WO2014051055A1 - Quinuclidine urea derivatives and medicinal use thereof - Google Patents

Quinuclidine urea derivatives and medicinal use thereof Download PDF

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WO2014051055A1
WO2014051055A1 PCT/JP2013/076272 JP2013076272W WO2014051055A1 WO 2014051055 A1 WO2014051055 A1 WO 2014051055A1 JP 2013076272 W JP2013076272 W JP 2013076272W WO 2014051055 A1 WO2014051055 A1 WO 2014051055A1
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和也 大角
将史 山本
拓実 青木
秀二 宇田川
林　賢一
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東レ株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

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  • the present invention relates to a quinuclidine urea derivative and its pharmaceutical use.
  • Nicotinic acetylcholine receptors are widely distributed throughout the central and peripheral tissues and are homo- or heteropentamers composed of combinations of ⁇ , ⁇ , ⁇ , ⁇ and ⁇ subunits, with various subtypes. Is present. Among them, nicotinic acetylcholine receptors expressed in the central nervous system such as brain, medulla and spinal cord are called central nicotinic acetylcholine receptors and exist as subtypes such as ⁇ 7, ⁇ 4 ⁇ 2, ⁇ 4 ⁇ 4, ⁇ 3 ⁇ 2, or ⁇ 3 ⁇ 4. However, ⁇ 4 ⁇ 2 and ⁇ 7 have been found to be major subtypes.
  • the ⁇ 4 ⁇ 2 subtype is a heteropentamer composed of two ⁇ 4 subunits, which are isoforms of ⁇ subunits, and three ⁇ 2 subunits, which are isoforms of ⁇ subunits.
  • the ⁇ 7 subtype is a homo pentamer composed of five ⁇ 7 subunits, and is expressed in the cerebral cortex and hippocampus (Non-patent Document 1).
  • Non-patent Document 1 There have been many reports on compounds that activate central nicotinic acetylcholine receptors (Patent Document 1 and Non-Patent Documents 2 to 6).
  • varenicline (7,8,9,10-tetrahydro-6H-6,10-methanopyrazino [2,3-h] [3] benzazepine) has been reported ( Non-patent document 2) and its tartrate salt is marketed as a smoking cessation aid.
  • Non-patent Document 3 As a compound that activates the ⁇ 4 ⁇ 2 subtype, (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine has been reported (Non-patent Document 3).
  • Non-patent Document 4 Compounds that activate the ⁇ 7 subtype include N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran -2-Carboxamide has been reported (Non-Patent Document 5), and recently, it has been reported in a phase 2 clinical trial that cognitive impairment and negative symptoms in schizophrenia have been improved (Non-Patent Document 6).
  • acetylcholine and nicotine that activate the nicotinic acetylcholine receptor are known as substances that cause pruritus in the skin (Non-patent Documents 7 and 8).
  • Pruritus is a skin-specific sensation, often caused by skin disease as the primary disease, but certain medical diseases (malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, gout, thyroid disease) , Blood disease and iron deficiency), hemodialysis, peritoneal dialysis, pregnancy, parasitic infection and multiple sclerosis occur as the primary disease, drug allergy (drug itch) and mental stress (psychogenic pruritus) ).
  • antihistamines are mainly used as internal preparations, and opioid ⁇ receptor agonists are sometimes used for hemodialysis patients.
  • opioid ⁇ receptor agonists are sometimes used for hemodialysis patients.
  • external preparations antihistamines, corticosteroids, immunosuppressants, or nonsteroidal anti-inflammatory agents are used.
  • compounds having a quinuclidine urea structure include (R) -1- (3,5-dichlorophenyl) -3- (quinuclidin-3-yl) urea (Patent Document 2) and 1- (2- (3 -Cyclopropyl-1,2,4-oxadiazol-5-yl) thiophen-3-yl) -3- (quinuclidin-3-yl) thiourea (Patent Document 3) as a serotonin receptor antagonist, 1,1-dibenzyl-3- (pyridin-2-yl) -3- (quinuclidin-3-yl) urea (Patent Document 4) has been reported as a leukotriene biosynthesis inhibitor.
  • N-phenyl-N′-methyl-N ′-(2- (pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] oct-3-yl) urea having no quinuclidine urea structure
  • Patent Document 5 The 3-substituted-2- (arylalkyl) -1-azabicycloalkane derivative (Patent Document 5) has been reported to activate the central nicotinic acetylcholine receptor ⁇ 7 subtype, but has a medicinal effect on pruritus Is not disclosed or suggested.
  • an object of the present invention is to provide a novel compound having a potent central nicotinic acetylcholine receptor activation action.
  • a further object of the present invention is to provide an antipruritic agent having a new mechanism of action whose effectiveness against pruritus is unknown.
  • the present invention provides a quinuclidine urea derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
  • R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms
  • R 2 represents A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with 1 to 6 halogen atoms, or a hydrogen atom substituted with R 4
  • R 3 represents an aryl group having 6 to 10 carbon atoms in which a hydrogen atom may be substituted with R 5 Or a heteroaryl group having 5 to 10 ring atoms
  • R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom
  • R 1 is an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms.
  • R 2 is a hydrogen atom, an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 4
  • R 3 is a hydrogen atom
  • R 4 is a halogen atom, a hydroxyl group, a nitrile group, or a hydrogen atom
  • the atom is an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an alkyloxy group having 1 to 4 carbon atoms which may be substituted with 1 to 3 halogen atoms
  • R 5 is , Halogen atom, hydro A xyl group, or an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon
  • R 1 is a methyl group or an ethyl group
  • R 2 is a hydrogen atom
  • R 3 is a phenyl group in which the hydrogen atom may be substituted with R 5.
  • the present invention also provides a medicine containing the above quinuclidine urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • the present invention also provides a central nicotinic acetylcholine receptor activator containing the quinuclidine urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • the central nicotinic acetylcholine receptor is preferably an ⁇ 7 subtype.
  • the present invention also provides an antidiarrheal agent containing the above quinuclidine urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof has a strong central nicotinic acetylcholine receptor activation action, and the pathological condition is improved by activating the central nicotinic acetylcholine receptor. Or it can be used as a medicine for a disease for which remission of symptoms is expected.
  • the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent antipruritic effect based on the central nicotinic acetylcholine receptor activation action.
  • the use of the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof as an antipruritic agent enables the treatment and prevention of pruritus showing therapeutic resistance to existing drugs, and patients This can contribute to improving the quality of life and stopping the “scratch scratching cycle”.
  • FIG. 6 shows the effect of the compound of Example 4 on substance P-induced scratching behavior. It is a figure which shows the effect
  • the nicotinic acetylcholine receptor antagonist mecamylamine hydrochloride
  • the quinuclidine urea derivative of the present invention is characterized by being represented by the following general formula (I).
  • R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms
  • R 2 represents A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with 1 to 6 halogen atoms, or a hydrogen atom substituted with R 4
  • R 4 represents an optionally substituted aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms
  • R 3 represents an aryl group having 6 to 10 carbon atoms in which a hydrogen atom may be substituted with R 5 Or a heteroaryl group having 5 to 10 ring atoms, wherein R 4 is a halogen atom
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • alkyl group having 1 to 6 carbon atoms means a linear saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms.
  • linear saturated hydrocarbon group include a methyl group, an ethyl group, a 1-propyl group, and a 1-butyl group.
  • branched saturated hydrocarbon group include an isopropyl group and an isobutyl group. Or a tert-butyl group is mentioned.
  • C3-C6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • C 1-6 alkyloxy group means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom.
  • H 1 is an alkyl group having 1 to 6 carbon atoms optionally substituted with 1 to 6 halogen atoms
  • the C 3-6 cycloalkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms means a carbon atom in which the hydrogen atom may be substituted with 1 to 6 halogen atoms Represents a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a 4,4-difluorocyclohexyl group.
  • the alkyloxy group having 1 to 6 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms means that the hydrogen atom bonded through an ether bond at the end of a single bond is 1 to This means a group in which an alkyl group having 1 to 6 carbon atoms which may be substituted with 6 halogen atoms is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, an isopropyloxy group, 1 -Butyloxy group, 2-butyloxy group, trifluoromethoxy group, 2-trifluoroethoxy group or 2-fluoroethoxy group.
  • aryl group having 6 to 10 carbon atoms examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
  • heteroaryl group having 5 to 10 ring atoms means a ring containing 1 to 4 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom
  • a heterocyclic aromatic group having 5 to 10 member atoms for example, thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group Oxadiazolyl group, tetrazolyl group, pyridyl group, 1-oxypyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, indolyl group, indazolyl group, benzothienyl group, thienopyridyl group, benz
  • Examples of the “aryl group having 6 to 10 carbon atoms in which the hydrogen atom may be substituted with R 4 ” include, for example, phenyl group, naphthyl group, chlorophenyl group, dichlorophenyl group, fluorophenyl group, bromophenyl group, iodophenyl group , Toluyl group, trifluoromethylphenyl group, hydroxyphenyl group, methoxyphenyl group or cyanophenyl group.
  • heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 4 examples include, for example, chlorothienyl group, methylthienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, Oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, 1-oxypyridyl, chloropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, chloropyrazinyl, triazinyl, indolyl Group, indazolyl group, benzothienyl group, chlorobenzothienyl group, fluorobenzothienyl group, hydroxybenzothienyl group, thienopyridyl group, benzofuryl group
  • Examples of the “aryl group having 6 to 10 carbon atoms in which the hydrogen atom may be substituted with R 5 ” include, for example, phenyl group, naphthyl group, chlorophenyl group, dichlorophenyl group, fluorophenyl group, chlorofluorophenyl group, bromophenyl Group, iodophenyl group, toluyl group, trifluoromethylphenyl group, hydroxyphenyl group, methoxyphenyl group, cyanophenyl group or biphenyl group.
  • heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 5 examples include, for example, thienyl group, chlorothienyl group, methylthienyl group, pyrrolyl group, furyl group, thiazolyl group, Imidazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, 1-oxypyridyl, chloropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, chloropyrazinyl, triazinyl Group, indolyl group, indazolyl group, benzothienyl group, chlorobenzothienyl group, fluorobenzothienyl group, hydroxybenzothienyl group, thienopyridy
  • R 1 is an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms, or 3 to 3 carbon atoms. 6 cycloalkyl group is preferable, and methyl group or ethyl group is more preferable.
  • R 2 is a hydrogen atom, or a heteroaryl group of the aryl group or ring constituent atoms of 5 to 10 of the hydrogen atoms
  • R 4 is carbon atoms 6 also be ⁇ 10 substituted with (R 4 is a halogen atom, a hydroxyl Group, nitrile group, or alkyl group having 1 to 4 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, or alkyl having 1 to 4 carbon atoms, in which a hydrogen atom may be substituted with 1 to 3 halogen atoms It is preferably an oxy group, more preferably a hydrogen atom.
  • R 3 is a hydrogen atom is a heteroaryl group the aryl group or ring members 5 to 10 are carbon atoms 6 also be ⁇ 10 substituted by R 5 (R 5 is a halogen atom, a hydroxyl group, or A hydrogen atom optionally substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, or 6 carbon atoms.
  • R 5 is a halogen atom, a hydroxyl group or 1 to 3 hydrogen atoms; Or an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a phenyl group, or a pyridyl group, which may be substituted with a halogen atom of prefer
  • R 4 represents a halogen atom, a hydroxyl group, a nitrile group, or an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, in which a hydrogen atom may be substituted with 1 to 3 halogen atoms.
  • an alkyloxy group having 1 to 4 carbon atoms is preferable.
  • R 5 represents a halogen atom, a hydroxyl group, a C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a carbon number in which a hydrogen atom may be substituted with 1 to 3 halogen atoms.
  • alkyloxy group having 1 to 4 carbon atoms it is preferably an alkyloxy group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heteroaryl group having 5 to 10 ring atoms, and having 1 to 3 halogen atoms, hydroxyl groups, or hydrogen atoms It is more preferably an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a phenyl group or a pyridyl group which may be substituted with a halogen atom.
  • the quinuclidine urea derivative represented by the above general formula (I) may have an optical isomer or a diastereomer. As well as racemic and diastereomeric mixtures.
  • Examples of the “pharmacologically acceptable salt” of the quinuclidine urea derivative (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, and the like.
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof may be an anhydride, or may form a solvate such as a hydrate.
  • the solvate is preferably a pharmacologically acceptable solvate.
  • the pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferable.
  • the solvent constituting the solvate include water, alcohol solvents such as methanol, ethanol and n-propanol, dimethylformamide and dimethyl sulfoxide.
  • the quinuclidine urea derivative (I) can be produced by an appropriate method based on characteristics derived from the basic skeleton and the type of substituent.
  • the starting materials and reagents used for the production of these compounds can generally be purchased or can be produced by known methods.
  • the quinuclidine urea derivative (I) and the intermediates and starting materials used for the production thereof can be isolated and purified by known means.
  • Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
  • each isomer can be obtained as a single compound by a known method.
  • Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.
  • the quinuclidine urea derivative (I) is obtained by reacting a quinuclidine-3-amine derivative (II) and an arylamine derivative (III) with a urea agent in the presence of a base. It can be obtained by reaction.
  • R 1 to R 3 are the same as defined above.
  • the amount of the arylamine derivative (III) used in the urea reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinuclidin-3-amine derivative (II).
  • urea agent used in the urea reaction examples include, for example, triphosgene, phosgene, trichloromethyl chloroformate, phenyl chloroformate, phenyl chloroformate such as p-nitrophenyl chloroformate, N, N′-carbonyldiimidazole, N, N'-disuccinimidyl carbonate may be mentioned, but triphosgene or phenyl chloroformate is preferred.
  • the amount of the urea agent used in the urea reaction is preferably 0.1 to 100 equivalents, and more preferably 0.3 to 30 equivalents, relative to the quinuclidin-3-amine derivative (II).
  • Examples of the base used in the urea reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, methyl Alkyl lithium such as lithium or butyl lithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof may be mentioned, and an organic base such as triethylamine or diisopropylethylamine is preferable.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogen carbonate or potassium carbonate
  • metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride
  • methyl Alkyl lithium such as lithium or butyl lithium
  • lithium amide such as lithium hexamethyldisilazide or lithium diisopropyl
  • the amount of the base used for the urea formation reaction is preferably 1 to 100 equivalents, more preferably 2 to 30 equivalents with respect to the quinuclidin-3-amine derivative (II).
  • the reaction solvent used for the urea reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a non-proton such as dimethylformamide, dimethylacetamide or dimethylsulfoxide.
  • Polar solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or A mixed solvent thereof may be mentioned, but a chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferred.
  • the reaction temperature of the urea reaction is preferably ⁇ 78 to 200 ° C., more preferably ⁇ 20 to 100 ° C.
  • reaction time of the urea reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.
  • the concentration of the quinuclidin-3-amine derivative (II) used for the urea reaction is preferably 1 mmol / L to 1 mol / L.
  • the quinuclidin-3-amine derivative (II) used for the urea reaction can be purchased, but can also be produced by a known method.
  • the quinuclidin-3-amine derivative (IIa) in which the substituent R 1 of the quinuclidin-3-amine derivative (II) represents R 7 is, for example, N-acyl- (quinuclidin-3-yl) as shown in Scheme 2. It can be obtained by a reduction reaction in which a reducing agent is allowed to act on the amine derivative (IV).
  • R 6 represents a hydrogen atom, an alkyloxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 5 carbon atoms in which a hydrogen atom may be substituted with a halogen atom having 1 to 6 carbon atoms
  • 7 represents a substituent represented by the following general formula (V).
  • R 8 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms).
  • Examples of the reducing agent used in the reduction reaction include lithium aluminum hydride, aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, lithium triethylborohydride, borohydride, borohydride / dimethyl sulfide complex, Examples thereof include metal hydride compounds such as boron hydride / tetrahydrofuran complex or 9-borabicyclo [3,3] -nonane (9-BBN), and lithium aluminum hydride is preferred.
  • the amount of the reducing agent used in the reduction reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the N-acyl- (quinuclidin-3-yl) -amine derivative (IV).
  • the reaction solvent used for the reduction reaction is appropriately selected depending on the type of reducing agent used, but is not particularly limited as long as it does not inhibit the reaction.
  • diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4- Ether solvents such as dioxane are preferred.
  • the reaction temperature of the reduction reaction is preferably ⁇ 78 to 200 ° C., more preferably ⁇ 20 to 100 ° C.
  • the reaction time of the reduction reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.
  • the concentration of the N-acyl- (quinuclidin-3-yl) -amine derivative (IV) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.
  • N-acyl- (quinuclidin-3-yl) -amine derivative (IV) used for the reduction reaction can be purchased or can be produced by a known method.
  • N-acyl- (quinuclidin-3-yl) -amine derivative (IV) is an acyl having an acylating agent acting on quinuclidin-3-amine (VI) in the presence of a base as shown in Scheme 3, for example. It can be obtained by a chemical reaction. [Wherein R 6 is the same as defined above. ]
  • acylating agent used in the acylation reaction examples include acid halides such as chloroformate and acid chloride, acid anhydrides, mixed acid anhydride azides, and activated carboxylic acid such as activated esters. Among them, ethyl chloroformate or acetyl chloride is preferable.
  • the amount of the acylating agent used in the acylation reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to quinuclidin-3-amine (VI).
  • Examples of the base used in the acylation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium bicarbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, lithium Examples thereof include lithium amides such as hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, and organic bases such as triethylamine or diisopropylethylamine are preferred.
  • the amount of the base used in the acylation reaction is preferably 1 to 100 equivalents and more preferably 2 to 30 equivalents with respect to quinuclidin-3-amine (VI).
  • the reaction solvent used in the acylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a non-proton such as dimethylformamide, dimethylacetamide, or dimethylsulfoxide.
  • Polar solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or A mixed solvent thereof may be mentioned, but a chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferred.
  • the quinuclidin-3-amine (VI) used for the acylation reaction may be a free form or a salt such as hydrochloride.
  • the reaction temperature of the acylation reaction is preferably ⁇ 78 to 200 ° C., more preferably ⁇ 20 to 100 ° C.
  • reaction time of the acylation reaction is appropriately selected according to conditions such as reaction temperature, but satisfactory results are usually obtained in about 1 to 30 hours.
  • the concentration of quinuclidin-3-amine (VI) used in the acylation reaction is preferably 1 mmol / L to 1 mol / L.
  • the quinuclidine-3-amine derivative (IIb) in which the substituent R 1 of the quinuclidin-3-amine derivative (II) represents R 11 is, for example, quinuclidin-3-amine (VI) and an aldehyde or It can be obtained by a reductive amination reaction with a ketone (VII).
  • R 9 are each independently hydrogen atom or a hydrogen atom an alkyl group containing from 1 to 6 halogen atoms optionally substituted A number even though carbon atoms
  • R 10 are each Independently, it represents a hydrogen atom or an alkyl group containing B carbon atoms optionally substituted with 1 to 6 halogen atoms (provided that the sum of A and B represents an integer of 1 to 5). Or a cycloalkyl group having 3 to 6 carbon atoms in which hydrogen atoms may be substituted with 1 to 6 halogen atoms by combining R 9 and R 10 together to form a ring.
  • R 11 represents a substituent represented by the following general formula (VIII). (Wherein R 9 and R 10 are the same as defined above)]
  • the amount of aldehyde or ketone used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to quinuclidin-3-amine (VI).
  • Examples of the reducing agent used in the reductive amination reaction include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, and sodium triacetoxyborohydride is preferable.
  • the amount of the reducing agent used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to quinuclidin-3-amine (VI).
  • the reaction solvent used for the reductive amination reaction is appropriately selected depending on the type of the reducing agent used, but is not particularly limited as long as it does not inhibit the reaction.
  • an alcohol solvent such as methanol or ethanol
  • examples include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, and 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, and mixed solvents thereof, such as methanol or ethanol.
  • Alcohol solvents are preferred.
  • the reaction temperature of the reductive amination reaction is preferably ⁇ 78 to 200 ° C., more preferably 0 to 100 ° C.
  • reaction time of the reductive amination reaction is appropriately selected according to conditions such as the reaction temperature, but satisfactory results are usually obtained in about 1 to 30 hours.
  • the concentration of quinuclidin-3-amine (VI) used in the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.
  • the arylamine derivative (III) used in the urea reaction shown in Scheme 1 can be purchased or can be produced by methods known to those skilled in the art.
  • the arylamine derivative (IIIa) in which the substituent R 2 of the arylamine derivative (III) represents R 7 is similar to the method shown in Scheme 3 with respect to the arylamine derivative (IX) as shown in Scheme 5, for example.
  • the N-acyl-arylamine derivative (X) thus obtained can be obtained by carrying out a reduction reaction under the same conditions as in the method shown in Scheme 2. [Wherein R 3 , R 6 and R 7 are the same as defined above. ]
  • the arylamine derivative (IIIb) in which the substituent R 2 of the arylamine derivative (III) represents R 11 is similar to the method shown in Scheme 4 with respect to the arylamine derivative (IX) as shown in Scheme 6, for example. It can obtain by performing reductive amination reaction with an aldehyde or ketone (VII) on condition of these. [Wherein R 3 and R 9 to R 11 are the same as defined above]. ]
  • the arylamine derivative (IIIc) in which the substituent R 2 of the arylamine derivative (III) represents R 12 is, for example, as shown in Scheme 7, in the presence of a palladium catalyst and a base, the arylamine derivative (IX), It can be obtained by a coupling reaction with an aryl group or aryl triflate (XI).
  • R 3 has the same definition as above, and R 12 represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R 4.
  • R 4 is the same as defined above
  • X represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group.
  • Examples of the palladium catalyst used in the coupling reaction include zerovalent palladium catalysts such as tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0), or bis (dibenzylideneacetone) palladium (0). .
  • the amount of the palladium catalyst used in the coupling reaction is preferably 0.001 to 10 equivalents, and more preferably 0.01 to 1 equivalents, relative to the arylamine derivative (IX).
  • Examples of the base used in the coupling reaction include an inorganic base such as cesium carbonate, a metal alkoxide such as tert-butyloxy sodium or tert-butyloxy potassium, or a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • an inorganic base such as cesium carbonate
  • a metal alkoxide such as tert-butyloxy sodium or tert-butyloxy potassium
  • a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide.
  • metal alkoxides such as sodium tert-butyloxy or potassium tert-butyloxy are preferred.
  • the amount of the base used for the coupling reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the arylamine derivative (IX).
  • the reaction solvent used for the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a non-proton such as dimethylformamide, dimethylacetamide or dimethylsulfoxide.
  • the reaction temperature for the coupling reaction is preferably 0 to 200 ° C, more preferably 30 to 150 ° C.
  • the reaction time of the coupling reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 48 hours.
  • the concentration of the arylamine derivative (IX) used for the coupling reaction is preferably 1 mmol / L to 1 mol / L.
  • the arylamine derivative (IX) used for the coupling reaction can be purchased or can be produced by a known method.
  • the arylamine derivative (IX) can be obtained, for example, by deprotecting the carbamic acid tert-butyl ester derivative (XII) in the presence of a deprotecting agent as shown in Scheme 8. [Wherein R 3 is the same as defined above. ]
  • Examples of the deprotecting agent used in the deprotecting reaction include acids such as hydrochloric acid, trifluoroacetic acid, and hydrofluoric acid, and hydrochloric acid or trifluoroacetic acid is preferable.
  • the amount of the deprotecting agent used in the deprotecting reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the carbamic acid tert-butyl ester derivative (XII).
  • the reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane.
  • An ether solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, an alcohol solvent such as methanol or ethanol, or a mixed solvent thereof.
  • ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane are preferred.
  • the reaction temperature for the deprotection reaction is preferably ⁇ 78 to 200 ° C., more preferably ⁇ 20 to 100 ° C.
  • the reaction time of the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.
  • the concentration of the carbamic acid tert-butyl ester derivative (XII) used for the deprotection reaction is preferably 1 mmol / L to 1 mol / L.
  • the carbamic acid tert-butyl ester derivative (XII) used for the deprotection reaction can be purchased or can be produced by a known method.
  • the carbamic acid tert-butyl ester derivative (XII) can be obtained, for example, by a Curtius rearrangement reaction of a carboxylic acid (XIII) in the presence of an azidating agent, a nucleophile and a base as shown in Scheme 9. [Wherein R 3 is the same as defined above. ]
  • azidating agent used in the Curtius rearrangement reaction examples include sodium azide and diphenylphosphoryl azide, and diphenylphosphoryl azide is preferred.
  • the amount of the azidating agent used in the Curtius rearrangement reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the carboxylic acid (XIII).
  • nucleophile used in the Curtius rearrangement reaction examples include metal alkoxides such as tert-butyloxy sodium and tert-butyloxy potassium, and tert-butanol, with tert-butanol being preferred.
  • the amount of the nucleophile used in the Curtius rearrangement reaction is preferably 10 to 100 equivalents relative to the carboxylic acid (XIII).
  • Examples of the base used in the Curtius rearrangement reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, lithium Examples thereof include lithium amides such as hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, and organic bases such as triethylamine or diisopropylethylamine are preferred.
  • the amount of the base used in the Curtius rearrangement reaction is preferably 1 to 100 equivalents, more preferably 2 to 30 equivalents, relative to the carboxylic acid (XIII).
  • the reaction solvent used in the Curtius rearrangement reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction.
  • a non-proton such as dimethylformamide, dimethylacetamide or dimethylsulfoxide Polar solvents, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, tert-butanol, or a mixed solvent thereof.
  • Tert-butanol is preferred.
  • the reaction temperature of the Curtius rearrangement reaction is preferably 0 to 200 ° C, more preferably 30 to 150 ° C.
  • the reaction time of the Curtius rearrangement reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 48 hours.
  • the acid azide and isocyanate that are intermediates may be isolated, or the reaction with a nucleophile may be performed without isolating the acid azide and isocyanate that are intermediates.
  • the concentration of carboxylic acid (XIII) used in the Curtius rearrangement reaction is preferably 1 mmol / L to 1 mol / L.
  • the medicament, central nicotinic acetylcholine receptor activator and antipruritic agent of the present invention are characterized by containing the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. .
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is characterized by activating a central nicotinic acetylcholine receptor (preferably an ⁇ 7 subtype of the central nicotinic acetylcholine receptor). It is said.
  • the central nicotinic acetylcholine receptor is involved in various diseases, and it is known that its activation can be expected to improve the pathological condition or ameliorate symptoms
  • the quinuclidine urea derivative (I) or a drug thereof Physiologically acceptable salt is used as a medicament for a disease for which improvement of pathological condition or amelioration of symptoms can be expected by activating central nicotinic acetylcholine receptor (preferably, ⁇ 7 subtype of central nicotinic acetylcholine receptor) be able to.
  • central nicotinic acetylcholine receptor is a nicotinic acetylcholine receptor expressed in the central nervous system such as the brain, medulla and spinal cord.
  • ⁇ 7, ⁇ 4 ⁇ 2, ⁇ 4 ⁇ 4, ⁇ 3 ⁇ 2 or ⁇ 3 ⁇ 4 can be exemplified, and the ⁇ 7 subtype is preferable. .
  • Activating the central nicotinic acetylcholine receptor means that when a ligand binds to the receptor, the channel portion of the receptor opens, and a cation flows from the outside of the cell. It means to promote polarization or transmission of intracellular signals.
  • central nicotinic acetylcholine receptors preferably the ⁇ 7 subtype of central nicotinic acetylcholine receptors
  • central nicotinic acetylcholine receptors preferably the ⁇ 7 subtype of central nicotinic acetylcholine receptors
  • varenicline tartrate N- (1-azabicyclo [2. 2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride and compounds of Reference Examples 23 to 32
  • Reference Examples 33 and 34 the central nicotinic acetylcholine receptor When activated, it exhibits an excellent inhibitory effect against pruritus.
  • a compound that activates the central nicotinic acetylcholine receptor (preferably the ⁇ 7 subtype of the central nicotinic acetylcholine receptor) exerts an excellent inhibitory effect on pruritus.
  • Varenicline tartrate, N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride, and central nicotinic acetylcholine described in Reference Examples 23 to 32 The characteristics of the compound that activates the receptor are shown below.
  • Varenicline (7,8,9,10-tetrahydro-6H-6,10-methanopyrazino [2,3-h] [3] benzazepine) and its derivatives are described in WO 99/35131 and the like. It mainly exhibits ⁇ 4 ⁇ 2 and ⁇ 7 subtype activating effects (Mihalak et al., Molecular Pharmacology, 2006, Vol. 70, p. 801).
  • (R) -2-Chloro-5- (2-azetidinylmethoxy) pyridine and its derivatives are described in International Publication No. 98/25920 and the like and mainly exhibit an ⁇ 4 ⁇ 2 subtype activating action (Donnelly).
  • N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran-2-carboxamide and its derivatives are It is described in Publication No. 09/018505, etc., and mainly exhibits an ⁇ 7 subtype activation action (Hauser et al., Biochemical Pharmacology, 2009, Vol. 78, p. 803).
  • N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide and its derivatives are described in European Publication No. 311724 and the like, and mainly have ⁇ 7 subtype activity. (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219).
  • (R) -7-Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and its derivatives are described in International Publication No. 03/055878 and the like. The type activating effect is shown (International Publication No. 2010/132423).
  • 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester and its derivatives are described in European Publication No. 1231212 and the like, and mainly have an ⁇ 7 subtype activation action. (Biton et al., Neuropsychopharmacology, 2007, vol. 32, p. 1). 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine and its derivatives are described in O'Donnell et al. (Journal of Medicinal Chemistry, 2010, Vol. 53, p.
  • Cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole and its derivatives are described in International Publication No. 05/028477, etc.
  • Activating the ⁇ 7 subtype (Tietje et al., CNS Neuroscience & Therapeutics, 2008, Vol. 14, p. 65).
  • (-)-N- (1-azabicyclo [2,2,2] octa-3 (S) -yl) carbamic acid 1 (S)-(2-fluorophenyl) ethyl ester and its derivatives are described in Jiang et al. Synthetic Communications, 2009, Vol. 39, p.
  • N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide and derivatives thereof are disclosed in International Publication No. WO 02/100787 and the like. It mainly describes ⁇ 7 subtype activation (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219).
  • N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide and its derivatives are described in WO 03 / No. 042210 and the like, mainly exhibiting an ⁇ 7 subtype activation action (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219).
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof has an activating action on a central nicotinic acetylcholine receptor (preferably an ⁇ 7 subtype of the central nicotinic acetylcholine receptor). Therefore, based on the said action mechanism, the inhibitory effect outstanding with respect to the pruritus is exhibited, and it can be used as an antipruritic agent.
  • “Itching” is a skin-specific sensation with a desire to scratch, such as atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis
  • Skin diseases such as sebum deficiency, senile skin pruritus, insect bite, photosensitivity, urticaria, urticaria, shingles, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris
  • Examples include pruritus, malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, blood disease, hemodialysis, peritoneal dialysis or multiple sclerosis, or pruritus caused by drug or psychosis.
  • pruritus is roughly divided into itch mediated by histamine and pruritus not mediated by histamine (refractory pruritus).
  • the antipruritic agent of the present invention is particularly itch free from histamine (refractory pruritus). It is effective against.
  • pruritus without histamine examples include atopic dermatitis, contact dermatitis, sebum deficiency, senile pruritus, urticaria, psoriasis, malignant tumor, liver disease, chronic kidney disease, renal failure In the case of blood diseases, hemodialysis, peritoneal dialysis, multiple sclerosis, etc., there is an itching that is resistant to antihistamines.
  • the antipruritic effect of the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof can be evaluated in an in vivo experimental system using a pruritus model animal, and various typified by histamine, chloroquine and substance P.
  • a pruritus model that uses as an index the scratching behavior of a mouse caused by a causative substance is common. For example, Togashi et al. (European Journal of Pharmacology, 2002, Vol. 435, p. 259) and Andoh et al. (European Journal of Pharmacology, 2002, Vol. 436, p. 436).
  • mice caused by substance P is suppressed by an opioid ⁇ receptor antagonist, it is recognized as a pruritus-related reaction, not a pain-related reaction (Journal of Pharmaceutical Therapies, 1998). Year, 286, pp. 1140-1145).
  • substance P-induced scratching behavior in mice is not suppressed by the immunosuppressive agent tacrolimus (Biological & Pharmaceutical Bulletin, 2008, Vol. 31, p. 752) and the anti-inflammatory agents indomethacin and diclofenac, but leukotriene B4 Scratch behavior is suppressed by steroids that are involved as an initiator and inhibit its production (Journal of Investigative Dermatology, 2001, Vol. 117, pp. 1621-1626).
  • Substance P-induced scratch behavior is exogenous.
  • Substance P and endogenous leukotriene B4 are induced by acute nerve stimulation, and are an itching model that does not mediate immune or inflammatory reactions It is those that can be use.
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is administered to a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human), particularly a human. In this case, it can be used as a useful medicament (in particular, a central nicotinic acetylcholine receptor activator or antipruritic agent).
  • a mammal eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human
  • a useful medicament in particular, a central nicotinic acetylcholine receptor activator or antipruritic agent.
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is used as it is.
  • additives such as excipients, stabilizers, preservatives, buffering agents, solubilizers, emulsifiers, diluents or tonicity agents may be appropriately mixed.
  • said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers as appropriate.
  • examples of the above-mentioned pharmaceutical administration forms include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. Examples include ointments, creams, patches, and the like. Further, it may be a known continuous preparation.
  • the above medicament preferably contains 0.001 to 90% by weight, preferably 0.01 to 70% by weight, of the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. Is more preferable.
  • the dose is appropriately selected according to symptoms, age, body weight, sex, administration method, etc.
  • the amount of active ingredient for adults is 0.001 mg to 5 g per day for injections and 0.01 mg to 10 g for oral preparations. Each can be administered once or in several divided doses.
  • Examples of the pharmacologically acceptable carrier or diluent of the above-mentioned pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, etc. Sorbitol, glycine, etc.) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.).
  • the above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic or preventive effect or reduce the dose.
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is used as an antipruritic agent, for example, it is usually used for the treatment of the following primary diseases that cause pruritus. Drugs.
  • Examples of skin diseases that are the primary diseases of pruritus include atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, senile Skin pruritus, insect bites, photosensitivity, urticaria, urticaria, herpes, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris.
  • examples of other primary diseases include malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, pregnancy, and multiple sclerosis.
  • hemodialysis, peritoneal dialysis or drugs cause pruritus, pregnancy or parasitic infection causes pruritus, or psychogenic pruritus.
  • drugs used for the treatment of atopic dermatitis include, for example, steroid external preparations (betamethasone, beclomethasone, clobetasone or prednisolone, etc.), calcineurin inhibitory (immunosuppressive) external preparations (tacrolimus, etc.), non-steroidal anti-inflammatory external preparations, antihistamines (Diphenhydramine, chlorpheniramine, cetirizine or oxatomide, loratadine, etc.), cyclosporine, oral steroids or humectants (urea, hirudoid, petrolatum, etc.).
  • steroid external preparations betamethasone, beclomethasone, clobetasone or prednisolone, etc.
  • calcineurin inhibitory (immunosuppressive) external preparations tacrolimus, etc.
  • non-steroidal anti-inflammatory external preparations antihistamines (D
  • drugs used for the treatment of multiple sclerosis include, for example, corticosteroids (such as prednisolone or methylprednisolone), immunosuppressants (methotrexate, azathioprine, cyclophosphamide, cyclosporin A, tacrolimus, mizoribine, etc.) Interferon preparation (such as interferon ⁇ or interferon ⁇ ), sphingosine-1-phosphate receptor modulator (FTY-720), copolymer I, immunoglobulin, T cell receptor vaccine, adhesion molecule inhibitor, TNF ⁇ inhibitor, relieve spasticity
  • examples include drugs (tizanidine, eperisone, afroqualone, baclofen, dantrolene, etc.) or analgesics (indomethacin, diclofenac, etc.).
  • the commercially available compound was used.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.).
  • the chemical shift is represented by ⁇ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), quint, respectively.
  • ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology).
  • amine silica gel amine silica gel DM1020 manufactured by Fuji Silysia Chemical Ltd. was used, and YFLC W-prep2XY (Yamazensha) was used for chromatography.
  • the obtained crude product was dissolved in 1,4-dioxane (7.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 7.1 mL, 28 mmol) was added at 0 ° C. After stirring at room temperature for 16 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • 1,4-dioxane 7.0 mL
  • a hydrogen chloride-1,4-dioxane solution 4.0 N, 7.1 mL, 28 mmol
  • Human central nicotinic acetylcholine receptor ⁇ 7 subtype (hereinafter, human ⁇ 7 receptor) agonist test Using cells stably expressing human ⁇ 7 receptor, the human ⁇ 7 receptor agonist activity of quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof was evaluated.
  • PCI-neo-hCHRNA7 in which the coding region of the human ⁇ 7 receptor gene (CHRNA7 gene; NCBI Reference Sequence NM — 000076.3) was cloned into the mammalian cell expression vector pCI-neo (Promega) was introduced into GH4C1 cells.
  • Rat pituitary-derived GH4C1 cells were purchased from ATCC (American Type Culture Collection). A single clone was obtained by limiting dilution from the cells into which the expression vector pCI-neo-hCHRNA7 was introduced, and human ⁇ 7 receptor stably expressing cells ( ⁇ 7 / GH4C1 cells) were prepared.
  • ⁇ 7 / GH4C1 cells are 2.5% fetal bovine serum (invitrogen, # 26140-079), 15% horse serum (Invitrogen, # 16050-122), 100 U / mL penicillin, 100 ⁇ g / mL streptomycin and 100 ⁇ g / mL Geneticin ( The culture was maintained in a 37 ° C., 5% CO 2 incubator using F-10 neutral mixture (Invitrogen, # 11550-043) containing invitrogen, # 10131-027).
  • ⁇ 7 / GH4C1 cells are suspended in the above culture medium (without Geneticin) and seeded at 8 ⁇ 10 4 cells in each well of 96 well black plate (Becton Dickinson, # 356640) at 37 ° C., 5% Cultivated overnight in CO 2 and used for the following evaluation.
  • the fluorescence intensity was measured for 10 minutes at an excitation wavelength of 470-495 nm and the fluorescence wavelength of 515-575 nm, 50 ⁇ L of the test compound was automatically added, and the fluorescence intensity was measured for 5 minutes at the same wavelength.
  • the fluorescence intensity when the test compound was not added was defined as 0% response value, and the fluorescence intensity when nicotine (Sigma, # N3876) (final concentration 10 ⁇ mol / L) showing human ⁇ 7 receptor agonist activity was added instead of the test compound.
  • the maximum response rate (%) of each test compound was determined as a 100% response value.
  • each test compound (representing 50% response to the maximum response rate) by non-linear regression using the response rate (%) at each concentration converted to 100% as the maximum response rate (%) of each test compound Concentration).
  • PNU-120596 each test compound and nicotine were dissolved in dimethyl sulfoxide and then diluted with an assay buffer. The final concentration of dimethyl sulfoxide in the reaction system was 0.2% or less.
  • the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof has a strong human ⁇ 7 receptor activating action.
  • Example 37 The inhibitory effect on the substance P-induced scratching behavior of a compound that activates a central nicotinic acetylcholine receptor: Substance P-induced scratching behavior of mice, which is an intractable pruritus model, was induced based on a method described in a known literature (Togashi et al., European Journal of Pharmacology, 2002, Vol. 435, p. 259, etc.). In addition, the evaluation of the scratching behavior is automatically detected using MicroAct (Neuroscience) based on a method described in a publicly known document (Hashimoto et al., Allergy International, 2004, Vol. 53, p.349). I went there.
  • mice a neodymium magnet coated with parafilm on the back of both hindlimbs of male ICR mice (Japan SLC, Inc.) aged 5 to 7 weeks under isoflurane anesthesia at least 5 days before drug efficacy evaluation ( 1 mm in diameter and 3 mm in length) was inserted.
  • drug efficacy evaluation 1 mm in diameter and 3 mm in length
  • the back of the neck of the mouse was shaved with a clipper under isoflurane anesthesia.
  • mice 6 to 8 weeks old were housed one by one in the measurement chamber (diameter 11 cm, height 18 cm) and acclimated.
  • substance P (5 mmol / L) or its buffer phosphate buffered saline (hereinafter PBS) was intradermally administered to the back of the neck (0.05 mL / site), and the number of scratching behaviors was measured immediately after. Started. The number of scratching behaviors was recorded by amplifying the current induced by the movement of the magnet inserted into the hind limb in a round coil around the measurement chamber. The measurement was performed in an unattended environment, and the efficacy evaluation was performed using the number of scratching behaviors for 15 minutes after the start of the measurement as an index.
  • PBS buffer phosphate buffered saline
  • test compound or its solvent was orally administered in a volume of 10 mL / kg.
  • the compound of Example 2 or Example 4 which is a test compound was used by dissolving in distilled water.
  • a group (test compound: 0 mg / kg, substance P: 0 nmol / site) administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) is the “induction control group”, substance P and the group administered with the test compound (test compound: 1, 3 or 10 mg / kg, substance P: 250 nmol / site) are “the compound administration of Example 2” Group "or" Compound administration group of Example 4 ".
  • FIG. 1 shows the effect of the compound of Example 2 on the number of scratching actions.
  • the horizontal axis represents the non-induced control group, the induced control group, and the compound administration group of Example 2 (1, 3 or 10 mg / kg).
  • # indicates statistically significant comparison with the induction control group (#p ⁇ 0.05, Aspin-Welch t-test), and * indicates comparison with the induction control group. Indicates statistical significance (* p ⁇ 0.025, Williams test (one side)).
  • FIG. 2 shows the effect of the compound of Example 4 on the number of scratching actions.
  • the horizontal axis represents the non-induced control group, the induced control group, and the compound administration group (1, 3 or 10 mg / kg) of Example 4.
  • the symbol “#” in the figure indicates statistical significance in comparison with the induction control group (#p ⁇ 0.05, Student's t test), and the symbol “*” indicates statistical comparison with the induction control group. It is shown to be clinically significant (* p ⁇ 0.025, Shirley-Williams test (one side)).
  • Substance P-induced scratching behavior was significantly suppressed by administration of the compound of Example 2 (3 or 10 mg / kg) or the compound of Example 4 (10 mg / kg). Therefore, it is clear that the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof significantly suppresses substance P-induced scratching behavior known as an intractable pruritus model and has an excellent antipruritic effect. It is.
  • the obtained colorless liquid was dissolved in dichloromethane (2.0 mL), and this was dissolved in o- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (0. 60 g, 1.6 mmol), triethylamine (0.73 mL, 1.6 mmol) and benzofuran-2-carboxylic acid (0.17 g, 1.1 mmol) in dichloromethane (2.0 mL) were added and stirred at room temperature. After 16 hours, distilled water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated.
  • o- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (0. 60 g, 1.6 mmol
  • triethylamine (0.73
  • Reference Example 26 Synthesis of 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester hydrochloride (hereinafter referred to as the compound of Reference Example 26): [First step] Synthesis of 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester: Diisopropylethylamine (0.40 mL, 2.4 mmol) was added to a dichloromethane solution (12 mL) of 1,4-diazabicyclo [3.2.2] nonane dihydrochloride (230 mg, 1.2 mmol), and the mixture was stirred at room temperature for 1 hour. .
  • Reference Example 31 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxyamide dihydrochloride (hereinafter referred to as Reference Example 31) Synthesis of compound: [First step] Synthesis of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide: O- (Benzotriazol-1-yl) -N, N, N ′, N in chloroform solution (10 mL) of furo [2,3-c] pyridine-5-carboxylic acid (0.16 g, 1.0 mmol) '-Tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol), diisopropylethylamine (0.70 mL, 4.0 mmol), (R) -quinuclidin-3-amine hydrochloride (0
  • Reference Example 32 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide hydrochloride (hereinafter referred to as “Reference Example 32”) Synthesis of the compound of Reference Example 32: [First step] Synthesis of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide: O- (Benzotriazol-1-yl) -N, N was added to a chloroform solution (10 mL) of 2,3-dihydro [b] [1,4] dioxin-6-carboxylic acid (0.18 g, 1.0 mmol).
  • N ′, N′-tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol)
  • diisopropylethylamine (0.70 mL, 4.0 mmol
  • (R) -quinuclidin-3-amine hydrochloride (0 .20 g, 1.0 mmol) was added and stirred at room temperature. After 16 hours, distilled water was added, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated.
  • Reference Example 33 Compound that activates central nicotinic acetylcholine receptor (Varenicline tartrate, N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride
  • Inhibitory effects of substance and compounds of Reference Examples 23 to 32 on substance P-induced scratching behavior Induction of substance P-induced scratching behavior and measurement of the number of times were performed in the same manner as in Example 37.
  • test compound or its solvent was administered at a volume of 10 mL / kg 30 to 60 minutes before the start of measurement of the number of scratching actions.
  • Varenicline tartrate (Tocris Bioscience) was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 60 minutes before the start of the measurement of the number of scratching behaviors.
  • N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride (PNU-282987) hydrate (Sigma-Aldrich) was dissolved in PBS, It was administered intraperitoneally at a dose of 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 23 was dissolved in PBS and administered intraperitoneally at a dose of 0.1 or 0.3 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 24 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 25 was dissolved in distilled water and orally administered at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of the measurement of the number of scratching behaviors.
  • the compound of Reference Example 26 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 27 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 28 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 29 was dissolved in PBS and administered intraperitoneally at a dose of 0.3, 1 or 3 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 30 was suspended in 0.5% methylcellulose and orally administered at a dose of 10 or 30 mg / kg 60 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 31 was dissolved in PBS and administered intraperitoneally at a dose of 0.1, 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
  • the compound of Reference Example 32 was dissolved in PBS and administered intraperitoneally at a dose of 0.1, 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
  • test compound administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) was designated as “induction control group”, and a group administered with substance P and test compound was designated as “test compound administration group”.
  • A, B, and C represent the average values of the number of scratching behaviors of the test compound administration group, the induced control group, and the non-induced control group, respectively.
  • Dunnett's test was performed as a test of the test compound administration group with respect to the induction control group. The significance level was 5% (both sides).
  • Tables 2 and 3 show the effect of each test compound on the number of scratching actions. * Mark in a table
  • Varenicline tartrate (0.3 mg / mL, Tocris Bioscience), mecamylamine hydrochloride (0.3 mg / mL, Tocris Bioscience), a mixed solution of varenicline tartrate and mecamylamine hydrochloride (both 0.3 mg / mL) or these PBS as a solvent was administered intraperitoneally at a volume of 10 mL / kg 60 minutes before the start of measurement of the number of scratching behaviors.
  • the horizontal axis represents the non-induced control group (test compound: 0 mg / kg, substance P: 0 nmol / site), the induced control group (test compound: 0 mg / kg, substance P: 250 nmol / site), the varenicline tartrate-administered group (valenicline).
  • this substance P-induced scratching behavior is considered to be an itching model that is induced by exogenous substance P and endogenous leukotriene B4 acutely stimulating nerves and does not mediate immune reaction or inflammatory reaction.
  • the scratching behavior is suppressed. This suggests that the activation of the gene directly suppressed the conduction and / or transmission of impulses by pruritus stimulation.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
  • the above parent product was dissolved in dimethylformamide (4.5 mL), and triethylamine (0.22 mL, 1.6 mmol) and diphenylphosphoryl azide (0.32 mL, 1.5 mmol) were added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof has a strong central nicotinic acetylcholine receptor activation action, the pathological condition is improved by activating the central nicotinic acetylcholine receptor.
  • it can be used as a medicine for a disease for which symptom remission is expected, and further, it exhibits an antipruritic effect based on the mechanism of action, so that it can be used as an antidiarrheal agent.

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Abstract

The purpose of the invention is to provide a novel compound having a powerful central nervous system nicotinic acetylcholine receptor activating action, and to provide an antipruritic having a novel mechanism of action not known to be effective against pruritus. The invention provides specific quinuclidine urea derivatives and pharmaceutically acceptable salts thereof.

Description

キヌクリジンウレア誘導体及びその医薬用途Quinuclidine urea derivative and its pharmaceutical use
　本発明は、キヌクリジンウレア誘導体及びその医薬用途に関する。 The present invention relates to a quinuclidine urea derivative and its pharmaceutical use.
　ニコチン性アセチルコリン受容体は、中枢及び末梢組織全体に広く分布しており、α、β、γ、δ及びεサブユニットの組み合わせで構成されるホモ又はヘテロの５量体であり、様々なサブタイプが存在している。中でも、脳、延髄及び脊髄等の中枢神経系に発現しているニコチン性アセチルコリン受容体は、中枢型ニコチン性アセチルコリン受容体と呼ばれ、α７、α４β２、α４β４、α３β２又はα３β４等のサブタイプとして存在し、α４β２及びα７が主要なサブタイプであることが明らかになっている。例えば、α４β２サブタイプは、αサブユニットのアイソフォームであるα４サブユニット２つと、βサブユニットのアイソフォームであるβ２サブユニット３つとから構成されるヘテロの５量体で、大脳皮質、視床及び海馬に発現し、α７サブタイプは、α７サブユニット５つから構成されるホモの５量体で、大脳皮質及び海馬に発現している（非特許文献１）。 Nicotinic acetylcholine receptors are widely distributed throughout the central and peripheral tissues and are homo- or heteropentamers composed of combinations of α, β, γ, δ and ε subunits, with various subtypes. Is present. Among them, nicotinic acetylcholine receptors expressed in the central nervous system such as brain, medulla and spinal cord are called central nicotinic acetylcholine receptors and exist as subtypes such as α7, α4β2, α4β4, α3β2, or α3β4. However, α4β2 and α7 have been found to be major subtypes. For example, the α4β2 subtype is a heteropentamer composed of two α4 subunits, which are isoforms of α subunits, and three β2 subunits, which are isoforms of β subunits. Expressed in the hippocampus, the α7 subtype is a homo pentamer composed of five α7 subunits, and is expressed in the cerebral cortex and hippocampus (Non-patent Document 1).
　中枢型ニコチン性アセチルコリン受容体を活性化する化合物については、これまでに多数の報告がある（特許文献１及び非特許文献２～６）。α４β２及びα７サブタイプを活性化する化合物としては、バレニクリン（７，８，９，１０－テトラヒドロ－６Ｈ－６，１０－メタノピラジノ［２，３－ｈ］［３］ベンズアゼピン）が報告されており（非特許文献２）、その酒石酸塩は禁煙補助薬として市販されている。α４β２サブタイプを活性化する化合物としては、（Ｒ）－２－クロロ－５－（２－アゼチジニルメトキシ）ピリジンが報告されており（非特許文献３）、最近では、糖尿病患者の神経障害性疼痛に対して鎮痛作用を発揮することが報告されている（非特許文献４）。α７サブタイプを活性化する化合物としては、Ｎ－（２（Ｓ）－（ピリジン－３－イルメチル）－１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－１－ベンゾフラン－２－カルボキシアミドが報告され（非特許文献５）、最近では、第２相臨床試験において統合失調症における認知障害及び陰性症状を改善したことが報告されている（非特許文献６）。このように、中枢型ニコチン性アセチルコリン受容体は様々な疾患に関与し、また、その活性化によって病態の改善又は症状の寛解が期待できることが知られている。なお、ニコチン性アセチルコリン受容体を活性化するアセチルコリン及びニコチンは、皮膚における掻痒を惹起する物質として知られている（非特許文献７及び８）。 There have been many reports on compounds that activate central nicotinic acetylcholine receptors (Patent Document 1 and Non-Patent Documents 2 to 6). As a compound that activates α4β2 and α7 subtypes, varenicline (7,8,9,10-tetrahydro-6H-6,10-methanopyrazino [2,3-h] [3] benzazepine) has been reported ( Non-patent document 2) and its tartrate salt is marketed as a smoking cessation aid. As a compound that activates the α4β2 subtype, (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine has been reported (Non-patent Document 3). Recently, neuropathy in diabetic patients has been reported. It has been reported that it exerts an analgesic action against sexual pain (Non-patent Document 4). Compounds that activate the α7 subtype include N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran -2-Carboxamide has been reported (Non-Patent Document 5), and recently, it has been reported in a phase 2 clinical trial that cognitive impairment and negative symptoms in schizophrenia have been improved (Non-Patent Document 6). Thus, it is known that the central nicotinic acetylcholine receptor is involved in various diseases, and its activation can be expected to improve the pathological condition or relieve symptoms. In addition, acetylcholine and nicotine that activate the nicotinic acetylcholine receptor are known as substances that cause pruritus in the skin (Non-patent Documents 7 and 8).
　掻痒は、皮膚特有の感覚であり、皮膚疾患が原疾患となって起こることが多いが、ある種の内科系疾患（悪性腫瘍、糖尿病、肝疾患、慢性腎疾患、腎不全、痛風、甲状腺疾患、血液疾患及び鉄欠乏）や血液透析、腹膜透析、妊娠、寄生虫感染及び多発性硬化症が原疾患となって起こる場合や、薬剤アレルギー（薬剤性掻痒）や心的ストレス（心因性掻痒）が原因となって起こる場合もある。 Pruritus is a skin-specific sensation, often caused by skin disease as the primary disease, but certain medical diseases (malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, gout, thyroid disease) , Blood disease and iron deficiency), hemodialysis, peritoneal dialysis, pregnancy, parasitic infection and multiple sclerosis occur as the primary disease, drug allergy (drug itch) and mental stress (psychogenic pruritus) ).
　掻痒の発現メカニズムは未だ十分には解明されていないが、生体内では、ヒスタミン、サブスタンスＰ、ブラジキニン、プロテイナーゼ、プロスタグランジン又はオピオイドペプチド等の内因性刺激物質が、表皮－真皮境界部に存在する多刺激対応性の神経終末（痒み受容器）に作用し、生じたインパルスが脊髄視床路、視床、大脳皮質の順に伝達されることにより、掻痒としての知覚が生じると考えられている（非特許文献９）。また、掻痒は、弱い痛みであると考えられていたこともあるが、現在では、掻痒と疼痛は異なる神経経路を介して伝達され、異なる機序で発生する感覚であることが明らかになってきている（非特許文献１０及び１１）。 The mechanism of pruritus has not been fully elucidated, but endogenous stimulators such as histamine, substance P, bradykinin, proteinase, prostaglandin or opioid peptide are present in the epidermis-dermis boundary in vivo. It acts on multi-stimulus compatible nerve endings (itch receptor), and the resulting impulses are transmitted in the order of spinal cord thalamic tract, thalamus, and cerebral cortex, which is thought to cause perception as pruritus (non-patented) Reference 9). Itching has also been thought to be a weak pain, but now it is becoming clear that pruritus and pain are transmitted through different neural pathways and occur in different mechanisms. (Non-Patent Documents 10 and 11).
　掻痒の治療には、内服剤としては主に抗ヒスタミン剤が用いられ、血液透析患者に対してはオピオイドκ受容体作動薬が用いられることもある。また、外用剤としては、抗ヒスタミン剤、副腎皮質ステロイド剤、免疫抑制剤又は非ステロイド系抗炎症剤が用いられている。 In the treatment of pruritus, antihistamines are mainly used as internal preparations, and opioid κ receptor agonists are sometimes used for hemodialysis patients. As external preparations, antihistamines, corticosteroids, immunosuppressants, or nonsteroidal anti-inflammatory agents are used.
