WO2013115294A1 - Dérivé de diazaspiro-urée et son utilisation pharmaceutique - Google Patents

Dérivé de diazaspiro-urée et son utilisation pharmaceutique Download PDF

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WO2013115294A1
WO2013115294A1 PCT/JP2013/052134 JP2013052134W WO2013115294A1 WO 2013115294 A1 WO2013115294 A1 WO 2013115294A1 JP 2013052134 W JP2013052134 W JP 2013052134W WO 2013115294 A1 WO2013115294 A1 WO 2013115294A1
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group
example compound
phenyl
mmol
diazaspiro
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祐子 加藤
信寛 渕
拓実 青木
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東レ株式会社
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    • 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
    • C07D487/04—Ortho-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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—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 both a protective effect on vascular endothelium that is beneficial to the human body and an inhibitory effect on blood pressure rise.
  • soluble epoxide hydrolase hereinafter referred to as sEH
  • sEH soluble epoxide hydrolase
  • DHETs dihydroxyeosatolineic acids
  • Non-patent Document 1 The expression of sEH is observed in many organs in the living body, but its expression is increased in the kidney of angiotensin II-induced hypertension model and spontaneous hypertension (hereinafter referred to as SHR) model (Non-patent Document 1). And 2), sEH knockout mice are known to have a lower average blood pressure than normal animals (Non-patent Document 3). From these facts, it is considered that the increased expression of sEH is involved in the pathology of hypertension.
  • sEH inhibitors soluble epoxide hydrolase inhibitors that suppress the action of sEH could be therapeutic agents for hypertension, but many of the sEH inhibitors found in recent years are SHR models. It has been reported that there is almost no therapeutic effect on spontaneous hypertension that develops in (Non-Patent Documents 4 to 6).
  • Examples of compounds having sEH inhibitory activity include 12- (3-adamantan-1-yl-ureido) -dedecanoic acid (AUDA) (Non-patent Document 7), N-cyclohexyl-N-dodecylurea (NCND) (Non-patent Document) 1), AR 9281 (Non-Patent Document 8), a compound having a spiro structure (Non-Patent Document 4), a piperidine compound substituted with a heteroaryl group at the 4-position (Non-Patent Document 5), and two substitutions at the 3-position A piperidine compound having a group (Non-patent Document 6) has been reported.
  • Patent Document 1 spirocyclic compounds
  • Patent Document 2 spiroheterocyclic compounds
  • Patent Document 3 spirocyclic amide compounds
  • diuretics calcium antagonists, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB), direct renin inhibitors, sympathetic blockers, ⁇ 2 receptor stimulants have been developed and are used as antihypertensive drugs in accordance with patient symptoms.
  • ACEI angiotensin converting enzyme inhibitors
  • ARB angiotensin receptor antagonists
  • direct renin inhibitors sympathetic blockers
  • sympathetic blockers ⁇ 2 receptor stimulants
  • Non-Patent Documents 4 to 6 Non-Patent Documents 4 to 6
  • sEH inhibitors can be antihypertensive agents that are antihypertensive for high blood pressure associated with the progression of the disease but do not exhibit antihypertensive effects for normal blood pressure. It was.
  • an object of the present invention is to provide a medicine 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.
  • X is —C ( ⁇ O) NHR 1 , —C ( ⁇ O) —ML or —S ( ⁇ O) 2 —ML
  • O) NHR 1 is —C ( ⁇ O) —ML or —S ( ⁇ O) 2 —ML
  • O) 2 -ML it is —C ( ⁇ O) NHR 1 , wherein L is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, carbon A cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 10 carbon atoms
  • M may be an alkylene group having 1 to 8 carbon atoms, a cycloalkylene group having 3 to 6 carbon atoms, or a heterocyclylene group having 3 to 6 ring atoms.
  • a phenylene group or a heteroarylene group having 5 to 10 ring atoms (in the alkylene group, the cycloalkylene group and the heterocyclylene group, hydrogen atoms are each independently substituted with 1 to 3 halogen atoms.
  • one methylene group constituting the ring may be replaced by —C ( ⁇ O) —
  • the phenylene group and the heteroarylene group may be R 1 is a phenyl group or a benzyl group (the phenyl group and the benzyl group each independently represent a hydrogen atom on the benzene ring, a halogen atom, a cyano group, or
  • the alkyl group and the alkyloxy group may be substituted with an alkyl group having 1 to 6 carbon atoms or an alkyloxy group.
  • hydrogen atoms may be independently substituted with 1 to 3 halogen atoms.
  • R 2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • A is a methylene group or an oxygen atom.
  • X is —C ( ⁇ O) —ML
  • Y is —C ( ⁇ O) NHR 1
  • R 1 is hydrogen at least at the 4-position on the benzene ring.
  • An atom is a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms (in the alkyl group and the alkyloxy group, hydrogen atoms are each independently substituted with 1 to 3 halogen atoms. It is preferably a phenyl group or a benzyl group substituted by
  • the inhibitory activity against sEH can be increased.
  • R 1 is an alkyl group or alkyloxy group in which at least the 4-position hydrogen atom on the benzene ring has 1 to 6 carbon atoms (the alkyl group and the alkyloxy group are each a hydrogen atom) Are each independently substituted with 1 to 3 halogen atoms), and A is more preferably an oxygen atom.
  • metabolic stability in the living body can be enhanced.
  • L is a hydrogen atom, a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms
  • M is a phenylene group or a ring structure which may be condensed with a heterocyclyl group. More preferably, it is a heteroarylene group having 5 to 10 atoms
  • R 1 is a phenyl group in which the hydrogen atom at the 4-position on the benzene ring is substituted with a trifluoromethyl group or a trifluoromethoxy group.
  • the present invention also provides a pharmaceutical and an sEH inhibitor containing the above diaza spiro urea derivative or a pharmacologically acceptable salt thereof as an active ingredient.
  • This medicament can be suitably used as a therapeutic or preventive agent for hypertension.
  • the diaza spiro urea derivative of the present invention has a high sEH inhibitory activity and exhibits a high therapeutic or preventive effect on hypertension.
  • the medicament of the present invention has a medicinal effect for treating or preventing hypertension based on the mechanism, and does not exhibit a rapid antihypertensive action against normal blood pressure, and therefore can be used as a pathologically selective antihypertensive agent.
