WO2013115294A1

WO2013115294A1 - Diazaspiro urea derivative and pharmaceutical use thereof

Info

Publication number: WO2013115294A1
Application number: PCT/JP2013/052134
Authority: WO
Inventors: 祐子加藤; 信寛渕; 拓実青木
Original assignee: 東レ株式会社
Priority date: 2012-01-31
Filing date: 2013-01-31
Publication date: 2013-08-08
Also published as: JPWO2013115294A1

Abstract

The purpose of the present invention is to provide a drug having a therapeutic effect on high blood pressure based on sEH inhibitory activity. This invention provides a diazaspiro urea derivative represented in the figure or a pharmaceutically acceptable salt.

Description

Diaza spiro urea derivative and its pharmaceutical use

The present invention relates to a diaza spiro urea derivative and its pharmaceutical use.

Epoxyeicosatrienoic acids (hereinafter referred to as EETs) 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. However, in vivo, soluble epoxide hydrolase (hereinafter referred to as sEH) is an inactive dihydroxyeicosatrienoic acid. It is promptly converted to (dihydroxyeosatolineic acids; hereinafter referred to as DHETs).

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.

For this reason, it was thought that soluble epoxide hydrolase inhibitors (hereinafter referred to as sEH 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.

Also, spirocyclic compounds (Patent Document 1), spiroheterocyclic compounds (Patent Document 2) and spirocyclic amide compounds (Patent Document 3) have been reported as compounds having a diaza spiro urea structure.

On the other hand, as therapeutic or preventive agents for hypertension, diuretics, calcium antagonists, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor antagonists (ARB), direct renin inhibitors, sympathetic blockers, α2 receptor stimulants have been developed and are used as antihypertensive drugs in accordance with patient symptoms.

International Publication No. 2006/006490 International Publication No. 2005/047286 International Publication No. 2007/103719

However, existing antihypertensive drugs can cause excessive hypotension due to overdose, which can cause strong dizziness, lightheadedness, dizziness, etc. The current situation is that there is a great burden on doctors and patients. For this reason, the development of a safe and easy-to-use antihypertensive agent that exhibits an antihypertensive effect on hypertension associated with the progression of the disease and does not exhibit an antihypertensive effect on normal blood pressure was considered to be urgent.

Although compounds having sEH inhibitory activity have been found so far, they do not always show a therapeutic effect on hypertension (Non-Patent Documents 4 to 6), and find a compound showing a therapeutic effect on hypertension. That was not easy. Moreover, it has not been considered that 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.

In addition, as a compound having sEH inhibitory activity, no compound having a diazaspirourea structure has been reported, and the disclosure and suggestion that a compound having a diazaspirourea structure is effective against hypertension It has never been done before.

Therefore, an object of the present invention is to provide a medicine that exhibits a therapeutic effect on hypertension based on sEH inhibitory activity.

As a result of intensive studies to solve the above problems, the present inventors have found that a novel diazaspirourea derivative having a sEH inhibitory activity and a salt thereof exhibit excellent therapeutic and preventive effects on hypertension. Was completed.

That is, this invention provides the diaza spiro urea derivative shown by the following general formula (I), or its pharmacologically acceptable salt.

[Wherein X is —C (═O) NHR ¹ , —C (═O) —ML or —S (═O) ₂ —ML, and Y is X being —C (= When O) NHR ¹ is —C (═O) —ML or —S (═O) ₂ —ML, and X is —C (═O) —ML or —S (= In the case of 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, a heterocyclyl group having 4 to 6 ring atoms, —C (═O) NHR ² , —NHC (═O) R ² , phenyl Or a heteroaryl group having 5 to 10 ring atoms (the alkyl group and the alkyloxy group are each independently a hydrogen atom; The phenyl group and the heteroaryl group may be substituted with 3 halogen atoms, and in the phenyl group and the heteroaryl group, each hydrogen atom is independently substituted with 1 to 3 halogen atoms or an alkyl group having 1 to 6 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. In the heterocyclylene group, one methylene group constituting the ring may be replaced by —C (═O) —, and 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. In the alkyl group and the 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, and A is a methylene group or an oxygen atom. ]

In the diaza spiro urea derivative, X is —C (═O) —ML, Y is —C (═O) NHR ¹ , and 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

By adding these limitations, the inhibitory activity against sEH can be increased.

