1H, dd, J=2.0, 14Hz), 3.61(3H, s), 3.80-3.87(1H,m), 4.10-4.18(2H, m), 4.24(2H, s), 7.08-7.27(5H, m),7.68(1H, d, J=8.8Hz), 8.26(1H, d, J=8.8Hz) Example 145 (3S)-3-[2-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethyl]-3-quinuclidinol
    [0414] 180 mg of the target compound was obtained using 200 mgof (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol(Example 10) in 2 ml of methanol at normalpressure in a hydrogen atmosphere wherein 10 mg of platinum(IV) oxide was used as a catalyst to carry out catalyticreduction.1H-NMR (CDCl3) δ =1.15-2.03(7H, m), 2.37-2.91(8H, m), 3.42(3H,s), 3.45-3.55(2H, m), 3.66-3.77(2H, m), 3.85-3.88(1H, m), 4.05(2H, s), 4.35-4.39(1H, m), 6.22(1H, d, J=8Hz), 7.13-7.18(1H,m), 7.20(1H, d, J=8Hz), 7.22-7.28(4H, m) Example 146 (3R)-3-[(E)-2-[2-Benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethenyl]-3-quinuclidinol
    [0415] 270 mg of (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol(Example 10) was dissolved in 10 ml of ethylether. 300 mg of lithium aluminum hydride was added thereto,followed by heating under reflux for 6 hours. While stirringin an ice-bath, 0.3 ml of water, 0.3 ml of an aqueous 5N sodiumhydroxide solution, 1 ml of water and 10 ml oftetrahydrofuran were added thereto. The mixture wasfiltered, and the filtrate was concentrated. The residuewas then subjected to NH-silica gel column chromatographyand eluted with 10% methanol/ethyl acetate, to give 165 mgof the target compound.1H-NMR (CDCl3) δ=1.31-1.55(3H, m), 1.72-1.77(1H, m), 2.00-2.10(1H,m), 2.55-2.65(1H, m), 2.67-2.83 (3H, m), 2.85-2.97 (2H,m), 3.42(3H, s), 3.47-3.59(2H, m), 3.68-3.79(2H, m), 3.84-3.89(1H,m), 4.09(2H, s), 4.37-4.40(1H, m), 5.97(1H, J=16H2),6.24(1H, d, J=9Hz), 6.65(1H, d, J=16Hz), 7.11-7.18(1H, m),7.19-7.25(4H, m), 7.51(1H, d, J=9Hz) Example 147 (3R)-3-[2-Benzyl-6-(2-methoxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0416] The target compound was synthesized in the same manneras in Example 12. 1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.55-1.65(1H, m), 1.83-1.93(1H,m), 1.98-2.08(2H, m), 2.7-2.93(4H, m), 3.02(1H, d,J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.41(3H, s), 3.69(2H, t,J=5Hz), 4.19(2H, s), 4.45(2H, t, J=5Hz), 6.59(1H, d, J=8Hz),7.14-7.30(5H, m), 7.53(1H, d, J=8Hz) Example 148 (3R)-3-[2-Benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0417] The target compound was synthesized in the same manneras in Example 12.1H-NMR (CDCl3) δ=1.38-1.48 (1H, m), 1.58-1.69(1H, m), 1.82-1.93(1H,m), 2.00(2H, quint, J=6.4Hz), 2.72-2.94(6H, m),3.03(1H, dd, J=1.2, 14Hz), 3.24(1H, dd, J=2.0, 14Hz), 3.34(3H,s), 3.51(2H, t, J=6.4Hz), 4.20(2H, s), 4.37(2H, t, J=6.4Hz),6.53(1H, d, J=8.4Hz), 7.18-7.31(5H, m), 7.54(1H, d, J=8.4Hz) Example 149 (3S)-3-[2-Benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0418] The target compound was synthesized in the same manneras in Example 12.1H-NMR (CDCl3) δ=1.38-1.48(1H, m), 1.58-1.69(1H, m), 1.82-1.93(1H,m), 2.00(2H, quint, J=6.4Hz), 2.72-2.94(6H, m),3.03(1H, dd, J=1.2, 14Hz), 3.24(1H, dd, J=2.0, 14Hz), 3.34(3H,s), 3.51(2H, t, J=6.4Hz), 4.20(2H, s), 4.37(2H, t, J=6.4Hz),6.53(1H, d, J=8.4Hz), 7.18-7.31(5H, m), 7.54(1H, d, J=8.4Hz) Example 150 (3R)-3-[2-Benzyl-6-(3-fluoropropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0419] The target compound was synthesized in the same manneras in Example 12. 1H-NMR(CDCl3) δ =1.36-1.44(1H, m), 1.58-1.65(1H, m), 1.85-1.93(1H,m), 1.99-2.17(4H, m), 2.74-2.92(4H, m), 3.04(1H, d,J=14Hz), 3.25(1H, d, J=14Hz), 4.20(2H, s), 4.42(2H, t, J=6Hz),4.58(2H, td, J=6, 47Hz), 6.53(1H, d, J=8Hz), 7,16-7.31(5H, m),7.55(1H, d, J=8Hz) Example 151 (3R)-3-[2-Benzyl-6-(4-fluorobutyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0420] The target compound was synthesized in the same manneras in Example 12.1H-NMR(CDCl3) δ=1.38-1.46(1H, m), 1.57-1.93(6H, m), 2.00-2.09(2H,m), 2.71-2.94(4H, m), 3.04(1H, d, J=14Hz), 3.25(1H,dd, J=2, 14Hz), 4.20(2H, s), 4.31-4.34(2H, m), 4.41-4.55(2H,m), 6.52(1H, d, J=8Hz), 7.17-7.31(5H, m), 7.54(1H, d, J=8Hz) Example 152 (3R)-3-[2-Benzyl-6-(4-chlorobutyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0421] The target compound was synthesized in the same manneras in Example 12.1H-NMR(CDCl3) δ=1.38-1.46(1H, m), 1.58-1.94(6H, m), 2.00-2.09(2H,m), 2.72-2.94(4H, m), 3.04(1H, d, J=14Hz), 3.25(1H,dd, J=2, 14Hz), 4.21(2H, s), 4.31-4.34(2H, m), 4.41-4.55(2H,m), 6.53(1H, d, J=8Hz), 7.17-7.34(5H, m), 7.55(1H, d, J=8Hz) Example 153 (3R)-3-[2-Benzyl-6-(1,3-dioxolan-2-yl)methyloxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0422] The target compound was synthesized in the same manneras in Example 12.1H-NMR(CDCl3) δ=1.38-1.46(1H, m), 1.57-1.66(1H, m), 1.85-1.92(1H,m), 2.00-2.07(2H, m), 2.75-2.94(4H, m), 3.03(1H, d, J=14Hz), 3.25(1H, dd, J=2, 14Hz), 3.92-4.05(4H, m), 4.20(2H,s), 4.38(2H, d, J=4Hz), 5.27(1H, t, J=4Hz), 6.62(1H, d, J=8Hz),7.17-7.30(5H, m), 7.56(1H, d, J=8Hz) Example 154 (3R)-3-[2-Benzyl-6-(2-pyridylmethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0423] The target compound was synthesized in the same manneras in Example 12.1H-NMR(CDCl3) δ=1.38-1.46(1H, m), 1.58-1.66(1H, m), 1.86-1.94(1H,m), 2.00-2.07(2H, m), 2.75-2.94(4H, m), 3.05(1H, d,J=14Hz), 3.27(1H, dd, J=2, 14Hz), 4.17(2H, s), 5.50(2H, s),6.67(1H, d, J=8Hz), 7.15-7.22(6H, m), 7.33(1H, d, J=8Hz),7.58(1H, d, J=8Hz), 7.62(1H, dt, J=2, 8Hz), 8.59-8.60(1H, m) Example 155 (3R)-3-[2-(4-Fluorobenzyl)-6-(3-fluoropropyloxy)-3-pyridyl]ethynyl-3-quinuclidinol
    [0424] The target compound was synthesized in the same manneras in Example 12 except that 2-benzyl-3-bromo-6-hydroxypyridinewas altered to 2-(4-fluorobenzyl)-3-bromo-6-hydroxypyridine.1H-NNR(CDCl3) δ=1.39-1.46(1H, m), 1.58-1.94(2H, m), 2.00-2.18(4H,m), 2.72-2.94(4H, m), 3.06(1H, d, J=14Hz), 3.27(1H,dd, J=2, 14Hz), 4.16(2H, s), 4.41(2H, t, J=6Hz), 4.59(2H, td,J=6, 47Hz), 6.54(1H, d, J=8Hz), 6.93-6.97(2H, m), 7.24-7.28(2H,m), 7.56(1H, d, J=8Hz) Example 156 (3R)-3-[2-(3-Fluorobenzyl)-6-(3-fluoropropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0425] The target compound was synthesized in the same manneras in Example 12 except that 2-benzyl-3-bromo-6-hydroxypyridine was altered to 2-(3-fluorobenzyl)-3-bromo-6-hydroxypyridinein Example 12.1H-NMR(CDCl3) δ=1.39-1.46(1H, m), 1.58-1.94 (2H, m), 2.00-2.18(4H,m), 2.72-2.94(4H, m), 3.06(1H, d, J=14Hz), 3.27(1H,dd, J=2, 14Hz), 4.19(2H, s), 4.40-4.44(2H, m), 4.52-4.64(2H,m), 6.56(1H, d, J=8Hz), 6.86-6.91(1H, m), 6.98-7.09(2H, m),7.20-7.28(1H, m), 7.56(1H, d, J=8Hz) Example 157 (3R)-3-[2-(4-Fluorobenzyl)-6-(2-methoxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0426] The target compound was synthesized in the same manneras in Example 12 except that 2-benzyl-3-bromo-6-hydroxypyridinewas altered to 2-(4-fluorobenzyl)-3-bromo-6-hydroxypyridinein Example 12.1H-NMR (CDCl3) δ=1.37-1.94(3H, m), 1.98-2.09 (2H, m), 2.70-3.95(4H,m), 3.06(1H, d, J=14Hz), 3.26(1H, dd, J=2, 14Hz),3.42 (3H, s), 3.69(2H, t, J=5Hz), 4,16 (2H, s), 4.43 (2H, t, J=5Hz),6.61(d, J=8Hz), 6.94(2H, t, J=9Hz), 7.25(2H, dd, J=6, 9Hz),7.55(1H, d, J=8Hz) Example 158 3-[2-Benzyl-6-(2-ethoxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Bromo-6-(2-ethoxyethyl)oxypyridine
    [0427] 1.7 g of 60%oily sodium hydride was suspended in 20 mlof N,N-dimethylformamide, followed by adding a solution of10 ml of N,N-dimethylformamide containing 4.1 ml of 2-ethoxyethanolthereto with stirring under ice-cooling.After stirring for 20 minutes, a solution of 10 ml ofN,N-dimethylformamide containing 5 g of 2,6-dibromopyridine was added thereto and the mixture was further stirred at roomtemperature for one hour. Then, water was added thereto,and the mixture was extracted with ethyl acetate. Theorganic phase was further washed with brine, dried overanhydrous sodium sulfate and the solvent was removed. Theresidue was subjected to silica gel column chromatographyusing 5% ethyl acetate/hexane as an eluent for separationand purification, to give 4.8 g of the target compound.1H-NMR(CDCl3) δ=1.24(3H, t, J=7.0Hz), 3.59(2H, q, J=7.0Hz),3.78(2H, t, J=4.8Hz), 4.47(2H, t, J=4.8Hz), 6.75(1H, dd,J=8.0Hz, 0.7Hz), 7.05(1H, dd, J=7.5Hz, 0.7Hz), 7.41(1H, dd,J=8.0Hz, 7.5Hz) b) 2-Benzyl-6-(2-ethoxyethyl)oxypyridine
    [0428] A 1.09 mol tetrahydrofuran solution containingbenzylmagnesium chloride was slowly added dropwise into amixture of 1 g of 2-bromo-6-(2-ethoxyethyl)oxypyriaine, 145mg of 1,3-bis(diphenylphosphino)propanenickel (II)chloride and 5 ml of tetrahydrofuran with stirring underice-cooling in a nitrogen atmosphere. After stirring for2.5 hours, an aqueous saturated ammonium chloride solutionwas added thereto and the mixture was extracted with ethylacetate. The organic phase was further washed with brine,dried over anhydrous sodium sulfate and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using 5% ethyl acetate/hexane as an eluentfor separation and purification, to give 1 g of the targetcompound. 1H-NMR(CDCl3) δ=1.23(3H, t, J=7.0Hz), 3.57(2H, q, J=7.0Hz),3.76(2H, t, J=4.9Hz), 4.00(2H, s), 4.47(2H, t, J=4.9Hz),6.59(1H, d, J=8.2Hz), 6.65(1H, d, J=7.2Hz), 7.19-7.30(5H, m)7.44(1H, dd, J=8.2Hz, 7.2Hz) c) 2-Benzyl-3-bromo-6-(2-ethoxyethyl)oxypyridine
    [0429] A mixture of 1 g of 2-benzyl-6-(2-ethoxyethyl)oxypyridine,125 mg of tetraethylammoniumchloride and 279 mg of potassium hydroxide was suspended in5 ml of an aqueous potassium bromide solution (2.5 g ofpotassium bromide was dissolved in 10 ml of water). Intothe suspension was added dropwise a mixture of 0.23 ml ofbromine and 5 ml of the aforementioned aqueous potassiumbromide solution by using a dropping funnel with stirringunder ice-cooling over 10 minutes. The mixture was returnedto room temperature and stirred overnight. Then, an aqueoussodium sulfite solution was added thereto, and the mixturewas extracted with ethyl acetate. The organic phase wasfurther washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 5% ethylacetate/hexane as an eluent for separation and purification,to give 1.2 g of the target compound.1H-NMR(CDCl3) δ=1.22(3H, t, J=7.0Hz), 3.55(2H, q, J=7.0Hz),3.72(2H, t, J=4.8Hz), 4.18(2H, s), 4.41(2H, t, J=4.8Hz),6.53(1H, d, J=8.6Hz), 7.19-7.34(5H, m), 7.30(1H, d, J=8.6Hz) d) 3-[2-Benzyl-6-(2-ethoxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0430] 7 ml of N,N-dimethylformamide was added to a mixture of2-benzyl-3-bromo-6-(2-ethoxyethyl)oxypyridine, 601 mg of3-ethynyl-3-quinuclidinol, 406 mg oftetrakis(triphenylphosphine)palladium(0), 220 mg ofcuprous iodide and 1.7 ml of triethylamine, followed byheating under stirring at 80°C in an oil bath for one hourin a nitrogen atmosphere. After cooling as it was, ethylacetate was added thereto. The mixture was filtered throughCelite, and it was washed with aqueous ammonia. The organicphase was washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The residue wassubjected to NH-silica gel column chromatography using ethylacetate/hexane as an eluent for separation and purification,to give 247 mg of the target compound.1H-NMR(CDCl3) δ=1.22(3H, t, J=7.1Hz), 1.38-1.48(1H, m),1.57-1.67(1H, m), 1.82-1.92(1H, m), 1.98-2.08(2H, m), 2.71-2.95(4H,m), 3.03(1H, d, J=14Hz), 3.24(1H, dd, J=2.0, 14Hz),3.56(2H, q, J=7.1Hz), 3.74(2H, t, J=4.8Hz), 4.20(2H, s),4.46(2H, t, J=4.8Hz), 6.60(1H, d, J=8.5Hz), 7.18-7.30(5H, m),7.54(1H, d, J=8.5Hz) Example 159 3-[2-Benzyl-6-(2-ethoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0431] The target compound was synthesized in the same manneras in Example 158.1H-NMR(CDCl3) δ=1.20(3H, t, J=6.9Hz), 1.37-1.47(1H, m),1.57-1.65(1H, m), 1.83-1.93(1H, m), 2.01(2H, quint, J=6.4Hz),2.00-2.08(2H, m), 2.72-2.94(4H, m), 3.05(1H, d, J=14Hz), 3.24(1H, dd, J=2.0, 14Hz), 3.48(2H, q, J=6.9Hz), 3.55(2H, t,J=6.4Hz), 4.20(2H, s), 4.37(2H, t, J=6.4Hz), 6.52(1H, d,J=8.6Hz), 7.18-7.31(5H, m), 7.53(1H, d, J=8.6Hz) Example 160 3-[2-(4-Fluorobenzyl)-6-[(3-tetrahydrofuranyl)methyloxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0432] The target compound was synthesized in the same manneras in Example 158.1H-NMR(CDCl3) δ=1.37-1.47(1H, m), 1.58-1.92(3H, m), 1.98-2.12(2H,m), 2.62-2.95(4H, m), 3.05(1H, dd, J=1.6, 14Hz),3.25(1H, dd, J=2.0, 14Hz), 3.65 (2H, dd, J=5.2, 8.8Hz),3.72-3.96(3H, m), 4.09-4.18(3H, m), 4.27(1H, dd, J=6.4, 11Hz),6.53(1H, d, J=8.4Hz), 6.95(2H, t, J=8.8Hz), 7.24(2H, dd, J=5.5,8.8Hz), 7.55(1H, d, J=8.4Hz) Example 161 3-[2-Benzyl-6-[(3-tetrahydrofuranyl)methyloxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0433] The target compound was synthesized in the same manneras in Example 158.1H-NMR(CDCl3) δ=1.35-1.45(1H, m), 1.55-1.64(1H, m), 1.67-1.75(1H,m), 1.83-1.95(1H, m), 1.98-2.10(2H, m), 2.62-2.92(4H,m), 3.02(1H, d, J=14Hz), 3.23(1H, dd, J=2.0, 14Hz), 3.65(2H,dd, J=5.7, 8.8Hz), 3.73-3.92 (3H, m), 4.10-4.21 (3H, m), 4.28(1H,dd, J=6.6, 11Hz), 6.52(1H, d, J=8.6Hz), 7.15-7.32(5H, m),7.54(1H, d, J=8.6Hz) Example 162 3-[2-(3-Fluorobenzyl)-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0434] The target compound was synthesized in the same manneras in Example 158.1H-NMR(CDCl3) δ =1.35-1.45(1H, m), 1.58 -1.68(1H, m), 1.82-1.92(1H,m), 2.00(2H, quint, J=6.4Hz), 2.00-2.10(2H, m),2.72-2.95(4H, m), 3.03(1H, d, J=14Hz), 3.23(1H, dd, J=2.0,14Hz), 3.34(3H, s) , 3.51(2H, t, J=6.4Hz), 4.17(2H, s), 4.36(2H,t, J=6.4Hz), 6.53(1H, d, J=8.4Hz), 6.82-7.25(4H, m), 7.53(1H,d, J=8.4Hz) Example 163 3-[2-Benzyl-6-(3-tetrahydrofuranyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0435] The target compound was synthesized in the same manneras in Example 158.1H-NMR (CDCl3) δ=1.38-1.97(3H, m), 2.00-2.25(4H, m), 2.70-2.95(4H,m), 3.05(1H, d, J=14Hz), 3.26(1H, dd, J=2, 14Hz),3.80-4.00(4H, m), 4.19(2H, s), 5.45-5.52(1H, m), 6.54(1H, d,J=8Hz), 7.14-7.30(5H, m), 7.55(1H, d, J=8Hz) Example 164 3-[2-benzyl-6-[2-(2-methoxyethyl)oxyethyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0436] The target compound was synthesized in the same manneras in Example 158.1H-NMR (CDCl3) δ=1.35-1.95(3H, m), 1.98-2.08(2H, m), 2.70-2.93(4H,m), 3.04(1H, d, J=14Hz), 3.25(1H, dd, J=2, 14Hz),3.38(3H, s), 3.54-3.57(2H, m), 3.65-3.69(2H, m), 3.81(2H, t,J=5Hz), 4.19(2H, s), 4.48(2H, t, J=5Hz), 6.59(1H, d, J=8Hz),7.14-7.30(5H, m), 7.55(1H, d, J=8Hz) Example 165 3-[2-Benzyl-6-(3-hydroxypropyl)oxy-3- pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-(3-hydroxypropyl)oxypyridine