  • the diaza spiro urea derivative of the present invention or a pharmacologically acceptable salt thereof is characterized by being represented by the following general formula (I).
  • X is —C ( ⁇ O) NHR 1 , —C ( ⁇ O) —ML or —S ( ⁇ O) 2 —ML
  • O) NHR 1 is —C ( ⁇ O) —ML or —S ( ⁇ O) 2 —ML
  • M may be an alkylene group having 1 to 8 carbon atoms, a cycloalkylene group having 3 to 6 carbon atoms, or a heterocyclylene group having 3 to 6 ring atoms.
  • a phenylene group or a heteroarylene group having 5 to 10 ring atoms (in the alkylene group, the cycloalkylene group and the heterocyclylene group, hydrogen atoms are each independently substituted with 1 to 3 halogen atoms.
  • one methylene group constituting the ring may be replaced by —C ( ⁇ O) —
  • the phenylene group and the heteroarylene group may be R 1 is a phenyl group or a benzyl group (the phenyl group and the benzyl group each independently represent a hydrogen atom on the benzene ring, a halogen atom, a cyano group, or
  • the alkyl group and the alkyloxy group may be substituted with an alkyl group having 1 to 6 carbon atoms or an alkyloxy group.
  • hydrogen atoms may be independently substituted with 1 to 3 halogen atoms.
  • R 2 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
  • A is a methylene group or an oxygen atom.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C1-C6 alkyl group means a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms, such as a methyl group, Examples thereof include an ethyl group, a 1-propyl group, a 2-propyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-2-propyl group (tert-butyl group), and a 2-methyl-1-propyl group.
  • C 1-6 alkyloxy group means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, -Propyloxy group, 1-butyloxy group or 2-butyloxy group.
  • hydrogen atoms may be independently substituted with 1 to 3 halogen atoms.
  • examples of the alkyl group include a trifluoromethyl group
  • 2- Examples include a fluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloromethyl group, or a 2,2,2-trichloroethyl group.
  • examples of the alkyloxy group include a trifluoromethoxy group, 2, 2,2-trifluoroethoxy group or 2-fluoroethoxy group may be mentioned.
  • C3-C6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • cycloalkyl group having 4 to 10 carbon atoms means a group in which a hydrogen atom of a methyl group, an ethyl group, a propyl group or a butyl group is substituted with the above cycloalkyl group having 3 to 6 carbon atoms.
  • examples thereof include a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclopropylbutyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.
  • 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.
  • Heteroaryl group having 5 to 10 ring atoms means a ring atom containing 1 to 4 identical or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • each hydrogen atom may be independently substituted with 1 to 3 halogen atoms or an alkyl group having 1 to 6 carbon atoms
  • the phenyl group in this case include a 2-fluorophenyl group, a 4-fluorophenyl group, a 2,6-difluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, and a 4-chlorophenyl group.
  • the heteroaryl group include 2-chloropyridyl group, 4-chloropyridyl group, 5-methylpyrazinyl group, 3-methylisoxazolyl group, and 1,3-dimethylpyrazolyl group.
  • the phenyl group in L of the general formula (I) and the above heteroaryl group may be condensed with a heterocyclyl group.
  • examples of the phenyl group include a 2,3-dihydrobenzofuranyl group, a benzoyl group, and the like.
  • examples of the heteroaryl group include 2,3-dihydrofuro [2,3-b] pyridinyl group and 2,3-dihydrofuro [2,3-c] pyridinyl group.
  • the “C 1-8 alkylene group” means a straight chain having 1 to 8 carbon atoms or a branched saturated hydrocarbon chain having 3 to 8 carbon atoms, such as a methylene group, Examples thereof include an ethylene group, a propylene group, an isopropylene group, a butylene group, an isobutylene group, a pentylene group, an isopentylene group, and a hexylene group.
  • C3-C6 cycloalkylene group means a cyclic saturated hydrocarbon chain having 3 to 6 carbon atoms, such as a cyclopropylene group, a cyclobutylene group, a cyclopentylene group or a cyclohexylene group. Is mentioned.
  • heterocyclylene group having 3 to 6 ring atoms refers to a ring atom containing one or two ring atoms that are the same or different from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • each hydrogen atom may be independently substituted with 1 to 3 halogen atoms.
  • alkylene group in this case include fluoromethylene Group, difluoromethylene group, 1-fluoroethylene group, 1,1-difluoroethylene group, 1,2-difluoroethylene group, 1,1-difluoropropylene group, 2,2-difluoropropylene group, 3,3-difluoropropylene Group, 1-fluoroisopropylene group, 2-fluoroisopropylene group, 1,2-difluoroisopropylene group, 2,2-difluoroisopropylene group, 1,2,2-trifluoroisopropylene group, 2,2, 2-trifluoroisopropylene group, 1,1-difluorobutylene group, 2,2-difluoro Tylene group, 3,3-difluorobutylene group, 4,4-difluorobutylene group, 1,
  • examples of the cycloalkylene group include a fluorocyclopropylene group, a 1,1-difluorocyclopropylene group, 1,2- Difluorocyclopropylene group, fluorocyclobutylene group, 1,1-difluorocyclobutylene group, fluorocyclopen And the like, in this case, as a heterocyclylene group, such as a ene group, a 1,1-difluorocyclopentylene group, a chlorocyclopentylene group, a fluorocyclohexylene group, a 1,1-difluorocyclohexylene group, or a chlorocyclohexylene group.
  • a heterocyclylene group such as a ene group, a 1,1-difluorocyclopentylene group, a chlorocyclopentylene group, a fluorocyclohexylene group, a 1,1-difluorocyclohex
  • a thiopyranylene group or a 4,4-difluorotetrahydrothiopyranylene group can be mentioned.
  • heterocyclylene group one methylene group constituting the ring may be replaced by —C ( ⁇ O) —.
  • examples of the heterocyclylene group include pyrrolidine-2-onylene.
  • “Heteroarylene group having 5 to 10 ring atoms” means 5 to 4 ring atoms containing the same or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom as ring atoms.
  • the condensed heteroaryl group include a quinolylene group and an isoquinolylene group.
  • Benzofuranylene group, isobenzofuran furanyl alkylene group, benzimidazolylthio alkylene group, benztriazolyl alkylene groups include benzoxazolyl alkylene group or a benzothiazolyl alkylene group.