In the diaza spiro urea derivative, 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.

By adding these limitations, metabolic stability in the living body can be enhanced.

In the diaza spiro urea derivative, L is a hydrogen atom, a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms, and 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, and 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.

In this case, not only can sEH inhibitory activity and in vivo metabolic stability be improved, but also the therapeutic effect on hypertension can be enhanced.

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. In addition, 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.

It is the figure which showed the blood pressure lowering effect of

Example compound

1, 2, 3, and 4 and the comparative example compound 2 in a hypertensive spontaneously hypertensive rat (SHR). It is the figure which showed the blood pressure lowering effect | action of the Example compound 1 and telmisartan in a normal rat (SD rat).

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).

“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.

The “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.

In the above alkyl group and alkyloxy group, hydrogen atoms may be independently substituted with 1 to 3 halogen atoms. In this case, 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. In this case, 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.

The “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.

The term “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 a saturated heterocyclic group of 4 to 6, for example, oxetanyl group, tetrahydrofuranyl group, tetrahydropyranyl group, dioxanyl group, morpholinylyl group, pyrrolidinyl group, piperidinyl group, tetrahydrothiophenyl group or tetrahydrothiopyranyl group It is done.

“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. Means a monocyclic or condensed heteroaromatic group having a number of 5 to 10, and examples of the monocyclic heteroaryl group include pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, 1,3, 5-triazinyl group, 1,2,4-triazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, 1,2,4-triazolyl group, tetrazolyl group, thienyl group, furanyl group, oxazolyl group, isoxazolyl group, thiazolyl group or Isothiazolyl group, and examples of the condensed heteroaryl group include quinolyl group, isoquinolyl group, benzofuranyl group, Group, indolyl group, indazolyl group, benzimidazolyl group, benztriazolyl groups include benzoxazolyl group or a benzothiazolyl group.

In the phenyl group and the above heteroaryl group in L of the general formula (I), each hydrogen atom may be independently substituted with 1 to 3 halogen atoms or an alkyl group having 1 to 6 carbon atoms, Examples of 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. Examples of the heteroaryl group include 2-chloropyridyl group, 4-chloropyridyl group, 5-methylpyrazinyl group, 3-methylisoxazolyl group, and 1,3-dimethylpyrazolyl group.

Further, the phenyl group in L of the general formula (I) and the above heteroaryl group may be condensed with a heterocyclyl group. In this case, examples of the phenyl group include a 2,3-dihydrobenzofuranyl group, a benzoyl group, and the like. [D] [2,3] dioxolyl group, 2,3-dihydrobenzo [b] [1,4] benzodioxinyl group, indolinyl group, isoindolinyl group or 3,4-dihydro-2H-benzo [b] [ 1,4] oxazinyl group. In this case, examples of the heteroaryl group include 2,3-dihydrofuro [2,3-b] pyridinyl group and 2,3-dihydrofuro [2,3-c] pyridinyl group. 2,3-dihydrofuro [3,2-b] pyridinyl group, 2,3-dihydrofuro [3,2-c] pyridinyl group, [1,3] dioxolo [4,5-b] pyridinyl [1,3] dioxolo [4,5-c] pyridinyl group, 1H-pyrrolo [2,3-b] pyridinyl group, 1H-pyrrolo [2,3-c] pyridinyl group, 1H-pyrrolo [3, 2-c] pyridinyl group, 1H-pyrrolo [3,2-b] pyridinyl group, 1H- [1,2,3] triazolylo [4,5-b] pyridinyl group or 1H- [1,2,3] triazolylo group [4,5-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.

