WO2013065712A1 - Dérivé de diazaspiro urea, et application pharmaceutique de celui-ci - Google Patents

Dérivé de diazaspiro urea, et application pharmaceutique de celui-ci Download PDF

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WO2013065712A1
WO2013065712A1 PCT/JP2012/078111 JP2012078111W WO2013065712A1 WO 2013065712 A1 WO2013065712 A1 WO 2013065712A1 JP 2012078111 W JP2012078111 W JP 2012078111W WO 2013065712 A1 WO2013065712 A1 WO 2013065712A1
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group
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mmol
phenyl
diazaspiro
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信寛 渕
祐子 加藤
拓実 青木
元 佐分
将輝 山田
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東レ株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention relates to a diaza spiro urea derivative and its pharmaceutical use.
  • Epoxyeicosatrienoic acids are one of endothelial cell-derived hyperpolarizing factors, and are produced by the metabolism of arachidonic acid by cytochrome P450 (CYP) epoxygenase.
  • EETs have a protective effect on vascular endothelium that is beneficial to the human body and an inhibitory effect on blood pressure rise, but in vivo, soluble epoxide hydrolase (hereinafter referred to as sEH) is an inactive form of dihydroxyeicosatrienoic acid (dihydroxyeosatrienoic acid). acid; hereinafter referred to as DHETs).
  • sEH inhibitor a soluble epoxide hydrolase inhibitor
  • Examples have not been reported (Non-Patent Documents 4 and 5).
  • Examples of compounds having sEH inhibitory activity include 12- (3-adamantan-1-yl-ureido) -dedecanoic acid (AUDA) (Non-patent Document 6), N-cyclohexyl-N-dodecylurea (NCND) (Non-patent Document) 1), AR 9281 (Non-patent Document 7) has been reported.
  • AUDA 3-adamantan-1-yl-ureido
  • NND N-cyclohexyl-N-dodecylurea
  • AR 9281 Non-patent Document 7
  • Examples of the compound having a diazaspirourea structure include a spirocyclic compound (Patent Document 1), an azacyclic compound (Patent Document 2), and a 2,8-diazaspiro [4.5] decane compound (Non-Patent Document 8). It has been reported.
  • Non-Patent Documents 1 to 3 Non-Patent Documents 1 to 3
  • sEH inhibitors can be candidate compounds for pathologically selective antihypertensive agents that exhibit antihypertensive effects on hypertension associated with the progression of the disease but do not exhibit antihypertensive effects on normal blood pressure. It wasn't received.
  • an object of the present invention is to provide a medicament that exhibits a therapeutic effect on hypertension based on sEH inhibitory activity.
  • this invention provides the diaza spiro urea derivative shown by the following general formula (I), or its pharmacologically acceptable salt.
  • R 1 and R 2 each independently represents a hydrogen atom, a halogen atom, a cyano group, an acetyl group, an alkyl group having 1 to 4 carbon atoms, an alkyloxy group, an alkylthio group, or —S ( ⁇ O ) Alkyl group or —S ( ⁇ O) 2 alkyl group (wherein the above alkyl group, alkyloxy group, alkylthio group, —S ( ⁇ O) alkyl group and —S ( ⁇ O) 2 alkyl group have a hydrogen atom)
  • R 3 may be R 4 C ( ⁇ O) — or R 5 S ( ⁇ O) 2 —, and R 4 may be substituted with 1 to 3 halogen atoms.
  • the alkenyl group and the cycloalkyl group each independently have a halogen atom having 1 to 3 hydrogen atoms, a methyl group, a hydroxyl group, a methoxy group, a cyclopropyl group, a phenyloxy group, a phenylthio group, a phenyl group, or a ring-constituting atom number.
  • the heterocyclyl group may be substituted with 5 to 10 heteroaryl groups, the heterocyclyl group may be condensed with a phenyl group, and the phenyl group and heteroaryl group may be condensed with a heterocyclyl group.
  • R 5 may be substituted with 3 to 6 R 6 ), and R 5 is an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a heteroaryl group having 5 to 10 ring atoms (wherein the alkyl group described above) , phenyl and heteroaryl groups are each independently, a hydrogen atom may be substituted with 1 to 3 halogen atoms or a methyl group), R 6 A halogen atom, a hydroxyl group, an amino group, a dimethylamino group, a morpholino group, an acetyl group, an acetamide group, a carboxamide group or a cyano group, or an alkyl group having 1 to 6 carbon atoms, an alkyloxy group or an alkylthio group, 3 to 6 cycloalkyl groups or alkyloxycarbonyl groups having 2 to 6 carbon atoms (wherein the above alkyl group, alkyloxy group, alkylthio group,
  • x is preferably 1 and y is preferably 2, and R 1 may be substituted with a halogen atom or 1 to 3 halogen atoms. It is more preferably an alkyl group having 1 to 4 carbon atoms or an alkyloxy group, R 2 is preferably a hydrogen atom, and R 3 is more preferably R 4 C ( ⁇ O) —.
  • the inhibitory activity against sEH can be increased.
  • R 1 is an alkyl group or alkyloxy group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms
  • R 2 is a hydrogen atom.
  • An atom R 3 is R 4 C ( ⁇ O) —, and R 4 is an alkyl group having 1 to 6 carbon atoms, or a hydrogen atom optionally substituted with 1 to 3 R 6 phenyl More preferably, R 6 is a halogen atom or an acetamido group, x is 1 and y is 2.
  • the present invention also provides a medicament containing the above diaza spiro urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • This medicament is preferably an sEH inhibitor, and more preferably a therapeutic or preventive agent for hypertension.
  • the diaza spiro urea derivative of the present invention has a high sEH inhibitory activity and can exert a therapeutic effect or a preventive effect on hypertension.
  • the medicament of the present invention has a medicinal effect for treating or preventing hypertension based on the mechanism, and can be used as a pathologically selective antihypertensive agent that does not exhibit a rapid antihypertensive action against normal blood pressure.
  • R 1 and R 2 each independently represents a hydrogen atom, a halogen atom, a cyano group or an acetyl group, or an alkyl group, an alkyloxy group, an alkylthio group, —S ( ⁇ O ) Alkyl group or —S ( ⁇ O) 2 alkyl group (wherein the above alkyl group, alkyloxy group, alkylthio group, —S ( ⁇ O) alkyl group and —S ( ⁇ O) 2 alkyl group have a hydrogen atom)
  • R 3 may be R 4 C ( ⁇ O) — or R 5 S ( ⁇ O) 2 —, and R 4 may be substituted with 1 to 3 halogen atoms.
  • the alkenyl group and the cycloalkyl group each independently have a halogen atom having 1 to 3 hydrogen atoms, a methyl group, a hydroxyl group, a methoxy group, a cyclopropyl group, a phenyloxy group, a phenylthio group, a phenyl group, or a ring-constituting atom number.
  • the heterocyclyl group may be substituted with 5 to 10 heteroaryl groups, the heterocyclyl group may be condensed with a phenyl group, and the phenyl group and heteroaryl group may be condensed with a heterocyclyl group.
  • R 5 may be substituted with ⁇ 3 R 6 ),
  • R 5 is an alkyl group having 1 to 6 carbon atoms, a phenyl group, or a heteroaryl group having 5 to 10 ring atoms (wherein the alkyl group is , phenyl and heteroaryl groups are each independently, a hydrogen atom may be substituted with 1 to 3 halogen atoms or a methyl group),
  • R 6 A halogen atom, a hydroxyl group, an amino group, a dimethylamino group, a morpholino group, an acetyl group, an acetamide group, a carboxamide group or a cyano group, or an alkyl group having 1 to 6 carbon atoms, an alkyloxy group or an alkylthio group, 3 to 3 carbon atoms 6 cycloalkyl groups or alkyloxycarbonyl groups having 2 to 6 carbon atoms (wherein the above alkyl group, alkyloxy group, al
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms means a carbon atom in which a hydrogen atom may be substituted with 1 to 3 halogen atoms.