　一方、キヌクリジンウレア構造を有する化合物としては、（Ｒ）－１－（３，５－ジクロロフェニル）－３－（キヌクリジン－３－イル）ウレア（特許文献２）及び１－（２－（３－シクロプロピル－１，２，４－オキサジアゾール－５－イル）チオフェン－３－イル）－３－（キヌクリジン－３－イル）チオウレア（特許文献３）がセロトニン受容体拮抗剤として、また、１，１－ジベンジル－３－（ピリジン－２－イル）－３－（キヌクリジン－３－イル）ウレア（特許文献４）がロイコトリエン生合成阻害剤として報告されているが、これらの化合物が中枢型ニコチン性アセチルコリン受容体を活性化することや、掻痒に対して薬効を示すことについては一切報告されていない。キヌクリジンウレア構造を有しないＮ－フェニル－Ｎ’－メチル－Ｎ’－（２－（ピリジン－３－イルメチル）－１－アザビシクロ［２．２．２］オクタ－３－イル）ウレア等の３－置換－２－（アリールアルキル）－１－アザビシクロアルカン誘導体（特許文献５）については、中枢型ニコチン性アセチルコリン受容体α７サブタイプを活性化することが報告されているが、掻痒に対する薬効については開示も示唆もされていない。 On the other hand, compounds having a quinuclidine urea structure include (R) -1- (3,5-dichlorophenyl) -3- (quinuclidin-3-yl) urea (Patent Document 2) and 1- (2- (3 -Cyclopropyl-1,2,4-oxadiazol-5-yl) thiophen-3-yl) -3- (quinuclidin-3-yl) thiourea (Patent Document 3) as a serotonin receptor antagonist, 1,1-dibenzyl-3- (pyridin-2-yl) -3- (quinuclidin-3-yl) urea (Patent Document 4) has been reported as a leukotriene biosynthesis inhibitor. There has been no report of activating nicotinic acetylcholine receptors or showing medicinal effects against pruritus. N-phenyl-N′-methyl-N ′-(2- (pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] oct-3-yl) urea having no quinuclidine urea structure The 3-substituted-2- (arylalkyl) -1-azabicycloalkane derivative (Patent Document 5) has been reported to activate the central nicotinic acetylcholine receptor α7 subtype, but has a medicinal effect on pruritus Is not disclosed or suggested.
国際公開第２０１０／１３２４２３号International Publication No. 2010/132423 特開平１－２０３３６５号公報JP-A-1-203365 特開平５－５０４３５８号公報JP-A-5-504358 国際公開第１９９７／０２４３２８号International Publication No. 1997/024328 特表２００６－５１８７４６号Special table 2006-518746
　しかしながら、中枢型ニコチン性アセチルコリン受容体の活性化によって病態の改善又は症状の寛解が期待される疾患について、臨床現場では未だに有効な治療法が不足しているのが現状であり、中枢型ニコチン性アセチルコリン受容体を活性化する新規化合物の開発が切望されている。 However, there is still a lack of effective treatments in the clinical setting for diseases for which improvement of disease state or amelioration of symptoms is expected by activation of central nicotinic acetylcholine receptor. The development of new compounds that activate the acetylcholine receptor is eagerly desired.
　また、掻痒においては、抗ヒスタミン剤等の既存の薬剤では、十分な薬効が認められない病態が臨床的に多数存在するのが現状であり、新たな作用メカニズムを有する止痒剤の開発が切望されている。 In pruritus, there are many clinical conditions in which existing drugs such as antihistamines are not effective enough, and the development of antipruritic drugs with new mechanisms of action is eagerly desired. Yes.
　そこで本発明は、強力な中枢型ニコチン性アセチルコリン受容体活性化作用を有する新規化合物を提供することを目的とする。さらに本発明は、掻痒に対する有効性が知られていない新たな作用メカニズムを有する止痒剤を提供することを目的とする。 Therefore, an object of the present invention is to provide a novel compound having a potent central nicotinic acetylcholine receptor activation action. A further object of the present invention is to provide an antipruritic agent having a new mechanism of action whose effectiveness against pruritus is unknown.
　本発明者らは、上記課題を解決するために鋭意研究を行った結果、中枢型ニコチン性アセチルコリン受容体を強力に活性化する新規なキヌクリジンウレア誘導体を見出すとともに、中枢型ニコチン性アセチルコリン受容体を活性化することが掻痒に対して有効であることを新たに発見し、新規なキヌクリジンウレア誘導体が当該作用メカニズムに基づき止痒効果を発揮することを実験的に明らかにして、本発明を完成するに至った。 As a result of diligent research to solve the above-mentioned problems, the present inventors have found a novel quinuclidine urea derivative that strongly activates a central nicotinic acetylcholine receptor, as well as a central nicotinic acetylcholine receptor. We newly discovered that activating the body is effective against pruritus, and experimentally clarified that a novel quinuclidine urea derivative exerts an antipruritic effect based on the mechanism of action. The invention has been completed.
　すなわち、本発明は、以下の一般式（Ｉ）で示されるキヌクリジンウレア誘導体又はその薬理学的に許容される塩を提供する。
Figure JPOXMLDOC01-appb-C000002
 ［式中、Ｒ１は、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基又は炭素数３～６のシクロアルキル基を表し、Ｒ２は、水素原子、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基若しくは炭素数３～６のシクロアルキル基、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基を表し、Ｒ３は、水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基を表し、Ｒ４は、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～６のアルキルオキシ基を表し、Ｒ５は、ハロゲン原子、ヒドロキシル基、ニトリル基、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～６のアルキルオキシ基、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基を表す。］ That is, the present invention provides a quinuclidine urea derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000002
 [Wherein R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms, and R 2 represents A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with 1 to 6 halogen atoms, or a hydrogen atom substituted with R 4 Represents an optionally substituted aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms, and R 3 represents an aryl group having 6 to 10 carbon atoms in which a hydrogen atom may be substituted with R 5 Or a heteroaryl group having 5 to 10 ring atoms, wherein R 4 is a halogen atom, a hydroxyl group, a nitrile group, or a hydrogen atom in which 1 to 6 halogen atoms may be substituted with 1 carbon atom 6 to 6 alkyl groups, 3 to 6 carbon atoms Cycloalkyl group or an alkyloxy group having 1 to 6 carbon atoms, R 5 is a halogen atom, a hydroxyl group, a nitrile group, a hydrogen atom is 1 to 6 carbon atoms, which may be substituted by a halogen atom 1 An alkyl group having 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms in which a hydrogen atom may be substituted with R 4 or a ring structure Represents a heteroaryl group having 5 to 10 atoms. ]
　上記のキヌクリジンウレア誘導体は、Ｒ１が、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基又は炭素数３～６のシクロアルキル基であり、Ｒ２が、水素原子、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基であり、Ｒ３が、水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基であり、Ｒ４が、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～４のアルキルオキシ基であり、Ｒ５が、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基であることが好ましい。 In the quinuclidine urea derivative, R 1 is an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms. , R 2 is a hydrogen atom, an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 4 , and R 3 is a hydrogen atom An aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which the atom may be substituted with R 5 , and R 4 is a halogen atom, a hydroxyl group, a nitrile group, or a hydrogen atom The atom is an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or an alkyloxy group having 1 to 4 carbon atoms which may be substituted with 1 to 3 halogen atoms, and R 5 is , Halogen atom, hydro A xyl group, or an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms In addition, an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms is preferable.
　この場合、より強い中枢型ニコチン性アセチルコリン受容体の活性化作用が発揮される。 In this case, a stronger central nicotinic acetylcholine receptor activation effect is exhibited.
　また、上記のキヌクリジンウレア誘導体は、Ｒ１が、メチル基又はエチル基であり、Ｒ２が、水素原子であり、Ｒ３が、水素原子がＲ５で置換されていてもよいフェニル基、ナフチル基、ピリジル基、キノリル基、イソキノリル基、フリル基、チエニル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、ピラゾリル基、イミダゾリル基、トリアゾリル基、ベンゾフリル基、フロピリジル基、ベンゾチエニル基、チエノピリジル基、ベンゾオキサゾリル基、オキサゾロピリジル基、ベンゾチアゾリル基又はチアゾロピリジル基であり、Ｒ５が、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、フェニル基若しくはピリジル基であることがより好ましい。 In the quinuclidine urea derivative, R 1 is a methyl group or an ethyl group, R 2 is a hydrogen atom, R 3 is a phenyl group in which the hydrogen atom may be substituted with R 5. , Naphthyl group, pyridyl group, quinolyl group, isoquinolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, benzofuryl group, furopyridyl group, benzothienyl group, A thienopyridyl group, a benzoxazolyl group, an oxazolopyridyl group, a benzothiazolyl group or a thiazolopyridyl group, wherein R 5 is substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, or a hydrogen atom An alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, carbon Alkyloxy group having 1 to 4, and more preferably a phenyl group or a pyridyl group.
　この場合、さらに強い中枢型ニコチン性アセチルコリン受容体の活性化作用が発揮される。 In this case, an even stronger central nicotinic acetylcholine receptor activation effect is exhibited.
　また本発明は、上記のキヌクリジンウレア誘導体又はその薬理学的に許容される塩を有効成分として含有する、医薬を提供する。 The present invention also provides a medicine containing the above quinuclidine urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
　また本発明は、上記のキヌクリジンウレア誘導体又はその薬理学的に許容される塩を有効成分として含有する、中枢型ニコチン性アセチルコリン受容体活性化剤を提供する。上記の中枢型ニコチン性アセチルコリン受容体は、α７サブタイプであることが好ましい。 The present invention also provides a central nicotinic acetylcholine receptor activator containing the quinuclidine urea derivative or a pharmacologically acceptable salt thereof as an active ingredient. The central nicotinic acetylcholine receptor is preferably an α7 subtype.
　また本発明は、上記のキヌクリジンウレア誘導体又はその薬理学的に許容される塩を有効成分として含有する、止痒剤を提供する。 The present invention also provides an antidiarrheal agent containing the above quinuclidine urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
　本発明のキヌクリジンウレア誘導体又はその薬理学的に許容される塩は、強力な中枢型ニコチン性アセチルコリン受容体活性化作用を有し、中枢型ニコチン性アセチルコリン受容体の活性化によって病態の改善又は症状の寛解が期待される疾患に対する医薬として用いることができる。また、本発明のキヌクリジンウレア誘導体又はその薬理学的に許容される塩は、中枢型ニコチン性アセチルコリン受容体活性化作用に基づき優れた止痒効果を発揮する。さらに、本発明のキヌクリジンウレア誘導体又はその薬理学的に許容される塩の止痒剤としての使用は、既存の薬剤に対して治療抵抗性を示す掻痒に対する治療及び予防を可能とし、患者のＱＯＬの改善と“痒み引っ掻きサイクル”の停止に貢献できる。 The quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof has a strong central nicotinic acetylcholine receptor activation action, and the pathological condition is improved by activating the central nicotinic acetylcholine receptor. Or it can be used as a medicine for a disease for which remission of symptoms is expected. In addition, the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof exhibits an excellent antipruritic effect based on the central nicotinic acetylcholine receptor activation action. Furthermore, the use of the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof as an antipruritic agent enables the treatment and prevention of pruritus showing therapeutic resistance to existing drugs, and patients This can contribute to improving the quality of life and stopping the “scratch scratching cycle”.
サブスタンスＰ誘発引っ掻き行動に対する実施例２の化合物の効果を示す図である。It is a figure which shows the effect of the compound of Example 2 with respect to a substance P induction | scratch scratching behavior. サブスタンスＰ誘発引っ掻き行動に対する実施例４の化合物の効果を示す図である。FIG. 6 shows the effect of the compound of Example 4 on substance P-induced scratching behavior. バレニクリン酒石酸塩のサブスタンスＰ誘発引っ掻き行動抑制効果に対するニコチン性アセチルコリン受容体拮抗薬（メカミラミン塩酸塩）の作用を示す図である。It is a figure which shows the effect | action of the nicotinic acetylcholine receptor antagonist (mecamylamine hydrochloride) with respect to the substance P-induced scratching behavior inhibitory effect of varenicline tartrate.
　本発明のキヌクリジンウレア誘導体は、以下の一般式（Ｉ）で示されることを特徴としている。
Figure JPOXMLDOC01-appb-C000003
 ［式中、Ｒ１は、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基又は炭素数３～６のシクロアルキル基を表し、Ｒ２は、水素原子、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基若しくは炭素数３～６のシクロアルキル基、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基を表し、Ｒ３は、水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基を表し、Ｒ４は、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～６のアルキルオキシ基を表し、Ｒ５は、ハロゲン原子、ヒドロキシル基、ニトリル基、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～６のアルキルオキシ基、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基を表す。］ The quinuclidine urea derivative of the present invention is characterized by being represented by the following general formula (I).
Figure JPOXMLDOC01-appb-C000003
 [Wherein R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms, and R 2 represents A hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, which may be substituted with 1 to 6 halogen atoms, or a hydrogen atom substituted with R 4 Represents an optionally substituted aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms, and R 3 represents an aryl group having 6 to 10 carbon atoms in which a hydrogen atom may be substituted with R 5 Or a heteroaryl group having 5 to 10 ring atoms, wherein R 4 is a halogen atom, a hydroxyl group, a nitrile group, or a hydrogen atom in which 1 to 6 halogen atoms may be substituted with 1 carbon atom 6 to 6 alkyl groups, 3 to 6 carbon atoms Cycloalkyl group or an alkyloxy group having 1 to 6 carbon atoms, R 5 is a halogen atom, a hydroxyl group, a nitrile group, a hydrogen atom is 1 to 6 carbon atoms, which may be substituted by a halogen atom 1 An alkyl group having 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms in which a hydrogen atom may be substituted with R 4 or a ring structure Represents a heteroaryl group having 5 to 10 atoms. ]
　本明細書で使用する次の用語は、特に断りがない限り、下記の定義のとおりである。 The following terms used in this specification are as defined below unless otherwise specified.
　「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を意味する。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　「炭素数１～６のアルキル基」とは、炭素原子を１～６個有する直鎖状の飽和炭化水素基又は炭素原子を３～６個有する分岐鎖状の飽和炭化水素基を意味する。直鎖状の飽和炭化水素基としては、例えば、メチル基、エチル基、１－プロピル基又は１－ブチル基が挙げられ、分岐鎖状の飽和炭化水素基としては、例えば、イソプロピル基、イソブチル基又はｔｅｒｔ－ブチル基が挙げられる。 The “alkyl group having 1 to 6 carbon atoms” means a linear saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms. Examples of the linear saturated hydrocarbon group include a methyl group, an ethyl group, a 1-propyl group, and a 1-butyl group. Examples of the branched saturated hydrocarbon group include an isopropyl group and an isobutyl group. Or a tert-butyl group is mentioned.
　「炭素数３～６のシクロアルキル基」とは、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基を意味する。 “C3-C6 cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
　「炭素数１～６のアルキルオキシ基」とは、上記の炭素数１～６のアルキル基が酸素原子に結合した基を意味し、例えば、メトキシ基、エトキシ基、１－プロピルオキシ基、１－ブチルオキシ基、イソプロピルオキシ基、イソブチルオキシ基又はｔｅｒｔ－ブチルオキシ基が挙げられる。 The “C 1-6 alkyloxy group” means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom. For example, a methoxy group, ethoxy group, 1-propyloxy group, 1 -Butyloxy group, isopropyloxy group, isobutyloxy group or tert-butyloxy group.
　「水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基」とは、水素原子が１～６個のハロゲン原子で置換されていてもよい、炭素原子を１～６個有する直鎖状の飽和炭化水素基又は炭素原子を３～６個有する分岐鎖状の飽和炭化水素基を意味し、例えば、メチル基、エチル基、１－プロピル基、イソプロピル基、１－ブチル基、２－ブチル基、ｔｅｒｔ－ブチル基、２－メチル－１－プロピル基、２，２－ジメチル－１－プロピル基、１－ペンチル基、２－ペンチル基、３－ペンチル基、トリフルオロメチル基、２－フルオロエチル基、トリフルオロエチル基、ペンタフルオロエチル基、トリクロロメチル基又はトリクロロエチル基が挙げられる。 “H 1 is an alkyl group having 1 to 6 carbon atoms optionally substituted with 1 to 6 halogen atoms” means a carbon atom in which a hydrogen atom is optionally substituted with 1 to 6 halogen atoms. A straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms, such as a methyl group, an ethyl group, a 1-propyl group, an isopropyl group 1-butyl group, 2-butyl group, tert-butyl group, 2-methyl-1-propyl group, 2,2-dimethyl-1-propyl group, 1-pentyl group, 2-pentyl group, 3-pentyl group Trifluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, pentafluoroethyl group, trichloromethyl group or trichloroethyl group.
　「水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数３～６のシクロアルキル基」とは、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素原子を３～６個有する環状の飽和炭化水素基を意味し、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基又は４，４－ジフルオロシクロヘキシル基が挙げられる。 “The C 3-6 cycloalkyl group in which the hydrogen atom may be substituted with 1 to 6 halogen atoms” means a carbon atom in which the hydrogen atom may be substituted with 1 to 6 halogen atoms Represents a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a 4,4-difluorocyclohexyl group.
　「水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキルオキシ基」とは、単結合の末端のエーテル結合を介して結合された、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基が酸素原子に結合した基を意味し、例えば、メトキシ基、エトキシ基、１－プロピルオキシ基、イソプロピルオキシ基、１－ブチルオキシ基、２－ブチルオキシ基、トリフルオロメトキシ基、２－トリフルオロエトキシ基又は２－フルオロエトキシ基が挙げられる。 “The alkyloxy group having 1 to 6 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms” means that the hydrogen atom bonded through an ether bond at the end of a single bond is 1 to This means a group in which an alkyl group having 1 to 6 carbon atoms which may be substituted with 6 halogen atoms is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, an isopropyloxy group, 1 -Butyloxy group, 2-butyloxy group, trifluoromethoxy group, 2-trifluoroethoxy group or 2-fluoroethoxy group.
　「炭素数６～１０のアリール基」としては、例えば、フェニル基、１－ナフチル基又は２－ナフチル基が挙げられる。 Examples of the “aryl group having 6 to 10 carbon atoms” include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.
　「環構成原子数５～１０のヘテロアリール基」とは、窒素原子（酸化されていてもよい）、酸素原子及び硫黄原子からなる群から任意に選択されるヘテロ原子１～４個を含む環構成原子が５～１０個である複素環式芳香族基を意味し、例えば、チエニル基、ピロリル基、フリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、ピラゾリル基、イソチアゾリル基、イソオキサゾリル基、トリアゾリル基、オキサジアゾリル基、テトラゾリル基、ピリジル基、１－オキシピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、トリアジニル基、インドリル基、インダゾリル基、ベンゾチエニル基、チエノピリジル基、ベンゾフリル基、フロピリジル基、ベンゾチアゾリル基、チアゾロピリジル基、ベンゾイミダゾリル基、イミダゾピリジル基、ベンゾオキサゾリル基、オキサゾロピリジル基、キノリル基又はイソキノリル基が挙げられる。 The term “heteroaryl group having 5 to 10 ring atoms” means a ring containing 1 to 4 heteroatoms arbitrarily selected from the group consisting of a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom Means a heterocyclic aromatic group having 5 to 10 member atoms, for example, thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group Oxadiazolyl group, tetrazolyl group, pyridyl group, 1-oxypyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, indolyl group, indazolyl group, benzothienyl group, thienopyridyl group, benzofuryl group, furopyridyl group, benzothiazolyl group, Thiazolopyridyl group, benzimidazolyl group, imida A pyridyl group, benzoxazolyl group, oxazolopyridyl group include a quinolyl group or an isoquinolyl group.
　「水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基」としては、例えば、フェニル基、ナフチル基、クロロフェニル基、ジクロロフェニル基、フルオロフェニル基、ブロモフェニル基、ヨードフェニル基、トルイル基、トリフルオロメチルフェニル基、ヒドロキシフェニル基、メトキシフェニル基又はシアノフェニル基が挙げられる。 Examples of the “aryl group having 6 to 10 carbon atoms in which the hydrogen atom may be substituted with R 4 ” include, for example, phenyl group, naphthyl group, chlorophenyl group, dichlorophenyl group, fluorophenyl group, bromophenyl group, iodophenyl group , Toluyl group, trifluoromethylphenyl group, hydroxyphenyl group, methoxyphenyl group or cyanophenyl group.
　「水素原子がＲ４で置換されていてもよい環構成原子数５～１０のヘテロアリール基」としては、例えば、クロロチエニル基、メチルチエニル基、ピロリル基、フリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、ピラゾリル基、イソチアゾリル基、イソオキサゾリル基、トリアゾリル基、オキサジアゾリル基、テトラゾリル基、ピリジル基、１－オキシピリジル基、クロロピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、クロロピラジニル基、トリアジニル基、インドリル基、インダゾリル基、ベンゾチエニル基、クロロベンゾチエニル基、フルオロベンゾチエニル基、ヒドロキシベンゾチエニル基、チエノピリジル基、ベンゾフリル基、フロピリジル基、ベンゾチアゾリル基、チアゾロピリジル基、ベンゾイミダゾリル基、イミダゾピリジル基、ベンゾオキサゾリル基、オキサゾロピリジル基、キノリル基又はイソキノリル基が挙げられる。 Examples of the “heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 4 ” include, for example, chlorothienyl group, methylthienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, Oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, 1-oxypyridyl, chloropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, chloropyrazinyl, triazinyl, indolyl Group, indazolyl group, benzothienyl group, chlorobenzothienyl group, fluorobenzothienyl group, hydroxybenzothienyl group, thienopyridyl group, benzofuryl group, furopyridyl group, benzothiazolyl group, thiazolopyridyl group, benzimidazole A zolyl group, an imidazopyridyl group, a benzoxazolyl group, an oxazolopyridyl group, a quinolyl group or an isoquinolyl group can be mentioned.
　「水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基」としては、例えば、フェニル基、ナフチル基、クロロフェニル基、ジクロロフェニル基、フルオロフェニル基、クロロフルオロフェニル基、ブロモフェニル基、ヨードフェニル基、トルイル基、トリフルオロメチルフェニル基、ヒドロキシフェニル基、メトキシフェニル基、シアノフェニル基又はビフェニル基が挙げられる。 Examples of the “aryl group having 6 to 10 carbon atoms in which the hydrogen atom may be substituted with R 5 ” include, for example, phenyl group, naphthyl group, chlorophenyl group, dichlorophenyl group, fluorophenyl group, chlorofluorophenyl group, bromophenyl Group, iodophenyl group, toluyl group, trifluoromethylphenyl group, hydroxyphenyl group, methoxyphenyl group, cyanophenyl group or biphenyl group.
　「水素原子がＲ５で置換されていてもよい環構成原子数５～１０のヘテロアリール基」としては、例えば、チエニル基、クロロチエニル基、メチルチエニル基、ピロリル基、フリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、ピラゾリル基、イソチアゾリル基、イソオキサゾリル基、トリアゾリル基、オキサジアゾリル基、テトラゾリル基、ピリジル基、１－オキシピリジル基、クロロピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、クロロピラジニル基、トリアジニル基、インドリル基、インダゾリル基、ベンゾチエニル基、クロロベンゾチエニル基、フルオロベンゾチエニル基、ヒドロキシベンゾチエニル基、チエノピリジル基、ベンゾフリル基、フロピリジル基、ベンゾチアゾリル基、チアゾロピリジル基、ベンゾイミダゾリル基、イミダゾピリジル基、ベンゾオキサゾリル基、オキサゾロピリジル基、キノリル基、イソキノリル基、フェニルピラゾリル基、フェニルチエニル基、フェニルチアゾリル基、ピリジルチエニル基が挙げられる。 Examples of the “heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 5 ” include, for example, thienyl group, chlorothienyl group, methylthienyl group, pyrrolyl group, furyl group, thiazolyl group, Imidazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, oxadiazolyl, tetrazolyl, pyridyl, 1-oxypyridyl, chloropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, chloropyrazinyl, triazinyl Group, indolyl group, indazolyl group, benzothienyl group, chlorobenzothienyl group, fluorobenzothienyl group, hydroxybenzothienyl group, thienopyridyl group, benzofuryl group, furopyridyl group, benzothiazolyl group, thiazopyridyl group, Examples thereof include benzoimidazolyl group, imidazopyridyl group, benzoxazolyl group, oxazolopyridyl group, quinolyl group, isoquinolyl group, phenylpyrazolyl group, phenylthienyl group, phenylthiazolyl group, and pyridylthienyl group.
　上記のキヌクリジンウレア誘導体は、一般式（Ｉ）において、Ｒ１は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基又は炭素数３～６のシクロアルキル基であることが好ましく、メチル基又はエチル基であることがより好ましい。 In the general formula (I), R 1 is an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms, or 3 to 3 carbon atoms. 6 cycloalkyl group is preferable, and methyl group or ethyl group is more preferable.
　Ｒ２は、水素原子、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基（Ｒ４は、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～４のアルキルオキシ基である）であることが好ましく、水素原子であることがより好ましい。 R 2 is a hydrogen atom, or a heteroaryl group of the aryl group or ring constituent atoms of 5 to 10 of the hydrogen atoms R 4 is carbon atoms 6 also be ~ 10 substituted with (R 4 is a halogen atom, a hydroxyl Group, nitrile group, or alkyl group having 1 to 4 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, or alkyl having 1 to 4 carbon atoms, in which a hydrogen atom may be substituted with 1 to 3 halogen atoms It is preferably an oxy group, more preferably a hydrogen atom.
　Ｒ３は、水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基である（Ｒ５は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基である）ことが好ましく、水素原子がＲ５で置換されていてもよいフェニル基、ナフチル基、ピリジル基、キノリル基、イソキノリル基、フリル基、チエニル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、ピラゾリル基、イミダゾリル基、トリアゾリル基、ベンゾフリル基、フロピリジル基、ベンゾチエニル基、チエノピリジル基、ベンゾオキサゾリル基、オキサゾロピリジル基、ベンゾチアゾリル基又はチアゾロピリジル基である（Ｒ５は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、フェニル基若しくはピリジル基である）ことがより好ましい。 R 3 is a hydrogen atom is a heteroaryl group the aryl group or ring members 5 to 10 are carbon atoms 6 also be ~ 10 substituted by R 5 (R 5 is a halogen atom, a hydroxyl group, or A hydrogen atom optionally substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, or 6 carbon atoms. A phenyl group, a naphthyl group, a pyridyl group, a quinolyl group, an isoquinolyl group in which the hydrogen atom may be substituted with R 5. , Furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, benzofuryl group, furopiryl A dil group, a benzothienyl group, a thienopyridyl group, a benzoxazolyl group, an oxazolopyridyl group, a benzothiazolyl group or a thiazolopyridyl group (R 5 is a halogen atom, a hydroxyl group or 1 to 3 hydrogen atoms; Or an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a phenyl group, or a pyridyl group, which may be substituted with a halogen atom of preferable.
　Ｒ４は、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～４のアルキルオキシ基であることが好ましい。 R 4 represents a halogen atom, a hydroxyl group, a nitrile group, or an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, in which a hydrogen atom may be substituted with 1 to 3 halogen atoms. Alternatively, an alkyloxy group having 1 to 4 carbon atoms is preferable.
　Ｒ５は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基であることが好ましく、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、フェニル基若しくはピリジル基であることがより好ましい。 R 5 represents a halogen atom, a hydroxyl group, a C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a carbon number in which a hydrogen atom may be substituted with 1 to 3 halogen atoms. It is preferably an alkyloxy group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heteroaryl group having 5 to 10 ring atoms, and having 1 to 3 halogen atoms, hydroxyl groups, or hydrogen atoms It is more preferably an alkyl group having 1 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, a phenyl group or a pyridyl group which may be substituted with a halogen atom.
　上記の一般式（Ｉ）で示されるキヌクリジンウレア誘導体（以下、キヌクリジンウレア誘導体（Ｉ））は、光学異性体やジアステレオマーが存在する場合があるが、単一異性体のみならず、ラセミ体及びジアステレオマー混合物も包含する。 The quinuclidine urea derivative represented by the above general formula (I) (hereinafter referred to as quinuclidine urea derivative (I)) may have an optical isomer or a diastereomer. As well as racemic and diastereomeric mixtures.
　上記のキヌクリジンウレア誘導体（Ｉ）の「薬理学的に許容される塩」としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩若しくはリン酸塩等の無機酸塩、又は、シュウ酸塩、マロン酸塩、クエン酸塩、フマル酸塩、乳酸塩、リンゴ酸塩、コハク酸塩、酒石酸塩、酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、グルコン酸塩、安息香酸塩、アスコルビン酸塩、グルタル酸塩、マンデル酸塩、フタル酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、カンファースルホン酸塩、アスパラギン酸塩、グルタミン酸塩若しくはケイ皮酸塩等の有機酸塩が挙げられるが、塩酸塩、硫酸塩、臭化水素酸塩、マレイン酸塩、安息香酸塩又はメタンスルホン酸塩が好ましい。 Examples of the “pharmacologically acceptable salt” of the quinuclidine urea derivative (I) include hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide, phosphate, and the like. Inorganic acid salt or oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, glucone Acid salt, benzoate, ascorbate, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, Organic acid salts such as aspartate, glutamate or cinnamate are mentioned, and hydrochloride, sulfate, hydrobromide, maleate, benzoate or methanesulfonate is preferable.
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩は、無水物であってもよいし、水和物等の溶媒和物を形成していても構わない。ここで溶媒和物としては、薬理学的に許容される溶媒和物が好ましい。薬理学的に許容される溶媒和物は、水和物又は非水和物のいずれであっても構わないが、水和物が好ましい。溶媒和物を構成する溶媒としては、水、メタノール、エタノール若しくはｎ－プロパノール等のアルコール系溶媒、ジメチルホルムアミド又はジメチルスルホキシドが挙げられる。 The quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof may be an anhydride, or may form a solvate such as a hydrate. Here, the solvate is preferably a pharmacologically acceptable solvate. The pharmacologically acceptable solvate may be either a hydrate or a non-hydrate, but a hydrate is preferable. Examples of the solvent constituting the solvate include water, alcohol solvents such as methanol, ethanol and n-propanol, dimethylformamide and dimethyl sulfoxide.
　キヌクリジンウレア誘導体（Ｉ）は、その基本骨格や置換基の種類に由来する特徴に基づいた適切な方法で製造することができる。なお、これらの化合物の製造に使用する出発物質と試薬は一般に購入することができるか、又は、公知の方法で製造できる。 The quinuclidine urea derivative (I) can be produced by an appropriate method based on characteristics derived from the basic skeleton and the type of substituent. The starting materials and reagents used for the production of these compounds can generally be purchased or can be produced by known methods.
　キヌクリジンウレア誘導体（Ｉ）並びにその製造に使用する中間体及び出発物質は、公知の手段によって単離精製することができる。単離精製のための公知の手段としては、例えば、溶媒抽出、再結晶又はクロマトグラフィーが挙げられる。 The quinuclidine urea derivative (I) and the intermediates and starting materials used for the production thereof can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
　キヌクリジンウレア誘導体（Ｉ）が、光学異性体又は立体異性体を含有する場合には、公知の方法により、それぞれの異性体を単一化合物として得ることができる。公知の方法としては、例えば、結晶化、酵素分割又はキラルクロマトグラフィーが挙げられる。 When the quinuclidine urea derivative (I) contains an optical isomer or a stereoisomer, each isomer can be obtained as a single compound by a known method. Known methods include, for example, crystallization, enzyme resolution, or chiral chromatography.
　キヌクリジンウレア誘導体（Ｉ）は、例えば、スキーム１に示すように、塩基存在下、キヌクリジン－３－アミン誘導体（ＩＩ）とアリールアミン誘導体（ＩＩＩ）とを、ウレア化剤と反応させるウレア化反応により得ることができる。
Figure JPOXMLDOC01-appb-C000004
 [式中、Ｒ１～Ｒ３は、上記定義に同じである。] For example, as shown in Scheme 1, the quinuclidine urea derivative (I) is obtained by reacting a quinuclidine-3-amine derivative (II) and an arylamine derivative (III) with a urea agent in the presence of a base. It can be obtained by reaction.
Figure JPOXMLDOC01-appb-C000004
 [Wherein R 1 to R 3 are the same as defined above. ]
　ウレア化反応に用いるアリールアミン誘導体（ＩＩＩ）の量は、キヌクリジン－３－アミン誘導体（ＩＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of the arylamine derivative (III) used in the urea reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the quinuclidin-3-amine derivative (II).
　ウレア化反応に用いるウレア化剤としては、例えば、トリホスゲン、ホスゲン、クロロギ酸トリクロロメチル、クロロギ酸フェニル若しくはクロロギ酸ｐ－ニトロフェニル等のクロロギ酸置換フェニル、Ｎ，Ｎ´－カルボニルジイミダゾール又はＮ，Ｎ´－ジスクシンイミジルカルボナートが挙げられるが、トリホスゲン又はクロロギ酸フェニルが好ましい。 Examples of the urea agent used in the urea reaction include, for example, triphosgene, phosgene, trichloromethyl chloroformate, phenyl chloroformate, phenyl chloroformate such as p-nitrophenyl chloroformate, N, N′-carbonyldiimidazole, N, N'-disuccinimidyl carbonate may be mentioned, but triphosgene or phenyl chloroformate is preferred.
　ウレア化反応に用いるウレア化剤の量は、キヌクリジン－３－アミン誘導体（ＩＩ）に対して０．１～１００当量が好ましく、０．３～３０当量がより好ましい。 The amount of the urea agent used in the urea reaction is preferably 0.1 to 100 equivalents, and more preferably 0.3 to 30 equivalents, relative to the quinuclidin-3-amine derivative (II).
　ウレア化反応に用いる塩基としては、例えば、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基、炭酸水素ナトリウム若しくは炭酸カリウム等の無機塩基、水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物、メチルリチウム若しくはブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物が挙げられるが、トリエチルアミン又はジイソプロピルエチルアミン等の有機塩基が好ましい。 Examples of the base used in the urea reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogen carbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, methyl Alkyl lithium such as lithium or butyl lithium, lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof may be mentioned, and an organic base such as triethylamine or diisopropylethylamine is preferable.
　ウレア化反応に用いる塩基の量は、キヌクリジン－３－アミン誘導体（ＩＩ）に対して１～１００当量が好ましく、２～３０当量がより好ましい。 The amount of the base used for the urea formation reaction is preferably 1 to 100 equivalents, more preferably 2 to 30 equivalents with respect to the quinuclidin-3-amine derivative (II).
　ウレア化反応に用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジメチルホルムアミド、ジメチルアセトアミド若しくはジメチルスルホキシド等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒が挙げられるが、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒が好ましい。 The reaction solvent used for the urea reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a non-proton such as dimethylformamide, dimethylacetamide or dimethylsulfoxide. Polar solvents, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or A mixed solvent thereof may be mentioned, but a chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferred.
　ウレア化反応の反応温度は、－７８～２００℃が好ましく、－２０～１００℃がより好ましい。 The reaction temperature of the urea reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.
　ウレア化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～３０時間程度で満足すべき結果が得られる。 The reaction time of the urea reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.
　ウレア化反応に用いるキヌクリジン－３－アミン誘導体（ＩＩ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the quinuclidin-3-amine derivative (II) used for the urea reaction is preferably 1 mmol / L to 1 mol / L.
　ウレア化反応に用いるキヌクリジン－３－アミン誘導体（ＩＩ）は、購入することができるが、公知の方法でも製造できる。 The quinuclidin-3-amine derivative (II) used for the urea reaction can be purchased, but can also be produced by a known method.
　キヌクリジン－３－アミン誘導体（ＩＩ）の置換基Ｒ１がＲ７を表すキヌクリジン－３－アミン誘導体（ＩＩａ）は、例えば、スキーム２に示すように、Ｎ－アシル－（キヌクリジン－３－イル）－アミン誘導体（ＩＶ）に対して還元剤を作用させる還元反応により得ることができる。
Figure JPOXMLDOC01-appb-C000005
 [式中、Ｒ６は、水素原子、炭素数１～６のアルキルオキシ基又は水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～５のアルキル基を表し、Ｒ７は、以下の一般式（Ｖ）で示される置換基を表す。
Figure JPOXMLDOC01-appb-C000006
 　（式中、Ｒ８は、水素原子、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～５のアルキル基を表す。）を表す。] The quinuclidin-3-amine derivative (IIa) in which the substituent R 1 of the quinuclidin-3-amine derivative (II) represents R 7 is, for example, N-acyl- (quinuclidin-3-yl) as shown in Scheme 2. It can be obtained by a reduction reaction in which a reducing agent is allowed to act on the amine derivative (IV).
Figure JPOXMLDOC01-appb-C000005
 [Wherein R 6 represents a hydrogen atom, an alkyloxy group having 1 to 6 carbon atoms, or an alkyl group having 1 to 5 carbon atoms in which a hydrogen atom may be substituted with a halogen atom having 1 to 6 carbon atoms; 7 represents a substituent represented by the following general formula (V).
Figure JPOXMLDOC01-appb-C000006
 (Wherein R 8 represents a hydrogen atom or an alkyl group having 1 to 5 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms). ]
　還元反応に用いる還元剤としては、例えば、水素化リチウムアルミニウム、水素化アルミニウム、水素化ビス（２－メトキシエトキシ）アルミニウムナトリウム、水素化トリエチルホウ素リチウム、水素化ホウ素、水素化ホウ素・ジメチルスルフィド錯体、水素化ホウ素・テトラヒドロフラン錯体又は９－ボラビシクロ［３，３］－ノナン（９－ＢＢＮ）等の水素化金属化合物が挙げられるが、水素化リチウムアルミニウムが好ましい。 Examples of the reducing agent used in the reduction reaction include lithium aluminum hydride, aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, lithium triethylborohydride, borohydride, borohydride / dimethyl sulfide complex, Examples thereof include metal hydride compounds such as boron hydride / tetrahydrofuran complex or 9-borabicyclo [3,3] -nonane (9-BBN), and lithium aluminum hydride is preferred.
　還元反応に用いる還元剤の量は、Ｎ－アシル－（キヌクリジン－３－イル）－アミン誘導体（ＩＶ）に対して０．５～１００当量が好ましく、１～３０当量がより好ましい。 The amount of the reducing agent used in the reduction reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the N-acyl- (quinuclidin-3-yl) -amine derivative (IV).
　還元反応に用いる反応溶媒としては、用いる還元剤の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン又は１，４－ジオキサン等のエーテル系溶媒が好ましい。 The reaction solvent used for the reduction reaction is appropriately selected depending on the type of reducing agent used, but is not particularly limited as long as it does not inhibit the reaction. For example, diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4- Ether solvents such as dioxane are preferred.
　還元反応の反応温度は、－７８～２００℃が好ましく、－２０～１００℃がより好ましい。 The reaction temperature of the reduction reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.
　還元反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～３０時間程度で満足すべき結果が得られる。 The reaction time of the reduction reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.
　還元反応に用いるＮ－アシル－（キヌクリジン－３－イル）－アミン誘導体（ＩＶ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the N-acyl- (quinuclidin-3-yl) -amine derivative (IV) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.
　還元反応に用いるＮ－アシル－（キヌクリジン－３－イル）－アミン誘導体（ＩＶ）は、購入することができるか、又は、公知の方法で製造することができる。 The N-acyl- (quinuclidin-3-yl) -amine derivative (IV) used for the reduction reaction can be purchased or can be produced by a known method.
　Ｎ－アシル－（キヌクリジン－３－イル）－アミン誘導体（ＩＶ）は、例えば、スキーム３に示すように、塩基存在下、キヌクリジン－３－アミン（ＶＩ）に対してアシル化剤を作用させるアシル化反応により得ることができる。
Figure JPOXMLDOC01-appb-C000007
 [式中、Ｒ６は、上記定義に同じである。] The N-acyl- (quinuclidin-3-yl) -amine derivative (IV) is an acyl having an acylating agent acting on quinuclidin-3-amine (VI) in the presence of a base as shown in Scheme 3, for example. It can be obtained by a chemical reaction.
Figure JPOXMLDOC01-appb-C000007
 [Wherein R 6 is the same as defined above. ]
　アシル化反応に用いるアシル化剤としては、例えば、クロロギ酸エステル若しくは酸クロリド等の酸ハロゲン化物、酸無水物、混合酸無水物酸アジド、又は、活性化エステル等のカルボン酸の活性化体が挙げられるが、クロロギ酸エチル又は塩化アセチルが好ましい。 Examples of the acylating agent used in the acylation reaction include acid halides such as chloroformate and acid chloride, acid anhydrides, mixed acid anhydride azides, and activated carboxylic acid such as activated esters. Among them, ethyl chloroformate or acetyl chloride is preferable.
　アシル化反応に用いるアシル化剤の量は、キヌクリジン－３－アミン（ＶＩ）に対して１～１０当量が好ましく、１～３当量がより好ましい。 The amount of the acylating agent used in the acylation reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to quinuclidin-3-amine (VI).
　アシル化反応に用いる塩基としては、例えば、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基、炭酸水素ナトリウム若しくは炭酸カリウム等の無機塩基、水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物が挙げられるが、トリエチルアミン又はジイソプロピルエチルアミン等の有機塩基が好ましい。 Examples of the base used in the acylation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium bicarbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, lithium Examples thereof include lithium amides such as hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, and organic bases such as triethylamine or diisopropylethylamine are preferred.
　アシル化反応に用いる塩基の量は、キヌクリジン－３－アミン（ＶＩ）に対して１～１００当量が好ましく、２～３０当量がより好ましい。 The amount of the base used in the acylation reaction is preferably 1 to 100 equivalents and more preferably 2 to 30 equivalents with respect to quinuclidin-3-amine (VI).
　アシル化反応に用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジメチルホルムアミド、ジメチルアセトアミド若しくはジメチルスルホキシド等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒が挙げられるが、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒が好ましい。 The reaction solvent used in the acylation reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a non-proton such as dimethylformamide, dimethylacetamide, or dimethylsulfoxide. Polar solvents, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, chlorine solvents such as dichloromethane, chloroform or 1,2-dichloroethane, or A mixed solvent thereof may be mentioned, but a chlorinated solvent such as dichloromethane, chloroform or 1,2-dichloroethane is preferred.
　アシル化反応に用いるキヌクリジン－３－アミン（ＶＩ）は、フリー体であってもよいし、塩酸塩等の塩であっても構わない。 The quinuclidin-3-amine (VI) used for the acylation reaction may be a free form or a salt such as hydrochloride.
　アシル化反応の反応温度は、－７８～２００℃が好ましく、－２０～１００℃がより好ましい。 The reaction temperature of the acylation reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.
　アシル化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～３０時間程度で満足すべき結果が得られる。 The reaction time of the acylation reaction is appropriately selected according to conditions such as reaction temperature, but satisfactory results are usually obtained in about 1 to 30 hours.
　アシル化反応に用いるキヌクリジン－３－アミン（ＶＩ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of quinuclidin-3-amine (VI) used in the acylation reaction is preferably 1 mmol / L to 1 mol / L.
　キヌクリジン－３－アミン誘導体（ＩＩ）の置換基Ｒ１がＲ１１を表すキヌクリジン－３－アミン誘導体（ＩＩｂ）は、例えば、スキーム４に示すように、キヌクリジン－３－アミン（ＶＩ）とアルデヒド又はケトン（ＶＩＩ）との還元的アミノ化反応により得ることができる。
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ｒ９は、それぞれ独立して、水素原子若しくは水素原子が１～６個のハロゲン原子で置換されていてもよいＡ個の炭素原子を含むアルキル基を表し、Ｒ１０は、それぞれ独立して、水素原子若しくは水素原子が１～６個のハロゲン原子で置換されていてもよいＢ個の炭素原子を含むアルキル基を表す（ただし、ＡとＢの和は１～５の整数を表す）か、又は、Ｒ９とＲ１０とが一緒になって環を形成することにより水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数３～６のシクロアルキル基を表し、Ｒ１１は、以下の一般式（ＶＩＩＩ）で示される置換基を表す。
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｒ９及びＲ１０は、上記定義に同じである。）］ The quinuclidine-3-amine derivative (IIb) in which the substituent R 1 of the quinuclidin-3-amine derivative (II) represents R 11 is, for example, quinuclidin-3-amine (VI) and an aldehyde or It can be obtained by a reductive amination reaction with a ketone (VII).
Figure JPOXMLDOC01-appb-C000008
 Wherein, R 9 are each independently hydrogen atom or a hydrogen atom an alkyl group containing from 1 to 6 halogen atoms optionally substituted A number even though carbon atoms, R 10 are each Independently, it represents a hydrogen atom or an alkyl group containing B carbon atoms optionally substituted with 1 to 6 halogen atoms (provided that the sum of A and B represents an integer of 1 to 5). Or a cycloalkyl group having 3 to 6 carbon atoms in which hydrogen atoms may be substituted with 1 to 6 halogen atoms by combining R 9 and R 10 together to form a ring. R 11 represents a substituent represented by the following general formula (VIII).
Figure JPOXMLDOC01-appb-C000009
 (Wherein R 9 and R 10 are the same as defined above)]
　還元的アミノ化反応に用いるアルデヒド又はケトンの量は、キヌクリジン－３－アミン（ＶＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of aldehyde or ketone used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to quinuclidin-3-amine (VI).
　還元的アミノ化反応に用いる還元剤としては、例えば、水素化リチウムアルミニウム、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム又は水素化トリアセトキシホウ素ナトリウムが挙げられるが、水素化トリアセトキシホウ素ナトリウムが好ましい。 Examples of the reducing agent used in the reductive amination reaction include lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride, and sodium triacetoxyborohydride is preferable.
　還元的アミノ化反応に用いる還元剤の量は、キヌクリジン－３－アミン（ＶＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of the reducing agent used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to quinuclidin-3-amine (VI).
　還元的アミノ化反応に用いる反応溶媒としては、用いる還元剤の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、メタノール若しくはエタノール等のアルコール系溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、又は、それらの混合溶媒が挙げられるが、メタノール若しくはエタノール等のアルコール系溶媒が好ましい。 The reaction solvent used for the reductive amination reaction is appropriately selected depending on the type of the reducing agent used, but is not particularly limited as long as it does not inhibit the reaction. For example, an alcohol solvent such as methanol or ethanol, Examples include ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, and 1,4-dioxane, chlorine solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, and mixed solvents thereof, such as methanol or ethanol. Alcohol solvents are preferred.
　還元的アミノ化反応の反応温度は、－７８～２００℃が好ましく、０～１００℃がより好ましい。 The reaction temperature of the reductive amination reaction is preferably −78 to 200 ° C., more preferably 0 to 100 ° C.
　還元的アミノ化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～３０時間程度で満足すべき結果が得られる。 The reaction time of the reductive amination reaction is appropriately selected according to conditions such as the reaction temperature, but satisfactory results are usually obtained in about 1 to 30 hours.
　還元的アミノ化反応に用いるキヌクリジン－３－アミン（ＶＩ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of quinuclidin-3-amine (VI) used in the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.
　スキーム１に示すウレア化反応に用いるアリールアミン誘導体（ＩＩＩ）は、購入することができるか、又は当業者に既知の方法で製造できる。 The arylamine derivative (III) used in the urea reaction shown in Scheme 1 can be purchased or can be produced by methods known to those skilled in the art.
　アリールアミン誘導体（ＩＩＩ）の置換基Ｒ２がＲ７を表すアリールアミン誘導体（ＩＩＩａ）は、例えば、スキーム５に示すように、アリールアミン誘導体（ＩＸ）に対して、スキーム３に示す方法と同様の条件でアシル化反応を行い、得られたＮ－アシル－アリールアミン誘導体（Ｘ）をスキーム２に示す方法と同様の条件で還元反応を行うことにより得ることができる。
Figure JPOXMLDOC01-appb-C000010
 ［式中、Ｒ３、Ｒ６及びＲ７は、上記定義に同じである。］ The arylamine derivative (IIIa) in which the substituent R 2 of the arylamine derivative (III) represents R 7 is similar to the method shown in Scheme 3 with respect to the arylamine derivative (IX) as shown in Scheme 5, for example. The N-acyl-arylamine derivative (X) thus obtained can be obtained by carrying out a reduction reaction under the same conditions as in the method shown in Scheme 2.
Figure JPOXMLDOC01-appb-C000010
 [Wherein R 3 , R 6 and R 7 are the same as defined above. ]
　アリールアミン誘導体（ＩＩＩ）の置換基Ｒ２がＲ１１を表すアリールアミン誘導体（ＩＩＩｂ）は、例えば、スキーム６に示すように、アリールアミン誘導体（ＩＸ）に対して、スキーム４に示す方法と同様の条件でアルデヒド又はケトン（ＶＩＩ）との還元的アミノ化反応を行うことにより得ることができる。
Figure JPOXMLDOC01-appb-C000011
 ［式中、Ｒ３及びＲ９～Ｒ１１は、上記定義に同じである。］ The arylamine derivative (IIIb) in which the substituent R 2 of the arylamine derivative (III) represents R 11 is similar to the method shown in Scheme 4 with respect to the arylamine derivative (IX) as shown in Scheme 6, for example. It can obtain by performing reductive amination reaction with an aldehyde or ketone (VII) on condition of these.
Figure JPOXMLDOC01-appb-C000011
 [Wherein R 3 and R 9 to R 11 are the same as defined above]. ]
　アリールアミン誘導体（ＩＩＩ）の置換基Ｒ２が、Ｒ１２を表すアリールアミン誘導体（ＩＩＩｃ）は、例えば、スキーム７に示すように、パラジウム触媒及び塩基存在下、アリールアミン誘導体（ＩＸ）と、ハロゲン化アリール又はアリールトリフラート（ＸＩ）とのカップリング反応により得ることができる。
Figure JPOXMLDOC01-appb-C000012
 ［式中、Ｒ３は上記定義に同じであり、Ｒ１２は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基（Ｒ４は、上記定義に同じである）を表し、Ｘは、塩素原子、臭素原子、ヨウ素原子又はトリフルオロメタンスルホニルオキシ基を表す。］ The arylamine derivative (IIIc) in which the substituent R 2 of the arylamine derivative (III) represents R 12 is, for example, as shown in Scheme 7, in the presence of a palladium catalyst and a base, the arylamine derivative (IX), It can be obtained by a coupling reaction with an aryl group or aryl triflate (XI).
Figure JPOXMLDOC01-appb-C000012
 [Wherein R 3 has the same definition as above, and R 12 represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R 4. (R 4 is the same as defined above), and X represents a chlorine atom, a bromine atom, an iodine atom or a trifluoromethanesulfonyloxy group. ]
　カップリング反応に用いるパラジウム触媒としては、テトラキストリフェニルホスフィンパラジウム（０）、トリス（ジベンジリデンアセトン）ジパラジウム（０）又はビス（ジベンジリデンアセトン）パラジウム（０）等の０価パラジウム触媒が挙げられる。 Examples of the palladium catalyst used in the coupling reaction include zerovalent palladium catalysts such as tetrakistriphenylphosphine palladium (0), tris (dibenzylideneacetone) dipalladium (0), or bis (dibenzylideneacetone) palladium (0). .
　カップリング反応に用いるパラジウム触媒の量は、アリールアミン誘導体（ＩＸ）に対して、０．００１～１０当量が好ましく、０．０１～１当量がより好ましい。 The amount of the palladium catalyst used in the coupling reaction is preferably 0.001 to 10 equivalents, and more preferably 0.01 to 1 equivalents, relative to the arylamine derivative (IX).
　カップリング反応に用いる塩基としては、例えば、炭酸セシウム等の無機塩基、ｔｅｒｔ－ブチルオキシナトリウム若しくはｔｅｒｔ－ブチルオキシカリウム等の金属アルコキシド、又は、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミドが挙げられるが、ｔｅｒｔ－ブチルオキシナトリウム若しくはｔｅｒｔ－ブチルオキシカリウム等の金属アルコキシドが好ましい。 Examples of the base used in the coupling reaction include an inorganic base such as cesium carbonate, a metal alkoxide such as tert-butyloxy sodium or tert-butyloxy potassium, or a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide. However, metal alkoxides such as sodium tert-butyloxy or potassium tert-butyloxy are preferred.
　カップリング反応に用いる塩基の量は、アリールアミン誘導体（ＩＸ）に対して、０．５～１００当量が好ましく、１～３０当量がより好ましい。 The amount of the base used for the coupling reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the arylamine derivative (IX).
　カップリング反応に用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジメチルホルムアミド、ジメチルアセトアミド若しくはジメチルスルホキシド等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、トルエン若しくはキシレン等の芳香族炭化水素系溶媒、又は、それらの混合溶媒が挙げられるが、トルエン若しくはキシレン等の芳香族炭化水素系溶媒が好ましい。 The reaction solvent used for the coupling reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a non-proton such as dimethylformamide, dimethylacetamide or dimethylsulfoxide. Polar solvents, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, or mixed solvents thereof, such as toluene or xylene Aromatic hydrocarbon solvents are preferred.
　カップリング反応の反応温度は、０～２００℃が好ましく、３０～１５０℃がより好ましい。 The reaction temperature for the coupling reaction is preferably 0 to 200 ° C, more preferably 30 to 150 ° C.
　カップリング反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～４８時間程度で満足すべき結果が得られる。 The reaction time of the coupling reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 48 hours.
　カップリング反応に用いるアリールアミン誘導体（ＩＸ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the arylamine derivative (IX) used for the coupling reaction is preferably 1 mmol / L to 1 mol / L.
　カップリング反応に用いるアリールアミン誘導体（ＩＸ）は、購入することができるか、又は、公知の方法で製造することができる。 The arylamine derivative (IX) used for the coupling reaction can be purchased or can be produced by a known method.
　アリールアミン誘導体（ＩＸ）は、例えば、スキーム８に示すように、脱保護剤存在下、カルバミン酸ｔｅｒｔ－ブチルエステル誘導体（ＸＩＩ）の脱保護反応により得ることができる。
Figure JPOXMLDOC01-appb-C000013
 ［式中、Ｒ３は、上記定義に同じである。］ The arylamine derivative (IX) can be obtained, for example, by deprotecting the carbamic acid tert-butyl ester derivative (XII) in the presence of a deprotecting agent as shown in Scheme 8.
Figure JPOXMLDOC01-appb-C000013
 [Wherein R 3 is the same as defined above. ]
　脱保護反応に用いる脱保護剤としては、例えば、塩酸、トリフルオロ酢酸又はフッ化水素酸等の酸が挙げられるが、塩酸又はトリフルオロ酢酸が好ましい。 Examples of the deprotecting agent used in the deprotecting reaction include acids such as hydrochloric acid, trifluoroacetic acid, and hydrofluoric acid, and hydrochloric acid or trifluoroacetic acid is preferable.
　脱保護反応に用いる脱保護剤の量は、カルバミン酸ｔｅｒｔ－ブチルエステル誘導体（ＸＩＩ）に対して０．５～１００当量が好ましく、１～３０当量がより好ましい。 The amount of the deprotecting agent used in the deprotecting reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the carbamic acid tert-butyl ester derivative (XII).