  • the phenylene group and the above heteroarylene group may be condensed with a heterocyclyl group.
  • examples of the phenylene group include a phenylene group, a 2,3-dihydrobenzofuranylene group, a benzo [d] [2, 3] Dioxorylene group, 2,3-dihydrobenzo [b] [1,4] benzodioxynylene group, indolinylene group, isoindolinylene group or 3,4-dihydro-2H-benzo [b] [1,4]
  • examples of the heteroarylene group include 2,3-dihydrofuro [2,3-b] pyridinylene group, 2,3-dihydrofuro [2,3-c] pyridinylene group, Dihydrofuro [3,2-b] pyridinylene group, 2,3-dihydrofuro [3,2-c] pyridylene group, [1,3] dioxolo [4,5-
  • the hydrogen atoms on the benzene ring are each independently a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group (the above alkyl group).
  • the alkyloxy group may be substituted with hydrogen atoms each independently substituted with 1 to 3 halogen atoms).
  • phenyl group for example, 4-tri Fluoromethylphenyl group, 4-trifluoromethoxyphenyl group, 4-difluoromethoxyphenyl group, 4-chlorophenyl group, 4-methylphenyl group, 4-cyanophenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4 -Tert-butylphenyl group, 3,4-dichlorophenyl group, 3-chloro-4-trifluoromethylphenyl , 3-chloro-4-trifluoromethoxyphenyl group, 3-methyl-4-chlorophenyl group, 3-methyl-4-trifluoromethylphenyl group or 3-methyl-4-trifluoromethoxyphenyl group.
  • benzyl group examples include 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-trifluoromethyl.
  • therapeutic agent or prophylactic agent includes not only those used for treatment or prevention but also those used simultaneously for both the purpose of treatment and prevention.
  • X is preferably —C ( ⁇ O) —ML
  • Y is preferably —C ( ⁇ O) NHR 1 .
  • L is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group (the alkyl group and the alkyloxy group have a hydrogen atom substituted with 1 to 3 halogen atoms).
  • a cycloalkylalkyl group having 4 to 10 carbon atoms or a cycloalkyl group having 3 to 6 carbon atoms is preferable, and a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms is more preferable. More preferably a halogen atom, a cyano group or a methyl group.
  • M represents an alkylene group having 1 to 8 carbon atoms (in the alkylene group, a hydrogen atom may be independently substituted with 1 to 3 halogen atoms) or a heterocyclyl group may be condensed. It is preferably a good phenylene group or a heteroarylene group having 5 to 10 ring atoms, more preferably a phenylene group which may be condensed with a heterocyclyl group or a heteroarylene group having 5 to 10 ring atoms, More preferably, it is a phenylene group or an isoxazolylene group.
  • R 1 is a hydrogen atom at least at the 4-position on the benzene ring, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms (the alkyl group and the alkyloxy group are each independently a hydrogen atom; Preferably a phenyl group or a benzyl group which may be substituted with 1 to 3 halogen atoms), and at least the hydrogen atom at the 4-position on the benzene ring is an alkyl having 1 to 6 carbon atoms.
  • a phenyl group substituted with a group or an alkyloxy group (wherein the alkyl group and the alkyloxy group are each independently substituted with 1 to 3 halogen atoms).
  • it is a phenyl group in which at least the 4-position hydrogen atom on the benzene ring is substituted with a trifluoromethyl group or a trifluoromethoxy group More preferably.
  • R 2 is preferably an alkyl group having 1 to 6 carbon atoms, and more preferably a methyl group.
  • A is preferably an oxygen atom.
  • diaza spiro urea derivative (I) examples include, for example, minerals such as sulfuric acid, hydrochloric acid or phosphoric acid. Salt with acid, salt with acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, organic acid such as methanesulfonic acid or benzenesulfonic acid, salt with amine such as trimethylamine or methylamine, sodium ion, potassium Examples thereof include salts with metal ions such as ions or calcium ions.
  • diazaspirourea derivative (I) As the starting materials and reagents used for the production of the diazaspirourea derivative (I), commercially available products may be used as they are, or known methods (WO 2009/085185, US Pat. No. 5,545,578) may be used. No. specification and International Publication No. 2007/030061) can also be chemically synthesized.
  • the compounds represented by the general formulas (Ia) and (Ib) are, for example, diazaspiroamines as shown in the following schemes 1 and 2. It can be produced by undergoing an amidation step or a sulfonamidation step for the derivative (II).
  • 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 1 below.
  • Scheme 1 can be performed.
  • Examples of the solvent used for the amidation reaction with acid chloride include dichloromethane, 1,2-dichloroethane, acetonitrile, N, N-dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), dioxane, diethyl ether or 1 , 2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • DMF dimethylformamide
  • THF tetrahydrofuran
  • 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 (hereinafter DIPEA), triethylamine, pyridine, and N-methylmorpholine, with DIPEA or triethylamine being preferred.
  • DIPEA diisopropylethylamine
  • pyridine pyridine
  • N-methylmorpholine a diisopropylethylamine
  • 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 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.
  • Examples of the condensing agent used in the condensation reaction with carboxylic acid 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 hexafluorophos
  • HBTU bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate
  • HATU 7-azabenzotriazol-1-yl
  • HATU As the solvent used in the condensation reaction with carboxylic acid, when HATU is used as the condensing agent, for example, DMF, THF, 1,4-dioxane, 1,3-dimethyl-2-imidazolidinone, diethyl ether or 1,2 -Dimethoxyethane is mentioned, but DMF or 1,3-dimethyl-2-imidazolidinone is preferred, and DMF is more preferred.
  • the equivalent of the condensing agent used for the condensation reaction with the carboxylic acid is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the diazaspiroamine derivative (II).
  • the equivalent of the carboxylic acid used in the condensation reaction with the carboxylic acid 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 for the condensation reaction with carboxylic acid include organic bases such as DIPEA, triethylamine, pyridine, and N-methylmorpholine, with DIPEA 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 with carboxylic acid 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 with carboxylic acid 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 diazaspiroamine derivative (II) in the condensation reaction with the carboxylic acid is preferably 0.01 to 100M, more preferably 0.01 to 10M, and even more 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) as shown in Scheme 2 below.