The term “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. Means a saturated heterocyclic chain having a number of 3 to 6, for example, oxetanylene group, tetrahydrofuranyl group, tetrahydropyranylene group, dioxanylene group, morpholinylene group, pyrrolidinylene group, piperidinylene group, tetrahydrothiophenylene group or tetrahydrothiopyranylene group Is mentioned.

In the above alkylene group, cycloalkylene group and heterocyclylene group, each hydrogen atom may be independently substituted with 1 to 3 halogen atoms. Examples of the 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, 1,1-difluoropentylene group, 2,2-difluoropentylene group, 3,3-difluoropentylene group, 4,4- Difluoropentylene group, 5,5-difluoropentylene group, 1,1-difluorohexylene group, 2,2-difluorohexylene group, 3,3-difluorohexylene group, 4,4-difluorohexylene group, Examples thereof include a 5,5-difluorohexylene group or a 6,6-difluorohexylene group. In this case, 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. For example, 3,3-difluorotetrahydropyranylene group, 4,4-difluorotetrahydropyranylene group, 3,3-difluoropiperidinylene group, 4,4-difluoropiperidinylene group, 3,3-difluorotetrahydro A thiopyranylene group or a 4,4-difluorotetrahydrothiopyranylene group can be mentioned.

In the above heterocyclylene group, one methylene group constituting the ring may be replaced by —C (═O) —. In this case, examples of the heterocyclylene group include pyrrolidine-2-onylene. Groups.
“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. Means a monocyclic or condensed heteroaromatic chain of 10 to 10, and examples of the monocyclic heteroarylene chain include a pyridylene group, a pyrimidinylene group, a pyrazinylene group, a pyridazinylene group, and a 1,3,5-triazinylene group. 1,2,4-triazinylene group, pyrrolylene group, imidazolylene group, pyrazolylene group, 1,2,4-triazolylene group, tetrazolylene group, thienylene group, furanylene group, oxazolylene group, isoxazolylene group, thiazolylene group or isothiazolylene Examples of 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. In this case, 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] In this case, 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-b] Lidinylene group, [1,3] dioxolo [4,5-c] pyridinylene group, 1H-pyrrolo [2,3-b] pyridinylene group, 1H-pyrrolo [2,3-c] pyridinylene group, 1H-pyrrolo [3 , 2-c] pyridinylene group, 1H-pyrrolo [3,2-b] pyridinylene group, 1H- [1,2,3] triazolylo [4,5-b] pyridinylene group or 1H- [1,2,3] And triazolylo [4,5-c] pyridinylene group.

In the phenyl group and benzyl group in R ¹ of the general formula (I), 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). And the alkyloxy group may be substituted with hydrogen atoms each independently substituted with 1 to 3 halogen atoms). In this case, as the 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. Examples of the benzyl group include 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-trifluoromethyl. Benzyl group, 3-trifluoromethylbenzyl group, 4-trifluoromethylbenzyl group, 2-trifluoromethoxybenzyl group, 3-trifluoromethoxybenzyl group, 4-trifluoromethoxybenzyl group 2,4-dichlorobenzyl group, 3,4-dichlorobenzyl group, 2-trifluoromethyl-4-chlorobenzyl Group, 2-trifluoromethoxy-4-chlorobenzyl group, 2-chloro-4-methylbenzyl group, 2-trifluoromethyl-4-methylbenzyl group, 2-trifluoromethoxy-4-methylbenzyl group, 2- Chloro-4-cyanobenzyl group, 2-trifluoromethyl-4-cyanobenzyl group, 2-trifluoromethoxy-4-cyanobenzyl group, 2-chloro-4-fluorobenzyl group, 2-trifluoromethyl-4- Examples thereof include a fluorobenzyl group and a 2-trifluoromethoxy-4-fluorobenzyl group.

In addition, “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.

In the diaza spiro urea derivative, in general formula (I), X is preferably —C (═O) —ML, and 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. More preferably 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). Preferably, 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.

Examples of the pharmacologically acceptable salt of the diaza spiro urea derivative (hereinafter referred to as diaza spiro urea derivative (I)) represented by the above general formula (I) 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.