  • the alkyloxy group having 1 to 4 carbon atoms in which the hydrogen atom may be substituted with 1 to 3 halogen atoms means the number of carbon atoms in which the hydrogen atom may be substituted with 1 to 3 halogen atoms.
  • alkylthio group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms refers to 1 carbon atom in which a hydrogen atom may be substituted with 1 to 3 halogen atoms.
  • a hydrogen atom may be substituted with 1 to 3 halogen atoms —S ( ⁇ O) alkyl group having 1 to 4 carbon atoms” means that a hydrogen atom is substituted with 1 to 3 halogen atoms.
  • C 1-6 alkyl group 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 examples include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • branched saturated hydrocarbon group examples include an isopropyl group, Examples thereof include an isobutyl group, a tert-butyl group, an isopentyl group, a 1-ethylpropyl group, and a 2-ethylbutyl group.
  • alkenyl group having 2 to 7 carbon atoms means a linear or branched unsaturated hydrocarbon group having 2 to 7 carbon atoms, such as vinyl group, 1-propenyl group, allyl group. , Isopropenyl group, 3-butenyl group, 2-butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group, 2-methyl A -2-propenyl group, a 2-methyl-1-propenyl group, a 3-methyl-2-butenyl group, a 4-pentenyl group, a 1-hexenyl group or a 1-heptenyl group can be mentioned.
  • cycloalkyl group having 3 to 6 carbon atoms means a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, and means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • the “C 2-6 alkyloxycarbonyl group” means a group in which a carbonyl group is bonded to an oxygen atom of an alkyloxy group having 1 to 5 carbon atoms, such as a methoxycarbonyl group, an ethoxycarbonyl group, 1- A propyloxycarbonyl group or a 2-propyloxycarbonyl group can be mentioned.
  • heterocyclyl group having 4 to 6 ring atoms means that the number of ring atoms is 1 or 2 that contain the same or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as ring atoms.
  • Means 4 to 6 saturated heterocyclic chains for example, oxetanylene group, tetrahydrofuranylene group, tetrahydropyranylene group, dioxanylene group, morpholinylene group, pyrrolidinylene group, piperidinylene group, tetrahydrothiophenylene group or tetrahydrothiopyranylene group It is done.
  • Heteroaryl group having 5 to 10 ring atoms means a monocyclic ring having 1 to 4 identical or different atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom as ring atoms Or a condensed heteroaromatic group, for example, as a monocyclic heteroaryl group, a pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, 1,3,5-triazinyl group, 1,2,4 -Triazinyl, pyrrolyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furanyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl Heteroaryl groups include quinolyl, isoquinolyl, benzofuranyl, isobenzofuranyl, indolyl, indazo
  • R 1 is a halogen atom or an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms Alternatively, it is preferably an alkyloxy group, more preferably an alkyl group having 1 to 4 carbon atoms or an alkyloxy group in which a hydrogen atom may be substituted with 1 to 3 halogen atoms, and a trifluoromethyl group Or it is more preferable that it is a trifluoromethoxy group.
  • R 2 is preferably a hydrogen atom, a halogen atom or a cyano group, or an alkyl group or alkyloxy group having 1 to 4 carbon atoms in which the hydrogen atom may be substituted with 1 to 3 halogen atoms, It is more preferably a hydrogen atom, a halogen atom or a cyano group, and further preferably a hydrogen atom.
  • R 3 is preferably R 4 C ( ⁇ O) —.
  • R 4 is preferably an alkyl group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with 1 to 3 R 6 hydrogen atoms, such as a cyclopropylmethyl group, 2,6-difluorophenyl. It is more preferably a group, a 2-fluorophenyl group or a 2-acetamidophenyl group.
  • R 5 is preferably a phenyl group optionally substituted with 1 to 3 halogen atoms or a methyl group, or a heteroaryl group having 5 to 10 ring atoms, and is a phenyl group or N— More preferred is a methylimidazolyl group.
  • R 6 is preferably a halogen atom or an alkyl group, an alkyloxy group, an acetyl group, or an acetamido group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with 1 to 3 halogen atoms, It is more preferably a halogen atom or an acetamide group, and further preferably a fluorine atom or an acetamide group.
  • X is preferably 1, and y is preferably 2.
  • diaza spiro urea derivative (I) examples include, for example, minerals such as sulfuric acid, hydrochloric acid or phosphoric acid. Salts with acids, and salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid or benzenesulfonic acid.
  • the starting materials and reagents used in the production of the above diazaspirourea derivative (I) may be commercially available products or may be used as they are, or known methods (WO 2007/007069, US Pat. No. 5,545,578). No. specification, International Publication No. 2007/030061) can also be chemically synthesized.
  • Said diaza spiro urea derivative (I) can be manufactured by passing through the amidation process or sulfonamidation process with respect to a diaza spiro amine derivative (II), as shown in the following scheme 1, for example.
  • Scheme 1 Scheme 1 [Wherein R 1 , R 2 and R 3 and x and y are the same as defined above. ]
  • the amidation step is an amidation reaction with an acid chloride in the presence of a base, or a condensation reaction with a carboxylic acid in the presence of a base and a condensing agent, as shown in Scheme 2 below.
  • Scheme 2 [Wherein R 1 , R 2 and R 4 and x and y are the same as defined above. ]
  • Examples of the solvent used for the amidation reaction with acid chloride include dichloromethane, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, and 1,2-dimethoxyethane.
  • Dichloromethane, 1,2-dichloroethane, acetonitrile or tetrahydrofuran is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the acid chloride used in the amidation reaction with the acid chloride is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, and even more preferably 1 to 1.5 equivalents with respect to the diazaspiroamine derivative (II). .
  • Examples of the base used in the amidation reaction with acid chloride include organic bases such as diisopropylethylamine, triethylamine, pyridine, and N-methylmorpholine, with diisopropylethylamine or triethylamine being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine acid derivative (II).
  • the reaction temperature of the amidation reaction with acid chloride is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time of the amidation reaction with acid chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and further preferably 30 minutes to 8 hours.
  • the concentration of the diazaspiroamine derivative (II) at the start of the reaction in the amidation reaction with acid chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.
  • condensing agent used in the condensation reaction examples include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 1- [bis ( Dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate (HATU) However, O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate (HATU) is preferred.
  • HATU O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate
  • N, N-dimethylformamide, tetrahydrofuran, Dioxane, 1,3-dimethyl-2-imidazolidinone, diethyl ether or DME may be mentioned, N, N-dimethylformamide or 1,3-dimethyl-2-imidazolidinone is preferred, and N, N-dimethylformamide Is more preferable.
  • the equivalent of the condensing agent used in the condensation reaction is preferably 1 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the diazaspiroamine derivative (II).
  • the equivalent amount of the carboxylic acid used in the condensation reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, and even more preferably 1 to 1.5 equivalents with respect to the diazaspiroamine derivative (II).
  • Examples of the base used in the condensation reaction include organic bases such as diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine, with diisopropylethylamine or triethylamine being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the diazaspiroamine derivative (II).
  • the reaction temperature of the condensation reaction is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time for the condensation reaction is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 8 hours.
  • the concentration of the diazaspiroamine derivative (II) at the start of the condensation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 3M.
  • the sulfonamidation step can be performed by sulfonamidation reaction with sulfonyl chloride in the presence of a base for the diazaspiroamine derivative (II).
  • Scheme 3 [Wherein R 1 , R 2 and R 5 and x and y are the same as defined above. ]
  • Examples of the solvent used for the sulfonamidation reaction with sulfonyl chloride include dichloromethane, 1,2-dichloroethane, acetonitrile, tetrahydrofuran, dioxane, diethyl ether, and 1,2-dimethoxyethane, but dichloromethane, 1,2- Dichloroethane, acetonitrile or tetrahydrofuran is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the sulfonyl chloride used in the sulfonamidation reaction is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, and even more preferably 1 to 1.5 equivalents with respect to the diazaspiroamine derivative (II).