  • Scheme 2 Scheme 2 [Wherein L, M, R 1 and A are the same as defined above. ]
  • Examples of the solvent used for the sulfonamidation reaction with sulfonyl chloride include dichloromethane, 1,2-dichloroethane, acetonitrile, THF, dioxane, diethyl ether, and 1,2-dimethoxyethane, but dichloromethane, 1,2- Dichloroethane, acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the sulfonyl chloride used in the sulfonamidation reaction with the sulfonyl chloride is preferably 1 to 10 equivalents, more preferably 1 to 3 equivalents, and further preferably 1 to 1.5 equivalents relative to the diazaspiroamine derivative (II). preferable.
  • Examples of the base used for the sulfonamidation reaction with sulfonyl chloride include organic bases such as DIPEA, triethylamine, pyridine and N-methylmorpholine, with DIPEA 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 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 3 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 formation with a urea agent and an amine in the presence of a base. It can be carried out by reaction.
  • Examples of the solvent used for the ureaization reaction with isocyanate include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether, and 1,2-dimethoxyethane. -Dichloroethane, acetonitrile or THF is preferred, 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 in the ureaation reaction with isocyanate include organic bases such as DIPEA, triethylamine, pyridine, and N-methylmorpholine, with DIPEA 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 ureation reaction with a urea agent and an amine include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether or 1,2-dimethoxyethane. 1,2-dichloroethane, acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • urea agent used in the urea reaction with an urea agent and an amine examples include N, N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl 4-chloroformate or phenyl 4-nitroformate. -Phenyl chloroformate or phenyl 4-nitroformate are preferred.
  • the equivalent of the urea agent 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 protected diazaspiroamine derivative (III).
  • the equivalent of the amine used in the urea reaction with the urea agent and the amine 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 for the ureaation reaction with a urea agent and an amine include organic bases such as DIPEA, triethylamine, pyridine and N-methylmorpholine, with DIPEA 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 amine 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 amine 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 ureaation reaction with a urea agent and an amine 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 diazaspirourea derivative (IV) can be carried out by the method of Green et al. (“Protective Groups in Organic Synthesis”, 3rd edition, John Wiley & Sons, Inc., 1999).
  • Green et al. Protective Groups in Organic Synthesis”, 3rd edition, John Wiley & Sons, Inc., 1999.
  • the protecting group of the protected diazaspirourea derivative (IV) is a benzyl group
  • the protecting group is removed by performing a hydrogenation reaction in the presence of a metal catalyst, and the diazaspiroamine derivative (II) Can lead to.
  • the compound represented by the general formula (Ic) or (Id) starts from the protected diaza spiro amine derivative (III) as shown in Scheme 4.
  • Substituent Y is introduced into a substance in the same manner as in the amidation step or sulfonamidation step to obtain intermediate (Va) or (Vb), and then the same method as in the above deprotection step To obtain an amine intermediate (VI-a) or (VI-b), which can be produced by the same method as in the urea step.
  • Scheme 4 [Wherein J represents a protecting group. L, M, R 1 and A 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.
  • 1-oxa-4,9-diazaspiro [5.5] undecane derivatives can be obtained by referring to International Publication No. 2009/085185 or International Publication No. 2009/098448. Can be manufactured.
  • the addition step can be performed by reaction with acrylonitrile in the presence of a base for the aldehyde derivative (VII).
  • a base for the aldehyde derivative (VII) As the aldehyde derivative (VII), a commercially available product may be used as it is, or it may be chemically synthesized with reference to International Publication No. 2009/108827.
  • Examples of the solvent used for the addition reaction with acrylonitrile include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, 1,4-dioxane, diethyl ether or 1,2-dimethoxyethane. 1,2-dichloroethane, acetonitrile, THF or 1,4-dioxane is preferred, and THF or 1,4-dioxane is more preferred.
  • the equivalent of acrylonitrile used for the addition reaction with acrylonitrile 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 aldehyde derivative (VII).
  • Examples of the base used for the addition reaction with acrylonitrile include, for example, organic acid salts such as sodium carbonate or potassium carbonate, inorganic bases such as sodium hydroxide or potassium hydroxide, or ammonium salts such as trimethylbenzylammonium hydroxide or tetraethylammonium hydroxide.
  • organic acid salts such as sodium carbonate or potassium carbonate
  • inorganic bases such as sodium hydroxide or potassium hydroxide
  • ammonium salts such as trimethylbenzylammonium hydroxide or tetraethylammonium hydroxide.
  • trimethylbenzylammonium hydroxide or tetraethylammonium hydroxide is preferable, and trimethylbenzylammonium hydroxide is more preferable.
  • the equivalent of the base is preferably from 0.01 to 100 equivalents, more preferably from 0.01 to 1 equivalent, based on the aldehyde derivative (VII).
  • the reaction temperature in the addition reaction with acrylonitrile is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time in the addition reaction with acrylonitrile is preferably 30 minutes to 72 hours, more preferably 3 hours to 72 hours, and even more preferably 12 hours to 72 hours.
  • the concentration at the start of the reaction of the aldehyde derivative (VII) in the addition reaction with acrylonitrile is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.
  • the reduction of the nitrile group and the reductive amination step can be performed by a hydrogenation reaction in the presence of a metal catalyst and an acid for the nitrile derivative (VIII).
  • Examples of the solvent used for the reduction of the nitrile group and the reductive amination reaction include ethyl acetate, ethanol, and methanol, and methanol or ethanol is preferable.
  • Examples of the metal catalyst used for the reduction of the nitrile group and the reductive amination reaction include platinum oxide, palladium hydroxide / carbon or palladium / carbon, with palladium hydroxide / carbon or palladium / carbon being preferred.
  • the equivalent amount of the metal catalyst used for the reduction of the nitrile group and the reductive amination reaction is preferably 0.01 to 10 equivalents, more preferably 0.05 to 3 equivalents, and more preferably 0.1 to 3 equivalents relative to the nitrile derivative (VIII). One equivalent is more preferred.
  • Examples of the acid used for the reduction of the nitrile group and the reductive amination reaction include hydrochloric acid, sulfuric acid, and nitric acid, with hydrochloric acid being preferred.
  • the equivalent of the acid is preferably from 0.1 to 10 equivalents, more preferably from 1 to 3 equivalents, and even more preferably from 1 to 1.5 equivalents based on the nitrile derivative (VIII).