    [0437] A mixture of 1.0 g of 2-benzyl-3-bromo-6-hydroxypyridineobtained in Production Example-3(b), 0.44ml of 3-bromopropanol, 780 mg of anhydrous potassiumcarbonate and 10 ml of N,N-dimethylformamide was heatedunder stirring in an oil bath kept at 80°C for one hour ina nitrogen atmosphere. The reaction solution waspartitioned between ethyl acetate-water, and the organicphase was washed with water and brine, dried over anhydrousmagnesium sulfate and then concentrated. The residue wassubjected to silica gel chromatography using 10-20% ethylacetate/hexane, to give 860 mg of the target compound.1H-NMR (CDCl3) δ=1.94(2H, quint, J=6Hz), 2.47(1H, br.s),3.69 (2H, br.t, J=6Hz), 4.20(2H, s), 4.43(2H, t, J=6Hz), 6.49(1H,d, J=8Hz), 7.18-7.34(5H, m), 7.66(1H, d, J=8Hz) b) 3-[2-Benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0438] A mixture of 860 mg of 2-benzyl-3-bromo-6-(3-hydroxypropyl)oxypyridine,400 mg of 3-ethynyl-3-quinuclidinol,150 mg oftetrakis(triphenylphosphine)palladium(0), 10 mg of cuprousiodide, 1.1 ml of triethylamine and 4 ml of N,N-dimethylformamidewas heated under stirring in an oil bathkept at 85°C for 3 hours in a nitrogen atmosphere. Thereaction solution was partitioned between ethyl acetate-aqueousdilute ammonia, and the organic phase was washed with water and brine, dried over anhydrous sodium sulfate and thenconcentrated. The residue was subjected to columnchromatography using NH-silica gel and diluted with 50-100%ethyl acetate/hexane and then with 2.5-5% methanol/ethylacetate, to give 470 mg of the target compound.1H-NMR (CDCl3) δ=1.36-1.46(1H, m), 1.55-1.66(1H, m), 1.83-2.08(5H,m), 2.68-2.96(4H, m), 3.02(1H, d, J=14Hz), 3,24(1H,dd, J=2, 14Hz), 3.68(2H, t, J=6Hz), 4.00(2H,s), 4.47(2H, t,J=6Hz), 6.55(1H, d, J=9Hz), 7.16-7.30(5H, m), 7.57(1H, d,J=9Hz) Example 166 (3R)-3-[2-Benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0439] The target compound was synthesized in the same manneras in Example 165.1H-NMR (CDCl3) δ=1.36-1.46(1H, m), 1.55-1.66(1H, m), 1.83-2.08(5H,m), 2.68-2.96(4H, m), 3.02(1H, d, J=14Hz), 3,24(1H,dd, J=2, 14Hz), 3.68(2H, t, J=6Hz), 4.00(2H,s), 4.47(2H, t,J=6Hz), 6.55(1H, d, J=9Hz), 7.16-7.30(5H, m), 7.57(1H, d,J=9Hz) Example 167 3-[2-Benzyl-6-(2-hydroxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0440] The target compound was synthesized in the same manneras in Example 165.1H-NMR (CDCl3) δ=1.37-1.93(3H, m), 1.98-2.08(2H, m), 2.70-2.95(4H,m), 3.04(1H, d, J=14Hz), 3.26(1H, dd, J=2, 14Hz),3.87-3.92(2H, m), 4.21(2H, s), 4.42-4.47(2H, m), 6.61(1H, d,J=8Hz), 7.16-7.32(5H, m), 7.59(1H, d, J=8Hz) Example 168 3-[2-Benzyl-6-[3-(3-methoxycarbonylpropanoyloxy)propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-[3-(3-methoxycarbonylpropanoyloxy)propyl]oxypyridine
    [0441] 509 mg of 2-benzyl-3-bromo-6-(3-hydroxypropyl)oxypyridine(Example 165a) was dissolved in5 ml of dichloromethane. While stirring under ice-cooling,0.33 ml of triethylamine and 0.29 ml of 3-methoxycarbonylpropionylchloride were added thereto.After the temperature of the reaction solution was returnedto room temperature and the reaction solution was stirredfor 30 minutes, water was added to the reaction solution.The mixture was extracted with ethyl acetate, and the organicphase was further washed with brine, dried over anhydroussodium sulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 20%ethyl acetate/hexane as an eluent for separation andpurification, to give 643 mg of the target compound.1H-NMR(CDCl3) δ=2.04(2H, tt, J=6.2, 6.4Hz), 2.63(4H, s),3.68(3H, s), 4.19(2H, s), 4.23(2H, t, J=6.4Hz), 4.32(2H, t,J=6.2Hz), 6.46(1H, d, J=8.6Hz), 7.20-7.36(5H, m), 7.63(1H, d,J=8.6Hz) b) 3-[2-Benzyl-6-[3-(3-methoxycarbonylpropanoyloxy)propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0442] 5 ml of N,N-dimethylformamide was added to a mixture of 643 mg of 2-benzyl-3-bromo-6-[3-(3-methoxycarbonylpropanoyloxy)propyl]oxypyridine,245 mg of3-ethynyl-3-quinuclidinol, 84 mg oftetrakis(triphenylphosphine)palladium(0), 10 mg of cuprousiodide and 0.72 ml of triethylamine, followed by heatingunder stirring at 80°C in an oil bath for two hours in anitrogen atmosphere. After cooling as it was, ethyl acetatewas added thereto and the mixture was washed with aqueousammonia. The organic phase was washed with brine, dried overanhydrous sodium sulfate and the solvent was removed. Theresidue was subjected to NH-silica gel column chromatographyusing 50% ethyl acetate/hexane and 2% methanol/ethyl acetateas eluents for separation and purification, to give 223 mgof the target compound.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.57-1.67(1H, m), 1.82-1.92(1H,m), 1.97-2.15(4H, m), 2.61(4H, s), 2.70-2.94(4H, m),3.04(1H, d, J=14Hz), 3.24(1H, dd, J=2.0, 14Hz), 3.68(3H, s),4.20(2H, s), 4.23(2H, t, J=6.4Hz), 4.36(2H, t, J=6.2Hz),6.53(1H, d, J=8.4Hz), 7.18-7.30(5H, m), 7.54(1H, d, J=8.4Hz) Example 169 3-[2-Benzyl-6-[3-[N-(tert-butoxycarbonyl)aranyloxy]propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0443] The target compound was synthesized in the same manneras in Example 168.1H-NMR(CDCl3) δ=1.27(3H, d, J=7.1Hz), 1.38-1.48(1H, m),1.44(9H, s), 1.58-1.68(1H, m), 1.82-1.94(1H, m), 2.00-2.10(2H,m), 2.08(2H, tt, J=6.2, 6.4Hz), 2.72-2.95(4H, m), 3.03(1H, d, J=14Hz), 3.25(1H, dd, J=2.0, 14Hz), 4.20(2H, s), 4.22-4.35(3H,m), 4.36(2H, t, J=6.2Hz), 5.04(1H, br.s), 6.53(1H, d, J=8.4Hz),7.18-7.30(5H, m), 7.55(1H, d, J=8.4Hz) Example 170 3-[2-Benzyl-6-[3-[N-(benzyloxycarbonyl)glycyloxylpropyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0444] The target compound was synthesized in the same manneras in Example 168.1H-NMR(CDCl3) δ =1.35-1.45(1H, m), 1.55-1.65(1H, m), 1.82-1.92(1H,m), 1.98-2.10(4H, m), 2.70-2.95(4H, m), 3.03(1H, d,J=14Hz), 3.24(1H, dd, J=2.0, 14Hz), 3.96(2H, d, J=5.5Hz),4.19(2H, s), 4.29(2H, t, J=6.4Hz) 4.35(2H, t, J=6.2Hz),5.12(2H, s), 5.28(1H, br.s), 6.51(1H, d, J=8.4Hz), 7.15-7.24(10H,m), 7.53(1H, d, J=8.4Hz) Example 171 3-[2-Benzyl-6-[3-(pivaloyloxy)propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0445] The target compound was synthesized in the same manneras in Example 168.1H-NMR(CDCl3) δ=1.18(9H, s), 1.35-1.45(1H, m), 1.55-1.65(1H,m), 1.85-2.12(5H, m), 2.70-2.92(4H, m), 3.03(1H, d, J=14Hz),3.25(1H, dd, J=2.0, 14Hz), 4.19(2H, t, J=6.2Hz), 4.20(2H, s),4.37(2H, t, J=6.4Hz), 6.52(1H, d, J=8.4Hz), 7,18-7.30(5H, m),7.54(1H, d, J=8.4Hz) Example 172 (3R)-3-[2-Benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]3-(methoxymethyloxy)pyridine
    [0446] Sodium hydride was added to a mixture of 456 mg of2-benzyl-6-iodo-3- (methoxymethyloxy)pyridine, 122 mg ofcuprous iodide and 3 ml of tetrahydropyran-2-methanol,followed by stirring at 90°C for 3 hours. An aqueousammonium chloride solution and ethyl acetate were added tothe reaction solution, followed by stirring at roomtemperature for one hour. Then, the organic phase was washedwith water and brine, dried over anhydrous magnesium sulfateand the solvent was removed. The residue was subjected tosilica gel column chromatography using 15% ethylacetate/hexane, to give 383 mg of the target compound.1H-NMR(CDCl3) δ=1.36-1.64(5H, m), 1.84-1.90 (1H, m), 3.40 (3H,s), 3.43-3.49(1H, m), 3.62-3.68(1H, m), 4.02-4.07(3H, m),4.15-4.29(2H, m), 5.03(2H, s), 6.59 (1H, d, J=8Hz), 7.14-7.34 (6H,m) b) 2-Benzyl-6-[(tetrahydro-4 H-pyran-2-yl)methyloxy]-3-pyridyltrifluoromethanesulfonate
    [0447] 2 ml of trifluoroacetic acid was added to a mixture of378 mg of 2-benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]3-(methoxymethyloxy)pyridineand 3 ml ofdichloromethane at room temperature, followed by stirringat the same temperature overnight. An aqueous saturatedsodium bicarbonate solution and diethyl ether were addedthereto to extract. The organic phase was washed with waterand brine, dried over anhydrous magnesium sulfate and thesolvent was removed. 424 mg of N-phenyltrifluoromethanesulfonimide,301 µl of triethylamine and 1.3 mg of 4-dimethylaminopyridine were added to asolution of 5 ml of dichloromethane containing the residue,followed by stirring at room temperature for 2 hours. Silicagel was added to the reaction solution, and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using 10% ethyl acetate/hexane, to give 428mg of the target compound.1H-NMR(CDCl3) δ=1.36-1.64(5H, m), 1.84-1.90(1H, m), 3.41-3.48(1H,m), 3.58-3.64(1H, m), 4.01-4.06(1H, m), 4.10(2H, s),4.18-4.30(2H, m), 6.70(1H, d, J=8Hz), 7.20-7.29(5H, m), 7.44(1H,d, J=8Hz) c) (3R)-3-[2-Benzyl-6-(tetrahydro-4 H-pyran-2-yl)methyloxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0448] A mixture of 428 mg of 2-benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]-3-pyridyltrifluoromethanesulfonate, 180 mg of (3R)-3-ethynyl-3-quinuclidinol,57.3 mg oftetrakis(triphenylphosphine)palladium(0), 1.9 mg ofcuprous iodide, 415µl of triethylamine and 5 ml of N,N-dimethylformamidewas stirred at 90°C for 3 hours in anitrogen atmosphere. NH-silica gel was added to thereaction solution, and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using3% methanol/ethyl acetate, to give 305 mg of the targetcompound.1H-NMR(CDCl3) δ=1.34-1.65(7H, m), 1.85-1.91(2H, m), 1.98-2.07(2H,m), 2.75-2.90(4H, m), 3.03(1H, d, J=14Hz), 3.24(1H, d, J=14Hz), 3.42-3.49(1H, m), 3.61-3.68(1H, m), 4.02-4.07(1H,m), 4.18-4.34(4H, m), 6.62(1H, d, J=8Hz), 7.14-7.29(5H, m),7.54(1H, d, J=8Hz) Example 173 3-[2-Benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-6-(2-hydroxyethyl)oxy-3-pyridyltrifluoromethane sulfonate
    [0449] The target compound was synthesized in the same manner asin Example 172a and b except that tetrahydropyran-2-methanolwas altered to ethylene glycol.1H-NMR(CDCl3) δ =3.87-3.89(2H, m), 4.12(2H, s), 4.39-4.42(2H,m), 6.68(1H, d, J=8Hz), 7.21-7.32(5H, m), 7.49(1H, d, J=8Hz) b) 2-Benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyltrifluoromethanesulfonate
    [0450] 473 mg of pyridinium dichromate was added to a mixtureof 395 mg of 2-benzyl-6-(2-hydroxyethyl)oxy-3-pyridyltrifluoromethanesulfonate, 1.4 g of molecular sieves 4A and5 ml of dichloromethane at room temperature, followed bystirring for 3 hours. The mixture was filtered throughCelite, and the solvent was removed. 236 µl of atetrahydrofuran solution containing 1.1 mol ofvinylmagnesium bromide was added to a solution of 5 ml ofdiethyl ether containing the residue at 0°C, followed bystirring at the same temperature for 40 minutes. An aqueoussaturated ammonium chloride solution and diethyl ether wereadded to the reaction solution, and the organic phase waswashed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 30%ethyl acetate/hexane, to give 46.5 mg of the target compound.1H-NMR(CDCl3) δ=2.67-2.68(1H, m), 4.13(2H, s), 4.19-4.24(1H,m), 4.37-4.41(1H, m), 4.46(1H, br s), 5.23-5.27(1H, m),5.36-5.41(1H, m), 5.84-5.93(1H, m), 6.70(1H, d, J=8Hz),7.21-7.32(5H, m), 7.49(1H, d, J=8Hz) c) 3-[2-Benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol
    [0451] A mixture of 46.5 mg of 2-benzyl-6-(2-hydroxy-3-butenyl)oxy-3-pyridyltrifluoromethane sulfonate, 22.7 mgof 3-ethynyl-3-quinuclidinol, 6.6 mg oftetrakis(triphenylphosphine)palladium(0), 0.1 mg ofcuprous iodide, 60.1 µl of diisopropylethylamine and 1 mlof N,N-dimethylformamide was stirred at 80°C for 3 hours ina nitrogen atmosphere. NH-silica gel was added to thereaction solution and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using5% methanol/ethyl acetate, to give 10.7 mg of the targetcompound.1H-NMR(CDCl3) δ=1.38-1.46(1H, m), 1.58-1.66(1H, m), 1.84-1.93(1H,m), 1.99-2.08(2H, m), 2.75-2.91(4H, m), 3.04(1H, d,J=14Hz), 3.25(1H, dd, J=2, 14Hz), 4.21(2H, s), 4.24-4.28(1H,m), 4.39-4.48(2H, m), 5.21-5.24(1H, m), 5.36-5.41(1H, m),5.85-5.94(1H, m), 6.60(1H, d, J=8Hz), 7.27-7.31(5H, m), 7.58(1H,d, J=8Hz) Example 174 3-[2-Benzyl-6-(3-methoxypropyl)thio-3- pyridyl]ethynyl-3-quinuclidinol a) 2-Benzyl-3-bromo-6-mercaptopyridine
    [0452] A mixture of 5.0 g of 2-benzyl-3-bromo-6-hydroxypyridineobtained in Production Example-3(b), 5.7 gof a Lawesson's reagent and 50 ml of toluene was heated understirring for 6 hours in an oil bath kept at 100°C. Chloroformand silica gel were added to the reaction solution, and themixture was concentrated to dryness. The residue wassubjected silica gel column chromatography using 10% ethylacetate/toluene, to give 3.5 g of the target compound.1H-NMR (CDCl3) δ=4.15(2H, s), 7.21-7.27(3H, m), 7.30-7.42(4H,m) b) 2-Benzyl-3-bromo-6-(3-methoxypropyl)thiopyridine
    [0453] A mixture of 500 mg of 2-benzyl-3-bromo-6-mercaptopyridine,360 mg of 3-methoxypropylmethanesulfonate, 370 mg of anhydrous potassium carbonate and 10ml of N,N-dimethylformamide was stirred at room temperaturefor one hour in a nitrogen atmosphere. The reaction solutionwas partitioned between ethyl acetate-water, and the organicphase was washed with water and brine, dried over anhydrousmagnesium sulfate and then concentrated. The residue wassubjected to silica gel column chromatography using 1-2%ethyl acetate/hexane, to give 425 mg of the target compound.1H-NMR (CDCl3) δ =1.85(2H, quint, J=7Hz), 3.13(2H, t, J=7Hz),3.32(3H, s), 3.41(2H, t, J=7Hz), 4.25(2H, s), 6.88(1H, d, J=8Hz),7.17-7.34 (5H, m), 7.56(1H, d, J=8Hz) c) 3-[2-Benzyl-6-(3-methoxypropyl)thio-3- pyridyl]ethynyl-3-quinuclidinol
    [0454] A mixture of 425 mg of 2-benzyl-3-bromo-6-(3-methoxypropyl)thiopyridine,200 mg of 3-ethynyl-3-quinuclidinol,70 mg oftetrakis(triphenylphosphine)palladium(0), 4.6 mg ofcuprous iodide, 0.5 ml of triethylamine and 2 ml of N,N-dimethylformamidewas heated under stirring in an oil bathkept at 85°C for 4 hours in a nitrogen atmosphere. Thereaction solution was partitioned between ethyl acetate-aqueousdilute ammonia, and the organic phase was washed withwater and brine, dried over anhydrous magnesium sulfate andthen concentrated. The residue was subjected to columnchromatography using NH-silica gel and eluted with 20-100%ethyl acetate/hexane and then with 2.5% methanol/ethylacetate, to give 300 mg of the target compound.1H-NMR (CDCl3) δ=1.36-1.93(5H, m), 1.98-2.08(2H, m), 2.70-2.94(4H,m), 3.03(1H, d, J=14Hz), 3.18(2H, t, J=7Hz), 3.24(1H,dd, J=2, 14Hz), 3.32(3H, s), 3.42(2H, t, J=7Hz), 4.26(2H, s),6.97(1H, d, J=8Hz), 7.16-7.31(5H, m), 7.43(1H, d, J=8Hz)Example 175 3-[2-Benzyl-6-(3-hydroxypropyl)thio-3-pyridyl]ethynyl-3-quinuclidinol
    [0455] The target compound was synthesized in the same manneras in Example 174.1H-NMR (CDCl3) δ=1.36-1.90(5H, m) , 1.98-2.06(2H, m), 2.68-2.94(4H,m), 3.02(1H, d, J=14Hz), 3.22(1H, dd, J=2, 14Hz),3.28(2H, t, J=6Hz), 3.67(2H, t, J=6Hz), 4.27(2H, s), 7.04(1H,d, J=8Hz), 7.16-7.31(5H, m), 7.47(1H, d, J=8Hz) Example 176 (3R)-3-[4-Benzyl-2-(3-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0456] The target compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ=1.38-1.92(3H, m), 2.00-2.11(2H, m), 2.70-3.00(4H,m), 3.06(1H, d, J=14Hz), 3.25(1H, dd, J=2, 14Hz),4.18(2H, s), 7.20(2H, d, J=7Hz), 7.22-7.29(1H, m), 7.32(2H, t,J=7Hz), 7.39(1H, dd, J=5, 7Hz), 7.49(1H, s), 8.22-8.27(1H, m),8.63(1H, dd, J=2, 5Hz), 8.74(1H, s), 9.13(1H, dd, J=1, 2Hz) Example 177 3-[4-Benzyl-2-(1-methyl-2-oxo-1,2-dihydropyridine-5-yl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0457] The target compound was synthesized in the same manner asin Example 1.1H-NMR (CDCl3) δ=1.36-1.46(1H, m), 1.56-1.89(2H, m), 1.99-2.10(2H,m), 2.68-2.96(4H, m), 3.05(1H, dd, J=2,14Hz), 3.23(1H,dd, J=2, 14Hz), 3.63(3H, s), 4.12(2H, s), 6.61(1H, d, J=10Hz),7.15-7.22(3H, m), 7.26(1H, t, J=7Hz), 7.32(2H, t, J=7Hz),7.76(1H, dd, J=2,10Hz), 8.15(1H, d, J=2Hz), 8.54(1H,s) Example 178 3-[4-Benzyl-2-(2-cyano-5-pyridyl)-5-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0458] The target compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ=1.38-1.92(3H, m), 2.00-2.17(2H, m), 2.70-3.00(4H,m), 3.06(1H, dd, J=2,14Hz), 3.26(1H, dd, J=2, 14Hz),4.21(2H, s), 7.20(2H, d, J=7Hz), 7.28(1H, t, J=7Hz), 7.34(2H,t, J=7Hz), 7.53(1H, s), 7.77(1H, dd, J=1,8Hz), 8.41(1H, dd,J=2,8Hz), 8.74(1H, s), 9.22(1H, dd, J=1,2Hz) Example 179(3R)-3-[4-Benzyl-2-(2-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0459] The target compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ=1.35-1.90(3H, m), 2.00-2.15(2H, m), 2.70-2.95(4H,m), 3.03(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz),4.21(2H, s) , 7.20-7.32(6H, m), 7.81(1H, dt, J=2, 8Hz), 8.29(1H,s), 8.38(1H, d, J=8Hz), 8.64-8.67(1H, m), 8.68(1H, s) Example 180 (3R)-3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0460] The target compound was synthesized in the same manneras in Example 1.1H-NMR (CDCl3) δ=1.30-1.95(3H, m), 2.00-2.15(2H, m), 2.65-2.95(4H,m), 3.03(1H, d, J=14Hz), 3.23(1H, d, J=14Hz), 4.15(2H,s), 6.01(2H, s), 6.87(1H, d, J=8Hz), 7.19(2H, d, J=8Hz),7.22-7.28(1H, m), 7.32(2H, t, J=7Hz), 7.40(1H, s), 7.42-7.46(2H,m), 8.65(1H, s) Example 181 3-[4-Benzyl-2-(2-pyrimidyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0461] The target compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ=1.32-1.44(1H, m), 1.61-1.63(1H, m), 1.84-1.99(1H,m), 2.05-2.09(2H, m), 2.75-2.92(4H, m), 3.08(1H, d,J=14Hz), 3.24(1H, dd, J=2, 14Hz), 4.23(2H, s), 7.19-7.32(6H,m), 8.38(1H, s), 8.84(1H, s), 8.90(2H, d, J=5Hz) Example 182 3-[4-Benzyl-2-(5-pyrimidyl)-5- pyridyl]ethynyl-3-quinuclidinol