  • Examples of the base used in the sulfonamidation reaction with sulfonyl chloride include organic bases such as diisopropylethylamine, triethylamine, pyridine and N-methylmorpholine, with diisopropylethylamine or triethylamine being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the cyanazaspiroamine derivative (II).
  • the reaction temperature of the sulfonamidation reaction with sulfonyl chloride is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time of the sulfonamidation reaction with sulfonyl chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and further preferably 30 minutes to 8 hours.
  • the concentration at the start of the reaction of the diazaspiroamine derivative (II) in the sulfonamidation reaction with sulfonyl chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M. .
  • the diazaspiroamine derivative (II) undergoes a ureation step for the protected diazaspiroamine derivative (III), followed by a deprotection step for the protected diazaspirourea derivative (IV), for example, as shown in Scheme 4 below.
  • the urea formation step is a urea reaction with an isocyanate in the presence of a base with respect to the protected diazaspiroamine derivative (III), or a urea reaction with an urea agent and aniline in the presence of a base. Can be performed.
  • Examples of the solvent used for the ureaation reaction with isocyanate include dichloromethane, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, dioxane, diethyl ether or 1,2-dimethoxyethane.
  • Dichloromethane, 1,2-dichloroethane, acetonitrile or tetrahydrofuran is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent of the isocyanate used in the ureaation reaction with the isocyanate is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, and more preferably 1 to 1.5 equivalents with respect to the protected diazaspiroamine derivative (III). preferable.
  • Examples of the base used for the ureaation reaction with isocyanate include organic bases such as diisopropylethylamine, triethylamine, pyridine and N-methylmorpholine, with diisopropylethylamine or triethylamine being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents, more preferably 1 to 10 equivalents, relative to the protected diazaspiroamine derivative (III).
  • the reaction temperature in the urea formation reaction with isocyanate is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time in the urea reaction with an isocyanate is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 8 hours.
  • the concentration at the start of the reaction of the protected diazaspiroamine derivative (III) in the urea reaction with an isocyanate is preferably 0.01 to 100M, more preferably 0.01 to 10M, still more preferably 0.1 to 10M. .
  • Examples of the solvent used for the urea reaction with the urea agent and aniline include dichloromethane, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide, tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane, and the like. Among them, dichloromethane, 1,2-dichloroethane, acetonitrile and tetrahydrofuran are preferable, and dichloromethane and 1,2-dichloroethane are more preferable.
  • urea agent used in the urea reaction with the urea agent and aniline examples include N, N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl 4-chloroformate or phenyl 4-nitroformate. Preference is given to phenyl formate or phenyl 4-nitroformate.
  • the equivalent of the urea agent used in the urea reaction with the urea agent and aniline is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents relative to the protected diazaspiroamine derivative (III). 5 equivalents are more preferred.
  • the equivalent amount of aniline used in the urea reaction with the urea agent and aniline is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, and more preferably 1 to 1.5 equivalents with respect to the protected diazaspiroamine derivative (III). Is more preferable.
  • Examples of the base used in the ureaation reaction with the urea agent and aniline include organic bases such as diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine, with diisopropylethylamine or triethylamine being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents, more preferably 1 to 10 equivalents, relative to the protected diazaspiroamine derivative (III).
  • the reaction temperature in the urea reaction with the urea agent and aniline is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time in the urea reaction with the urea agent and aniline is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 8 hours.
  • the concentration at the beginning of the reaction of the protected diazaspiroamine derivative (III) in the ureaation reaction with the urea agent and aniline is preferably 0.01 to 100M, more preferably 0.01 to 10M, and more preferably 0.1 to 10M. Is more preferable.
  • the deprotection step of the protected diazaspiroamine derivative (III) is a method described in known literature (Green et al., “Protective Groups in Organic Synthesis”, 3rd edition, John Wiley & Sons, Inc., 1999 and its cited references). Can be done by For example, when the protecting group of the protected diazaspiroamine derivative (III) is a tert-butoxycarbonyl group, the protecting group is removed by the action of an acid, leading to the diazaspiroamine derivative (II). Can do.
  • the diaza spiro urea derivative (I) is substituted with a protected diazaspiroamine derivative (III) as a starting material in the same manner as in the amidation step or sulfonamidation step. It can also be produced by introducing R 3 to obtain intermediate (V), and subsequently obtaining amine intermediate (VI) by the same method as in the deprotection step, followed by the same method as in the urea formation step.
  • Scheme 5 [Wherein R 1 , R 2 and R 3 , x and y and P are the same as defined above. ]
  • the protected diazaspiroamine derivative (III) may be a commercially available product, or may be produced by a known method.
  • 2,7-diazaspiro [4.4] nonane derivative can be produced with reference to a patent document (International Publication No. 2007/030061).
  • diazaspirourea derivative (I) or a pharmacologically acceptable salt thereof obtained as described above, or an intermediate, a raw material compound or a reagent used in the production of the diazaspirourea derivative (I) is: If necessary, it may be isolated and purified by a method such as extraction, distillation, chromatography or recrystallization.
  • the medicament of the present invention is characterized in that it contains the diaza spiro urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient, and circulates including hypertension as an sEH inhibitor. It can be suitably used as a therapeutic or prophylactic agent for organ diseases.
  • the “sEH inhibitor” means a compound that inhibits the action of sEH that catalyzes the hydrolysis of EETs, that is, a compound that exhibits sEH inhibitory activity or a composition containing the compound as an active ingredient.
  • the sEH inhibitory activity exhibited by the sEH inhibitor is measured, for example, by reacting human-derived sEH with its substrate EETs in the presence of the sEH inhibitor and comparing the amount of DHET produced with the control. be able to.
  • a commercially available measurement kit Soluable Epoxide Hydrose Inhibitor Screening Assay Kit; Cayman
  • Inhibitor activity can be measured.
  • the enzyme (0.24 ⁇ M human sEH) was added to the phosphate before the substrate (40 ⁇ M) was introduced. Incubate with sEH inhibitor for 5 minutes at 30 ° C. in sodium buffer (0.1 M, pH 7.4) and measure the appearance of 405 nm 4-nitrophenolate anion at 30 ° C.
  • the diaza spiro urea derivative (I) or a pharmacologically acceptable salt thereof exhibits sEH inhibitory activity, and therefore circulation including hypertension, which is a disease caused by a decrease in EETs associated with sEH activation. It is effective in the treatment or prevention of organ diseases.
  • the therapeutic effect on hypertension of the diaza spiro urea derivative (I) or a pharmacologically acceptable salt thereof can be evaluated using an animal model.
  • animal models include angiotensin II-induced hypertension model, SHR model, and salt-sensitive hypertension onset model.
  • the diaza spiro urea derivative (I) or a pharmacologically acceptable salt thereof has a strong inhibitory action on sEH in vivo, and in addition, a physiological activity showing a therapeutic effect on hypertension in animal tests. Since it is a substance, it can be used as an active ingredient such as pharmaceuticals or agricultural chemicals.
  • a medicament containing the above diazaspiroura derivative (I) or a pharmaceutically acceptable salt thereof as an active ingredient is a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or Human), particularly when administered to humans, it exhibits a strong inhibitory effect on sEH and can exhibit an excellent therapeutic effect on hypertension.
  • a mammal eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or Human
  • the therapeutic or prophylactic agent containing the diaza spiro urea derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient is directly used as a powder or as a pharmaceutical composition in an appropriate dosage form.
  • Oral or parenteral eg, transdermal, intravenous, rectal, inhalation, administration
  • mammals eg, mice, rats, hamsters, rabbits, dogs, monkeys, cows, sheep or humans
  • Nasal administration or ophthalmic administration eg, transdermal, intravenous, rectal, inhalation, administration
  • Examples of the dosage form for administration to mammals include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions or suppositories, or known continuous preparations. Is mentioned. These dosage forms can be produced by a known method and contain a carrier generally used in the pharmaceutical field. Examples of such carriers include excipients, lubricants, binders, disintegrants (solvents in liquid preparations), solubilizers, suspending agents, and soothing agents in solid preparations. Moreover, you may use additives, such as a tonicity agent, a buffering agent, antiseptic
  • additives such as a tonicity agent, a buffering agent, antiseptic
  • excipient examples include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • lubricant examples include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • binder examples include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose or sodium carboxymethylcellulose.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil or corn oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, or sodium citrate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose. , Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.
  • Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the isotonic agent include glucose, sodium chloride, D-sorbitol, and D-mannitol.
  • buffer solutions such as phosphate, acetate, carbonate or citrate.
  • preservative examples include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidant examples include sulfite and ascorbic acid.
  • the medicament preferably contains 0.001 to 99% by weight, more preferably 0.01 to 99% by weight, of the diazaspirourea derivative (I) or a pharmacologically acceptable salt thereof.
  • the effective dose and frequency of administration of the diaza spiro urea derivative (I) or a pharmacologically acceptable salt thereof vary depending on the dosage form, patient age, body weight, nature or severity of symptoms to be treated. In general, 1 to 1000 mg, preferably 1 to 300 mg per day for an adult can be administered in one or several divided doses.
  • the above medicines may be administered alone, but may be combined with other drugs or used in combination with other drugs in order to supplement or enhance the therapeutic effect, preventive effect, or reduce the dose of the disease. It can also be used.
  • drugs examples include, for example, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, Examples include thrombotic agents or cachexia improving agents (hereinafter referred to as concomitant drugs).
  • the administration timing of the above medicine and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, with a time difference. May be administered.
  • the concomitant drug may be a low molecular compound, or may be a high molecular protein, polypeptide, antibody, vaccine or the like.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the above medicine and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom or combination.
  • the concomitant drug may be used at a compounding ratio of 0.01 to 99.99 with respect to the diazaspirourea derivative (I) or a pharmacologically acceptable salt thereof. .
  • diabetes therapeutic agents include animal insulin preparations extracted from bovine or porcine pancreas, human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast, insulin zinc, protamine insulin zinc, insulin fragments or derivatives, etc.
  • Insulin preparations insulin resistance improvers such as pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, ⁇ -glucosidase inhibitors such as voglibose, acarbose, miglitol or emiglitate, biguanides such as phenformin, metformin or buformin, Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybzo Insulin secretion promoters such as repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof, am
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat or fidarestat, neurotrophic factors such as NGF, NT-3 or BDNF, neurotrophic factors Examples include production / secretion promoters, PKC inhibitors, AGE inhibitors, active oxygen scavengers such as thioctic acid, and cerebral vasodilators such as thioprid or mexiletine.
  • aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat or fidarestat
  • neurotrophic factors such as NGF, NT-3 or BDNF
  • neurotrophic factors include production / secretion promoters, PKC inhibitors, AGE inhibitors, active oxygen scavengers such as thioctic acid, and cerebral vasodilators such as thi
  • HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripanstat, cerivastatin, and itavastatin, bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate , Clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pilifibrate, lonifibrate, fibrate compounds such as simfibrate or theofibrate, squalene synthase inhibitors, ACAT inhibitors such as avasimib or eflucimate , Anion exchange resins such as cholestyramine, probucol, nicomol or niceritrol Cochin acid drugs or ethyl icosapentate,
  • Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors such as captopril, enalapril or delapril, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan or tasosartan and other angiotensin II antagonists, manidipine, nifedipine, nicardipine, Calcium antagonists such as amlodipine or efonidipine, potassium channel openers such as lebuchromacalim, clonidine or aliskiren.
  • angiotensin converting enzyme inhibitors such as captopril, enalapril or delapril
  • candesartan cilexetil losartan
  • eprosartan valsantan
  • telmisartan telmisartan
  • anti-obesity agents include central anti-obesity agents such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine or clobenzorex, pancreatic lipase such as orlistat Peptide appetite suppressants such as inhibitors, ⁇ 3 agonists, leptin or CNTF (ciliary neurotrophic factor) or cholecystokinin agonists such as lynchtripto.
  • central anti-obesity agents such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine or clobenzorex, pancreatic lipase such as orlistat Peptide appetite suppressants such as inhibitors, ⁇ 3 agonists, leptin or CNTF (
  • diuretic examples include xanthine derivatives such as sodium theobromide salicylate or calcium theobromide, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, thiazide preparations such as benchylhydrochlorothiazide, penflutide, polythiazide or methycrothiazide.
  • xanthine derivatives such as sodium theobromide salicylate or calcium theobromide
  • ethiazide cyclopenthiazide
  • trichloromethiazide hydrochlorothiazide
  • hydroflumethiazide hydroflumethiazide
  • thiazide preparations such as benchylhydrochlorothiazide, penflutide, polythiazide or methycrothiazide.
  • Antialdosterone preparations such as spironolactone or triamterene, carbonic anhydrase inhibitors such as acetazolamide, chlorbenzenesulfonamide preparations such as chlorthalidone, mefluside or indapamide, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide or furosemide.
  • chemotherapeutic agents include alkylating agents such as cyclophosphamide or ifosfamide, antimetabolite agents such as methotrexate or 5-fluorouracil, anticancer antibiotics such as mitomycin or adriamycin, plants such as vincristine, vindesine or taxol. Derived anticancer agents, cisplatin, oxaloplatin, carboplatin, etopoxide and the like.
  • immunotherapeutic agent examples include muramyl dipeptide derivatives, picibanil, lentinan, schizophyllan, krestin, interferon, interleukin (IL), granulocyte colony stimulating factor or erythropoietin.
  • Antithrombotic agents include, for example, heparin such as heparin sodium, heparin calcium or sodium dalteparin, warfarin such as warfarin potassium, antithrombin drugs such as argatroban, thrombolytic agents such as urokinase, tisokinase,reteplase, nateplase, monteplase or pamiteplase. Or platelet aggregation inhibitors such as ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium or sarpogrelate hydrochloride.
  • heparin such as heparin sodium, heparin calcium or sodium dalteparin
  • warfarin such as warfarin potassium
  • antithrombin drugs such as argatroban
  • thrombolytic agents such as urokinase, tisokinase, alteplase, nateplase, mont
  • cachexia-improving agents examples include cyclooxygenase inhibitors such as indomethacin or diclofenac, progesterone derivatives such as megesterol acetate, carbohydrate steroids such as dexamethasone, metoclopramide drugs, tetrahydrocannabinol drugs, and fats such as eicosapentaenoic acid.
  • cyclooxygenase inhibitors such as indomethacin or diclofenac
  • progesterone derivatives such as megesterol acetate
  • carbohydrate steroids such as dexamethasone
  • metoclopramide drugs tetrahydrocannabinol drugs
  • fats such as eicosapentaenoic acid.
  • examples thereof include antibodies to TNF- ⁇ , LIF, IL-6, or oncostatin M, which are agents that induce metabolism, growth hormone, IGF-1, or cachexia.
  • Example 1 Synthesis of 2- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-8-carboxamide (hereinafter, Example Compound 1): [Step 1] Synthesis of 1-tert-butyl 4-ethyl 4- (2-methoxy-2-oxoethyl) piperidine-1,4-dicarboxylate (Reference Example Compound 1): A solution of diisopropylamine (2.44 mL, 17.1 mmol) in tetrahydrofuran (30 mL) was cooled to ⁇ 78 ° C.
  • Step 2 Synthesis of tert-butyl 2-benzyl-1,3-dioxo-2,8-diazaspiro [4.5] decane-8-carboxylate (Reference Example Compound 2): 1-tert-butyl 4-ethyl 4- (2-methoxy-2-oxoethyl) piperidine-1,4-dicarboxylate (Reference Example Compound 1) (817 mg, 2.48 mmol) was converted to benzylamine (2.7 mL, 24 8 mmol) and stirred at 160 ° C. for 18 hours.