　脱保護反応の反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、メタノール若しくはエタノール等のアルコール系溶媒、又は、それらの混合溶媒が挙げられるが、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒が好ましい。 The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane. An ether solvent such as ethyl acetate or propyl acetate, a chlorine solvent such as dichloromethane, chloroform or 1,2-dichloroethane, an alcohol solvent such as methanol or ethanol, or a mixed solvent thereof. However, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane, or 1,4-dioxane are preferred.
　脱保護反応の反応温度は、－７８～２００℃が好ましく、－２０～１００℃がより好ましい。 The reaction temperature for the deprotection reaction is preferably −78 to 200 ° C., more preferably −20 to 100 ° C.
　脱保護反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～３０時間程度で満足すべき結果が得られる。 The reaction time of the deprotection reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 30 hours.
　脱保護反応に用いるカルバミン酸ｔｅｒｔ－ブチルエステル誘導体（ＸＩＩ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the carbamic acid tert-butyl ester derivative (XII) used for the deprotection reaction is preferably 1 mmol / L to 1 mol / L.
　脱保護反応に用いるカルバミン酸ｔｅｒｔ－ブチルエステル誘導体（ＸＩＩ）は、購入することができるか、又は、公知の方法で製造することができる。 The carbamic acid tert-butyl ester derivative (XII) used for the deprotection reaction can be purchased or can be produced by a known method.
　カルバミン酸ｔｅｒｔ－ブチルエステル誘導体（ＸＩＩ）は、例えば、スキーム９に示すように、アジド化剤、求核剤及び塩基存在下、カルボン酸（ＸＩＩＩ）のクルチウス転位反応により得ることができる。
Figure JPOXMLDOC01-appb-C000014
 ［式中、Ｒ３は、上記定義に同じである。］ The carbamic acid tert-butyl ester derivative (XII) can be obtained, for example, by a Curtius rearrangement reaction of a carboxylic acid (XIII) in the presence of an azidating agent, a nucleophile and a base as shown in Scheme 9.
Figure JPOXMLDOC01-appb-C000014
 [Wherein R 3 is the same as defined above. ]
　クルチウス転位反応で用いるアジド化剤としては、例えば、アジ化ナトリウム又はジフェニルホスホリルアジドが挙げられるが、ジフェニルホスホリルアジドが好ましい。 Examples of the azidating agent used in the Curtius rearrangement reaction include sodium azide and diphenylphosphoryl azide, and diphenylphosphoryl azide is preferred.
　クルチウス転位反応で用いるアジド化剤の量は、カルボン酸（ＸＩＩＩ）に対して、０．５～１００当量が好ましく、１～３０当量がより好ましい。 The amount of the azidating agent used in the Curtius rearrangement reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents, relative to the carboxylic acid (XIII).
　クルチウス転位反応で用いる求核剤としては、例えば、ｔｅｒｔ－ブチルオキシナトリウム、ｔｅｒｔ－ブチルオキシカリウム等の金属アルコキシド又はｔｅｒｔ－ブタノールが挙げられるが、ｔｅｒｔ－ブタノールが好ましい。 Examples of the nucleophile used in the Curtius rearrangement reaction include metal alkoxides such as tert-butyloxy sodium and tert-butyloxy potassium, and tert-butanol, with tert-butanol being preferred.
　クルチウス転位反応で用いる求核剤の量は、カルボン酸（ＸＩＩＩ）に対して、１０～１００当量用いるのが好ましい。 The amount of the nucleophile used in the Curtius rearrangement reaction is preferably 10 to 100 equivalents relative to the carboxylic acid (XIII).
　クルチウス転位反応に用いる塩基としては、例えば、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基、炭酸水素ナトリウム若しくは炭酸カリウム等の無機塩基、水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミド、又は、それらの混合物が挙げられるが、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基が好ましい。 Examples of the base used in the Curtius rearrangement reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, metal hydride compounds such as sodium hydride, potassium hydride or calcium hydride, lithium Examples thereof include lithium amides such as hexamethyldisilazide or lithium diisopropylamide, or mixtures thereof, and organic bases such as triethylamine or diisopropylethylamine are preferred.
　クルチウス転位反応に用いる塩基の量は、カルボン酸（ＸＩＩＩ）に対して１～１００当量が好ましく、２～３０当量がより好ましい。 The amount of the base used in the Curtius rearrangement reaction is preferably 1 to 100 equivalents, more preferably 2 to 30 equivalents, relative to the carboxylic acid (XIII).
　クルチウス転位反応で用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジメチルホルムアミド、ジメチルアセトアミド若しくはジメチルスルホキシド等の非プロトン性極性溶媒、ジエチルエーテル、テトラヒドロフラン、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、トルエン若しくはキシレン等の芳香族炭化水素系溶媒、ｔｅｒｔ－ブタノール、又は、それらの混合溶媒が挙げられるが、ｔｅｒｔ－ブタノールが好ましい。 The reaction solvent used in the Curtius rearrangement reaction is appropriately selected depending on the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction. For example, a non-proton such as dimethylformamide, dimethylacetamide or dimethylsulfoxide Polar solvents, ether solvents such as diethyl ether, tetrahydrofuran, dimethoxyethane or 1,4-dioxane, aromatic hydrocarbon solvents such as toluene or xylene, tert-butanol, or a mixed solvent thereof. Tert-butanol is preferred.
　クルチウス転位反応の反応温度は、０～２００℃が好ましく、３０～１５０℃がより好ましい。 The reaction temperature of the Curtius rearrangement reaction is preferably 0 to 200 ° C, more preferably 30 to 150 ° C.
　クルチウス転位反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、通常１～４８時間程度で満足すべき結果が得られる。 The reaction time of the Curtius rearrangement reaction is appropriately selected according to the reaction temperature and other conditions, but satisfactory results are usually obtained in about 1 to 48 hours.
　クルチウス転位反応は、中間体である酸アジド及びイソシアナートを単離してもよいし、中間体である酸アジド及びイソシアナートを単離することなく求核剤との反応を行っても構わない。 In the Curtius rearrangement reaction, the acid azide and isocyanate that are intermediates may be isolated, or the reaction with a nucleophile may be performed without isolating the acid azide and isocyanate that are intermediates.
　クルチウス転位反応に用いるカルボン酸（ＸＩＩＩ）の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of carboxylic acid (XIII) used in the Curtius rearrangement reaction is preferably 1 mmol / L to 1 mol / L.
　本発明の医薬、中枢型ニコチン性アセチルコリン受容体活性化剤及び止痒剤は、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩を有効成分として含有することを特徴としている。 The medicament, central nicotinic acetylcholine receptor activator and antipruritic agent of the present invention are characterized by containing the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. .
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩は、中枢型ニコチン性アセチルコリン受容体（好ましくは、中枢型ニコチン性アセチルコリン受容体のα７サブタイプ）を活性化することを特徴としている。中枢型ニコチン性アセチルコリン受容体は様々な疾患に関与し、また、その活性化によって病態の改善又は症状の寛解が期待できることが知られていることから、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩は、中枢型ニコチン性アセチルコリン受容体（好ましくは、中枢型ニコチン性アセチルコリン受容体のα７サブタイプ）活性化によって病態の改善又は症状の寛解が期待できる疾患に対する医薬として用いることができる。 The quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is characterized by activating a central nicotinic acetylcholine receptor (preferably an α7 subtype of the central nicotinic acetylcholine receptor). It is said. Since the central nicotinic acetylcholine receptor is involved in various diseases, and it is known that its activation can be expected to improve the pathological condition or ameliorate symptoms, the quinuclidine urea derivative (I) or a drug thereof Physiologically acceptable salt is used as a medicament for a disease for which improvement of pathological condition or amelioration of symptoms can be expected by activating central nicotinic acetylcholine receptor (preferably, α7 subtype of central nicotinic acetylcholine receptor) be able to.
　「中枢型ニコチン性アセチルコリン受容体」とは、脳、延髄及び脊髄等の中枢神経系に発現しているニコチン性アセチルコリン受容体のことであり、中枢性ニコチン性アセチルコリン受容体、神経性ニコチン性アセチルコリン受容体又は神経型ニコチン性アセチルコリン受容体とも呼ばれる。 The “central nicotinic acetylcholine receptor” is a nicotinic acetylcholine receptor expressed in the central nervous system such as the brain, medulla and spinal cord. Central nicotinic acetylcholine receptor, neuronal nicotinic acetylcholine receptor Also called receptor or neuronal nicotinic acetylcholine receptor.
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩が活性化する中枢型ニコチン性アセチルコリン受容体としては、α７、α４β２、α４β４、α３β２又はα３β４が例示でき、α７サブタイプが好ましい。 As the central nicotinic acetylcholine receptor activated by the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof, α7, α4β2, α4β4, α3β2 or α3β4 can be exemplified, and the α7 subtype is preferable. .
　「中枢型ニコチン性アセチルコリン受容体を活性化する」とは、リガンドが当該受容体に結合することにより、当該受容体のチャネル部分が開口して、細胞外から陽イオンが流入し、細胞膜の脱分極又は細胞内シグナルの伝達等を促進することを意味する。 “Activating the central nicotinic acetylcholine receptor” means that when a ligand binds to the receptor, the channel portion of the receptor opens, and a cation flows from the outside of the cell. It means to promote polarization or transmission of intracellular signals.
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩が中枢型ニコチン性アセチルコリン受容体を活性化することは、Ｄｕｎｌｏｐらの文献（Ｂｉｏｃｈｅｍｉｃａｌ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００７年、第７４巻、ｐ．１１７２）に準じた方法により、中枢型ニコチン性アセチルコリン受容体を発現した細胞を用いたｉｎ　ｖｉｔｒｏの実験系で評価できる。例えば、中枢型ニコチン性アセチルコリン受容体の一つであるα７サブタイプをラット脳下垂体由来のＧＨ４Ｃ１細胞に発現させ、化合物の作用による細胞内カルシウム濃度の上昇を蛍光指示薬の蛍光強度を測定することで、活性化の強度を評価する方法である。 The fact that the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof activates the central nicotinic acetylcholine receptor is described in Dunlop et al. (Biochemical Pharmacology, 2007, Vol. 74, p. 1172) can be evaluated in an in vitro experimental system using cells expressing a central nicotinic acetylcholine receptor. For example, expressing α7 subtype, one of central nicotinic acetylcholine receptors, in GH4C1 cells derived from rat pituitary gland, and measuring the fluorescence intensity of the fluorescent indicator to increase intracellular calcium concentration due to the action of the compound In this method, the strength of activation is evaluated.
　中枢型ニコチン性アセチルコリン受容体（好ましくは、中枢型ニコチン性アセチルコリン受容体のα７サブタイプ）を活性化することが知られている化合物（例えば、バレニクリン酒石酸塩、Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－４－クロロベンズアミド塩酸塩、及び参考例２３～３２の化合物）は、参考例３３及び３４に示すように、中枢型ニコチン性アセチルコリン受容体を活性化することにより掻痒に対して優れた抑制効果を発揮する。したがって、中枢型ニコチン性アセチルコリン受容体（好ましくは、中枢型ニコチン性アセチルコリン受容体のα７サブタイプ）を活性化する化合物が、掻痒に対して優れた抑制効果を発揮することは明らかである。なお、バレニクリン酒石酸塩、Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－４－クロロベンズアミド塩酸塩、及び参考例２３～３２に記載の中枢型ニコチン性アセチルコリン受容体を活性化する化合物について、その特徴を下記に示す。 Compounds known to activate central nicotinic acetylcholine receptors (preferably the α7 subtype of central nicotinic acetylcholine receptors) (eg, varenicline tartrate, N- (1-azabicyclo [2. 2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride and compounds of Reference Examples 23 to 32), as shown in Reference Examples 33 and 34, the central nicotinic acetylcholine receptor When activated, it exhibits an excellent inhibitory effect against pruritus. Therefore, it is clear that a compound that activates the central nicotinic acetylcholine receptor (preferably the α7 subtype of the central nicotinic acetylcholine receptor) exerts an excellent inhibitory effect on pruritus. Varenicline tartrate, N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride, and central nicotinic acetylcholine described in Reference Examples 23 to 32 The characteristics of the compound that activates the receptor are shown below.
　バレニクリン（７，８，９，１０－テトラヒドロ－６Ｈ－６，１０－メタノピラジノ［２，３－ｈ］［３］ベンズアゼピン）及びその誘導体は、国際公開第９９／３５１３１号等に記載されており、主にα４β２及びα７サブタイプ活性化作用を示す（Ｍｉｈａｌａｋら、Ｍｏｌｅｃｕｌａｒ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００６年、第７０巻、ｐ．８０１）。（Ｒ）－２－クロロ－５－（２－アゼチジニルメトキシ）ピリジン及びその誘導体は、国際公開第９８／２５９２０号等に記載されており、主にα４β２サブタイプ活性化作用を示す（Ｄｏｎｎｅｌｌｙ－Ｒｏｂｅｒｔｓら、Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ　ａｎｄ　Ｅｘｐｅｒｉｍｅｎｔａｌ　Ｔｈｅｒａｐｅｕｔｉｃｓ、１９９８年、第２８５巻、ｐ．７７７）。Ｎ－（２（Ｓ）－（ピリジン－３－イルメチル）－１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－１－ベンゾフラン－２－カルボキシアミド及びその誘導体は、国際公開第０９／０１８５０５号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｈａｕｓｅｒら、Ｂｉｏｃｈｅｍｉｃａｌ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００９年、第７８巻、ｐ．８０３）。Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－４－クロロベンズアミド及びその誘導体は、欧州公開第３１１７２４号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｗａｌｋｅｒら、Ｂｉｏｏｒｇａｎｉｃ　＆　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、２００６年、第１４巻、ｐ．８２１９）。（Ｒ）－７－クロロ－Ｎ－（キヌクリジン－３－イル）ベンゾ［ｂ］チオフェン－２－カルボキシアミド及びその誘導体は、国際公開第０３／０５５８７８号等に記載されており、主にα７サブタイプ活性化作用を示す（国際公開第２０１０／１３２４２３号）。１，４－ジアザビシクロ［３．２．２］ノナン－４－カルボキシリックアシッド　４－ブロモフェニルエステル及びその誘導体は、欧州公開第１２３１２１２号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｂｉｔｏｎら、Ｎｅｕｒｏｐｓｙｃｈｏｐｈａｒｍａｃｏｌｏｇｙ、２００７年、第３２巻、ｐ．１）。２－（１，４－ジアザビシクロ［３．２．２］ノナ－４－イル）－５－メチルオキサゾロ［４，５－ｂ］ピリジン及びその誘導体は、Ｏ’Ｄｏｎｎｅｌｌら（Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、２０１０年、第５３巻、ｐ．１２２２）の報告等に記載されており、主にα７サブタイプ活性化作用を示す（Ｏ’Ｄｏｎｎｅｌｌら、Ｊｏｕｒｎａｌ　ｏｆ　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、２０１０年、第５３巻、ｐ．１２２２）。５－（４－モルホリニル）－Ｎ－（４－（３－ピリジル）フェニル）ペンタンアミド及びその誘導体は、国際公開第０６／００８１３３号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｈａｙｄａｒら、Ｂｉｏｏｒｇａｎｉｃ　＆　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、２００９年、第１７巻、ｐ．５２４７）。ｃｉｓ－２－メチル－５－（６－フェニルピリダジン－３－イル）パーヒドロピロロ［３，４－ｃ］ピロール及びその誘導体は、国際公開第０５／０２８４７７号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｔｉｅｔｊｅら、ＣＮＳ　Ｎｅｕｒｏｓｃｉｅｎｃｅ　＆　Ｔｈｅｒａｐｅｕｔｉｃｓ、２００８年、第１４巻、ｐ．６５）。（－）－Ｎ－（１－アザビシクロ［２，２，２］オクタ－３（Ｓ）－イル）カルバミックアシッド　１（Ｓ）－（２－フルオロフェニル）エチルエステル及びその誘導体は、Ｊｉａｎｇら（Ｓｙｎｔｈｅｔｉｃ　Ｃｏｍｍｕｎｉｃａｔｉｏｎｓ、２００９年、第３９巻、ｐ．２６４０）の報告等に記載されており、主にα７サブタイプ活性化作用を示す（Ｆｅｕｅｒｂａｃｈら、Ｎｅｕｒｏｓｃｉｅｎｃｅ　Ｌｅｔｔｅｒｓ、２００７年、第４１６巻、ｐ．６１）。Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）フロ［２，３－ｃ］ピリジン－５－カルボキシアミド及びその誘導体は、国際公開第０２／１００８５７号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｗａｌｋｅｒら、Ｂｉｏｏｒｇａｎｉｃ　＆　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、２００６年、第１４巻、ｐ．８２１９）。Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－２，３－ジヒドロ－１，４－ベンゾジオキシン－６－カルボキシアミド及びその誘導体は、国際公開第０３／０４２２１０号等に記載されており、主にα７サブタイプ活性化作用を示す（Ｗａｌｋｅｒら、Ｂｉｏｏｒｇａｎｉｃ　＆　Ｍｅｄｉｃｉｎａｌ　Ｃｈｅｍｉｓｔｒｙ、２００６年、第１４巻、ｐ．８２１９）。 Varenicline (7,8,9,10-tetrahydro-6H-6,10-methanopyrazino [2,3-h] [3] benzazepine) and its derivatives are described in WO 99/35131 and the like. It mainly exhibits α4β2 and α7 subtype activating effects (Mihalak et al., Molecular Pharmacology, 2006, Vol. 70, p. 801). (R) -2-Chloro-5- (2-azetidinylmethoxy) pyridine and its derivatives are described in International Publication No. 98/25920 and the like and mainly exhibit an α4β2 subtype activating action (Donnelly). -Roberts et al., Journal of Pharmacology and Experimental Therapeutics, 1998, 285, p. 777). N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran-2-carboxamide and its derivatives are It is described in Publication No. 09/018505, etc., and mainly exhibits an α7 subtype activation action (Hauser et al., Biochemical Pharmacology, 2009, Vol. 78, p. 803). N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide and its derivatives are described in European Publication No. 311724 and the like, and mainly have α7 subtype activity. (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219). (R) -7-Chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide and its derivatives are described in International Publication No. 03/055878 and the like. The type activating effect is shown (International Publication No. 2010/132423). 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester and its derivatives are described in European Publication No. 1231212 and the like, and mainly have an α7 subtype activation action. (Biton et al., Neuropsychopharmacology, 2007, vol. 32, p. 1). 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine and its derivatives are described in O'Donnell et al. (Journal of Medicinal Chemistry, 2010, Vol. 53, p. 1222) and the like, mainly exhibiting an α7 subtype activation action (O'Donnell et al., Journal of Medicinal Chemistry, 2010, Vol. 53, p. 122). 1222). 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide and its derivatives are described in WO 06/008133 and the like, and mainly have an α7 subtype activation action. (Haydar et al., Bioorganic & Medicinal Chemistry, 2009, Vol. 17, p. 5247). Cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole and its derivatives are described in International Publication No. 05/028477, etc. Activating the α7 subtype (Tietje et al., CNS Neuroscience & Therapeutics, 2008, Vol. 14, p. 65). (-)-N- (1-azabicyclo [2,2,2] octa-3 (S) -yl) carbamic acid 1 (S)-(2-fluorophenyl) ethyl ester and its derivatives are described in Jiang et al. Synthetic Communications, 2009, Vol. 39, p. 2640) and the like, which mainly exhibit an α7 subtype activation action (Feuerbach et al., Neuroscience Letters, 2007, Vol. 416, p. 61). ). N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide and derivatives thereof are disclosed in International Publication No. WO 02/100787 and the like. It mainly describes α7 subtype activation (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219). N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide and its derivatives are described in WO 03 / No. 042210 and the like, mainly exhibiting an α7 subtype activation action (Walker et al., Bioorganic & Medicinal Chemistry, 2006, Vol. 14, p. 8219).
　したがって、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩は、中枢型ニコチン性アセチルコリン受容体（好ましくは、中枢型ニコチン性アセチルコリン受容体のα７サブタイプ）活性化作用を有するため、当該作用メカニズムに基づき掻痒に対して優れた抑制効果を発揮し、止痒剤として用いることができる。 Therefore, the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof has an activating action on a central nicotinic acetylcholine receptor (preferably an α7 subtype of the central nicotinic acetylcholine receptor). Therefore, based on the said action mechanism, the inhibitory effect outstanding with respect to the pruritus is exhibited, and it can be used as an antipruritic agent.
　「掻痒」とは、引っ掻く欲求を伴う皮膚特有の感覚であり、例えば、アトピー性皮膚炎、神経性皮膚炎、接触性皮膚炎、脂漏性皮膚炎、自己感作性皮膚炎、毛虫皮膚炎、皮脂欠乏症、老人性皮膚掻痒、虫刺症、光線過敏症、蕁麻疹、痒疹、疱疹、膿痂疹、湿疹、白癬、苔癬、乾癬、疥癬若しくは尋常性座瘡等の皮膚疾患を原疾患とする掻痒、悪性腫瘍、糖尿病、肝疾患、慢性腎疾患、腎不全、血液疾患、血液透析、腹膜透析若しくは多発性硬化症を原疾患とする掻痒又は薬剤性若しくは心因性で起こる掻痒が挙げられる。また、掻痒は、ヒスタミンが介在する掻痒と、ヒスタミンが介在しない掻痒（難治性掻痒）とに大別されるが、本発明の止痒剤は、特に、ヒスタミンが介在しない掻痒（難治性掻痒）に対して有効である。ヒスタミンが介在しない掻痒（難治性掻痒）としては、例えば、アトピー性皮膚炎、接触性皮膚炎、皮脂欠乏症、老人性皮膚掻痒、蕁麻疹、乾癬、悪性腫瘍、肝疾患、慢性腎疾患、腎不全、血液疾患、血液透析、腹膜透析又は多発性硬化症等において抗ヒスタミン剤に対して治療抵抗性の掻痒が挙げられる。 “Itching” is a skin-specific sensation with a desire to scratch, such as atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis Skin diseases such as sebum deficiency, senile skin pruritus, insect bite, photosensitivity, urticaria, urticaria, shingles, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris Examples include pruritus, malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, blood disease, hemodialysis, peritoneal dialysis or multiple sclerosis, or pruritus caused by drug or psychosis. It is done. In addition, pruritus is roughly divided into itch mediated by histamine and pruritus not mediated by histamine (refractory pruritus). The antipruritic agent of the present invention is particularly itch free from histamine (refractory pruritus). It is effective against. Examples of pruritus without histamine (refractory pruritus) include atopic dermatitis, contact dermatitis, sebum deficiency, senile pruritus, urticaria, psoriasis, malignant tumor, liver disease, chronic kidney disease, renal failure In the case of blood diseases, hemodialysis, peritoneal dialysis, multiple sclerosis, etc., there is an itching that is resistant to antihistamines.
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩の止痒効果は、掻痒モデル動物を用いたｉｎ　ｖｉｖｏの実験系で評価でき、ヒスタミン、クロロキン又サブスタンスＰに代表される各種起痒物質によって惹起されるネズミの引っ掻き行動を指標とする掻痒モデルが一般的である。例えば、Ｔｏｇａｓｈｉらの文献（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００２年、第４３５巻、ｐ．２５９）やＡｎｄｏｈらの文献（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００２年、第４３６巻、ｐ．２３５）に記載されている、マウスを用いたサブスタンスＰ誘発引っ掻き行動や、Ｔａｋａｎｏらの文献（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００３年、第４７１巻、ｐ．２２３）に記載されている、ＮＣ／Ｎｇａ系マウスを用いた自発的引っ掻き行動は、ヒスタミンが介在しない難治性掻痒モデルの一つとして利用できるものである。 The antipruritic effect of the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof can be evaluated in an in vivo experimental system using a pruritus model animal, and various typified by histamine, chloroquine and substance P. A pruritus model that uses as an index the scratching behavior of a mouse caused by a causative substance is common. For example, Togashi et al. (European Journal of Pharmacology, 2002, Vol. 435, p. 259) and Andoh et al. (European Journal of Pharmacology, 2002, Vol. 436, p. 436). Substance P-induced scratching behavior using mice, and spontaneous scratching using NC / Nga mice described in Takano et al. (European Journal of Pharmacology, 2003, Vol. 471, p. 223). Behavior can be used as one of the intractable pruritus models not mediated by histamine.
　なお、サブスタンスＰが惹起するマウスの引っ掻き行動は、オピオイドμ受容体拮抗薬で抑制されるため、疼痛関連反応ではなく、掻痒関連反応であるとして認知されている（Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ　ａｎｄ　Ｅｘｐｅｒｉｍｅｎｔａｌ　Ｔｈｅｒａｐｅｕｔｉｃｓ、１９９８年、第２８６巻、ｐ．１１４０－１１４５）。 In addition, since the scratching behavior of mice caused by substance P is suppressed by an opioid μ receptor antagonist, it is recognized as a pruritus-related reaction, not a pain-related reaction (Journal of Pharmaceutical Therapies, 1998). Year, 286, pp. 1140-1145).
　また、マウスのサブスタンスＰ誘発引っ掻き行動は、免疫抑制剤のタクロリムス（Ｂｉｏｌｏｇｉｃａｌ　＆　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｂｕｌｌｅｔｉｎ、２００８年、第３１巻、ｐ．７５２）並びに抗炎症剤であるインドメタシン及びジクロフェナクによって抑制されないが、ロイコトリエンＢ４が起痒物質として関与し、その産生を阻害するステロイドによって引っ掻き行動が抑制されるため（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｎｖｅｓｔｉｇａｔｉｖｅ　Ｄｅｒｍａｔｏｌｏｇｙ、２００１年、第１１７巻、ｐ．１６２１－１６２６）、サブスタンスＰ誘発引っ掻き行動は、外因性のサブスタンスＰと内因性のロイコトリエンＢ４が急性的に神経を刺激することにより惹起され、免疫反応や炎症反応を介在しない掻痒モデルとして利用できるものである。 Moreover, substance P-induced scratching behavior in mice is not suppressed by the immunosuppressive agent tacrolimus (Biological & Pharmaceutical Bulletin, 2008, Vol. 31, p. 752) and the anti-inflammatory agents indomethacin and diclofenac, but leukotriene B4 Scratch behavior is suppressed by steroids that are involved as an initiator and inhibit its production (Journal of Investigative Dermatology, 2001, Vol. 117, pp. 1621-1626). Substance P-induced scratch behavior is exogenous. Substance P and endogenous leukotriene B4 are induced by acute nerve stimulation, and are an itching model that does not mediate immune or inflammatory reactions It is those that can be use.
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、イヌ、サル、ウシ、ヒツジ又はヒト）、特にヒトに対して投与した場合に、有用な医薬（特に、中枢型ニコチン性アセチルコリン受容体活性化剤又は止痒剤）として用いることができる。キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩を医薬として臨床で使用する際には、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩をそのまま用いてもよいし、賦形剤、安定化剤、保存剤、緩衝剤、溶解補助剤、乳化剤、希釈剤又は等張化剤等の添加剤が適宜混合されていてもよい。また、上記の医薬は、これらの薬剤用担体を適宜用いて、通常の方法によって製造することができる。上記の医薬の投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、散剤若しくはシロップ剤等による経口剤、吸入剤、注射剤、座剤若しくは液剤等による非経口剤又は局所投与をするための軟膏剤、クリーム剤若しくは貼付剤等が挙げられる。また、公知の持続型製剤としても構わない。 The quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is administered to a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human), particularly a human. In this case, it can be used as a useful medicament (in particular, a central nicotinic acetylcholine receptor activator or antipruritic agent). When clinically using the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof as a pharmaceutical, the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is used as it is. Alternatively, additives such as excipients, stabilizers, preservatives, buffering agents, solubilizers, emulsifiers, diluents or tonicity agents may be appropriately mixed. Moreover, said pharmaceutical can be manufactured by a normal method using these pharmaceutical carriers as appropriate. Examples of the above-mentioned pharmaceutical administration forms include oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or liquids, or topical administration. Examples include ointments, creams, patches, and the like. Further, it may be a known continuous preparation.
　上記の医薬は、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩を有効成分として０．００１～９０重量％含有することが好ましく、０．０１～７０重量％含有することがより好ましい。用量は症状、年齢、体重、性別、投与方法等に応じて適宜選択されるが、成人に対する有効成分量として、注射剤の場合１日０．００１ｍｇ～５ｇ、経口剤の場合０．０１ｍｇ～１０ｇであり、それぞれ１回又は数回に分けて投与することができる。 The above medicament preferably contains 0.001 to 90% by weight, preferably 0.01 to 70% by weight, of the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient. Is more preferable. The dose is appropriately selected according to symptoms, age, body weight, sex, administration method, etc. The amount of active ingredient for adults is 0.001 mg to 5 g per day for injections and 0.01 mg to 10 g for oral preparations. Each can be administered once or in several divided doses.
　上記の医薬の薬理学的に許容される担体又は希釈剤としては、例えば、結合剤（シロップ、ゼラチン、アラビアゴム、ソルビトール、ポリビニルクロリド又はトラガント等）、賦形剤（砂糖、乳糖、コーンスターチ、リン酸カルシウム、ソルビトール又はグリシン等）又は滑沢剤（ステアリン酸マグネシウム、ポリエチレングリコール、タルク又はシリカ等）を挙げることができる。 Examples of the pharmacologically acceptable carrier or diluent of the above-mentioned pharmaceutical include, for example, binders (syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride, tragacanth, etc.), excipients (sugar, lactose, corn starch, calcium phosphate, etc. Sorbitol, glycine, etc.) or lubricants (magnesium stearate, polyethylene glycol, talc, silica, etc.).
　上記の医薬は、その治療若しくは予防効果の補完若しくは増強又は投与量の低減のために、他の薬剤と適量配合又は併用して使用しても構わない。 The above medicines may be used in combination with or in combination with other drugs in order to supplement or enhance the therapeutic or preventive effect or reduce the dose.
　キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩を止痒剤として用いる際に併用し得る薬物としては、例えば、掻痒の原因となる以下の原疾患の治療に通常用いられる薬剤が挙げられる。 As a drug that can be used together when the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof is used as an antipruritic agent, for example, it is usually used for the treatment of the following primary diseases that cause pruritus. Drugs.
　掻痒の原疾患となる皮膚疾患としては、例えば、アトピー性皮膚炎、神経性皮膚炎、接触性皮膚炎、脂漏性皮膚炎、自己感作性皮膚炎、毛虫皮膚炎、皮脂欠乏症、老人性皮膚掻痒、虫刺症、光線過敏症、蕁麻疹、痒疹、疱疹、膿痂疹、湿疹、白癬、苔癬、乾癬、疥癬又は尋常性座瘡が挙げられる。また、その他の原疾患としては、例えば、悪性腫瘍、糖尿病、肝疾患、慢性腎疾患、腎不全、妊娠又は多発性硬化症が挙げられる。さらに、血液透析、腹膜透析又は薬剤が掻痒の原因となる場合や、妊娠、寄生虫感染が掻痒の原因となる場合や、心因性の掻痒も知られている。 Examples of skin diseases that are the primary diseases of pruritus include atopic dermatitis, neurodermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum deficiency, senile Skin pruritus, insect bites, photosensitivity, urticaria, urticaria, herpes, impetigo, eczema, ringworm, lichen, psoriasis, scabies or acne vulgaris. In addition, examples of other primary diseases include malignant tumor, diabetes, liver disease, chronic kidney disease, renal failure, pregnancy, and multiple sclerosis. Furthermore, it is also known that hemodialysis, peritoneal dialysis or drugs cause pruritus, pregnancy or parasitic infection causes pruritus, or psychogenic pruritus.
　アトピー性皮膚炎の治療に用いられる薬剤としては、例えば、ステロイド外用剤（ベタメタゾン、ベクロメタゾン、クロベタゾン又はプレドニゾロン等）、カルシニューリン阻害（免疫抑制）外用剤（タクロリムス等）、非ステロイド系消炎外用剤、抗ヒスタミン剤（ジフェンヒドラミン、クロルフェニラミン、セチリジン又はオキサトミド、ロラタジン等）、シクロスポリン、ステロイド内服又は保湿剤（尿素、ヒルドイド又はワセリン等）が挙げられる。また、多発性硬化症の治療に用いられる薬剤としては、例えば、副腎皮質ステロイド（プレドニゾロン又はメチルプレドニゾロン等）、免疫抑制剤（メトトレキサート、アザチオプリン、シクロフォスファミド、シクロスポリンＡ、タクロリムス又はミゾリビン等）、インターフェロン製剤（インターフェロンα又はインターフェロンβ等）、スフィンゴシン－１－リン酸受容体調節剤（ＦＴＹ－７２０）、コポリマーＩ、免疫グロブリン、Ｔ細胞レセプターワクチン、接着分子阻害剤、ＴＮＦα阻害剤、痙性を和らげる薬剤（チザニジン、エペリゾン、アフロクァロン、バクロフェン又はダントロレン等）又は鎮痛剤（インドメタシン、ジクロフェナク等）が挙げられる。 Examples of drugs used for the treatment of atopic dermatitis include, for example, steroid external preparations (betamethasone, beclomethasone, clobetasone or prednisolone, etc.), calcineurin inhibitory (immunosuppressive) external preparations (tacrolimus, etc.), non-steroidal anti-inflammatory external preparations, antihistamines (Diphenhydramine, chlorpheniramine, cetirizine or oxatomide, loratadine, etc.), cyclosporine, oral steroids or humectants (urea, hirudoid, petrolatum, etc.). Examples of drugs used for the treatment of multiple sclerosis include, for example, corticosteroids (such as prednisolone or methylprednisolone), immunosuppressants (methotrexate, azathioprine, cyclophosphamide, cyclosporin A, tacrolimus, mizoribine, etc.) Interferon preparation (such as interferon α or interferon β), sphingosine-1-phosphate receptor modulator (FTY-720), copolymer I, immunoglobulin, T cell receptor vaccine, adhesion molecule inhibitor, TNFα inhibitor, relieve spasticity Examples include drugs (tizanidine, eperisone, afroqualone, baclofen, dantrolene, etc.) or analgesics (indomethacin, diclofenac, etc.).
　以下の実施例により本発明をさらに詳細に説明するが、本発明は、これらによって限定されるものではない。 The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
　なお、実施例化合物の合成に使用される化合物で合成法の記載のないものについては、市販の化合物を使用した。ＮＭＲデータ中に示される溶媒名は、測定に使用した溶媒を示している。また、４００　ＭＨｚ　ＮＭＲスペクトルは、ＪＮＭ－ＡＬ４００型核磁気共鳴装置（日本電子社）を用いて測定した。ケミカルシフトは、テトラメチルシランを基準として、δ（単位：ｐｐｍ）で表し、シグナルはそれぞれｓ（一重線）、ｄ（二重線）、ｔ（三重線）、ｑ（四重線）、ｑｕｉｎｔ（五重線）、ｓｅｐｔ（七重線）、ｍ（多重線）、ｂｒ（幅広）、ｄｄ（二重二重線）、ｄｔ（二重三重線）、ｄｄｄ（二重二重二重線）、ｄｑ（二重四重線）、ｔｄ（三重二重線）、ｔｔ（三重三重線）で表した。ＥＳＩ－ＭＳスペクトルは、Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ　１２００　Ｓｅｒｉｅｓ、Ｇ６１３０Ａ（ＡｇｉｌｅｎｔＴｅｃｈｎｏｌｏｇｙ製）を用いて測定した。アミンシリカゲルは富士シリシア化学製アミンシリカゲルＤＭ１０２０を用い、クロマトグラフィーはＹＦＬＣ　Ｗ－ｐｒｅｐ２ＸＹ（山善社）を用いた。 In addition, about the compound which is not described in the synthesis method by the compound used for the synthesis | combination of an Example compound, the commercially available compound was used. The solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruplex line), quint, respectively. (Quintet), sept (sevent), m (multiple line), br (wide), dd (double double line), dt (double triple line), ddd (double double line) , Dq (double quadruple line), td (triple double line), and tt (triple triple line). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology). As the amine silica gel, amine silica gel DM1020 manufactured by Fuji Silysia Chemical Ltd. was used, and YFLC W-prep2XY (Yamazensha) was used for chromatography.
（参考例１）　（Ｒ）－Ｎ－メチルキヌクリジン－３－アミンの合成：
Figure JPOXMLDOC01-appb-C000015
 　（Ｒ）－キヌクリジン－３－アミン　二塩酸塩（２．０ｇ、１０ｍｍｏｌ）をジクロロメタン（３０ｍＬ）に懸濁し、ジイソプロピルエチルアミン（７．０ｍＬ、４０ｍｍｏｌ）、クロロギ酸エチル（１．２ｍＬ、１２ｍｍｏｌ）を０℃で加えた。室温で３０分間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Reference Example 1 Synthesis of (R) -N-methylquinuclidin-3-amine:
Figure JPOXMLDOC01-appb-C000015
 (R) -Quinuclidin-3-amine dihydrochloride (2.0 g, 10 mmol) was suspended in dichloromethane (30 mL), and diisopropylethylamine (7.0 mL, 40 mmol) and ethyl chloroformate (1.2 mL, 12 mmol) were suspended in 0. Added at ° C. After stirring at room temperature for 30 minutes, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をテトラヒドロフラン（３０ｍＬ）に溶解し、水素化リチウムアルミニウム（０．７６ｇ、２０ｍｍｏｌ）を０℃で加えた。６０℃で４時間攪拌した後、反応溶液を室温まで冷却し、飽和ロッシェル塩水溶液を０℃で加えて、室温で１時間攪拌して、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．６１ｇ（４３％）を淡黄色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．２９－１．３７（ｍ、１Ｈ）、１．４３－１．５０（ｍ、１Ｈ）、１．６３－１．７１（ｍ、１Ｈ）、１．７５－１．８４（ｍ、２Ｈ）、２．３９（ｓ、３Ｈ）、２．４１－２．４３（ｍ、１Ｈ）、２．５８－２．６２（ｍ、１Ｈ）、２．７２－２．９１（ｍ、４Ｈ）、３．０９－３．１５（ｍ、１Ｈ）． The above crude product was dissolved in tetrahydrofuran (30 mL) and lithium aluminum hydride (0.76 g, 20 mmol) was added at 0 ° C. After stirring at 60 ° C. for 4 hours, the reaction solution was cooled to room temperature, a saturated Rochelle salt aqueous solution was added at 0 ° C., stirred at room temperature for 1 hour, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.61 g (43%) was obtained as a pale yellow liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.29-1.37 (m, 1H), 1.43-1.50 (m, 1H), 1.63-1.71 (m, 1H), 1.75-1.84 (m 2H), 2.39 (s, 3H), 2.41-2.43 (m, 1H), 2.58-2.62 (m, 1H), 2.72-2.91 (m, 4H) ), 3.09-3.15 (m, 1H).
（参考例２）　ベンゾ［ｂ］チオフェン－２－アミンの合成：
Figure JPOXMLDOC01-appb-C000016
 　ベンゾ［ｂ］チオフェン－２－カルボン酸（０．７５ｇ、４．２ｍｍｏｌ）をｔｅｒｔ－ブタノール（８．４ｍＬ）に溶解し、トリエチルアミン（０．７０ｍＬ、５．１ｍｍｏｌ）、ジフェニルホスホリルアジド（０．９９ｍＬ、４．６ｍｍｏｌ）を室温で加えた。８０℃で４時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Reference Example 2 Synthesis of benzo [b] thiophen-2-amine:
Figure JPOXMLDOC01-appb-C000016
 Benzo [b] thiophene-2-carboxylic acid (0.75 g, 4.2 mmol) was dissolved in tert-butanol (8.4 mL), triethylamine (0.70 mL, 5.1 mmol), diphenylphosphoryl azide (0.99 mL). 4.6 mmol) was added at room temperature. After stirring at 80 ° C. for 4 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物を１，４－ジオキサン（４．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、１３ｍＬ、５１ｍｍｏｌ）を０℃で加えた。室温で２時間攪拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物０．５０ｇ（７９％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:４．０３（ｂｒｓ、２Ｈ）、６．２９（ｓ、１Ｈ）、７．０７－７．１１（ｍ、１Ｈ）、７．２１－７．２６（ｍ、１Ｈ）、７．４２（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、７．５７（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）． The above crude product was dissolved in 1,4-dioxane (4.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 13 mL, 51 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 80/20) to give 0.50 g (79%) of the title compound as a brown solid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 4.03 (brs, 2H), 6.29 (s, 1H), 7.07-7.11 (m, 1H), 7.21-7.26 (m, 1H), 7.42 ( d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H).
（実施例１）　（Ｒ）－３－（ベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000017
 　トリホスゲン（０．１２ｇ、０．４１ｍｍｏｌ）をジクロロメタン（３．０ｍＬ）に溶解し、ベンゾ［ｂ］チオフェン－２－アミン（０．１８ｇ、１．２ｍｍｏｌ）、トリエチルアミン（０．５０ｍＬ、３．６ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ジクロロメタン（３．０ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１７ｇ、１．２ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．２４ｇ（６２％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０－１．５８（ｍ、１Ｈ）、１．６２－１．６７（ｍ、１Ｈ）、１．７６－１．８４（ｍ、２Ｈ）、２．０３－２．０４（ｍ、１Ｈ）、２．８７－２．９７（ｍ、４Ｈ）、３．０２－３．０６（ｍ、１Ｈ）、３．１５（ｓ、３Ｈ）、３．３０－３．３７（ｍ、１Ｈ）、４．３８－４．４２（ｍ、１Ｈ）、６．８１（ｓ、１Ｈ）、７．１８－７．２１（ｍ、１Ｈ）、７．２８－７．３０（ｍ、１Ｈ）、７．４０（ｂｒｓ、１Ｈ）、７．５６（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．７１（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３１６［Ｍ＋Ｈ］＋． Example 1 Synthesis of (R) -3- (benzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000017
 Triphosgene (0.12 g, 0.41 mmol) was dissolved in dichloromethane (3.0 mL) and benzo [b] thiophen-2-amine (0.18 g, 1.2 mmol), triethylamine (0.50 mL, 3.6 mmol). Was added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.17 g, 1.2 mmol) dissolved in dichloromethane (3.0 mL) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.24 g (62%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.58 (m, 1H), 1.62-1.67 (m, 1H), 1.76-1.84 (m, 2H), 2.03-2.04 (m 1H), 2.87-2.97 (m, 4H), 3.02-3.06 (m, 1H), 3.15 (s, 3H), 3.30-3.37 (m, 1H) ) 4.38-4.42 (m, 1H), 6.81 (s, 1H), 7.18-7.21 (m, 1H), 7.28-7.30 (m, 1H), 7.40 (brs, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H).
MS (ESI): 316 [M + H] < +>.
（実施例２）　（Ｒ）－３－（ベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000018
 　（Ｒ）－３－（ベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．４０ｇ、１．２７ｍｍｏｌ）を１，４－ジオキサン（２５ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．４８ｍＬ、１．９ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．３５ｇ（７８％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７５－１．８２（ｍ、１Ｈ）、１．８４－１．９４（ｍ、２Ｈ）、１．９６－２．０６（ｍ、１Ｈ）、２．２１－２．２３（ｍ、１Ｈ）、３．０８（ｓ、３Ｈ）、３．１８－３．３１（ｍ、４Ｈ）、３．３６－３．４２（ｍ、１Ｈ）、３．６０－３．６６（ｍ、１Ｈ）、４．４０－４．４４（ｍ、１Ｈ）、６．９７（ｓ、１Ｈ）、７．１３（ｔ、Ｊ＝６．８Ｈｚ、１Ｈ）、７．２４（ｔ、Ｊ＝６．８Ｈｚ、１Ｈ）、７．５９（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．７３（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、１０．０８（ｓ、１Ｈ）、１０．１４（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３１６［Ｍ＋Ｈ］＋． Example 2 Synthesis of (R) -3- (benzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000018
 (R) -3- (Benzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.40 g, 1.27 mmol) was added to 1,4-dioxane (25 mL). And a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.48 mL, 1.9 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.35 g (78%) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.75-1.82 (m, 1H), 1.84-1.94 (m, 2H), 1.96-2.06 (m, 1H), 2.21-2.23 (m 1H), 3.08 (s, 3H), 3.18-3.31 (m, 4H), 3.36-3.42 (m, 1H), 3.60-3.66 (m, 1H) ), 4.40-4.44 (m, 1H), 6.97 (s, 1H), 7.13 (t, J = 6.8 Hz, 1H), 7.24 (t, J = 6.8 Hz) 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 10.08 (s, 1H), 10.14 (brs, 1H) ).
MS (ESI): 316 [M + H] < +>.
（参考例３）　３－（ジメチルアミノ）－２－ホルミルアクリル酸エチルの合成：
Figure JPOXMLDOC01-appb-C000019
 　３，３－ジエトキシプロパン酸エチル（２．６ｇ、１４ｍｍｏｌ）をジクロロメタン（１４ｍＬ）に溶解し、トリフルオロ酢酸（８．０ｍＬ、１０ｍｍｏｌ）、蒸留水（８．０ｍＬ）を室温で加えた。同温度で２時間攪拌した後、クロロホルムで抽出した。有機層を飽和食塩水にて洗浄後、無水硫酸ナトリウムにより乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の粗生成物にジメチルホルムアミドジメチルアセタール（９．２ｍＬ、６８ｍｍｏｌ）を室温で加えた。８０℃で２時間撹拌した後、反応溶液を室温まで冷却し、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０－２５／７５、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．９５ｇ（４１％）を黄色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．３１（ｔ、Ｊ＝７．２Ｈｚ、３Ｈ）、３．１６（ｓ、３Ｈ）、３．３２（ｓ、３Ｈ）、４．２３（ｑ、Ｊ＝７．２Ｈｚ、２Ｈ）、７．７４（ｓ、１Ｈ）、９．７１（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：１７２［Ｍ＋Ｈ］＋． Reference Example 3 Synthesis of ethyl 3- (dimethylamino) -2-formylacrylate:
Figure JPOXMLDOC01-appb-C000019
 Ethyl 3,3-diethoxypropanoate (2.6 g, 14 mmol) was dissolved in dichloromethane (14 mL), and trifluoroacetic acid (8.0 mL, 10 mmol) and distilled water (8.0 mL) were added at room temperature. The mixture was stirred at the same temperature for 2 hours and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
Dimethylformamide dimethyl acetal (9.2 mL, 68 mmol) was added to the above crude product at room temperature. After stirring at 80 ° C. for 2 hours, the reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-25 / 75, chloroform only-chloroform / methanol = 95/5) to give 0.95 g (41%) of the title compound. Obtained as a yellow liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.31 (t, J = 7.2 Hz, 3H), 3.16 (s, 3H), 3.32 (s, 3H), 4.23 (q, J = 7.2 Hz, 2H), 7.74 (s, 1H), 9.71 (s, 1H).
MS (ESI): 172 [M + H] < +>.
（参考例４）　１－フェニル－１Ｈ－ピラゾール－４－カルボン酸エチルの合成：
Figure JPOXMLDOC01-appb-C000020
 　３－（ジメチルアミノ）－２－ホルミルアクリル酸エチル（０．３８ｇ、２．２ｍｍｏｌ）をエタノール（１５ｍＬ）に溶解し、フェニルヒドラジン（０．２４ｇ、２．２ｍｍｏｌ）を室温で加えた。８０℃で３時間撹拌した後、反応溶液を室温まで冷却し、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７８／２２）で精製し、表題化合物０．４７ｇ（９８％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．３８（ｔ、Ｊ＝７．２Ｈｚ、３Ｈ）、４．３４（ｑ、Ｊ＝７．２Ｈｚ、２Ｈ）、７．３３－７．３９（ｍ、１Ｈ）、７．４６－７．５３（ｍ、２Ｈ）、７．６７－７．７３（ｍ、２Ｈ）、８．１０（ｂｒｓ、１Ｈ）、８．４１（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２１７［Ｍ＋Ｈ］＋． Reference Example 4 Synthesis of ethyl 1-phenyl-1H-pyrazole-4-carboxylate:
Figure JPOXMLDOC01-appb-C000020
 Ethyl 3- (dimethylamino) -2-formylacrylate (0.38 g, 2.2 mmol) was dissolved in ethanol (15 mL), and phenylhydrazine (0.24 g, 2.2 mmol) was added at room temperature. After stirring at 80 ° C. for 3 hours, the reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 78/22) to obtain 0.47 g (98%) of the title compound as a colorless liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.38 (t, J = 7.2 Hz, 3H), 4.34 (q, J = 7.2 Hz, 2H), 7.33-7.39 (m, 1H), 7.46-7 .53 (m, 2H), 7.67-7.73 (m, 2H), 8.10 (brs, 1H), 8.41 (brs, 1H).
MS (ESI): 217 [M + H] < +>.
（参考例５）　１－フェニル－１Ｈ－ピラゾール－４－カルボン酸の合成：
Figure JPOXMLDOC01-appb-C000021
 　１－フェニル－１Ｈ－ピラゾール－４－カルボン酸エチル（０．４７ｇ、２．２ｍｍｏｌ）をメタノール（７．０ｍＬ）に溶解し、１．０Ｎ水酸化ナトリウム水溶液（６．５ｍＬ、６．５ｍｍｏｌ）を０℃で加えた。５０℃で３時間撹拌した後、室温まで冷却し、反応溶液を減圧濃縮し、酢酸エチルで抽出した。水層に１．０Ｎ塩酸水溶液を０℃で加えて、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮し、表題化合物０．３９ｇ（９５％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ７．３５－７．４１（ｍ、１Ｈ）、７．４７－７．５３（ｍ、２Ｈ）、７．７０－７．７４（ｍ、２Ｈ）、８．１７（ｂｒｓ、１Ｈ）、８．４７（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：１８９［Ｍ＋Ｈ］＋． Reference Example 5 Synthesis of 1-phenyl-1H-pyrazole-4-carboxylic acid:
Figure JPOXMLDOC01-appb-C000021
 Ethyl 1-phenyl-1H-pyrazole-4-carboxylate (0.47 g, 2.2 mmol) was dissolved in methanol (7.0 mL), and 1.0N aqueous sodium hydroxide solution (6.5 mL, 6.5 mmol) was added. Added at 0 ° C. After stirring at 50 ° C. for 3 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and extracted with ethyl acetate. A 1.0N hydrochloric acid aqueous solution was added to the aqueous layer at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to give 0.39 g (95%) of the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 7.35-7.41 (m, 1H), 7.47-7.53 (m, 2H), 7.70-7.74 (m, 2H), 8.17 (brs, 1H), 8.47 (brs, 1H).
MS (ESI): 189 [M + H] < +>.
（参考例６）　１－フェニル－１Ｈ－ピラゾール－４－アミンの合成：
Figure JPOXMLDOC01-appb-C000022
 　１－フェニル－１Ｈ－ピラゾール－４－カルボン酸（０．５０ｇ、２．７ｍｍｏｌ）をｔｅｒｔ－ブタノール（７．０ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．５１ｍＬ、２．９ｍｍｏｌ）、ジフェニルホスホリルアジド（０．６９ｍＬ、３．２ｍｍｏｌ）を室温で加えた。８０℃で４時間撹拌した後、反応溶液を室温まで冷却し、水を加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７８／２２）で精製した。 Reference Example 6 Synthesis of 1-phenyl-1H-pyrazol-4-amine:
Figure JPOXMLDOC01-appb-C000022
 1-Phenyl-1H-pyrazole-4-carboxylic acid (0.50 g, 2.7 mmol) was dissolved in tert-butanol (7.0 mL), and diisopropylethylamine (0.51 mL, 2.9 mmol), diphenylphosphoryl azide ( 0.69 mL, 3.2 mmol) was added at room temperature. After stirring at 80 ° C. for 4 hours, the reaction solution was cooled to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 78/22).
　上記の生成物を１，４－ジオキサン（３．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、８．０ｍＬ、３２ｍｍｏｌ）を０℃で加えた。室温で１６時間撹拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。溶媒を濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７９／２１、クロロホルムのみ－クロロホルム／メタノール＝８５／１５）で精製し、表題化合物０．２６ｇ（６１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ３．００－３．１５（ｍ、２Ｈ）、７．２０－７．２６（ｍ、２Ｈ）、７．３８－７．４４（ｍ、２Ｈ）、７．５２（ｓ、１Ｈ）、７．５９－７．６３（ｍ、２Ｈ）． 
ＭＳ（ＥＳＩ）：１６０［Ｍ＋Ｈ］＋． The above product was dissolved in 1,4-dioxane (3.0 mL), and hydrogen chloride-1,4-dioxane solution (4.0 N, 8.0 mL, 32 mmol) was added at 0 ° C. After stirring at room temperature for 16 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After concentrating the solvent, the obtained crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 79/21, chloroform only-chloroform / methanol = 85/15) to give 0.26 g of the title compound. (61%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 3.00-3.15 (m, 2H), 7.20-7.26 (m, 2H), 7.38-7.44 (m, 2H), 7.52 (s, 1H), 7.59-7.63 (m, 2H).
MS (ESI): 160 [M + H] + .
（実施例３）　（Ｒ）－１－メチル－３－（１－フェニル－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000023
 　１－フェニル－１Ｈ－ピラゾール－４－アミン（０．０６８ｇ、０．４３ｍｍｏｌ）をジクロロメタン（２．１ｍＬ）に溶解し、トリホスゲン（０．０４３ｇ、０．１５ｍｍｏｌ）、トリエチルアミン（０．１８ｍＬ、１．３ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌した後、ジクロロメタン（２．１ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０６０ｇ、０．４３ｍｍｏｌ）を０℃で滴下した。室温で３時間撹拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ－クロロホルム／メタノール＝９０／１０）で精製し、表題化合物０．０４６ｇ（３３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．５７－１．８５（ｍ、４Ｈ）、１．９４－２．００（ｍ、１Ｈ）、２．７７－３．０５（ｍ、５Ｈ）、３．１３（ｓ、３Ｈ）、３．２２－３．３２（ｍ、１Ｈ）、４．３４－４．４２（ｍ、１Ｈ）、６．２８－６．３３（ｍ、１Ｈ）、７．２２－７．３０（ｍ、１Ｈ）、７．４２（ｄｄ、Ｊ＝８．０、８．０Ｈｚ、２Ｈ）、７．６０（ｓ、１Ｈ）、７．６８（ｄ、Ｊ＝８．０Ｈｚ、２Ｈ）、８．３５（ｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］＋． Example 3 Synthesis of (R) -1-methyl-3- (1-phenyl-1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000023
 1-Phenyl-1H-pyrazol-4-amine (0.068 g, 0.43 mmol) was dissolved in dichloromethane (2.1 mL), triphosgene (0.043 g, 0.15 mmol), triethylamine (0.18 mL, 1. 3 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.060 g, 0.43 mmol) dissolved in dichloromethane (2.1 mL) was added dropwise at 0 ° C. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel column chromatography (chloroform only-chloroform / methanol = 90/10) to obtain 0.046 g (33%) of the title compound as a white solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.57-1.85 (m, 4H), 1.94-2.00 (m, 1H), 2.77-3.05 (m, 5H), 3.13 (s, 3H), 3.22-3.32 (m, 1H), 4.34-4.42 (m, 1H), 6.28-6.33 (m, 1H), 7.22-7.30 (m, 1H) ), 7.42 (dd, J = 8.0, 8.0 Hz, 2H), 7.60 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 8.35 (s) 1H).