    [0462] The target compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ=1.42-1.46(1H, m), 1.64-1.88(2H, m), 2.05-2.08(2H,m), 2.75-2.89(4H, m), 3.06(1H, d, J=14Hz), 3.26(1H,dd, J=2, 14Hz), 4.12(2H, s), 7.18-7.36(5H, m), 7.48(1H, s),8.74 (1H, s), 9.23 (1H, s), 9.26 (2H, s) Example 183 3-[4-Benzyl-2-(4-pyrimidyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0463] The title compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ =1.42-1.47(1H, m), 1.62-1.86(2H, m),2.05-2.06(2H, m), 2.74-2.91(4H, m), 3.05(1H, dd, J=2, 14Hz),3.25(1H, dd, J=2, 14Hz), 4.23(2H, s), 7.21-7.33(5H, m),8.33-8.35(2H, m), 8.71(1H, s) , 8.85(1H, d, J=5Hz), 9.25(1H,d, J=1Hz) Example 184 3-[4-Benzyl-2-(3-pyridazyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0464] The title compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ=1.42-1.47(1H, m), 1.64-1.87(2H, m), 2.00-2.07(2H,m), 2.77-2.88(4H, m), 3.06(1H, d, J=14Hz), 3.26(1H,dd, J=2, 14Hz), 4.23(2H, s), 7.22-7.32(5H, m), 7.57-7.61(1H,m), 8.53(1H, dd, J=1.6, 8.6Hz), 8.58(1H, s), 8.70(1H, s),9.18(1H, dd, J=1.6, 4.9Hz) Example 185 3-[4-Benzyl-2-(4-pyridazyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0465] The title compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ=1.40-1.47(1H, m), 1.62-1.88(2H, m), 2.05-2.09(2H,m), 2.75-2.92(4H, m), 3.07(1H, dd, J=2, 14Hz), 3.26(1H,dd, J=2, 14Hz), 4.20(2H, s), 7.18-7.36(5H, m), 7.57(1H, s),7.98(1H, dd, J=2, 5Hz), 8.76(1H, s), 9.26(1H, dd, J=1, 5Hz),9.71(1H, dd, J=1, 2Hz) Example 186 (3R)-3-[4-Benzyl-2-(1,4-dioxene-2-yl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0466] The title compound was synthesized in the same manneras in Example 1.1H-NMR(CDCl3) δ=1.31-1.49(1H, m), 1.57-1.90(2H, m),2.02-2.08(2H, m), 2.73-2.87(4H, m), 3.01(1H, d, J=14Hz),3.20(1H, dd, J=2, 14Hz), 4.09(2H, s), 4.15-4.24(4H, m),7.15-7.31(7H, m), 8.47(1H, s) Example 187 3-[4-Benzyl-2-(3-oxo-1-cyclohexenyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0467] The title compound was synthesized in the same manneras in Example 1 by using (3-oxo-1-cyclohexenyl)tributyltinsynthesized according to a method described in literature(Tetrahedron Letters, Vol. 31, No. 13, 1837 (1990)).1H-NMR(CDCl3) δ=1.42-1.44(1H, m), 1.62-1.89(2H, m), 2.02-2.16(4H,m), 2.47-2.50(2H, m), 2.76-2.87(6H, m), 3.05(1H, d,J=14Hz), 3.24(1H, d, J=14Hz), 4.14(2H, s), 6.63(1H, s),7.15-7.43(6H, m), 8.66(1H, s) Example 188 3-[4-Benzyl-2-(3,4-dihydro-2H-6-pyranyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0468] The title compound was synthesized in the same manneras in Example 1 by using (3,4-dihydro-2H-6-pyranyl)tributyltinsynthesized with reference to a methoddescribed in literature (Synlett 152 (1994)).1H-NMR(CDCl3) δ=1.37-1.40(1H, m), 1.52-1.89(2H, m), 1.89-1.96(2H,m), 2.01-2.05 (2H, m), 2.24-2.28 (2H, m), 2.51-2.94(4H,m), 3.01 (1H, m), 3.19 (1H, d, J=14Hz), 4.10 (2H, s), 4.13-4.18 (2H,m), 6.04-6.06(1H, m), 7.14-7.30(5H, m), 7.38(1H, s), 8.55(1H,s) Example 189 3-[4-Benzyl-2-(3-hydroxy-1-butynyl)-5-pyridyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine
    [0469] 650 mg of 4-benzyl-5-bromo-2-pyridyltrifluoromethanesulfonate (Production Example 1), 115 mg of1-butyne-3-ol, 100 mg oftetrakis (triphenylphosphine)palladium(0), 30 mg of cuprousiodide and 1 ml of triethylamine were mixed with 5 ml ofN,N-dimethylformamide, followed by stirring for one hour inan oil bath kept at 60°C. After cooling as it was, aqueousammonia was added thereto and the mixture was extracted withethyl acetate. The extract was washed with brine and thenevaporated. The residue was subjected to silica gel columnchromatography and eluted with 30% ethyl acetate/hexane, togive 410 mg of the target compound.1H-NMR (CDCl3) δ=1.54(3H, d, J=7Hz), 2.01(1H, d, J=5Hz), 4.05(2H,s), 4.67-4.77(1H, m), 7.12(1H, s), 7.18(2H, d, J=7Hz), 7.29(1H,t, J=7Hz), 7.35(2H, t, J=7Hz), 8.63(1H, s) b) 3-[4-Benzyl-2-(3-hydroxy-1-butynyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0470] 110 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine,53 mg of 3-ethynyl-3-quinuclidinol, 50 mgof tetrakis(triphenylphosphine)palladium(0), 7 mg ofcuprous iodide and 0.5 ml of triethylamine were added to 2ml of 1-methyl-2-pyrrolidinone, followed by stirring for onehour in an oil bath kept at 100°C. After cooling as it was,it was evaporated. The residue was subjected to NH-silicagel column chromatography and eluted with 5% methanol/ethylacetate, to synthesize 32 mg of the target compound.1H-NMR (CDCl3) δ=1.35-1.88 (6H, m), 2.01-2.12(2H, m), 2.69-2.94(4H,m), 3.09(1H, d, J=14Hz), 3.24(1H, dd, J=2,14Hz),4.04(2H, s), 4.72(1H, q, J=7Hz), 7.12-7.16(3H, m), 7.22-7.33(3H,m), 8.55(1H, d, J=2Hz) Example 190 3-[4-Benzyl-2-(3-hydroxybutyl)-5-pyridyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-(3-hydroxybutyl)pyridine
    [0471] 200 mg of 4-benzyl-5-bromo-2-(3-hydroxy-1-butynyl)pyridine(Example 189a) and 10 mg of platinum (IV)oxide were added to 10 ml of methanol, 10 ml oftetrahydrofuran and 10 ml of ethyl acetate, followed bystirring at room temperature at normal pressure in a hydrogenatmosphere overnight. The catalyst was filtered off and thefiltrate was evaporated, to give 50 mg of the targetcompound.1H-NMR (CDCl3) δ=1.20(3H, d, J=6Hz), 1.70-1.89(2H, m), 2.77-2.89(2H, m), 3.25-3.38(1H, brs), 3.76-3.85(1H, m),4.05(2H, s), 6.90(1H, s), 7.18(2H, d, J=7Hz), 7.27(1H, t, J=7Hz),7.33(2H, t, J=7Hz), 8.56(1H, s) b) 3-[4-Benzyl-2-(3-hydroxybutyl)-5-pyridyl]ethynyl-3-quinuclidinol
    [0472] 50 mg of 4-benzyl-5-bromo-2-(3-hydroxybutyl)pyridine,20 mg of 3-ethynyl-3-quinuclidinol, 20 mg oftetrakis(triphenylphosphine)palladium(0), 5 mg of cuprousiodide and 0.5 ml of triethylamine were added to 2 ml of1-methyl-2-pyrrolidinone, followed by stirring for one hourin an oil bath kept at 110°C. After cooling as it was, itwas evaporated. The residue was subjected to NH-silica gelcolumn chromatography and eluted with 5% methanol/ethylacetate, to give 30 mg of the target compound.1H-NMR (CDCl3) δ=1.20(3H, d, J=6Hz), 1.35-1.90(5H, m),1.99-2.09(2H, m), 2.68-2.95(6H, m), 3.04(1H, dd, J=2,14Hz),3.22(1H, dd, J=2,14Hz), 3.76-3.85(1H, m), 4.09(2H, s), 6.94(1H,s), 7.15 (2H, d, J=7Hz), 7.24(1H, t, J=7Hz), 7.31(2H, t, J=7Hz),8.56(1H, s) Example 191 3-[4-Benzyl-2-(4-hydroxypiperidino)-5-pyridyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-(4-hydroxypiperidino)pyridine
    [0473] A mixture of 550 mg of 4-benzyl-5-bromo-2-pyridyltrifluoromethanesulfonate (Production Example 1), 600 mg of4-hydroxypiperidine hydrochloride, 1 ml of triethylamineand 2 ml of N,N-dimethylformamide was heated under stirringfor 3 hours in an oil bath kept at 100°C in a nitrogen atmosphere. After cooling as it was, the reaction mixturewas extracted with ethyl acetate/water. The organic phasewas washed with water and brine, dried over anhydrousmagnesium sulfate and evaporated. The residue wassubjected to silica gel column chromatography and elutedwith 50% ethyl acetate/hexane, to give 270 mg of the targetcompound.1H-NMR (CDCl3) δ=1.44-1.60(2H, m), 1.88-1.97(2H, m), 3.03-3.12(2H,m), 3.75-3.96(3H, m), 3.99(2H, s), 6.41(1H, s),7.19(2H, d, J=7Hz), 7.25(1H, t, J=7Hz), 7.32(2H, t, J=7Hz),8.20(1H, s) b) 3-[4-Benzyl-2-(4-hydroxypiperidino)-5-pyridyl]ethynyl-3-quinuclidinol
    [0474] A mixture of 270 mg of 4-benzyl-5-bromo-2-(4-hydroxypiperidino)pyridine,130 mg of 3-ethynyl-3-quinuclidinol,50 mg oftetrakis(triphenylphosphine)palladium(0), 2 mg of cuprousiodide, 0.35 ml of triethylamine and 2 ml of N,N-dimethylformamidewas stirred at 100°C for 3 hours in anitrogen atmosphere. After cooling as it was, the reactionsolution was extracted with ethyl acetate-aqueous diluteammonia. The organic phase was washed with water and brine,dried over anhydrous magnesium sulfate and evaporated. Theresidue was subjected to NH-silica gel column chromatographyand eluted with 20-100% ethyl acetate/hexane and then with5% methanol/ethyl acetate, to give 120 mg of the targetcompound. 1H-NMR (CDCl3) δ=1.33-1.87(5H, m), 1.90-2.05(4H, m),2.65-2.94 (4H, m), 2.98(1H, dd, J=2,14Hz), 3,12-3.20(3H, m),3.88-3.96(1H, m), 3.98-4.07(4H, m), 6.41(1H, s), 7.14-7.32(5H,m), 8.22(1H, s) Example 192 3-[4-Benzyl-2-(morpholino)-5-pyridyl]ethynyl-3-quinuclidinol
    [0475] The title compound was synthesized in the same manneras in Example 191.1H-NMR (CDCl3) δ=1.34-1.87 (3H, m), 1.95-2.07 (2H, m), 2.64-2.92(4H,m), 3.04(1H, d, J=14Hz), 3.18(1H, dd, J=2,14Hz),3.48(4H, t, J=5Hz), 3.78(4H, t, J=5Hz), 4.03(2H, s), 6.36 (1H,s) , 7.17 (2H, d, J=8Hz), 7.22 (1H, t, J=8Hz), 7.30(2H, t, J=8Hz),8.24 (1H, s) Example 193 3- [4-Benzyl-2-(3-methoxypropylamino)-5-pyridyl]ethynyl-3-quinuclidinol
    [0476] The title compound was synthesized in the same manneras in Example 191.1H-NMR (CDCl3) δ=1.33-1.89(5H, m), 1.97-2.07(2H, m), 2.65-2.93(4H,m), 2.99(1H, dd, J=2,14Hz), 3.18(1H, dd, J=2,14Hz),3.32(3H, s), 3.35(2H, q, J=6Hz), 3.47(2H, t, J=6Hz), 3.99(2H,s), 4.92(1H, t, J=6Hz), 6.11(1H, s), 7.14-7.32(5H, m), 8.16(1H,s) Example 194 3-[4-Benzyl-2-(thiomorpholino)-5-pyridyl]ethynyl-3-quinuclidinol
    [0477] The title compound was synthesized in the same manneras in Example 191.1H-NMR (CDCl3) δ=1.34-1.86(3H, m), 1.95-2.06(2H, m), 2.58-2.94(8H, m), 2.99(1H, dd, J=2,14Hz), 3.17(1H, dd, J=2,14Hz),3.89-3.94(4H, m), 4.02(2H, s), 6.35(1H, s), 7.14-7.32(5H, m),8.22(1H, s) Example 195 (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-5-pyridyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine
    [0478] A mixture of 4.0 g of 4-benzyl-5-bromo-2-pyridyltrifluoromethanesulfonate, 1.8 g of (3R,4R)-3,4-dihydroxypyrrolidineacetate, 3 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and 5 ml of tetrahydrofuranwas heated under stirring for 3 hours in an oil bath keptat 70°C in a nitrogen atmosphere. After cooling as it was,the reaction mixture was extracted with ethyl acetate-water.The organic phase was washed with water and brine, dried overanhydrous magnesium sulfate and evaporated. The residuewas subjected to silica gel column chromatography and elutedwith 10% methanol/ethyl acetate, to give 1.67 g of the targetcompound.1H-NMR (CDCl3) δ=3.27-3.33(2H, m), 3.61-3.67(2H, m), 3.99(2H,s), 4.17-4.21(2H, m), 6.14(1H, s), 7.20(2H, d, J=7Hz), 7.24(1H,t, J=7Hz), 7.31(2H, t, J=7Hz), 8.09(1H, s) b) 4-Benzyl-5-bromo-2-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine
    [0479] 190 mg of 60% oily sodium hydride and 0.3 ml of methyliodide were added to a solution of 1.67 g of 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine in tetrahydrofuran, followed by stirring for 6 hours. Then,the reaction solution was extracted with ethyl acetate-water,and the organic phase was washed with water and brine, driedover anhydrous magnesium sulfate and evaporated. Theresidue was subjected to silica gel column chromatographyand eluted with 50% ethyl acetate, to give 560 mg of the targetcompound.1H-NMR (CDCl3) δ=3.34-3.47(2H, m), 3.40(3H, s), 3.58-3.67(2H,m), 3.82-3.86(1H, m), 3.99(2H, s), 4.37-4.41(1H, m), 6.08(1H,s), 7.19(2H, d, J=7Hz), 7.24(1H, t, J=7Hz), 7.31(2H, t, J=7Hz),8.18(1H, s) c) (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-5-pyridyl]ethynyl-3-quinuclidinol
    [0480] The target compound was synthesized in the same manneras in Example 191 by using (3R)-3-ethynyl-3-quinuclidinol.1H-NMR (CDCl3+CD3OD) δ=1.35-1.45(1H, m), 1.52-1.62(1H, m),1.78-1.88(1H, m), 1.97-2.08(2H, m), 2.60-2.90(4H, m), 2.95(1H,d, J=14Hz), 3.13(1H, dd, J=2,14Hz), 3.40(3H, s), 3.40-3.50(2H,m), 3.58-3.68(2H, m), 3.82-3.86(1H, m), 4.02(2H, s), 4.32-4.36(1H,m), 6.13(1H, s), 7.17(2H, d, J=7Hz), 7.21(1H, t, J=7Hz),7.29(2H, d, J=7Hz), 8.13(1H, s) Example 196 (3R)-3-[4-Benzyl-2-[(3R,4R)-3,4-dimethoxypyrrolidine-1-yl]-5-pyridyl]ethynyl-3-quinuclidinol
    [0481] The target compound was synthesized in the same manner as in Example 195 by using two equivalents of methyl iodideand sodium hydride to 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]pyridine(Example 195a).1H-NMR (CDCl3) δ=1.30-1.88(3H, m), 1.95-2.08(2H, m), 2.60-2.90(4H, m), 2.99(1H, d, J=14Hz), 3.17(1H, d, J=14Hz), 3.40(6H,s), 3.50-3.65(4H, m), 3.92(2H, brs), 4.02(2H, s), 6.10(1H, s),7.15-7.32(5H, m), 8.22(1H, s) Example 197 3-[4-Benzyl-2-(2-thiazolyl)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0482] The target compound was synthesized in the same manneras in Example 18.1H-NMR(CDCl3) δ=1.40-1.48(1H, m), 1.61-1.69(1H, m), 1.79-1.87(1H,m), 2.00-2.09(2H, m), 2.75-2.94(4H, m), 3.05(1H, dd,J=1, 14Hz), 3.23(1H, dd, J=2, 14Hz), 4.37(2H, s), 7.21-7.34(5H,m), 7.56(1H, d, J=3Hz), 8.06(1H, d, J=3Hz), 8.75(1H, s) Example 198 3-[4-Benzyl-2-(2-thienyl)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0483] The target compound was synthesized in the same manneras in Example 18.1H-NMR(CDCl3) δ=1.40-1.48(1H, m), 1.61-1.68(1H, m), 1.81-1.89(1H,m), 2.01-2.08(2H, m), 2.73-2.95(4H, m), 3.06(1H, d,J=14Hz), 3.25(1H, dd, J=2, 14Hz), 4.27(2H, s), 7.15(1H, dd, J=4,5Hz), 7.20-7.34(5H, m), 7.50(1H, dd, J=1, 5Hz), 8.01(1H, dd,J=1, 4Hz), 8.61(1H, s) Example 199 3-[4-Benzyl-2-(2-furyl)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0484] The target compound was synthesized in the same manner as in Example 18.1H-NMR(CDCl3) δ =1.39-1.47(1H, m) , 1.60-1.68(1H, m), 1.78-1.86(1H,m), 2.01-2.08(2H, m), 2.70-2.94(4H, m), 3.04(1H, dd,J=1, 14Hz), 3.22(1H, dd, J=2, 14Hz), 4.30(2H, s), 6.58(1H, dd,J=2, 3Hz), 7.20-7.31(5H, m), 7.36(1H, d, J=3Hz), 7.65(1H, d,J=2Hz), 8.67(1H, s) Example 200 3-[4-Benzyl-2-(2-methoxypyridine-5-yl)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0485] The target compound was synthesized in the same manneras in Example 18 except that (3-pyridyl)tributyltin wasaltered to (2-methoxypyridine-5-yl)tributyltin.1H-NMR(CDCl3) δ=1.40-1.48(1H, m), 1.61-1.68(1H, m), 1.83-1.92(1H,m), 2.01-2.10(2H, m), 2.78-2.94(4H, m), 3.07(1H, d,J=14Hz), 3.28(1H, dd, J=2, 14Hz), 4.02(3H, s), 4.29(2H, s),6.82(1H, d, J=9Hz), 7.20-7.36(5H, m), 8.57(1H, dd, J=2, 9Hz),8.68(1H, s), 9.25(1H, d, J=2Hz) Example 201 (3R)-3-[4-Benzyl-2-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyrimidyl]ethynyl-3-quinuclidinol a) 4-Benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]-3-pyrimidine