  • the hydrogen pressure in the nitrile group reduction and reductive amination reaction is preferably 1 to 10 atm, more preferably 1 to 5 atm, and further preferably 3 to 5 atm.
  • the concentration at the start of the reaction of the nitrile derivative (VIII) in the reduction of the nitrile group and the reductive amination reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and even more preferably 0.05 to 1M.
  • the reagent may be isolated and purified by a method such as extraction, distillation, chromatography or recrystallization, if necessary.
  • 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 and 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 can be 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. .
  • 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 introduction of the substrate (40 ⁇ M). 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 diazaspirourea derivative (I) or a pharmacologically acceptable salt thereof can be evaluated using an animal model.
  • animal models include an angiotensin II-induced hypertension model, SHR model, or salt-sensitive hypertension 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 of pharmaceuticals.
  • 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 agent 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
  • 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 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, combination or the like.
  • 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, antimetabolites 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 or etopoxide.
  • 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 9- (2-Fluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 1) Synthesis of: [Step 1] Synthesis of 4- (aminomethyl) -1-benzylpiperidin-4-ol (Reference Example Compound 1): Trimethylsilyl cyanide (16 g, 0.12 mol) was added dropwise to a mixture of 1-benzylpiperidin-4-one (20 g, 0.11 mol) and triethylamine (3.7 mL, 0.026 mol) at room temperature under an argon atmosphere. .
  • Step 3 Synthesis of 9-benzyl-1-oxa-4,9-diazaspiro [5.5] undecan-3-one (Reference Example Compound 3): To a solution of potassium tert-butoxide (0.44 g, 3.9 mmol) in THF (5.0 mL) at ⁇ 78 ° C., N-((1-benzyl-4-hydroxypiperidin-4-yl) methyl) -2- A solution of chloroacetamide (Reference Example Compound 2) (0.50 g, 1.7 mmol) in THF (5.0 mL) was added dropwise. After stirring at room temperature for 35 minutes, the reaction solution was concentrated under reduced pressure.
  • Step 4 Synthesis of 9-benzyl-1-oxa-4,9-diazaspiro [5.5] undecane (Reference Example Compound 4): Under ice cooling, 9-benzyl-1-oxa-4,9-diazaspiro [5.5] undecan-3-one (reference) was added to a solution of lithium aluminum hydride (0.17 g, 4.6 mmol) in THF (10 mL).
  • Example compound 3) (0.60 g, 2.3 mmol
  • THF (10 mL) was added dropwise. After stirring for 30 minutes under ice cooling, the mixture was stirred for 30 minutes at room temperature.
  • Step 5 Synthesis of 9-benzyl-N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 5): Under ice-cooling, 9-benzyl-1-oxa-4,9-diazaspiro [5.5] undecane (Reference Example Compound 4) (2.3 g, 9.3 mmol) in chloroform (20 mL) solution in 4- (tri Fluoromethoxy) phenyl isocyanate (1.9 g, 9.3 mmol) was added. After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure.
  • Example 2 9- (5-methylisoxazole-3-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide Synthesis of Example Compound 2): Under ice cooling, N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.40 g, 1.
  • Example Compound 2 was obtained. ) obtained.
  • Example 3 9- (4-Cyanobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 3) Synthesis of: [Step 1] Synthesis of 9-benzyl-N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 7): Under ice-cooling, 9-benzyl-1-oxa-4,9-diazaspiro [5.5] undecane (Reference Example Compound 4) (2.0 g, 8.1 mmol) in chloroform (20 mL) was added to 4- (tri Fluoromethyl) phenyl isocyanate (1.7 g, 8.9 mmol) was added.
  • Example 4 9- (4-Chloropicolinoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter referred to as Example Compound 4) ) Synthesis: Under ice-cooling, N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.15 g, 0.
  • Example Compound 4 was obtained. ) obtained.
  • Example 5 9- (2,6-Difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter referred to as Example compound) 5) Synthesis: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.020 g, 0.056 mmol), 2 , 6-Difluorobenzoyl chloride (0.012 g, 0.067 mmol) was used to carry out the same reaction as in Example 1 [Step 7] to obtain 0.027 g (96%) of Example Compound 5.
  • Example 6 Synthesis of 9-pivaloyl-N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 6): N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 0.021 g (86%) of Example Compound 6 was obtained by carrying out the same reaction as in Example 1 [Step 7] using baroyl chloride (0.0084 g, 0.070 mmol).
  • Example 7 9- (2-acetamidobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (hereinafter, Example Compound 7) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8) (0.018 g, 0.052 mmol), N -By using the same reaction as in Example 2 using acetylanthranilic acid (0.011 g, 0.064 mmol), 0.0038 g (14%) of Example Compound 7 was obtained.
  • Example 8 9- (2-acetamido-4-methylpentanoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Synthesis of Example Compound 8): N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8) (0.018 g, 0.046 mmol), 2 The same reaction as in Example 2 was carried out using -acetamido-4-methylpentanoic acid (0.011 g, 0.064 mmol) to obtain 0.012 g (50%) of Example Compound 8.
  • Example 9 Synthesis of 9-benzoyl-N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 9): N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.024 g, 0.070 mmol), benzoyl 0.022 g (71%) of Example Compound 9 was obtained by performing the same reaction as Example 1 [Step 7] using chloride (0.022 g, 0.10 mmol).
  • Example 10 9- (furan-2-carbonyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 10) ) Synthesis: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 2 -By the same reaction as Example 1 [Step 7] using furoyl chloride (0.0091 g, 0.070 mmol), 0.0040 g (16%) of Example Compound 10 was obtained.
  • Example 11 9- (5-methylpyrazine-2-carbonyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide Synthesis of Example Compound 11): N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.030 g, 0.087 mmol), 5 The same reaction as in Example 2 was performed using -methylpyrazine-2-carboxylic acid (0.013 g, 0.096 mmol) to obtain 0.016 g (40%) of Example Compound 11.
  • Example 12 Synthesis of 9-picolinoyl-N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 12): N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), picoline 0.011 g (41%) of Example Compound 12 was obtained by performing the same reaction as Example 1 [Step 7] using acid chloride hydrochloride (0.030 g, 0.17 mmol).
  • Example 13 9- (2-Cyclopropylacetyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 13) ) Synthesis: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.030 g, 0.086 mmol), cyclo The same reaction as in Example 2 was performed using propylacetic acid (0.013 g, 0.13 mmol) to obtain 0.014 g (39%) of Example Compound 13.