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.

Of the diaza spiro urea derivatives (I), 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).

As shown in the following scheme 1, 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. Can be performed.
(Scheme 1)

[Wherein L, M, R ¹ and A 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 (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.

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. 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 A fert (hereinafter referred to as HATU) is exemplified, and HATU is preferable.

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)

[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. Can be manufactured.
(Scheme 3)

[Wherein J represents a protecting group. R ¹ and A are the same as defined above. ]

As shown in Scheme 3, 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.

Examples of the urea agent used in the urea reaction with an urea agent and an amine 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. In addition, 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). For example, when 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.

Further, among the diaza spiro urea derivatives (I), 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.

For example, among the protected diazaspiroamine derivatives (III), 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.

In addition, 2,9-diazaspiro [5.5] undecane derivative (III-a) is added to aldehyde derivative (VII) with acrylonitrile, followed by nitrile derivative (VIII) as shown in, for example, Scheme 5 below. It can be produced through a reduction of a nitrile group and a reductive amination step.
(Scheme 5)

[Wherein J represents a protecting group. ]

As shown in Scheme 5, the addition step can be performed by reaction with acrylonitrile in the presence of 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. However, 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 diaza spiro urea derivative (I) obtained as described above, a pharmacologically acceptable salt thereof, or an intermediate, a raw material compound or a compound used for the production of the diaza spiro urea derivative (I) The reagent may be isolated and purified by a method such as extraction, distillation, chromatography or recrystallization, if necessary.

In addition, 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. . In addition, a commercially available measurement kit (Soluable Epoxide Hydrose Inhibitor Screening Assay Kit; Cayman) is used, or publicly known literature (Analytical Biochemistry, 2005, Vol. 343, p. 66-75, method E according to s, etc.). Inhibitor activity can be measured.

In addition, using racemic 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate as a substrate, the enzyme (0.24 μM human sEH) was added to the phosphate before introduction of the substrate (40 μM). 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. for 1 minute (Spectramax 200; Molecular Devices) or using cyano (6-methoxy-naphthalen-2-yl) methyltrans-[(3-phenyloxiran-2-yl) methyl] carbonate as a substrate, the enzyme (0.96 nM human sEH) with BisTr together with the sEH inhibitor prior to the introduction of substrate (5 μM). Also by incubating in s-HCl buffer (25 mM, pH 7.0, containing 0.1 mg / mL BSA) for 5 minutes at 30 ° C. and monitoring the appearance of 6-methoxy-2-naphthaldehyde The sEH inhibitory activity of the sEH inhibitor can be measured.

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. Examples of such 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.

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) to mammals (eg, mice, rats, hamsters, rabbits, dogs, monkeys, cows, sheep or humans) (Nasal administration or ophthalmic 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 | preservative, an antioxidant, a coloring agent, a sweetener, an adsorbent, or a wetting agent, as needed.

Examples of the excipient include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid.

Examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.

Examples of the binder include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose or sodium carboxymethylcellulose.

Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.

Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil or corn oil.
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, or sodium citrate.

Examples of the suspending agent 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.

Examples of soothing agents include benzyl alcohol.

Examples of the isotonic agent include glucose, sodium chloride, D-sorbitol, and D-mannitol.

Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate or citrate.

Examples of the preservative include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

Examples of the antioxidant 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.

Examples of other drugs that can be combined or used in combination 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).

When using the above medicines in combination with a concomitant drug, 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. In addition, 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.

When the above medicine is used in combination with a concomitant drug, 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. For example, when the administration subject is a human, 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. .

Examples of 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, α-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, amylin agonists such as pramlintide, phosphotyrosine phosphatase inhibitors such as vanadic acid, DPP-IV inhibitors such as sitagliptin, vildagliptin and alogliptin, exenatide, liraglutide GLP-1-like agents such as glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists or SGLUT inhibitors.

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.