    [0486] 644 µl of 1,8-diazabicyclo[5.4.0]-7-undecene was addedto a mixture of 509 mg of 4-benzyl-5-bromo-2-chloropyrimidine(Production Example 15), 351 mg of(3R,4R)-3,4-dihydroxypyrrolidine acetate and 5 ml of 1-methyl-2-pyrrolidinoneat room temperature, followed bystirring at 70°C for one hour. Water and ethyl acetate were added thereto, and the organic phase was washed with waterand brine, dried over anhydrous magnesium sulfate and thesolvent was removed. The residue was subjected to silicagel column chromatography using 20% hexane/ethyl acetate,to give 766 mg of the target compound.1H-NMR(CDCl3) δ=3.60(2H, d, J=12Hz), 3.85(2H, dd, J=4, 12Hz),4.08(2H, s), 4.31(2H, br.s), 7.20-7.37(5H, m), 8.26(1H, s) b) (3R)-3-[4-Benzyl-2-[(3R, 4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyrimidyl]ethynyl-3-quinuclidinol
    [0487] 70.0 mg of 60% oily sodium hydride was added to a mixtureof 766 mg of 4-benzyl-5-bromo-2-[(3R,4R)-3,4-dihydroxypyrrolidine-1-yl]-3-pyrimidineand 10 ml oftetrahydrofuran under ice-cooling, followed by adding 99.6µl of methyl iodide thereto. After stirring at roomtemperature for 6 hours, water and ethyl acetate were addedto the reaction solution. The organic phase was washed withwater and brine, dried over anhydrous magnesium sulfate andthe solvent was evaporated. A mixture of the residue, 4.5mg of tetrakis(triphenylphosphine)palladium(0), 0.1 mg ofcuprous iodide, 32.6 µl of triethylamine and 1 ml ofN,N-dimethylformamide was stirred at 90°C for 3 hours in anitrogen atmosphere. NH-silica gel was added to thereaction solution and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using5% methanol/ethyl acetate, to give 22.0 mg of the targetcompound. 1H-NMR(CDCl3) δ=1.36-1.43(1H, m), 1.55-1.62(1H, m), 1.78-1.85(1H,m), 2.01-2.08(2H, m), 2.67-2.90(4H, m), 2.95-3.00(1H,m), 3.13-3.18(1H, m), 3.41(3H, s), 3.64-3.84(5H, m), 4.06(2H,s), 4.37(1H, br.s), 7.18-7.30(5H, m), 8.29(1H, s) Example 202 (3R)-3-[4-Benzyl-2-(2-furylmethoxy)-5-pyrimidyl]ethynyl-3-quinuclidinol a) 4-Benzyl-2-(2-furylmethoxy)-5-bromopyrimidine
    [0488] 14.1 mg of 60% oily sodium hydride was added to a mixtureof 73.3 mg of 4-benzyl-5-bromo-2-chloropyrimidine(Production Example 15), 1 ml of furfuryl alcohol and 14.8mg of cuprous iodide at room temperature, followed bystirring at 90°C for 2 hours. Water and diethyl ether wereadded to the reaction solution, and the organic phase waswashed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 10%ethyl acetate/hexane, to give 50.9 mg of the target compound.1H-NMR(CDCl3) δ=4.19(2H, s), 5.33(2H, s), 6.32-6.37(2H, m),7.22-7.41(6H, m), 8.48(1H, s) b) (3R)-3-[4-Benzyl-2-(2-furylmethoxy)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0489] A mixture of 50.9 mg of 4-benzyl-2-(2-furylmethoxy)-5-bromopyrimidine,26.8 mg of (3R)-3-ethynyl-3-quinuclidinol,8.5 mg oftetrakis(triphenylphosphine)palladium(0), 0.3 mg ofcuprous iodide, 61.5 µl of triethylamine and 1 ml ofN,N-dimethylformamide was stirred at 90°C for 4 hours in a nitrogen atmosphere. NH-silica gel was added to thereaction solution and the solvent was removed. The residuewas subjected to NH-silica gel column chromatography using3% methanol/ethyl acetate, to give 29.0 mg of the targetcompound.1H-NMR(CDCl3) δ=1.38-1.46(1H, m), 1.60-1.89(2H, m), 2.00-2.07(2H,m), 2.73-2.93(4H, m), 3.05(1H, d, J=14Hz), 3.25(1H,dd, J=2, 14Hz), 4.19(2H, s), 5.38(2H, s), 6.32-6.39(2H, m),7.21-7.30(5H, m), 7.40-7.41(1H, m), 8.48(1H, s) Example 203 (3R)-3-[4-Benzyl-2-(3-hydroxypropyloxy)-5-pyrimidyl]ethynyl-3-quinuclidinol
    [0490] The target compound was synthesized in the same manneras in Example 202 except that furfuryl alcohol was alteredto 1,3-propanediol.1H-NMR(CDCl3) δ=1.38-1.46 (1H, m), 1.58-1.67(1H, m), 1.79-1.89(1H,m), 1.99-2.07(4H, m), 2.71-2.93(4H, m), 3.04(1H, d,J=14Hz), 3.22(1H, d, J=14Hz), 3.77(2H, t, J=6Hz), 4,17(2H, s),4.52(2H, t, J=6Hz), 7.20-7.29(5H, m), 8.45(1H, s) Example 204 3-(3-Phenyl-5-benzyl-6-pyridazyl)ethynyl-3-quinuclidinol a) 3-Phenyl-6-methoxypyridazine
    [0491] A mixture of 3.0 g of 3-chloro-6-methoxypyridazine, 3.8g of phenylboric acid, 2.4 g oftetrakis(triphenylphosphine)palladium(0), 160 ml oftoluene, 40 ml of methanol, 80 ml of an aqueous 2 mol sodiumcarbonate solution and 30 ml of tetrahydrofuran was stirredunder heating at 85°C for one hour. After cooling as it was, the reaction solution was extracted with ethyl acetate. Theorganic phase was washed with brine and eluted with ethylacetate through NH-silica gel (Fuji Silicia). Afterremoving the solvent, the residue was crystallized, to give1.8 g of the target compound.1H-NMR(CDCl3) δ =4.20(3H, s), 7.06(1H, d, J=9Hz), 7.44-7.52(3H,m), 7.79(1H, d, J=9Hz), 7.99-8.03(2H, m) b) 5-(α-Hydroxybenzyl)3-phenyl-6-methoxypyridazine
    [0492] 7,7 ml of a hexane solution containing 1.52 mol of normalbutyllithium was slowly added dropwise into a solution of50 ml of tetrahydrofuran containing 2.0 ml of 2,2,6,6-tetramethylpiperidineunder ice-cooling. After stirringfor one hour under ice-cooling, it was cooled to -78°C and10 ml of a tetrahydrofuran solution containing 1.68 g of3-phenyl-6-methoxypyridazine was slowly added dropwisethereinto. After stirirng at -78°C for 2 hours,benzaldehyde was slowly added dropwise thereinto. Afterstirring at -78°C for further 30 minutes, it was stirred atroom temperature overnight. Water was added to the reactionsolution, extracted with ethyl acetate and the organic phasewas washed with brine. After removing the solvent, theresidue was subjected to NH-silica gel (Fuji Silicia)chromatography and eluted with hexane/ethyl acetate (3:1)and then with hexane/ethyl acetate (1:1), to give 1.39 g ofthe target compound.1H-NMR(CDCl3) δ=4.15(3H, s), 5.99(1H, s), 7.17-7.69(9H, m),7.99-8.04 (2H,m) c) 5-(α-Acetoxybenzyl)3-phenyl-6-methoxypyridazine
    [0493] 5.0 ml of acetic acid anhydride was slowly added dropwiseinto a solution of 1.39 g of 5- (α-hydroxybenzyl)-3-phenyl-6-methoxypyridazine,174 mg of 4-dimethylaminopyridineand 1.0 ml of triethylamine in 10 mlof dichloromethane under ice-cooling. After stirring atroom temperature for one hour, water was added to thereaction solution. After extracting with dichloromethane,the organic phase was washed with brine. After removing thesolvent, the residue was subjected to NH-silica gel (FujiSilicia) and eluted with ethyl acetate, to give 1.58 g ofthe target compound.1H-NMR(CDCl3) δ=2.20(3H, s), 4.16 (3H, s), 7.02 (1H, s),7.34-7.54(9H, m), 8.00 - 8.02 (2H, m) d) 3-Phenyl-5-benzyl-6-methoxypyridazine
    [0494] 600 mg of 10% palladium carbon was added to a mixtureof 1.58 g of 5-(α-acetoxybenzyl)-3-phenyl-6-methoxypyridazine,2.0 ml of triethylamine and 10 ml ofethanol, and the mixture was subjected to hydrocracking ina hydrogen atmosphere. The catalyst was filtered off, andthe solvent was removed. Then, the residue was subjectedto NH-silica gel (Fuji Silicia) and eluted with ethyl acetate,to give 1.31 g of the target compound.1H-NMR(CDCl3) δ=3.98(2H, s), 4.22(3H,s), 7.23-7.73(9H,m),7.89-7.93(2H,m) e) 3-Phenyl-5-benzyl-6-pyridazyltrifluoromethanesulfonate
    [0495] 10 ml of 47% hydrobromic acid was added to 1.31 g of3-phenyl-5-benzyl-6-methoxypyridazine, followed byheating under stirring in an oil bath kept at 90°C for 3 hours.After cooling as it was, the reaction solution was addedlittle by little to an aqueous potassium carbonate solutionto neutralize. After extracting with ethyl acetate, theorganic phase was washed with brine and the solvent wasremoved, to give 1.18 g of a crude product. A mixture of1.18 g of the crude product, 1.93 g of N-phenyltrifluoromethanesulfonimide,165 mg of 4-dimethylaminopyridine,943 µl of triethylamine and 10 ml ofdichloromethane was stirred at room temperature overnight.After the reaction solution was concentrated, the residuewas subjected to silica gel chromatography to elute withhexane/ethyl acetate (10:1) and then with hexane/ethylacetate (7:1), to give 484 mg of the target compound.1H-NMR(CDCl3) δ=4.12(2H, s), 7.23-7.64(9H, m), 7.94-7.96(2H,m) f) 3-(3-Phenyl-5-benzyl-6-pyridazyl)ethynyl-3-quinuclidinol
    [0496] A mixture of 484 mg of 3-phenyl-5-benzyl-6-pyridazyltrifluoromethane sulfonate, 223 mg of 3-ethynyl-3-quinuclidinol,284 mg oftetrakis(triphenylphosphine)palladium(0), 47 mg of cuprousiodide, 513 µl of triethylamine and 5.0 ml of N,N-dimethylformamidewas heated under stirring at 80°C for 2hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and the mixture wasextracted with ethyl acetate. The organic phase was washedwith brine and the solvent was removed. The residue wassubjected to NH-silica gel (Fuji Silicia) columnchromatography and eluted with hexane/ethyl acetate (1:1)and then with ethyl acetate/methanol (20:1) and thencrystallized from hexane/ethyl acetate, to give 413 mg ofthe target compound.1H-NMR(CDCl3) δ=1.25-1.99(3H, m), 2.02-2.15(2H, m), 2.78-2.95(4H,m), 3.08(1H, d, J=14Hz), 3.30(1H, d, J=14Hz), 4.18(2H,s), 7.07-7.38(5H, m), 7.48-7.52.(4H, m), 7.99-8.02(2H, m) Example 205 3-[3-(3-Pyridyl)-5-benzyl-6-pyridazyl]ethynyl-3-quinuclidinol
    [0497] The target compound was synthesized in the same manneras in Example 204.1H-NMR(CDCl3) δ=1.38-1.96(3H, m), 2.03-2.17 (2H, m), 2.81-2.98(4H,m), 3.11(1H, d, J=14Hz), 3.32(1H, dd, J=2, 14Hz),4.19(2H, s), 7.19-7.38(5H, m), 7.43-7.46(1H, m), 7.53(1H, s),8.39-8.42 (1H, m), 8.70-8.71(1H, m), 9.14(1H, d, J=2Hz) Example 206 3-(2-Benzyl-3-thienyl)ethynyl-3-quinuclidinol a) 2-Methoxycarbonyl-3-thienyl trifluoromethanesulfonate
    [0498] A mixture of 4.12 g of 3-hydroxy-2-methoxycarbonylthiophene,9.76 g of N-phenyltrifluoromethanesulfonimide,5.44 ml oftriethylamine, 318 mg of 4-dimethylaminopyridine and 70 mlof dichloromethane was stirred at room temperature overnight.Silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to silicagel column chromatography using 10% ethyl acetate/hexane,to give 6.21 g of the target compound.1H-NMR(CDCl3) δ=3.92(3H, s), 7.01(1H, d, J=5Hz), 7.55(1H, d,J=5Hz) b) 2-Methoxycarbonyl-3-(trimethylsilylethynyl)thiophene
    [0499] A mixture of 2.07 g of 2-methoxycarbonyl-3-thienyltrifluoromethane sulfonate, 2.02 ml oftrimethylsilylacetylene, 1.57 g of tetrakis(triphenylphosphine)palladium(0), 272 mg of cuprous iodide,2.98 ml of triethylamine and 30 ml of N,N-dimethylformamidewas stirred at 65°C for 3 hours in a nitrogen atmosphere.Silica gel was added to the reaction solution, and thesolvent was removed. The residue was subjected to silicagel column chromatography using 6% ethyl acetate/hexane, togive 1.78 g of the target compound.1H-NMR (CDCl3) δ=0.29(9H, s), 3.90(3H, s), 7.14(1H, d, J=5Hz),7.41(1H, d, J=5Hz) c) 3-Ethynyl-2-(α-hydroxybenzyl)thiophene
    [0500] 131 mg of lithium aluminum hydride was added to a mixtureof 821 mg of 2-methoxycarbonyl-3-(trimethylsilylethynyl)thiopheneand 10 ml oftetrahydrofuran, followed by heating under reflux for 1.5hours. After cooling as it was, 131 µl of water, 131 µl ofan aqueous 1N sodium hydroxide solution and 393 µl of waterwere successively added thereto, followed by filteringthrough Celite. After removing the solvent, 5.25 g of manganese dioxide was added to a solution of 10 ml ofdichloromethane containing the residue, followed bystirring at room temperature overnight. The mixture wasfiltered through Celite, and the solvent was removed. 3.5ml of a cyclohexane-diethyl ether solution containing 1.8mol of phenyl lithium was added dropwise to a mixture of theresidue and 5 ml of diethyl ether at -78°C, followed bystirring at the same temperature for 20 minutes. Aqueousammonium chloride was added to the reaction solution and thetemperature of the system was raised to room temperature.Ethyl acetate was added thereto, and the organic phase waswashed with water and brine, dried over anhydrous magnesiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 10%ethyl acetate/hexane, to give 85.7 mg of the target compound.1H-NMR(CDCl3) δ=2.59(1H, d, J=3Hz), 3.26(1H, s), 6.34(1H, d,J=3Hz), 7.02(1H, d, J=5Hz), 7.17(1H, d, J=5Hz), 7.22-7.38(3H,m), 7.49-7.51(2H,m) d) 2-Benzyl-3-ethynylthiophene
    [0501] 201 mg of sodium cyanotrihydroborate was added to amixture of 85.7 mg of 3-ethynyl-2-(α-hydroxybenzyl)thiophene,192 mg of zinc iodide and 1.5 mlof 1,2-dichloroethane at room temperature, followed bystirring at the same temperature overnight. 5 ml of diethylether was added to the reaction solution, followed byfiltering through Celite. After the solvent was removed,the residue was subjected to silica gel column chromatography using 2% ethyl acetate/hexane, to give 45.2mg of the target compound.1H-NMR(CDCl3) δ=3.21(1H, s), 4.25(2H, s), 7.02(1H, d, J=5Hz),7.05(1H, d, J=5Hz), 7.21-7.32(5H, m) e) 3-(2-Benzyl-3-thienyl)ethynyl-3-quinuclidinol
    [0502] 0.200 ml of a hexane solution containing 1.8 mol of butyllithium was added dropwise to a mixture of 45.2 mg of 2-benzyl-3-ethynylthiopheneand 1 ml of tetrahydrofuran at-78°C, followed by stirring at the same temperature for 20hours. A solution of 0.5 ml of tetrahydrofuran containing39.9 mg of 3-quinuclidinone was added dropwise to thereaction solution at the same temperature, followed bystirring and then at room temperature for 4 hours. 0.5 mlof water and NH-silica gel were added to the reactionsolution, and the solvent was removed. The residue wassubjected to NH-silica gel column chromatography using ethylacetate, to give 39.5 mg of the target compound.1H-NMR(CDCl3) δ=1.36-1.44(1H, m), 1.56-1.64(1H, m), 1.86-1.95(1H,m), 1.98-2.07(2H, m), 2.72-2.92(4H, m), 3.02(1H, d,J=14Hz), 3.24(1H, dd, J=2, 14Hz), 4.21(2H, s), 6.98(1H, d,J=5Hz), 7.06(1H, d, J=5Hz), 7.20(5H,m) Example 207 3-(3-Benzyl-5-pyrazyl-2-thienyl)ethynyl-3-quinuclidinol a) 1-Phenyl-1-(3-thienyl)methanol
    [0503] 10 ml of 3-thiophenecarboxyaldehyde was dissolved in 50ml of tetrahydrofuran. To the mixture was added dropwise64 ml of a hexane/cyclohexane solution containing 1.8 mol of phenyl lithium in a dry ice/acetone bath. After anaqueous ammonium chloride solution was added to the mixture,it was extracted with ethyl acetate. The extract was washedwith brine, dried over anhydrous magnesium sulfate andevaporated. The residue was subjected to silica gel columnchromatography and eluted with 10% ethyl acetate/hexane, togive the target compound.1H-NMR (CDCl3) δ=2.20(1H, d, J=4Hz), 5.90(1H, d, J=4Hz), 7.00(1H,dd, J=1,5Hz), 7.17-7.21(1H, m), 7.26-7.42(6H, m) b) 3-Benzoylthiophene
    [0504] 6.2 g of 1-phenyl-1-(3-thienyl)methanol was dissolvedin 50 ml of chloroform. To the mixture was added 30 g ofmanganese dioxide, followed by stirring overnight.Manganese dioxide was filtered off, and the filtrate wasevaporated, to give 6.08 g of the target compound.1H-NMR (CDCl3) δ=7.39(1H, dd, J=3,5Hz), 7.49(2H, t, J=7Hz),7.56-7.62(2H,m), 7.84-7.87(2H, m), 7.94(1H, dd, J=1,3Hz) c) 3-Benzoyl-5-bromothiophene
    [0505] 3.0 g of 3-benzoylthiophene was dissolved in 10 ml ofN,N-dimethylacetamide and 1 ml of acetic acid, and 2.83 gof N-bromosuccinimide was added thereto, followed bystirring overnight. Water was added to the reactionsolution, followed by extracting with diethyl ether. Theextract was washed with an aqueous saturated sodiumbicarbonate solution, dried over anhydrous magnesium andthen evaporated. The residue was subjected to silica gelcolumn chromatography and eluted with 10% ethyl acetate/hexan, to give 2.7 g of the target compound.1H-NMR (CDCl3) δ=7.50(2H,t,J=8Hz), 7.55(1H, d, J=2Hz), 7.60(1H,t, J=8Hz), 7.79-7.84(3H, m) d) 3-(3-Benzyl-5-pyrazyl-2-thienyl)ethynyl-3-quinuclidinol
