WO2014051055A1 - キヌクリジンウレア誘導体及びその医薬用途 - Google Patents

キヌクリジンウレア誘導体及びその医薬用途 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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hydrogen atom
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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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Publication number Priority date Publication date Assignee Title
CN105601629A (zh) * 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 (R)-7-氯-N-(奎宁环-3-基)苯并[b]噻吩-2-甲酰胺的盐酸盐的新晶型
US10611734B2 (en) 2015-02-24 2020-04-07 Bayer Cropscience Aktiengesellschaft Process for the preparation of triazoles

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