MS (ESI): 326 [M + H] < +>.
（実施例４）　（Ｒ）－１－メチル－３－（１－フェニル－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000024
 （Ｒ）－１－メチル－３－（１－フェニル－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア（０．４１ｇ、１．３ｍｍｏｌ）をジエチルエーテル（１３ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．４１ｍＬ、１．６ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌した後、ろ過し、ろ取した固体をジエチルエーテルで洗浄後に乾燥し、表題化合物０．３７ｇ（８１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、Ｄ２Ｏ）
δ: １．８２－２．１５（ｍ、５Ｈ）、２．８１（ｓ、３Ｈ）、３．１４－３．４３（ｍ、５Ｈ）、３．５４－３．６３（ｍ、１Ｈ）、４．２３－４．３２（ｍ、１Ｈ）、７．２５－７．３０（ｍ、１Ｈ）、７．４０－７．５８（ｍ、５Ｈ）、７．８７（ｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］＋． Example 4 Synthesis of (R) -1-methyl-3- (1-phenyl-1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000024
 (R) -1-methyl-3- (1-phenyl-1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea (0.41 g, 1.3 mmol) was added to diethyl ether (13 mL). Dissolved and hydrogen chloride-1,4-dioxane solution (4.0 N, 0.41 mL, 1.6 mmol) was added at 0 ° C. The mixture was stirred at the same temperature for 30 minutes, filtered, and the solid collected by filtration was washed with diethyl ether and dried to give 0.37 g (81%) of the title compound as a white solid.
1 H-NMR (400 MHz, D 2 O)
δ: 1.82-2.15 (m, 5H), 2.81 (s, 3H), 3.14-3.43 (m, 5H), 3.54-3.63 (m, 1H), 4.23-4.32 (m, 1H), 7.25-7.30 (m, 1H), 7.40-7.58 (m, 5H), 7.87 (s, 1H).
MS (ESI): 326 [M + H] < +>.
（実施例５）　（Ｒ）－１－メチル－３－フェニル－１－（キヌクリジン－３－イル）ウレアの合成
Figure JPOXMLDOC01-appb-C000025
 　アニリン（０．０６０ｇ、０．６４ｍｍｏｌ）をジクロロメタン（３．２ｍＬ）に溶解し、トリホスゲン（０．０６５ｇ、０．２２ｍｍｏｌ）、トリエチルアミン（０．２７ｍＬ、１．９ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌した後、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０９０ｇ、０．６４ｍｍｏｌ）を加えた。室温で３時間撹拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．０４９ｇ（２９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．４２－１．５２（ｍ、１Ｈ）、１．５５－１．８１（ｍ、３Ｈ）、１．９１－１．９６（ｍ、１Ｈ）、２．７２－３．００（ｍ、５Ｈ）、３．０７（ｓ、３Ｈ）、３．１８－３．２６（ｍ、１Ｈ）、４．２７－４．３４（ｍ、１Ｈ）、６．４６－６．５４（ｍ、１Ｈ）、６．９８－７．０５（ｍ、１Ｈ）、７．２３－７．２９（ｍ、２Ｈ）、７．３６－７．３９（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：２６０［Ｍ＋Ｈ］＋． Example 5 Synthesis of (R) -1-methyl-3-phenyl-1- (quinuclidin-3-yl) urea
Figure JPOXMLDOC01-appb-C000025
 Aniline (0.060 g, 0.64 mmol) was dissolved in dichloromethane (3.2 mL), and triphosgene (0.065 g, 0.22 mmol) and triethylamine (0.27 mL, 1.9 mmol) were added at 0 ° C. After stirring for 30 minutes at the same temperature, (R) -N-methylquinuclidin-3-amine (0.090 g, 0.64 mmol) was added. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel column chromatography (chloroform only-chloroform / methanol = 95/5) to give 0.049 g (29%) of the title compound as a white solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.42-1.52 (m, 1H), 1.55-1.81 (m, 3H), 1.91-1.96 (m, 1H), 2.72-3.00 (m 5H), 3.07 (s, 3H), 3.18-3.26 (m, 1H), 4.27-4.34 (m, 1H), 6.46-6.54 (m, 1H) ), 6.98-7.05 (m, 1H), 7.23-7.29 (m, 2H), 7.36-7.39 (m, 2H).
MS (ESI): 260 [M + H] < +>.
（参考例７）　（Ｒ）－Ｎ－エチルキヌクリジン－３－アミンの合成：
Figure JPOXMLDOC01-appb-C000026
 　（Ｒ）－キヌクリジン－３－アミン　二塩酸塩（１．５ｇ、７．５ｍｍｏｌ）をジクロロメタン（２３ｍＬ）に懸濁し、トリエチルアミン（４．２ｍＬ、３０ｍｍｏｌ）、塩化アセチル（０．６４ｍＬ、９．０ｍｍｏｌ）を０℃で加えた。室温で２時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Reference Example 7 Synthesis of (R) -N-ethylquinuclidin-3-amine:
Figure JPOXMLDOC01-appb-C000026
 (R) -Quinuclidin-3-amine dihydrochloride (1.5 g, 7.5 mmol) was suspended in dichloromethane (23 mL), triethylamine (4.2 mL, 30 mmol), acetyl chloride (0.64 mL, 9.0 mmol). Was added at 0 ° C. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をテトラヒドロフラン（２３ｍＬ）に溶解し、水素化リチウムアルミニウム（０．５７ｇ、１５ｍｍｏｌ）を０℃で加えた。６０℃で５時間攪拌した後、反応溶液を室温まで冷却し、飽和ロッシェル塩水溶液を０℃で加え、室温で１時間攪拌して、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．６２ｇ（５３％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．１１（ｔ、Ｊ＝７．２Ｈｚ、３Ｈ）、１．２９－１．３５（ｍ、１Ｈ）、１．４４－１．５０（ｍ、１Ｈ）、１．６２－１．６８（ｍ、１Ｈ）、１．７５－１．８３（ｍ、２Ｈ）、２．３９（ｄｑ、Ｊ＝２．４、１３．６Ｈｚ、１Ｈ）、２．５４－２．９０（ｍ、７Ｈ）、３．１３（ｄｑ、Ｊ＝２．４、８．８Ｈｚ、１Ｈ）． The above crude product was dissolved in tetrahydrofuran (23 mL) and lithium aluminum hydride (0.57 g, 15 mmol) was added at 0 ° C. After stirring at 60 ° C. for 5 hours, the reaction solution was cooled to room temperature, a saturated Rochelle salt aqueous solution was added at 0 ° C., stirred at room temperature for 1 hour, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.62 g (53%) was obtained as a colorless liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.11 (t, J = 7.2 Hz, 3H), 1.29-1.35 (m, 1H), 1.44-1.50 (m, 1H), 1.62-1.68 (M, 1H), 1.75-1.83 (m, 2H), 2.39 (dq, J = 2.4, 13.6 Hz, 1H), 2.54-2.90 (m, 7H) 3.13 (dq, J = 2.4, 8.8 Hz, 1H).
（実施例６）　（Ｒ）－３－（ベンゾ［ｂ］チオフェン－２－イル）－１－エチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000027
 　トリホスゲン（０．１２ｇ、０．４１ｍｍｏｌ）をジクロロメタン（３．０ｍＬ）に溶解し、ベンゾ［ｂ］チオフェン－２－アミン（０．１８ｇ、１．２ｍｍｏｌ）、トリエチルアミン（０．５０ｍＬ、３．６ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ジクロロメタン（３．０ｍＬ）に溶解した（Ｒ）－Ｎ－エチルキヌクリジン－３－アミン（０．１９ｇ、１．２ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１８ｇ（４５％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．１９（ｔ、Ｊ＝７．２Ｈｚ、３Ｈ）、１．６１－１．６８（ｍ、１Ｈ）、１．９１－２．００（ｍ、２Ｈ）、２．０８－２．１２（ｍ、１Ｈ）、２．２７－２．２９（ｍ、１Ｈ）、３．０６－３．１０（ｍ、１Ｈ）、３．１９－３．２８（ｍ、４Ｈ）、３．４５－３．５０（ｍ、１Ｈ）、３．８０－３．８６（ｍ、２Ｈ）、４．１８－４．２０（ｍ、１Ｈ）、７．１６－７．２０（ｍ、２Ｈ）、７．２６－７．３０（ｍ、１Ｈ）、７．５７（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．７０（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３３０［Ｍ＋Ｈ］＋． Example 6 Synthesis of (R) -3- (benzo [b] thiophen-2-yl) -1-ethyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000027
 Triphosgene (0.12 g, 0.41 mmol) was dissolved in dichloromethane (3.0 mL) and benzo [b] thiophen-2-amine (0.18 g, 1.2 mmol), triethylamine (0.50 mL, 3.6 mmol). Was added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-ethylquinuclidin-3-amine (0.19 g, 1.2 mmol) dissolved in dichloromethane (3.0 mL) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.18 g (45%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.19 (t, J = 7.2 Hz, 3H), 1.61-1.68 (m, 1H), 1.91-2.00 (m, 2H), 2.08-2.12 (M, 1H), 2.27-2.29 (m, 1H), 3.06-3.10 (m, 1H), 3.19-3.28 (m, 4H), 3.45-3 .50 (m, 1H), 3.80-3.86 (m, 2H), 4.18-4.20 (m, 1H), 7.16-7.20 (m, 2H), 7.26 -7.30 (m, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H).
MS (ESI): 330 [M + H] < +>.
（実施例７）　（Ｒ）－３－（ベンゾ［ｂ］チオフェン－２－イル）－１－エチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000028
 　（Ｒ）－３－（ベンゾ［ｂ］チオフェン－２－イル）－１－エチル－１－（キヌクリジン－３－イル）ウレア（０．１８ｇ、０．５４ｍｍｏｌ）を１，４－ジオキサン（１１ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．２０ｍＬ、０．８０ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１５ｇ（７６％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．２４（ｔ、Ｊ＝７．２Ｈｚ、３Ｈ）、１．４８－１．５４（ｍ、１Ｈ）、１．６２－１．１．８０（ｍ、４Ｈ）、１．９９－２．０１（ｍ、１Ｈ）、２．７８－２．８８（ｍ、４Ｈ）、２．９０－３．０４（ｍ、１Ｈ）、３．２９－３．３５（ｍ、１Ｈ）、３．４６－３．６１（ｍ、２Ｈ）、４．２２－４．２７（ｍ、１Ｈ）、６．７４（ｓ、１Ｈ）、７．１３（ｓ、１Ｈ）、７．１７－７．２１（ｍ、１Ｈ）、７．２６－７．３０（ｍ、１Ｈ）、７．５５（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．７１（ｄ、Ｊ＝６．８Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３３０［Ｍ＋Ｈ］＋． Example 7 Synthesis of (R) -3- (benzo [b] thiophen-2-yl) -1-ethyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000028
 (R) -3- (Benzo [b] thiophen-2-yl) -1-ethyl-1- (quinuclidin-3-yl) urea (0.18 g, 0.54 mmol) was added to 1,4-dioxane (11 mL). And a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.20 mL, 0.80 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.15 g (76%) of the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.24 (t, J = 7.2 Hz, 3H), 1.48-1.54 (m, 1H), 1.62-1.80 (m, 4H), 1.99-2 .01 (m, 1H), 2.78-2.88 (m, 4H), 2.90-3.04 (m, 1H), 3.29-3.35 (m, 1H), 3.46 -3.61 (m, 2H), 4.22-4.27 (m, 1H), 6.74 (s, 1H), 7.13 (s, 1H), 7.17-7.21 (m 1H), 7.26-7.30 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 6.8 Hz, 1H).
MS (ESI): 330 [M + H] < +>.
（参考例８）　７－クロロベンゾ［ｂ］チオフェン－２－カルボン酸の合成：
Figure JPOXMLDOC01-appb-C000029
 　水酸化カリウム（３．６ｇ、６４ｍｍｏｌ）を蒸留水（６４ｍＬ）に溶解し、２，３－ジクロロベンズアルデヒド（５．０ｇ、２９ｍｍｏｌ）、２－メルカプト酢酸（２．０ｍＬ、２９ｍｍｏｌ）を室温で加えた。１２０℃で６時間撹拌した後、反応溶液を室温まで冷却し、析出した固体が溶解するまで蒸留水を加えた後、ジエチルエーテルで抽出した。水層に対して０℃で１．０Ｎ塩酸を加え、同温度で３０分間攪拌した後、ろ過し、ろ取した固体をジエチルエーテル、ヘキサンで洗浄後に乾燥し、表題化合物４．８ｇ（７８％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ：７．５２（ｄｄ、Ｊ＝７．６、８．０Ｈｚ、１Ｈ）、７．６５（ｄｄ、Ｊ＝０．８、７．６Ｈｚ、１Ｈ）、８．０２（ｄｄ、Ｊ＝０．８、８．０Ｈｚ、１Ｈ）、８．２０（ｓ、１Ｈ）、１３．７９（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２１３［Ｍ＋Ｈ］＋． Reference Example 8 Synthesis of 7-chlorobenzo [b] thiophene-2-carboxylic acid:
Figure JPOXMLDOC01-appb-C000029
 Potassium hydroxide (3.6 g, 64 mmol) was dissolved in distilled water (64 mL), and 2,3-dichlorobenzaldehyde (5.0 g, 29 mmol) and 2-mercaptoacetic acid (2.0 mL, 29 mmol) were added at room temperature. . After stirring at 120 ° C. for 6 hours, the reaction solution was cooled to room temperature, distilled water was added until the precipitated solid was dissolved, and the mixture was extracted with diethyl ether. 1.0N Hydrochloric acid was added to the aqueous layer at 0 ° C., and the mixture was stirred at the same temperature for 30 min and filtered. The solid collected by filtration was washed with diethyl ether and hexane and dried to give 4.8 g (78%) of the title compound. ) Was obtained as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 7.52 (dd, J = 7.6, 8.0 Hz, 1H), 7.65 (dd, J = 0.8, 7.6 Hz, 1H), 8.02 (dd, J = 0.0). 8, 8.0 Hz, 1H), 8.20 (s, 1H), 13.79 (brs, 1H).
MS (ESI): 213 [M + H] < +>.
（参考例９）　７－クロロベンゾ［ｂ］チオフェン－２－アミンの合成：
Figure JPOXMLDOC01-appb-C000030
 　７－クロロベンゾ［ｂ］チオフェン－２－カルボン酸（０．５０ｇ、２．４ｍｍｏｌ）をｔｅｒｔ－ブタノール（４．７ｍＬ）に溶解し、トリエチルアミン（０．３９ｍＬ、２．６ｍｍｏｌ）、ジフェニルホスホリルアジド（０．５６ｍＬ、２．６ｍｍｏｌ）を室温で加えた。８０℃で８時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Reference Example 9 Synthesis of 7-chlorobenzo [b] thiophen-2-amine:
Figure JPOXMLDOC01-appb-C000030
 7-Chlorobenzo [b] thiophene-2-carboxylic acid (0.50 g, 2.4 mmol) was dissolved in tert-butanol (4.7 mL), triethylamine (0.39 mL, 2.6 mmol), diphenylphosphoryl azide (0 .56 mL, 2.6 mmol) was added at room temperature. After stirring at 80 ° C. for 8 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物を１，４－ジオキサン（２．４ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、７．１ｍＬ、２８ｍｍｏｌ）を０℃で加えた。室温で６時間攪拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝９７／３－８０／２０）で精製し、表題化合物０．３５ｇ（８１％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:４．１３（ｂｒｓ、２Ｈ）、６．３０（ｓ、１Ｈ）、７．０８（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．１７（ｄｄ、Ｊ＝７．６、８．０Ｈｚ、１Ｈ）、７．３１（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）． The above crude product was dissolved in 1,4-dioxane (2.4 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 7.1 mL, 28 mmol) was added at 0 ° C. After stirring at room temperature for 6 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane / ethyl acetate = 97 / 3-80 / 20) to give 0.35 g (81%) of the title compound as a brown solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 4.13 (brs, 2H), 6.30 (s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.17 (dd, J = 7.6, 8.0 Hz) 1H), 7.31 (d, J = 7.6 Hz, 1H).
（実施例８）　（Ｒ）－３－（７－クロロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000031
 　トリホスゲン（０．１１ｇ、０．４１ｍｍｏｌ）をジクロロメタン（２．１ｍＬ）に溶解し、７－クロロベンゾ［ｂ］チオフェン－２－アミン（０．１９ｇ、１．０ｍｍｏｌ）、トリエチルアミン（０．４８ｍＬ、３．４ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ジクロロメタン（２．１ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１２ｇ、０．８６ｍｍｏｌ）を０℃で滴下した。同温度で２時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．０８２ｇ（２７％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０－１．５８（ｍ、１Ｈ）、１．６０－１．７０（ｍ、１Ｈ）、１．７１－１．８０（ｍ、２Ｈ）、１．９８－２．００（ｍ、１Ｈ）、２．８０－３．００（ｍ、５Ｈ）、３．１６（ｓ、３Ｈ）、３．２３－３．３０（ｍ、１Ｈ）、４．３８－４．４２（ｍ、１Ｈ）、６．７６（ｓ、１Ｈ）、７．１６－７．２４（ｍ、２Ｈ）、７．４３－７．４５（ｍ、１Ｈ）．
ＭＳ（ＥＳＩ）：３５０［Ｍ＋Ｈ］＋． Example 8 Synthesis of (R) -3- (7-chlorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000031
 Triphosgene (0.11 g, 0.41 mmol) was dissolved in dichloromethane (2.1 mL), 7-chlorobenzo [b] thiophen-2-amine (0.19 g, 1.0 mmol), triethylamine (0.48 mL, 3. 4 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.12 g, 0.86 mmol) dissolved in dichloromethane (2.1 mL) was added dropwise at 0 ° C. After stirring at the same temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.082 g (27%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.58 (m, 1H), 1.60-1.70 (m, 1H), 1.71-1.80 (m, 2H), 1.98-2.00 (m 1H), 2.80-3.00 (m, 5H), 3.16 (s, 3H), 3.23-3.30 (m, 1H), 4.38-4.42 (m, 1H) ), 6.76 (s, 1H), 7.16-7.24 (m, 2H), 7.43-7.45 (m, 1H).
MS (ESI): 350 [M + H] &lt; + &gt;.
（実施例９）　（Ｒ）－３－（７－クロロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000032
 　（Ｒ）－３－（７－クロロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．０８２ｇ、０．２４ｍｍｏｌ）を１，４－ジオキサン（４．７ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．０８８ｍＬ、０．３５ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．０７３ｇ（８０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．７８－１．８２（ｍ、１Ｈ）、１．９０－１．９６（ｍ、１Ｈ）、２．０４－２．１８（ｍ、２Ｈ）、２．３３－２．３５（ｍ、１Ｈ）、３．１５（ｓ、３Ｈ）、３．１３－３．２８（ｍ、２Ｈ）、３．３２－３．４１（ｍ、２Ｈ）、３．４４－３．５３（ｍ、１Ｈ）、３．８４－３．８８（ｍ、１Ｈ）、４．４１－４．４３（ｍ、１Ｈ）、７．１５－７．１７（ｍ、１Ｈ）、７．１８－７．２４（ｍ、２Ｈ）、７．４５－７．４７（ｍ、１Ｈ）．
ＭＳ（ＥＳＩ）：３５０［Ｍ＋Ｈ］＋． Example 9 Synthesis of (R) -3- (7-chlorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000032
 (R) -3- (7-Chlorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.082 g, 0.24 mmol) was added to 1,4-dioxane ( (4.7 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.088 mL, 0.35 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.073 g (80%) of the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.78-1.82 (m, 1H), 1.90-1.96 (m, 1H), 2.04-2.18 (m, 2H), 2.33-2.35 (m 1H), 3.15 (s, 3H), 3.13-3.28 (m, 2H), 3.32-3.41 (m, 2H), 3.44-3.53 (m, 1H) ), 3.84-3.88 (m, 1H), 4.41-4.43 (m, 1H), 7.15-7.17 (m, 1H), 7.18-7.24 (m) 2H), 7.45-7.47 (m, 1H).
MS (ESI): 350 [M + H] &lt; + &gt;.
（実施例１０）　（Ｒ）－３－（ベンゾ［ｄ］チアゾール－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000033
 　ベンゾ［ｄ］チアゾール－２－アミン（０．２０ｇ、１．３ｍｍｏｌ）をジクロロメタン（６．６ｍＬ）に懸濁し、ジイソプロピルエチルアミン（０．２８ｍＬ、１．６ｍｍｏｌ）、クロロギ酸フェニル（０．１８ｍＬ、１．４ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、飽和重曹水を０℃で加えて、水層をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Example 10 Synthesis of (R) -3- (benzo [d] thiazol-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000033
 Benzo [d] thiazol-2-amine (0.20 g, 1.3 mmol) was suspended in dichloromethane (6.6 mL), diisopropylethylamine (0.28 mL, 1.6 mmol), phenyl chloroformate (0.18 mL, 1 .4 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物を１，２－ジクロロエタン（１３ｍＬ）に懸濁し、ジイソプロピルエチルアミン（０．９３ｍＬ、５．３ｍｍｏｌ）、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１９ｇ、１．３ｍｍｏｌ）を室温で加えた。８０℃で１５分攪拌した後、反応溶液を室温まで冷却し、１．０Ｎ水酸化ナトリウム水溶液を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．２８ｇ（６７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．６４－１．７７（ｍ、２Ｈ）、１．８２－１．８７（ｍ、２Ｈ）、２．００－２．０２（ｍ、１Ｈ）、２．８６－３．０４（ｍ、５Ｈ）、３．１６（ｓ、３Ｈ）、３．３０－３．３７（ｍ、１Ｈ）、４．５０（ｔ、Ｊ＝８．４Ｈｚ、１Ｈ）、７．２１－７．２６（ｍ、２Ｈ）、７．３７（ｄｄｄ、Ｊ＝１．２、７．６、８．４Ｈｚ、１Ｈ）、７．５５（ｄ、Ｊ＝８．４Ｈｚ、１Ｈ）、７．７３（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３１７［Ｍ＋Ｈ］＋． The above crude product was suspended in 1,2-dichloroethane (13 mL) and diisopropylethylamine (0.93 mL, 5.3 mmol), (R) -N-methylquinuclidin-3-amine (0.19 g, 1 .3 mmol) was added at room temperature. After stirring at 80 ° C. for 15 minutes, the reaction solution was cooled to room temperature, 1.0N aqueous sodium hydroxide solution was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.28 g (67%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.64-1.77 (m, 2H), 1.82-1.87 (m, 2H), 2.00-2.02 (m, 1H), 2.86-3.04 (m 5H), 3.16 (s, 3H), 3.30-3.37 (m, 1H), 4.50 (t, J = 8.4 Hz, 1H), 7.21-7.26 (m) 2H), 7.37 (ddd, J = 1.2, 7.6, 8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 7.6 Hz, 1H).
MS (ESI): 317 [M + H] < +>.
（実施例１１）　（Ｒ）－３－（ベンゾ［ｄ］チアゾール－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000034
 　（Ｒ）－３－（ベンゾ［ｄ］チアゾール－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．２４ｇ、０．７６ｍｍｏｌ）を１，４－ジオキサン（１５ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．５７ｍＬ、２．３ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．２０ｇ（６９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．８８－２．１０（ｍ、３Ｈ）、２．２１－２．２４（ｍ、１Ｈ）、２．４０－２．４２（ｍ、１Ｈ）、３．１６（ｓ、３Ｈ）、３．２０－３．２２（ｍ、１Ｈ）、３．３３－３．３４（ｍ、２Ｈ）、３．６０－３．６５（ｍ、２Ｈ）、３．９１－３．９５（ｍ、１Ｈ）、４．４８－４．５３（ｍ、１Ｈ）、７．２０－７．２６（ｍ、２Ｈ）、７．３５（ｄｄｄ、Ｊ＝０．８、７．６、８．４Ｈｚ、１Ｈ）、７．５０（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、７．６４（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、１１．９８（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３１７［Ｍ＋Ｈ］＋． Example 11 Synthesis of (R) -3- (benzo [d] thiazol-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000034
 (R) -3- (Benzo [d] thiazol-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.24 g, 0.76 mmol) was added to 1,4-dioxane (15 mL). And a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.57 mL, 2.3 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.20 g (69%) of the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.88-2.10 (m, 3H), 2.21-2.24 (m, 1H), 2.40-2.42 (m, 1H), 3.16 (s, 3H), 3.20-3.22 (m, 1H), 3.33-3.34 (m, 2H), 3.60-3.65 (m, 2H), 3.91-3.95 (m, 1H) ), 4.48-4.53 (m, 1H), 7.20-7.26 (m, 2H), 7.35 (ddd, J = 0.8, 7.6, 8.4 Hz, 1H) 7.50 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 11.98 (brs, 1H).
MS (ESI): 317 [M + H] < +>.
（参考例１０）　（５－メチルチオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチルの合成：
　５－メチルチオフェン－２－カルボン酸（１．０ｇ、７．０ｍｍｏｌ）をｔｅｒｔ－ブタノール（２１ｍＬ）に溶解し、トリエチルアミン（１．２ｍＬ、８．４ｍｍｏｌ）、ジフェニルホスホリルアジド（１．７ｍＬ、７．７ｍｍｏｌ）を室温で加えた。８０℃で１１時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝９０／１０）で精製し、表題化合物１．３ｇ（８６％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０（ｓ、９Ｈ）、２．３８（ｄ、Ｊ＝１．２Ｈｚ、３Ｈ）、６．３２（ｄ、Ｊ＝３．６Ｈｚ、１Ｈ）、６．４４（ｄｑ、Ｊ＝１．２、３．６Ｈｚ、１Ｈ）、６．７５（ｂｒｓ、１Ｈ）． Reference Example 10 Synthesis of tert-butyl (5-methylthiophen-2-yl) carbamate:
5-Methylthiophene-2-carboxylic acid (1.0 g, 7.0 mmol) is dissolved in tert-butanol (21 mL), triethylamine (1.2 mL, 8.4 mmol), diphenylphosphoryl azide (1.7 mL, 7. 7 mmol) was added at room temperature. After stirring at 80 ° C. for 11 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 90/10) to give 1.3 g (86%) of the title compound as a pale yellow solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50 (s, 9H), 2.38 (d, J = 1.2 Hz, 3H), 6.32 (d, J = 3.6 Hz, 1H), 6.44 (dq, J = 1) .2, 3.6 Hz, 1H), 6.75 (brs, 1H).
（実施例１２）　（Ｒ）－１－メチル－３－（５－メチルチオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000036
 　（５－メチルチオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチル（０．２０ｇ、０．９４ｍｍｏｌ）を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、２．８ｍＬ、１１ｍｍｏｌ）を０℃で加えた。室温で５時間攪拌した後、溶媒を濃縮し、得られた粗生成物を精製することなく、続く反応に用いた。 Example 12 Synthesis of (R) -1-methyl-3- (5-methylthiophen-2-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000036
 Tert-butyl (5-methylthiophen-2-yl) carbamate (0.20 g, 0.94 mmol) was dissolved in 1,4-dioxane (1.0 mL), and a hydrogen chloride-1,4-dioxane solution (4 0N, 2.8 mL, 11 mmol) was added at 0 ° C. After stirring at room temperature for 5 hours, the solvent was concentrated and the resulting crude product was used in the subsequent reaction without purification.
　上記の粗生成物をジクロロメタン（４．７ｍＬ）に懸濁し、ジイソプロピルエチルアミン（０．４９ｍＬ、２．８ｍｍｏｌ）、クロロギ酸フェニル（０．１４ｍＬ、１．１ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、１．０Ｎ塩酸水溶液を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 The above crude product was suspended in dichloromethane (4.7 mL), and diisopropylethylamine (0.49 mL, 2.8 mmol) and phenyl chloroformate (0.14 mL, 1.1 mmol) were added at 0 ° C. After stirring at the same temperature for 30 minutes, 1.0N hydrochloric acid aqueous solution was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をクロロホルム（３．６ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．２５ｍＬ、１．４ｍｍｏｌ）、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１０ｇ、０．７２ｍｍｏｌ）を室温で加えた。６０℃で６時間攪拌した後、反応溶液を室温まで冷却し、１．０Ｎ水酸化ナトリウム水溶液を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．０７９ｇ（７０％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．４７－１．５４（ｍ、１Ｈ）、１．５９－１．６７（ｍ、１Ｈ）、１．７０－１．８０（ｍ、２Ｈ）、１．９４－１．９６（ｍ、１Ｈ）、２．３９（ｄ、Ｊ＝０．８Ｈｚ、３Ｈ）、２．８０－３．００（ｍ、５Ｈ）、３．０９（ｓ、３Ｈ）、３．２１－３．２８（ｍ、１Ｈ）、４．３２－４．３７（ｍ、１Ｈ）、６．３４（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、６．４４（ｄｑ、Ｊ＝０．８、４．０Ｈｚ、１Ｈ）、６．７８（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２８０［Ｍ＋Ｈ］＋． The above crude product was dissolved in chloroform (3.6 mL) and diisopropylethylamine (0.25 mL, 1.4 mmol), (R) -N-methylquinuclidin-3-amine (0.10 g, 0.72 mmol). ) Was added at room temperature. After stirring at 60 ° C. for 6 hours, the reaction solution was cooled to room temperature, 1.0N aqueous sodium hydroxide solution was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.079 g (70%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.47-1.54 (m, 1H), 1.59-1.67 (m, 1H), 1.70-1.80 (m, 2H), 1.94-1.96 (m 1H), 2.39 (d, J = 0.8 Hz, 3H), 2.80-3.00 (m, 5H), 3.09 (s, 3H), 3.21-3.28 (m 1H), 4.32-4.37 (m, 1H), 6.34 (d, J = 4.0 Hz, 1H), 6.44 (dq, J = 0.8, 4.0 Hz, 1H) 6.78 (brs, 1H).
MS (ESI): 280 [M + H] + .
（実施例１３）　（Ｒ）－１－メチル－３－（５－メチルチオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000037
 　（Ｒ）－１－メチル－３－（５－メチルチオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレア（０．１９ｇ、０．６８ｍｍｏｌ）を１，４－ジオキサン（１４ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．２６ｍＬ、１．０ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１７ｇ（８０％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７２－１．８０（ｍ、１Ｈ）、１．８４－１．９０（ｍ、２Ｈ）、１．９７－１．９９（ｍ、１Ｈ）、２．１７－２．１８（ｍ、１Ｈ）、２．２９（ｄ、Ｊ＝０．８Ｈｚ、３Ｈ）、３．００（ｓ、３Ｈ）、３．１５－３．２５（ｍ、４Ｈ）、３．５６－３．６２（ｍ、１Ｈ）、４．３３－４．３７（ｍ、１Ｈ）、６．４４－６．４５（ｍ、２Ｈ）、９．５４（ｓ、１Ｈ）、１０．２９（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：２８０［Ｍ＋Ｈ］＋． Example 13 Synthesis of (R) -1-methyl-3- (5-methylthiophen-2-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000037
 (R) -1-methyl-3- (5-methylthiophen-2-yl) -1- (quinuclidin-3-yl) urea (0.19 g, 0.68 mmol) was added to 1,4-dioxane (14 mL). After dissolution, a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.26 mL, 1.0 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.17 g (80%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.72-1.80 (m, 1H), 1.84-1.90 (m, 2H), 1.97-1.99 (m, 1H), 2.17-2.18 (m 1H), 2.29 (d, J = 0.8 Hz, 3H), 3.00 (s, 3H), 3.15-3.25 (m, 4H), 3.56-3.62 (m 1H), 4.33-4.37 (m, 1H), 6.44-6.45 (m, 2H), 9.54 (s, 1H), 10.29 (brs, 1H).
MS (ESI): 280 [M + H] + .
（実施例１４）　（Ｒ）－１－（ベンゾ［ｂ］チオフェン－２－イル）－３－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000038
 　トリホスゲン（０．０５５ｇ、０．１９ｍｍｏｌ）をジクロロメタン（１．０ｍＬ）に溶解し、ジクロロメタン（２．０ｍＬ）に溶解したベンゾ［ｂ］チオフェン－２－アミン（０．０７５ｇ、０．５０ｍｍｏｌ）、ジイソプロピルアミン（０．０９７ｍＬ、０．５５ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、ジクロロメタン（１．０ｍＬ）に溶解した（Ｒ）－キヌクリジン－３－アミン　二塩酸塩（０．１０ｇ、０．５０ｍｍｏｌ）、ジイソプロピルエチルアミン（０．２９ｍＬ、１．６６ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１２ｇ（８１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．４１－１．４４（ｍ、１Ｈ）、１．６０－１．６５（ｍ、３Ｈ）、１．９５－１．９８（ｍ、１Ｈ）、２．４７（ｄｄｄ、Ｊ＝２．０、４．８、１４．４Ｈｚ、１Ｈ）、２．７１－２．７９（ｍ、４Ｈ）、３．３３（ｄｄ、Ｊ＝２．０、１４．４Ｈｚ、１Ｈ）、３．９０－３．９１（ｍ、１Ｈ）、５．４１（ｂｒｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、６．７８（ｓ、１Ｈ）、７．２０－７．２６（ｍ、１Ｈ）、７．２８－７．３２（ｍ、１Ｈ）、７．５８（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、７．７１（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３０２［Ｍ＋Ｈ］＋． Example 14 Synthesis of (R) -1- (benzo [b] thiophen-2-yl) -3- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000038
 Triphosgene (0.055 g, 0.19 mmol) was dissolved in dichloromethane (1.0 mL), benzo [b] thiophen-2-amine (0.075 g, 0.50 mmol), diisopropyl dissolved in dichloromethane (2.0 mL). Amine (0.097 mL, 0.55 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -quinuclidin-3-amine dihydrochloride (0.10 g, 0.50 mmol), diisopropylethylamine (0.29 mL, 1.66 mmol) dissolved in dichloromethane (1.0 mL). ) Was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.12 g (81%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.41-1.44 (m, 1H), 1.60-1.65 (m, 3H), 1.95-1.98 (m, 1H), 2.47 (ddd, J = 2) 0.0, 4.8, 14.4 Hz, 1H), 2.71-2.79 (m, 4H), 3.33 (dd, J = 2.0, 14.4 Hz, 1H), 3.90- 3.91 (m, 1H), 5.41 (brd, J = 7.6 Hz, 1H), 6.78 (s, 1H), 7.20-7.26 (m, 1H), 7.28- 7.32 (m, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 7.6 Hz, 1H).
MS (ESI): 302 [M + H] < +>.
（実施例１５）　（Ｒ）－１－（ベンゾ［ｂ］チオフェン－２－イル）－３－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000039
 　（Ｒ）－１－（ベンゾ［ｂ］チオフェン－２－イル）－３－（キヌクリジン－３－イル）ウレア（０．１５ｇ、０．５０ｍｍｏｌ）を１，４－ジオキサン（１０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．１９ｍＬ、０．７６ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１４ｇ（８２％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７２－１．８２（ｍ、１Ｈ）、１．８５－１．９０（ｍ、２Ｈ）、２．００－２．１０（ｍ、２Ｈ）、２．９６－３．０５（ｍ、１Ｈ）、３．１６－３．２４（ｍ、４Ｈ）、３．５９－３．６５（ｍ、１Ｈ）、４．０２－４．０６（ｍ、１Ｈ）、６．７０（ｓ、１Ｈ）、７．１２（ｄｄ、Ｊ＝７．６、７．６Ｈｚ、１Ｈ）、７．２４（ｄｄ、Ｊ＝７．６、７．６Ｈｚ、１Ｈ）、７．４３（ｂｒｄ、Ｊ＝６．４Ｈｚ、１Ｈ）、７．５５（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、７．７３（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、９．８９（ｂｒｓ、１Ｈ）、１０．０１（ｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３０２［Ｍ＋Ｈ］＋． Example 15 Synthesis of (R) -1- (benzo [b] thiophen-2-yl) -3- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000039
 (R) -1- (benzo [b] thiophen-2-yl) -3- (quinuclidin-3-yl) urea (0.15 g, 0.50 mmol) was dissolved in 1,4-dioxane (10 mL), Hydrogen chloride-1,4-dioxane solution (4.0 N, 0.19 mL, 0.76 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.14 g (82%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.72-1.82 (m, 1H), 1.85-1.90 (m, 2H), 2.00-2.10 (m, 2H), 2.96-3.05 (m 1H), 3.16-3.24 (m, 4H), 3.59-3.65 (m, 1H), 4.02-4.06 (m, 1H), 6.70 (s, 1H) ), 7.12 (dd, J = 7.6, 7.6 Hz, 1H), 7.24 (dd, J = 7.6, 7.6 Hz, 1H), 7.43 (brd, J = 6. 4 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 9.89 (brs, 1 H), 10.01 (s, 1H).
MS (ESI): 302 [M + H] < +>.
（参考例１１）　（５－クロロチオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000040
 　５－クロロチオフェン－２－カルボン酸（１．０ｇ、６．２ｍｍｏｌ）をｔｅｒｔ－ブタノール（１９ｍＬ）に溶解し、トリエチルアミン（１．０ｍＬ、７．４ｍｍｏｌ）、ジフェニルホスホリルアジド（１．５ｍＬ、６．８ｍｍｏｌ）を室温で加えた。８０℃で１１時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝９０／１０）で精製し、表題化合物１．１ｇ（７３％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．５１（ｓ、９Ｈ）、６．２３（ｄ、Ｊ＝３．６Ｈｚ、１Ｈ）、６．６２（ｄ、Ｊ＝３．６Ｈｚ、１Ｈ）、６．９１（ｂｒｓ、１Ｈ）． Reference Example 11 Synthesis of tert-butyl (5-chlorothiophen-2-yl) carbamate:
Figure JPOXMLDOC01-appb-C000040
 5-Chlorothiophene-2-carboxylic acid (1.0 g, 6.2 mmol) was dissolved in tert-butanol (19 mL), triethylamine (1.0 mL, 7.4 mmol), diphenylphosphoryl azide (1.5 mL, 6. 8 mmol) was added at room temperature. After stirring at 80 ° C. for 11 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 90/10) to obtain 1.1 g (73%) of the title compound as a pale yellow solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.51 (s, 9H), 6.23 (d, J = 3.6 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.91 (brs, 1H).
（実施例１６）　（Ｒ）－３－（５－クロロチオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000041
 　（５－クロロチオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチル（０．２０ｇ、０．８６ｍｍｏｌ）を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、２．６ｍＬ、１０ｍｍｏｌ）を０℃で加えた。室温で１２時間攪拌した後、ろ液を減圧濃縮し、得られた粗生成物を精製することなく、続く反応に用いた。 Example 16 Synthesis of (R) -3- (5-chlorothiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000041
 Tert-butyl (5-chlorothiophen-2-yl) carbamate (0.20 g, 0.86 mmol) was dissolved in 1,4-dioxane (1.0 mL), and a hydrogen chloride-1,4-dioxane solution (4 0 N, 2.6 mL, 10 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, the filtrate was concentrated under reduced pressure, and the resulting crude product was used in the subsequent reaction without purification.
　上記の粗生成物をジクロロメタン（８．６ｍＬ）に懸濁し、ジイソプロピルエチルアミン（０．４５ｍＬ、２．６ｍｍｏｌ）、クロロギ酸フェニル（０．１２ｍＬ、０．９４ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 The above crude product was suspended in dichloromethane (8.6 mL), and diisopropylethylamine (0.45 mL, 2.6 mmol) and phenyl chloroformate (0.12 mL, 0.94 mmol) were added at 0 ° C. After stirring at the same temperature for 30 minutes, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をジクロロエタン（７．１ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．５０ｍＬ、２．９ｍｍｏｌ）、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１０ｇ、０．７１ｍｍｏｌ）を室温で加えた。６０℃で３０分間攪拌した後、反応溶液を室温まで冷却し、１．０Ｎ水酸化ナトリウム水溶液を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１２ｇ（５７％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．４８－１．５４（ｍ、１Ｈ）、１．６２－１．６４（ｍ、１Ｈ）、１．７０－１．７９（ｍ、２Ｈ）、１．９５（ｄｔ、Ｊ＝２．４、３．２Ｈｚ、１Ｈ）、２．８０－２．９８（ｍ、４Ｈ）、３．１１（ｓ、３Ｈ）、３．２１－３．２８（ｍ、１Ｈ）、４．３２－４．３６（ｍ、１Ｈ）、６．２６（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、６．６３（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、６．９３（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３００［Ｍ＋Ｈ］＋． The above crude product was dissolved in dichloroethane (7.1 mL) and diisopropylethylamine (0.50 mL, 2.9 mmol), (R) -N-methylquinuclidin-3-amine (0.10 g, 0.71 mmol). ) Was added at room temperature. After stirring at 60 ° C. for 30 minutes, the reaction solution was cooled to room temperature, 1.0N aqueous sodium hydroxide solution was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.12 g (57%) was obtained as a brown solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.48-1.54 (m, 1H), 1.62-1.64 (m, 1H), 1.70-1.79 (m, 2H), 1.95 (dt, J = 2) .4, 3.2 Hz, 1H), 2.80-2.98 (m, 4H), 3.11 (s, 3H), 3.21-3.28 (m, 1H), 4.32-4 .36 (m, 1H), 6.26 (d, J = 8.0 Hz, 1H), 6.63 (d, J = 8.0 Hz, 1H), 6.93 (brs, 1H).
MS (ESI): 300 [M + H] + .
（実施例１７）　（Ｒ）－３－（５－クロロチオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000042
 　（Ｒ）－３－（５－クロロチオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．２５ｇ、０．８３ｍｍｏｌ）を１，４－ジオキサン（１７ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．３１ｍＬ、１．２ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．２３ｇ（８１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７８－２．０１（ｍ、４Ｈ）、２．１８－２．１９（ｍ、１Ｈ）、３．０２（ｓ、３Ｈ）、３．１８－３．２２（ｍ、４Ｈ）、３．３４－３．３８（ｍ、１Ｈ）、３．５７－３．６２（ｍ、１Ｈ）、４．３８－４．４２（ｍ、１Ｈ）、６．５３（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、６．７８（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、１０．０５（ｓ、１Ｈ）、１０．２８（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３００［Ｍ＋Ｈ］＋． Example 17 Synthesis of (R) -3- (5-chlorothiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000042
 (R) -3- (5-Chlorothiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.25 g, 0.83 mmol) in 1,4-dioxane (17 mL) After dissolution, a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.31 mL, 1.2 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.23 g (81%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.78-2.01 (m, 4H), 2.18-2.19 (m, 1H), 3.02 (s, 3H), 3.18-3.22 (m, 4H), 3.34-3.38 (m, 1H), 3.57-3.62 (m, 1H), 4.38-4.42 (m, 1H), 6.53 (d, J = 8.0 Hz) 1H), 6.78 (d, J = 8.0 Hz, 1H), 10.05 (s, 1H), 10.28 (brs, 1H).
MS (ESI): 300 [M + H] + .
（参考例１２）　１－フェニル－１Ｈ－ピラゾール－３－カルボン酸エチルの合成：
Figure JPOXMLDOC01-appb-C000043
 　１Ｈ－ピラゾール－３－カルボン酸エチル（１．０ｇ、７．１ｍｍｏｌ）を１，４－ジオキサン（２４ｍＬ）に溶解し、炭酸カリウム（１．５ｇ、７．１ｍｍｏｌ）、Ｎ，Ｎ－ジメチルエタン－１，２－ジアミン（０．６１ｍＬ、５．７ｍｍｏｌ）、ヨウ化フェニル（１．５ｇ、７．１ｍｍｏｌ）、ヨウ化銅（Ｉ）（０．２７ｇ、１．４ｍｍｏｌ）を室温で加えた。１２０℃で４時間撹拌した後、反応溶液をセライトろ過し、ろ液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９８／２－８６／１４）で精製し、表題化合物１．２ｇ（７８％）を黄色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．４３（ｔ、Ｊ＝６．８Ｈｚ、３Ｈ）、４．４５（ｑ、Ｊ＝６．８Ｈｚ、２Ｈ）、７．００（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）、７．３９（ｄｄ、Ｊ＝８．０、８．０Ｈｚ、１Ｈ）、７．４８（ｄｄ、Ｊ＝８．０、８．０Ｈｚ、２Ｈ）、７．７３－７．７７（ｍ、２Ｈ）、７．９３（ｄ、Ｊ＝２．０Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：２１７［Ｍ＋Ｈ］＋． Reference Example 12 Synthesis of ethyl 1-phenyl-1H-pyrazole-3-carboxylate:
Figure JPOXMLDOC01-appb-C000043
 Ethyl 1H-pyrazole-3-carboxylate (1.0 g, 7.1 mmol) was dissolved in 1,4-dioxane (24 mL), and potassium carbonate (1.5 g, 7.1 mmol), N, N-dimethylethane- 1,2-diamine (0.61 mL, 5.7 mmol), phenyl iodide (1.5 g, 7.1 mmol), copper (I) iodide (0.27 g, 1.4 mmol) were added at room temperature. After stirring at 120 ° C. for 4 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 98 / 2-86 / 14) to obtain 1.2 g (78%) of the title compound as a yellow liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.43 (t, J = 6.8 Hz, 3H), 4.45 (q, J = 6.8 Hz, 2H), 7.00 (d, J = 2.0 Hz, 1H), 7.39 (Dd, J = 8.0, 8.0 Hz, 1H), 7.48 (dd, J = 8.0, 8.0 Hz, 2H), 7.73-7.77 (m, 2H), 7. 93 (d, J = 2.0 Hz, 1H).
MS (ESI): 217 [M + H] < +>.
（参考例１３）　１－フェニル－（１Ｈ）－ピラゾール－３－カルボン酸の合成：
Figure JPOXMLDOC01-appb-C000044
 　１－フェニル－１Ｈ－ピラゾール－３－カルボン酸エチル（１．２ｇ、５．６ｍｍｏｌ）をメタノール（２８ｍＬ）に溶解し、１．０Ｎ水酸化ナトリウム水溶液（２８ｍＬ、２８ｍｍｏｌ）を０℃で加えた。６０℃で１時間撹拌した後、反応溶液を室温まで冷却し、溶媒を濃縮し、クロロホルムで逆抽出した。水層に１．０Ｎ塩酸を加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮し、表題化合物０．７５ｇ（７１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ７．０７（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、７．３２－７．４２（ｍ、１Ｈ）、７．５０（ｄｄ、Ｊ＝８．０、８．０Ｈｚ、２Ｈ）、７．７２－７．７７（ｍ、２Ｈ）、７．９８（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：１８９［Ｍ＋Ｈ］＋． Reference Example 13 Synthesis of 1-phenyl- (1H) -pyrazole-3-carboxylic acid:
Figure JPOXMLDOC01-appb-C000044
 Ethyl 1-phenyl-1H-pyrazole-3-carboxylate (1.2 g, 5.6 mmol) was dissolved in methanol (28 mL), and 1.0 N aqueous sodium hydroxide solution (28 mL, 28 mmol) was added at 0 ° C. After stirring at 60 ° C. for 1 hour, the reaction solution was cooled to room temperature, the solvent was concentrated, and back extracted with chloroform. 1.0N hydrochloric acid was added to the aqueous layer, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 0.75 g (71%) of the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 7.07 (d, J = 2.4 Hz, 1H), 7.32-7.42 (m, 1H), 7.50 (dd, J = 8.0, 8.0 Hz, 2H), 7 .72-7.77 (m, 2H), 7.98 (d, J = 2.4 Hz, 1H).
MS (ESI): 189 [M + H] < +>.
（参考例１４）　１－フェニル－（１Ｈ）－ピラゾール－３－アミンの合成：
Figure JPOXMLDOC01-appb-C000045
 　１－フェニル－（１Ｈ）－ピラゾール－３－カルボン酸（０．３５ｇ、１．９ｍｍｏｌ）をｔｅｒｔ－ブタノール（３．８ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．３６ｍＬ、２．０ｍｍｏｌ）、ジフェニルホスホリルアジド（０．４８ｍＬ、２．２ｍｍｏｌ）を室温で加えた。８０℃で４時間撹拌した後、反応溶液を室温まで冷却し、水を加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７８／２２）で精製した。 Reference Example 14 Synthesis of 1-phenyl- (1H) -pyrazol-3-amine:
Figure JPOXMLDOC01-appb-C000045
 1-Phenyl- (1H) -pyrazole-3-carboxylic acid (0.35 g, 1.9 mmol) was dissolved in tert-butanol (3.8 mL), diisopropylethylamine (0.36 mL, 2.0 mmol), diphenylphosphoryl Azide (0.48 mL, 2.2 mmol) was added at room temperature. After stirring at 80 ° C. for 4 hours, the reaction solution was cooled to room temperature, water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 78/22).
　上記の生成物を１，４－ジオキサン（５．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、５．６ｍＬ、２２ｍｍｏｌ）を０℃で加えた。室温で１６時間撹拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７９／２１、クロロホルムのみ－クロロホルム／メタノール＝８５／１５）で精製し、表題化合物０．１２ｇ（４１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ５．８５（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）、７．１５－７．２１（ｍ、１Ｈ）、７．３６－７．４２（ｍ、２Ｈ）、７．５４－７．５８（ｍ、２Ｈ）、７．６９（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：１６０［Ｍ＋Ｈ］＋． The above product was dissolved in 1,4-dioxane (5.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 5.6 mL, 22 mmol) was added at 0 ° C. After stirring at room temperature for 16 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 79/21, chloroform only-chloroform / methanol = 85/15), and 0.12 g (41%) of the title compound was white. Obtained as a solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 5.85 (d, J = 2.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.36-7.42 (m, 2H), 7.54-7.58 (M, 2H), 7.69 (d, J = 2.8 Hz, 1H).
MS (ESI): 160 [M + H] + .
（実施例１８）　（Ｒ）－１－メチル－３－（１－フェニル－（１Ｈ）－ピラゾール－３－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000046
 　１－フェニル－（１Ｈ）－ピラゾール－３－アミン（０．０６０ｇ、０．３８ｍｍｏｌ）をジクロロメタン（２．０ｍＬ）に溶解させ、トリホスゲン（０．０３７ｇ、０．１２ｍｍｏｌ）、トリエチルアミン（０．１６ｍＬ、１．１ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌した後、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０６３ｇ、０．４５ｍｍｏｌ）を０℃で加えた。室温で４時間撹拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１１ｇ（８９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．４７－１．８５（ｍ、４Ｈ）、１．９５－２．００（ｍ、１Ｈ）、２．８０－３．０４（ｍ、５Ｈ）、３．１４（ｓ、３Ｈ）、３．２３－３．３２（ｍ、１Ｈ）、４．３５－４．４２（ｍ、１Ｈ）、６．８４（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）、７．０９－７．１３（ｍ、１Ｈ）、７．４０－７．４５（ｍ、２Ｈ）、７．５６－７．６１（ｍ、２Ｈ）、７．８０（ｄ、Ｊ＝２．４Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］＋． Example 18 Synthesis of (R) -1-methyl-3- (1-phenyl- (1H) -pyrazol-3-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000046
 1-Phenyl- (1H) -pyrazol-3-amine (0.060 g, 0.38 mmol) was dissolved in dichloromethane (2.0 mL) and triphosgene (0.037 g, 0.12 mmol), triethylamine (0.16 mL, 1.1 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.063 g, 0.45 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel column chromatography (chloroform only-chloroform / methanol = 95/5) to give 0.11 g (89%) of the title compound as a white solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.47-1.85 (m, 4H), 1.95-2.00 (m, 1H), 2.80-3.04 (m, 5H), 3.14 (s, 3H), 3.23-3.32 (m, 1H), 4.35-4.42 (m, 1H), 6.84 (d, J = 2.4 Hz, 1H), 7.09-7.13 (m 1H), 7.40-7.45 (m, 2H), 7.56-7.61 (m, 2H), 7.80 (d, J = 2.4 Hz, 1H).
MS (ESI): 326 [M + H] < +>.
（実施例１９）　（Ｒ）－１－メチル－３－（１－フェニル－（１Ｈ）－ピラゾール－３－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
　（Ｒ）－１－メチル－３－（１－フェニル－（１Ｈ）－ピラゾール－３－イル）－１－（キヌクリジン－３－イル）ウレア（０．１１ｇ、０．３４ｍｍｏｌ）をジエチルエーテル（３．０ｍＬ）に溶解し、塩化水素－ジエチルエーテル溶液（２．０Ｎ、０．２２ｍＬ、０．４４ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌した後、ろ過し、ろ取した固体をジエチルエーテルで洗浄後に乾燥し、表題化合０．０８９ｇ（７３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、Ｄ２Ｏ）
δ: １．９４－２．１４（ｍ、３Ｈ）、２．１６－２．２８（ｍ、１Ｈ）、２．４０－２．４７（ｍ、１Ｈ）、３．１６（ｓ、３Ｈ）、３．２６－３．５６（ｍ、５Ｈ）、３．７２－３．８２（ｍ、１Ｈ）、４．４８－４．５８（ｍ、１Ｈ）、６．４９－６．５２（ｍ、１Ｈ）、７．３６－７．４３（ｍ、１Ｈ）、７．５２－７．５７（ｍ、２Ｈ）、７．６５－７．６９（ｍ、２Ｈ）、８．１１－８．１４（ｍ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］＋． Example 19 Synthesis of (R) -1-methyl-3- (1-phenyl- (1H) -pyrazol-3-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
(R) -1-methyl-3- (1-phenyl- (1H) -pyrazol-3-yl) -1- (quinuclidin-3-yl) urea (0.11 g, 0.34 mmol) was added to diethyl ether (3 In 0 mL) and a hydrogen chloride-diethyl ether solution (2.0 N, 0.22 mL, 0.44 mmol) was added at 0 ° C. The mixture was stirred at the same temperature for 30 minutes, filtered, and the collected solid was washed with diethyl ether and dried to give the title compound (0.089 g, 73%) as a white solid.
1 H-NMR (400 MHz, D 2 O)
δ: 1.94-2.14 (m, 3H), 2.16-2.28 (m, 1H), 2.40-2.47 (m, 1H), 3.16 (s, 3H), 3.26-3.56 (m, 5H), 3.72-3.82 (m, 1H), 4.48-4.58 (m, 1H), 6.49-6.52 (m, 1H) ), 7.36-7.43 (m, 1H), 7.52-7.57 (m, 2H), 7.65-7.69 (m, 2H), 8.11-8.14 (m) 1H).
MS (ESI): 326 [M + H] < +>.