    [0506] 2.7 g of 3-benzoyl-5-bromothiophene, 3.0 g ofpyrazyltributyltin and 1.0 g oftetrakis(triphenylphosphine)palladium(0) were mixed with30 ml of xylene, followed by heating under reflux in anitrogen stream. The reaction solution was subjected toNH-silica gel chromatography and eluted with 10% ethylacetate/hexane, to give 1.23 g of a product. 500 mg of theproduct was dissolved in 5 ml of tetrahydrofuran and 20 mlof methanol. 60 mg of sodium borohydride was added thereto,followed by stirring at room temperature. Water was addedto the reaction solution and the mixture was extracted withethyl acetate. The extract was dried over anhydrousmagnesium sulfate and then evaporated. To the residue wereadded 1 ml of triethylsilane and 10 ml of trifluoroaceticacid, followed by stirring in an ice bath. After the mixturewas neutralized by adding an aqueous saturated sodiumcarbonate solution, it was extracted with ethyl acetate andevaporated. To the residue was added 10 ml of N,N-dimethylformamide,and to the mixture was further added 40mg of N-bromosuccinimide in an ice bath, followed by stirringfor one hour. Water was added thereto, followed byextracting with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and thenevaporated. To the residue were added 300 mg of 3-ethynyl-3-quinuclidinol,100 mg oftetrakis(triphenylphosphine)palladium(0), 50 mg of cuprousiodide, 1 ml of triethylamine and 10 ml of N,N-dimethylformamide,followed by heating under stirring in anoil bath kept at 100°C. The reaction solution was evaporated,and the residue was subjected to NH-silica gelchromatography, to give 225 mg of the target compound.1H-NMR (CDCl3) δ =1.37-1.68(2H, m), 1.86-1.96(1H, m), 1.98-2.10(2H,m), 2.76-2.96(4H, m), 3.06(1H, d, J=14Hz), 3.29(1H,dd, J=2, 14Hz), 4.05(2H, s), 7.21-7.34(5H, m), 7.36(1H, s),8.39(1H, d, J=3Hz), 8.47(1H, dd, J=1,3Hz), 8.83(1H, d, J=1Hz) Example 208 3-[3-Benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahedrobenzo[ b]thiophene-2-yl]ethynyl-3-quinuclidinol a) Ethyl-4-oxo-1-cyclohexane carboxylate
    [0507] 120 ml of a Jone's reagent was added dropwise into asolution of 800 ml of acetone containing 81.1 g of ethyl4-hydroxycyclohexane carboxylate over 30 minutes in an icebath. After stirring at the same temperature for 20 minutes,2-propanol was added thereto. The reaction solution waspoured into water, followed by extracting with ethyl acetate.The organic phase was washed with brine, dried over anhydrousmagnesium sulfate and the solvent was removed, to give 80.0g of the target compound.1H-NMR(CDCl3) δ=1.28(3H, t, J=7Hz), 1.98-2.10(2H, m), 2.18-2.25(2H,m), 2.31-2.39(2H, m), 2.45-2.51(2H, m), 2.71-2.77(1H, m), 4.18(2H, q, J=7Hz) b) 2-Amino-3-benzoyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene
    [0508] A mixture of 25.2 g of ethyl-4-oxo-1-cyclohexanecarboxylate, 21.4 g of benzoylacetonitrile, 25.2 ml ofdiethylamine and 250 ml of ethanol was heated under refluxfor 45 minutes. 4.7 g of sulfur was added to the mixtureall at once while heating under reflux, followed by heatingunder reflux for further 2 hours. After cooling as it was,the solvent was removed, and the residue was crystallizedfrom methanol, to give 13.4 g of the target compound.1H-NMR(CDCl3) δ=1.24(3H, t, J=7Hz), 1.52 -1.61(1H, m), 1.82-1.99(3H,m), 2.05-2.79(3H, m), 4.10-4.18(2H, m), 6.66(2H, br.s),7.37-7.48(5H, m) c) 3-(α-Hydroxybenzyl)-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene
    [0509] A mixture of 21.5 g of 2-amino-3-benzoyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene,12.5g of cuprous iodide, 26.3 ml of diiodomethane, 26.3 ml ofisopentyl nitrite and 250 ml of tetrahydrofuran was heatedunder reflux for 1.5 hours. After cooling as it was, 500ml of ethyl acetate was added to the reaction solution. Theinsoluble matters were filtered off, the mixture wassubjected to silica gel column chromatography, and elutedwith hexane and then with hexane/ethyl acetate (10:1), togive 17.4 g of a crude product. 1.5 g of sodium borohydridewas added little by little to a solution of 200 ml of ethanol containing 17.4 g of this crude product under ice-cooling.After stirring at room temperature for one hour, the solventwas removed. Ethyl acetate and water were added to theresidue, followed by extracting with ethyl acetate. Theorganic phase was washed with brine and the solvent wasremoved. The residue was subjected to silica gel columnchromatography, and eluted with hexane and then withhexane/ethyl acetate (4:1), to give 11.2 g of the targetcompound.1H-NMR(CDCl3) δ=1.23-1.28 (3H, m), 1.72-1.85(1H, m), 2.09-2.28(2H,m), 2.47-2.76(2H, m), 2.93-3.06(2H, m), 4.13-4.18(2H,m), 5.75-5.76(1H, m), 7.27-7.38(6H, m) d) 3-Benzyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene
    [0510] A mixture of 8.3 g of 3-(α-hydroxybenzyl)-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 12.5g of zinc iodide, 2.0 g of sodium cyanoborohydride and 150ml of dichloromethane was stirred at room temperature for3 hours. After adding methanol to the reaction solution,insoluble matters were filtered off. The solvent wasremoved, and the residue was subjected to silica gel columnchromatography and eluted with hexane and then withhexane/ethyl acetate (10:1), to give 5.9 g of the targetcompound.1H-NMR(CDCl3) δ=1.26(3H, t, J=7Hz), 1.77-1.87(1H, m), 2.16-2.22(1H,m), 2.33-2.42(1H, m), 2.54-2.75(2H, m), 2.93-3.06(2H,m) , 3.75-3.86(2H, m), 4.16(2H, q, J=7Hz), 6.64(1H, s), 7.16-7.30(5H, m) e) 3-Benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[ b]thiophene
    [0511] A solution of 10 ml of diethyl ether containing 2.8 gof 3-benzyl-6-ethoxycarbonyl-4,5,6,7-tetrahydrobenzo[b] thiophene was slowly added dropwise intoa suspension of 100 ml of diethyl ether containing 421 mgof lithium aluminum hydride under ice-cooling. Afterstirring as it was for 30 minutes, 0.4 ml of water, 0.4 mlof an aqueous 1N sodium hydroxide solution and 0.4 ml of waterwere successively added to the reaction solution and themixture was dried over anhydrous magnesium sulfate. Afterfiltering, the solvent was removed, to give 2.5 g of thetarget compound.1H-NMR(CDCl3) δ=1.39-1.50(1H, m), 1.94-2.09(2H, m), 2.32-2.59(3H, m), 2.88-2.94(1H, m), 3.63-3.64(2H, m), 3.77-3.86(2H,m), 6.62(1H, s), 7.16-7.31(5H, m) f) 2-Bromo-3-benzyl-6-hydroxymethyl-4,5,6,7-tetrahydrobenzo[ b]thiophene
    [0512] 103 mg of N-bromosuccinimide was added little by littleto a solution of 5.0 ml of N,N-dimethylformamide containing136 mg of 3-benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiopheneunder ice-cooling. Afterstirring for one hour, water was added to the reactionsolution and the mixture was extracted with ethyl acetate.The organic phase was washed with water and brine, and thesolvent was removed. Then, the residue was subjected to silica gel column chromatography and eluted with hexane andthen with hexane/ethyl acetate (2:1), to give 164 mg of thetarget compound.1H-NMR(CDCl3) δ=1.34-1.44(1H, m), 1.87-1.99(2H, m), 2.23-2.8(3H,m), 2.78-2.83(1H, m), 3.59-3.60(2H, m), 3.81-3.92(2H,m), 7.13-7.28(5H, m) g) 3-[3-Benzyl-6-(hydroxymethyl)-4,5,6,7-tetrahedrobenzo[ b]thiophene-2-yl]ethynyl-3-quinuclidinol
    [0513] A mixture of 164 mg of 2-bromo-3-benzyl-6-hydroxymethyl-4,5,6,7-tetrahydrobenzo[b]thiophene,88 mgof 3-ethynyl-3-quinuclidinol, 112 mg oftetrakis (triphenylphosphine) palladium(0), 19 mg of cuprousiodide, 203 µl of triethylamine and 5.0 ml of N;N-dimethylformamidewas heated under stirring at 80°C for onehour in a nitrogen atmosphere. After cooling as it was, thesolvent was removed and the residue was subjected to NH-silicagel (Fuji Silicia) column chromatography and elutedwith hexane/ethyl acetate (1:1) and then with ethylacetate/methanol (20:1), to give 113 mg of the targetcompound.1H-NMR(CDCl3) δ=1.33-1.44(2H, m), 1.52-1.60(1H, m), 1.84-2.01(5H,m), 2.23-2.31(1H, m), 2.39-2.45(2H, m), 2.71-2.90(5H,m), 2.99(1H, d, J=14Hz), 3.23(1H, dd, J=2, 14Hz), 3.57-3.59(2H,m), 3.86-3.98(2H, m), 7.14-7.34(5H, m) Example 209 3-(2-Benzyl-7-pyrazyl-3-quinolyl)ethynyl-3-quinuclidinol a) 1-Methoxy-3-phenyl-2-propanol
    [0514] 35 ml of a 28% sodium methoxide methanol solution wasadded to a solution of 100 ml of methanol containing 14.0g of benzyloxirane, followed by heating under stirring for2 hours in an oil bath kept at 80°C. After cooling as itwas, the solvent was removed. Water was added thereto,followed by extracting with ethyl acetate. The organicphase was washed with brine and the solvent was removed, togive 17.3 g of the target compound.1H-NMR(CDCl3) δ=2.75-2.84(2H, m), 3.28-3.32 (1H, m), 3.38(3H,s), 3.39-3.43(1H, m), 4.01-4.03(1H, m), 7.22-7.33(5H, m) b) 1-Methoxy-3-phenylacetone
    [0515] 20.4 ml of a Jone's reagent was slowly added dropwiseinto 200 ml of an acetone solution containing 5.1 g of1-methoxy-3-phenyl-2-propanol. After stirring for 30minutes at room temperature, 30 ml of 2-propanol was slowlyadded to the reaction solution. After removing the solvent,water was added thereto and the mixture was extracted withethyl acetate. The organic phase was washed with brine andthe solvent was removed. The residue was subjected to silicagel column chromatography and elute with hexane/ethylacetate (6:1), to give 3.7 g of the target compound.1H-NMR(CDCl3) δ=3.39(3H, s), 3.76(2H, s), 4.06(2H, s),7.22-7.36(5H, m) c) 2-Amino-4-bromobenzaldehyde
    [0516] 16.1 ml of an aqueous 29% ammonia solution was added toa mixture of 5.0 g of 2-nitro-4-bromobenzaldehyde, 60.4 gof iron (II) sulfate heptahydrate, 200 ml of methanol, 100 ml of water and 335 µl of concentrated hydrochloric acid inan oil bath kept at 90°C, followed by heating under stirringfor 10 minutes. After cooling as it was, insoluble matterswere filtered through Celite and the filtrate was extractedwith ethyl acetate. The organic phase was washed with brineand the solvent was removed, to give 3.9 g of the targetcompound1H-NMR(CDCl3) δ =6.17(2H, br.s), 6.84-6.89(2H, m), 7.33(1H, d,J=8Hz), 9.82(1H, s) d) 2-Benzyl-7-bromo-3-methoxyquinoline
    [0517] A mixture of 3.3 g of 2-amino-4-bromobenzaldehyde, 3.3g of 1-methoxy-3-phenylacetone, an aqueous potassiumhydroxide solution (10 g of potassium hydroxide wasdissolved in 10 ml of water) and 20 ml of ethanol was heatedunder stirring at 100°C for 4 hours in a sealed tube. Aftercooling as it was, the reaction solution was poured intowater and the mixture was extracted with diethyl ether. Theorganic phase was washed with brine and the solvent wasremoved. The residue was crystallized from hexane/ethylacetate, to give 3.7 g of the target compound.1H-NMR(CDCl3) δ=3.90(3H, s), 4.34(2H, s), 7.15-7.27 (4H, m),7.32-7.35(2H, m), 7.51-7.56(2H, m), 8.20-8.21(1H, m) e) 2-Benzyl-7-pyrazyl-3-methoxyquinoline
    [0518] A mixture of 200 mg of 2-benzyl-7-bromo-3-methoxyquinoline,337 mg of pyrazyltributyltin, 141 mg oftetrakis(triphenylphosphine)palladium(0) and 10 ml ofxylene was heated under stirring for 3 hours in an oil bath kept at 150°C in a nitrogen atmosphere. After cooling asit was, the solvent was removed. The residue was subjectedto silica gel column chromatography and eluted withhexane/ethyl acetate (5:1) and then with hexane/ethylacetate (1:1), to give 126 mg of the target compound.1H-NMR(CDCl3) δ=3.95(3H, s), 4.39(2H, s), 7.16-7.28(3H, s),7.35-7.39(3H, m), 7.83(1H, d, J=8Hz), 8.20-8.23(1H, m), 8.53(1H,d, J=3Hz), 8.66-8.68(2H, m), 9.22(1H, m) f) 2-Benzyl-7-pyrazyl-3-quinolyltrifluoromethanesulfonate
    [0519] A mixture of 127 mg of 2-benzyl-7-pyrazyl-3-methoxyquinoline,40 mg of n-hexadecyl-tri-n-butylphosphoniumbromide and 10 ml of 47% hydrobromic acid was heated understirring for 48 hours in an oil bath kept at 120°C. The reactionsolution was slowly poured into an aqueous potassium carbonatesolution, the mixture was extracted with diethyl ether and thesolvent was removed. To the residue were added 274 mg ofN-phenyltrifluoromethanesulfonimide, 133 µl of triethylamine,23 mg of 4-dimethylaminopyridine, 10 ml of dichloromethane and3.0 ml of N,N-dimethylformamide, followed by stirring at roomtemperature overnight. After removing the solvent, theresidue was subjected to silica gel column chromatography andeluted with hexane/ethyl acetate (4:1) and then withhexane/ethyl acetate (2:1), to give 134 mg of the targetcompound.1H-NMR(CDCl3) δ=4.46(2H, s), 7.25-7.40(5H, m), 7.77(1H, d,J=8Hz), 8.09(1H, s), 8.34-8.37(1H, m), 8.61(1H, d, J=2Hz), 8.72-8.76(2H, m), 9.25(1H, m) g) 3-(2-Benzyl-7-pyrazyl-3-quinolyl)ethynyl-3-quinuclidinol
    [0520] A mixture of 134 mg of 2-benzyl-7-pyrazyl-3-quinolyltrifluoromethanesulfonate, 55 mg of 3-ethynyl-3-quinuclidinol,70 mg oftetrakis(triphenylphosphine)palladium(0), 11 mg of cuprousiodide, 126 µl of triethylamine and 5.0 ml of N,N-dimethylformamidewas heated under stirring at 85°C for 30minutes in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia, and the mixture wasextracted with ethyl acetate. Then, the organic phase waswashed with brine and the solvent was removed, to give 76mg of the target compound.1H-NMR(CDCl3) δ=1.41-1.46 (1H, m), 1.60-1.93(2H, m), 2.05-2.06(2H,m), 2.77-2.89(4H, m), 3.04(1H, d, J=14Hz), 3.21-3.25(1H,m), 4.55(2H, s), 7.20-7.36(5H, m), 7.89(1H, d, J=9Hz),8.25(1H, s), 8.27-8.29(1H, m), 8.58(1H, d, J=3Hz), 8.69-8.71(2H,m), 9.24(1H, d, J=1Hz) Example 210 3-(2-Benzyl-7-ethoxycarbonyl-3-quinolyl)ethynyl-3-quinuclidinol a) 2-Benzyl-7-bromo-3-hydroxyquinoline
    [0521] A mixture of 1.28 g of 2-benzyl-7-bromo-3-methoxyquinolineobtained in Example 209d, 990 mg of n-hexadecyl-tri-n-butylphosphoniumbromide, 12 ml of 47%hydrobromic acid and 10 ml of acetic acid was heated underreflux for 12 hours. After cooling as it was, the reaction solution was slowly poured into an aqueous potassiumcarbonate solution and the mixture was extracted withdiethyl ether. The organic phase was washed with brine andthe solvent was removed, to give 1.8 g of the target compound(including n-hexadecyl-tri-n-butylphosphonium bromide) asa crude product. b) 2-Benzyl-7-cyano-3-hydroxyquinoline
    [0522] A mixture of 370 mg of 2-benzyl-7-bromo-3-hydroxyquinoline(including n-hexadecyl-tri-n-butylphosphoniumbromide), 208 mg of zinc cyanide, 272 mgof tetrakis(triphenylphosphine)palladium(0) and 10 ml ofN,N-dimethylformamide was heated under stirring for 7 hoursin an oil bath kept at 90°C. After cooling as it was,insoluble matters were filtered through Celite and anaqueous potassium carbonate solution was added to thefiltrate. The mixture was extracted with ethyl acetate, andthe organic phase was washed with brine and the solvent wasremoved. The residue was subjected to silica gel columnchromatography and eluted with hexane/ethyl acetate (3:1)and then with hexane/ethyl acetate (2:1), to give 203 mg ofthe target compound.1H-NMR(CDCl3) δ=4.28(2H, s), 7.15-7.30(5H, m), 7.54(1H, s),7.71-7.74(1H, m), 7.95(1H, d, J=9Hz), 8.37(1H, s) c) 2-Benzyl-7-ethoxycarbonyl-3-hydroxyquinoline
    [0523] A mixture of 203 mg of 2-benzyl-7-cyano-3-hydroxyquinoline,2.6 g of potassium hydroxide, 5.5 ml ofwater and 20 ml of ethanol was heated under reflux for 2 hours. After cooling as it was, dilute hydrochloric acid was addedthereto. The mixture was extracted with diethyl ether andthe solvent was removed. To the residue were added 30 mlof ethanol and 3.0 ml of concentrated sulfuric acid, followedby heating under reflux for one hour. After cooling as itwas, the solvent was removed. Diethyl ether and an aqueouspotassium carbonate solution were added thereto, followedby extracting with diethyl ether. The organic phase waswashed with brine and the solvent was removed, to give 204mg of the target compound.1H-NMR(CDCl3) δ=1.43(3H, t), 4.40-4.45(4H, m), 7.20-7.38(6H,m), 7.67(1H, d, J=8Hz), 8.05-8.08(1H, m), 8.79(1H, s) d) 2-Benzyl-7-ethoxycarbonyl-3-quinolyltrifluoromethanesulfonate