  • Example 14 9- (5-methylpyrazine-2-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter referred to as implementation) Synthesis of Example Compound 14): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.049 g, 0.14 mmol), 5 The same reaction as in Example 2 was performed using -methylpyrazine-2-carboxylic acid (0.025 g, 0.18 mmol) to obtain 0.049 g (75%) of Example Compound 14.
  • Example 15 9- (2-Chlorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 15) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 2 -By using chlorobenzoyl chloride (0.011 g, 0.064 mmol) and carrying out the same reaction as in Example 1 [Step 7], 0.028 g (quantitative) of Example Compound 15 was obtained.
  • Example 16 9- (4-Chlorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 16) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 4 -By using the same reaction as in Example 1 [Step 7] using -chlorobenzoyl chloride (0.011 g, 0.064 mmol), 0.026 g (92%) of Example Compound 16 was obtained.
  • Example 17 9- (3-Cyanobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (hereinafter, Example Compound 17) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 3 -The same reaction as in Example 2 was performed using cyanobenzoic acid (0.0094 g, 0.064 mmol) to obtain 0.017 g (63%) of Example Compound 17.
  • Example 18 9- (2-cyanobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 18) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 2 -The same reaction as in Example 2 was performed using cyanobenzoic acid (0.0094 g, 0.064 mmol) to obtain 0.015 g (53%) of Example Compound 18.
  • Example 19 9- (3-Chlorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (hereinafter, Example Compound 19) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 3 -By using the same reaction as in Example 1 [Step 7] using -chlorobenzoyl chloride (0.011 g, 0.064 mmol), 0.019 g (66%) of Example Compound 19 was obtained.
  • Example 20 9- (3-Hydroxybenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 20) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 3 The reaction was conducted in the same manner as in Example 2 using -hydroxybenzoic acid (0.018 g, 0.064 mmol) to obtain 0.016 g (57%) of Example Compound 20.
  • Example 21 9- (3-acetamidobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 21) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 3 -Acetamide benzoic acid (0.011 g, 0.064 mmol) was used to carry out the same reaction as in Example 2 to obtain 0.028 g (96%) of Example Compound 21.
  • Example 22 9- (2-acetamidobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 22) Synthesis of: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.024 g, 0.068 mmol) at room temperature ), DIPEA (0.025 mL, 0.14 mmol) was added to a solution of phthalimide (0.010 g, 0.068 mmol) in acetonitrile (1.0 mL).
  • Example 23 9- (5-Cyclopropylisoxazole-4-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide Synthesis of Example Compound 23): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.020 g, 0.056 mmol), 5 The same reaction as in Example 2 was carried out using -cyclopropylisoxazole-4-carboxylic acid (0.0094 g, 0.061 mmol) to obtain 0.0089 g (32%) of Example Compound 23.
  • Example 24 N- (4- (trifluoromethoxy) phenyl) -9- (1- (trifluoromethyl) cyclopropanecarbonyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide Synthesis of Example Compound 24): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.021 g, 0.058 mmol), 1 The same reaction as in Example 2 was performed using-(trifluoromethyl) cyclopropanecarboxylic acid (0.0090 g, 0.058 mmol) to obtain 0.010 g (34%) of Example Compound 24.
  • Example 25 9- (1-phenylcyclopropanecarbonyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter referred to as Example compound) 25) Synthesis: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.022 g, 0.061 mmol), 1 -By using phenylcyclopropanecarboxylic acid (0.015 g, 0.092 mmol) in the same manner as in Example 2, 0.020 g (65%) of Example Compound 25 was obtained.
  • Example 26 9- (2- (2-methoxyphenyl) acetyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Synthesis of Example Compound 26): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.012 g, 0.033 mmol), 2 The reaction was conducted in the same manner as in Example 2 using-(2-methoxyphenyl) acetic acid (0.0083 g, 0.050 mmol) to obtain 0.0098 g (58%) of Example Compound 26.
  • Example 27 9- (2- (2-Pyridin-2-yl) acetyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide Synthesis of Example Compound 27 below: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.020 g, 0.056 mmol), 2 The same reaction as in Example 2 was performed using-(2-pyridin-2-yl) acetic acid hydrochloride (0.014 g, 0.083 mmol) to obtain 0.021 g (80%) of Example Compound 27. It was.
  • Example 28 9- (4-Acetamidobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 28) Synthesis of: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.025 g, 0.070 mmol), 4 -Acetamide benzoic acid (0.015 g, 0.083 mmol) was used to carry out the same reaction as in Example 2 to obtain 0.029 g (80%) of Example Compound 28.
  • Example 29 9- (4-Acetamidobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 29) Synthesis of: N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8) (0.020 g, 0.058 mmol), 4 -Acetamide benzoic acid (0.016 g, 0.087 mmol) was used to carry out the same reaction as in Example 2 to obtain 0.020 g (69%) of Example Compound 29.
  • Example 30 9- (2-oxyindoline-5-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter referred to as implementation) Synthesis of Example Compound 30): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.013 g, 0.036 mmol), 2 The same reaction as in Example 2 was performed using -oxyindoline-5-carboxylic acid (0.012 g, 0.068 mmol) to obtain 0.010 g (54%) of Example Compound 30.
  • Example 31 9- (2- (4-methoxyphenyl) acetyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Synthesis of Example Compound 31): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.050 g, 0.14 mmol), 2 The reaction was conducted in the same manner as in Example 2 using-(4-methoxyphenyl) acetic acid (0.023 g, 0.14 mmol) to obtain 0.060 g (85%) of Example Compound 31.
  • Example 32 9- (2- (3-Methylisoxazol-5-yl) acetyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4- Synthesis of Carboxamide (hereinafter Example Compound 32): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.032 g, 0.090 mmol), 2 The same reaction as in Example 2 was performed using-(3-methylisoxazol-5-yl) acetic acid (0.019 g, 0.13 mmol) to obtain 0.026 g (79%) of Example Compound 32. It was.
  • Example 33 9- (3-Cyclopropyl-1H-pyrazole-4-carbonyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide Synthesis of (Example Compound 33): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.020 g, 0.056 mmol), 3 The same reaction as in Example 2 was performed using -cyclopropyl-1H-pyrazole-4-carboxylic acid (0.011 g, 0.072 mmol) to obtain 0.0040 g (15%) of Example Compound 33. .