Examples of the therapeutic agent for hyperlipidemia include 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, plant sterols such as soysterol or gamma oryzanol.

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.

Examples of 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, β3 agonists, leptin or CNTF (ciliary neurotrophic factor) or cholecystokinin agonists such as lynchtripto.

Examples of the diuretic 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. , 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.

Examples of 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.

Examples of the immunotherapeutic agent 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, alteplase, nateplase, monteplase or pamiteplase. Or platelet aggregation inhibitors such as ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium or sarpogrelate hydrochloride.

Examples of cachexia-improving agents 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. Examples thereof include antibodies to TNF-α, LIF, IL-6, or oncostatin M, which are agents that induce metabolism, growth hormone, IGF-1, or cachexia.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto.

(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. . After stirring for 10 minutes at room temperature, the reaction solution was added dropwise to a solution of lithium aluminum hydride (5.2 g, 0.14 mol) in THF (0.10 L) under ice cooling. After refluxing for 3 hours, water (5.2 mL), 1N aqueous sodium hydroxide solution (5.2 mL), and water (10 mL) were added to the reaction solution under ice cooling. After stirring for 10 minutes under ice cooling, the reaction solution was filtered through Celite, and the obtained filtrate was concentrated under reduced pressure to obtain 20 g (87%) of Reference Example Compound 1.

[Step 2]
Synthesis of N-((1-benzyl-4-hydroxypiperidin-4-yl) methyl) -2-chloroacetamide (Reference Example Compound 2):
Under ice cooling, 4- (aminomethyl) -1-benzylpiperidin-4-ol (Reference Example Compound 1) (0.50 g, 2.3 mmol), triethylamine (0.47 mL, 3.4 mmol) in dichloromethane (10 mL) To the solution, 2-chloroacetyl chloride (0.22 mL, 2.7 mmol) was added dropwise. After stirring for 10 minutes at room temperature, 1N hydrochloric acid (9.0 mL) was added to the reaction solution. After stirring at room temperature for 10 minutes, 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (Fuji Silysia Chemical Amine Silica Gel DM1020, eluent; hexane: ethyl acetate = 7: 3 → 4: 6), and 0.43 g (64%) of Reference Example Compound 2 was obtained. )Obtained.

[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. The obtained crude product was purified by silica gel column chromatography (Fuji Silysia Chemical Amine Silica Gel DM1020, eluent; chloroform: methanol = 99: 1 → 91: 9) to give 0.32 g (72%) of Reference Example Compound 3. Obtained.

[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) in THF (10 mL) was added dropwise. After stirring for 30 minutes under ice cooling, the mixture was stirred for 30 minutes at room temperature. After refluxing for 10 minutes, water (0.17 mL), 1N aqueous sodium hydroxide solution (0.17 mL), and water (0.35 mL) were added to the reaction solution under ice cooling. After stirring for 10 minutes under ice-cooling, the reaction solution was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain 0.46 g (82%) of Reference Example Compound 4.

[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. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3 → ethyl acetate only) to obtain 3.8 g (90%) of Reference Example Compound 5.

[Step 6]
Synthesis of N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6):
9-benzyl-N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 5) (3.8 g, 8. 4 mmol) in methanol (50 mL) was added 20 wt% palladium hydroxide / carbon (1.8 g). After stirring at room temperature for 16 hours under a hydrogen atmosphere, the reaction solution was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain 2.6 g (88%) of Reference Example Compound 6.

[Step 7]
Synthesis of 9- (2-fluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Example Compound 1) :
Under ice-cooling, N- (4- (trifluoromethoxy) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 6) (1.6 g, 4. 2-fluorobenzoyl chloride (0.87 g, 5.5 mmol) was added to a solution of 6 mmol) and triethylamine (1.9 mL, 14 mmol) in dichloromethane (15 mL). After stirring for 5 minutes under ice cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3 → 2: 8) to obtain 1.9 g (84%) of Example Compound 1.