    [0524] 204 mg of 2-benzyl-7-ethoxycarbonyl-3-hydroxyquinoline,285 mg of N-phenyltrifluoromethanesulfonimide,134 µl of triethylamine,24 mg of 4-dimethylaminopyridine and 20 ml ofdichloromethane were mixed, followed by stirring at roomtemperature for 2 hours. After removing the solvent, theresidue was subjected to silica gel chromatography andeluted with hexane/ethyl acetate (10:1) and then withhexane/ethyl acetate (5:1), to give 220 mg of the targetcompound.1H-NMR(CDCl3) δ=1.46(3H, t), 4.44-4.50(4H, m), 7.21-7.34(5H,m), 7.87(1H, d, J=8Hz), 8.08(1H, s), 8.19-8.22(1H, m), 8.84(1H,d, J=1Hz) e) 3-(2-Benzyl-7-ethoxycarbonyl-3-quinolyl)ethynyl-3-quinuclidinol
    [0525] A mixture of 220 mg of 2-benzyl-7-ethoxycarbonyl-3-quinolyltrifluoromethane sulfonate, 83 mg of 3-ethynyl-3-quinuclidinol,116 mg oftetrakis(triphenylphosphine)palladium(0), 19 mg of cuprousiodide, 209 µl of triethylamine and 5.0 ml of N,N-dimethylformamidewas stirred at room temperature for 45minutes in a nitrogen atmosphere. The reaction solution waspoured into aqueous dilute ammonia, followed by extractingwith ethyl acetate. Then, the organic phase was washed withbrine and the solvent was removed. The residue was subjectedto NH-silica gel (Fuji Silicia) chromatography and elutedwith hexane/ethyl acetate (1:1) and then with ethylacetate/methanol (15:1), to give 220 mg of the targetcompound.1H-NMR(CDCl3) δ=1.41-1.68(5H, t), 1.81-1.88(1H, m), 2.01-2.09(2H, m), 2.73-2.92 (4H, m), 3.02-3.06 (1H, m), 3.19-3.24 (1H,m), 4.46 (2H, q), 4.54(2H, s), 7.20-7.58 (5H, m), 7.80 (1H, d,J=8Hz), 8.21-8.49(1H, m), 8.23(1H, s), 8.79 - 8.81(1H, m) Example 211 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-thiazolyl]ethynyl-3-quinuclidinol a) Benzyl chloromethyl ketone
    [0526] 100 ml of diethyl ether anhydride was added to 12.4 gof magnesium (used for the synthesis of a Grignard's reagent),to which were then added dropwise a mixture of 45 ml of benzylbromide and 50 ml of an ether anhydride by using a dropping funnel over 30 minutes in a nitrogen atmosphere in a mannerthat the solution was mildly refluxed. This diethyl ethersolution of benzylmagnesium bromide was added dropwise toa mixture of 40 ml of chloroacetyl chloride, 778 mg of cuprousiodide and 100 ml of tetrahydrofuran by using a droppingfunnel over 2 hours in a nitrogen atmosphere such that thesystem temperature was kept at -60°C. After the additionwas completed, the mixture was further stirred for 2.5 hours.Then, an aqueous saturated ammonium chloride solution wasadded thereto, and the mixture was extracted with ethylacetate. The organic phase was further washed with brine,dried over anhydrous sodium sulfate and the solvent wasremoved. The residue was subjected to silica gel columnchromatography using 1-3% ethyl acetate/hexane as an eluentfor separation and purification, to give 20.4 g of the targetcompound.1H-NMR(CDCl3) δ=3.89(2H, s), 4.12(2H, s), 7.22-7.38(5H, m) b) 3,4-Methylenedioxythiobenzamide
    [0527] 882 mg of 3,4-methylenedioxybenzoyl chloride wasdissolved in 20 ml of acetone, to which was then added 1 mlof aqueous 36% ammonia and the mixture was stirred at roomtemperature for 20 minutes. Then, water was added thereto,and the mixture was extracted with ethyl acetate. Theorganic phase was washed with brine, dried over anhydroussodium sulfate and the solvent was removed. The resultingresidue was dissolved in 20 ml of tetrahydrofuran, to whichwas then added 1.9 g of a Lawesson's reagent and the mixture was refluxed under heating for 3 hours. After cooling asit was, the solvent was removed and the residue was subjectedto silica gel column chromatography using 25% ethylacetate/hexane as an eluent for separation and purification,to give 637 mg of the target compound. c) 4-Benzyl-2-(3,4-methylenedioxyphenyl)thiazole
    [0528] A mixture of 372 mg of 3,4-methylenedioxythiobenzamideand 343 mg of benzyl chloromethyl ketone was dissolved in20 ml of ethanol, followed by heating under reflux for 3 hours.After cooling as it was, the solvent was removed, and theresulting crystals were collected by filtration, to give 367mg of the target compound.1H-NMR (CDCl3) δ=4.53(2H, s), 6.11(2H, s), 6.73 (1H, s), 6.99 (1H,d, J=8.2Hz), 7.27-7.40(5H,m), 7.80(1H,d,J=1.9Hz),8.03(1H,dd,J=1.9,8.2Hz) d) 4-Benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)thiazole
    [0529] 367 mg of 4-benzyl-2-(3,4-methylenedioxyphenyl)thiazolewas dissolved in 2 ml ofN,N-dimethylformamide. 244 mg of N-bromosuccinimide wasadded thereto under ice-cooling, followed by stirringovernight. Then, ethyl acetate was added to the reactionsolution, followed by washing with water. The organic phasewas further washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. The residue wassubjected to silica gel column chromatography using 3% ethylacetate/hexane as an eluent for separation and purification,to give 377 mg of the target compound. 1H-NMR (CDCl3) δ =4.12(2H, s), 6.01(2H, s), 6.82(1H, d, J=8.1Hz),7.19-7.37 (7H, m) e) 3-[4-Benzyl-2-(3,4-methylenedioxyphenyl)-5-thiazolyl]ethynyl-3-quinuclidinol
    [0530] 5 ml of N,N-dimethylformamide was added to a mixture of377 mg of 4-benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)thiazole,178 mg of 3-ethynyl-3-quinuclidinol,68 mg oftetrakis(triphenylphosphine)palladium (0), 18 mg of cuprousiodide and 0.5 ml of triethylamine, followed by heating understirring at 100°C in an oil bath for 15 minutes in a nitrogenatmosphere. After cooling as it was, ethyl acetate andaqueous ammonia were added thereto, and the mixture wasextracted with ethyl acetate. The organic phase was furtherwashed with brine, dried over anhydrous sodium sulfate andthe solvent was removed. The resulting crystals werecollected by filtration, to give 253 mg of the targetcompound.1H-NMR(CDCl3) δ=1.38-1.48(1H, m), 1.59-1.69(1H, m), 1.85-1.98(1H,m), 2.00-2.12(2H, m), 2.77-2.98(4H, m), 3.03(1H, d,J=14Hz), 3.25(1H, dd, J=1.9, 14Hz), 4.18(2H, s), 6.01(2H, s),6.81(1H, d, J=8.0Hz), 7.19-7.40(7H, m) Example 212 3-[4-Benzyl-2-(2-pyridyl)-5-thiazolyl]ethynyl-3-quinuclidinol a) 4-Benzyl-2-(2-pyridyl)thiazole
    [0531] 532 mg of 2-cyanopyridine was dissolved in 2 ml of1,3-dimethyl-2-imidazolidinone. A mixture of 474 mg of sodium methoxide, 2.2 ml of bis(trimethylsilyl) sulfide and4 ml of 1,3-dimethyl-2-imidazolidinone was added thereto,followed by heating under stirring at 40°C in an oil bathovernight. After cooling as it was, water was added theretoand the mixture was extracted with ether. The organic phasewas further washed with brine, dried over anhydrous sodiumsulfate and the solvent was removed. To the resultingresidue were added 560 mg of benzyl chloromethyl ketone(Example 211a) and 20 ml of ethanol, followed by heatingunder reflux for 5 hours. After cooling as it was, thesolvent was removed and the residue was subjected to silicagel column chromatography using 11% ethyl acetate/hexane asan eluent for separation and purification, to give 302 mgof the target compound.1H-NMR(CDCl3) δ=4.21(2H, s), 6.89(1H, s), 7.21-7.38(6H, m),7.78(1H, dd, J=7.7, 9.3Hz), 8.18(1H, d, J=7.7Hz), 8.60(1H, d,J=4.9Hz) b) 3-[4-Benzyl-2-(2-pyridyl)-5-thiazolyl]ethynyl-3-quinuclidinol
    [0532] The target compound was synthesized in the same manneras in Example 211.1H-NMR(CDCl3) δ=1.40-1.50(1H, m), 1.62-1.72(1H, m), 1.85-1.95(1H,m), 2.02-2.10 (2H, m), 2.78-2.95(4H, m), 3.04(1H, d,J=14Hz), 3.26(1H, dd, J=2.0, 14Hz), 4.24(2H, s), 7.20-7.35(6H,m), 7.76(1H, dd, 7.7, 9.3Hz), 8.14(1H, d, 7.7Hz), 8.57(1H, d,J=4.0Hz) Example 213 3-[4-Benzyl-2-(4-pyridyl)-5 thiazolyl]ethynyl-3-quinuclidinol a) 4-Benzyl-2-(4-pyridyl)thiazole
    [0533] 1 g of 4-cyanopyridine and 2 ml of triethylamine weredissolved in 20 ml of pyridine. Hydrogen sulfide gas wasintroduced into the reaction solution for 30 minutes whilethe reaction solution was stirred under heating at 50°C inan oil bath. After cooling as it was, hydrogen sulfide gasin the system was replaced by nitrogen gas and the solventwas removed. To the resulting residue were added 619 mg ofbenzyl chloromethyl ketone (Example 211a) and 20 ml ofethanol, followed by heating under reflux for 3 hours. Aftercooling as it was, the solvent was removed and the residuewas subjected to silica gel column chromatography using 20%ethyl acetate/hexane as an eluent for separation andpurification, to give 215 mg of the target compound.1H-NMR(CDCl3) δ=4.21(2H, s), 6.91(1H, s), 7.22-7.40(5H, m),7.80(2H, dd, J=4.6Hz, 1.6Hz), 8.69(2H, dd, J=4.6Hz, 1.6Hz) b) 3-[4-Benzyl-2-(4-pyridyl)-5-thiazolyl]ethynyl-3-quinuclidinol
    [0534] The target compound was synthesized in the same manneras in Example 211.1H-NMR(CDCl3) δ=1.40-1.50(1H, m), 1.62-1.72(1H, m), 1.82-1.92(1H,m), 2.00-2.10(2H, m), 2.78-2.95(4H, m), 3.06(1H, d,J=14Hz), 3.26 (1H, dd, J=14Hz, 2.0Hz), 4.23 (2H, s), 7.20-7.35 (5H,m), 7.71(2H, dd, J=1.6, 4.4Hz), 8.66(2H, dd, J=1.6, 4.4Hz) Example 214 3-[4-Benzyl-2-(3-pyridyl)-5-thiazolyl]ethynyl-3-quinuclidinol a) 2-Amino-4-benzylthiazole
    [0535] 5.0 g of benzyl chloromethyl ketone (Example 211a) wasdissolved in 20 ml of ethanol and 2.3 g of thiourea was addedthereto, followed by heating under reflux for 3 hours. Aftercooling as it was, the solvent was removed and the residuewas subjected to NH-silica gel column chromatography using50% ethyl acetate/hexane and ethyl acetate as an eluent forseparation and purification, to give 1.7 g of the targetcompound.1H-NMR(CDCl3) δ=3.86(2H, s), 5.06(2H, br.s), 6.01(1H, s),7.21-7.32(5H,m) b) 4-Benzyl-2-iodothiazole
    [0536] A mixture of 504 mg of 2-amino-4-benzylthiazole, 520 mgof cuprous iodide, 1.1 ml of diiodomethane and 1.1 ml ofisoamyl nitrite was suspended in 10 ml of tetrahydrofuran,followed by heating under stirring in an oil bath at 80°Cfor one hour in a nitrogen atmosphere. After cooling as itwas, insoluble matters were filtered off through Celite.The filtrate was washed with tetrahydrofuran and the solventwas removed. The resulting residue was subjected to silicagel column chromatography using 2-4% ethyl acetate/hexaneas an eluent for separation and purification, to give 468mg of the target compound.1H-NMR(CDCl3) δ=4.15(2H, s), 6.73(1H, s), 7.24-7.35(5H, m) c) 4-Benzyl-2-(3-pyridyl)thiazole
    [0537] 5 ml of xylene was added to a mixture of 468 mg of4-benzyl-2-iodothiazole, 580 mg of (3-pyridyl)tributyltin and 90 mg of tetrakis(triphenylphosphine)palladium(0),followed by heating under stirring at 150°C in an oil bathfor 2.5 hours. After cooling as it was, insoluble matterswere filtered off through Celite and the solvent was removed.The residue was subjected to silica gel columnchromatography using 20-25% ethyl acetate/hexane as aneluent for separation and purification, to give 101 mg ofthe target compound.1H-NMR(CDCl3) δ=4.21(2H, s), 6.84(1H, s), 7.33-7.40(6H, m),8.24(1H, dd, J=1.7, 8.1Hz), 8.64(1H, dd, J=1.7, 4.9Hz), 9.15(1H,s) d) 3-[4-Benzyl-2-(3-pyridyl)-5-thiazolyl]ethynyl-3-quinuclidinol
    [0538] The title compound was synthesized in the same manneras in Example 211.1H-NMR(CDCl3) δ=1.48-1.58(1H, m), 1.60-1.70(1H, m), 1.85-1.95(1H,m), 2.03-2.12(2H, m), 2.75-2.98(4H, m), 3.06(1H, d,J=14Hz), 3.27(1H, dd, J=2.0, 14Hz), 4.20(2H, s), 7.19-7.38(6H,m), 8.12(1H, dd, J=1.7, 8.0Hz), 8.61(1H, dd, J=1.7, 4.8Hz),9.06(1H, s)
















    权利要求:
    Claims (32)
    [1] A compound (I) represented by the following formula,a salt thereof or a hydrate of them.
    [2] The compound as claimed in Claim 1, a salt thereof ora hydrate of them, wherein R1 represents (1) hydrogen atom or (2) hydroxyl group; HAr is a 5- to 14-membered aromaticheterocycle which contains 1 to 4 atoms selected from nitrogenatom, sulfur atom and oxygen atom and may be substituted with1 to 3 groups selected from (1) a halogen atom, (2) hydroxylgroup, (3) thiol group, (4) nitro group, (5) nitrile group, (6)a C1-6 chain hydrocarbon group which may be substituted, (7) aC3-8 cyclic hydrocarbon group which may be substituted, (8) aC6-14 aromatic cyclic hydrocarbon group which may be substituted,(9) a 5- to 14-membered aromatic heterocyclic group which maybe substituted, (10) a 4- to 10-membered non-aromaticheterocyclic group which may be substituted, (11) a C1-6 alkoxygroup which may be substituted, (12) a C3-8 cycloalkyloxy groupwhich may be substituted, (13) a C1-6 chain hydrocarbon-thiogroup which may be substituted, (14) a C3-8 cyclichydrocarbon-thio group which may be substituted, (15) a C6-14aromatic hydrocarbon-oxy group which may be substituted, (16)a 5- to 14-membered heterocycle-oxy group which may besubstituted, (17) a C6-14 aromatic hydrocarbon-thio group whichmay be substituted, (18) a 5- to 14-membered heterocycle-thiogroup which may be substituted, (19) an amino group which maybe substituted, (20) azide group, (21) guanidino group, (22)carbamide group, (23) formyl group, (24) a C1-6 imidoyl groupwhich may be substituted, (25) a substituted carbonyl group,(26) a substituted carbonyl-oxy group, (27) a carboxyl groupwhich may form a salt, (28) a carbamoyl group which may besubstituted, (29) a C1-4 alkylenedioxy group which may besubstituted, (30) a sulfinyl group which may be substituted and (31) a sulfonyl group which may be substituted; Ar is a C6-14aromatic hydrocarbon ring or a 5- to 14-membered aromaticheterocycle which may be substituted with one or more groupsselected from (1) hydroxyl group, (2) a halogen atom, (3) a C1-6chain hydrocarbon group which may be substituted, (4) a C3-8cyclic hydrocarbon group which may be substituted, (5) a C1-6alkoxy group which may be substituted, (6) a C3-8 cycloalkyloxygroup which may be substituted, (7) a C1-6 chain hydrocarbon-thiogroup which may be substituted, (8) a C3-8 cyclichydrocarbon-thio group, (9) a C6-14 aromatic hydrocarbon cyclicgroup which may be substituted, (10) a 5- to 14-memberedheterocyclic group which may be substituted, (11) an amino groupwhich may be substituted with a C1-6 alkyl group and (12) a C1-4alkylenedioxy group; W is a chain represented by (1) -CH2-CH2-which may be substituted, (2) -CH=CH- which may be substituted,(3) -C≡C-, (4) -NH-CO-, (5) -CO-NH-, (6) -NH-CH2-, (7) -CH2-NH-,(8) -CH2-CO-, (9) -CO-CH2-, (10) -NH-S(O)1-, (11) -S(O)1-NH-,(12) -CH2-S(O)1- or (13) -S(O)1-CH2- (1 denotes 0, 1 or 2) ; andX represents a chain represented by (1) a single bond, (2) aC1-6 alkylene chain which may be substituted, (3) a C2-6 alkenylenechain which may be substituted, (4) a C2-6 alkynylene chain whichmay be substituted, (5) the formula -Q- (wherein Q representsoxygen atom, sulfur atom, CO or N(R2) (wherein R2 representsa C1-6 alkyl group or a C1-6 alkoxy group)), (6) -NH-CO-, (7)-CO-NH-, (8) -NH-CH2-, (9) -CH2-NH-, (10) -CH2-CO-, (11) -CO-CH2-,(12) -NH-S(O)m-, (13) -S(O)m-NH-, (14) -CH2-S(O)m-, (15)-S(O)m-CH2- (wherein m denotes 0, 1 or 2) or (16) -(CH2)n-O- (wherein n represents an integer from 1 to 6).
    [3] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which R1 is hydroxyl group.
    [4] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which W is -CH2-CH2-, -CH=CH- or-C≡C-.
    [5] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which X is a single bond, -CH2-,-CH2-CH2-, -CH=CH- or -CO-.