  • Step 3 Synthesis of 2-benzyl-2,8-diazaspiro [4.5] decane-1,3-dione (Reference Example Compound 3): To a solution of tert-butyl 2-benzyl-1,3-dioxo-2,8-diazaspiro [4.5] decane-8-carboxylate (Reference Example Compound 2) (512 mg, 1.43 mmol) in methanol (4 mL), A hydrogen chloride / methanol solution (6 mL) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was neutralized with 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The resulting organic layer was washed with saturated brine, dried over sodium sulfate, concentrated, and 325 mg (88 mg) of Reference Example Compound 3 was obtained. %)Obtained.
  • Step 5 Synthesis of 2-benzyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-8-carboxamide
  • Reference Example Compound 5 2-Benzyl-2,8-diazaspiro [4.5] decane (Reference Example Compound 4) (48 mg, 0.21 mmol), 4-trifluoromethylphenyl isocyanate (35.7 ⁇ L, 0.25 mmol) in dichloromethane (1 mL ) Diisopropylethylamine (90 ⁇ L, 0.52 mmol) was added to the solution and stirred at room temperature for 16 hours.
  • Example Compound 1 was obtained by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 27 mg (95%) of Example Compound 1.
  • Example 2 Synthesis of 2- (phenylsulfonyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decan-8-carboxamide (hereinafter, Example Compound 2): The reaction was conducted in the same manner as in Example 1 [Step 7] using benzenesulfonyl chloride (8.66 ⁇ L, 0.067 mmol), whereby 24 mg (83%) of Example Compound 2 was obtained.
  • Example 3 Synthesis of 9- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -3,9-diazaspiro [5.5] undecane-3-carboxamide (hereinafter, Example Compound 3): [Step 1] Synthesis of diethyl 2,2 ′-(1-benzylpiperidine-4,4-diyl) diacetate (Reference Example Compound 7): 1-Benzyl-4-piperidone (10 g, 53 mmol) and ethyl cyanoacetate (11.3 mL, 106 mmol) were dissolved in a saturated ammonia-ethanol (30 mL) solution and allowed to stand at 0 ° C.
  • Triethylamine (0.11 mL, 0.79 mmol) was added to a solution of the concentrate and 2,6-difluorobenzoyl chloride (66.1 ⁇ L, 0.53 mmol) in dichloromethane (1 mL), and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with dichloromethane, and the resulting organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 153 mg (91%) of Reference Example Compound 12.
  • Example 4 Synthesis of N- (4-chlorophenyl) -9- (2,6-difluorobenzoyl) -3,9-diazaspiro [5.5] undecane-3-carboxamide (hereinafter, Example Compound 4): The same reaction as in Example 3 [Step 7] was carried out using 4-chlorophenyl isocyanate (11.5 mg, 0.068 mmol) to obtain 24 mg (80%) of Example Compound 4.
  • Example 5 Synthesis of 8- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 5): [Step 1] Synthesis of (2-benzyl-2,8-diazaspiro [4.5] decan-8-yl) (2,6-difluorophenyl) methanone (Reference Example Compound 13): To a solution of 2-benzyl-2,8-diazaspiro [4.5] decane (Reference Example Compound 4) (120 mg, 0.52 mmol), 2,6-difluorobenzoyl chloride (76 ⁇ L, 0.6 mmol) in dichloromethane (3 mL) , Diisopropylethylamine (145 ⁇ L, 1.04 mmol) was added and stirred at room temperature for 2 hours.
  • Example Compound 5 was obtained by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 47 mg (56%) of Example Compound 5.
  • Example 6 Synthesis of 2-benzoyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-8-carboxamide (hereinafter, Example Compound 6): The reaction was conducted in the same manner as in Example 1 [Step 7] using benzoyl chloride (16 ⁇ L, 0.13 mmol) to obtain 42 mg (80%) of Example Compound 6.
  • Example 7 Synthesis of 2-picolinoyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decan-8-carboxamide (hereinafter, Example Compound 7): To a solution of picolinic acid (18 mg, 0.15 mmol) in N, N-dimethylformamide (1 mL) was added O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate (56 mg, 0.15 mmol).
  • Example 8 Synthesis of 2-nicotinoyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decan-8-carboxamide (hereinafter, Example Compound 8): The same reaction as in Example 7 was performed using nicotinic acid (18 mg, 0.15 mmol) to obtain 10 mg (19%) of Example Compound 8.
  • Example 9 Synthesis of 2-isonicotinoyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decan-8-carboxamide (hereinafter, Example Compound 9): The same reaction as in Example 7 was performed using isonicotinic acid (18 mg, 0.15 mmol) to obtain 10 mg (19%) of Example Compound 9.
  • Example 10 Synthesis of 2- (methylsulfonyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decan-8-carboxamide (hereinafter, Example Compound 10): 45 mg (91%) of Example Compound 10 was obtained by performing the same reaction as Example 1 [Step 7] using methanesulfonyl chloride (11 ⁇ L, 0.13 mmol).
  • Example 11 Synthesis of N- (4-cyanophenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decan-2-carboxamide (hereinafter, Example Compound 11): Using 4-cyanophenyl isocyanate (9.3 mg, 0.065 mmol) and carrying out the same reaction as in Example 5 [Step 3], 3.6 mg (16%) of Example Compound 11 was obtained.
  • Example 12 Synthesis of 8- (2,6-difluorobenzoyl) -N- (4-methoxyphenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 12): By using 4-methoxyphenyl isocyanate (9.6 mg, 0.064 mmol) and carrying out the same reaction as in Example 5 [Step 3], 15 mg (65%) of Example Compound 12 was obtained.
  • Example 13 Synthesis of N- (4-acetylphenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 13): 8.7 mg (38%) of Example Compound 13 was obtained by performing the same reaction as in Example 5 [Step 3] using 4-acetylphenyl isocyanate (9.3 mg, 0.064 mmol).
  • Example 14 Synthesis of N- (4- (tert-butyl) phenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 14): Using 4- (tert-butyl) phenyl isocyanate (11 mg, 0.064 mmol) and carrying out the same reaction as in Example 5 [Step 3], 6.7 mg (27%) of Example Compound 14 was obtained. .
  • Example 15 Synthesis of 8- (2,6-difluorobenzoyl) -N- (4- (methylthio) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 15): By using 4- (methylthio) phenyl isocyanate (71 mg, 0.43 mmol) and carrying out the same reaction as in Example 5 [Step 3], 130 mg (82%) of Example Compound 15 was obtained.
  • Example 16 Synthesis of 8- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 16): (2,6-Difluorophenyl) (2,8-diazaspiro [4.5] decan-8-yl) methanone (Reference Example Compound 14) (100 mg, 0.36 mmol), 4-trifluoromethoxyphenyl isocyanate (91 mg , 0.45 mmol) in dichloromethane (2 mL) was added diisopropylethylamine (100 ⁇ L, 0.58 mmol) and stirred at room temperature for 16 hours.
  • Example Compound 16 (2,6-Difluorophenyl) (2,8-diazaspiro [4.5] decan-8-yl) methanone (Reference Example Compound 14) (100 mg, 0.36 m
  • Example 17 Synthesis of 8- (2,6-difluorobenzoyl) -N- (3- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 17): The same reaction as in Example 5 [Step 3] was performed using 3-trifluoromethylphenyl isocyanate (16 mg, 0.087 mmol) to obtain 17 mg (77%) of Example Compound 17.
  • Example 18 Synthesis of N- (4-chlorophenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decan-2-carboxamide (hereinafter, Example Compound 18): By using 4-chlorophenyl isocyanate (14 mg, 0.091 mmol) and carrying out the same reaction as in Example 5 [Step 3], 19 mg (71%) of Example Compound 18 was obtained.
  • Example 19 N- (4-Chloro-3- (trifluoromethyl) phenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter referred to as Example Compound 19) ) Synthesis: To a solution of 4-nitrophenyl chloroformate (36 mg, 0.18 mmol) in dichloromethane (0.50 mL) was added 4-chloro-3- (trifluoromethyl) aniline (35 mg, 0.18 mmol), diisopropylethylamine (31 ⁇ L, 0 .18 mmol) in dichloromethane (1.0 mL) was added and stirred at room temperature for 5 minutes.