(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. 1 mmol), 5-methylisoxazole-3-carboxylic acid (0.14 g, 1.1 mmol), DIPEA (0.49 mL, 2.8 mmol) in DMF (4.2 mL) was added to HATU (0.66 g, 1 mmol). .7 mmol) was added. After stirring at room temperature for 63 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Fuji Silysia Chemical Amine Silica Gel DM1020, eluent; hexane: ethyl acetate = 7: 3 → 1: 9), and 0.47 g (92%) of 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. After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3 → ethyl acetate only) to obtain 2.5 g (72%) of Reference Example Compound 7.

[Step 2]
Synthesis of N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8):
9-Benzyl-N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 7) (2.0 g, 4. 6 wt) in methanol (20 mL) was added 20 wt% palladium hydroxide / carbon (3.1 g). After stirring for 72 hours at room temperature under a hydrogen atmosphere, the reaction solution was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain 1.4 g (88%) of Reference Example Compound 8.

[Step 3]
Synthesis of 9- (4-cyanobenzoyl) -N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Example Compound 3) :
Under ice cooling, N- (4- (trifluoromethyl) phenyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 8) (2.5 g, 7. 2-Cyanobenzoyl chloride (1.4 g, 8.6 mmol) was added to a solution of 2 mmol) and triethylamine (1.0 mL, 7.2 mmol) in dichloromethane (20 mL). After stirring for 5 minutes under ice cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3 → 2: 8) to obtain 2.7 g (78%) of Example Compound 3.

(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. 42 mmol), 4-chloropicolinic acid (0.079 g, 0.50 mmol), DIPEA (0.18 mL, 1.0 mmol) in DMF (1.0 mL) solution, HATU (0.24 g, 0.63 mmol) was added. It was. After stirring at room temperature for 15 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Fuji Silysia Chemical Amine Silica Gel DM1020, eluent; hexane: ethyl acetate = 7: 3 → 1: 9), and 0.14 g (68%) of 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). After stirring at 80 ° C. for 21 hours, phthalimide (0.0080 g, 0.054 mmol) and DMF (0.10 mL) were added to the reaction solution. After stirring at 100 ° C. for 4 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed with 1N hydrochloric acid and 1N aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 99: 1 → 90: 10) to obtain 0.0043 g (15%) of Example Compound 22.

(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.

(Examples 38 to 49)
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. 6) A solution of (0.015 g, 0.042 mmol) in DMF (0.10 mL) was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was purified by LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax® Extended-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: 10 mM hydrogen carbonate. Example compounds 38 to 49 were obtained by performing (aqueous ammonium solution-acetonitrile).

For the Example compounds 38 to 49, the LC retention time and [M + H] ⁺ or [MH] ⁻ were measured using the analysis method described below. The analysis method is as follows: LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extend-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: A = acetonitrile B = 10 mM aqueous ammonium hydrogen carbonate, gradient: A / B = 20/90 → 95/5 (6 minutes), flow rate: 4 mL / min.

(Example 50)
N- (2,4-dichlorobenzyl) -9- (5-methylisoxazole-3-carbonyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (hereinafter, Examples Synthesis of compound 50):
[Step 1]
Synthesis of tert-butyl 4-((2,4-dichlorobenzyl) carbamoyl) -1-oxa-4,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 9):
At room temperature, tert-butyl 1-oxa-4,9-diazaspiro [5.5] undecane-9-carboxylate (0.30 g, 1.2 mmol), triethylamine (0.20 mL, 1.4 mmol) in chloroform (5 0.04 mL) solution was added 2,4-dichloro-1- (isocyanatomethyl) benzene (0.26 g, 1.3 mmol). After stirring at room temperature for 10 minutes, the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 5: 5) to obtain 0.54 g (quantitative) of Reference Example Compound 9.

[Step 2]
Synthesis of N- (2,4-dichlorobenzyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Reference Example Compound 10):
Under ice cooling, tert-butyl 4-((2,4-dichlorobenzyl) carbamoyl) -1-oxa-4,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 9) (0. 54 g, 1.2 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (hereinafter TFA) (1.5 mL, 19 mmol). After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with 1N aqueous sodium hydroxide solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 0.42 g (quantitative) of Reference Example Compound 10.