    [6] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, wherein HAr is a 5- to 14-membered aromaticheterocycle containing 1 to 4 atoms selected from nitrogen atom,sulfur atom and oxygen atom and may be substituted with 1 to3 groups selected from (1) hydroxyl group, (2) a halogen atom,(3) thiol group, (4) nitro group, (5) nitrile group, (6) a C1-6alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, which maybe substituted with one or two groups selected from (a) ahydroxyl group which may be protected, (b) a halogen atom, (c)nitrile group, (d) carboxyl group, (e) a C3-8 cycloalkyl group,C3-8 cycloalkenyl group or C3-8 cycloalkynyl group, which may behydroxylated or halogenated, (f) a C1-6 alkoxy group which maybe substituted with a group selected from a halogen atom,hydroxyl group, a C6-14 aryl group, a 5- to 14-membered heteroarylgroup and a C6-14 aryl-C1-6 alkoxy group, (g) a C3-8 cycloalkyloxygroup which may be halogenated or hydroxylated, (h) a C3-8cycloalkenyloxy group which may be halogenated or hydroxylated,(i) a 5- to 14 membered aryl-oxy group which may be halogenated or hydroxylated, (j) a 5- to 14 membered non-aromatic cycle-oxygroup which may be halogenated or hydroxylated, (k) a C1-6alkoxy-carbonyl group, (l) a C1-4 alkylenedioxy group which maybe halogenated, (m) a C1-6 alkanoyl group which may be substitutedwith a group selected from hydroxyl group, a C1-6 alkoxy groupand a C1-6 alkanoyloxy group, (n) a C6-14 aryl group which may besubstituted with a group selected from a halogen atom, a C1-6alkyl group and a C1-6 alkoxy group, (o) a 5- to 14-memberedaromatic heterocyclic group which may be substituted with agroup selected from a halogen atom, a C1-6 alkyl group, a C3-8alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (p)a 5- to 10-membered non-aromatic heterocyclic group which maybe substituted with a group selected from a halogen atom, a C1-6alkyl group, a C3-8 alkenyl group, a C3-8 alkynyl group and a C1-6alkoxy group, (q) a group (EtO)2PO-, (r) acetyl group, (s) asulfonyl group which may be substituted with a group selectedfrom a C1-6 hydrocarbon group, a mono-(C1-6 hydrocarbon) -aminogroup and a di- (C1-6 hydrocarbon) -amino group, (t) an amino groupwhich may be substituted with a C1-6 hydrocarbon group, (u) aC1-6 hydrocarbon group-thio group which may be hydroxylated orhalogenated and (v) a carbamoyl group which may be substitutedwith a C1-6 hydrocarbon group, (7) a C3-8 cycloalkyl group or C3-8cycloalkenyl group which may be substituted with one or twogroups selected from (a) hydroxyl group, (b) a halogen atom,(c) nitrile group, (d) carboxyl group, (e) a C1-6 alkyl groupwhich may be substituted with a group selected from a C1-6alkoxygroup which may be hydroxylated or halogenated, a C1-6 hydrocarbon-thio group which may be halogenated, an amino groupwhich may be substituted with a C1-6 hydrocarbon group and a C1-6alkanoyl group, (f) a C1-6 alkenyl group which may be substitutedwith a group selected from a C1-6 alkoxy group which may behydroxylated or halogenated, a C1-6 hydrocarbon-thio group whichmay be halogenated, an amino group which may be substituted witha C1-6 hydrocarbon group and a C1-6 alkanoyl group, (g) a C1-6alkynyl group which may be substituted with a group selectedfrom a C1-6 alkoxy group which may be hydroxylated or halogenated,a C1-6 hydrocarbon-thio group which may be halogenated, an aminogroup which may be substituted with a C1-6 hydrocarbon group anda C1-6 alkanoyl group, (h) an amino group which may be substitutedwith a group selected from a C1-6 alkoxy group which may behydroxylated or halogenated, a C1-6 hydrocarbon-thio group whichmay be halogenated, a C1-6 alkanoyl group and a C1-6 hydrocarbongroup, (i) a C1-6 alkoxy group which may be substituted with agroup selected from a C1-6 alkyl group which may be hydroxylatedor halogenated, a C1-6 alkoxy group which may be hydroxylatedor halogenated, a C1-6 hydrocarbon-thio group which may behalogenated, an amino group which may be substituted with a C1-6hydrocarbon group and a C1-6 alkanoyl group, (j) a C1-6hydrocarbon-thio group which may be substituted with a groupselected from a C1-6 alkyl group which may be hydroxylated orhalogenated, a C1-6 alkenyl group which may be halogenated, aC1-6 alkynyl group which may be halogenated, a C1-6 alkoxy groupwhich may be hydroxylated or halogenated, a C1-6 hydrocarbon-thiogroup which may be halogenated, an amino group which may be substituted with a C1-6 hydrocarbon group and a C1-6 alkanoyl group,(k) a C1-6 alkanoyl group which may be substituted with a groupselected from hydroxyl group, a C1-6 alkoxy group and a C1-6alkanoyloxy group, (l) a C6-14 aryl group which may be substitutedwith a group selected from a halogen atom, a C1-6 alkyl groupand a C1-6 alkoxy group, (m) a 5- to 14-membered aromaticheterocyclic group which may be substituted with a groupselected from a halogen atom, a C1-6 alkyl group, a C3-8 alkenylgroup, a C3-8 alkynyl group and a C1-6 alkoxy group, (n) anon-aromatic heterocyclic group which may be substituted witha group selected from a halogen atom, a C1-6 alkyl group, a C3-8alkenyl group, a C3-8 alkynyl group and a C1-6 alkoxy group, (o)a C1-6 alkoxy-carbonyl group, (p) a C1-4 alkylenedioxy group whichmay be halogenated, (q) a group (EtO)2PO- and (r) acetyl group,(8) a C6-14 aromatic hydrocarbon group which may be substitutedwith one or more groups selected from (a) hydroxyl group, (b)a halogen atom, (c) a C1-6 alkyl-sulfonyl group, C1-6alkenyl-sulfonyl group and C1-6 alkynyl-sulfonyl group, whichmay be halogenated, (d) a C1-4 alkylenedioxy group which may behalogenated, (e) a C1-6 alkoxy group which may be halogenated,(f) a C1-6 hydrocarbon-thio group which may be halogenated, (g)a C1-6 alkoxy-carbonyl group, (h) a C6-14 aryl-C1-6 alkoxy group,(i) a C1-7 alkanoylamino group, (j) a C1-6 alkyl-carbamoyl group,(k) a C1-6 alkenyl-carbamoyl group, (1) a C1-6 alkynyl-carbamoylgroup and (m) an amino group which may be substituted with aC1-6 hydrocarbon group, (9) a 5- to 14-membered aromaticheterocyclic group which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a halogen atom,(c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group orC1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxygroup which may be halogenated, (f) a C1-6 alkylthio group, C1-6alkenylthio group or C1-6 alkynylthio group which may behalogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group,(i) an C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon) -aminogroup, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6hydrocarbon)-amino group, (10) a 4- to 10-membered non-aromaticheterocyclic group which may be substituted with one or moregroups selected from (a) hydroxyl group, (b) a halogen atom,(c) nitrile group, (d) a C1-6 alkyl group, C1-6 alkenyl group orC1-6 alkynyl group, which may be halogenated, (e) a C1-6 alkoxygroup which may be halogenated, (f) a C1-6 alkylthio group, C1-6alkenylthio group or C1-6 alkynylthio group, which may behalogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h) acetyl group,(i) a C1-6 alkanoyl group, (j) a mono-(C1-6 hydrocarbon) -aminogroup, (k) a di-(C1-6 hydrocarbon)-amino group and (l) a tri-(C1-6hydrocarbon) -amino group, (m) a C1-4 alkylenedioxy group and (n)an oxo group, (11) a C1-6 alkoxy group which may be substitutedwith one or more groups selected from (a) hydroxyl group, (b)a halogen atom, (c) a C1-6 alkyl group, C1-6 alkenyl group or C1-6alkynyl group, which may be substituted with a group selectedfrom hydroxyl group, a halogen atom, a 5- to 14-memberedaromatic heterocyclic group and a 4 to 10-membered non-aromaticheterocyclic group, (d) a C3-8 cycloalkyl group or C3-8cycloalkenyl group which may be hydroxylated or halogenated, (e) a C1-6 alkoxy group which may be hydroxylated or halogenated,(f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6alkynylthio group, which may be halogenated, (g) a C3-8cycloalkyloxy group or C3-8 cycloalkenyloxy group which may behalogenated, (h) a C3-8 cycloalkylthio group or C3-8cycloalkenylthio group which may be halogenated, (i) a C6-14 arylgroup, (j) a C1-6 alkanoyl group which may be halogenated, (k)a 5- to 14-membered aromatic heterocyclic group and (l) a 4-to10-membered non-aromatic heterocyclic group, (12) a C3-8cycloalkyloxy group which may be substituted with one or twogroups selected from (a) hydroxyl group, (b) a halogen atom,(c) a C1-6 a hydrocarbon group which may be substituted with agroup selected from hydroxyl group, a halogen atom, a C1-6 alkoxygroup and a C1-6 alkanoyl group, (d) a C1-6 alkoxy group whichmay be substituted with a group selected from a halogen atom,a C1-6 alkoxy group and a C1-6 alkanoyl group and (e) a C1-6hydrocarbon-thio group which may be substituted with a groupselected from a halogen atom, a C1-6 alkoxy group and a C1-6alkanoyl group, (13) a C1-6 alkylthio group, C1-6 alkenylthiogroup or C1-6 alkynylthio group, which may be substituted withone or two groups selected from (a) hydroxyl group, (b) a halogenatom, (c) a C1-6 alkyl group, C1-6 alkenyl group or C1-6 alkynylgroup which may be substituted with a group selected fromhydroxyl group, a halogen atom, a 5- to 14-membered aromaticheterocyclic group and 4- to 10-membered non-aromaticheterocyclic group, (d) a C3-8 cycloalkyl group, C3-8 cycloalkenylgroup or C3-8 cycloalkynyl group, which may be hydroxylated or halogenated, (e) a C1-6 alkoxy group which may be hydroxylatedor halogenated, (f) a C1-6 alkylthio group, C1-6 alkenylthio groupor C1-6 alkynylthio group, which may be halogenated, (g) a C3-8cycloalkyloxy group or C3-8 cycloalkenyloxy group which may behalogenated, (h) a C3-8 cycloalkylthio group or C3-8cycloalkenylthio group which may be halogenated, (i) a C6-14 arylgroup, (j) a C1-6 alkanoyl group which may be halogenated, (k)a 5- to 14-membered aromatic heterocyclic group and (l) a 4-to10-membered non-aromatic heterocycle, (14) a C3-8cycloalkylthio group or a C3-8 cycloalkenylthio group which maybe substituted with one or two groups selected from (a) hydroxylgroup, (b) a halogen atom, (c) a C3-8 alkyl group, C3-8 alkenylgroup or C3-8 alkynyl group, which may be halogenated, (d) a C1-6alkoxy group which may be halogenated, (e) a C1-6hydrocarbon-thio group which may be halogenated and (f) a C1-6alkanoyl group which may be halogenated, (15) an amino grouprepresented by the formula -N(R3)R4 (wherein R3 and R4 are thesame as or different from each other and each represents a groupselected from (a) an aromatic heterocyclic group, (b) anon-aromatic heterocyclic group, (c) a C1-6 alkyl group, C1-6alkenyl group or C1-6 alkynyl group, which may be substitutedwith a halogen atom or a C1-6 alkoxy group, (d) a C3-8 cycloalkylgroup or a C3-8 cycloalkenyl group which may be halogenated, (e)a carbonyl group which is substituted with a C1-6 alkyl group,C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated,a C3-8 cycloalkyl group or C3-8 cycloalkenyl group, which may behalogenated, a C1-6 alkoxy group which may be halogenated, a C6-14 aryl group or an aromatic heterocyclic group, (f) a C1-6 alkanoylgroup which may be substituted with a group selected from a C6-14aryl group and an aromatic heterocyclic group, (g) a carbamoylgroup which may be substituted with a C1-6 alkyl group, a C1-6alkenyl group, a C1-6 alkynyl group, a C6-14 aryl group or anaromatic heterocyclic group and (h) a sulfonyl group which issubstituted with a C1-6 alkyl group, a C1-6 alkenyl group or aC1-6 alkynyl group, and also, (i) R3 and R4 may be combined andunited to form a 3- to 10-membered ring and the cyclic aminogroup may be substituted with one or more groups selected fromhydroxyl group, a halogen atom, a C1-6 alkyl group, a C1-6 alkenylgroup, a C1-6 alkynyl group, a C1-6 alkoxy group, a C1-6hydrocarbon-thio group and a C1-4 alkylenedioxy group), (16) aC6-14 aryl-oxy group which may be substituted with one or moregroups selected from (a) hydroxyl group, (b) a halogen atom,(c) a C1-6 alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group orC1-6 alkynyl-sulfonyl group which may be halogenated, (d) a C1-4alkylenedioxy group which may be halogenated, (e) a C1-6 alkoxygroup which may be halogenated, (f) a C1-6 hydrocarbon-thio groupwhich may be halogenated, (g) a C1-6 alkoxy-carbonyl group, (h)a C6-14 aryl-C1-6 alkoxy group, (i) a C1-7 alkanoylamino group, (j)a C1-6 alkyl-carbamoyl group, (k) a C1-6 alkenyl-carbamoyl group,(l) a C1-6 alkynyl-carbamoyl group and (m) an amino group whichmay be substituted with a C1-6 hydrocarbon group, (17) a C6-14aryl-thio group which may be substituted with one or more groupsselected from (a) hydroxyl group, (b) a halogen atom, (c) a C1-6alkyl-sulfonyl group, C1-6 alkenyl-sulfonyl group or C1-6 alkynyl-sulfonyl group, which may be halogenated, (d) a C1-4alkylenedioxy group which may be halogenated, (e) a C1-6 alkoxygroup which may be halogenated, (f) a C1-6 hydrocarbon-thio groupwhich may be halogenated, (g) a C1-6 alkoxy-carbonyl group, (h)a C6-14 aryl-C1-6 alkoxy group, (i) a C1-7 alkanoylamino group (j)a C1-6 alkyl-carbamoyl group, (k) a C1-6 alkenyl-carbamoyl group,(l) a C1-6 alkynyl-carbamoyl group and (m) an amino group whichmay be substituted with a C1-6 hydrocarbon group, (18) a 5- to15-membered aromatic heterocycle-oxy group which may besubstituted one or more groups selected from (a) hydroxyl group,(b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group,C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated,(e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group,which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h)acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-aminogroup and (1) a tri-(C1-6 hydrocarbon)-amino group, (19) a 5-to15-membered aromatic heterocycle-thio group which may besubstituted one or more groups selected from (a) hydroxyl group,(b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group,C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated,(e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio group,which may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h)acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6hydrocarbon) -amino group, (k) a di-(C1-6 hydrocarbon) -amino group and (l) a tri-(C1-6 hydrocarbon)-amino group, (20) a 4-to10-membered non-aromatic heterocycle-oxy group which may besubstituted one or more groups selected from (a) hydroxyl group,(b) a halogen atom, (c) nitrile group, (d) a C1-6 alkyl group,C1-6 alkenyl group or C1-6 alkynyl group, which may be halogenated,(e) a C1-6 alkoxy group which may be halogenated, (f) a C1-6alkylthio group, C1-6 alkenylthio group or C1-6 alkynylthio groupwhich may be halogenated, (g) a C1-6 alkoxy-C1-6 alkyl group, (h)acetyl group, (i) a C1-6 alkanoyl group, (j) a mono-(C1-6hydrocarbon)-amino group, (k) a di-(C1-6 hydrocarbon)-aminogroup and (l) a tri-(C1-6 hydrocarbon)-amino group, (21) a 4-to10-membered non-aromatic heterocycle-thio group which maybe substituted one or more groups selected from (a) hydroxylgroup, (b) a halogen atom, (c) nitrile group, (d) a C1-6 alkylgroup, C1-6 alkenyl group or C1-6 alkynyl group, which may behalogenated, (e) a C1-6 alkoxy group which may be halogenated,(f) a C1-6 alkylthio group, C1-6 alkenylthio group or C1-6alkynylthio group which may be halogenated, (g) a C1-6 alkoxy-C1-6alkyl group, (h) acetyl group, (i) a C1-6 alkanoyl group, (j)a mono-(C1-6 hydrocarbon) -amino group, (k) a di-(C1-6hydrocarbon) -amino group and (l) a tri-(C1-6 hydrocarbon) -aminogroup, (22) azide group, (23) guanidino group, (24) carbamidegroup, (25) formyl group, (26) a C1-6 imidoyl group which maybe substituted, (27) a C1-6 alkanoyl group which may besubstituted with a C1-6 alkoxy group, (28) a C1-6 alkanoyl-oxygroup which may be substituted with a C1-6 alkoxy group, (29)a carboxyl group which may form a salt, (30) a carbonyl group which is substituted with a group selected from (a) a C1-6 alkoxygroup, (b) a C6-14 aryl group and (c) a 5- to 14-membered aromaticheterocyclic group, (31) a carbamoyl group represented by theformula -CO-N(R5)R6 (wherein R5 and R6 are the same as or differentfrom each other and each represents a group selected from (a)hydrogen atom, (b) a C1-6 alkyl group, (c) a C1-6 alkenyl group,(d) a C1-6 alkynyl group, (e) a C3-8 cycloalkyl group, (f) a C3-8cycloalkenyl group, (g) a C6-14 aryl group and (h) an aromaticheterocyclic group or (i) R5 and R6 may be combined and unitedto form a 3- to 8-membered ring), (32) a C1-4 alkylenedioxy groupwhich may be substituted with (a) hydroxyl group or (b) a halogenatom, (33) a sulfinyl group which may be substituted with a groupselected from (a) a C1-6 hydrocarbon group which may behalogenated and (b) an amino group which may be mono-substitutedor di-substituted with a C1-6 hydrocarbon group which may behalogenated and (34) a sulfonyl group which may be substitutedwith (a) a C1-6 hydrocarbon group which may be halogenated or(b) an amino group which may be mono-substituted or di-substitutedwith a C1-6 hydrocarbon group which may behalogenated.
    [7] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, wherein HAr is a 5 - to 14 -membered aromaticheterocycle which may be substituted with, in addition to asubstituent -X-Ar, 1 to 3 groups selected from (1) a 5- or6-membered aromatic heterocycle which may be substituted witha C1-6 alkyl group, (2) a 5- to 6-membered non-aromaticheterocycle which may be substituted with one or more groups selected from (a) hydroxyl group, (b) a C1-6 alkyl group and (c)a C1-6 alkoxy group, (3) a C6-10 aromatic hydrocarbon ring whichmay be substituted with one or more groups selected from (a)a halogen atom, (b) a C1-6 alkoxy group, (c) a C1-4 alkylenedioxygroup and (d) a sulfonyl group which may be substituted witha C1-6 alkyl group, (4) a C1-6 alkyl group which may be substitutedwith one or more groups selected from (a) hydroxyl group, (b)a halogen atom, (c) a 5- or 6-membered aromatic heterocycle and(d) a C1-6 alkoxy group and (5) a C1-6 alkoxy group which may besubstituted with (a) a halogen atom or (b) a C1-6 alkoxy group.
    [8] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, wherein HAr is a 5- to 10-membered aromaticheterocycle which may be substituted with, in addition to asubstituent -X-Ar, 1 to 3 groups selected from (1) a benzenering which may be substituted with a C1-4 alkylenedioxy group,(2) pyridine ring, (3) pyrimidine ring, (4) pyridazine ring,(5) pyrazine ring, (6) thiophene ring, (7) a piperidine ringwhich may be substituted with a C1-6 alkoxy group, (8) apiperazine ring which may be substituted with a C1-6 alkoxy group,(9) a pyrrolidine ring which may be substituted with a C1-6 alkoxygroup, (10) a piperidine ring which is substituted with hydroxylgroup and a C1-6 alkoxy group, (11) a piperazine ring which issubstituted with hydroxyl group and a C1-6 alkoxy group, (12)a pyrrolidine ring which is substituted with hydroxyl group anda C1-6 alkoxy group, (13) morpholine ring, (14) a C1-6 alkyl groupwhich may be substituted with a C1-6 alkoxy group and (15) a C1-6alkoxy group which may be substituted with hydroxyl group or a C1-6 alkoxy group.