  • Example 20 Synthesis of 8- (2,6-difluorobenzoyl) -N- (4-ethoxyphenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 20): The same reaction as in Example 19 was carried out using 4-ethoxyaniline (29 mg, 0.21 mmol) to obtain 55 mg (65%) of Example Compound 20.
  • Example 21 Synthesis of N- (2,4-dichlorophenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 21): 38 mg (71%) of Example Compound 21 was obtained by carrying out the same reaction as in Example 5 [Step 3] using 2,4-dichlorophenyl isocyanate (34 mg, 0.18 mmol).
  • Example 22 8- (2,6-difluorobenzoyl) -N- (3- (2,2,2-trifluoroethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Examples Synthesis of compound 22): The same reaction as in Example 19 was carried out using 3- (2,2,2-trifluoroethoxy) aniline (34 mg, 0.18 mmol) to obtain 49 mg (61%) of Example Compound 22.
  • Example 23 8- (2,6-Difluorobenzoyl) -N- (4- (2,2,2-trifluoroethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Examples Synthesis of compound 23): The same reaction as in Example 19 was carried out using 4- (2,2,2-trifluoroethoxy) aniline (24 mg, 0.13 mmol) to obtain 34 mg (71%) of Example Compound 23.
  • Example 24 Synthesis of 8- (2-methylcyclopropanecarbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Example Compound 24 [Step 1] Synthesis of tert-butyl 2-benzyl-2,8-diazaspiro [4.5] decane-8-carboxylate
  • Reference Example Compound 15 To an aqueous solution (20 mL) of 2-benzyl-2,8-diazaspiro [4.5] decane (Reference Example Compound 4) (5.0 g, 21 mmol) was added dicarbonate-di-tert-butyl dicarbonate (7.2 g, 33 mmol).
  • Example Compound 18 (60 mg, 0.18 mmol) was added and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The resulting 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 (eluent; hexane: ethyl acetate) to obtain 74 mg (100%) of Example Compound 24.
  • Example 25 8- (5-methylpyrazine-2-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter referred to as Example Compound 25) Synthesis: The same reaction as in Example 24 [Step 5] was performed using 5-methyl-2-pyrazinecarboxylic acid (36 mg, 0.26 mmol) to obtain 76 mg (94%) of Example Compound 25.
  • Example 26 8- (5-Cyclopropylisoxazole-4-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter referred to as Example Compound 26) ) Synthesis: The same reaction as in Example 24 [Step 5] was carried out using 5-cyclopropylisoxazole-4-carboxylic acid (40 mg, 0.26 mmol) to obtain 16 mg (19%) of Example Compound 26.
  • Example 27 Synthesis of 8- (2-ethylbutanoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 27): The same reaction as in Example 24 [Step 5] was performed using 2-ethylbutyric acid (400 mg, 3.50 mmol) to obtain 95 mg (9%) of Example Compound 27.
  • Example 28 Synthesis of 8- (2-acetylbenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 28): The reaction was conducted using 2-acetylbenzoic acid (574 mg, 3.50 mmol) in the same manner as in Example 24 [Step 5] to give 99 mg (9%) of Example Compound 28.
  • Example 29 Synthesis of N- (3,4-dichlorophenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 29): Using 3,4-dichlorophenyl isocyanate (26 mg, 0.14 mmol) and carrying out the same reaction as in Example 5 [Step 3], 42 mg (70%) of Example Compound 29 was obtained.
  • Example 30 Synthesis of N- (4-chloro-3-methylphenyl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 30): The same reaction as in Example 19 was carried out using 4-chloro-3-methylaniline (26 mg, 0.19 mmol) to obtain 40 mg (62%) of Example Compound 30.
  • Example 31 8- (2,6-difluorobenzoyl) -N- (4-methoxy-3- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 31) ) Synthesis: The same reaction as in Example 19 was carried out using 4-methoxy-3- (trifluoromethyl) aniline (36 mg, 0.19 mmol) to obtain 37 mg (51%) of Example Compound 31.
  • Example 32 8-((1-methyl-1H-imidazol-4-yl) sulfonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Synthesis of Example Compound 32): N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (Reference Example Compound 18) (50 mg, 0.15 mmol), 1-methyl-1H-imidazole- To a solution of 4-sulfonyl chloride (39.5 mg, 0.22 mmol) in dichloromethane (1.5 mL) was added diisopropylethylamine (38 ⁇ L, 0.22 mmol), and the mixture was stirred at room temperature for 2 hours.
  • Example Compound 32 was purified by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 61 mg (86%) of Example Compound 32.
  • Example 33 8- (2-methylfuran-3-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter referred to as Example Compound 33) Synthesis: The reaction was conducted in the same manner as in Example 24 [Step 5] using 2-methylfuran-3-carboxylic acid (24 mg, 0.20 mmol) to give 42 mg (71%) of Example Compound 33.
  • Example 34 Synthesis of 8-acetyl-N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 34): The same reaction as in Example 32 was performed using acetyl chloride (17 mg, 0.22 mmol) to obtain 40 mg (71%) of Example Compound 34.
  • Example 35 8- (3- (3-hydroxyphenyl) propanoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 35) Synthesis of: The same reaction as in Example 24 [Step 5] was carried out using 3- (3-hydroxyphenyl) propionic acid (36 mg, 0.22 mmol) to obtain 54 mg (71%) of Example Compound 35.
  • Example 36 Synthesis of 8- (2-fluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 36): To a solution of 2-fluorobenzoic acid (31 mg, 0.22 mmol) in N, N-dimethylformamide (1 mL) was added O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate (83 mg, 0 .22 mmol), diisopropylethylamine (38 ⁇ L, 0.22 mmol), N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (Reference Example Compound 18) (50 mg 0.15 mmol) and stirred at room temperature for 16 hours.
  • Example Compound 36 was purified by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 59 mg (87%) of Example Compound 36.
  • Example 37 Synthesis of 8- (methylsulfonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 37): The same reaction as in Example 32 was carried out using methanesulfonyl chloride (25 mg, 0.22 mmol) to obtain 50 mg (81%) of Example Compound 37.
  • Example 38 Synthesis of 8- (cyclohexanecarbonyl) -N- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 38): The same reaction as in Example 32 was performed using cyclohexanecarbonyl chloride (32 mg, 0.22 mmol) to obtain 27 mg (41%) of Example Compound 38.
  • Example 39 Synthesis of 8-pivaloyl-N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 39): The same reaction as in Example 32 was carried out using pivaloyl chloride (26 mg, 0.22 mmol) to obtain 17 mg (28%) of Example Compound 39.
  • Example 40 Synthesis of 8- (2-butenoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 40): The same reaction as in Example 32 was carried out using crotonic acid chloride (23 mg, 0.22 mmol) to obtain 27 mg (45%) of Example Compound 40.
  • Example 41 Synthesis of 8-pentanoyl-N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 41): The same reaction as in Example 32 was carried out using pentanoic acid chloride (26 mg, 0.22 mmol) to obtain 40 mg (65%) of Example Compound 41.
  • Example 42 8- (Tetrahydro-2H-pyran-4-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 41) Synthesis of: The same reaction as in Example 24 [Step 5] was carried out using tetrahydropyran-4-carboxylic acid (67 mg, 0.52 mmol) to obtain 79 mg (50%) of Example Compound 42.
  • Example 43 8- (2-Fluoro-5-hydroxybenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 43) Synthesis: The same reaction as in Example 24 [Step 5] was carried out using 2-fluoro-5-hydroxybenzoic acid (27 mg, 0.18 mmol) to obtain 38 mg (68%) of Example Compound 43.