（実施例２０）　（Ｒ）－３－（ベンゾ［ｄ］オキサゾール－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000048
 　ベンゾ［ｄ］オキサゾール－２－アミン（０．１０ｇ、０．７５ｍｍｏｌ）をジクロロメタン（３．７ｍＬ）に懸濁し、ジイソプロピルエチルアミン（０．１６ｍＬ、０．９０ｍｍｏｌ）、クロロギ酸フェニル（０．１０ｍＬ、０．８２ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、飽和重曹水を０℃で加えて、水層をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Example 20 Synthesis of (R) -3- (Benzo [d] oxazol-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000048
 Benzo [d] oxazol-2-amine (0.10 g, 0.75 mmol) is suspended in dichloromethane (3.7 mL), diisopropylethylamine (0.16 mL, 0.90 mmol), phenyl chloroformate (0.10 mL, 0 mL). .82 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をクロロホルム（３．７ｍＬ）に懸濁し、ジイソプロピルエチルアミン（０．２６ｍＬ、１．５ｍｍｏｌ）、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１１ｇ、０．７５ｍｍｏｌ）を室温で加えた。６０℃で１０時間攪拌した後、反応溶液を室温まで冷却し、１．０Ｎ水酸化ナトリウム水溶液を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．０５３ｇ（２４％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．４８－１．５２（ｍ、１Ｈ）、１．６２－１．６５（ｍ、１Ｈ）、１．７９－１．９０（ｍ、２Ｈ）、１．９５－１．９７（ｍ、１Ｈ）、２．８２－３．０２（ｍ、５Ｈ）、３．１９（ｓ、３Ｈ）、３．２０－３．２８（ｍ、１Ｈ）、４．５８－４．６８（ｍ、１Ｈ）、７．０９－７．２１（ｍ、３Ｈ）、７．２６－７．２９（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：３０１［Ｍ＋Ｈ］＋． The above crude product was suspended in chloroform (3.7 mL) and diisopropylethylamine (0.26 mL, 1.5 mmol), (R) -N-methylquinuclidin-3-amine (0.11 g, 0.75 mmol). ) Was added at room temperature. After stirring at 60 ° C. for 10 hours, the reaction solution was cooled to room temperature, 1.0N aqueous sodium hydroxide solution was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.053 g (24%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.48-1.52 (m, 1H), 1.62-1.65 (m, 1H), 1.79-1.90 (m, 2H), 1.95-1.97 (m 1H), 2.82-3.02 (m, 5H), 3.19 (s, 3H), 3.20-3.28 (m, 1H), 4.58-4.68 (m, 1H) ), 7.09-7.21 (m, 3H), 7.26-7.29 (m, 2H).
MS (ESI): 301 [M + H] < +>.
（実施例２１）　（Ｒ）－３－（ベンゾ［ｄ］オキサゾール－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000049
 　（Ｒ）－３－（ベンゾ［ｄ］オキサゾール－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．０４１ｇ、０．１４ｍｍｏｌ）を１，４－ジオキサン（２．７ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．１０ｍＬ、０．４０ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．０２６ｇ（５１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７６－１．９１（ｍ、３Ｈ）、２．００－２．０６（ｍ、１Ｈ）、２．２３－２．２４（ｍ、１Ｈ）、３．１０（ｓ、３Ｈ）、３．１９－３．２５（ｍ、３Ｈ）、３．３２－３．４２（ｍ、２Ｈ）、３．６０－３．６６（ｍ、１Ｈ）、４．５２－４．６８（ｍ、１Ｈ）、７．１６－７．２６（ｍ、２Ｈ）、７．３４（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、７．４４（ｄ、Ｊ＝７．６Ｈｚ、１Ｈ）、１０．１２（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３０１［Ｍ＋Ｈ］＋． Example 21 Synthesis of (R) -3- (benzo [d] oxazol-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000049
 (R) -3- (Benzo [d] oxazol-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.041 g, 0.14 mmol) was added to 1,4-dioxane (2. 7 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.10 mL, 0.40 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.026 g (51%) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.76-1.91 (m, 3H), 2.00-2.06 (m, 1H), 2.23-2.24 (m, 1H), 3.10 (s, 3H), 3.19-3.25 (m, 3H), 3.32-3.42 (m, 2H), 3.60-3.66 (m, 1H), 4.52-4.68 (m, 1H) ), 7.16-7.26 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 10.12 (brs) 1H).
MS (ESI): 301 [M + H] < +>.
（実施例２２）　（Ｒ）－１，３－ジメチル－３－フェニル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000050
 　トリホスゲン（０．０７８ｇ、０．２６ｍｍｏｌ）をクロロホルム（１．０ｍＬ）に溶解し、クロロホルム（３．０ｍＬ）に溶解したＮ－メチルアニリン（０．０７７ｍＬ、０．７１ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１４ｍＬ、０．７９ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、クロロホルム（３．０ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１０ｇ、０．７１ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１４ｍＬ、０．７９ｍｍｏｌ）を０℃で滴下した。５０℃で１６時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９９／１）で精製し、表題化合物０．０５１ｇ（２６％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．３３－１．３８（ｍ、１Ｈ）、１．５２－１．６１（ｍ、３Ｈ）、１．８７－１．８９（ｍ、１Ｈ）、２．５４（ｓ、３Ｈ）、２．６８－２．８８（ｍ、５Ｈ）、３．１９－３．２５（ｍ、１Ｈ）、３．２４（ｓ、３Ｈ）、３．７０－３．７５（ｍ、１Ｈ）、７．１１－７．１６（ｍ、３Ｈ）、７．３２－７．３８（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：２７４［Ｍ＋Ｈ］＋． Example 22 Synthesis of (R) -1,3-dimethyl-3-phenyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000050
 Triphosgene (0.078 g, 0.26 mmol) was dissolved in chloroform (1.0 mL), N-methylaniline (0.077 mL, 0.71 mmol), diisopropylethylamine (0.14 mL) dissolved in chloroform (3.0 mL). , 0.79 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.10 g, 0.71 mmol) dissolved in chloroform (3.0 mL), diisopropylethylamine (0.14 mL, 0 .79 mmol) was added dropwise at 0 ° C. After stirring at 50 ° C. for 16 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 99/1) to give the title compound. 0.051 g (26%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.33-1.38 (m, 1H), 1.52-1.61 (m, 3H), 1.87-1.89 (m, 1H), 2.54 (s, 3H), 2.68-2.88 (m, 5H), 3.19-3.25 (m, 1H), 3.24 (s, 3H), 3.70-3.75 (m, 1H), 7. 11-7.16 (m, 3H), 7.32-7.38 (m, 2H).
MS (ESI): 274 [M + H] < +>.
（実施例２３）　（Ｒ）－１，３－ジメチル－３－フェニル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000051
 　（Ｒ）－１，３－ジメチル－３－フェニル－１－（キヌクリジン－３－イル）ウレア（０．０５１ｇ、０．１９ｍｍｏｌ）を１，４－ジオキサン（３．７ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．０７０ｍＬ、０．２８ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．０４６ｇ（７９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．７４－１．７８（ｍ、１Ｈ）、１．８７－２．０４（ｍ、３Ｈ）、２．３０－２．３２（ｍ、１Ｈ）、２．４７（ｓ、３Ｈ）、３．１６－３．３３（ｍ、４Ｈ）、３．２４（ｓ、３Ｈ）、３．６３－３．６９（ｍ、１Ｈ）、３．８２－３．８７（ｍ、１Ｈ）、７．１２－７．１５（ｍ、２Ｈ）、７．２０－７．２３（ｍ、１Ｈ）、７．３６－７．４２（ｍ、２Ｈ）、１２．４４（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２７４［Ｍ＋Ｈ］＋． Example 23 Synthesis of (R) -1,3-dimethyl-3-phenyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000051
 (R) -1,3-dimethyl-3-phenyl-1- (quinuclidin-3-yl) urea (0.051 g, 0.19 mmol) was dissolved in 1,4-dioxane (3.7 mL), and hydrogen chloride was added. A 1,4-dioxane solution (4.0 N, 0.070 mL, 0.28 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.046 g (79%) of the title compound as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.74-1.78 (m, 1H), 1.87-2.04 (m, 3H), 2.30-2.32 (m, 1H), 2.47 (s, 3H), 3.16-3.33 (m, 4H), 3.24 (s, 3H), 3.63-3.69 (m, 1H), 3.82-3.87 (m, 1H), 7. 12-7.15 (m, 2H), 7.20-7.23 (m, 1H), 7.36-7.42 (m, 2H), 12.44 (s, 1H).
MS (ESI): 274 [M + H] < +>.
（参考例１５）　（５－フェニルチオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000052
 　５－フェニルチオフェン－２－カルボン酸（０．５０ｇ、２．５ｍｍｏｌ）をｔｅｒｔ－ブタノール（４．９ｍＬ）に溶解し、トリエチルアミン（０．４１ｍＬ、２．９ｍｍｏｌ）、ジフェニルホスホリルアジド（０．５８ｍＬ、２．７ｍｍｏｌ）を室温で加えた。８０℃で１２時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物０．２３ｇ（４２％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５４（ｓ、９Ｈ）、６．４８（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、６．９６（ｂｒｓ、１Ｈ）、７．０３（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．２２－７．２４（ｍ、１Ｈ）、７．３２－７．３５（ｍ、２Ｈ）、７．５４－７．５６（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：２７６［Ｍ＋Ｈ］＋． Reference Example 15 Synthesis of tert-butyl (5-phenylthiophen-2-yl) carbamate:
Figure JPOXMLDOC01-appb-C000052
 5-Phenylthiophene-2-carboxylic acid (0.50 g, 2.5 mmol) was dissolved in tert-butanol (4.9 mL), triethylamine (0.41 mL, 2.9 mmol), diphenylphosphoryl azide (0.58 mL, 2.7 mmol) was added at room temperature. After stirring at 80 ° C. for 12 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 80/20) to give 0.23 g (42%) of the title compound as a pale yellow solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.54 (s, 9H), 6.48 (d, J = 4.0 Hz, 1H), 6.96 (brs, 1H), 7.03 (d, J = 4.0 Hz, 1H), 7.22-7.24 (m, 1H), 7.32-7.35 (m, 2H), 7.54-7.56 (m, 2H).
MS (ESI): 276 [M + H] < +>.
（実施例２４）　（Ｒ）－１－メチル－３－（５－フェニルチオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000053
 　（５－フェニルチオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチル（０．２９ｇ、１．０ｍｍｏｌ）を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、３．１ｍＬ、１２ｍｍｏｌ）を０℃で加えた。室温で１２時間攪拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Example 24 Synthesis of (R) -1-methyl-3- (5-phenylthiophen-2-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000053
 Tert-butyl (5-phenylthiophen-2-yl) carbamate (0.29 g, 1.0 mmol) was dissolved in 1,4-dioxane (1.0 mL), and a hydrogen chloride-1,4-dioxane solution (4 0.0N, 3.1 mL, 12 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　トリホスゲン（０．１３ｇ、０．３８ｍｍｏｌ）をジクロロメタン（２．５ｍＬ）に溶解し、ジクロロメタン（５．０ｍＬ）に溶解した上記の粗生成物、ジイソプロピルエチルアミン（０．２０ｍＬ、１．１ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、ジクロロメタン（２．５ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１４ｇ、１．０ｍｍｏｌ）、ジイソプロピルエチルアミン（０．２０ｍＬ、１．１ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．２０ｇ（５８％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．４９－１．５６（ｍ、１Ｈ）、１．６１－１．８０（ｍ、３Ｈ）、１．９８－２．００（ｍ、１Ｈ）、２．８２－３．００（ｍ、５Ｈ）、３．１４（ｓ、３Ｈ）、３．２７（ｄｄｄ、Ｊ＝２．４、１０．４、１４．４Ｈｚ、１Ｈ）、４．３８－４．４２（ｍ、１Ｈ）、６．５１（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．０１（ｂｒｓ、１Ｈ）、７．０４（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．１９－７．２３（ｍ、１Ｈ）、７．３１－７．３５（ｍ、２Ｈ）、７．５６－７．５８（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：３４２［Ｍ＋Ｈ］＋． Triphosgene (0.13 g, 0.38 mmol) was dissolved in dichloromethane (2.5 mL), and the above crude product, diisopropylethylamine (0.20 mL, 1.1 mmol) dissolved in dichloromethane (5.0 mL) was dissolved at 0 ° C. It was dripped at. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.14 g, 1.0 mmol), diisopropylethylamine (0.20 mL, 1 mL) dissolved in dichloromethane (2.5 mL) were stirred. 0.1 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.20 g (58%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.49-1.56 (m, 1H), 1.61-1.80 (m, 3H), 1.98-2.00 (m, 1H), 2.82-3.00 (m 5H), 3.14 (s, 3H), 3.27 (ddd, J = 2.4, 10.4, 14.4 Hz, 1H), 4.38-4.42 (m, 1H), 6 .51 (d, J = 4.0 Hz, 1H), 7.01 (brs, 1H), 7.04 (d, J = 4.0 Hz, 1H), 7.19-7.23 (m, 1H) , 7.31-7.35 (m, 2H), 7.56-7.58 (m, 2H).
MS (ESI): 342 [M + H] < +>.
（実施例２５）　（Ｒ）－１－メチル－３－（５－フェニルチオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000054
 　（Ｒ）－１－メチル－３－（５－フェニルチオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレア（０．２０ｇ、０．５９ｍｍｏｌ）を１，４－ジオキサン（１２ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．２２ｍＬ、０．８８ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１８ｇ（７７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７６－１．８２（ｍ、１Ｈ）、１．８４－１．９０（ｍ、２Ｈ）、１．９５－２．０２（ｍ、１Ｈ）、２．２１－２．２２（ｍ、１Ｈ）、３．０５（ｓ、３Ｈ）、３．２０－３．２６（ｍ、４Ｈ）、３．３８－３．４０（ｍ、１Ｈ）、３．６０－３．６６（ｍ、１Ｈ）、４．３７－４．４０（ｍ、１Ｈ）、６．７０（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．１８－７．２１（ｍ、２Ｈ）、７．３５（ｄｄ、Ｊ＝８．０、８．０Ｈｚ、２Ｈ）、７．５３（ｄ、Ｊ＝８．０Ｈｚ、２Ｈ）、９．８９（ｓ、１Ｈ）、１０．０５（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３４２［Ｍ＋Ｈ］＋． Example 25 Synthesis of (R) -1-methyl-3- (5-phenylthiophen-2-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000054
 (R) -1-methyl-3- (5-phenylthiophen-2-yl) -1- (quinuclidin-3-yl) urea (0.20 g, 0.59 mmol) was added to 1,4-dioxane (12 mL). After dissolution, a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.22 mL, 0.88 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.18 g (77%) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.76-1.82 (m, 1H), 1.84-1.90 (m, 2H), 1.95-2.02 (m, 1H), 2.21-2.22 (m 1H), 3.05 (s, 3H), 3.20-3.26 (m, 4H), 3.38-3.40 (m, 1H), 3.60-3.66 (m, 1H) ), 4.37-4.40 (m, 1H), 6.70 (d, J = 4.0 Hz, 1H), 7.18-7.21 (m, 2H), 7.35 (dd, J = 8.0, 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 9.89 (s, 1H), 10.05 (brs, 1H).
MS (ESI): 342 [M + H] < +>.
（参考例１６）　（５－（ピリジン－２－イル）チオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000055
 　５－（ピリジン－２－イル）チオフェン－２－カルボン酸（０．５０ｇ、２．５ｍｍｏｌ）をｔｅｒｔ－ブタノール（４．９ｍＬ）に溶解し、トリエチルアミン（０．４１ｍＬ、２．９ｍｍｏｌ）、ジフェニルホスホリルアジド（０．５８ｍＬ、２．７ｍｍｏｌ）を室温で加えた。８０℃で１２時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７０／３０）で精製し、表題化合物０．５７ｇ（８４％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．５４（ｓ、９Ｈ）、６．５８（ｄ、Ｊ＝３．６Ｈｚ、１Ｈ）、７．０２（ｂｒｓ、１Ｈ）、７．０６（ｄｄｄ、Ｊ＝１．２、４．８、７．２Ｈｚ、１Ｈ）、７．３５（ｄ、Ｊ＝３．６Ｈｚ、１Ｈ）、７．５３（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．６１（ｄｄｄ、Ｊ＝１，２、７．２、８．０Ｈｚ、１Ｈ）、８，５０（ｄｄｄ、Ｊ＝０．８、１．２、４．８Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：２７７［Ｍ＋Ｈ］＋． Reference Example 16 Synthesis of tert-butyl (5- (pyridin-2-yl) thiophen-2-yl) carbamate:
Figure JPOXMLDOC01-appb-C000055
 5- (Pyridin-2-yl) thiophene-2-carboxylic acid (0.50 g, 2.5 mmol) was dissolved in tert-butanol (4.9 mL), triethylamine (0.41 mL, 2.9 mmol), diphenylphosphoryl Azide (0.58 mL, 2.7 mmol) was added at room temperature. After stirring at 80 ° C. for 12 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 70/30) to obtain 0.57 g (84%) of the title compound as a yellow solid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.54 (s, 9H), 6.58 (d, J = 3.6 Hz, 1H), 7.02 (brs, 1H), 7.06 (ddd, J = 1.2, 4.8) , 7.2 Hz, 1 H), 7.35 (d, J = 3.6 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.61 (ddd, J = 1, 2, 7.2, 8.0 Hz, 1 H), 8, 50 (ddd, J = 0.8, 1.2, 4.8 Hz, 1 H).
MS (ESI): 277 [M + H] < +>.
（実施例２６）　（Ｒ）－１－メチル－３－（５－（ピリジン－２－イル）チオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000056
 　（５－（ピリジン－２－イル）チオフェン－２－イル）カルバミン酸　ｔｅｒｔ－ブチル（０．４０ｇ、１．５ｍｍｏｌ）を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、２．９ｍＬ、１２ｍｍｏｌ）を０℃で加えた。室温で１２時間攪拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Example 26 Synthesis of (R) -1-methyl-3- (5- (pyridin-2-yl) thiophen-2-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000056
 (5- (Pyridin-2-yl) thiophen-2-yl) carbamate tert-butyl (0.40 g, 1.5 mmol) was dissolved in 1,4-dioxane (1.0 mL), and hydrogen chloride-1, 4-Dioxane solution (4.0 N, 2.9 mL, 12 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　トリホスゲン（０．１０ｇ、０．３５ｍｍｏｌ）をジクロロメタン（２．５ｍＬ）に溶解し、ジクロロメタン（５．０ｍＬ）に溶解した上記の粗生成物、ジイソプロピルエチルアミン（０．２０ｍＬ、１．１ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、ジクロロメタン（２．５ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１４ｇ、１．０ｍｍｏｌ）、ジイソプロピルエチルアミン（０．２０ｍＬ、１．１ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．２１ｇ（５９％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．５０－１．５４（ｍ、１Ｈ）、１．６４－１．７８（ｍ、３Ｈ）、１．９９－２．０１（ｍ、１Ｈ）、２．８３－３．０１（ｍ、５Ｈ）、３．１４（ｓ、３Ｈ）、３．２６－３．３２（ｍ、１Ｈ）、４．３５－４．４０（ｍ、１Ｈ）、６．６０（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．０５（ｄｄ、Ｊ＝４．８、７．６Ｈｚ、１Ｈ）、７．１５（ｂｒｓ、１Ｈ）、７．３９（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．５２（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）、７．６０（ｄｄｄ、Ｊ＝１．６、７．６、８．０Ｈｚ、１Ｈ）、８．５０（ｄ、Ｊ＝４．８Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３４３［Ｍ＋Ｈ］＋． Triphosgene (0.10 g, 0.35 mmol) was dissolved in dichloromethane (2.5 mL), and the above crude product, diisopropylethylamine (0.20 mL, 1.1 mmol) dissolved in dichloromethane (5.0 mL) was dissolved at 0 ° C. It was dripped at. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.14 g, 1.0 mmol), diisopropylethylamine (0.20 mL, 1 mL) dissolved in dichloromethane (2.5 mL) were stirred. 0.1 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.21 g (59%) was obtained as a brown solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.54 (m, 1H), 1.64-1.78 (m, 3H), 1.99-2.01 (m, 1H), 2.83-3.01 (m 5H), 3.14 (s, 3H), 3.26-3.32 (m, 1H), 4.35-4.40 (m, 1H), 6.60 (d, J = 4.0 Hz) 1H), 7.05 (dd, J = 4.8, 7.6 Hz, 1H), 7.15 (brs, 1H), 7.39 (d, J = 4.0 Hz, 1H), 7.52 (D, J = 8.0 Hz, 1H), 7.60 (ddd, J = 1.6, 7.6, 8.0 Hz, 1H), 8.50 (d, J = 4.8 Hz, 1H).
MS (ESI): 343 [M + H] < +>.
（実施例２７）　（Ｒ）－１－メチル－３－（５－（ピリジン－２－イル）チオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレア　二塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000057
 　（Ｒ）－１－メチル－３－（５－（ピリジン－２－イル）チオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレア（０．２０ｇ、０．５８ｍｍｏｌ）を１，４－ジオキサン（１２ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．４４ｍＬ、１．８ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１７ｇ（７０％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７６－１．８０（ｍ、１Ｈ）、１．８６－１．９２（ｍ、２Ｈ）、１．９８－２．０４（ｍ、１Ｈ）、２．２３－２．２４（ｍ、１Ｈ）、３．０８（ｓ、３Ｈ）、３．１７－３．３２（ｍ、４Ｈ）、３．３８－３．４２（ｍ、１Ｈ）、３．５９－３．６４（ｍ、１Ｈ）、４．４０－４．４６（ｍ、１Ｈ）、６．９１（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）、７．３４－７．３８（ｍ、１Ｈ）、７．８５－７．９０（ｍ、２Ｈ）、８．００－８．０４（ｍ、１Ｈ）、８．４７（ｄ、Ｊ＝４．８Ｈｚ、１Ｈ）、１０．４２（ｂｒｓ、１Ｈ）、１０．４６（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３４３［Ｍ＋Ｈ］＋． Example 27 Synthesis of (R) -1-methyl-3- (5- (pyridin-2-yl) thiophen-2-yl) -1- (quinuclidin-3-yl) urea dihydrochloride:
Figure JPOXMLDOC01-appb-C000057
 (R) -1-methyl-3- (5- (pyridin-2-yl) thiophen-2-yl) -1- (quinuclidin-3-yl) urea (0.20 g, 0.58 mmol) -Dissolved in dioxane (12 mL) and hydrogen chloride-1,4-dioxane solution (4.0 N, 0.44 mL, 1.8 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.17 g (70%) of the title compound as a yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.76-1.80 (m, 1H), 1.86-1.92 (m, 2H), 1.98-2.04 (m, 1H), 2.23-2.24 (m 1H), 3.08 (s, 3H), 3.17-3.32 (m, 4H), 3.38-3.42 (m, 1H), 3.59-3.64 (m, 1H) ), 4.40-4.46 (m, 1H), 6.91 (d, J = 4.0 Hz, 1H), 7.34-7.38 (m, 1H), 7.85-7.90 (M, 2H), 8.00-8.04 (m, 1H), 8.47 (d, J = 4.8 Hz, 1H), 10.42 (brs, 1H), 10.46 (brs, 1H) ).
MS (ESI): 343 [M + H] < +>.
（実施例２８）　（Ｒ）－１－メチル－３－（５－フェニルチアゾール－２－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000058
 　５－フェニルチアゾール－２－アミン（０．１３ｇ、０．７２ｍｍｏｌ）を１，４－ジオキサン（４．０ｍＬ）、蒸留水（２．０ｍＬ）に溶解し、炭酸水素ナトリウム（０．１２ｇ、１．４ｍｍｏｌ）、クロロギ酸フェニル（０．１０ｍＬ、０．７９ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Example 28 Synthesis of (R) -1-methyl-3- (5-phenylthiazol-2-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000058
 5-Phenylthiazol-2-amine (0.13 g, 0.72 mmol) was dissolved in 1,4-dioxane (4.0 mL) and distilled water (2.0 mL), and sodium bicarbonate (0.12 g, 1.2. 4 mmol), phenyl chloroformate (0.10 mL, 0.79 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をジクロロエタン（６．１ｍＬ）に懸濁し、トリエチルアミン（０．２５ｍＬ、１．８ｍｍｏｌ）、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０８５ｇ、０．６１ｍｍｏｌ）を室温で加えた。８０℃で３０分間攪拌した後、反応溶液を室温まで冷却し、１．０Ｎ水酸化ナトリウム水溶液を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．２０ｇ（９７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．４９－１．５６（ｍ、１Ｈ）、１．６３－１．６９（ｍ、１Ｈ）、１．７１－１．８１（ｍ、２Ｈ）、１．９９－２．０１（ｍ、１Ｈ）、２．７６－３．０２（ｍ、５Ｈ）、３．１５（ｓ、３Ｈ）、３．２５－３．３２（ｍ、１Ｈ）、４．３６－４．４０（ｍ、１Ｈ）、７．２６－７．３０（ｍ、１Ｈ）、７．３６－７．３９（ｍ、２Ｈ）、７．５２－７．５４（ｍ、３Ｈ）．
ＭＳ（ＥＳＩ）：３４３［Ｍ＋Ｈ］＋． The above crude product was suspended in dichloroethane (6.1 mL), triethylamine (0.25 mL, 1.8 mmol), (R) -N-methylquinuclidin-3-amine (0.085 g, 0.61 mmol). Was added at room temperature. After stirring at 80 ° C. for 30 minutes, the reaction solution was cooled to room temperature, 1.0N aqueous sodium hydroxide solution was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.20 g (97%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.49-1.56 (m, 1H), 1.63-1.69 (m, 1H), 1.71-1.81 (m, 2H), 1.99-2.01 (m 1H), 2.76-3.02 (m, 5H), 3.15 (s, 3H), 3.25-3.32 (m, 1H), 4.36-4.40 (m, 1H) ), 7.26-7.30 (m, 1H), 7.36-7.39 (m, 2H), 7.52-7.54 (m, 3H).
MS (ESI): 343 [M + H] < +>.
（実施例２９）　（Ｒ）－１－メチル－３－（５－フェニルチアゾール－２－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000059
 　（Ｒ）－１－メチル－３－（５－フェニルチアゾール－２－イル）－１－（キヌクリジン－３－イル）ウレア（０．１０ｇ、０．２９ｍｍｏｌ）を１，４－ジオキサン（５．８ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．２２ｍＬ、０．８８ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１２ｇ（９７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７６－１．８２（ｍ、１Ｈ）、１．８４－１．９２（ｍ、２Ｈ）、１．９８－２．１０（ｍ、１Ｈ）、２．２３－２．２４（ｍ、１Ｈ）、３．０８（ｓ、３Ｈ）、３．１９－３．２１（ｍ、３Ｈ）、３．２９（ｄｄ、Ｊ＝７．２、１３．２Ｈｚ、１Ｈ）、３．３７－３．４３（ｍ、１Ｈ）、３．５７－３．６５（ｍ、１Ｈ）、４．４２－４．４６（ｍ、１Ｈ）、７．２７（ｄｄ、Ｊ＝０．８、７．６Ｈｚ、１Ｈ）、７．４０（ｄｄ、Ｊ＝７．６、８．０Ｈｚ、２Ｈ）、７．５６（ｄｄ、Ｊ＝０．８、８．０Ｈｚ、２Ｈ）、７．７８（ｓ、１Ｈ）、１０．２７（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３４３［Ｍ＋Ｈ］＋． Example 29 Synthesis of (R) -1-methyl-3- (5-phenylthiazol-2-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000059
 (R) -1-methyl-3- (5-phenylthiazol-2-yl) -1- (quinuclidin-3-yl) urea (0.10 g, 0.29 mmol) was added to 1,4-dioxane (5.8 mL). And a hydrogen chloride-1,4-dioxane solution (4.0 N, 0.22 mL, 0.88 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.12 g (97%) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.76-1.82 (m, 1H), 1.84-1.92 (m, 2H), 1.98-2.10 (m, 1H), 2.23-2.24 (m 1H), 3.08 (s, 3H), 3.19-3.21 (m, 3H), 3.29 (dd, J = 7.2, 13.2 Hz, 1H), 3.37-3 .43 (m, 1H), 3.57-3.65 (m, 1H), 4.42-4.46 (m, 1H), 7.27 (dd, J = 0.8, 7.6 Hz, 1H), 7.40 (dd, J = 7.6, 8.0 Hz, 2H), 7.56 (dd, J = 0.8, 8.0 Hz, 2H), 7.78 (s, 1H), 10.27 (brs, 1H).
MS (ESI): 343 [M + H] < +>.
（参考例１７）　（１－メチル－１Ｈ－ピラゾール－４－イル）カルバミン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000060
 　１－メチル－１Ｈ－ピラゾール－４－カルボン酸（０．５０ｇ、４．０ｍｍｏｌ）をｔｅｒｔ－ブタノール（１２ｍＬ）に溶解し、トリエチルアミン（０．６６ｍＬ、４．８ｍｍｏｌ）、ジフェニルホスホリルアジド（０．９４ｍＬ、４．４ｍｍｏｌ）を室温で加えた。８０℃で９時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝５０／５０）で精製し、表題化合物０．５５ｇ（７０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０（ｓ、９Ｈ）、３．８４（ｓ、３Ｈ）、６．３０（ｂｒｓ、１Ｈ）、７．２９（ｓ、１Ｈ）、７．６２（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：１９８［Ｍ＋Ｈ］＋． Reference Example 17 Synthesis of tert-butyl (1-methyl-1H-pyrazol-4-yl) carbamate:
Figure JPOXMLDOC01-appb-C000060
 1-Methyl-1H-pyrazole-4-carboxylic acid (0.50 g, 4.0 mmol) was dissolved in tert-butanol (12 mL), triethylamine (0.66 mL, 4.8 mmol), diphenylphosphoryl azide (0.94 mL). 4.4 mmol) was added at room temperature. After stirring at 80 ° C. for 9 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 50/50) to give 0.55 g (70%) of the title compound as a white solid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50 (s, 9H), 3.84 (s, 3H), 6.30 (brs, 1H), 7.29 (s, 1H), 7.62 (brs, 1H).
MS (ESI): 198 [M + H] + .
（実施例３０）　（Ｒ）－１－メチル－３－（１－メチル－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000061
 　（１－メチル－１Ｈ－ピラゾール－４－イル）カルバミン酸　ｔｅｒｔ－ブチル（０．２０ｇ、０．９４ｍｍｏｌ）を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、２．１ｍＬ、８．４ｍｍｏｌ）を０℃で加えた。室温で１２時間攪拌した後、溶媒を濃縮し、得られた粗生成物を精製することなく、続く反応に用いた。 Example 30 Synthesis of (R) -1-methyl-3- (1-methyl-1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000061
 (1-Methyl-1H-pyrazol-4-yl) carbamate tert-butyl (0.20 g, 0.94 mmol) was dissolved in 1,4-dioxane (1.0 mL), and hydrogen chloride-1,4-dioxane was used. The solution (4.0 N, 2.1 mL, 8.4 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, the solvent was concentrated and the resulting crude product was used in the subsequent reaction without purification.
　トリホスゲン（０．０７８ｇ、０．２６ｍｍｏｌ）をジクロロメタン（１．８ｍＬ）に溶解し、ジクロロメタン（３．５ｍＬ）に溶解した上記の粗生成物、ジイソプロピルエチルアミン（０．２７ｍＬ、１．６ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、ジクロロメタン（１．８ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０９９ｇ、０．７１ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１４ｍＬ、０．７８ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１７ｇ（９０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．４８－１．５５（ｍ、１Ｈ）、１．６２－１．６８（ｍ、１Ｈ）、１．７２－１．８０（ｍ、２Ｈ）、１．９３－１．９６（ｍ、１Ｈ）、２．８１－２．９１（ｍ、４Ｈ）、２．９５－３．０１（ｍ、１Ｈ）、３．０９（ｓ、３Ｈ）、３．２２－３．２９（ｍ、１Ｈ）、３．８４（ｓ、３Ｈ）、４．３１－４．３５（ｍ、１Ｈ）、６．１８（ｂｒｓ、１Ｈ）、７．３３（ｓ、１Ｈ）、７．７３（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２６４［Ｍ＋Ｈ］＋． Triphosgene (0.078 g, 0.26 mmol) was dissolved in dichloromethane (1.8 mL), and the above crude product, diisopropylethylamine (0.27 mL, 1.6 mmol) dissolved in dichloromethane (3.5 mL) was added at 0 ° C. It was dripped at. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.099 g, 0.71 mmol), diisopropylethylamine (0.14 mL, 0) dissolved in dichloromethane (1.8 mL) was stirred. .78 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.17 g (90%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.48-1.55 (m, 1H), 1.62-1.68 (m, 1H), 1.72-1.80 (m, 2H), 1.93-1.96 (m 1H), 2.81-2.91 (m, 4H), 2.95-3.01 (m, 1H), 3.09 (s, 3H), 3.22-3.29 (m, 1H) ), 3.84 (s, 3H), 4.31-4.35 (m, 1H), 6.18 (brs, 1H), 7.33 (s, 1H), 7.73 (s, 1H) .
MS (ESI): 264 [M + H] < +>.
（参考例１８）　チオフェン－２－イルカルバミン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000062
 　チオフェン－２－カルボン酸（１．０ｇ、７．８ｍｍｏｌ）をｔｅｒｔ－ブタノール（１６ｍＬ）に溶解し、トリエチルアミン（１．３ｍＬ、９．４ｍｍｏｌ）、ジフェニルホスホリルアジド（１．９ｍＬ、８．６ｍｍｏｌ）を室温で加えた。８０℃で８時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物０．８０ｇ（５１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５２（ｓ、９Ｈ）、６．５２（ｄｄ、Ｊ＝１．６、３．６Ｈｚ、１Ｈ）、６．７９－６．８３（ｍ、２Ｈ）、６．９２（ｂｒｓ、１Ｈ）． Reference Example 18 Synthesis of tert-butyl thiophen-2-ylcarbamate:
Figure JPOXMLDOC01-appb-C000062
 Thiophene-2-carboxylic acid (1.0 g, 7.8 mmol) was dissolved in tert-butanol (16 mL), triethylamine (1.3 mL, 9.4 mmol), diphenylphosphoryl azide (1.9 mL, 8.6 mmol) were added. Added at room temperature. After stirring at 80 ° C. for 8 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 80/20) to give 0.80 g (51%) of the title compound as a pale yellow solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.52 (s, 9H), 6.52 (dd, J = 1.6, 3.6 Hz, 1H), 6.79-6.83 (m, 2H), 6.92 (brs, 1H) ).
（実施例３１）　（Ｒ）－１－メチル－３－（チオフェン－２－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000063
 　チオフェン－２－イルカルバミン酸　ｔｅｒｔ－ブチル（０．１２ｇ、０．６１ｍｍｏｌ）を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、１．８ｍＬ、７．２ｍｍｏｌ）を０℃で加えた。室温で１２時間攪拌した後、溶媒を濃縮し、得られた粗生成物を精製することなく、続く反応に用いた。 Example 31 Synthesis of (R) -1-methyl-3- (thiophen-2-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000063
 Tert-butyl thiophen-2-ylcarbamate (0.12 g, 0.61 mmol) was dissolved in 1,4-dioxane (1.0 mL) and a hydrogen chloride-1,4-dioxane solution (4.0 N, 1.N) was dissolved. 8 mL, 7.2 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, the solvent was concentrated and the resulting crude product was used in the subsequent reaction without purification.
　上記の粗生成物を１，４－ジオキサン（２．４ｍＬ）、蒸留水（１．２ｍＬ）に溶解し、炭酸水素ナトリウム（０．１５ｇ、１．８ｍｍｏｌ）、クロロギ酸フェニル（０．０８１ｍＬ、０．６７ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、粗生成物を精製することなく、続く反応に用いた。
　上記の粗生成物をクロロホルム（５．７ｍＬ）に溶解し、トリエチルアミン（０．２４ｍＬ、１．７ｍｍｏｌ）、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０８０ｇ、０．５７ｍｍｏｌ）を室温で加えた。６０℃で３０分間攪拌した後、反応溶液を室温まで冷却し、１．０Ｎ水酸化ナトリウム水溶液を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．０３３ｇ（２２％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．４９－１．５５（ｍ、１Ｈ）、１．６０－１．８１（ｍ、３Ｈ）、１．９７－２．０１（ｍ、１Ｈ）、２．８１－３．００（ｍ、５Ｈ）、３．１２（ｓ、３Ｈ）、３．２２－３．２９（ｍ、１Ｈ）、４．３６－４．４０（ｍ、１Ｈ）、６．５５（ｄｄ、Ｊ＝２．４、２．８Ｈｚ、１Ｈ）、６．８０（ｂｒｄ、Ｊ＝２．０Ｈｚ、２Ｈ）、７．０８（ｂｒｓ、１Ｈ）．
ＭＳ（ＥＳＩ）２６６［Ｍ＋Ｈ］＋． The above crude product was dissolved in 1,4-dioxane (2.4 mL), distilled water (1.2 mL), sodium hydrogen carbonate (0.15 g, 1.8 mmol), phenyl chloroformate (0.081 mL, 0 mL). .67 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the crude product was used in the subsequent reaction without purification.
The above crude product was dissolved in chloroform (5.7 mL), triethylamine (0.24 mL, 1.7 mmol), (R) -N-methylquinuclidin-3-amine (0.080 g, 0.57 mmol). Was added at room temperature. After stirring at 60 ° C. for 30 minutes, the reaction solution was cooled to room temperature, 1.0N aqueous sodium hydroxide solution was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.033 g (22%) was obtained as a brown solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.49-1.55 (m, 1H), 1.60-1.81 (m, 3H), 1.97-2.01 (m, 1H), 2.81-3.00 (m 5H), 3.12 (s, 3H), 3.22-3.29 (m, 1H), 4.36-4.40 (m, 1H), 6.55 (dd, J = 2.4) 2.8 Hz, 1H), 6.80 (brd, J = 2.0 Hz, 2H), 7.08 (brs, 1H).
MS (ESI) 266 [M + H] < +>.
（参考例１９）　７－フルオロベンゾ［ｂ］チオフェン－２－カルボン酸エチルの合成：
Figure JPOXMLDOC01-appb-C000064
 　２，３－ジフルオロベンズアルデヒド（０．５０ｇ、３．５ｍｍｏｌ）をジメチルホルムアミド（５．０ｍＬ）に溶解し、２－メルカプト酢酸エチル（０．４２ｇ、３．５ｍｍｏｌ）を室温で加えた。６０℃で８時間撹拌した後、反応溶液を室温まで冷却し、セライト濾過し、ろ液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８８／１２－６６／３４）で精製し、表題化合物０．５３ｇ（６７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ: １．４３（ｔ、Ｊ＝６．８Ｈｚ、３Ｈ）、４．４２（ｑ、Ｊ＝６．８Ｈｚ、２Ｈ）、７．１２－７．１９（ｍ、１Ｈ）、７．３５－７．４２（ｍ、１Ｈ）、７．６７（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ），８．０８（ｄ、Ｊ＝４．０Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：２２５［Ｍ＋Ｈ］＋． Reference Example 19 Synthesis of ethyl 7-fluorobenzo [b] thiophene-2-carboxylate:
Figure JPOXMLDOC01-appb-C000064
 2,3-Difluorobenzaldehyde (0.50 g, 3.5 mmol) was dissolved in dimethylformamide (5.0 mL) and ethyl 2-mercaptoacetate (0.42 g, 3.5 mmol) was added at room temperature. After stirring at 60 ° C. for 8 hours, the reaction solution was cooled to room temperature, filtered through celite, distilled water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 88 / 12-66 / 34) to give 0.53 g (67%) of the title compound as a white solid. Obtained.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.43 (t, J = 6.8 Hz, 3H), 4.42 (q, J = 6.8 Hz, 2H), 7.12-7.19 (m, 1H), 7.35-7 .42 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 4.0 Hz, 1H).
MS (ESI): 225 [M + H] < +>.
（参考例２０）　７－フルオロベンゾ［ｂ］チオフェン－２－アミンの合成：
Figure JPOXMLDOC01-appb-C000065
 　７－フルオロベンゾ［ｂ］チオフェン－２－カルボン酸エチル（０．５３ｇ、２．４ｍｍｏｌ）をメタノール（７．０ｍＬ）に溶解し、水酸化ナトリウム水溶液（１．０Ｎ、７．１ｍＬ、７．１ｍｍｏｌ）を室温で加えた。５０℃で３時間撹拌した後、溶媒を濃縮し、酢酸エチルで抽出した。水層に１．０Ｎ塩酸を加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Reference Example 20 Synthesis of 7-fluorobenzo [b] thiophen-2-amine:
Figure JPOXMLDOC01-appb-C000065
 Ethyl 7-fluorobenzo [b] thiophene-2-carboxylate (0.53 g, 2.4 mmol) was dissolved in methanol (7.0 mL) and an aqueous sodium hydroxide solution (1.0 N, 7.1 mL, 7.1 mmol). ) Was added at room temperature. After stirring at 50 ° C. for 3 hours, the solvent was concentrated and extracted with ethyl acetate. 1.0N hydrochloric acid was added to the aqueous layer, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物をｔｅｒｔ－ブタノール（４．７ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．４５ｍＬ、２．６ｍｍｏｌ）、ジフェニルホスホリルアジド（０．６１ｍＬ、２．８ｍｍｏｌ）を室温で加えた。８０℃で６時間撹拌した後、水を加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝６７／３３）で精製した。 The above crude product was dissolved in tert-butanol (4.7 mL), and diisopropylethylamine (0.45 mL, 2.6 mmol) and diphenylphosphoryl azide (0.61 mL, 2.8 mmol) were added at room temperature. After stirring at 80 ° C. for 6 hours, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 67/33).
　得られた粗精製物を１，４－ジオキサン（７．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、７．１ｍＬ、２８ｍｍｏｌ）を０℃で加えた。室温で１６時間撹拌した後、飽和重曹水を加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝６７／３３）で精製し、表題化合物０．２３ｇ（５９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ４．０４－４．１８（ｍ、２Ｈ）、６．３０（ｄ、Ｊ＝３．２Ｈｚ、１Ｈ）、６．７６－６．８３（ｍ、１Ｈ）、７．１４－７．２２（ｍ、２Ｈ）． 
ＭＳ（ＥＳＩ）：１６８［Ｍ＋Ｈ］＋． The obtained crude product was dissolved in 1,4-dioxane (7.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 7.1 mL, 28 mmol) was added at 0 ° C. After stirring at room temperature for 16 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 67/33) to give 0.23 g (59%) of the title compound as a white solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 4.04-4.18 (m, 2H), 6.30 (d, J = 3.2 Hz, 1H), 6.76-6.83 (m, 1H), 7.14-7.22 (M, 2H).
MS (ESI): 168 [M + H] < +>.
（実施例３２）　（Ｒ）－３－（７－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000066
 　７－フルオロベンゾ［ｂ］チオフェン－２－アミン（０．１０ｇ、０．６０ｍｍｏｌ）をジクロロメタン（３．０ｍＬ）に溶解し、トリホスゲン（０．０６０ｇ、０．２０ｍｍｏｌ）、トリエチルアミン（０．２５ｍＬ、１．８ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌後、（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．０８４ｇ、０．６０ｍｍｏｌ）を０℃で加えた。室温で３時間撹拌した後、飽和重曹水を加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルカラムクロマトグラフィー（クロロホルムのみ－クロロホルム／メタノール＝８０／２０）で精製し、表題化合物０．０６０ｇ（３０％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: １．４５－１．８０（ｍ、４Ｈ）、１．９４－２．００（ｍ、１Ｈ）、２．７５－３．０２（ｍ、５Ｈ）、３．１４（ｓ、３Ｈ）、３．２０－３．３０（ｍ、１Ｈ）、４．３４－４．４２（ｍ、１Ｈ）、６．７６（ｄ、Ｊ＝３．２Ｈｚ、１Ｈ）、６．８４－６．９０（ｍ、１Ｈ）、７．１８－７．４０（ｍ、３Ｈ）． 
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 32 Synthesis of (R) -3- (7-fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000066
 7-Fluorobenzo [b] thiophen-2-amine (0.10 g, 0.60 mmol) was dissolved in dichloromethane (3.0 mL), triphosgene (0.060 g, 0.20 mmol), triethylamine (0.25 mL, 1 mL). .8 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.084 g, 0.60 mmol) was added at 0 ° C. After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate was added, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel column chromatography (chloroform only-chloroform / methanol = 80/20) to give 0.060 g (30%) of the title compound as a colorless liquid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.4-1.80 (m, 4H), 1.94-2.00 (m, 1H), 2.75-3.02 (m, 5H), 3.14 (s, 3H), 3.20-3.30 (m, 1H), 4.34-4.42 (m, 1H), 6.76 (d, J = 3.2 Hz, 1H), 6.84-6.90 (m 1H), 7.18-7.40 (m, 3H).
MS (ESI): 334 [M + H] < +>.
（実施例３３）　（Ｒ）－３－（７－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000067
 　（Ｒ）－３－（７－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．０６０ｇ、０．１８ｍｍｏｌ）をジエチルエーテル（２．０ｍＬ）に溶解し、塩化水素－ジエチルエーテル溶液（２．０Ｎ、０．１２ｍＬ、０．２４ｍｍｏｌ）を０℃で加えた。同温度で３０分間撹拌した後、ろ過し、ろ取した固体をジエチルエーテルで洗浄後に乾燥し、表題化合物０．０４５ｇ（６７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、Ｄ２Ｏ）
δ: １．９０－２．２３（ｍ、４Ｈ）、２．３５－２．４２（ｍ、１Ｈ）、３．１０（ｓ、３Ｈ）、３．２８－３．５３（ｍ、５Ｈ）、３．７０－３．７９（ｍ、１Ｈ）、４．４６－４．５３（ｍ、１Ｈ）、６．９５－７．０８（ｍ、２Ｈ）、７．３４－７．４１（ｍ、１Ｈ）、７．５０（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 33 Synthesis of (R) -3- (7-fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000067
 (R) -3- (7-Fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.060 g, 0.18 mmol) was added to diethyl ether (2. 0 mL) and a hydrogen chloride-diethyl ether solution (2.0 N, 0.12 mL, 0.24 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with diethyl ether and then dried to obtain 0.045 g (67%) of the title compound as a white solid.
1 H-NMR (400 MHz, D 2 O)
δ: 1.90-2.23 (m, 4H), 2.35-2.42 (m, 1H), 3.10 (s, 3H), 3.28-3.53 (m, 5H), 3.70-3.79 (m, 1H), 4.46-4.53 (m, 1H), 6.95-7.08 (m, 2H), 7.34-7.41 (m, 1H) ), 7.50 (d, J = 8.0 Hz, 1H).
MS (ESI): 334 [M + H] < +>.
（参考例２１）　チエノ［２，３－ｂ］ピリジン－２－カルボン酸メチルの合成：
Figure JPOXMLDOC01-appb-C000068
 　２－クロロピリジン－３－カルボアルデヒド（０．８０ｇ、５．７ｍｍｏｌ）をジメチルホルムアミド（１７ｍＬ）に溶解し、炭酸カリウム（２．３ｇ、１７ｍｍｏｌ）、２－メルカプト酢酸メチル（０．５６ｍＬ、６．２ｍｍｏｌ）を室温で加えた。８０℃で２時間撹拌した後、反応溶液を室温まで冷却し、蒸留水を加えて、ジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物０．８６ｇ（７９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ３．９７（ｓ、３Ｈ）、７．３７（ｄｄｄ、Ｊ＝０．８、４．８、８．０Ｈｚ、１Ｈ）、８．０１（ｄ、Ｊ＝１．２Ｈｚ、１Ｈ）、８．１６（ｄｄｄ、Ｊ＝１．２、１．６、８．０Ｈｚ、１Ｈ）、８．６９（ｄｄｄ、Ｊ＝１．２、１．６、４．８Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：１９４［Ｍ＋Ｈ］＋． Reference Example 21 Synthesis of thieno [2,3-b] pyridine-2-carboxylate methyl:
Figure JPOXMLDOC01-appb-C000068
 2-Chloropyridine-3-carbaldehyde (0.80 g, 5.7 mmol) was dissolved in dimethylformamide (17 mL), potassium carbonate (2.3 g, 17 mmol), methyl 2-mercaptoacetate (0.56 mL, 6. 2 mmol) was added at room temperature. After stirring at 80 ° C. for 2 hours, the reaction solution was cooled to room temperature, distilled water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 80/20) to give 0.86 g (79%) of the title compound as a white solid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 3.97 (s, 3H), 7.37 (ddd, J = 0.8, 4.8, 8.0 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 8 .16 (ddd, J = 1.2, 1.6, 8.0 Hz, 1H), 8.69 (ddd, J = 1.2, 1.6, 4.8 Hz, 1H).
MS (ESI): 194 [M + H] < +>.
（参考例２２）　チエノ［２，３－ｂ］ピリジン－２－アミンの合成：
Figure JPOXMLDOC01-appb-C000069
 　チエノ［２，３－ｂ］ピリジン－２－カルボン酸メチル（０．１０ｇ、０．５２ｍｍｏｌ）を１，４－ジオキサン（１．６ｍＬ）に溶解し、１．０Ｎ水酸化ナトリウム水溶液（０．７８ｍＬ、０．７８ｍｍｏｌ）を０℃で加えた。室温で５時間撹拌した後、Ｄｏｗｅｘ　５０ＷＸ２を０℃で加えて、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の粗生成物をｔｅｒｔ－ブタノール（２．０ｍＬ）、ジメチルホルムアミド（１．０ｍＬ）に溶解し、トリエチルアミン（０．１１ｍＬ、０．７８ｍｍｏｌ）、ジフェニルホスホリルアジド（０．０９２ｍＬ、０．４３ｍｍｏｌ）を室温で加えた。８０℃で８時間攪拌した後、反応溶液を室温まで冷却し、飽和重曹水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。 Reference Example 22 Synthesis of thieno [2,3-b] pyridin-2-amine:
Figure JPOXMLDOC01-appb-C000069
 Thieno [2,3-b] pyridine-2-carboxylate methyl (0.10 g, 0.52 mmol) was dissolved in 1,4-dioxane (1.6 mL) and 1.0N aqueous sodium hydroxide solution (0.78 mL) was dissolved. , 0.78 mmol) was added at 0 ° C. After stirring at room temperature for 5 hours, Dowex 50WX2 was added at 0 ° C. and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above crude product was dissolved in tert-butanol (2.0 mL) and dimethylformamide (1.0 mL), and triethylamine (0.11 mL, 0.78 mmol) and diphenylphosphoryl azide (0.092 mL, 0.43 mmol) were added. Added at room temperature. After stirring at 80 ° C. for 8 hours, the reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
　上記の粗生成物を１，４－ジオキサン（１．０ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、１．１ｍＬ、４．４ｍｍｏｌ）を０℃で加えた。室温で８時間攪拌した後、飽和重曹水を０℃で加えて、水層を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０－５０／５０）で精製し、表題化合物０．０２５ｇ（４３％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ: ４．１９（ｂｒｓ、２Ｈ）、６．１３（ｓ、１Ｈ）、７．１３（ｄｄ、Ｊ＝４．８、８．０Ｈｚ、１Ｈ）、７．６１（ｄｄ、Ｊ＝１．６、８．０Ｈｚ、１Ｈ）、８．２４（ｄｄ、Ｊ＝１．６、４．８Ｈｚ、１Ｈ）． 
ＭＳ（ＥＳＩ）：１５１［Ｍ＋Ｈ］＋． The above crude product was dissolved in 1,4-dioxane (1.0 mL), and a hydrogen chloride-1,4-dioxane solution (4.0 N, 1.1 mL, 4.4 mmol) was added at 0 ° C. After stirring at room temperature for 8 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane / ethyl acetate = 90 / 10-50 / 50) to give 0.025 g (43%) of the title compound as a brown solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 4.19 (brs, 2H), 6.13 (s, 1H), 7.13 (dd, J = 4.8, 8.0 Hz, 1H), 7.61 (dd, J = 1.6) , 8.0 Hz, 1H), 8.24 (dd, J = 1.6, 4.8 Hz, 1H).
MS (ESI): 151 [M + H] < +>.
（実施例３４）　（Ｒ）－１－メチル－１－（キヌクリジン－３－イル）－３－（チエノ［２，３－ｂ］ピリジン－２－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000070
 　トリホスゲン（０．０９５ｇ、０．３２ｍｍｏｌ）をジクロロメタン（２．３ｍＬ）に溶解し、ジクロロメタン（４．５ｍＬ）に溶解したチエノ［２，３－ｂ］ピリジン－２－アミン（０．１３ｇ、０．８７ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１７ｍＬ、０．９５ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、ジクロロメタン（２．３ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１２ｇ、０．８７ｍｍｏｌ）、ジイソプロピルエチルアミン（０．１７ｍＬ、０．９５ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１４ｇ（５２％）を淡褐色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０－１．５８（ｍ、１Ｈ）、１．６２－１．８０（ｍ、３Ｈ）、１．９７－２．０１（ｍ、１Ｈ）、２．８０－２．９９（ｍ、５Ｈ）、３．１７（ｓ、３Ｈ）、３．２６（ｄｄｄ、Ｊ＝２．０、１０．４、１４．４Ｈｚ、１Ｈ）、４．３８－４．４３（ｍ、１Ｈ）、６．６６（ｓ、１Ｈ）、７．２０（ｄｄ、Ｊ＝４．８，８．０Ｈｚ、１Ｈ）、７．２８（ｂｒｓ、１Ｈ）、７．７７（ｄｄ、Ｊ＝１．６、８．０Ｈｚ、１Ｈ）、８．３９（ｄｄ、Ｊ＝１．６、４．８Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３１７［Ｍ＋Ｈ］＋． Example 34 Synthesis of (R) -1-methyl-1- (quinuclidin-3-yl) -3- (thieno [2,3-b] pyridin-2-yl) urea:
Figure JPOXMLDOC01-appb-C000070
 Triphosgene (0.095 g, 0.32 mmol) was dissolved in dichloromethane (2.3 mL) and thieno [2,3-b] pyridin-2-amine (0.13 g, 0.002 mL) dissolved in dichloromethane (4.5 mL). 87 mmol) and diisopropylethylamine (0.17 mL, 0.95 mmol) were added dropwise at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.12 g, 0.87 mmol), diisopropylethylamine (0.17 mL, 0) dissolved in dichloromethane (2.3 mL) was stirred. .95 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.14 g (52%) was obtained as a light brown solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.58 (m, 1H), 1.62-1.80 (m, 3H), 1.97-2.01 (m, 1H), 2.80-2.99 (m 5H), 3.17 (s, 3H), 3.26 (ddd, J = 2.0, 10.4, 14.4 Hz, 1H), 4.38-4.43 (m, 1H), 6 .66 (s, 1H), 7.20 (dd, J = 4.8, 8.0 Hz, 1H), 7.28 (brs, 1H), 7.77 (dd, J = 1.6, 8. 0 Hz, 1H), 8.39 (dd, J = 1.6, 4.8 Hz, 1H).
MS (ESI): 317 [M + H] < +>.