    [9] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which HAr is a pyridine ring, pyrimidinering, pyridazine ring, pyrazine ring, indole ring, quinolinering, thiophene ring or benzothiophene ring which may besubstituted with 1 to 3 groups.
    [10] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, wherein HAr is a pyridine ring, pyrimidinering, pyridazine ring, pyrazine ring, indole ring, quinolinering, thiophene ring or benzothiophene ring, which may besubstituted with, in addition to a substituent -X-Ar, 1 to 3groups selected from (1) a 5- or 6-membered aromatic heterocyclewhich may be substituted with a C1-6 alkyl group, (2) a 5- or6-membered aromatic heterocycle which may be substituted withone or more groups selected from (a) hydroxyl group, (b) a C1-6alkyl group and (c) a C1-6 alkoxy group, (3) a C6-10 aromatichydrocarbon ring which may be substituted with one or moregroups selected from (a) a halogen atom, (b) a C1-6 alkoxy group,(c) a C1-4 alkylenedioxy group and (d) a sulfonyl group whichmay be substituted with a C1-6 alkyl group, (4) a C1-6 alkyl groupwhich may be substituted with one or more groups selected from(a) hydroxyl group, (b) a halogen atom, (c) a 5- or 6-memberedheterocycle and (d) a C1-6 alkoxy group and (5) a C1-6 alkoxy groupwhich may be substituted with (a) a halogen atom and (b) a C1-6alkoxy group.
    [11] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, wherein Ar is a C6-14 aromatic hydrocarbon ring or 5- to 14-membered aromatic heterocycle, which may have1 to 3 substituents selected from (1) a halogen atom, (2) a C1-6alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, which maybe substituted with one or more groups selected from (a) ahalogen atom, (b) a C1-6 alkoxy group and (c) a sulfonyl groupwhich may be substituted, (3) a C1-6 alkoxy group which may behalogenated, (4) a mono-(C1-6 alkyl) -amino group, (5) a di-(C1-6alkyl) -amino group and (6) a C1-4 alkylenedioxy group which maybe halogenated.
    [12] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which Ar is an optionally substitutedbenzene ring or pyridine ring.
    [13] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which Ar is a C6-14 aromatic hydrocarbonring or 5- to 14-membered aromatic heterocycle, which may have1 to 3 substituents selected from (1) a halogen atom, (2) a C1-6alkyl group, C2-6 alkenyl group or C2-6 alkynyl group, which maybe substituted with one or more groups selected from (a) ahalogen atom, (b) a C1-6 alkoxy group and (c) a sulfonyl groupwhich may be substituted, (3) a C1-6 alkoxy group which may behalogenated, (4) a mono- (C1-6 alkyl)-amino group, (5) a di- (C1-6alkyl)-amino group and (6) a C1-4 alkylenedioxy group which maybe halogenated.
    [14] The compound as claimed in Claim 1 or 2, a salt thereofor a hydrate of them, in which X is -CH2-; and Ar is benzenering.
    [15] The compound as claimed in Claim 1 or 2, a salt thereof or a hydrate of them, in which the compound is represented bythe following formula.
    [16] The compound as claimed in Claim 15, a salt thereofor a hydrate of them, in which HAr is a pyridine ring, pyrazinering, pyrimidine ring or pyridazine ring, which may besubstituted with, in addition to a substituent -X-Ar, one ormore groups selected from (1) a 5- or 6-membered aromaticheterocycle, (2) a 5- or 6-membered non-aromatic heterocyclewhich may be substituted with a C1-6 alkoxy group and (3) a C6-10aromatic hydrocarbon ring; Ar is a benzene ring or pyridine ringwhich may be halogenated; and X is -CH2-.
    [17] The compound as claimed in Claim 15, a salt thereofor a hydrate of them, in which HAr is a pyridine ring, pyrazinering, pyrimidine ring or pyridazine ring, which may besubstituted with, in addition to a substituent -X-Ar, a groupselected from (1) a C1-6 alkoxy group which may be substitutedwith hydroxyl group, (2) a C1-6 alkoxy-C1-6 alkoxy group and (3)a C1-6 alkoxy-C1-6 alkyl-amino group; Ar is an optionallyhalogenated benzene or pyridine ring; and X is -CH2-.
    [18] The compound as claimed in Claim 15, a salt thereofor a hydrate of them, wherein HAr is a pyridine ring, pyrazinering, pyrimidine ring or pyridazine ring, which may besubstituted with, in addition to a substituent -X-Ar, 1 to 3groups selected from (1) a benzene ring which may be substitutedwith a C1-4 alkylenedioxy group, (2) pyridine ring, (3)pyrimidine ring, (4) pyridazine ring, (5) pyrazine ring, (6) thiophene ring, (7) a piperidine ring which may be substitutedwith a C1-6 alkoxy group, (8) a piperazine ring which may besubstituted with a C1-6 alkoxy group, (9) a pyrrolidine ring whichmay be substituted with a C1-6 alkoxy group, (10) a piperidinering which is substituted with hydroxyl group and a C1-6 alkoxygroup, (11) a piperazine ring which is substituted with hydroxylgroup and a C1-6 alkoxy group, (12) a pyrrolidine ring which issubstituted with hydroxyl group and a C1-6 alkoxy group, (13)morpholine ring, (14) a C1-6 alkyl group which may be substitutedwith a C1-6 alkoxy group and (15) a C1-6 alkoxy group which maybe substituted with hydroxyl group or a C1-6 alkoxy group; Aris a benzene ring or pyridine ring, which may be halogenated;and X is -CH2-.
    [19] The compound as claimed in Claim 1, a salt thereof ora hydrate of them, in which the compound is any one selectedfrom:
    3-(4-benzyl-2-phenyl-5-pyrimidyl)ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(2-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol;
    3-[3-benzyl-5-(2-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol;
    3-(3-benzyl-5-phenyl-2-pyridyl)ethynyl-3-quinuclidinol;
    3-[3-benzyl-5-(3-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol;
    3-[3-benzyl-5-(4-pyridyl)-2-pyridyl]ethynyl-3-quinuclidinol;
    3-(3-benzyl-5-pyrazyl-2-pyridyl)ethynyl-3-quinuclidinol;
    3-[3-benzyl-5-(2-ethoxycarbonylethyl)-2-pyridyl]ethynyl-3-quinuclidinol;
    3-[3-benzyl-5-(3-oxobutyl)-2-pyridyl]ethynyl-3-quinuclidinol;
    3- [3-benzyl-5-(3-hydroxybutyl)-2-pyridyl]ethynyl-3-quinuclidinol;
    3-[2-benzyl-6-(3-methoxypropylamino)-3-pyridyl]ethynyl-3-quinuclidinol;
    3-[2-benzyl-6- (2-methoxyethyloxy) -3-pyridyl]ethynyl-3-quinuclidinol;
    3-[2-benzyl-6-(3-methoxypropyloxy)-3-pyridyl]ethynyl-3-quinuclidinol;
    3-[2-benzyl-6-(4-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol;
    3-[2-benzyl-6-(3-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol;
    3-(2-benzyl-6-pyrazyl-3-pyridyl)ethynyl-3-quinuclidinol;
    3-[2-benzyl-6-(2-pyridyl)-3-pyridyl]ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(3-pyridyl)-5-pyrimidyl]ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyrimidyl]ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    3-(4-benzyl-2-pyrazyl-5-pyridyl)ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(4-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    3-[4-benzyl-2-(2-methoxyethoxy)-5-pyridyl]ethynyl-3-quinuclidinol;
    3- [2-benzyl-6-(4-ethoxycarbonylpiperidino)-3-pyridyl]ethynyl-3-quinuclidinol;
    3-(2-benzyl-6-morpholino-3-pyridyl)ethynyl-3-quinuclidinol;
    3- [2-benzyl-6-(4-methoxypiperidino)-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-(2-methoxyethyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    (3S)-3-[2-benzyl-6-(3-methoxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3- [2-benzyl-6-(3-fluoropropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-(1,3-dioxolan-2-yl)methyloxy-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-(3-hydroxypropyl)oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    3- [2-benzyl-6- [3- (3-methoxycarbonylpropanoyloxy)propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    3-[2-benzyl-6-[3-[N-(tert-butoxycarbonyl)alanyloxy]propyl]oxy-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[4-benzyl-2-(3-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[4-benzyl-2-(2-pyridyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[4-benzyl-2-(3,4-methylenedioxyphenyl)-5-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3S,4R)-3-fluoro-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-5-chloro-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3- [2-benzyl-5-bromo-6-[(3R,4R) -3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R) -3- [2-benzyl-6-(3,3-ethylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-5-chloro-6-(3,3-ethylenedioxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R,4R)-3,4-dimethoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R,4R)-4-hydroxy-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-(3,3-ethylenedioxy-2-pyrrolidinone-1-yl)-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R) -3-hydroxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[2-benzyl-6-[(3R)-3-methoxy-2-pyrrolidinone-1-yl]-3-pyridyl]ethynyl-3-quinuclidinol;
    (3R)-3-[4-benzyl-2-(1,4-dioxene-2-yl)-5-pyridyl]ethynyl-3-quinuclidinol;and
    (3R)-3-[4-benzyl-2-[(3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-yl]-3-pyrimidyl]ethynyl-3-quinuclidinol.
    [20] A squalene synthesizing enzyme inhibitor comprisingthe compound as claimed in any of Claims 1 to 19, a salt thereofor a hydrate of them.
    [21] A medicinal composition comprising a compound (I)represented by the following formula, a salt thereof or ahydrate of them.
    [22] The medicinal composition according to Claim 21, whichis a preventive or curative agent for a disease against whichsqualene synthesizing enzyme inhibition is efficacious.
    [23] The medicinal composition according to Claim 21, whichis a cholesterol biosynthesis inhibitor.
    [24] The medicinal composition according to Claim 21, which is a triglyceride biosynthesis inhibitor.
    [25] The medicinal composition according to Claim 21, whichis an agent for preventing or curing hyper lipidemia.
    [26] The medicinal composition according to Claim 21, whichis an agent for preventing or curing arterial sclerosis diseasesor ischemic heart diseases.
    [27] The medicinal composition according to Claim 21, whichis an agent for preventing or curing hypertension, coronarydiseases, cerebrovascular diseases, aortic diseases,peripheral arterial diseases, angina pectoris, acute coronarysyndromes or cardiac infarction.
    [28] A method for producing a quinuclidine compound (IV)represented by the following formula:
    [29] A method for producing a quinuclidine compound (VI)represented by the following formula:
    [30] A method for producing a quinuclidine compound (VIII)represented by the following formula:
    [31] A method of preventing or curing a disease againstwhich squalene synthesizing enzyme inhibition is efficacious,by administering a pharmacologically effective amount of thecompound as claimed in Claim 1, a salt thereof or a hydrate ofthem to a patient.
    [32] Use of the compound as claimed in Claim 1, a saltthereof or a hydrate of them, for producing an agent forpreventing or treating a disease against which squalenesynthesizing enzyme inhibition is efficacious.
    类似技术:
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    同族专利:
    公开号 | 公开日
    IL148631A|2010-04-29|
    DK1217001T3|2006-03-20|
    JP4206212B2|2009-01-07|
    DE60024651D1|2006-01-12|
    RU2266905C2|2005-12-27|
    NO20021528D0|2002-03-26|
    AU782114B2|2005-07-07|
    NZ517788A|2003-11-28|
    MXPA02003167A|2003-10-06|
    ES2252063T3|2006-05-16|
    AT312100T|2005-12-15|
    CA2385995C|2009-06-16|
    WO2001023383A1|2001-04-05|
    CN1377349A|2002-10-30|
    AU7446400A|2001-04-30|
    CN100334085C|2007-08-29|
    CA2385995A1|2001-04-05|
    HU0203514A2|2003-03-28|
    EP1217001B1|2005-12-07|
    US6599917B1|2003-07-29|
    NO328218B1|2010-01-11|
    NO20021528L|2002-05-28|
    EP1217001A4|2002-12-18|
    IL148631D0|2002-09-12|
    KR20020034197A|2002-05-08|
    TWI282794B|2007-06-21|
    HU0203514A3|2004-01-28|
    KR100694687B1|2007-03-13|
    BR0014331A|2003-06-10|
    DE60024651T2|2006-09-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO1992015579A1|1991-03-08|1992-09-17|Rhone-Poulenc Rorer International Inc.|Multicyclic tertiary amine polyaromatic squalene synthetase inhibitors|
    US5654315A|1991-12-23|1997-08-05|Imperial Chemical Industries Plc|Quinuclidine compounds useful in treating diseases|
    EP0560604A1|1992-03-12|1993-09-15|Mitsubishi Chemical Corporation|Cinnoline-3-carboxylic acid derivatives as 5-HT3 antagonists|
    WO1993021183A1|1992-04-10|1993-10-28|Zeneca Limited|Quinuclidine derivatives as squalene synthase inhibitors|
    WO1995031458A1|1992-10-13|1995-11-23|Rhone-Poulenc Rorer Pharmaceuticals Inc.|3-hydroxyquinuclidin-3-ylphenylquinolines as squalene synthase inhibitors|
    WO1995035295A1|1994-06-17|1995-12-28|Zeneca Limited|Quinuclidine derivatives as squalene synthase inhibitors|
    JPH08134067A|1994-11-11|1996-05-28|Yamanouchi Pharmaceut Co Ltd|Quinuclidine derivative|
    JPH08269056A|1995-03-29|1996-10-15|Chugai Pharmaceut Co Ltd|Quinuclidine derivative having squalene synthase inhibitory action|
    WO1997044339A1|1996-05-20|1997-11-27|Merck & Co., Inc.|Antagonists of gonadotropin releasing hormone|US8067589B2|2007-02-26|2011-11-29|Pfizer Inc|Heterocyclic compounds useful in treating diseases and conditions|
    US8106066B2|2005-09-23|2012-01-31|Memory Pharmaceuticals Corporation|Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, pyrazolopyridines, isothiazolopyridines, and preparation and uses thereof|
    US8134003B2|2002-09-25|2012-03-13|Memory Pharmaceuticals Corporation|Indazoles, benzothiazoles, and benzoisothiazoles, and preparation and uses thereof|
    US8263619B2|2004-03-25|2012-09-11|Memory Pharmaceuticals Corporation|Indazoles, benzothiazoles, benzoisothiazoles, benzisoxazoles, and preparation and uses thereof|US5135935A|1991-05-17|1992-08-04|Merck & Co., Inc.|Squalene synthetase inhibitors|
    GB9218334D0|1992-08-28|1992-10-14|Ici Plc|Heterocyclic compounds|
    GB9226573D0|1992-12-21|1993-02-17|Ici Plc|Heterocyclic compounds|
    IL109451D0|1993-04-29|1994-07-31|Zeneca Ltd|Heterocyclic derivatives|
    US5712270A|1995-11-06|1998-01-27|American Home Products Corporation|2-arylamidothiazole derivatives with CNS activity|GB0010955D0|2000-05-05|2000-06-28|Novartis Ag|Organic compounds|
    JP4225787B2|2001-03-27|2009-02-18|エーザイ・アール・アンド・ディー・マネジメント株式会社|N-aryl cyclic amine derivative and pharmaceutical containing it as an active ingredient|
    EP1256573A1|2001-05-09|2002-11-13|Eisai Co., Ltd.|Process for producing stereoisomer of pyrrolidine derivative|
    US7361668B2|2001-10-17|2008-04-22|Ucb, S.A.|Quinuclidine derivatives processes for preparing them and their uses as m2 and/or m3 muscarinic receptor inhibitors|
    US7361671B2|2001-11-15|2008-04-22|The Institute For Pharmaceutical Discovery, Inc.|Substituted heteroarylalkanoic acids|
    DE10225537A1|2002-06-10|2003-12-18|Bayer Ag|N-alkylated thiazolium salts and process for their preparation|
    GB0218876D0|2002-08-13|2002-09-25|Merck Sharp & Dohme|Therapeutic agents|
    DE10334724A1|2003-07-30|2005-02-24|Bayer Healthcare Ag|N-biaryl|
    BRPI0415179A|2003-10-07|2006-11-28|Renovis Inc|amide derivatives such as ion channel ligands and pharmaceutical compositions and methods of employing them|
    TW201111385A|2009-08-27|2011-04-01|Biocryst Pharm Inc|Heterocyclic compounds as janus kinase inhibitors|
    US8420661B2|2010-04-13|2013-04-16|Hoffmann-La Roche Inc.|Arylethynyl derivatives|
    WO2011150356A1|2010-05-28|2011-12-01|Biocryst Pharmaceuticals, Inc.|Heterocyclic compounds as janus kinase inhibitors|
    PE20142454A1|2011-12-28|2015-02-07|Global Blood Therapeutics Inc|SUBSTITUTE BENZALDEHYDE COMPOUNDS AND METHODS FOR THEIR USE IN INCREASING TISSUE OXYGENATION|
    US9012450B2|2011-12-28|2015-04-21|Global Blood Therapeutics, Inc.|Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation|
    WO2014060381A1|2012-10-18|2014-04-24|Bayer Cropscience Ag|Heterocyclic compounds as pesticides|
    JP2016503395A|2012-10-31|2016-02-04|バイエル・クロップサイエンス・アクチェンゲゼルシャフト|Heterocyclic compounds as pest control agents|
    US9458139B2|2013-03-15|2016-10-04|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    US20140274961A1|2013-03-15|2014-09-18|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    US9802900B2|2013-03-15|2017-10-31|Global Blood Therapeutics, Inc.|Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin|
    US8952171B2|2013-03-15|2015-02-10|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    US9422279B2|2013-03-15|2016-08-23|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    US10450269B1|2013-11-18|2019-10-22|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    US10100043B2|2013-03-15|2018-10-16|Global Blood Therapeutics, Inc.|Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation|
    US9604999B2|2013-03-15|2017-03-28|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    MX2015011448A|2013-03-15|2016-06-06|Global Blood Therapeutics Inc|Compounds and uses thereof for the modulation of hemoglobin.|
    US10266551B2|2013-03-15|2019-04-23|Global Blood Therapeutics, Inc.|Compounds and uses thereof for the modulation of hemoglobin|
    DK3102208T3|2014-02-07|2021-03-08|Global Blood Therapeutics Inc|CRYSTALLINIC POLYMORPH OF THE FREE BASE OF 2-HYDROXY-6 -PYRIDIN-3-YL) METHOXY) BENZALDEHYDE|
    AU2016243428B2|2015-03-30|2020-12-24|Global Blood Therapeutics, Inc.|Aldehyde compounds for treating pulmonary fibrosis, hypoxia, and connective tissue and autoimmune disease|
    WO2017096230A1|2015-12-04|2017-06-08|Global Blood Therapeutics, Inc.|Dosing regimens for 2-hydroxy-6-pyridin-3-yl)methoxy)benzaldehyde|
    TWI663160B|2016-05-12|2019-06-21|全球血液治療公司|Process for synthesizing 2-hydroxy-6--pyridin-3-yl)methoxy)benzaldehyde|
    TW201815384A|2016-10-12|2018-05-01|美商全球血液治療公司|Tablets comprising 2-hydroxy-6-pyridin-3-yl)methoxy)benzaldehyde|
    WO2020061103A1|2018-09-18|2020-03-26|Nikang Therapeutics, Inc.|Fused tricyclic ring derivatives as src homology-2 phosphatase inhibitors|
    WO2020072377A1|2018-10-01|2020-04-09|Global Blood Therapeutics, Inc.|Modulators of hemoglobin for the treatment of sickle cell disease|
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    申请号 | 申请日 | 专利标题
    JP27390599||1999-09-28||
    JP27390599||1999-09-28||
    JP2000179352||2000-06-15||
    JP2000179352||2000-06-15||
    PCT/JP2000/006665|WO2001023383A1|1999-09-28|2000-09-27|Quinuclidine compounds and drugs containing the same as the active ingredient|
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