  • Example 44 Synthesis of 8- (tetrahydrofuran-3-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 44): The same reaction as in Example 24 [Step 5] was performed using tetrahydrofuran-3-carboxylic acid (25 mg, 0.22 mmol) to obtain 47 mg (69%) of Example Compound 44.
  • Example 45 Synthesis of 8- (quinoline-5-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 45): The same reaction as in Example 24 [Step 5] was performed using 4-quinolinecarboxylic acid (38 mg, 0.22 mmol) to obtain 70 mg (96%) of Example Compound 45.
  • Example 46 8- (1H-benzo [d] imidazole-4-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter referred to as Example compound) 46) Synthesis: The reaction was conducted in the same manner as in Example 24 [Step 5] using 5-benzimidazolecarboxylic acid (35 mg, 0.22 mmol), to obtain 53 mg (75%) of Example Compound 46.
  • Example 47 8- (5-methylisoxazole-3-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 47) Synthesis of: The same reaction as in Example 24 [Step 5] was performed using 5-methylisoxazole-3-carboxylic acid (28 mg, 0.22 mmol) to obtain 20 mg (30%) of Example Compound 47.
  • Example 49 Synthesis of 8- (4-hydroxycyclohexanecarbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decan-2-carboxamide (hereinafter, Example Compound 49): The same reaction as in Example 24 [Step 5] was performed using 4-hydroxycyclohexanecarboxylic acid (32 mg, 0.22 mmol) to obtain 20 mg (29%) of Example Compound 49.
  • Example 50 Synthesis of 8- (furan-2-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decan-2-carboxamide (hereinafter, Example Compound 50): The same reaction as in Example 32 was carried out using furan-2-carboxylic acid chloride (29 mg, 0.22 mmol) to obtain 60 mg (94%) of Example Compound 50.
  • Example 51 Synthesis of 8- (2-chlorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 51): The same reaction as in Example 32 was carried out using 2-chlorobenzoyl chloride (38 mg, 0.22 mmol) to obtain 63 mg (90%) of Example Compound 51.
  • Example 53 N- (4- (trifluoromethoxy) phenyl) -8- (1- (trifluoromethyl) cyclopropanecarbonyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 53) ) Synthesis: The same reaction as in Example 24 [Step 5] was performed using 1-trifluoromethylcyclopropane-1-carboxylic acid (22 mg, 0.15 mmol) to obtain 26 mg (37%) of Example Compound 53. .
  • Example 54 8- (2,2-difluorocyclopropanecarbonyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 54) Synthesis: The same reaction as in Example 24 [Step 5] was performed using 2,2-difluorocyclopropanecarboxylic acid (18 mg, 0.15 mmol) to obtain 31 mg (48%) of Example Compound 54.
  • Example 56 Synthesis of 8- (2-cyclopropylacetyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 56): To a solution of cyclopropylacetic acid (18 mg, 0.18 mmol) in N, N-dimethylformamide (0.5 mL) was added O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate (83 mg, 0 .22 mmol), diisopropylethylamine (38 ⁇ L, 0.22 mmol), N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (Reference Example Compound 18) (50 mg 0.15 mmol) and stirred at room temperature for 16 hours.
  • Example 57 Synthesis of 8- (2,6-difluorobenzoyl) -N- (3- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 57): The same reaction as in Example 19 was performed using 3-trifluoromethoxyaniline (54 mg, 0.31 mmol) to obtain 59 mg (51%) of Example Compound 57.
  • Example 58 8- (2,6-difluorobenzoyl) -N- (4-((trifluoromethyl) thio) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 58) Synthesis of: The same reaction as in Example 19 was carried out using 3-trifluoromethoxyaniline (53 mg, 0.28 mmol) to obtain 64 mg (56%) of Example Compound 58.
  • Example 59 8- (2,6-difluorobenzoyl) -N- (4-((trifluoromethyl) sulfinyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Example Compound 59 Synthesis of: 8- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) thio) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Example Compound 58 (24 mg , 0.048 mmol) in dichloromethane (2.0 mL) was added metachloroperbenzoic acid (10 mg, 0.058 mmol), and the mixture was stirred for 19 hours under ice cooling.
  • Example Compound 59 A saturated aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over sodium sulfate, concentrated, and the resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 14 mg (57%) of Example Compound 59. It was.
  • Example 60 Synthesis of 2- (2-fluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-8-carboxamide (hereinafter, Example Compound 60): The same reaction as in Example 1 [Step 7] was carried out using 2-fluorobenzoyl chloride (17 mg, 0.11 mmol) to obtain 17 mg (41%) of Example Compound 60.
  • Example 61 Synthesis of 2-pivaloyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-8-carboxamide (hereinafter, Example Compound 61): The same reaction as in Example 1 [Step 7] was performed using pivaloyl chloride (13 mg, 0.11 mmol) to obtain 28 mg (74%) of Example Compound 61.
  • Example 62 Synthesis of 2- (2-methoxybenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decan-8-carboxamide (hereinafter, Example Compound 62): The reaction was conducted in the same manner as in Example 24 [Step 5] using 2-methoxybenzoic acid (17 mg, 0.11 mmol), to obtain 44 mg (100%) of Example Compound 62.
  • Example 63 Synthesis of 2- (quinoline-4-carbonyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-8-carboxamide (hereinafter, Example Compound 63): The reaction was conducted in the same manner as in Example 24 [Step 5] using 4-quinolinecarboxylic acid (19 mg, 0.11 mmol), to obtain 41 mg (93%) of Example Compound 63.
  • Example 64 8- (2,6-Difluorobenzoyl) -N- (4-((trifluoromethyl) sulfonyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Example Compound 64 Synthesis of: 8- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) sulfinyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (Example Compound 59) (12 mg , 0.023 mmol) in dichloromethane (1.0 mL) was added metachloroperbenzoic acid (20 mg, 0.12 mmol) and stirred for 22 hours under ice cooling.
  • Example Compound 64 ( 49%).
  • Example 65 Synthesis of 7- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide
  • Example Compound 65 [Step 1] Synthesis of (7-benzyl-2,7-diazaspiro [4.4] nonan-2-yl) (2,6-difluorophenyl) methanone
  • Reference Example Compound 20 To a solution of 2-benzyl-2,7-diazaspiro [4.4] nonane dihydrochloride (100 mg, 0.35 mmol), 2,6-difluorobenzoyl chloride (52 ⁇ L, 0.41 mmol) in dichloromethane (2 mL) was added diisopropylethylamine.
  • Example 66 Synthesis of 7- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide (hereinafter, Example Compound 66): 35 mg (95%) of Example Compound 66 was obtained by carrying out the same reaction as in Example 65 [Step 2] using 4-trifluoromethoxyphenyl isocyanate (14 ⁇ L, 0.099 mmol).
  • Example 67 Synthesis of 8-pivaloyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Example Compound 67 [Step 1] Synthesis of tert-butyl 2-((4- (trifluoromethyl) phenyl) carbamoyl) -2,8-diazaspiro [4.5] decane-8-carboxylate
  • Reference Example Compound 19 By performing the same reaction as in Example 24 [Step 3] using 4-trifluoromethylphenyl isocyanate (2.2 g, 9.15 mmol), 3.5 g (90%) of Reference Example Compound 19 was obtained. .
  • Step 3 Synthesis of 8-pivaloyl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Example Compound 67 N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide
  • Reference Example Compound 21 (20 mg, 0.061 mmol), pivaloyl chloride (8.8 mg, 0 0.073 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (16.1 ⁇ L, 0.092 mmol) and stirred at room temperature for 2 hours.
  • Example Compound 67 was purified by silica gel column chromatography (eluent; hexane: ethyl acetate) to obtain 22 mg (87%) of Example Compound 67.
  • Example 68 Synthesis of 8-isobutyryl-N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 68): The same reaction as in Example 67 [Step 3] was carried out using isobutyryl chloride (7.8 mg, 0.073 mmol) to give 22 mg (90%) of Example Compound 68.