（実施例３５）　（Ｒ）－１－メチル－１－（キヌクリジン－３－イル）－３－（チエノ［２，３－ｂ］ピリジン－２－イル）ウレア　二塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000071
 　（Ｒ）－１－メチル－１－（キヌクリジン－３－イル）－３－（チエノ［２，３－ｂ］ピリジン－２－イル）ウレア（０．１４ｇ、０．４４ｍｍｏｌ）を１，４－ジオキサン（８．８ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．３３ｍＬ、１．３ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１７ｇ（９９％）を淡茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７６－２．０６（ｍ、４Ｈ）、２．２３－２．２４（ｍ、１Ｈ）、３．１０（ｓ、３Ｈ）、３．１８－３．３２（ｍ、４Ｈ）、３．３８－３．４２（ｍ、１Ｈ）、３．６１－３．６７（ｍ、１Ｈ）、４．４５－４．４９（ｍ、１Ｈ）、６．９９（ｓ、１Ｈ）、７．３５（ｄｄ、Ｊ＝４．８、８．０Ｈｚ、１Ｈ）、８．０５（ｄｄ、Ｊ＝１．２、８．０Ｈｚ、１Ｈ）、８．３５（ｄｄ、Ｊ＝１．２、４．８Ｈｚ、１Ｈ）、１０．２６（ｂｒｓ、１Ｈ）、１０．３８（ｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３１７［Ｍ＋Ｈ］＋． Example 35 Synthesis of (R) -1-methyl-1- (quinuclidin-3-yl) -3- (thieno [2,3-b] pyridin-2-yl) urea dihydrochloride:
Figure JPOXMLDOC01-appb-C000071
 (R) -1-methyl-1- (quinuclidin-3-yl) -3- (thieno [2,3-b] pyridin-2-yl) urea (0.14 g, 0.44 mmol) was added to 1,4- Dissolved in dioxane (8.8 mL), hydrogen chloride-1,4-dioxane solution (4.0 N, 0.33 mL, 1.3 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.17 g (99%) of the title compound as a light brown solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.76-2.06 (m, 4H), 2.23-2.24 (m, 1H), 3.10 (s, 3H), 3.18-3.32 (m, 4H), 3.38-3.42 (m, 1H), 3.61-3.67 (m, 1H), 4.45-4.49 (m, 1H), 6.99 (s, 1H), 7. 35 (dd, J = 4.8, 8.0 Hz, 1H), 8.05 (dd, J = 1.2, 8.0 Hz, 1H), 8.35 (dd, J = 1.2, 4.H). 8 Hz, 1H), 10.26 (brs, 1H), 10.38 (s, 1H).
MS (ESI): 317 [M + H] < +>.
（比較例１）　（Ｒ）－１－メチル－１－フェニル－３－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000072
 　トリホスゲン（０．１１ｇ、０．３７ｍｍｏｌ）をクロロホルム（２．５ｍＬ）に溶解し、クロロホルム（５．０ｍＬ）に溶解したジイソプロピルアミン（０．５８ｍＬ、３．３ｍｍｏｌ）、（Ｒ）－キヌクリジン－３－アミン　二塩酸塩（０．２０ｇ、１．０ｍｍｏｌ）を０℃で滴下した。同温度で３０分間攪拌した後、クロロホルム（２．５ｍＬ）に溶解したＮ－メチルアニリン（０．１１ｍＬ、１．０ｍｍｏｌ）を０℃で滴下した。室温で６時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１４ｇ（５５％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．２９－１．３５（ｍ、２Ｈ）、１．６１（ｄｔ、Ｊ＝２．４、３．６Ｈｚ、２Ｈ）、１．８３（ｄｔ、Ｊ＝２．８、３．６Ｈｚ、１Ｈ）、２．２７（ｄｄｄ、Ｊ＝１．２、４．４、１４．４Ｈｚ、１Ｈ）、２．５９－２．７７（ｍ、４Ｈ）、３．２４－３．３０（ｍ、１Ｈ）、３．２７（ｓ、３Ｈ）、３．７９－３．８４（ｍ、１Ｈ）、４．４３（ｂｒｄ、Ｊ＝６．０Ｈｚ、１Ｈ）、７．２６－７．２８（ｍ、２Ｈ）、７．３０－７．３４（ｍ、１Ｈ）、７．４３－７．４６（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：２６０［Ｍ＋Ｈ］＋． Comparative Example 1 Synthesis of (R) -1-methyl-1-phenyl-3- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000072
 Triphosgene (0.11 g, 0.37 mmol) was dissolved in chloroform (2.5 mL), and diisopropylamine (0.58 mL, 3.3 mmol), (R) -quinuclidine-3-dissolved in chloroform (5.0 mL). Amine dihydrochloride (0.20 g, 1.0 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 30 minutes, N-methylaniline (0.11 mL, 1.0 mmol) dissolved in chloroform (2.5 mL) was added dropwise at 0 ° C. After stirring at room temperature for 6 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.14 g (55%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.29-1.35 (m, 2H), 1.61 (dt, J = 2.4, 3.6 Hz, 2H), 1.83 (dt, J = 2.8, 3.6 Hz) 1H), 2.27 (ddd, J = 1.2, 4.4, 14.4 Hz, 1H), 2.59-2.77 (m, 4H), 3.24-3.30 (m, 1H) ), 3.27 (s, 3H), 3.79-3.84 (m, 1H), 4.43 (brd, J = 6.0 Hz, 1H), 7.26-7.28 (m, 2H) ), 7.30-7.34 (m, 1H), 7.43-7.46 (m, 2H).
MS (ESI): 260 [M + H] < +>.
（実施例３６）　ヒト中枢型ニコチン性アセチルコリン受容体α７サブタイプ（以下、ヒトα７受容体）作動性試験：
　ヒトα７受容体を安定発現した細胞を用いて、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩のヒトα７受容体作動性を評価した。 (Example 36) Human central nicotinic acetylcholine receptor α7 subtype (hereinafter, human α7 receptor) agonist test:
Using cells stably expressing human α7 receptor, the human α7 receptor agonist activity of quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof was evaluated.
　ヒトα７受容体遺伝子（ＣＨＲＮＡ７遺伝子；ＮＣＢＩ　Ｒｅｆｅｒｅｎｃｅ　Ｓｅｑｕｅｎｃｅ　ＮＭ＿０００７４６．３）のコーディング領域を哺乳細胞発現ベクターｐＣＩ－ｎｅｏ（Ｐｒｏｍｅｇａ）にクローン化したｐＣＩ－ｎｅｏ－ｈＣＨＲＮＡ７をＧＨ４Ｃ１細胞に導入した。ラット脳下垂体由来のＧＨ４Ｃ１細胞はＡＴＣＣ（Ａｍｅｒｉｃａｎ　Ｔｙｐｅ　Ｃｕｌｔｕｒｅ　Ｃｏｌｌｅｃｔｉｏｎ）から購入した。発現ベクターｐＣＩ－ｎｅｏ－ｈＣＨＲＮＡ７を導入した細胞から限界希釈法にて単一クローンを取得し、ヒトα７受容体安定発現細胞（α７／ＧＨ４Ｃ１細胞）を作製した。α７／ＧＨ４Ｃ１細胞は、２．５％　ウシ胎児血清（ｉｎｖｉｔｒｏｇｅｎ、＃２６１４０－０７９）、１５％　ウマ血清（Ｉｎｖｉｔｒｏｇｅｎ、＃１６０５０－１２２）、１００Ｕ／ｍＬ　ペニシリン、１００μｇ／ｍＬ　ストレプトマイシン及び１００μｇ／ｍＬ　Ｇｅｎｅｔｉｃｉｎ（ｉｎｖｉｔｒｏｇｅｎ、＃１０１３１－０２７）を含むＦ－１０　ｎｕｔｒｉｅｎｔ　ｍｉｘｔｕｒｅ（Ｉｎｖｉｔｒｏｇｅｎ、＃１１５５０－０４３）を培養液として用いて、３７℃、５％ＣＯ２インキュベーター中で培養維持した。 PCI-neo-hCHRNA7 in which the coding region of the human α7 receptor gene (CHRNA7 gene; NCBI Reference Sequence NM — 000076.3) was cloned into the mammalian cell expression vector pCI-neo (Promega) was introduced into GH4C1 cells. Rat pituitary-derived GH4C1 cells were purchased from ATCC (American Type Culture Collection). A single clone was obtained by limiting dilution from the cells into which the expression vector pCI-neo-hCHRNA7 was introduced, and human α7 receptor stably expressing cells (α7 / GH4C1 cells) were prepared. α7 / GH4C1 cells are 2.5% fetal bovine serum (invitrogen, # 26140-079), 15% horse serum (Invitrogen, # 16050-122), 100 U / mL penicillin, 100 μg / mL streptomycin and 100 μg / mL Geneticin ( The culture was maintained in a 37 ° C., 5% CO 2 incubator using F-10 neutral mixture (Invitrogen, # 11550-043) containing invitrogen, # 10131-027).
　α７／ＧＨ４Ｃ１細胞を上記培養液（ただし、Ｇｅｎｅｔｉｃｉｎ不含）に懸濁し、９６ｗｅｌｌ　ｂｌａｃｋ　ｐｌａｔｅ（Ｂｅｃｔｏｎ　Ｄｉｃｋｉｎｓｏｎ、＃３５６６４０）の各ウェルに８×１０４個になるように播種し、３７℃、５％ＣＯ２で一晩培養し、以下の評価に用いた。 α7 / GH4C1 cells are suspended in the above culture medium (without Geneticin) and seeded at 8 × 10 4 cells in each well of 96 well black plate (Becton Dickinson, # 356640) at 37 ° C., 5% Cultivated overnight in CO 2 and used for the following evaluation.
　ヒトα７受容体作動性の評価は、ヒトα７受容体の活性化による細胞内のカルシウム濃度の上昇を測定することで行った。細胞内のカルシウム濃度の測定には、ＦＬＩＰＲ（登録商標）　Ｃａｌｃｉｕｍ５　Ａｓｓａｙ　Ｋｉｔ（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ、＃Ｒ８１８５）を用いた。アッセイバッファーとして、２０ｍｍｏｌ／Ｌ　ＨＥＰＥＳ（ｐＨ７．４）（Ａｍｒｅｓｃｏ、＃Ｊ８４８）を含むＨａｎｋ’ｓ　ｂａｌａｎｃｅｄ　ｓａｌｔ　ｓｏｌｕｔｉｏｎ（以下、ＨＢＳＳ；Ｉｎｖｉｔｒｏｇｅｎ、＃１４０６５－０５６）に２．５ｍｍｏｌ／Ｌ　プロベネシド（Ｓｉｇｍａ、＃８７６１）を加えたものを用いた。 Evaluation of human α7 receptor operability was performed by measuring an increase in intracellular calcium concentration due to activation of human α7 receptor. For measurement of intracellular calcium concentration, FLIPR (registered trademark) Calcium 5 Assay Kit (Molecular Devices, # R8185) was used. As an assay buffer, 2.5 mmol / L probenecid (Sigma, ##) in Hank's balanced salt solution (hereinafter referred to as HBSS; Invitrogen, # 14065-056) containing 20 mmol / L HEPES (pH 7.4) (Amresco, # J848). 8761) was used.
　細胞を播種したプレートの培地を除去し、各ｗｅｌｌにアッセイバッファーを１００μＬと、上記Ｋｉｔに添付の説明書に従いアッセイバッファーで溶解したＣｏｍｐｏｎｅｎｔ　Ａ（蛍光指示薬；上記Ｋｉｔに含まれる）を１００μＬ加え、遮光下３７℃、５％ＣＯ２で４５分間培養し、さらに室温、遮光下で１５分間静置した。ＦＬＩＰＲ（登録商標）　ＴＥＴＲＡ（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ）を用いて、ヒトα７受容体のＰＡＭ（ｐｏｓｉｔｉｖｅ　ａｌｌｏｓｔｅｒｉｃ　ｍｏｄｕｒａｔｏｒ）であるＰＮＵ－１２０５９６を検出感度上昇のために各ｗｅｌｌに５０μＬ自動添加し（最終濃度３μｍｏｌ／Ｌ）、励起波長４７０－４９５ｎｍ、蛍光波長５１５－５７５ｎｍで蛍光強度を１０分間測定後、被験化合物を５０μＬ自動添加し、同波長で蛍光強度を５分間測定した。各被験化合物の評価は、公比３の濃度で、各濃度につきｎ＝３で実施した。被験化合物非添加時の蛍光強度を０％反応値とし、ヒトα７受容体作動性を示すニコチン（Ｓｉｇｍａ、＃Ｎ３８７６）（最終濃度１０μｍｏｌ／Ｌ）を被験化合物の代わりに添加したときの蛍光強度を１００％反応値として、各被験化合物の最大反応率（％）を求めた。各被験化合物の最大反応率（％）を１００％として換算した各濃度における反応率（％）を用いて非線形回帰により各被験化合物のＥＣ５０値（最大反応率に対して５０％の反応を示す濃度）を求めた。なお、ＰＮＵ－１２０５９６、各被験化合物及びニコチンはジメチルスルホキシドに溶解した後、アッセイバッファーで希釈したものを用い、反応系でのジメチルスルホキシドの最終濃度は０．２％以下とした。 Remove the medium from the plate on which the cells were seeded, add 100 μL of assay buffer to each well, and add 100 μL of component A (fluorescent indicator; included in the kit) dissolved in the assay buffer according to the instructions attached to the kit. The cells were cultured at 37 ° C. and 5% CO 2 for 45 minutes, and further allowed to stand at room temperature for 15 minutes under light shielding. Using FLIPR (registered trademark) TETRA (Molecular Devices), 50 μL of PNU-120596, which is a PAM (positive allosteric modulator) of human α7 receptor, was automatically added to each well to increase detection sensitivity (final concentration: 3 μmol / L). ), The fluorescence intensity was measured for 10 minutes at an excitation wavelength of 470-495 nm and the fluorescence wavelength of 515-575 nm, 50 μL of the test compound was automatically added, and the fluorescence intensity was measured for 5 minutes at the same wavelength. Each test compound was evaluated at a common ratio of 3 and n = 3 for each concentration. The fluorescence intensity when the test compound was not added was defined as 0% response value, and the fluorescence intensity when nicotine (Sigma, # N3876) (final concentration 10 μmol / L) showing human α7 receptor agonist activity was added instead of the test compound. The maximum response rate (%) of each test compound was determined as a 100% response value. EC 50 value of each test compound (representing 50% response to the maximum response rate) by non-linear regression using the response rate (%) at each concentration converted to 100% as the maximum response rate (%) of each test compound Concentration). PNU-120596, each test compound and nicotine were dissolved in dimethyl sulfoxide and then diluted with an assay buffer. The final concentration of dimethyl sulfoxide in the reaction system was 0.2% or less.
　各被験化合物のＥＣ５０値を表１に示す。表１の結果から明らかな通り、実施例１、３、５、９、１０、１２、１５、１６、２１、２４、２６、２８、３１、３３、３５、４１、４３、４５、４７、４９及び５１の化合物は、強力なヒトα７受容体活性化作用を示した。一方、比較例１の化合物は極めて弱いヒトα７受容体活性化作用を示した。 The EC 50 values for each test compound are shown in Table 1. As is apparent from the results in Table 1, Examples 1, 3, 5, 9, 10, 12, 15, 16, 21, 24, 26, 28, 31, 33, 35, 41, 43, 45, 47, 49 Compounds 51 and 51 showed potent human α7 receptor activation action. On the other hand, the compound of Comparative Example 1 showed a very weak human α7 receptor activating action.
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
　したがって、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩が、強力なヒトα７受容体活性化作用を有することは明らかである。 Therefore, it is clear that the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof has a strong human α7 receptor activating action.
（実施例３７）　中枢型ニコチン性アセチルコリン受容体を活性化する化合物のサブスタンスＰ誘発引っ掻き行動に対する抑制効果：
　難治性掻痒モデルであるマウスのサブスタンスＰ誘発引っ掻き行動は、公知文献（Ｔｏｇａｓｈｉら、Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００２年、第４３５巻、ｐ．２５９等）記載の方法に基づき、惹起した。また、引っ掻き行動の評価は、公知文献（Ｈａｓｈｉｍｏｔｏら、Ａｌｌｅｒｇｏｌｏｇｙ　Ｉｎｔｅｒｎａｔｉｏｎａｌ、２００４年、第５３巻、ｐ．３４９）記載の方法に基づき、ＭｉｃｒｏＡｃｔ（ニューロサイエンス社）を用いて自動的に検出し、客観的に行った。 (Example 37) The inhibitory effect on the substance P-induced scratching behavior of a compound that activates a central nicotinic acetylcholine receptor:
Substance P-induced scratching behavior of mice, which is an intractable pruritus model, was induced based on a method described in a known literature (Togashi et al., European Journal of Pharmacology, 2002, Vol. 435, p. 259, etc.). In addition, the evaluation of the scratching behavior is automatically detected using MicroAct (Neuroscience) based on a method described in a publicly known document (Hashimoto et al., Allergy International, 2004, Vol. 53, p.349). I went there.
　具体的には、薬効評価の少なくとも５日前に、イソフルラン麻酔下にて、５～７週齢の雄性ＩＣＲ系マウス（日本エスエルシー社）の両後肢甲部皮下にパラフィルムでコーティングしたネオジム磁石（直径１ｍｍ、長さ３ｍｍ）を挿入した。薬効評価日の前日又は２日前に、イソフルラン麻酔下にて、マウスの頸背部をバリカンで毛刈りした。引っ掻き行動回数の測定開始の少なくとも１時間前に、測定用チャンバー（直径１１ｃｍ、高さ１８ｃｍ）内へマウス（６～８週齢）を１匹ずつ収容し馴化させた。馴化後、サブスタンスＰ（５ｍｍｏｌ／Ｌ）又はその溶媒であるリン酸緩衝生理食塩液（以下、ＰＢＳ）を頸背部へ皮内投与（０．０５ｍＬ／ｓｉｔｅ）し、直後より引っ掻き行動回数の測定を開始した。引っ掻き行動回数は、測定用チャンバー周囲のラウンドコイル内で、後肢に挿入された磁石の動きによって誘導された電流を増幅して記録した。測定は無人環境下で行い、薬効評価は測定開始後１５分間の引っ掻き行動回数を指標に実施した。 Specifically, a neodymium magnet coated with parafilm on the back of both hindlimbs of male ICR mice (Japan SLC, Inc.) aged 5 to 7 weeks under isoflurane anesthesia at least 5 days before drug efficacy evaluation ( 1 mm in diameter and 3 mm in length) was inserted. On the day before or 2 days before the medicinal evaluation date, the back of the neck of the mouse was shaved with a clipper under isoflurane anesthesia. At least one hour before the start of the measurement of the number of scratching behaviors, mice (6 to 8 weeks old) were housed one by one in the measurement chamber (diameter 11 cm, height 18 cm) and acclimated. After acclimatization, substance P (5 mmol / L) or its buffer phosphate buffered saline (hereinafter PBS) was intradermally administered to the back of the neck (0.05 mL / site), and the number of scratching behaviors was measured immediately after. Started. The number of scratching behaviors was recorded by amplifying the current induced by the movement of the magnet inserted into the hind limb in a round coil around the measurement chamber. The measurement was performed in an unattended environment, and the efficacy evaluation was performed using the number of scratching behaviors for 15 minutes after the start of the measurement as an index.
　引っ掻き行動回数の測定開始の３０分前に、被験化合物又はその溶媒を１０ｍＬ／ｋｇの容量で経口投与した。被験化合物である実施例２又は実施例４の化合物は蒸留水に溶解して用いた。溶媒のみを投与した群（被験化合物：０ｍｇ／ｋｇ、サブスタンスＰ：０ｎｍｏｌ／ｓｉｔｅ）を「非惹起対照群」、サブスタンスＰを投与し被験化合物を投与していない群（被験化合物：０ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）を「惹起対照群」、サブスタンスＰ及び被験化合物を投与した群（被験化合物：１、３又は１０ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）を「実施例２の化合物投与群」又は「実施例４の化合物投与群」とした。 30 minutes before the start of measurement of the number of scratching behaviors, the test compound or its solvent was orally administered in a volume of 10 mL / kg. The compound of Example 2 or Example 4 which is a test compound was used by dissolving in distilled water. A group (test compound: 0 mg / kg, substance P: 0 nmol / site) administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) is the “induction control group”, substance P and the group administered with the test compound (test compound: 1, 3 or 10 mg / kg, substance P: 250 nmol / site) are “the compound administration of Example 2” Group "or" Compound administration group of Example 4 ".
　図１に引っ掻き行動回数に対する実施例２の化合物の効果を示す。縦軸は１５分間の引っ掻き行動回数（平均値±標準誤差、ｎ＝５～８）を示す。横軸は、非惹起対照群、惹起対照群、実施例２の化合物投与群（１、３又は１０ｍｇ／ｋｇ）を示す。図中の＃印は、惹起対照群との比較で統計学的に有意であることを示し（＃ｐ＜０．０５、Ａｓｐｉｎ－Ｗｅｌｃｈのｔ検定）、＊印は、惹起対照群との比較で統計学的に有意であることを示す（＊ｐ＜０．０２５、Ｗｉｌｌｉａｍｓ検定（片側））。 FIG. 1 shows the effect of the compound of Example 2 on the number of scratching actions. The vertical axis represents the number of scratching actions for 15 minutes (average value ± standard error, n = 5 to 8). The horizontal axis represents the non-induced control group, the induced control group, and the compound administration group of Example 2 (1, 3 or 10 mg / kg). In the figure, # indicates statistically significant comparison with the induction control group (#p <0.05, Aspin-Welch t-test), and * indicates comparison with the induction control group. Indicates statistical significance (* p <0.025, Williams test (one side)).
　図２に引っ掻き行動回数に対する実施例４の化合物の効果を示す。縦軸は１５分間の引っ掻き行動回数（平均値±標準誤差、ｎ＝５～８）を示す。横軸は、非惹起対照群、惹起対照群、実施例４の化合物投与群（１、３又は１０ｍｇ／ｋｇ）を示す。図中の＃印は、惹起対照群との比較で統計学的に有意であることを示し（＃ｐ＜０．０５、Ｓｔｕｄｅｎｔのｔ検定）、＊印は、惹起対照群との比較で統計学的に有意であることを示す（＊ｐ＜０．０２５、Ｓｈｉｒｌｅｙ－Ｗｉｌｌｉａｍｓ検定（片側））。 FIG. 2 shows the effect of the compound of Example 4 on the number of scratching actions. The vertical axis represents the number of scratching actions for 15 minutes (average value ± standard error, n = 5 to 8). The horizontal axis represents the non-induced control group, the induced control group, and the compound administration group (1, 3 or 10 mg / kg) of Example 4. The symbol “#” in the figure indicates statistical significance in comparison with the induction control group (#p <0.05, Student's t test), and the symbol “*” indicates statistical comparison with the induction control group. It is shown to be clinically significant (* p <0.025, Shirley-Williams test (one side)).
　実施例２の化合物（３又は１０ｍｇ／ｋｇ）又は実施例４の化合物（１０ｍｇ／ｋｇ）の投与により、サブスタンスＰ誘発引っ掻き行動は有意に抑制された。したがって、キヌクリジンウレア誘導体（Ｉ）又はその薬理学的に許容される塩が、難治性掻痒モデルとして知られるサブスタンスＰ誘発引っ掻き行動を顕著に抑制し、優れた止痒効果を有することは明らかである。 Substance P-induced scratching behavior was significantly suppressed by administration of the compound of Example 2 (3 or 10 mg / kg) or the compound of Example 4 (10 mg / kg). Therefore, it is clear that the quinuclidine urea derivative (I) or a pharmacologically acceptable salt thereof significantly suppresses substance P-induced scratching behavior known as an intractable pruritus model and has an excellent antipruritic effect. It is.
（参考例２３）　（Ｒ）－２－クロロ－５－（２－アゼチジニルメトキシ）ピリジン塩酸塩（以下、参考例２３の化合物）の合成：
〔第１工程〕
　２－クロロ－５－（（１－（ｔｅｒｔ－ブトキシカルボニル））－２－（Ｒ）－アゼチジニルメトキシ）ピリジンの合成：
Figure JPOXMLDOC01-appb-C000074
 　ジイソプロピルアゾジカルボキシレート（０．１９ｍＬ，１．０ｍｍｏｌ）のテトラヒドロフラン溶液（２．５ｍＬ）にトリフェニルホスフィン（０．２６ｇ，１．０ｍｍｏｌ）を０℃で加え、０℃に保ち攪拌した。０．５時間後、１－（ｔｅｒｔ－ブトキシカルボニル）－２－（Ｒ）－アゼチジニルメタノール（０．１９ｇ，１．０ｍｍｏｌ）、６－クロロピリジン－３－オール（０．１３ｇ，１．０ｍｍｏｌ）を加え、室温で攪拌した。４時間後、反応溶液を濃縮しシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９５／５－７０／３０）で精製し、表題化合物（０．２７ｇ；９０％）を黄色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．４１（９Ｈ，ｓ），２．２３－２．４０（２Ｈ，ｍ），３．８７－３．９１（２Ｈ，ｍ），４．０９－４．１４（１Ｈ，ｍ），４．２８－４．３７（１Ｈ，ｍ），４．４７－４．５４（１Ｈ，ｍ），７．２１－７．２８（２Ｈ，ｍ），８．１０（１Ｈ，ｄ，Ｊ＝３．６Ｈｚ）．
ＭＳ（ＥＳＩ）：２９９［Ｍ＋Ｈ］＋． Reference Example 23 Synthesis of (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine hydrochloride (hereinafter referred to as the compound of Reference Example 23):
[First step]
Synthesis of 2-chloro-5-((1- (tert-butoxycarbonyl))-2- (R) -azetidinylmethoxy) pyridine:
Figure JPOXMLDOC01-appb-C000074
 Triphenylphosphine (0.26 g, 1.0 mmol) was added to a tetrahydrofuran solution (2.5 mL) of diisopropyl azodicarboxylate (0.19 mL, 1.0 mmol) at 0 ° C., and the mixture was kept at 0 ° C. and stirred. After 0.5 hour, 1- (tert-butoxycarbonyl) -2- (R) -azetidinylmethanol (0.19 g, 1.0 mmol), 6-chloropyridin-3-ol (0.13 g,. 0 mmol) was added and stirred at room temperature. After 4 hours, the reaction solution was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5-70 / 30) to obtain the title compound (0.27 g; 90%) as a yellow liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.41 (9H, s), 2.23-2.40 (2H, m), 3.87-3.91 (2H, m), 4.09-4.14 (1H, m), 4.28-4.37 (1H, m), 4.47-4.54 (1H, m), 7.21-7.28 (2H, m), 8.10 (1H, d, J = 3) .6 Hz).
MS (ESI): 299 [M + H] < +>.
〔第２工程〕
　（Ｒ）－２－クロロ－５－（２－アゼチジニルメトキシ）ピリジンの合成：
Figure JPOXMLDOC01-appb-C000075
 　２－クロロ－５－（（１－（ｔｅｒｔ－ブトキシカルボニル））－２－（Ｒ）－アゼチジニルメトキシ）ピリジン（０．２７ｇ，０．９０ｍｍｏｌ）のジクロロメタン溶液（１０ｍＬ）にトリフルオロ酢酸（２．５ｍＬ，３３ｍｍｏｌ）を加え、室温で攪拌した。２時間後、反応溶液に１．０Ｎ水酸化ナトリウム水溶液をｐＨ＝１０となるまで加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝８５／１５）で精製し、表題化合物（０．１２ｇ；５６％）を黄色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：２．２１－２．４３（２Ｈ，ｍ），３．４２－３．４８（１Ｈ，ｍ），３．６８－３．７５（１Ｈ，ｍ），３．９７－４．０６（２Ｈ，ｍ），４．２３－４．３１（１Ｈ，ｍ），７．２１－７．２２（２Ｈ，ｍ），８．０６－８．０８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：１９９［Ｍ＋Ｈ］＋ [Second step]
Synthesis of (R) -2-chloro-5- (2-azetidinylmethoxy) pyridine:
Figure JPOXMLDOC01-appb-C000075
 To a solution of 2-chloro-5-((1- (tert-butoxycarbonyl))-2- (R) -azetidinylmethoxy) pyridine (0.27 g, 0.90 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (10 mL). 2.5 mL, 33 mmol) was added and stirred at room temperature. After 2 hours, 1.0N aqueous sodium hydroxide solution was added to the reaction solution until pH = 10, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 85/15) to obtain the title compound (0.12 g; 56%) as a yellow liquid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.21-2.43 (2H, m), 3.42-3.48 (1H, m), 3.68-3.75 (1H, m), 3.97-4.06 (2H M), 4.23-4.31 (1H, m), 7.21-7.22 (2H, m), 8.06-8.08 (1H, m).
MS (ESI): 199 [M + H] +
〔第３工程〕
　参考例２３の化合物の合成：
Figure JPOXMLDOC01-appb-C000076
 　（Ｒ）－２－クロロ－５－（２－アゼチジニルメトキシ）ピリジン（０．１２ｇ，０．６１ｍｍｏｌ）の酢酸エチル溶液（１．０ｍＬ）に塩化水素－酢酸エチル溶液（４．０Ｍ，０．１８ｍＬ，０．６８ｍｍｏｌ）をゆっくり加え、室温で攪拌した。０．５時間後、得られた固体を濾取し、ヘキサンで洗浄し、乾燥することで、参考例２３の化合物（０．１０ｇ；７０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）
δ：２．６３－２．７２（２Ｈ，ｍ），４．０２－４．１８（２Ｈ，ｍ），４．４０（２Ｈ，ｄ，Ｊ＝４．０Ｈｚ），４．９０－４．９７（１Ｈ，ｍ），７．４６（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５６（１Ｈ，ｄｄ，Ｊ＝２．８，８．８Ｈｚ），８．１２－８．１５（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：１９９［Ｍ＋Ｈ］＋ [Third step]
Synthesis of the compound of Reference Example 23:
Figure JPOXMLDOC01-appb-C000076
 (R) -2-Chloro-5- (2-azetidinylmethoxy) pyridine (0.12 g, 0.61 mmol) in ethyl acetate (1.0 mL) was added to a hydrogen chloride-ethyl acetate solution (4.0 M, 0 .18 mL, 0.68 mmol) was slowly added and stirred at room temperature. After 0.5 hour, the obtained solid was collected by filtration, washed with hexane, and dried to obtain the compound of Reference Example 23 (0.10 g; 70%) as a white solid.
1 H-NMR (400 MHz, D 2 O)
δ: 2.63-2.72 (2H, m), 4.02-4.18 (2H, m), 4.40 (2H, d, J = 4.0 Hz), 4.90-4.97 (1H, m), 7.46 (1H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 2.8, 8.8 Hz), 8.12-8.15 (1H, m).
MS (ESI): 199 [M + H] +
（参考例２４）　Ｎ－（２（Ｓ）－（ピリジン－３－イルメチル）－１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－１－ベンゾフラン－２－カルボキシアミド（以下、参考例２４の化合物）の合成：
〔第１工程〕
　２－（３－ピリジニル）メチレン－１－アザビシクロ［２．２．２］オクタン－３－オンの合成：
Figure JPOXMLDOC01-appb-C000077
 　３－キヌクリジノン塩酸塩（６．０ｇ，３７ｍｍｏｌ）に水酸化カリウム（２．３ｇ，４１ｍｍｏｌ）のメタノール溶液（３６ｍＬ）、３－ピリジンアルデヒド（４．４ｇ，４１ｍｍｏｌ）を加え、室温で攪拌した。１６時間後、反応溶液に蒸留水（３０ｍＬ）を加え、４℃まで冷却し１６時間放置した。得られた固体を濾取し、蒸留水で洗浄し、乾燥することで、表題化合物（７．６ｇ；９６％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：２．００－２．０８（４Ｈ，ｍ），２．６４－２．６８（１Ｈ，ｍ），２．９４－３．０４（２Ｈ，ｍ），３．１３－３．２２（２Ｈ，ｍ），６．９８（１Ｈ，ｓ），７．２８－７．３２（１Ｈ，ｍ），８．４４－８．５０（１Ｈ，ｍ），８．５１－８．５５（１Ｈ，ｍ），９．０４（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
ＭＳ（ＥＳＩ）：２１５［Ｍ＋Ｈ］＋ Reference Example 24 N- (2 (S)-(pyridin-3-ylmethyl) -1-azabicyclo [2.2.2] octa-3 (R) -yl) -1-benzofuran-2-carboxamide ( Hereinafter, the synthesis of the compound of Reference Example 24):
[First step]
Synthesis of 2- (3-pyridinyl) methylene-1-azabicyclo [2.2.2] octan-3-one:
Figure JPOXMLDOC01-appb-C000077
 A methanol solution (36 mL) of potassium hydroxide (2.3 g, 41 mmol) and 3-pyridinealdehyde (4.4 g, 41 mmol) were added to 3-quinuclidinone hydrochloride (6.0 g, 37 mmol), and the mixture was stirred at room temperature. After 16 hours, distilled water (30 mL) was added to the reaction solution, cooled to 4 ° C., and allowed to stand for 16 hours. The obtained solid was collected by filtration, washed with distilled water, and dried to give the title compound (7.6 g; 96%) as a yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.00-2.08 (4H, m), 2.64-2.68 (1H, m), 2.94-3.04 (2H, m), 3.13-3.22 (2H , M), 6.98 (1H, s), 7.28-7.32 (1H, m), 8.44-8.50 (1H, m), 8.51-8.55 (1H, m ), 9.04 (1H, d, J = 2.0 Hz).
MS (ESI): 215 [M + H] +
〔第２工程〕
　２－（（３－ピリジニル）メチル）－１－アザビシクロ［２．２．２］オクタン－３－オンの合成：
Figure JPOXMLDOC01-appb-C000078
 　２－（３－ピリジニル）メチレン－１－アザビシクロ［２．２．２］オクタン－３－オン（７．６ｇ，３６ｍｍｏｌ）のメタノール溶液（８０ｍＬ）にＰｄ／Ｃ（１０％ｗｅｔ，０．６４ｇ，０．６０ｍｍｏｌ）、塩酸（６．０Ｎ，９．０ｍＬ，５４ｍｍｏｌ）を加え、水素雰囲気下、室温で攪拌した。１６時間後、反応溶液をセライトで濾過し、濾液を濃縮した。得られた粗生成物に２．０Ｎ水酸化ナトリウム水溶液をｐＨ＝１０となるまで加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０－５９／４１，クロロホルムのみ－クロロホルム／メタノール＝７８／２２）で精製し、表題化合物（５．４ｇ；７１％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．９２－２．１０（４Ｈ，ｍ），２．４７－２．５１（１Ｈ，ｍ），２．７３－２．９２（３Ｈ，ｍ），３．０５－３．２４（３Ｈ，ｍ），３．２９－３．３５（１Ｈ，ｍ），７．２０－７．２４（１Ｈ，ｍ），７．５７－７．６２（１Ｈ，ｍ），８．４４－８．４８（１Ｈ，ｍ），８．５２（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）．
ＭＳ（ＥＳＩ）：２１７［Ｍ＋Ｈ］＋ [Second step]
Synthesis of 2-((3-pyridinyl) methyl) -1-azabicyclo [2.2.2] octan-3-one:
Figure JPOXMLDOC01-appb-C000078
 To a methanol solution (80 mL) of 2- (3-pyridinyl) methylene-1-azabicyclo [2.2.2] octane-3-one (7.6 g, 36 mmol) was added Pd / C (10% wet, 0.64 g, 0.60 mmol) and hydrochloric acid (6.0 N, 9.0 mL, 54 mmol) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 16 hours, the reaction solution was filtered through celite, and the filtrate was concentrated. To the resulting crude product, 2.0N aqueous sodium hydroxide solution was added until pH = 10, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-59 / 41, chloroform only-chloroform / methanol = 78/22) to give the title compound (5.4 g; 71%) Was obtained as a colorless liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.92-2.10 (4H, m), 2.47-2.51 (1H, m), 2.73-2.92 (3H, m), 3.05-3.24 (3H M), 3.29-3.35 (1H, m), 7.20-7.24 (1H, m), 7.57-7.62 (1H, m), 8.44-8.48. (1H, m), 8.52 (1H, d, J = 2.0 Hz).
MS (ESI): 217 [M + H] +
〔第３工程〕
　参考例２４の化合物の合成：
Figure JPOXMLDOC01-appb-C000079
 　２－（（３－ピリジニル）メチル）－１－アザビシクロ［２．２．２］オクタン－３－オン（５．０ｇ，２３ｍｍｏｌ）のメタノール溶液（３４ｍＬ）に二塩化亜鉛（６３０ｍｇ，４．６ｍｍｏｌ）を加え、室温で攪拌した。０．５時間後、ギ酸アンモニウム（１７ｇ，２８０ｍｍｏｌ）を加え、室温で攪拌した。１時間後、ナトリウムシアノボロヒドリド（２．９ｇ，４６ｍｍｏｌ）を加え、室温で攪拌した。１６時間後、５０℃に昇温し攪拌した。３時間後、反応溶液に蒸留水、５．０Ｎ水酸化ナトリウム水溶液を加え、中和した後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝８９／１１）で精製した。得られた精製物に対し、メタノール（１６ｍＬ）、（＋）－ジ－パラトルオイル－（Ｄ）－酒石酸（４．０ｇ，１０ｍｍｏｌ）を加え、９０℃で攪拌した。１時間後、反応溶液を濃縮し、メタノール（４．０ｍＬ）を加え、９０℃に昇温し溶解した。反応溶液を１時間かけて室温、４時間かけて５℃、続いて０℃にゆっくり冷却して１６時間放置した。得られた沈殿物を濾取し、メタノール（３．０ｍＬ）を用いて再結晶した。得られた固体に２．０Ｎ水酸化ナトリウム水溶液（３．０ｍＬ）、クロロホルム（３．０ｍＬ）を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し濃縮した。得られた無色液体をジクロロメタン（２．０ｍＬ）に溶解し、これをｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルウロニウムヘキサフルオロホスファート（０．６０ｇ，１．６ｍｍｏｌ）、トリエチルアミン（０．７３ｍＬ，１．６ｍｍｏｌ）、ベンゾフラン－２－カルボン酸（０．１７ｇ，１．１ｍｍｏｌ）のジクロロメタン溶液（２．０ｍＬ）に加え、室温で攪拌した。１６時間後、蒸留水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルムのみ－クロロホルム／メタノール＝９９／１）で精製し、参考例２４の化合物（０．２１ｇ；３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．５０－１．５９（１Ｈ，ｍ），１．６６－１．８４（３Ｈ，ｍ），２．００－２．０６（１Ｈ，ｍ），２．７２－２．８２（２Ｈ，ｍ），２．９２－２．９９（４Ｈ，ｍ），３．０５－３．１４（１Ｈ，ｍ），３．９４－３．９９（１Ｈ，ｍ），６．５５－６．６０（１Ｈ，ｍ），７．１２－７．１６（１Ｈ，ｍ），７．２９－７．３２（１Ｈ，ｍ），７．４０－７．４５（２Ｈ，ｍ），７．５１（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），７．５６－７．６０（１Ｈ，ｍ），７．６７（１Ｈ，ｄ，Ｊ＝８．４Ｈｚ），８．３５（１Ｈ，ｄｄ，Ｊ＝１．６，４．４Ｈｚ），８．５１（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）．
ＭＳ（ＥＳＩ）：３６２［Ｍ＋Ｈ］＋ [Third step]
Synthesis of the compound of Reference Example 24:
Figure JPOXMLDOC01-appb-C000079
 2-((3-pyridinyl) methyl) -1-azabicyclo [2.2.2] octan-3-one (5.0 g, 23 mmol) in methanol (34 mL) with zinc dichloride (630 mg, 4.6 mmol) And stirred at room temperature. After 0.5 hour, ammonium formate (17 g, 280 mmol) was added and stirred at room temperature. After 1 hour, sodium cyanoborohydride (2.9 g, 46 mmol) was added and stirred at room temperature. After 16 hours, the temperature was raised to 50 ° C. and stirred. Three hours later, distilled water and 5.0N aqueous sodium hydroxide solution were added to the reaction solution for neutralization, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 89/11). Methanol (16 mL) and (+)-di-paratoluyl- (D) -tartaric acid (4.0 g, 10 mmol) were added to the purified product obtained, and the mixture was stirred at 90 ° C. After 1 hour, the reaction solution was concentrated, methanol (4.0 mL) was added, and the mixture was heated to 90 ° C. and dissolved. The reaction solution was cooled slowly to room temperature over 1 hour, 5 ° C. over 4 hours, then to 0 ° C. and left for 16 hours. The resulting precipitate was collected by filtration and recrystallized from methanol (3.0 mL). To the obtained solid, 2.0N aqueous sodium hydroxide solution (3.0 mL) and chloroform (3.0 mL) were added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained colorless liquid was dissolved in dichloromethane (2.0 mL), and this was dissolved in o- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (0. 60 g, 1.6 mmol), triethylamine (0.73 mL, 1.6 mmol) and benzofuran-2-carboxylic acid (0.17 g, 1.1 mmol) in dichloromethane (2.0 mL) were added and stirred at room temperature. After 16 hours, distilled water was added and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (chloroform only-chloroform / methanol = 99/1) to obtain the compound of Reference Example 24 (0.21 g; 3%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.59 (1H, m), 1.66-1.84 (3H, m), 2.00-2.06 (1H, m), 2.72-2.82 (2H) M), 2.92-2.99 (4H, m), 3.05-3.14 (1H, m), 3.94-3.99 (1H, m), 6.55-6.60 (1H, m), 7.12-7.16 (1H, m), 7.29-7.32 (1H, m), 7.40-7.45 (2H, m), 7.51 (1H , D, J = 8.4 Hz), 7.56-7.60 (1H, m), 7.67 (1H, d, J = 8.4 Hz), 8.35 (1H, dd, J = 1. 6, 4.4 Hz), 8.51 (1H, d, J = 2.4 Hz).
MS (ESI): 362 [M + H] +
（参考例２５）　（Ｒ）－７－クロロ－Ｎ－（キヌクリジン－３－イル）ベンゾ［ｂ］チオフェン－２－カルボキシアミド塩酸塩（以下、参考例２５の化合物）の合成：
〔第１工程〕
　（Ｒ）－７－クロロ－Ｎ－（キヌクリジン－３－イル）ベンゾ［ｂ］チオフェン－２－カルボキシアミドの合成：
Figure JPOXMLDOC01-appb-C000080
 　７－クロロ－１－ベンゾチオフェン－２－カルボキシリックアシッド（２１０ｍｇ，１．０ｍｍｏｌ）のクロロホルム溶液（１０ｍＬ）にｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルウロニウムヘキサフルオロホスファート（５７０ｍｇ，１．５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．７０ｍＬ，４．０ｍｍｏｌ）を加えた後、（Ｒ）－キヌクリジン－３－アミン塩酸塩（２００ｍｇ，１．０ｍｍｏｌ）を加え、室温で攪拌した。１６時間後、蒸留水、１．０Ｎ水酸化ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（１７０ｍｇ；５３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：１．２２－１．３８（１Ｈ，ｍ），１．５３－１．６２（２Ｈ，ｍ），１．７５－１．８２（２Ｈ，ｍ），２．６３－２．７３（４Ｈ，ｍ），２．８４－２．９４（１Ｈ，ｍ），３．０７－３．１８（１Ｈ，ｍ），３．９０－４．００（１Ｈ，ｍ），７．４９（１Ｈ，ｄｄ，Ｊ＝７．６，８．０Ｈｚ），７．５９（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．３１（１Ｈ，ｓ），８．６２－８．６６（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２１［Ｍ＋Ｈ］＋ Reference Example 25 Synthesis of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide hydrochloride (hereinafter referred to as compound of Reference Example 25):
[First step]
Synthesis of (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide:
Figure JPOXMLDOC01-appb-C000080
 To a chloroform solution (10 mL) of 7-chloro-1-benzothiophene-2-carboxylic acid (210 mg, 1.0 mmol), o- (benzotriazol-1-yl) -N, N, N ′, N′-tetra After adding methyluronium hexafluorophosphate (570 mg, 1.5 mmol) and diisopropylethylamine (0.70 mL, 4.0 mmol), (R) -quinuclidin-3-amine hydrochloride (200 mg, 1.0 mmol) was added. It was added and stirred at room temperature. After 16 hours, distilled water and 1.0N aqueous sodium hydroxide solution were added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 90/10) to obtain the title compound (170 mg; 53%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.22-1.38 (1H, m), 1.53-1.62 (2H, m), 1.75-1.82 (2H, m), 2.63-2.73 (4H M), 2.84-2.94 (1H, m), 3.07-3.18 (1H, m), 3.90-4.00 (1H, m), 7.49 (1H, dd) , J = 7.6, 8.0 Hz), 7.59 (1H, d, J = 7.6 Hz), 7.96 (1H, d, J = 8.0 Hz), 8.31 (1H, s) , 8.62-8.66 (1H, m).
MS (ESI): 321 [M + H] +
〔第２工程〕
　参考例２５の化合物の合成：
Figure JPOXMLDOC01-appb-C000081
 　（Ｒ）－７－クロロ－Ｎ－（キヌクリジン－３－イル）ベンゾ［ｂ］チオフェン－２－カルボキシアミド（１７０ｍｇ，０．５３ｍｍｏｌ）の酢酸エチル溶液（２．０ｍＬ）に塩化水素－酢酸エチル溶液（４．０Ｍ，０．２０ｍＬ，０．８０ｍｍｏｌ）を加え、室温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、参考例２５の化合物（１７０ｍｇ；９０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：１．７０－１．７８（１Ｈ，ｍ），１．８６－１．９４（２Ｈ，ｍ），２．１０－２．１９（２Ｈ，ｍ），３．１８－３．３５（５Ｈ，ｍ），３．６３－３．７２（１Ｈ，ｍ），４．２７－４．３６（１Ｈ，ｍ），７．５０（１Ｈ，ｄ，Ｊ＝７．６，８．０Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．９８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），８．３８（１Ｈ，ｓ），９．０７－９．１０（１Ｈ，ｍ），９．８０－９．８５（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２１［Ｍ＋Ｈ］＋ [Second step]
Synthesis of the compound of Reference Example 25:
Figure JPOXMLDOC01-appb-C000081
 Hydrogen chloride-ethyl acetate solution in (R) -7-chloro-N- (quinuclidin-3-yl) benzo [b] thiophene-2-carboxamide (170 mg, 0.53 mmol) in ethyl acetate solution (2.0 mL) (4.0 M, 0.20 mL, 0.80 mmol) was added and stirred at room temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 25 (170 mg; 90%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.70-1.78 (1H, m), 1.86-1.94 (2H, m), 2.10-2.19 (2H, m), 3.18-3.35 (5H) , M), 3.63-3.72 (1H, m), 4.27-4.36 (1H, m), 7.50 (1H, d, J = 7.6, 8.0 Hz), 7 .61 (1H, d, J = 7.6 Hz), 7.98 (1H, d, J = 8.0 Hz), 8.38 (1H, s), 9.07-9.10 (1H, m) , 9.80-9.85 (1H, m).
MS (ESI): 321 [M + H] +
（参考例２６）　１，４－ジアザビシクロ［３．２．２］ノナン－４－カルボキシリックアシッド　４－ブロモフェニルエステル塩酸塩（以下、参考例２６の化合物）の合成：
〔第１工程〕
　１，４－ジアザビシクロ［３．２．２］ノナン－４－カルボキシリックアシッド　４－ブロモフェニルエステルの合成：
Figure JPOXMLDOC01-appb-C000082
 　１，４－ジアザビシクロ［３．２．２］ノナン二塩酸塩（２３０ｍｇ，１．２ｍｍｏｌ）のジクロロメタン溶液（１２ｍＬ）にジイソプロピルエチルアミン（０．４０ｍＬ，２．４ｍｍｏｌ）を加え、室温で１時間攪拌した。トリホスゲン（１１０ｍｇ，０．３８ｍｍｏｌ）のジクロロメタン溶液（１２ｍＬ）に４－ブロモフェノール（２００ｍｇ，１．２ｍｍｏｌ）とジイソプロピルエチルアミン（０．２０ｍＬ，１．２ｍｍｏｌ）のテトラヒドロフラン溶液（１２ｍＬ）をゆっくり加え、室温で攪拌した。１時間後、この溶液に先ほど調製した１，４－ジアザビシクロ［３．２．２］ノナン二塩酸塩溶液をゆっくり加え、室温で攪拌した。４時間後、反応溶液に水を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９５／５－７０／３０，クロロホルムのみ－クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（０．２４ｇ；６５％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．６８－１．８１（２Ｈ，ｍ），２．００－２．１４（２Ｈ，ｍ），２．９５－３．１９（６Ｈ，ｍ），３．７２－３．８５（２Ｈ，ｍ），４．３４－４．４５（１Ｈ，ｍ），６．９８－７．０６（２Ｈ，ｍ），７．４４－７．５０（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］＋ Reference Example 26 Synthesis of 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester hydrochloride (hereinafter referred to as the compound of Reference Example 26):
[First step]
Synthesis of 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester:
Figure JPOXMLDOC01-appb-C000082
 Diisopropylethylamine (0.40 mL, 2.4 mmol) was added to a dichloromethane solution (12 mL) of 1,4-diazabicyclo [3.2.2] nonane dihydrochloride (230 mg, 1.2 mmol), and the mixture was stirred at room temperature for 1 hour. . To a solution of triphosgene (110 mg, 0.38 mmol) in dichloromethane (12 mL) was slowly added a tetrahydrofuran solution (12 mL) of 4-bromophenol (200 mg, 1.2 mmol) and diisopropylethylamine (0.20 mL, 1.2 mmol) at room temperature. Stir. After 1 hour, the 1,4-diazabicyclo [3.2.2] nonane dihydrochloride solution prepared earlier was slowly added to this solution and stirred at room temperature. After 4 hours, water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 95 / 5-70 / 30, chloroform only-chloroform / methanol = 90/10) to give the title compound (0.24 g; 65%) Was obtained as a colorless liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.68-1.81 (2H, m), 2.00-2.14 (2H, m), 2.95-3.19 (6H, m), 3.72-3.85 (2H M), 4.34-4.45 (1H, m), 6.98-7.06 (2H, m), 7.44-7.50 (2H, m).
MS (ESI): 326 [M + H] +
〔第２工程〕
　参考例２６の化合物の合成：
Figure JPOXMLDOC01-appb-C000083
 　１，４－ジアザビシクロ［３．２．２］ノナン－４－カルボキシリックアシッド　４－ブロモフェニルエステル（２５０ｍｇ，０．７５ｍｍｏｌ）の酢酸エチル溶液（４．０ｍＬ）に塩化水素－酢酸エチル溶液（４．０Ｍ，０．２８ｍＬ，１．１ｍｍｏｌ）を加え、室温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、参考例２６の化合物（２４０ｍｇ；８８％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：１．９５－２．２６（４Ｈ，ｍ）、３．３２－３．４７（６Ｈ，ｍ），３．８１－３．８５（１Ｈ，ｍ），３．９４－４．００（１Ｈ，ｍ），４．３５－４．５６（１Ｈ，ｍ），７．１４（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ），７．５９（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）１０．２－１１．０（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３２６［Ｍ＋Ｈ］＋ [Second step]
Synthesis of the compound of Reference Example 26:
Figure JPOXMLDOC01-appb-C000083
 1,4-diazabicyclo [3.2.2] nonane-4-carboxylic acid 4-bromophenyl ester (250 mg, 0.75 mmol) in ethyl acetate solution (4.0 mL) and hydrogen chloride-ethyl acetate solution (4. (0M, 0.28 mL, 1.1 mmol) was added, and the mixture was stirred at room temperature. Ten minutes later, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 26 (240 mg; 88%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.95-2.26 (4H, m), 3.32-3.47 (6H, m), 3.81-3.85 (1H, m), 3.94-4.00 (1H) M), 4.35-4.56 (1H, m), 7.14 (2H, d, J = 8.8 Hz), 7.59 (2H, d, J = 8.8 Hz) 10.2- 11.0 (1H, m).
MS (ESI): 326 [M + H] +
（参考例２７）　２－（１，４－ジアザビシクロ［３．２．２］ノナ－４－イル）－５－メチルオキサゾロ［４，５－ｂ］ピリジン塩酸塩（以下、参考例２７の化合物）の合成：
〔第１工程〕
　２－アミノ－６－メチルピリジン－３－オールの合成：
Figure JPOXMLDOC01-appb-C000084
 　６－メチル－２－ニトロピリジン－３－オール（１．６ｇ，１０ｍｍｏｌ）のエタノール溶液（２０ｍＬ）にＰｄ／Ｃ（１０％ｗｅｔ，０．４０ｇ，０．３８ｍｍｏｌ）、酢酸（０．０５０ｍＬ，０．８７ｍｍｏｌ）を加え、水素雰囲気下室温で攪拌した。６時間後、反応溶液をセライトで濾過し、濾液を濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝８８／１２）で精製し、表題化合物（１．２ｇ；９３％）を黄色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：２．３２（３Ｈ，ｓ），６．３８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），６．８２－６．８６（１Ｈ，ｍ）． Reference Example 27 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine hydrochloride (hereinafter referred to as the compound of Reference Example 27) ) Synthesis:
[First step]
Synthesis of 2-amino-6-methylpyridin-3-ol:
Figure JPOXMLDOC01-appb-C000084
 Pd / C (10% wet, 0.40 g, 0.38 mmol), acetic acid (0.050 mL, 0 mL) in an ethanol solution (20 mL) of 6-methyl-2-nitropyridin-3-ol (1.6 g, 10 mmol). .87 mmol) was added and stirred at room temperature under a hydrogen atmosphere. After 6 hours, the reaction solution was filtered through celite, and the filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 88/12) to obtain the title compound (1.2 g; 93%) as a yellow liquid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.32 (3H, s), 6.38 (1H, d, J = 8.0 Hz), 6.82-6.86 (1H, m).
〔第２工程〕
　５－メチルオキサゾロ［４，５－ｂ］ピリジン－２－チオールの合成：
Figure JPOXMLDOC01-appb-C000085
 　２－アミノ－６－メチルピリジン－３－オール（１．２ｇ，９．７ｍｍｏｌ）のエタノール溶液（２５ｍＬ）にカリウムエチルキサンテート（３．１ｇ，１９ｍｍｏｌ）を加え、８０℃で攪拌した。４時間後、反応溶液を濃縮し蒸留水を加え、酢酸をｐＨ＝５となるまで加えた。得られた固体を濾取し、蒸留水で洗浄し、乾燥することで表題化合物（１．２ｇ；７７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：２．４５（３Ｈ，ｓ），７．０３－７．０７（１Ｈ，ｍ），７．６４－７．７０（１Ｈ，ｍ）． [Second step]
Synthesis of 5-methyloxazolo [4,5-b] pyridine-2-thiol:
Figure JPOXMLDOC01-appb-C000085
 To an ethanol solution (25 mL) of 2-amino-6-methylpyridin-3-ol (1.2 g, 9.7 mmol) was added potassium ethyl xanthate (3.1 g, 19 mmol), and the mixture was stirred at 80 ° C. After 4 hours, the reaction solution was concentrated, distilled water was added, and acetic acid was added until pH = 5. The obtained solid was collected by filtration, washed with distilled water, and dried to give the title compound (1.2 g; 77%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.45 (3H, s), 7.03-7.07 (1H, m), 7.64-7.70 (1H, m).
〔第３工程〕
　５－メチル－２－（メチルチオ）オキサゾロ［４，５－ｂ］ピリジンの合成：
Figure JPOXMLDOC01-appb-C000086
 　５－メチルオキサゾロ［４，５－ｂ］ピリジン－２－チオール（１．２ｇ，７．５ｍｍｏｌ）のＮ，Ｎ－ジメチルホルムアミド溶液（２０ｍＬ）に炭酸カリウム（１．０ｇ，７．５ｍｍｏｌ）、ヨウ化メチル（０．５６ｍＬ，９．０ｍｍｏｌ）を加え、室温で攪拌した。３時間後、蒸留水を加え、酢酸エチルで抽出した。有機層を蒸留水、飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝８８／１２－６５／３５，クロロホルムのみ－クロロホルム／メタノール＝９８／２）で精製し、表題化合物（１．２ｇ；９０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：２．５３（３Ｈ，ｓ），２．７７（３Ｈ，ｓ），７．１８（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．９４（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ）． [Third step]
Synthesis of 5-methyl-2- (methylthio) oxazolo [4,5-b] pyridine:
Figure JPOXMLDOC01-appb-C000086
 To a solution of 5-methyloxazolo [4,5-b] pyridine-2-thiol (1.2 g, 7.5 mmol) in N, N-dimethylformamide (20 mL), potassium carbonate (1.0 g, 7.5 mmol), Methyl iodide (0.56 mL, 9.0 mmol) was added and stirred at room temperature. After 3 hours, distilled water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 88 / 12-65 / 35, chloroform only-chloroform / methanol = 98/2) to give the title compound (1.2 g; 90%) Was obtained as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 2.53 (3H, s), 2.77 (3H, s), 7.18 (1H, d, J = 8.0 Hz), 7.94 (1H, d, J = 8.0 Hz).