  • Example 34 9- (4-Cyanobenzoyl) -N- (4-trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 34) Synthesis: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.030 g, 0.083 mmol), 4 -By using cyanobenzoyl chloride (0.017 g, 0.10 mmol) and carrying out the same reaction as in Example 1 [Step 7], 0.033 g (80%) of Example Compound 34 was obtained.
  • Example 35 9- (4-Fluorobenzoyl) -N- (4-trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter referred to as Example Compound 35) Synthesis: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.030 g, 0.083 mmol), 4 Using 0.0-fluorobenzoyl chloride (0.016 g, 0.10 mmol), the same reaction as in Example 1 [Step 7] was carried out to obtain 0.032 g (80%) of Example Compound 35.
  • Example 36 9- (1,3-Dimethyl-1H-pyrazole-5-carbonyl) -N- (4-trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide Synthesis of (Example Compound 36): N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (0.030 g, 0.083 mmol), 1 , 3-Dimethyl-1H-pyrazole-5-carbonyl chloride (0.016 g, 0.10 mmol) was used for the same reaction as in Example 1 [Step 7] to give 0.033 g of Example Compound 36 ( 80%).
  • Example 37 9- (6-Chloropicolinoyl) -N- (4-trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 37) Synthesis of: N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 6) (0.15 g, 0.42 mmol), 6 -By using the same reaction as in Example 2 using chloropicolinic acid (0.079 g, 0.50 mmol), 0.14 g (68%) of Example Compound 37 was obtained.
  • MiniBlock®-XT (48-position; Mettler Toledo Bohdan) reaction tube was charged with carboxylic acid (1 equivalent to Reference Compound 6), HATU (0.024 g, 0.063 mmol) in DMF (0. 50 mL) solution was added DIPEA (0.018 mL, 0.10 mmol) in DMF (0.10 mL). After stirring at room temperature for 5 minutes, N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound) was added to the reaction solution.
  • Example compounds 38 to 49 the LC retention time and [M + H] + or [MH] ⁇ were measured using the analysis method described below.
  • Example 51 Synthesis of N- (2,4-dichlorobenzyl) -9- (2-fluorobenzoyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 51) : Performed with N- (2,4-dichlorobenzyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 10) (0.030 g, 0.084 mmol) The reaction was conducted in the same manner as in Example 1 [Step 7] to obtain 0.034 g (85%) of Example Compound 51.
  • Example 52 9- (2-cyclopropylacetyl) -N- (2,4-dichlorobenzyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Example Compound 52) Synthesis: N- (2,4-dichlorobenzyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (Reference Example Compound 10) (0.030 g, 0.084 mmol), cyclopropylacetic acid 0.024 g (60%) of Example Compound 52 was obtained by performing the same reaction as in Example 2 using (0.010 g, 0.10 mmol).
  • Example 53 N- (2,4-dichlorobenzyl) -9- (5-methylpyrazine-2-carbonyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4-carboxamide (hereinafter referred to as Example compound) 53) Synthesis: N- (2,4-dichlorobenzyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 10) (0.030 g, 0.084 mmol), 5-methyl The same reaction as in Example 2 was performed using pyrazine-2-carboxylic acid (0.014 g, 0.10 mmol) to obtain 0.040 g (quantitative) of Example Compound 53.
  • Example 54 9-((1-Methyl-1H-imidazol-4-yl) sulfonyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecan-4- Synthesis of Carboxamide (hereinafter Example Compound 54): N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8) (0.045 g, 0.13 mmol) at room temperature ), DIPEA (0.069 mL, 0.40 mmol) in dichloromethane (2.0 mL) was added 1-methyl-1H-imidazole-4-sulfonyl chloride (0.024 g, 0.13 mmol).
  • Example 55 4- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-9-carboxamide (hereinafter referred to as Example compound) 55) Synthesis: 9-Benzyl-1-oxa-4,9-diazaspiro [5.5] undecane (Reference Example Compound 4) (0.018 g, 0.071 mmol), triethylamine (0.015 mL, 0.11 mmol) in dichloromethane at room temperature To the (1.0 mL) solution was added 2,6-difluorobenzoyl chloride (0.014 g, 0.079 mmol).
  • Example 56 Synthesis of 9- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (hereinafter, Example Compound 56) : [Step 1] Synthesis of tert-butyl 4-formylpiperidine-1-carboxylate (Reference Example Compound 11): Under ice cooling, des Martin reagent (1.1 g, 2.6 mmol) was added to a solution of tert-butyl 4- (hydroxymethyl) piperidine-1-carboxylate (0.50 g, 2.3 mmol) in dichloromethane (10 mL). It was.
  • Step 2 Synthesis of tert-butyl 4- (2-cyanoethyl) -4-formylpiperidine-1-carboxylate (Reference Example Compound 12): Under ice cooling, tert-butyl 4-formylpiperidine-1-carboxylate (Reference Example Compound 11) (0.26 g, 1.2 mmol) in 1,4-dioxane (0.50 mL) solution in acrylonitrile (0.088 mL, 1 .3 mmol), 10% aqueous benzyltriethylammonium hydroxide (0.020 mL) was added.
  • Step 3 Synthesis of tert-butyl 2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 13): To a solution of tert-butyl 4- (2-cyanoethyl) -4-formylpiperidine-1-carboxylate (Reference Example Compound 12) (0.13 g, 0.49 mmol) in ethanol (6.5 mL) was added 10% by weight palladium / Carbon (0.11 g), 10% hydrogen chloride / methanol solution (0.15 mL) was added. The mixture was stirred at room temperature for 25 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, and the resulting filtrate was concentrated under reduced pressure.
  • Example 57 Synthesis of 9- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide
  • Example Compound 57 [Step 1] Synthesis of tert-butyl 2-((4- (trifluoromethoxy) phenyl) carbamoyl) -2,9-diazaspiro [5.5] undecane-9-carboxylate
  • Reference Example Compound 15 tert-Butyl 2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 13) (0.053 g, 0.21 mmol), 4- (trifluoromethyl) phenyl isocyanate (0.072 mL, By performing the same reaction as in Example 50 [Step 1] using 0.79 mmol), 0.068 g (50%) of Reference Example Compound 15
  • Example Compound 57 N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (Reference Example Compound 16) (0.0044 g, 0.013 mmol), 2,6-difluoro 0.0058 g (93%) of Example Compound 57 was obtained by performing the same reaction as in Example 1 [Step 7] using benzoyl chloride (0.0025 g, 0.014 mmol).