  • Example 69 Synthesis of 7-pivaloyl-N- (4- (trifluoromethyl) phenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide
  • Example Compound 69 [Step 1] Synthesis of 7-benzyl-N- (4- (trifluoromethyl) phenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide
  • Reference Example Compound 22 To a solution of 2-benzyl-2,7-diazaspiro [4.4] nonane dihydrochloride (100 mg, 0.35 mmol), 4-trifluoromethylphenyl isocyanate (71 mg, 0.38 mmol) in dichloromethane (1 mL) was added diisopropyl.
  • Example 70 Synthesis of 7-pivaloyl-N- (4- (trifluoromethoxy) phenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide
  • Example Compound 70 [Step 1] Synthesis of 7-benzyl-N- (4- (trifluoromethoxy) phenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide
  • Reference Example Compound 23 was obtained by conducting the same reaction as in Example 69 [Step 1] using 4-trifluoromethoxyphenyl isocyanate (77 mg, 0.38 mmol).
  • Example 71 Synthesis of 8- (2-acetamidobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 71): 8.6 mg (17%) of Example Compound 71 was obtained by carrying out the same reaction as in Example 24 [Step 5] using N-acetylanthranilic acid (20 mg, 0.11 mmol).
  • Example 72 8-((1-methyl-1H-imidazol-4-yl) sulfonyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Synthesis of Example Compound 72): 31 mg (54%) of Example Compound 72 was obtained by conducting the same reaction as in Example 67 [Step 3] using 1-methyl-1H-imidazole-4-sulfonyl chloride (24 mg, 0.13 mmol). .
  • Example 73 Synthesis of 8- (2-carbamoylbenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 73): The same reaction as in Example 24 [Step 5] was performed using phthalamic acid (28 mg, 0.17 mmol) to obtain 11 mg (15%) of Example Compound 73.
  • Example 74 Synthesis of 8- (2-cyclopropylacetyl) -N- (4- (trifluoromethyl) phenyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Example Compound 74): 30 mg (87%) of Example Compound 74 was obtained by carrying out a reaction similar to Example 24 [Step 5] using cyclopropylacetic acid (13 mg, 0.13 mmol).
  • Example compounds 75 to 156 the LC retention time and [M + H] + were measured using the analysis method described below.
  • Comparative Example 1 Synthesis of 7-benzyl-N- (4-phenoxyphenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide (hereinafter referred to as Comparative Example Compound 1): The same reaction as in Example 69 [Step 1] was carried out using 4-phenoxyphenyl isocyanate (145 mg, 0.69 mmol), to obtain 124 mg (47%) of Comparative Compound 1.
  • Example 15-7 Evaluation test of human sEH inhibitory activity in vitro: The following sEH inhibitory activity test was conducted using human sEH based on the method described in a known literature (Analytical Biochemistry, 2005, Vol. 343, p. 66-75). This was performed in order to measure the sEH inhibitory activity of I) and evaluate its usefulness.
  • the fluorescence intensity with no sEH added and no test compound added was defined as 0% sEH enzyme reaction rate, and the fluorescence intensity with sEH added and no test compound added was defined as 100% sEH enzyme reaction rate. Each sEH enzyme reaction rate was calculated and IC 50 was determined.
  • the diaza spiro urea derivative (I) has a high inhibitory activity on the enzyme reaction of human sEH.
  • Example 158 Drug efficacy evaluation test on blood pressure of spontaneously hypertensive model rat (SHR rat):
  • the present Example is a comparative example described in Example Compound 16, Example Compounds 36, 56 and 150, and known literature (International Publication No. 2007/007069) which is a preferred embodiment as an active ingredient of the therapeutic agent for hypertension. This was carried out in order to examine the therapeutic effect of hypertension due to the administration of the above diazaspirourea derivative (I) using the direct method by cannulation of femoral artery for compound 1.
  • a blood pressure transducer (Nihon Koden Kogyo Co., Ltd.) is connected to the tube inserted into the femoral artery, and the blood pressure is amplified by Blood Pressure Amplifier (Nihon Koden Kogyo Co., Ltd.) and then by the PowerabLab system (Nihon Koden Kogyo Co., Ltd.). A waveform was obtained.
  • Example Compound 16, 36, 56 or 150 or Comparative Example Compound 1 was suspended in 0.5% methylcellulose solution containing 0.5% Tween 80 and orally administered at a dose of 30 mg / kg body weight.
  • the solvent administration group was similarly administered with a 0.5% methylcellulose solution containing 0.5% Tween80.
  • Mean blood pressure (hereinafter referred to as MBP) was measured until 6 hours after administration.
  • the values in the graph are the values calculated as the difference between the average value of MBP for 6 minutes after administration and the average value of MBP for 90 minutes before administration as the average value of MBP after 5-6 hours after administration. The results are shown in FIG.
  • Example Compound 16 administration group the Example Compound 36 administration group, the Example Compound 56 administration group, and the Example Compound 150 administration group
  • the blood pressure was reduced as compared with the solvent administration group.
  • no decrease in blood pressure was observed in the Comparative Example Compound 1 administration group.
  • Example 159 Effect evaluation test on blood pressure of normal rat (SD rat):
  • the above-mentioned dialysis was performed using a direct method by intrafemoral artery cannulation. This was performed in order to examine the influence on the normal blood pressure by administration of the zaspirourea derivative (I).
  • Rats (Sprague-Dawley (SD), male, 8-11 weeks old, Nippon Charles River Co., Ltd.) were anesthetized, and the crotch and back neck were depilated, and the surgical field using isodine solution Was disinfected. After incision of the crotch and back neck skin, the muscle layer of the crotch was bluntly incised using tweezers, the femoral artery was peeled and exposed, a small incision was made, and a polyethylene tube was inserted and placed.
  • a blood pressure transducer (Nihon Koden Kogyo Co., Ltd.) is connected to the tube inserted into the femoral artery, and the blood pressure is amplified with a Blood Pressure Amplifier (Nihon Koden Kogyo Co., Ltd.) and then with a Power Lab system (Nihon Koden Kogyo Co., Ltd.). A waveform was obtained.
  • Example Compound 16, 36, 56 or 150 or Telmisartan was suspended in a 0.5% methylcellulose solution containing 0.5% Tween 80, and Example Compound 16, Example Compound 36, Example Compound 56 were suspended. And 150 were orally administered at a dose of 30 mg / kg body weight, and telmisartan was orally administered at a dose of 3 mg / kg body weight.
  • a 0.5% methylcellulose solution containing 0.5% Tween 80 was similarly administered to the solvent administration group.
  • MBP was measured up to 6 hours after administration. The values in the graph are the difference between the average value of MBP for 6 minutes after administration and the average value of MBP for 90 minutes before administration as the average value of MBP after 5 to 6 hours after administration. The results are shown in FIG.
  • Example Compound 16 administration group There was no change in blood pressure in the Example Compound 16 administration group, the Example Compound 36 administration group, the Example Compound 56 administration group, the Example Compound 150 administration group and the solvent administration group.
  • blood pressure was significantly reduced in the telmisartan administration group.
  • the * and ** marks in the figure indicate statistical significance in comparison with the solvent administration group (t test, p ⁇ 0.05 and 0.01).
  • the diazaspirourea derivative of the present invention inhibits the activity of sEH and increases EETs in the body, thereby exhibiting an antihypertensive action and a protective action on vascular endothelium. It can be used as a therapeutic or prophylactic agent for diseases.

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Abstract

L'invention fournit un composé possédant un effet inhibiteur d'époxyde hydrolase soluble (sEH), et fournit en outre un produit pharmaceutique révélant un effet thérapeutique basé sur un mécanisme agissant contre les maladies cardiovasculaires, tout particulièrement contre l'hypertension artérielle. Plus spécifiquement, l'invention fournit un dérivé de diazaspiro urea représenté par la formule, ou un sel pharmaceutiquement admissible de celui-ci.
PCT/JP2012/078111 2011-10-31 2012-10-31 Dérivé de diazaspiro urea, et application pharmaceutique de celui-ci WO2013065712A1 (fr)

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