〔第４工程〕
　２－（１，４－ジアザビシクロ［３．２．２］ノナ－４－イル）－５－メチルオキサゾロ［４，５－ｂ］ピリジンの合成：
Figure JPOXMLDOC01-appb-C000087
 　１，４－ジアザビシクロ［３．２．２］ノナン二塩酸塩（９００ｍｇ，４．５ｍｍｏｌ）に対し、水酸化ナトリウム水溶液（１．０Ｎ，１１ｍＬ，１１ｍｍｏｌ）を加え、室温で攪拌した。２時間後、反応溶液をクロロホルム－メタノール混合溶液（９：１）で抽出し、有機層を蒸留水、飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物に対し、イソプロピルアルコール（２．７ｍＬ）、５－メチル－２－（メチルチオ）オキサゾロ［４，５－ｂ］ピリジン（３００ｍｇ，１．７ｍｍｏｌ）を加え、１００℃で攪拌した。２２時間後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物（３２０ｍｇ；７４％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）
δ：１．７４－１．８５（２Ｈ，ｍ），２．１０－２．２１（２Ｈ，ｍ），２．５３（３Ｈ，ｓ），２．９５－３．０６（２Ｈ，ｍ），３．１０－３．１９（４Ｈ，ｍ），３．９５（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），４．５３－４．５７（１Ｈ，ｍ），６．７２（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ）．
ＭＳ（ＥＳＩ）：２５９［Ｍ＋Ｈ］＋ [Fourth step]
Synthesis of 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine:
Figure JPOXMLDOC01-appb-C000087
 To 1,4-diazabicyclo [3.2.2] nonane dihydrochloride (900 mg, 4.5 mmol) was added an aqueous sodium hydroxide solution (1.0 N, 11 mL, 11 mmol), and the mixture was stirred at room temperature. After 2 hours, the reaction solution was extracted with a chloroform-methanol mixed solution (9: 1), and the organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. To the obtained crude product, isopropyl alcohol (2.7 mL) and 5-methyl-2- (methylthio) oxazolo [4,5-b] pyridine (300 mg, 1.7 mmol) were added and stirred at 100 ° C. . After 22 hours, the resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical Amine Silica Gel DM1020, chloroform only-chloroform / methanol = 95/5) to give the title compound (320 mg; 74%) as a white solid. Obtained.
1 H-NMR (400 MHz, CD 3 OD)
δ: 1.74-1.85 (2H, m), 2.10-2.21 (2H, m), 2.53 (3H, s), 2.95-3.06 (2H, m), 3.10-3.19 (4H, m), 3.95 (2H, t, J = 6.0 Hz), 4.53-4.57 (1H, m), 6.72 (1H, d, J = 7.6 Hz), 7.28 (1H, d, J = 7.6 Hz).
MS (ESI): 259 [M + H] +
〔第５工程〕
参考例２７の化合物の合成：
Figure JPOXMLDOC01-appb-C000088
 　２－（１，４－ジアザビシクロ［３．２．２］ノナ－４－イル）－５－メチルオキサゾロ［４，５－ｂ］ピリジン（３２０ｍｇ，１．２ｍｍｏｌ）の酢酸エチル溶液（１．０ｍＬ）に塩化水素－酢酸エチル溶液（４．０Ｍ，０．４７ｍＬ，１．９ｍｍｏｌ）を加え、室温で攪拌した。０．５時間後、得られた白色固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで参考例２７の化合物（２９０ｍｇ；８０％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：２．０５－２．１７（２Ｈ，ｍ），２．２２－２．３４（２Ｈ，ｍ），２．４９（３Ｈ，ｓ），３．３５－３．４４（４Ｈ，ｍ），３．４８－３．５４（２Ｈ，ｍ），４．０９－４．１２（２Ｈ，ｍ），４．５９－４．６５（１Ｈ，ｍ），６．９９（１Ｈ，ｄ，Ｊ＝８．０Ｈｚ），７．８２－７．８７（１Ｈ，ｍ），１１．４－１１．５（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２５９［Ｍ＋Ｈ］＋
２５９ [Fifth step]
Synthesis of the compound of Reference Example 27:
Figure JPOXMLDOC01-appb-C000088
 2- (1,4-diazabicyclo [3.2.2] non-4-yl) -5-methyloxazolo [4,5-b] pyridine (320 mg, 1.2 mmol) in ethyl acetate (1.0 mL) ) Was added a hydrogen chloride-ethyl acetate solution (4.0 M, 0.47 mL, 1.9 mmol), and the mixture was stirred at room temperature. After 0.5 hour, the obtained white solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 27 (290 mg; 80%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 2.05-2.17 (2H, m), 2.22-2.34 (2H, m), 2.49 (3H, s), 3.35-3.44 (4H, m), 3.48-3.54 (2H, m), 4.09-4.12 (2H, m), 4.59-4.65 (1H, m), 6.99 (1H, d, J = 8 .0Hz), 7.82-7.87 (1H, m), 11.4-11.5 (1H, m).
MS (ESI): 259 [M + H] +
259
（参考例２８）　５－（４－モルホリニル）－Ｎ－（４－（３－ピリジル）フェニル）ペンタンアミド塩酸塩（以下、参考例２８の化合物）の合成：
〔第１工程〕
　５－ブロモ－Ｎ－（４－ブロモフェニル）ペンタンアミドの合成：
Figure JPOXMLDOC01-appb-C000089
 　４－ブロモアニリン（２．８ｇ，１７ｍｍｏｌ）のジクロロメタン溶液（６０ｍＬ）にトリエチルアミン（２．３ｍＬ，１７ｍｍｏｌ）を加えた後、０℃で５－ブロモペンタノイルクロライド（２．４ｍＬ，１８ｍｍｏｌ）をゆっくり加え、０℃に保ち攪拌した。３時間後、反応溶液を室温まで昇温し、０．４０Ｎ炭酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮することで、表題化合物（５．５ｇ；９９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．８５－２．００（４Ｈ，ｍ），２．４０（２Ｈ，ｔ，Ｊ＝６．８Ｈｚ），３．４５（２Ｈ，ｔ，Ｊ＝６．０Ｈｚ），７．０８－７．１２（１Ｈ，ｍ），７．３９－７．４３（４Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３３６［Ｍ＋Ｈ］＋ Reference Example 28 Synthesis of 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide hydrochloride (hereinafter referred to as the compound of Reference Example 28):
[First step]
Synthesis of 5-bromo-N- (4-bromophenyl) pentanamide:
Figure JPOXMLDOC01-appb-C000089
 Triethylamine (2.3 mL, 17 mmol) was added to a dichloromethane solution (60 mL) of 4-bromoaniline (2.8 g, 17 mmol), and then 5-bromopentanoyl chloride (2.4 mL, 18 mmol) was slowly added at 0 ° C. The mixture was kept at 0 ° C. and stirred. After 3 hours, the reaction solution was warmed to room temperature, 0.40N aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (5.5 g; 99%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.85-2.00 (4H, m), 2.40 (2H, t, J = 6.8 Hz), 3.45 (2H, t, J = 6.0 Hz), 7.08-7 .12 (1H, m), 7.39-7.43 (4H, m).
MS (ESI): 336 [M + H] +
〔第２工程〕
　５－モルホリン－４－イル－ペンタノイックアシッド（４－ブロモフェニル）アミドの合成：
Figure JPOXMLDOC01-appb-C000090
 　５－ブロモ－Ｎ－（４－ブロモフェニル）ペンタンアミド（２．７ｇ，８．１ｍｍｏｌ）の２－ブタノン溶液（６０ｍＬ）にヨウ化ナトリウム（１．２ｇ，８．１ｍｍｏｌ）、モルホリン（０．７８ｍＬ，８．９ｍｍｏｌ）を加え、７０℃で攪拌した。６時間後、１．０Ｎ水酸化ナトリウム水溶液を加え、濃縮した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８０／２０，クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物（２．３ｇ；８３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．５３－１．６２（２Ｈ，ｍ），１．７２－１．８０（２Ｈ，ｍ），２．３５－２．４５（８Ｈ，ｍ），３．６７－３．７２（４Ｈ，ｍ），７．１６－７．２１（１Ｈ，ｍ），７．３９－７．４２（４Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３４２［Ｍ＋Ｈ］＋ [Second step]
Synthesis of 5-morpholin-4-yl-pentanoic acid (4-bromophenyl) amide:
Figure JPOXMLDOC01-appb-C000090
 To a solution of 5-bromo-N- (4-bromophenyl) pentanamide (2.7 g, 8.1 mmol) in 2-butanone (60 mL) was added sodium iodide (1.2 g, 8.1 mmol) and morpholine (0.78 mL). 8.9 mmol) and stirred at 70 ° C. After 6 hours, 1.0N aqueous sodium hydroxide solution was added, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 80/20, chloroform only-chloroform / methanol = 95/5) to give the title compound (2.3 g; 83%). Obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.53-1.62 (2H, m), 1.72-1.80 (2H, m), 2.35-2.45 (8H, m), 3.67-3.72 (4H) M), 7.16-7.21 (1H, m), 7.39-7.42 (4H, m).
MS (ESI): 342 [M + H] +
〔第３工程〕
　５－（４－モルホリニル）－Ｎ－（４－（３－ピリジル）フェニル）ペンタンアミドの合成：
Figure JPOXMLDOC01-appb-C000091
 　５－モルホリン－４－イル－ペンタノイックアシッド（４－ブロモフェニル）アミド（５００ｍｇ，１．５ｍｍｏｌ）のアセトニトリル溶液（８．０ｍＬ）にピリジン－３－ボロニックアシッド（２００ｍｇ，１．６ｍｍｏｌ）、炭酸ナトリウム水溶液（０．４Ｍ，８．０ｍＬ）を加えた後、テトラキストリフェニルホスフィンパラジウム（８５ｍｇ，０．０７３ｍｍｏｌ）を加え、マイクロウェーブ照射下、９０℃で攪拌した。２０分後、反応溶液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルムのみ－クロロホルム／メタノール＝８０／２０）で精製し、表題化合物（３５０ｍｇ；７１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：１．４０－１．５０（２Ｈ，ｍ），１．５４－１．６５（２Ｈ，ｍ），２．２４－２．３６（８Ｈ，ｍ），３．５２－３．６７（４Ｈ，ｍ），７．４２－７．４７（１Ｈ，ｍ），７．６５－７．７３（４Ｈ，ｍ），８．００－８．０５（１Ｈ，ｍ），８．４９－８．５４（１Ｈ，ｍ），８．８３－８．８７（１Ｈ，ｍ），９．９８－１０．０（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３４０［Ｍ＋Ｈ］＋ [Third step]
Synthesis of 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide:
Figure JPOXMLDOC01-appb-C000091
 Pyridine-3-boronic acid (200 mg, 1.6 mmol) in acetonitrile solution (8.0 mL) of 5-morpholin-4-yl-pentanoic acid (4-bromophenyl) amide (500 mg, 1.5 mmol), After adding an aqueous sodium carbonate solution (0.4 M, 8.0 mL), tetrakistriphenylphosphine palladium (85 mg, 0.073 mmol) was added, and the mixture was stirred at 90 ° C. under microwave irradiation. After 20 minutes, the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (chloroform only-chloroform / methanol = 80/20) to obtain the title compound (350 mg; 71%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.40-1.50 (2H, m), 1.54-1.65 (2H, m), 2.24-2.36 (8H, m), 3.52-3.67 (4H M), 7.42-7.47 (1H, m), 7.65-7.73 (4H, m), 8.00-8.05 (1H, m), 8.49-8.54. (1H, m), 8.83-8.87 (1H, m), 9.98-10.0 (1H, m).
MS (ESI): 340 [M + H] +
〔第４工程〕
　参考例２８の化合物の合成：
Figure JPOXMLDOC01-appb-C000092
 　５－（４－モルホリニル）－Ｎ－（４－（３－ピリジル）フェニル）ペンタンアミド（３６０ｍｇ，１．０ｍｍｏｌ）のメタノール溶液（２．０ｍＬ）に塩酸（１．０Ｎ，１．０ｍＬ，１．０ｍｍｏｌ）を加え、室温で攪拌した。１０分後、固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、参考例２８の化合物（３４０ｍｇ；８７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：１．５９－１．７８（４Ｈ，ｍ），２．３９－２．４５（２Ｈ，ｍ），２．９６－３．１４（４Ｈ，ｍ），３．３３－３．４２（２Ｈ，ｍ），３．７１－３．８１（２Ｈ，ｍ），３．８８－３．９６（２Ｈ，ｍ），７．７８－７．８２（４Ｈ，ｍ），７．８６－７．９４（１Ｈ，ｍ），８．５５－８．６５（１Ｈ，ｍ），８．７１－８．７６（１Ｈ，ｍ），９．１０－９．１４（１Ｈ，ｍ），１０．３－１０．４（１Ｈ，ｍ），１０．７－１０．８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３４０［Ｍ＋Ｈ］＋ [Fourth step]
Synthesis of the compound of Reference Example 28:
Figure JPOXMLDOC01-appb-C000092
 To a methanol solution (2.0 mL) of 5- (4-morpholinyl) -N- (4- (3-pyridyl) phenyl) pentanamide (360 mg, 1.0 mmol) in hydrochloric acid (1.0 N, 1.0 mL, 1. 0 mmol) was added and stirred at room temperature. After 10 minutes, the solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 28 (340 mg; 87%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.59-1.78 (4H, m), 2.39-2.45 (2H, m), 2.96-3.14 (4H, m), 3.33-3.42 (2H M), 3.71-3.81 (2H, m), 3.88-3.96 (2H, m), 7.78-7.82 (4H, m), 7.86-7.94. (1H, m), 8.55-8.65 (1H, m), 8.71-8.76 (1H, m), 9.10-9.14 (1H, m), 10.3-10 .4 (1H, m), 10.7-10.8 (1H, m).
MS (ESI): 340 [M + H] +
（参考例２９）　ｃｉｓ－２－メチル－５－（６－フェニルピリダジン－３－イル）パーヒドロピロロ［３，４－ｃ］ピロールフマル酸塩（以下、参考例２９の化合物）の合成：
〔第１工程〕
　ｔｅｒｔ－ブチル　ｃｉｓ－５－（６－フェニルピリダジン－３－イル）－ヘキサヒドロ－ピロロ［３，４－ｃ］－ピロール－２（１Ｈ）－カルボキシレートの合成：
Figure JPOXMLDOC01-appb-C000093
 　３－クロロ－６－フェニルピリダジン（０．９０ｇ，４．７ｍｍｏｌ）のジメチルスルホキシド溶液（５．０ｍＬ）にｔｅｒｔ－ブチル　ｃｉｓ－ヘキサヒドロピロロ[３，４－ｃ]ピロール－２（１Ｈ）－カルボキシレート（１．０ｇ，４．７ｍｍｏｌ）、ジイソプロピルエチルアミン（２．９ｍＬ，１６ｍｍｏｌ）を加え、１０５℃で攪拌した。２１時間後、反応溶液を４０℃まで冷却し、水を加え、攪拌した。１時間後、得られた固体を濾取し、水、ジエチルエーテルで洗浄し、乾燥することで表題化合物（０．９８ｇ；５７％）を茶色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）
δ：１．４６（９Ｈ，ｓ），３．０７－３．１６（２Ｈ，ｍ），３．３０－３．３５（２Ｈ，ｍ），３．４６－３．５２（２Ｈ，ｍ），３．６２－３．７２（２Ｈ，ｍ），３．７７－３．８４（２Ｈ，ｍ），７．００－７．０５（１Ｈ，ｍ），７．３７－７．４３（１Ｈ，ｍ），７．４３－７．５０（２Ｈ，ｍ），７．８１－７．８６（１Ｈ，ｍ），７．８９－７．９４（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：３６７［Ｍ＋Ｈ］＋ Reference Example 29 Synthesis of cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole fumarate (hereinafter referred to as the compound of Reference Example 29):
[First step]
Synthesis of tert-butyl cis-5- (6-phenylpyridazin-3-yl) -hexahydro-pyrrolo [3,4-c] -pyrrole-2 (1H) -carboxylate:
Figure JPOXMLDOC01-appb-C000093
 To a solution of 3-chloro-6-phenylpyridazine (0.90 g, 4.7 mmol) in dimethyl sulfoxide (5.0 mL) was added tert-butyl cis-hexahydropyrrolo [3,4-c] pyrrole-2 (1H) -carboxyl. A rate (1.0 g, 4.7 mmol) and diisopropylethylamine (2.9 mL, 16 mmol) were added, and the mixture was stirred at 105 ° C. After 21 hours, the reaction solution was cooled to 40 ° C., water was added, and the mixture was stirred. After 1 hour, the obtained solid was collected by filtration, washed with water and diethyl ether, and dried to obtain the title compound (0.98 g; 57%) as a brown solid.
1 H-NMR (400 MHz, CD 3 OD)
δ: 1.46 (9H, s), 3.07-3.16 (2H, m), 3.30-3.35 (2H, m), 3.46-3.52 (2H, m), 3.62-3.72 (2H, m), 3.77-3.84 (2H, m), 7.00-7.05 (1H, m), 7.37-7.43 (1H, m ), 7.43-7.50 (2H, m), 7.81-7.86 (1H, m), 7.89-7.94 (2H, m).
MS (ESI): 367 [M + H] +
〔第２工程〕
　ｃｉｓ－２－メチル－５－（６－フェニルピリダジン－３－イル）パーヒドロピロロ［３，４－ｃ］ピロールの合成：
Figure JPOXMLDOC01-appb-C000094
 　ｔｅｒｔ－ブチル　ｃｉｓ－５－（６－フェニルピリダジン－３－イル）－ヘキサヒドロ－ピロロ［３，４－ｃ］－ピロール－２（１Ｈ）－カルボキシレート（０．５０ｇ，１．４ｍｍｏｌ）のギ酸水溶液（２．５ｍＬ）にホルマリン（３０％，０．０８９ｍＬ，１．５ｍｍｏｌ）を加え、１００℃で攪拌した。１時間後、反応溶液を室温まで冷却し濃縮した後、重曹水を加え、中和した。クロロホルムで抽出した後、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物（０．２９ｇ；７６％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）
δ：２．２８（３Ｈ，ｓ），２．４４－２．５０（２Ｈ，ｍ），２．７５－２．８０（２Ｈ，ｍ），３．００－３．０８（２Ｈ，ｍ），３．４５－３．５２（２Ｈ，ｍ），３．６２－３．６８（２Ｈ，ｍ），７．０１（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．３１－７．４４（３Ｈ，ｍ），７．７８（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．８５（２Ｈ，ｄ，Ｊ＝８．０Ｈｚ）．
ＭＳ（ＥＳＩ）：２８１［Ｍ＋Ｈ］＋ [Second step]
Synthesis of cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole:
Figure JPOXMLDOC01-appb-C000094
 tert-Butyl cis-5- (6-phenylpyridazin-3-yl) -hexahydro-pyrrolo [3,4-c] -pyrrole-2 (1H) -carboxylate (0.50 g, 1.4 mmol) aqueous formic acid solution Formalin (30%, 0.089 mL, 1.5 mmol) was added to (2.5 mL), and the mixture was stirred at 100 ° C. After 1 hour, the reaction solution was cooled to room temperature and concentrated, and then neutralized with an aqueous sodium bicarbonate solution. After extraction with chloroform, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 95/5) to obtain the title compound (0.29 g; 76%) as a white solid. .
1 H-NMR (400 MHz, CD 3 OD)
δ: 2.28 (3H, s), 2.44-2.50 (2H, m), 2.75-2.80 (2H, m), 3.00-3.08 (2H, m), 3.45-3.52 (2H, m), 3.62-3.68 (2H, m), 7.01 (1H, d, J = 9.6 Hz), 7.31-7.44 (3H M), 7.78 (1H, d, J = 9.6 Hz), 7.85 (2H, d, J = 8.0 Hz).
MS (ESI): 281 [M + H] +
〔第３工程〕
　参考例２９の化合物の合成：
Figure JPOXMLDOC01-appb-C000095
 　ｃｉｓ－２－メチル－５－（６－フェニルピリダジン－３－イル）パーヒドロピロロ［３，４－ｃ］ピロール（０．２９ｇ，１．０ｍｍｏｌ）のメタノール－ジエチルエーテル混合溶液（１／１０，１０ｍＬ）にフマル酸（０．１２ｇ，１．０ｍｍｏｌ）のメタノール－ジエチルエーテル混合溶液（１／１０，１０ｍＬ）を加え、室温で攪拌した。１時間後、固体を濾取し、得られた白色固体をジエチルエーテル、ヘキサンで洗浄し、乾燥することで、参考例２９の化合物（３６０ｍｇ；８８％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：２．３２（３Ｈ，ｓ），２．５８－２．６４（２Ｈ，ｍ），２．６８－２．７６（２Ｈ，ｍ），２．９５－３．０５（２Ｈ，ｍ），３．４３－３．４９（２Ｈ，ｍ），３．６４－３．７１（２Ｈ，ｍ），６．５６（２Ｈ，ｓ），７．０１（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），７．３５－７．５０（３Ｈ，ｍ），７．９１（１Ｈ，ｄ，Ｊ＝９．６Ｈｚ），８．００（２Ｈ，ｄ，Ｊ＝７．２Ｈｚ）．
ＭＳ（ＥＳＩ）：２８１［Ｍ＋Ｈ］＋ [Third step]
Synthesis of the compound of Reference Example 29:
Figure JPOXMLDOC01-appb-C000095
 cis-2-methyl-5- (6-phenylpyridazin-3-yl) perhydropyrrolo [3,4-c] pyrrole (0.29 g, 1.0 mmol) in methanol-diethyl ether mixed solution (1/10, 10 mL) was added a fumaric acid (0.12 g, 1.0 mmol) methanol-diethyl ether mixed solution (1/10, 10 mL), and the mixture was stirred at room temperature. After 1 hour, the solid was collected by filtration, and the obtained white solid was washed with diethyl ether and hexane and dried to obtain the compound of Reference Example 29 (360 mg; 88%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 2.32 (3H, s), 2.58-2.64 (2H, m), 2.68-2.76 (2H, m), 2.95-3.05 (2H, m), 3.43-3.49 (2H, m), 3.64-3.71 (2H, m), 6.56 (2H, s), 7.01 (1H, d, J = 9.6 Hz), 7.35-7.50 (3H, m), 7.91 (1H, d, J = 9.6 Hz), 8.00 (2H, d, J = 7.2 Hz).
MS (ESI): 281 [M + H] +
（参考例３０）　（－）－Ｎ－（１－アザビシクロ［２，２，２］オクタ－３（Ｓ）－イル）カルバミックアシッド　１（Ｓ）－（２－フルオロフェニル）エチルエステル（以下、参考例３０の化合物）の合成：
〔第１工程〕
　（Ｓ）－１－（２－フルオロフェニル）エタノールの合成：
Figure JPOXMLDOC01-appb-C000096
 　（Ｒ）－メチルオキシアザボロリジン（０．３２ｇ，１．２ｍｍｏｌ）のｔｅｒｔ－ブチルアルコール溶液（６０ｍＬ）にＮ，Ｎ－ジエチルアニリンボラン（２．６ｇ，１６ｍｍｏｌ）を加えた後、１－（２－フルオロフェニル）エタノン（２．０ｇ，１４ｍｍｏｌ）のｔｅｒｔ－ブチルアルコール溶液（１５０ｍＬ）を４５℃で加え、攪拌した。１時間後、反応溶液を室温まで冷却し、メタノールを加え、濃縮した。１．０Ｎ塩酸を加え、酢酸エチルで抽出し有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８５／１５）で精製し、表題化合物（１．９ｇ；９２％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．５２（３Ｈ，ｄ，Ｊ＝６．８Ｈｚ），５．１７－５．２４（１Ｈ，ｍ），６．９８－７．０５（１Ｈ，ｍ），７．１５（１Ｈ，ｄｄｄ，Ｊ＝１．２，７．６，７．６Ｈｚ），７．２１－７．２８（１Ｈ，ｍ），７．４９（１Ｈ，ｄｄｄ，Ｊ＝１．６，７．６，７．６Ｈｚ）． Reference Example 30 (-)-N- (1-azabicyclo [2,2,2] octa-3 (S) -yl) carbamic acid 1 (S)-(2-fluorophenyl) ethyl ester Synthesis of Compound of Reference Example 30:
[First step]
Synthesis of (S) -1- (2-fluorophenyl) ethanol:
Figure JPOXMLDOC01-appb-C000096
 N, N-diethylaniline borane (2.6 g, 16 mmol) was added to a tert-butyl alcohol solution (60 mL) of (R) -methyloxyazaborolidine (0.32 g, 1.2 mmol), and then 1- ( A solution of 2-fluorophenyl) ethanone (2.0 g, 14 mmol) in tert-butyl alcohol (150 mL) was added at 45 ° C. and stirred. After 1 hour, the reaction solution was cooled to room temperature, methanol was added, and the mixture was concentrated. 1.0N Hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (hexane only-hexane / ethyl acetate = 85/15) to obtain the title compound (1.9 g; 92%) as a colorless liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.52 (3H, d, J = 6.8 Hz), 5.17-5.24 (1H, m), 6.98-7.05 (1H, m), 7.15 (1H, ddd) , J = 1.2, 7.6, 7.6 Hz), 7.21-7.28 (1H, m), 7.49 (1H, ddd, J = 1.6, 7.6, 7.6 Hz) ).
〔第２工程〕
　イミダゾール－１－カルボキシリックアシッド　（Ｓ）－１－（２－フルオロフェニル）エチルエステルの合成：
Figure JPOXMLDOC01-appb-C000097
 　１，１’－カルボニルジイミダゾール（３．３ｇ，２０ｍｍｏｌ）のテトラヒドロフラン溶液（１６ｍＬ）に（Ｓ）－１－（２－フルオロフェニル）エタノール（１．９ｇ，１３ｍｍｏｌ）のテトラヒドロフラン溶液（４．０ｍＬ）を５０℃でゆっくり加え、攪拌した。４時間後、蒸留水を加え、酢酸エチルで抽出し有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝９０／１０－７０／３０）で精製し、表題化合物（３．１ｇ；９９％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．７５（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），６．３３（１Ｈ，ｑ，Ｊ＝６．４Ｈｚ），７．０６－７．１３（２Ｈ，ｍ），７．１８（１Ｈ，ｄｄｄ，Ｊ＝１．２，７．２，７．６Ｈｚ），７．３１－７．４６（３Ｈ，ｍ），８．１６（１Ｈ，ｓ）．
ＭＳ（ＥＳＩ）：２３５［Ｍ＋Ｈ］＋ [Second step]
Synthesis of imidazole-1-carboxylic acid (S) -1- (2-fluorophenyl) ethyl ester:
Figure JPOXMLDOC01-appb-C000097
 A tetrahydrofuran solution (4.0 mL) of (S) -1- (2-fluorophenyl) ethanol (1.9 g, 13 mmol) in a tetrahydrofuran solution (16 mL) of 1,1′-carbonyldiimidazole (3.3 g, 20 mmol). Was slowly added at 50 ° C. and stirred. After 4 hours, distilled water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 90 / 10-70 / 30) to give the title compound (3.1 g; 99%) as a colorless liquid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.75 (3H, d, J = 6.4 Hz), 6.33 (1H, q, J = 6.4 Hz), 7.06-7.13 (2H, m), 7.18 (1H , Ddd, J = 1.2, 7.2, 7.6 Hz), 7.31-7.46 (3H, m), 8.16 (1H, s).
MS (ESI): 235 [M + H] +
〔第３工程〕
　参考例３０の化合物の合成：
Figure JPOXMLDOC01-appb-C000098
 　３－アミノキヌクリジン二塩酸塩（１．４ｇ，７．０ｍｍｏｌ）のテトラヒドロフラン溶液（１４ｍＬ）に対し、ｎ－ブチルリチウム（２．６Ｍ　ヘキサン溶液，５．２ｍＬ，１４ｍｍｏｌ）を０℃でゆっくり加えた。室温で１時間攪拌した後、イミダゾール－１－カルボキシリックアシッド　（Ｓ）－１－（２－フルオロフェニル）エチルエステル（１．５ｇ，６．４ｍｍｏｌ）を０℃でゆっくり加えた。室温で１時間攪拌した後、５５℃で２時間攪拌し、蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝９８／２）で精製し、参考例３０の化合物（４８０ｍｇ；２６％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．３６－１．５０（１Ｈ，ｍ），１．５５（３Ｈ，ｄ，Ｊ＝６．４Ｈｚ），１．５３－１．６５（３Ｈ，ｍ），１．８３－１．９０（１Ｈ，ｍ），２．４４－２．５２（１Ｈ，ｍ），２．６９－２．８５（４Ｈ，ｍ），３．２８－３．３８（１Ｈ，ｍ），３．６６－３．７４（１Ｈ，ｍ），４．８４－４．９４（１Ｈ，ｍ），６．０１－６．０８（１Ｈ，ｍ），７．００－７．０６（１Ｈ，ｍ），７．１３（１Ｈ，ｄｄ，Ｊ＝６．８，７．６Ｈｚ），７．２２－７．２９（１Ｈ，ｍ），７．３７（１Ｈ，ｄｄ，Ｊ＝５．２，６．８Ｈｚ）．
ＭＳ（ＥＳＩ）：２９３［Ｍ＋Ｈ］＋ [Third step]
Synthesis of the compound of Reference Example 30:
Figure JPOXMLDOC01-appb-C000098
 To a tetrahydrofuran solution (14 mL) of 3-aminoquinuclidine dihydrochloride (1.4 g, 7.0 mmol), n-butyllithium (2.6 M hexane solution, 5.2 mL, 14 mmol) was slowly added at 0 ° C. It was. After stirring at room temperature for 1 hour, imidazole-1-carboxylic acid (S) -1- (2-fluorophenyl) ethyl ester (1.5 g, 6.4 mmol) was slowly added at 0 ° C. After stirring at room temperature for 1 hour, it stirred at 55 degreeC for 2 hours, distilled water was added, and ethyl acetate extracted. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 98/2) to obtain the compound of Reference Example 30 (480 mg; 26%) as a white solid. It was.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.36-1.50 (1H, m), 1.55 (3H, d, J = 6.4 Hz), 1.53-1.65 (3H, m), 1.83-1.90 (1H, m), 2.44-2.52 (1H, m), 2.69-2.85 (4H, m), 3.28-3.38 (1H, m), 3.66-3 .74 (1H, m), 4.84-4.94 (1H, m), 6.01-6.08 (1H, m), 7.00-7.06 (1H, m), 7.13 (1H, dd, J = 6.8, 7.6 Hz), 7.22-7.29 (1H, m), 7.37 (1H, dd, J = 5.2, 6.8 Hz).
MS (ESI): 293 [M + H] +
（参考例３１）　Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）フロ［２，３－ｃ］ピリジン－５－カルボキシアミド二塩酸塩（以下、参考例３１の化合物）の合成：
〔第１工程〕
　Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）フロ［２，３－ｃ］ピリジン－５－カルボキシアミドの合成：
Figure JPOXMLDOC01-appb-C000099
 　フロ［２，３－ｃ］ピリジン－５－カルボキシリックアシッド（０．１６ｇ，１．０ｍｍｏｌ）のクロロホルム溶液（１０ｍＬ）にｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ'，Ｎ'－テトラメチルウロニウムヘキサフルオロホスファート（０．５７ｇ，１．５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．７０ｍＬ，４．０ｍｍｏｌ）、（Ｒ）－キヌクリジン－３－アミン塩酸塩（０．２０ｇ，１．０ｍｍｏｌ）を加え、室温で攪拌した。１６時間後、蒸留水を加えた後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝９８／２）で精製し、表題化合物（０．１８ｍｇ；６６％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．４０－１．５５（１Ｈ，ｍ），１．６５－１．７４（２Ｈ，ｍ），１．８０－１．９０（１Ｈ，ｍ），２．０２－２．０６（１Ｈ，ｍ），２．６３－２．７０（１Ｈ，ｍ），２．７５－３．００（４Ｈ，ｍ），３．３９－３．４６（１Ｈ，ｍ），４．１２－４．２０（１Ｈ，ｍ），６．８９－６．９２（１Ｈ，ｍ），７．８０（１Ｈ，ｄ，Ｊ＝２．０Ｈｚ）８．２５－８．３５（１Ｈ，ｍ），８．４６－８．４９（１Ｈ，ｍ），８．７５－８．７８（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２７２［Ｍ＋Ｈ］＋ Reference Example 31 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxyamide dihydrochloride (hereinafter referred to as Reference Example 31) Synthesis of compound:
[First step]
Synthesis of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide:
Figure JPOXMLDOC01-appb-C000099
 O- (Benzotriazol-1-yl) -N, N, N ′, N in chloroform solution (10 mL) of furo [2,3-c] pyridine-5-carboxylic acid (0.16 g, 1.0 mmol) '-Tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol), diisopropylethylamine (0.70 mL, 4.0 mmol), (R) -quinuclidin-3-amine hydrochloride (0.20 g, 1. 0 mmol) was added and stirred at room temperature. After 16 hours, distilled water was added, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 98/2) to obtain the title compound (0.18 mg; 66%) as a colorless liquid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.40-1.55 (1H, m), 1.65-1.74 (2H, m), 1.80-1.90 (1H, m), 2.02-2.06 (1H M), 2.63-2.70 (1H, m), 2.75-3.00 (4H, m), 3.39-3.46 (1H, m), 4.12-4.20 (1H, m), 6.89-6.92 (1H, m), 7.80 (1H, d, J = 2.0 Hz) 8.25-8.35 (1H, m), 8.46- 8.49 (1H, m), 8.75-8.78 (1H, m).
MS (ESI): 272 [M + H] +
〔第２工程〕
　参考例３１の化合物の合成：
Figure JPOXMLDOC01-appb-C000100
 　Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）フロ［２，３－ｃ］ピリジン－５－カルボキシアミド（１８０ｍｇ，０．６６ｍｍｏｌ）の酢酸エチル溶液（２．０ｍＬ）に塩化水素－酢酸エチル溶液（４．０Ｍ，０．５０ｍＬ，２．０ｍｍｏｌ）を加え、室温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、参考例３１の化合物（１９０ｍｇ；８４％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，Ｄ２Ｏ）
δ：１．７６－２．１８（４Ｈ，ｍ），２．２６－２．３２（１Ｈ，ｍ），３．１５－３．３５（５Ｈ，ｍ），３．６８－３．７６（１Ｈ，ｍ），４．３５－４．４０（１Ｈ，ｍ），７．０１－７．０５（１Ｈ，ｍ），８．００－８．０４（１Ｈ，ｍ），８．３２－８．３４（１Ｈ，ｍ），８．８０－８．８２（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２７２［Ｍ＋Ｈ］＋ [Second step]
Synthesis of the compound of Reference Example 31:
Figure JPOXMLDOC01-appb-C000100
 A solution of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) furo [2,3-c] pyridine-5-carboxamide (180 mg, 0.66 mmol) in ethyl acetate (2. 0 mL) was added a hydrogen chloride-ethyl acetate solution (4.0 M, 0.50 mL, 2.0 mmol), and the mixture was stirred at room temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 31 (190 mg; 84%) as a white solid.
1 H-NMR (400 MHz, D 2 O)
δ: 1.76-2.18 (4H, m), 2.26-2.32 (1H, m), 3.15-3.35 (5H, m), 3.68-3.76 (1H M), 4.35-4.40 (1H, m), 7.01-7.05 (1H, m), 8.00-8.04 (1H, m), 8.32-8.34. (1H, m), 8.80-8.82 (1H, m).
MS (ESI): 272 [M + H] +
（参考例３２）　Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－２，３－ジヒドロ－１，４－ベンゾジオキシン－６－カルボキシアミド塩酸塩（以下、参考例３２の化合物）の合成：
〔第１工程〕
　Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－２，３－ジヒドロ－１，４－ベンゾジオキシン－６－カルボキシアミドの合成：
Figure JPOXMLDOC01-appb-C000101
 　２，３－ジヒドロ［ｂ］［１，４］ジオキシン－６－カルボキシリックアシッド（０．１８ｇ，１．０ｍｍｏｌ）のクロロホルム溶液（１０ｍＬ）にｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ、Ｎ'，Ｎ'－テトラメチルウロニウムヘキサフルオロホスファート（０．５７ｇ，１．５ｍｍｏｌ）、ジイソプロピルエチルアミン（０．７０ｍＬ，４．０ｍｍｏｌ）、（Ｒ）－キヌクリジン－３－アミン塩酸塩（０．２０ｇ，１．０ｍｍｏｌ）を加え、室温で攪拌した。１６時間後、蒸留水を加えた後、クロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムにより乾燥し濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（富士シリシア化学アミンシリカゲルＤＭ１０２０、クロロホルムのみ－クロロホルム／メタノール＝９８／２）で精製し、表題化合物（０．２２ｍｇ；７６％）を無色液体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）
δ：１．４４－１．５５（１Ｈ，ｍ），１．６５－１．７６（３Ｈ，ｍ），１．９８－２．０３（１Ｈ，ｍ），２．５１－２．５８（１Ｈ，ｍ），２．７５－２．９０（４Ｈ，ｍ），３．３７－３．４６（１Ｈ，ｍ），４．０５－４．１４（１Ｈ，ｍ），４．２５－４．３５（４Ｈ，ｍ），６．０８－６．１８（１Ｈ，ｍ），６．８６－６．９０（１Ｈ，ｍ），７．２４－７．３１（２Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２８９［Ｍ＋Ｈ］＋ Reference Example 32 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide hydrochloride (hereinafter referred to as “Reference Example 32”) Synthesis of the compound of Reference Example 32:
[First step]
Synthesis of N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide:
Figure JPOXMLDOC01-appb-C000101
 O- (Benzotriazol-1-yl) -N, N was added to a chloroform solution (10 mL) of 2,3-dihydro [b] [1,4] dioxin-6-carboxylic acid (0.18 g, 1.0 mmol). , N ′, N′-tetramethyluronium hexafluorophosphate (0.57 g, 1.5 mmol), diisopropylethylamine (0.70 mL, 4.0 mmol), (R) -quinuclidin-3-amine hydrochloride (0 .20 g, 1.0 mmol) was added and stirred at room temperature. After 16 hours, distilled water was added, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (Fuji Silysia Chemical amine silica gel DM1020, chloroform only-chloroform / methanol = 98/2) to obtain the title compound (0.22 mg; 76%) as a colorless liquid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.44 to 1.55 (1H, m), 1.65 to 1.76 (3H, m), 1.98 to 2.03 (1H, m), 2.51 to 2.58 (1H) M), 2.75-2.90 (4H, m), 3.37-3.46 (1H, m), 4.05-4.14 (1H, m), 4.25-4.35. (4H, m), 6.08-6.18 (1H, m), 6.86-6.90 (1H, m), 7.24-7.31 (2H, m).
MS (ESI): 289 [M + H] +
〔第２工程〕
　参考例３２の化合物の合成：
Figure JPOXMLDOC01-appb-C000102
 　Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－２，３－ジヒドロ－１，４－ベンゾジオキシン－６－カルボキシアミド（２２０ｍｇ，０．７６ｍｍｏｌ）の酢酸エチル溶液（２．０ｍＬ）に塩化水素－酢酸エチル溶液（４．０Ｍ，０．２８ｍＬ，１．１ｍｍｏｌ）を加え、室温で攪拌した。１０分後、得られた固体を濾取し、酢酸エチル、ヘキサンで洗浄し、乾燥することで、参考例３２の化合物（１１０ｍｇ；４３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）
δ：１．６４－１．７４（１Ｈ，ｍ），１．８２－１．９１（２Ｈ，ｍ），１．９７－２．１６（２Ｈ，ｍ），３．１０－３．３５（５Ｈ，ｍ），３．５５－３．６３（１Ｈ，ｍ），４．２２－４．３０（５Ｈ，ｍ），６．９１－６．９５（１Ｈ，ｍ），７．４０－７．４６（２Ｈ，ｍ），８．４２－８．４５（１Ｈ，ｍ），１０．２－１０．３（１Ｈ，ｍ）．
ＭＳ（ＥＳＩ）：２８９［Ｍ＋Ｈ］＋ [Second step]
Synthesis of the compound of Reference Example 32:
Figure JPOXMLDOC01-appb-C000102
 N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -2,3-dihydro-1,4-benzodioxin-6-carboxamide (220 mg, 0.76 mmol) in ethyl acetate To the solution (2.0 mL) was added a hydrogen chloride-ethyl acetate solution (4.0 M, 0.28 mL, 1.1 mmol), and the mixture was stirred at room temperature. After 10 minutes, the obtained solid was collected by filtration, washed with ethyl acetate and hexane, and dried to obtain the compound of Reference Example 32 (110 mg; 43%) as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.64-1.74 (1H, m), 1.82-1.91 (2H, m), 1.97-2.16 (2H, m), 3.10-3.35 (5H) M), 3.55-3.63 (1H, m), 4.22-4.30 (5H, m), 6.91-6.95 (1H, m), 7.40-7.46 (2H, m), 8.42-8.45 (1H, m), 10.2-10.3 (1H, m).
MS (ESI): 289 [M + H] +
（参考例３３）　中枢型ニコチン性アセチルコリン受容体を活性化する化合物（バレニクリン酒石酸塩、Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－４－クロロベンズアミド塩酸塩、及び参考例２３～３２の化合物）のサブスタンスＰ誘発引っ掻き行動に対する抑制効果：
　サブスタンスＰ誘発引っ掻き行動の惹起及び回数測定は、実施例３７と同様の方法で実施した。 Reference Example 33 Compound that activates central nicotinic acetylcholine receptor (Varenicline tartrate, N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride Inhibitory effects of substance and compounds of Reference Examples 23 to 32 on substance P-induced scratching behavior:
Induction of substance P-induced scratching behavior and measurement of the number of times were performed in the same manner as in Example 37.
　被験化合物又はその溶媒は、１０ｍＬ／ｋｇの容量で、引っ掻き行動回数の測定開始の３０～６０分前に投与した。バレニクリン酒石酸塩（Ｔｏｃｒｉｓ　Ｂｉｏｓｃｉｅｎｃｅ社）は、ＰＢＳに溶解し、１、３又は１０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の６０分前に腹腔内投与した。Ｎ－（１－アザビシクロ［２．２．２］オクタ－３（Ｒ）－イル）－４－クロロベンズアミド塩酸塩（ＰＮＵ－２８２９８７）水和物（Ｓｉｇｍａ－Ａｌｄｒｉｃｈ社）は、ＰＢＳに溶解し、０．３又は１ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の４５分前に腹腔内投与した。参考例２３の化合物は、ＰＢＳに溶解し、０．１又は０．３ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の３０分前に腹腔内投与した。参考例２４の化合物は、ＰＢＳに溶解し、１、３又は１０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の４５分前に腹腔内投与した。参考例２５の化合物は、蒸留水に溶解し、１、３又は１０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の３０分前に経口投与した。参考例２６の化合物は、ＰＢＳに溶解し、１、３又は１０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の４５分前に腹腔内投与した。参考例２７の化合物は、ＰＢＳに溶解し、１、３又は１０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の３０分前に腹腔内投与した。参考例２８の化合物は、ＰＢＳに溶解し、１、３又は１０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の３０分前に腹腔内投与した。参考例２９の化合物は、ＰＢＳに溶解し、０．３、１又は３ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の４５分前に腹腔内投与した。参考例３０の化合物は、０．５％メチルセルロースに懸濁し、１０又は３０ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の６０分前に経口投与した。参考例３１の化合物は、ＰＢＳに溶解し、０．１、０．３又は１ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の４５分前に腹腔内投与した。参考例３２の化合物は、ＰＢＳに溶解し、０．１、０．３又は１ｍｇ／ｋｇの用量で、引っ掻き行動回数の測定開始の４５分前に腹腔内投与した。 The test compound or its solvent was administered at a volume of 10 mL / kg 30 to 60 minutes before the start of measurement of the number of scratching actions. Varenicline tartrate (Tocris Bioscience) was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 60 minutes before the start of the measurement of the number of scratching behaviors. N- (1-azabicyclo [2.2.2] octa-3 (R) -yl) -4-chlorobenzamide hydrochloride (PNU-282987) hydrate (Sigma-Aldrich) was dissolved in PBS, It was administered intraperitoneally at a dose of 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 23 was dissolved in PBS and administered intraperitoneally at a dose of 0.1 or 0.3 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 24 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 25 was dissolved in distilled water and orally administered at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of the measurement of the number of scratching behaviors. The compound of Reference Example 26 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 27 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 28 was dissolved in PBS and administered intraperitoneally at a dose of 1, 3 or 10 mg / kg 30 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 29 was dissolved in PBS and administered intraperitoneally at a dose of 0.3, 1 or 3 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 30 was suspended in 0.5% methylcellulose and orally administered at a dose of 10 or 30 mg / kg 60 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 31 was dissolved in PBS and administered intraperitoneally at a dose of 0.1, 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors. The compound of Reference Example 32 was dissolved in PBS and administered intraperitoneally at a dose of 0.1, 0.3 or 1 mg / kg 45 minutes before the start of measurement of the number of scratching behaviors.
　溶媒のみを投与した群（被験化合物：０ｍｇ／ｋｇ、サブスタンスＰ：０ｎｍｏｌ／ｓｉｔｅ）を「非惹起対照群」、サブスタンスＰを投与し被験化合物を投与していない群（被験化合物：０ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）を「惹起対照群」、サブスタンスＰ及び被験化合物を投与した群を「被験化合物投与群」とした。 A group (test compound: 0 mg / kg, substance P: 0 nmol / site) administered with only the solvent was a “non-induced control group”, and a group administered with substance P but not administered a test compound (test compound: 0 mg / kg, Substance P: 250 nmol / site) was designated as “induction control group”, and a group administered with substance P and test compound was designated as “test compound administration group”.
　被験化合物による引っ掻き行動の抑制率（％）は、次式より算出した。
　　　　抑制率（％）＝［１－（Ａ－Ｃ）／（Ｂ－Ｃ）］×１００
　ここで、Ａ、Ｂ、Ｃはそれぞれ、被験化合物投与群、惹起対照群、非惹起対照群の引っ掻き行動回数の平均値を表す。 The inhibition rate (%) of scratching behavior by the test compound was calculated from the following formula.
Inhibition rate (%) = [1− (AC) / (BC)] × 100
Here, A, B, and C represent the average values of the number of scratching behaviors of the test compound administration group, the induced control group, and the non-induced control group, respectively.
　統計学的処理としては、惹起対照群に対する被験化合物投与群の検定としてＤｕｎｎｅｔｔ検定を行った。有意水準は５％（両側）とした。 As a statistical treatment, Dunnett's test was performed as a test of the test compound administration group with respect to the induction control group. The significance level was 5% (both sides).
　表２及び表３に各被験化合物の引っ掻き行動回数に対する効果を示す。表中の＊印は、惹起対照群との比較で統計学的に有意であることを示す（＊ｐ＜０．０５、Ｄｕｎｎｅｔｔ検定）。 Tables 2 and 3 show the effect of each test compound on the number of scratching actions. * Mark in a table | surface shows that it is statistically significant compared with an induction | guidance | derivation control group (* p <0.05, Dunnett test).
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
　これらの結果から、中枢型ニコチン性アセチルコリン受容体を活性化する化合物は、難治性掻痒モデルとして知られるサブスタンスＰ誘発引っ掻き行動を顕著に抑制し、優れた止痒効果を有することは明らかである。 From these results, it is clear that a compound that activates the central nicotinic acetylcholine receptor significantly suppresses substance P-induced scratching behavior known as an intractable pruritus model and has an excellent antipruritic effect.
（参考例３４）バレニクリンのサブスタンスＰ誘発引っ掻き行動抑制効果に対するニコチン性アセチルコリン受容体拮抗薬の作用
　サブスタンスＰ誘発引っ掻き行動の惹起及び回数測定は、実施例３７と同様の方法で実施した。 (Reference Example 34) Action of a nicotinic acetylcholine receptor antagonist on the inhibitory effect of varenicline on substance P-induced scratching behavior Induction and frequency measurement of substance P-induced scratching behavior was carried out in the same manner as in Example 37.
　バレニクリン酒石酸塩（０．３ｍｇ／ｍＬ、Ｔｏｃｒｉｓ　Ｂｉｏｓｃｉｅｎｃｅ社）、メカミラミン塩酸塩（０．３ｍｇ／ｍＬ、Ｔｏｃｒｉｓ　Ｂｉｏｓｃｉｅｎｃｅ社）、バレニクリン酒石酸塩とメカミラミン塩酸塩（ともに０．３ｍｇ／ｍＬ）の混合溶液又はこれらの溶媒であるＰＢＳは、１０ｍＬ／ｋｇの容量で、引っ掻き行動回数の測定開始の６０分前に腹腔内投与した。 Varenicline tartrate (0.3 mg / mL, Tocris Bioscience), mecamylamine hydrochloride (0.3 mg / mL, Tocris Bioscience), a mixed solution of varenicline tartrate and mecamylamine hydrochloride (both 0.3 mg / mL) or these PBS as a solvent was administered intraperitoneally at a volume of 10 mL / kg 60 minutes before the start of measurement of the number of scratching behaviors.
　評価結果を図３に示す。縦軸は、１５分間の引っ掻き行動回数（平均値±標準誤差、ｎ＝５～８）を示す。横軸は、非惹起対照群（被験化合物：０ｍｇ／ｋｇ、サブスタンスＰ：０ｎｍｏｌ／ｓｉｔｅ）、惹起対照群（被験化合物：０ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）、バレニクリン酒石酸塩投与群（バレニクリン酒石酸塩：３ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）、メカミラミン塩酸塩投与群（メカミラミン塩酸塩：３ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）及びバレニクリン酒石酸塩＋メカミラミン塩酸塩投与群（バレニクリン酒石酸塩：３ｍｇ／ｋｇ、メカミラミン塩酸塩：３ｍｇ／ｋｇ、サブスタンスＰ：２５０ｎｍｏｌ／ｓｉｔｅ）を示す。図中の＊印は、惹起対照群との比較で統計学的に有意であることを示し（＊ｐ＜０．０５、Ａｓｐｉｎ－Ｗｅｌｃｈのｔ検定）、＃印は、バレニクリン酒石酸塩投与群との比較で統計学的に有意であることを示す（＃ｐ＜０．０５、Ａｓｐｉｎ－Ｗｅｌｃｈのｔ検定）。 Evaluation results are shown in FIG. The vertical axis represents the number of scratching actions for 15 minutes (average value ± standard error, n = 5 to 8). The horizontal axis represents the non-induced control group (test compound: 0 mg / kg, substance P: 0 nmol / site), the induced control group (test compound: 0 mg / kg, substance P: 250 nmol / site), the varenicline tartrate-administered group (valenicline). Tartrate: 3 mg / kg, substance P: 250 nmol / site), mecamylamine hydrochloride administration group (mecamylamine hydrochloride: 3 mg / kg, substance P: 250 nmol / site) and varenicline tartrate + mecamylamine hydrochloride administration group (valenicline tartrate : 3 mg / kg, mecamylamine hydrochloride: 3 mg / kg, substance P: 250 nmol / site). In the figure, * indicates statistically significant comparison with the induction control group (* p <0.05, Aspin-Welch t-test), and # indicates the varenicline tartrate administration group. (#P <0.05, Aspin-Welch t test).
　ニコチン性アセチルコリン受容体拮抗薬であるメカミラミン塩酸塩を併用したところ、バレニクリン酒石酸塩のサブスタンスＰ誘発引っ掻き行動抑制効果は完全に消失した。これらの結果から、中枢型ニコチン性アセチルコリン受容体を活性化する化合物の引っ掻き行動抑制効果は、ニコチン性アセチルコリン受容体が特異的に活性化した結果であることが明らかとなった。 When combined with mecamylamine hydrochloride, which is a nicotinic acetylcholine receptor antagonist, the effect of inhibiting substance P-induced scratching behavior of varenicline tartrate completely disappeared. From these results, it was clarified that the effect of suppressing the scratching behavior of the compound that activates the central nicotinic acetylcholine receptor is a result of specific activation of the nicotinic acetylcholine receptor.
　また、このサブスタンスＰ誘発引っ掻き行動は、外因性のサブスタンスＰと内因性のロイコトリエンＢ４が急性的に神経を刺激することにより惹起され、免疫反応や炎症反応を介在しない掻痒モデルであると考えられている（Ａｎｄｏｈら、Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、１９９８年、第３５３巻、ｐ．９３；Ａｎｄｏｈら、Ｊｏｕｒｎａｌ　ｏｆ　Ｉｎｖｅｓｔｉｇａｔｉｖｅ　Ｄｅｒｍａｔｏｌｏｇｙ、２００１年、第１１７巻、ｐ．１６２１）。サブスタンスＰ誘発引っ掻き行動惹起の３０～６０分前に中枢型ニコチン性アセチルコリン受容体を活性化する化合物を単回投与することにより、引っ掻き行動が抑制されたという結果は、中枢型ニコチン性アセチルコリン受容体の活性化が掻痒刺激によるインパルスの伝導及び／又は伝達を直接的に抑制したことを示唆するものであった。 Further, this substance P-induced scratching behavior is considered to be an itching model that is induced by exogenous substance P and endogenous leukotriene B4 acutely stimulating nerves and does not mediate immune reaction or inflammatory reaction. (Andoh et al., European Journal of Pharmacology, 1998, volume 353, p. 93; Andoh et al., Journal of Investigative Dermatology, 2001, volume 117, p. 1621). As a result of a single administration of a compound that activates the central nicotinic acetylcholine receptor 30 to 60 minutes before substance P-induced scratching is induced, the result is that the scratching behavior is suppressed. This suggests that the activation of the gene directly suppressed the conduction and / or transmission of impulses by pruritus stimulation.