  • Example 58 Synthesis of 9-pivaloyl-N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (hereinafter, Example Compound 58): N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (Reference Example Compound 16) (0.0064 g, 0.019 mmol), pivaloyl chloride ( 0.0027 g (0.022 mmol) was used to carry out the same reaction as in Example 1 [Step 7] to obtain 0.0060 g (75%) of Example Compound 58.
  • Example 59 Synthesis of 2- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,9-diazaspiro [5.5] undecane-9-carboxamide
  • Example Compound 59 [Step 1] Synthesis of tert-butyl 2- (2,6-difluorobenzoyl) -2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 17): tert-Butyl 2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 13) (0.037 g, 0.14 mmol), 2,6-difluorobenzoyl chloride (0.026 g, 0.14 mmol) ) Was used to carry out the same reaction as in Example 1 [Step 7] to obtain 0.017 g (88%) of Reference Example Compound 17.
  • Comparative Example 2 Synthesis of 7-benzyl-N- (4-phenoxyphenyl) -2,7-diazaspiro [4.4] nonane-2-carboxamide (hereinafter, Comparative Compound 2):
  • Example 50 [2-benzyl-2,7-diazaspiro [4.4] nonane dihydrochloride (0.010 g, 0.35 mmol), 4-phenoxyphenyl isocyanate (0.015 g, 0.69 mmol) was used. The same reaction as in Step 1] was carried out to obtain 0.012 g (47%) of Comparative Example Compound 2.
  • Example 60 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 diaza spiro urea derivative (I) has a high inhibitory activity on the enzyme reaction of human sEH.
  • Example 61 Drug efficacy evaluation test on blood pressure of spontaneously hypertensive model rat (SHR): This example relates to Example Compound 1, 2, 3 and 4 and Comparative Example Compound 2 described in publicly known literature (International Publication No. 2007/007069) which is a preferred embodiment as an active ingredient of the above-mentioned therapeutic agent for hypertension. This was carried out in order to examine the therapeutic effect of hypertension by the administration of the above diazaspirourea derivative (I) using the direct method by cannulation of the femoral artery.
  • SHR spontaneously hypertensive model rat
  • 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 1, 2, 3 or 4 or Comparative Compound 2 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 average value of MBP 3-4 hours after administration, the MBP value 4 hours after administration, the average value of MBP 4-5 hours after administration, the MBP value 5 hours after administration, and 5-6 hours after administration.
  • the average value of the subsequent MBP was taken as the MBP value 6 hours after administration, and was calculated as the difference from the average value of 90 minutes before administration. The results are shown in FIG.
  • Example Compound 1 administration group
  • Example Compound 2 administration group
  • Example Compound 3 administration group
  • Example Compound 4 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 2 administration group.
  • Mark in a figure shows that it is statistically significant compared with a solvent administration group (t test, p ⁇ 0.05).
  • Example 62 Effect evaluation test on blood pressure of normal rat (SD rat):
  • the diazaspirourea derivative (I) was obtained by directly using the femoral artery cannulated direct insertion of Example Compound 1 and telmisartan, which are preferred embodiments as active ingredients of the above-mentioned therapeutic agent for hypertension. ) was conducted in order to examine the effect on normal blood pressure.
  • 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 1 or telmisartan was suspended in a 0.5% methylcellulose solution containing 0.5% Tween 80, and Example Compound 1 was orally administered at a dose of 30 mg / kg body weight. It was orally administered at a dose of 3 mg or 10 mg per kg. 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 average value of MBP 3-4 hours after administration, the MBP value 4 hours after administration, the average value of MBP 4-5 hours after administration, the MBP value 5 hours after administration, and 5-6 hours after administration
  • the average value of the subsequent MBP is defined as the MBP value 6 hours after administration, and is the difference from the average value of MBP for 90 minutes before administration. The results are shown in FIG.
  • the diazaspirourea derivative of the present invention inhibits sEH activity and increases EETs in the body, thereby exhibiting an antihypertensive action and a protective action on vascular endothelium. Or it can be used as a preventive agent.

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  • Chemical & Material Sciences (AREA)
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Abstract

L'objet de la présente invention consiste en un médicament présentant un effet thérapeutique sur une tension sanguine élevée basé sur l'activité inhibitrice dirigée contre sEH. La présente invention concerne un dérivé de diazaspiro-urée représenté dans la figure ou un sel pharmaceutiquement acceptable.
PCT/JP2013/052134 2012-01-31 2013-01-31 Dérivé de diazaspiro-urée et son utilisation pharmaceutique WO2013115294A1 (fr)

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RU2779618C2 (ru) * 2015-11-16 2022-09-12 Эстев Фармасьютикалз, С. А. Оксадиазаспиросоединения для лечения злоупотребления наркотическими средствами и зависимости от них
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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Publication number Priority date Publication date Assignee Title
JP2017516817A (ja) * 2014-06-02 2017-06-22 ラボラトリオス・デル・デエレ・エステベ・エセ・ア 疼痛に対する多様な活性を有する１−オキサ−４，９−ジアザスピロウンデカン化合物のアミド誘導体
WO2017084752A1 (fr) * 2015-11-16 2017-05-26 Laboratorios Del Dr. Esteve, S.A. Composés oxadiazaspiro pour le traitement de l'abus de drogues et de la toxicomanie
AU2016356488B2 (en) * 2015-11-16 2020-10-22 Esteve Pharmaceuticals, S.A. Oxadiazaspiro compounds for the treatment of drug abuse and addiction
US10927128B2 (en) 2015-11-16 2021-02-23 Esteve Pharmaceuticals. S.A. Oxadiazaspiro compounds for the treatment of drug abuse and addiction
RU2779618C2 (ru) * 2015-11-16 2022-09-12 Эстев Фармасьютикалз, С. А. Оксадиазаспиросоединения для лечения злоупотребления наркотическими средствами и зависимости от них
US11649248B2 (en) 2015-11-16 2023-05-16 Esteve Pharmaceuticals, S.A. Oxadiazaspiro compounds for the treatment of drug abuse and addiction
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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