（実施例３８）　（Ｒ）－３－（６－クロロピリジン－３－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成： 
Figure JPOXMLDOC01-appb-C000105
 
 
　トリホスゲン（０．０７２ｇ、０．２４ｍｍｏｌ）をジクロロメタン（１．３ｍＬ）に溶解し、６－クロロピリジン－３－アミン（０．０９２ｇ、０．７１ｍｍｏｌ）、トリエチルアミン（０．０８０ｍＬ、０．７８ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ジクロロメタン（２．６ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１０ｇ、０．７１ｍｍｏｌ）、トリエチルアミン（０．０８０ｍＬ、０．７８ｍｍｏｌ）を０℃で滴下した。同温度で１時間攪拌した後、飽和重曹水を０℃で加えて、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．１６ｇ（７７％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５１－１．５７（ｍ、１Ｈ）、１．６２－１．８８（ｍ、３Ｈ）、１．９６－１．９７（ｍ、１Ｈ）、２．８１－３．０１（ｍ、５Ｈ）、３．１５（ｓ、３Ｈ）、３．２３－３．３０（ｍ、１Ｈ）、４．３０－４．３６（ｍ、１Ｈ）、６．４５（ｂｒｓ、１Ｈ）、７．２５－７．２７（ｍ、１Ｈ）、８．０２（ｄｄ、Ｊ＝２．８、８．８Ｈｚ、１Ｈ）、８．２４（ｄ、Ｊ＝２．８Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：２９５［Ｍ＋Ｈ］＋． Example 38 Synthesis of (R) -3- (6-chloropyridin-3-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000105


Triphosgene (0.072 g, 0.24 mmol) was dissolved in dichloromethane (1.3 mL), and 6-chloropyridin-3-amine (0.092 g, 0.71 mmol) and triethylamine (0.080 mL, 0.78 mmol) were added. Added at 0 ° C. After stirring at the same temperature for 30 minutes, (R) -N-methylquinuclidin-3-amine (0.10 g, 0.71 mmol), triethylamine (0.080 mL, 0.001) dissolved in dichloromethane (2.6 mL) was stirred. 78 mmol) was added dropwise at 0 ° C. After stirring at the same temperature for 1 hour, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.16 g (77%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.51-1.57 (m, 1H), 1.62-1.88 (m, 3H), 1.96-1.97 (m, 1H), 2.81-3.01 (m 5H), 3.15 (s, 3H), 3.23-3.30 (m, 1H), 4.30-4.36 (m, 1H), 6.45 (brs, 1H), 7. 25-7.27 (m, 1H), 8.02 (dd, J = 2.8, 8.8 Hz, 1H), 8.24 (d, J = 2.8 Hz, 1H).
MS (ESI): 295 [M + H] < +>.
（実施例３９）　（Ｒ）－１－メチル－３－（ピリジン－３－イル）－１－（キヌクリジン－３－イル）ウレアの合成： 
Figure JPOXMLDOC01-appb-C000106
　（Ｒ）－３－（６－クロロピリジン－３－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．０２０ｇ、０．０６８ｍｍｏｌ）をメタノール（１．４ｍL）に溶解し、１０％パラジウムー炭素（２０ｍｇ、１００ｗｔ％）を室温で加えた。反応系内を水素ガスで置換して、水素雰囲気下で１２時間攪拌した後、反応溶液をセライトろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０－酢酸エチルのみ、クロロホルムのみ－クロロホルム／メタノール＝９５／５）で精製し、表題化合物０．０１２ｇ（６９％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５３－１．５７（ｍ、１Ｈ）、１．６２－１．７２（ｍ、１Ｈ）、１．７５－１．８３（ｍ、２Ｈ）、１．９９－２．０１（ｍ、１Ｈ）、２．８７－３．０４（ｍ、５Ｈ）、３．１５（ｓ、３Ｈ）、３．２８－３．３４（ｍ、１Ｈ）、４．３３－４．３６（ｍ、１Ｈ）、６．７９（ｂｒｓ、１Ｈ）、７．２１－７．２５（ｍ、１Ｈ）、８．００－８．０２（ｍ、１Ｈ）、８．２６－８．２７（ｍ、１Ｈ）、８．４９（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２６１［Ｍ＋Ｈ］＋． Example 39 Synthesis of (R) -1-methyl-3- (pyridin-3-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000106
(R) -3- (6-Chloropyridin-3-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.020 g, 0.068 mmol) was dissolved in methanol (1.4 mL). 10% palladium on carbon (20 mg, 100 wt%) was added at room temperature. The reaction system was replaced with hydrogen gas and stirred for 12 hours in a hydrogen atmosphere, and the reaction solution was filtered through Celite. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (hexane / ethyl acetate = 50 / 50-ethyl acetate only, chloroform only-chloroform / methanol = 95/5) to give the title compound. 0.012 g (69%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.53-1.57 (m, 1H), 1.62-1.72 (m, 1H), 1.75-1.83 (m, 2H), 1.99-2.01 (m 1H), 2.87-3.04 (m, 5H), 3.15 (s, 3H), 3.28-3.34 (m, 1H), 4.33-4.36 (m, 1H) ), 6.79 (brs, 1H), 7.21-7.25 (m, 1H), 8.00-8.02 (m, 1H), 8.26-8.27 (m, 1H), 8.49 (s, 1H).
MS (ESI): 261 [M + H] < +>.
（実施例４０）　（Ｒ）－１－メチル－３－（２－フェニル－２Ｈ－１，２，３－トリアゾール－４－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000107
　２－フェニルー２Ｈ－１，２，３－トリアゾールー４－カルボン酸（０．２０ｇ、１．１ｍｍｏｌ）をジメチルホルミアミド（３．６ｍＬ）に溶解し、トリエチルアミン（０．１７ｍＬ、１．２ｍｍｏｌ）、ジフェニルホスホリルアジド（０．２５ｍＬ、１．１ｍｍｏｌ）を０℃で加えた。同温度で２時間攪拌した後、水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物を１，４－ジオキサン（３．５ｍＬ）に溶解し、８０℃で１２時間攪拌した。反応溶液を室温まで冷却し、１，４－ジオキサン（３．５ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１０ｇ、０．７１ｍｍｏｌ）を室温で滴下した。同温度で１２時間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をジエチルエーテルで洗浄した。水層に飽和重曹水を加えて塩基性にし、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（酢酸エチルのみ－酢酸エチル／メタノール＝９５／５）で精製し、表題化合物０．０５９ｇ（２５％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５１－１．５７（ｍ、１Ｈ）、１．６６－１．８１（ｍ、３Ｈ）、１．９８－２．００（ｍ、１Ｈ）、２．８４－３．０１（ｍ、５Ｈ）、３．１６（ｓ、３Ｈ）、３．２４－３．２８（ｍ、１Ｈ）、４．３６－４．４０（ｍ、１Ｈ）、７．１７－７．１９（ｍ、２Ｈ）、７．２７－７．３０（ｍ、１Ｈ）、７．４４－７．４８（ｍ、２Ｈ）、７．９３－７．９５（ｍ、２Ｈ）．
ＭＳ（ＥＳＩ）：３２７［Ｍ＋Ｈ］＋． Example 40 Synthesis of (R) -1-methyl-3- (2-phenyl-2H-1,2,3-triazol-4-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000107
2-Phenyl-2H-1,2,3-triazole-4-carboxylic acid (0.20 g, 1.1 mmol) was dissolved in dimethylformamide (3.6 mL), triethylamine (0.17 mL, 1.2 mmol), Diphenylphosphoryl azide (0.25 mL, 1.1 mmol) was added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in 1,4-dioxane (3.5 mL) and stirred at 80 ° C. for 12 hours. The reaction solution was cooled to room temperature, and (R) -N-methylquinuclidin-3-amine (0.10 g, 0.71 mmol) dissolved in 1,4-dioxane (3.5 mL) was added dropwise at room temperature. After stirring at the same temperature for 12 hours, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (ethyl acetate only-ethyl acetate / methanol = 95/5) to give 0.059 g (25%) of the title compound as a white solid. Obtained.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.51-1.57 (m, 1H), 1.66-1.81 (m, 3H), 1.98-2.00 (m, 1H), 2.84-3.01 (m 5H), 3.16 (s, 3H), 3.24-3.28 (m, 1H), 4.36-4.40 (m, 1H), 7.17-7.19 (m, 2H) ), 7.27-7.30 (m, 1H), 7.44-7.48 (m, 2H), 7.93-7.95 (m, 2H).
MS (ESI): 327 [M + H] < +>.
（実施例４１）　（Ｒ）－１－メチル－３－（２－フェニル－２Ｈ－１，２，３－トリアゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000108
　（Ｒ）－１－メチル－３－（２－フェニル－２Ｈ－１，２，３－トリアゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア（０．０５９ｇ、０．１８ｍｍｏｌ）を酢酸エチル（３．６ｍＬ）に溶解し、塩化水素－酢酸エチル溶液（４．０Ｎ、０．０６８ｍＬ、０．２７ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．０５１ｇ（７９％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７４－１．８１（ｍ、１Ｈ）、１．８４－１．９１（ｍ、２Ｈ）、１．９７－２．０５（ｍ、１Ｈ）、２．２２－２．２３（ｍ、１Ｈ）、３．０６（ｓ、３Ｈ）、３．１７－３．３０（ｍ、４Ｈ）、３．３６－３．４３（ｍ、１Ｈ）、３．５８－３．６４（ｍ、１Ｈ）、４．４０（ｔ、Ｊ＝８．５Ｈｚ、１Ｈ）、７．３７（ｄｄ、Ｊ＝７．３、７．８Ｈｚ、１Ｈ）、７．５５（ｄｄ、Ｊ＝７．８、７．８Ｈｚ、１Ｈ）、７．９２（ｄｄ、Ｊ＝７．３、７．８Ｈｚ、１Ｈ）、８．０７（ｓ、１Ｈ）、９．８７（ｓ、１Ｈ）、１０．１５（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３２７［Ｍ＋Ｈ］＋． Example 41 Synthesis of (R) -1-methyl-3- (2-phenyl-2H-1,2,3-triazol-4-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000108
(R) -1-methyl-3- (2-phenyl-2H-1,2,3-triazol-4-yl) -1- (quinuclidin-3-yl) urea (0.059 g, 0.18 mmol) was added. Dissolved in ethyl acetate (3.6 mL), hydrogen chloride-ethyl acetate solution (4.0 N, 0.068 mL, 0.27 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.051 g (79%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.74-1.81 (m, 1H), 1.84-1.91 (m, 2H), 1.97-2.05 (m, 1H), 2.22-2.23 (m 1H), 3.06 (s, 3H), 3.17-3.30 (m, 4H), 3.36-3.43 (m, 1H), 3.58-3.64 (m, 1H) ), 4.40 (t, J = 8.5 Hz, 1H), 7.37 (dd, J = 7.3, 7.8 Hz, 1H), 7.55 (dd, J = 7.8, 7. 8Hz, 1H), 7.92 (dd, J = 7.3, 7.8Hz, 1H), 8.07 (s, 1H), 9.87 (s, 1H), 10.15 (brs, 1H) .
MS (ESI): 327 [M + H] < +>.
（参考例３５）　１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－カルボン酸エチルの合成：
Figure JPOXMLDOC01-appb-C000109
　１Ｈ－ピラゾール－４－カルボン酸エチル（０．５０ｇ、３．６ｍｍｏｌ）をジクロロメタンに溶解し、ピリジン－Ｎ－オキシド（０．３４ｇ、３．６ｍｍｏｌ）、ヘキサフルオロリン酸ブロモトリス（ピロリジノ）ホスホニウム（１．８ｇ、３．９ｍｍｏｌ）、ジイソプロピルエチルアミン（１．９ｍＬ、１０．７ｍｍｏｌ）を０℃で加えた。室温で４時間攪拌した後、飽和重曹水を０℃で加え、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝７０／３０）で精製し、表題化合物０．６０ｇ（７７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．３８（ｔ、Ｊ＝７．１Ｈｚ、３Ｈ）、４．３４（ｑ、Ｊ＝７．１Ｈｚ、２Ｈ）、７．２５－７．２６（ｍ、１Ｈ）、７．８３－７．８８（ｍ、１Ｈ）、８．００－８．０２（ｍ、１Ｈ）、８．１１（ｓ、１Ｈ）、８．４４－８．４６（ｍ、１Ｈ）、９．０４（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２１８［Ｍ＋Ｈ］＋． Reference Example 35 Synthesis of ethyl 1- (pyridin-2-yl) -1H-pyrazole-4-carboxylate:
Figure JPOXMLDOC01-appb-C000109
Dissolve ethyl 1H-pyrazole-4-carboxylate (0.50 g, 3.6 mmol) in dichloromethane, pyridine-N-oxide (0.34 g, 3.6 mmol), bromotris (pyrrolidino) phosphonium hexafluorophosphate (1 0.8 g, 3.9 mmol), diisopropylethylamine (1.9 mL, 10.7 mmol) were added at 0 ° C. After stirring at room temperature for 4 hours, saturated aqueous sodium hydrogen carbonate was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 70/30) to obtain 0.60 g (77%) of the title compound as a white solid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.38 (t, J = 7.1 Hz, 3H), 4.34 (q, J = 7.1 Hz, 2H), 7.25-7.26 (m, 1H), 7.83-7 .88 (m, 1H), 8.00-8.02 (m, 1H), 8.11 (s, 1H), 8.44-8.46 (m, 1H), 9.04 (s, 1H) ).
MS (ESI): 218 [M + H] < +>.
（参考例３６）　１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－カルボン酸の合成：
Figure JPOXMLDOC01-appb-C000110
　１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－カルボン酸エチル（０．２０ｇ、０．９２ｍｍｏｌ）を１，４－ジオキサン（２．８ｍＬ）に溶解し、１．０Ｎ水酸化ナトリウム水溶液（１．４ｍＬ、１．４ｍｍｏｌ）を０℃で加えた。室温で１２時間攪拌した後、Ｄｏｗｅｘ　５０ＷＸ２を０℃で加え、反応溶液をろ過した。ろ液を濃縮した後、表題化合物０．１８ｇ（定量的）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ:７．４２－７．４５８（ｍ、１Ｈ）、７．９６（ｄ、Ｊ＝８．３Ｈｚ、１Ｈ）、８．０３－８．０６（ｍ、１Ｈ）、８．０７（ｓ、１Ｈ）、８．５２－８．５３（ｍ、１Ｈ）、８．８９（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：１９０［Ｍ＋Ｈ］＋． Reference Example 36 Synthesis of 1- (pyridin-2-yl) -1H-pyrazole-4-carboxylic acid:
Figure JPOXMLDOC01-appb-C000110
Dissolve ethyl 1- (pyridin-2-yl) -1H-pyrazole-4-carboxylate (0.20 g, 0.92 mmol) in 1,4-dioxane (2.8 mL) and add 1.0 N aqueous sodium hydroxide solution. (1.4 mL, 1.4 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, Dowex 50WX2 was added at 0 ° C., and the reaction solution was filtered. After concentrating the filtrate, 0.18 g (quantitative) of the title compound was obtained as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 7.42-7.458 (m, 1H), 7.96 (d, J = 8.3 Hz, 1H), 8.03-8.06 (m, 1H), 8.07 (s, 1H) ), 8.52-8.53 (m, 1H), 8.89 (s, 1H).
MS (ESI): 190 [M + H] < +>.
（実施例４２）　（Ｒ）－１－メチル－３－（１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000111
　１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－カルボン酸（０．１７ｇ、０．９２ｍｍｏｌ）をジメチルホルミアミド（５．１ｍＬ）に溶解し、トリエチルアミン（０．１５ｍＬ、１．１ｍｍｏｌ）、ジフェニルホスホリルアジド（０．２１ｍＬ、１．０ｍｍｏｌ）を０℃で加えた。同温度で２時間攪拌した後、水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物を１，４－ジオキサン（２．６ｍＬ）に溶解し、８０℃で１２時間攪拌した。反応溶液を室温まで冷却し、１，４－ジオキサン（２．６ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１１ｇ、０．７７ｍｍｏｌ）を室温で滴下した。同温度で３０分攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をジエチルエーテルで洗浄した。水層に飽和重曹水を加えて塩基性にし、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（酢酸エチルのみ－酢酸エチル／メタノール＝９５／５）で精製し、表題化合物０．０７６ｇ（３１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５１－１．５４（ｍ、１Ｈ）、１．６２－１．６８（ｍ、１Ｈ）、１．７６－１．８３（ｍ、２Ｈ）、１．９６－１．９７（ｍ、１Ｈ）、２．８４－３．００（ｍ、５Ｈ）、３．１２（ｓ、３Ｈ）、３．２４－３．３０（ｍ、１Ｈ）、４．３６－４．３８（ｍ、１Ｈ）、６．３７（ｓ、１Ｈ）、７．１１－７．１５（ｍ、１Ｈ）、７．７４－７．７８（ｍ、２Ｈ）、７．９０（ｄ、Ｊ＝８．３Ｈｚ、１Ｈ）、８．３６－８．３８（ｍ、１Ｈ）、８．６８（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３２７［Ｍ＋Ｈ］＋． Example 42 Synthesis of (R) -1-methyl-3- (1- (pyridin-2-yl) -1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000111
1- (Pyridin-2-yl) -1H-pyrazole-4-carboxylic acid (0.17 g, 0.92 mmol) was dissolved in dimethylformamide (5.1 mL) and triethylamine (0.15 mL, 1.1 mmol) was dissolved. ), Diphenylphosphoryl azide (0.21 mL, 1.0 mmol) was added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in 1,4-dioxane (2.6 mL) and stirred at 80 ° C. for 12 hours. The reaction solution was cooled to room temperature, and (R) -N-methylquinuclidin-3-amine (0.11 g, 0.77 mmol) dissolved in 1,4-dioxane (2.6 mL) was added dropwise at room temperature. After stirring at the same temperature for 30 minutes, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (ethyl acetate only-ethyl acetate / methanol = 95/5) to give 0.076 g (31%) of the title compound as a white solid. Obtained.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.51-1.54 (m, 1H), 1.62-1.68 (m, 1H), 1.76-1.83 (m, 2H), 1.96-1.97 (m 1H), 2.84-3.00 (m, 5H), 3.12 (s, 3H), 3.24-3.30 (m, 1H), 4.36-4.38 (m, 1H) ), 6.37 (s, 1H), 7.11-7.15 (m, 1H), 7.74-7.78 (m, 2H), 7.90 (d, J = 8.3 Hz, 1H ), 8.36-8.38 (m, 1H), 8.68 (s, 1H).
MS (ESI): 327 [M + H] < +>.
（実施例４３）　（Ｒ）－１－メチル－３－（１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア　二塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000112
　（Ｒ）－１－メチル－３－（１－（ピリジン－２－イル）－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア（０．０７５ｇ、０．２３ｍｍｏｌ）を１，４－ジオキサン（４．６ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．１７ｍＬ、０．６９ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．０７５ｇ（８２％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７４－１．８１（ｍ、１Ｈ）、１．８５－１．９２（ｍ、２Ｈ）、１．９９－２．０６（ｍ、１Ｈ）、２．１９－２．２１（ｍ、１Ｈ）、３．０３（ｓ、３Ｈ）、３．１７－３．３０（ｍ、４Ｈ）、３．３７－３．４３（ｍ、１Ｈ）、３．５８－３．６５（ｍ、１Ｈ）、４．３６－４．４０（ｍ、１Ｈ）、７．２９（ｄｄｄ、Ｊ＝１．０、４．８、７．３Ｈｚ、１Ｈ）、７．８５（ｓ、１Ｈ）、７．８６（ｄ、Ｊ＝８．０Ｈｚ、１Ｈ）７．９４（ｄｄｄ、Ｊ＝２．０、７．３、８．０Ｈｚ、１Ｈ）、８．４３（ｄｄｄ、Ｊ＝１．０、２．０、４．８Ｈｚ、１Ｈ）、８．６４（ｓ、１Ｈ）、８．９５（ｓ、１Ｈ）、１０．１３（ｂｒｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３２７［Ｍ＋Ｈ］＋． Example 43 Synthesis of (R) -1-methyl-3- (1- (pyridin-2-yl) -1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea dihydrochloride :
Figure JPOXMLDOC01-appb-C000112
(R) -1-methyl-3- (1- (pyridin-2-yl) -1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea (0.075 g, 0.23 mmol) Dissolved in 1,4-dioxane (4.6 mL), hydrogen chloride-1,4-dioxane solution (4.0 N, 0.17 mL, 0.69 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.075 g (82%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.74-1.81 (m, 1H), 1.85-1.92 (m, 2H), 1.99-2.06 (m, 1H), 2.19-2.21 (m 1H), 3.03 (s, 3H), 3.17-3.30 (m, 4H), 3.37-3.43 (m, 1H), 3.58-3.65 (m, 1H) ) 4.36-4.40 (m, 1H), 7.29 (ddd, J = 1.0, 4.8, 7.3 Hz, 1H), 7.85 (s, 1H), 7.86 (D, J = 8.0 Hz, 1H) 7.94 (ddd, J = 2.0, 7.3, 8.0 Hz, 1H), 8.43 (ddd, J = 1.0, 2.0, 4.8 Hz, 1H), 8.64 (s, 1H), 8.95 (s, 1H), 10.13 (brs, 1H).
MS (ESI): 327 [M + H] < +>.
（参考例３７）　１－（チオフェン－２－イル）－１Ｈ－ピラゾール－４－カルボン酸エチルの合成：
Figure JPOXMLDOC01-appb-C000113
　１Ｈ－ピラゾール－４－カルボン酸エチル（１．０ｇ、７．１ｍｍｏｌ）を１，４－ジオキサン（７．１ｍＬ）に溶解し、ヨウ化銅（Ｉ）（０．２７ｇ、１．４ｍｍｏｌ）、炭酸カリウム（１．５ｇ、１１ｍｍｏｌ）、２－ヨードチオフェン（０．８７ｍＬ、８．６ｍｍｏｌ）、Ｎ，Ｎ‘－ジメチルエチレンジアミン（０．６１ｍＬ、５．７ｍｍｏｌ）を室温で加えた。１００℃で２４時間攪拌した後、１．０Ｎ塩酸を０℃で加え、水層を酢酸エチルで抽出した。有機層を１．０Ｎ塩酸、飽和重曹水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をシリカゲルクロマトグラフィー（ヘキサンのみ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物０．５６ｇ（３６％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．３７（ｔ、Ｊ＝７．１Ｈｚ、３Ｈ）、４．３４（ｑ、Ｊ＝７．１Ｈｚ、２Ｈ）、６．９６－６．９９（ｍ、１Ｈ）、７．１１－７．１２（ｍ、２Ｈ）、８．０５（ｓ、１Ｈ）、８．２８（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：２２３［Ｍ＋Ｈ］＋． Reference Example 37 Synthesis of ethyl 1- (thiophen-2-yl) -1H-pyrazole-4-carboxylate:
Figure JPOXMLDOC01-appb-C000113
Ethyl 1H-pyrazole-4-carboxylate (1.0 g, 7.1 mmol) is dissolved in 1,4-dioxane (7.1 mL), and copper (I) iodide (0.27 g, 1.4 mmol) is added to carbonic acid. Potassium (1.5 g, 11 mmol), 2-iodothiophene (0.87 mL, 8.6 mmol), N, N′-dimethylethylenediamine (0.61 mL, 5.7 mmol) were added at room temperature. After stirring at 100 ° C. for 24 hours, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with 1.0N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by silica gel chromatography (hexane only-hexane / ethyl acetate = 80/20) to give 0.56 g (36%) of the title compound as a white solid. .
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.37 (t, J = 7.1 Hz, 3H), 4.34 (q, J = 7.1 Hz, 2H), 6.96-6.99 (m, 1H), 7.11-7 .12 (m, 2H), 8.05 (s, 1H), 8.28 (s, 1H).
MS (ESI): 223 [M + H] < +>.
（実施例４４）　（Ｒ）－１－メチル－３－（１－（チオフェン－２－イル）－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000114
　１－（チオフェン－２－イル）－１Ｈ－ピラゾール－４－カルボン酸エチル（０．３０ｇ、１．４ｍｍｏｌ）を１，４－ジオキサン（５．４ｍＬ）に溶解し、１．０Ｎ水酸化ナトリウム水溶液（２．７ｍＬ、２．７ｍｍｏｌ）を０℃で加えた。室温で６時間攪拌した後、１．０Ｎ塩酸を０℃で加え、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物をジメチルホルミアミド（４．５ｍＬ）に溶解し、トリエチルアミン（０．２２ｍＬ、１．６ｍｍｏｌ）、ジフェニルホスホリルアジド（０．３２ｍＬ、１．５ｍｍｏｌ）を０℃で加えた。同温度で２時間攪拌した後、水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物を１，４－ジオキサン（４．５ｍＬ）に溶解し、８０℃で１２時間攪拌した。反応溶液を室温まで冷却し、１，４－ジオキサン（４．５ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１３ｇ、０．８９ｍｍｏｌ）を室温で滴下した。同温度で３０分攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をジエチルエーテルで洗浄した。水層に飽和重曹水を加えて塩基性にし、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（酢酸エチルのみ－酢酸エチル／メタノール＝９５／５）で精製し、表題化合物０．０７６ｇ（６８％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０－１．５５（ｍ、１Ｈ）、１．６２－１．８０（ｍ、３Ｈ）、１．９４－１．９６（ｍ、１Ｈ）、２．８３－２．９９（ｍ、５Ｈ）、３．１１（ｓ、３Ｈ）、３．２２－３．２９（ｍ、１Ｈ）、４．３３－４．３８（ｍ、１Ｈ）、６．３２（ｓ、１Ｈ）、６．９０－６．９３（ｍ、１Ｈ）、６．９６－６．９９（ｍ、１Ｈ）、７．５３（ｓ、１Ｈ）、８．２４（ｓ、１Ｈ）．
ＭＳ（ＥＳＩ）：３３２［Ｍ＋Ｈ］＋． Example 44 Synthesis of (R) -1-methyl-3- (1- (thiophen-2-yl) -1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000114
Dissolve ethyl 1- (thiophen-2-yl) -1H-pyrazole-4-carboxylate (0.30 g, 1.4 mmol) in 1,4-dioxane (5.4 mL) and add 1.0 N aqueous sodium hydroxide solution. (2.7 mL, 2.7 mmol) was added at 0 ° C. After stirring at room temperature for 6 hours, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in dimethylformamide (4.5 mL), and triethylamine (0.22 mL, 1.6 mmol) and diphenylphosphoryl azide (0.32 mL, 1.5 mmol) were added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in 1,4-dioxane (4.5 mL) and stirred at 80 ° C. for 12 hours. The reaction solution was cooled to room temperature, and (R) -N-methylquinuclidin-3-amine (0.13 g, 0.89 mmol) dissolved in 1,4-dioxane (4.5 mL) was added dropwise at room temperature. After stirring at the same temperature for 30 minutes, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the resulting crude product was purified by amine silica gel chromatography (ethyl acetate only-ethyl acetate / methanol = 95/5) to give 0.076 g (68%) of the title compound as a white solid. Obtained.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.55 (m, 1H), 1.62-1.80 (m, 3H), 1.94-1.96 (m, 1H), 2.83-2.99 (m 5H), 3.11 (s, 3H), 3.22-3.29 (m, 1H), 4.33-4.38 (m, 1H), 6.32 (s, 1H), 6. 90-6.93 (m, 1H), 6.96-6.99 (m, 1H), 7.53 (s, 1H), 8.24 (s, 1H).
MS (ESI): 332 [M + H] < +>.
（実施例４５）　（Ｒ）－１－メチル－３－（１－（チオフェン－２－イル）－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000115
　（Ｒ）－１－メチル－３－（１－（チオフェン－２－イル）－１Ｈ－ピラゾール－４－イル）－１－（キヌクリジン－３－イル）ウレア（０．２０ｇ、０．６０ｍｍｏｌ）を１，４－ジオキサン（１２ｍＬ）に溶解し、塩化水素－１，４－ジオキサン溶液（４．０Ｎ、０．２３ｍＬ、０．９１ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１９ｇ（９７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７４－１．８０（ｍ、１Ｈ）、１．８４－１．９０（ｍ、２Ｈ）、１．９７－２．０１（ｍ、１Ｈ）、２．２１－２．１９（ｍ、１Ｈ）、３．０１（ｓ、３Ｈ）、３．１９－３．３０（ｍ、４Ｈ）、３．３７－３．４３（ｍ、１Ｈ）、３．５８－３．６４（ｍ、１Ｈ）、４．３５－４．３９（ｍ、１Ｈ）、６．９８（ｄｄ、Ｊ＝３．８、５．２Ｈｚ、１Ｈ）、７．２０－７．２２（ｍ、２Ｈ）、７．６７（ｓ、１Ｈ）、８．２７（ｓ、１Ｈ）、８．８７（ｓ、１Ｈ）、９．８６（ｂｒｓ、１Ｈ）
ＭＳ（ＥＳＩ）：３３２［Ｍ＋Ｈ］＋． Example 45 Synthesis of (R) -1-methyl-3- (1- (thiophen-2-yl) -1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000115
(R) -1-Methyl-3- (1- (thiophen-2-yl) -1H-pyrazol-4-yl) -1- (quinuclidin-3-yl) urea (0.20 g, 0.60 mmol) Dissolved in 1,4-dioxane (12 mL), hydrogen chloride-1,4-dioxane solution (4.0 N, 0.23 mL, 0.91 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.19 g (97%) of the title compound as a white solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.74-1.80 (m, 1H), 1.84-1.90 (m, 2H), 1.97-2.01 (m, 1H), 2.21-2.19 (m 1H), 3.01 (s, 3H), 3.19-3.30 (m, 4H), 3.37-3.43 (m, 1H), 3.58-3.64 (m, 1H) ), 4.35-4.39 (m, 1H), 6.98 (dd, J = 3.8, 5.2 Hz, 1H), 7.20-7.22 (m, 2H), 7.67 (S, 1H), 8.27 (s, 1H), 8.87 (s, 1H), 9.86 (brs, 1H)
MS (ESI): 332 [M + H] < +>.
（実施例４６）　（Ｒ）－３－（６－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000116
　６－フルオロベンゾチオフェンー２－カルボン酸（０．２５ｇ、１．３ｍｍｏｌ）をジメチルホルミアミド（４．３ｍＬ）に溶解し、トリエチルアミン（０．２２ｍＬ、１．５ｍｍｏｌ）、ジフェニルホスホリルアジド（０．３０ｍＬ、１．４ｍｍｏｌ）を０℃で加えた。同温度で２時間攪拌した後、水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物を１，４－ジオキサン（４．３ｍＬ）に溶解し、８０℃で１２時間攪拌した。反応溶液を室温まで冷却し、１，４－ジオキサン（４．３ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１２ｇ、０．８６ｍｍｏｌ）を室温で滴下した。同温度で１時間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をジエチルエーテルで洗浄した。水層に飽和重曹水を加えて塩基性にし、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（酢酸エチルのみ－酢酸エチル／メタノール＝９５／５）で精製し、表題化合物０．１６ｇ（５５％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５３－１．８０（ｍ、４Ｈ）、１．９８－２．００（ｍ、１Ｈ）、２．８１－２．９９（ｍ、５Ｈ）、３．１６（ｓ、３Ｈ）、３．２４－３．３０（ｍ、１Ｈ）、４．３７－４．４１（ｍ、１Ｈ）、６．７０（ｓ、１Ｈ）、７．００－７．１０（ｍ、１Ｈ）、７．１０（ｂｒｓ、１Ｈ）、７．４１（ｄｄ、Ｊ＝２．２、８．７Ｈｚ、１Ｈ）、７．４７（ｄｄ、Ｊ＝５．１、８．７Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 46 Synthesis of (R) -3- (6-Fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000116
6-Fluorobenzothiophene-2-carboxylic acid (0.25 g, 1.3 mmol) is dissolved in dimethylformamide (4.3 mL), triethylamine (0.22 mL, 1.5 mmol), diphenylphosphoryl azide (0. 30 mL, 1.4 mmol) was added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in 1,4-dioxane (4.3 mL) and stirred at 80 ° C. for 12 hours. The reaction solution was cooled to room temperature, and (R) -N-methylquinuclidin-3-amine (0.12 g, 0.86 mmol) dissolved in 1,4-dioxane (4.3 mL) was added dropwise at room temperature. After stirring at the same temperature for 1 hour, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by amine silica gel chromatography (ethyl acetate only-ethyl acetate / methanol = 95/5) to give 0.16 g (55%) of the title compound as a pale yellow solid. Got as.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.53-1.80 (m, 4H), 1.98-2.00 (m, 1H), 2.81-2.99 (m, 5H), 3.16 (s, 3H), 3.24-3.30 (m, 1H), 4.37-4.41 (m, 1H), 6.70 (s, 1H), 7.00-7.10 (m, 1H), 7. 10 (brs, 1H), 7.41 (dd, J = 2.2, 8.7 Hz, 1H), 7.47 (dd, J = 5.1, 8.7 Hz, 1H).
MS (ESI): 334 [M + H] < +>.
（実施例４７）　（Ｒ）－３－（６－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000117
　（Ｒ）－３－（６－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．１５ｇ、０．４５ｍｍｏｌ）を酢酸エチル（９．０ｍＬ）に溶解し、塩化水素－酢酸エチル溶液（４．０Ｎ、０．１７ｍＬ、０．６８ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１４ｇ（８４％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７５－１．８１（ｍ、１Ｈ）、１．８５－１．９３（ｍ、２Ｈ）、１．９９－２．０６（ｍ、１Ｈ）、２．２２－２．２４（ｍ、１Ｈ）、３．０８（ｓ、３Ｈ）、３．１４－３．３１（ｍ、４Ｈ）、３．３５－３．４４（ｍ、１Ｈ）、３．６０－３．６６（ｍ、１Ｈ）、４．４０－４．４５（ｍ、１Ｈ）、６．９６（ｓ、１Ｈ）、７．１１（ｄｄ、Ｊ＝８．８、５．１Ｈｚ、１Ｈ）、７．６０（ｄｄｄ、Ｊ＝９．４、８．８、２．６Ｈｚ、１Ｈ）、７．６５（ｄｄ、Ｊ＝９．４、２，６Ｈｚ、１Ｈ）、１０．０９（ｂｒｓ、２Ｈ）． 
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 47 Synthesis of (R) -3- (6-Fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000117
(R) -3- (6-Fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.15 g, 0.45 mmol) was added to ethyl acetate (9. 0 mL) and a hydrogen chloride-ethyl acetate solution (4.0 N, 0.17 mL, 0.68 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.14 g (84%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.75-1.81 (m, 1H), 1.85-1.93 (m, 2H), 1.99-2.06 (m, 1H), 2.22-2.24 (m 1H), 3.08 (s, 3H), 3.14-3.31 (m, 4H), 3.35-3.44 (m, 1H), 3.60-3.66 (m, 1H) ), 4.40-4.45 (m, 1H), 6.96 (s, 1H), 7.11 (dd, J = 8.8, 5.1 Hz, 1H), 7.60 (ddd, J = 9.4, 8.8, 2.6 Hz, 1H), 7.65 (dd, J = 9.4, 2, 6 Hz, 1H), 10.09 (brs, 2H).
MS (ESI): 334 [M + H] < +>.
（実施例４８）　（Ｒ）－３－（５－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000118
　５－フルオロベンゾチオフェンー２－カルボン酸（０．２５ｇ、１．３ｍｍｏｌ）をジメチルホルミアミド（４．３ｍＬ）に溶解し、トリエチルアミン（０．２２ｍＬ、１．５ｍｍｏｌ）、ジフェニルホスホリルアジド（０．３０ｍＬ、１．４ｍｍｏｌ）を０℃で加えた。同温度で２時間攪拌した後、水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物を１，４－ジオキサン（４．３ｍＬ）に溶解し、８０℃で１２時間攪拌した。反応溶液を室温まで冷却し、１，４－ジオキサン（４．３ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１２ｇ、０．８６ｍｍｏｌ）を室温で滴下した。同温度で１時間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をジエチルエーテルで洗浄した。水層に飽和重曹水を加えて塩基性にし、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（酢酸エチルのみ－酢酸エチル／メタノール＝９５／５）で精製し、表題化合物０．１５ｇ（５１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０－１．７６（ｍ、４Ｈ）、１．９８－２．００（ｍ、１Ｈ）、２．８１－２．９９（ｍ、５Ｈ）、３．１６（ｓ、３Ｈ）、３．２４－３．３０（ｍ、１Ｈ）、４．３７－４．４１（ｍ、１Ｈ）、６．６９（ｓ、１Ｈ）、６．９１－６．９６（ｍ、１Ｈ）、７．１９－７．２２（ｍ、２Ｈ）、７．６０－７．６３（ｍ、１Ｈ）．
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 48 Synthesis of (R) -3- (5-fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000118
5-Fluorobenzothiophene-2-carboxylic acid (0.25 g, 1.3 mmol) is dissolved in dimethylformamide (4.3 mL), triethylamine (0.22 mL, 1.5 mmol), diphenylphosphoryl azide (0. 30 mL, 1.4 mmol) was added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in 1,4-dioxane (4.3 mL) and stirred at 80 ° C. for 12 hours. The reaction solution was cooled to room temperature, and (R) -N-methylquinuclidin-3-amine (0.12 g, 0.86 mmol) dissolved in 1,4-dioxane (4.3 mL) was added dropwise at room temperature. After stirring at the same temperature for 1 hour, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by amine silica gel chromatography (ethyl acetate only-ethyl acetate / methanol = 95/5) to give 0.15 g (51%) of the title compound as a pale yellow solid. Got as.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.76 (m, 4H), 1.98-2.00 (m, 1H), 2.81-2.99 (m, 5H), 3.16 (s, 3H), 3.24-3.30 (m, 1H), 4.37-4.41 (m, 1H), 6.69 (s, 1H), 6.91-6.96 (m, 1H), 7. 19-7.22 (m, 2H), 7.60-7.63 (m, 1H).
MS (ESI): 334 [M + H] < +>.
（実施例４９）　（Ｒ）－３－（５－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000119
　（Ｒ）－３－（５－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．１４ｇ、０．４２ｍｍｏｌ）を酢酸エチル（８．４ｍＬ）に溶解し、塩化水素－酢酸エチル溶液（４．０Ｎ、０．１６ｍＬ、０．６３ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．１４ｇ（８７％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７５－１．８１（ｍ、１Ｈ）、１．８５－１．９３（ｍ、２Ｈ）、１．９８－２．０５（ｍ、１Ｈ）、２．２２－２．２４（ｍ、１Ｈ）、３．０８（ｓ、３Ｈ）、３．１７－３．３１（ｍ、４Ｈ）、３．３７－３．４４（ｍ、１Ｈ）、３．６０－３．６６（ｍ、１Ｈ）、４．４１－４．４５（ｍ、１Ｈ）、６．９７（ｓ、１Ｈ）、６．９７（ｄｄｄ、Ｊ＝２．６、８．５、９．０Ｈｚ、１Ｈ）、７．４１（ｄｄ、Ｊ＝２．６、１０．４Ｈｚ、１Ｈ）、７．７５（ｄｄ、Ｊ＝５．１、８．５Ｈｚ、１Ｈ）、１０．１９（ｂｒｓ、２Ｈ）．
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 49 Synthesis of (R) -3- (5-fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000119
(R) -3- (5-Fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.14 g, 0.42 mmol) was added to ethyl acetate (8. 4 mL), and a hydrogen chloride-ethyl acetate solution (4.0 N, 0.16 mL, 0.63 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, filtration was performed, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.14 g (87%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.75-1.81 (m, 1H), 1.85-1.93 (m, 2H), 1.98-2.05 (m, 1H), 2.22-2.24 (m 1H), 3.08 (s, 3H), 3.17-3.31 (m, 4H), 3.37-3.44 (m, 1H), 3.60-3.66 (m, 1H) ), 4.41-4.45 (m, 1H), 6.97 (s, 1H), 6.97 (ddd, J = 2.6, 8.5, 9.0 Hz, 1H), 7.41 (Dd, J = 2.6, 10.4 Hz, 1H), 7.75 (dd, J = 5.1, 8.5 Hz, 1H), 10.19 (brs, 2H).
MS (ESI): 334 [M + H] < +>.
（実施例５０）　（Ｒ）－３－（４－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレアの合成：
Figure JPOXMLDOC01-appb-C000120
　４－フルオロベンゾチオフェンー２－カルボン酸（０．２５ｇ、１．３ｍｍｏｌ）をジメチルホルミアミド（４．３ｍＬ）に溶解し、トリエチルアミン（０．２２ｍＬ、１．５ｍｍｏｌ）、ジフェニルホスホリルアジド（０．３０ｍＬ、１．４ｍｍｏｌ）を０℃で加えた。同温度で２時間攪拌した後、水を０℃で加えて、水層をジエチルエーテルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物を精製することなく、続く反応に用いた。
　上記の祖生成物を１，４－ジオキサン（４．３ｍＬ）に溶解し、８０℃で１２時間攪拌した。反応溶液を室温まで冷却し、１，４－ジオキサン（４．３ｍＬ）に溶解した（Ｒ）－Ｎ－メチルキヌクリジン－３－アミン（０．１２ｇ、０．８６ｍｍｏｌ）を室温で滴下した。同温度で１時間攪拌した後、１．０Ｎ塩酸を０℃で加えて、水層をジエチルエーテルで洗浄した。水層に飽和重曹水を加えて塩基性にし、水層をクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧濃縮した後、得られた粗生成物をアミンシリカゲルクロマトグラフィー（酢酸エチルのみ－酢酸エチル／メタノール＝９５／５）で精製し、表題化合物０．１５ｇ（５１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ３）
δ:１．５０－１．５６（ｍ、１Ｈ）、１．６６－１．８１（ｍ、３Ｈ）、１．９８－２．００（ｍ、１Ｈ）、２．８３－２．９９（ｍ、５Ｈ）、３．１７（ｓ、３Ｈ）、３．２４－３．３０（ｍ、１Ｈ）、４．３７－４．４１（ｍ、１Ｈ）、６．８１（ｓ、１Ｈ）、６．９３－６．９８（ｍ、１Ｈ）、７．１０－７．１５（ｍ、１Ｈ）、７．４８（ｄ、Ｊ＝７．８Ｈｚ、１Ｈ）．
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 50 Synthesis of (R) -3- (4-fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea:
Figure JPOXMLDOC01-appb-C000120
4-Fluorobenzothiophene-2-carboxylic acid (0.25 g, 1.3 mmol) was dissolved in dimethylformamide (4.3 mL), triethylamine (0.22 mL, 1.5 mmol), diphenylphosphoryl azide (0. 30 mL, 1.4 mmol) was added at 0 ° C. After stirring at the same temperature for 2 hours, water was added at 0 ° C., and the aqueous layer was extracted with diethyl ether. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. After the filtrate was concentrated under reduced pressure, the obtained crude product was used in the subsequent reaction without purification.
The above parent product was dissolved in 1,4-dioxane (4.3 mL) and stirred at 80 ° C. for 12 hours. The reaction solution was cooled to room temperature, and (R) -N-methylquinuclidin-3-amine (0.12 g, 0.86 mmol) dissolved in 1,4-dioxane (4.3 mL) was added dropwise at room temperature. After stirring at the same temperature for 1 hour, 1.0N hydrochloric acid was added at 0 ° C., and the aqueous layer was washed with diethyl ether. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by amine silica gel chromatography (ethyl acetate only-ethyl acetate / methanol = 95/5) to give 0.15 g (51%) of the title compound as a pale yellow solid. Got as.
1 H-NMR (400 MHz, CDCl 3 )
δ: 1.50-1.56 (m, 1H), 1.66-1.81 (m, 3H), 1.98-2.00 (m, 1H), 2.83-2.99 (m 5H), 3.17 (s, 3H), 3.24-3.30 (m, 1H), 4.37-4.41 (m, 1H), 6.81 (s, 1H), 6. 93-6.98 (m, 1H), 7.10-7.15 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H).
MS (ESI): 334 [M + H] < +>.
（実施例５１）　（Ｒ）－３－（４－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000121
　（Ｒ）－３－（４－フルオロベンゾ［ｂ］チオフェン－２－イル）－１－メチル－１－（キヌクリジン－３－イル）ウレア（０．１４ｇ、０．４２ｍｍｏｌ）を酢酸エチル（８．４ｍＬ）に溶解し、塩化水素－酢酸エチル溶液（４．０Ｎ、０．１６ｍＬ、０．６３ｍｍｏｌ）を０℃で加えた。同温度で３０分間攪拌した後、ろ過し、ろ取した固体をヘキサン、酢酸エチルで洗浄後に乾燥し、表題化合物０．０９４ｇ（６１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ、ＤＭＳＯ－ｄ６）
δ: １．７５－１．８１（ｍ、１Ｈ）、１．８５－１．９４（ｍ、２Ｈ）、１．９７－２．０６（ｍ、１Ｈ）、２．２２－２．２４（ｍ、１Ｈ）、３．０９（ｓ、３Ｈ）、３．１５－３．３０（ｍ、４Ｈ）、３．３８－３．４５（ｍ、１Ｈ）、３．６１－３．６７（ｍ、１Ｈ）、４．４２－４．４７（ｍ、１Ｈ）、７．０２（ｓ、１Ｈ）、７．０７（ｄｄｄ、Ｊ＝０．６、８．０、１０．６Ｈｚ、１Ｈ）、７．１５（ｄｄｄ、Ｊ＝５．１、７．８、８．０Ｈｚ、１Ｈ）、７．６０（ｄ、Ｊ＝７．８Ｈｚ、１Ｈ）、１０．０６（ｂｒｓ、１Ｈ）、１０．２４（ｓ、１Ｈ）． 
ＭＳ（ＥＳＩ）：３３４［Ｍ＋Ｈ］＋． Example 51 Synthesis of (R) -3- (4-fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea hydrochloride:
Figure JPOXMLDOC01-appb-C000121
(R) -3- (4-Fluorobenzo [b] thiophen-2-yl) -1-methyl-1- (quinuclidin-3-yl) urea (0.14 g, 0.42 mmol) was added to ethyl acetate (8. 4 mL), and a hydrogen chloride-ethyl acetate solution (4.0 N, 0.16 mL, 0.63 mmol) was added at 0 ° C. After stirring at the same temperature for 30 minutes, the mixture was filtered, and the collected solid was washed with hexane and ethyl acetate and then dried to obtain 0.094 g (61%) of the title compound as a pale yellow solid.
1 H-NMR (400 MHz, DMSO-d 6 )
δ: 1.75-1.81 (m, 1H), 1.85-1.94 (m, 2H), 1.97-2.06 (m, 1H), 2.22-2.24 (m 1H), 3.09 (s, 3H), 3.15-3.30 (m, 4H), 3.38-3.45 (m, 1H), 3.61-3.67 (m, 1H) 4.42-4.47 (m, 1H), 7.02 (s, 1H), 7.07 (ddd, J = 0.6, 8.0, 10.6 Hz, 1H), 7.15 (Ddd, J = 5.1, 7.8, 8.0 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 10.06 (brs, 1H), 10.24 (s, 1H).
MS (ESI): 334 [M + H] < +>.
　本発明のキヌクリジンウレア誘導体又はその薬理学的に許容される塩は、強力な中枢型ニコチン性アセチルコリン受容体活性化作用を有するため、中枢型ニコチン性アセチルコリン受容体の活性化によって病態の改善又は症状の寛解が期待される疾患に対する医薬として利用でき、さらに、当該作用メカニズムに基づき止痒効果を発揮するため、止痒剤として利用できる。 Since the quinuclidine urea derivative of the present invention or a pharmacologically acceptable salt thereof has a strong central nicotinic acetylcholine receptor activation action, the pathological condition is improved by activating the central nicotinic acetylcholine receptor. Alternatively, it can be used as a medicine for a disease for which symptom remission is expected, and further, it exhibits an antipruritic effect based on the mechanism of action, so that it can be used as an antidiarrheal agent.

Claims (7)

  1. 　以下の一般式（Ｉ）で示されるキヌクリジンウレア誘導体又はその薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ｒ１は、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基又は炭素数３～６のシクロアルキル基を表し、
    　Ｒ２は、水素原子、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基若しくは炭素数３～６のシクロアルキル基、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基を表し、
    　Ｒ３は、水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基を表し、
    　Ｒ４は、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～６のアルキルオキシ基を表し、
    　Ｒ５は、ハロゲン原子、ヒドロキシル基、ニトリル基、水素原子が１～６個のハロゲン原子で置換されていてもよい炭素数１～６のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～６のアルキルオキシ基、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基を表す。］     A quinuclidine urea derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, in which a hydrogen atom may be substituted with 1 to 6 halogen atoms,
    R 2 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which the hydrogen atom may be substituted with 1 to 6 halogen atoms, or a hydrogen atom represented by R 4 An aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms which may be substituted with
    R 3 represents an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R 5 ;
    R 4 represents a halogen atom, a hydroxyl group, a nitrile group, or an alkyl group having 1 to 6 carbon atoms and a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 6 halogen atoms. Or an alkyloxy group having 1 to 6 carbon atoms,
    R 5 represents a halogen atom, a hydroxyl group, a nitrile group, a hydrogen atom in which a hydrogen atom may be substituted with 1 to 6 halogen atoms, a cycloalkyl group having 3 to 6 carbon atoms, or carbon It represents an alkyloxy group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R 4 . ]
  2. 　Ｒ１は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基又は炭素数３～６のシクロアルキル基であり、
    　Ｒ２は、水素原子、又は、水素原子がＲ４で置換されていてもよい炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基であり、
    　Ｒ３は、水素原子がＲ５で置換されていてもよい炭素数６～１０のアリール基又は環構成原子数５～１０のヘテロアリール基であり、
    　Ｒ４は、ハロゲン原子、ヒドロキシル基、ニトリル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基若しくは炭素数１～４のアルキルオキシ基であり、
    　Ｒ５は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、炭素数６～１０のアリール基若しくは環構成原子数５～１０のヘテロアリール基である、請求項１記載のキヌクリジンウレア誘導体又はその薬理学的に許容される塩。     R 1 is an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms,
    R 2 is a hydrogen atom, an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which the hydrogen atom may be substituted with R 4 ;
    R 3 is an aryl group having 6 to 10 carbon atoms or a heteroaryl group having 5 to 10 ring atoms in which a hydrogen atom may be substituted with R 5 ;
    R 4 represents a halogen atom, a hydroxyl group, a nitrile group, or an alkyl group having 1 to 4 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms, in which a hydrogen atom may be substituted with 1 to 3 halogen atoms. Or an alkyloxy group having 1 to 4 carbon atoms,
    R 5 represents a halogen atom, a hydroxyl group, a C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a carbon number in which a hydrogen atom may be substituted with 1 to 3 halogen atoms. The quinuclidine urea derivative according to claim 1 or a pharmacologically acceptable one thereof, which is an alkyloxy group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, or a heteroaryl group having 5 to 10 ring atoms. salt.
  3. 　Ｒ１は、メチル基又はエチル基であり、
    　Ｒ２は、水素原子であり、
    　Ｒ３は、水素原子がＲ５で置換されていてもよいフェニル基、ナフチル基、ピリジル基、キノリル基、イソキノリル基、フリル基、チエニル基、オキサゾリル基、イソオキサゾリル基、チアゾリル基、イソチアゾリル基、ピラゾリル基、イミダゾリル基、トリアゾリル基、ベンゾフリル基、フロピリジル基、ベンゾチエニル基、チエノピリジル基、ベンゾオキサゾリル基、オキサゾロピリジル基、ベンゾチアゾリル基又はチアゾロピリジル基であり、
    　Ｒ５は、ハロゲン原子、ヒドロキシル基、又は、水素原子が１～３個のハロゲン原子で置換されていてもよい炭素数１～４のアルキル基、炭素数３～６のシクロアルキル基、炭素数１～４のアルキルオキシ基、フェニル基又はピリジル基である、請求項１記載のキヌクリジンウレア誘導体又はその薬理学的に許容される塩。     R 1 is a methyl group or an ethyl group,
    R 2 is a hydrogen atom,
    R 3 represents a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group, an isoquinolyl group, a furyl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a pyrazolyl group in which a hydrogen atom may be substituted with R 5 Group, imidazolyl group, triazolyl group, benzofuryl group, furopyridyl group, benzothienyl group, thienopyridyl group, benzoxazolyl group, oxazolopyridyl group, benzothiazolyl group or thiazolopyridyl group,
    R 5 represents a halogen atom, a hydroxyl group, a C 1-4 alkyl group, a C 3-6 cycloalkyl group, or a carbon number in which a hydrogen atom may be substituted with 1 to 3 halogen atoms. The quinuclidine urea derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is an alkyloxy group, a phenyl group or a pyridyl group having 1 to 4 alkyl groups.
  4. 　請求項１～３いずれか一項記載のキヌクリジンウレア誘導体又はその薬理学的に許容される塩を有効成分として含有する、医薬。 A pharmaceutical comprising the quinuclidine urea derivative according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.
  5. 　請求項１～３いずれか一項記載のキヌクリジンウレア誘導体又はその薬理学的に許容される塩を有効成分として含有する、中枢型ニコチン性アセチルコリン受容体活性化剤。 A central nicotinic acetylcholine receptor activator comprising the quinuclidine urea derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.
  6. 　中枢型ニコチン性アセチルコリン受容体は、α７サブタイプである、請求項５記載の中枢型ニコチン性アセチルコリン受容体活性化剤。 6. The central nicotinic acetylcholine receptor activator according to claim 5, wherein the central nicotinic acetylcholine receptor is α7 subtype.
  7. 　請求項１～３いずれか一項記載のキヌクリジンウレア誘導体又はその薬理学的に許容される塩を有効成分として含有する、止痒剤。 An antidiarrheal agent containing the quinuclidine urea derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 3 as an active ingredient.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105601629A (en) * 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride
US10611734B2 (en) 2015-02-24 2020-04-07 Bayer Cropscience Aktiengesellschaft Process for the preparation of triazoles

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012254A1 (en) * 1990-02-16 1991-08-22 Novo Nordisk A/S Substituted urea compounds and their preparation and use
JPH0881374A (en) * 1994-07-13 1996-03-26 Yoshitomi Pharmaceut Ind Ltd Skin pruritus preventive/therapeutic agent
WO2004069141A2 (en) * 2003-02-05 2004-08-19 Strakan Limited Transdermal granisetron
WO2004076449A2 (en) * 2003-02-21 2004-09-10 Targacept, Inc. 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof
WO2008019372A2 (en) * 2006-08-07 2008-02-14 Albany Molecular Research, Inc. 2-aminobenzoxazole carboxamides as 5ht3 modulators
WO2008096870A1 (en) * 2007-02-09 2008-08-14 Astellas Pharma Inc. Aza-bridged-ring compound

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991012254A1 (en) * 1990-02-16 1991-08-22 Novo Nordisk A/S Substituted urea compounds and their preparation and use
JPH0881374A (en) * 1994-07-13 1996-03-26 Yoshitomi Pharmaceut Ind Ltd Skin pruritus preventive/therapeutic agent
WO2004069141A2 (en) * 2003-02-05 2004-08-19 Strakan Limited Transdermal granisetron
WO2004076449A2 (en) * 2003-02-21 2004-09-10 Targacept, Inc. 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof
WO2008019372A2 (en) * 2006-08-07 2008-02-14 Albany Molecular Research, Inc. 2-aminobenzoxazole carboxamides as 5ht3 modulators
WO2008096870A1 (en) * 2007-02-09 2008-08-14 Astellas Pharma Inc. Aza-bridged-ring compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DE KLOE, GERDIEN E. ET AL.: "Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor a7 Ligands", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 19, 2010, pages 7192 - 7201 *
H. SCHWORER ET AL.: "Improvement of cholestatic pruritus by ondansetron", LANCET, vol. 341, no. 8855, 1993, pages 1277 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105601629A (en) * 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride
US10611734B2 (en) 2015-02-24 2020-04-07 Bayer Cropscience Aktiengesellschaft Process for the preparation of triazoles

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