[Step 3]
N- (2,4-dichlorobenzyl) -9- (5-methylisoxazole-3-carbonyl) -1-oxa-4,9-diazaspiro [5.5] undecane-4-carboxamide (Example Compound 50) ) Synthesis:
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) By performing the same reaction as in Example 2, 0.024 g (60%) of Example Compound 50 was obtained.

(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). After stirring at room temperature for 5 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform: methanol = 99: 1 → 90: 10) to obtain 0.022 g (34%) of Example Compound 54.

(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). After stirring at room temperature for 5 minutes, 1N aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3 → 2: 8) to obtain a crude product. At room temperature, 20 wt% palladium hydroxide / carbon (0.010 g) was added to a solution of the resulting crude product in methanol (1.0 mL). After stirring for 12 hours at room temperature under a hydrogen atmosphere, the reaction solution was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure. At room temperature, 4- (trifluoromethoxy) phenyl isocyanate (0.0085 g, 0.042 mmol) was added to a chloroform (1.0 mL) solution of the obtained crude product, triethylamine (0.0080 mL, 0.058 mmol). added. After stirring at room temperature for 5 minutes, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: chloroform: methanol = 99: 1 → 90: 10) to obtain 0.0058 g (3 steps, 37%) of Example Compound 55.

(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. After stirring at room temperature for 2 hours, an aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution. After stirring for 5 minutes at room temperature, the reaction solution was extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 6: 4) to obtain 0.26 g (53%) of Reference Example Compound 11.

[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. After stirring at room temperature for 10 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 6: 4) to obtain 0.19 g (60%) of Reference Example Compound 12.

[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. The obtained crude product was dissolved in 1N hydrochloric acid and washed with ethyl acetate. The aqueous layer was neutralized with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 0.041 g (29%) of Reference Example Compound 13.

[Step 4]
Synthesis of tert-butyl 2-((4- (trifluoromethoxy) phenyl) carbamoyl) -2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 14):
tert-Butyl 2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 13) (0.19 g, 0.76 mmol), 4- (trifluoromethoxy) phenyl isocyanate (0.13 mL, 0.87 mmol) was used to carry out the same reaction as in Example 50 [Step 1] to obtain 0.17 g (50%) of Reference Example Compound 14.

[Step 5]
Synthesis of 9- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (Example Compound 56):
Under ice cooling, tert-butyl 2-((4- (trifluoromethoxy) phenyl) carbamoyl) -2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 14) (0.030 g, To a solution of 0.067 mmol) in dichloromethane (2.0 mL) was added TFA (0.50 mL). After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, and the resulting crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Under ice cooling, a solution of the obtained crude product in dichloromethane (2.0 mL) was added to triethylamine (0.070 mL, 0.50 mmol), 2,6-difluoro. Benzoyl chloride (0.021 g, 0.12 mmol) was added. After stirring at room temperature for 10 minutes, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 3: 7) to obtain 0.024 g (71%) of Example Compound 56.

(Example 57)
Synthesis of 9- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (hereinafter, 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 was obtained.

[Step 2]
Synthesis of N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (Reference Example Compound 16):
tert-Butyl 2-((4- (trifluoromethyl) phenyl) carbamoyl) -2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 15) (0.068 g, 0.15 mmol) Was used to carry out the same reaction as in Example 50 [Step 2] to obtain 0.037 g (70%) of Reference Example Compound 16.

[Step 3]
Synthesis of 9- (2,6-difluorobenzoyl) -N- (4- (trifluoromethyl) phenyl) -2,9-diazaspiro [5.5] undecane-2-carboxamide (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 (hereinafter, 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.

[Step 2]
Synthesis of 2- (2,6-difluorobenzoyl) -N- (4- (trifluoromethoxy) phenyl) -2,9-diazaspiro [5.5] undecane-9-carboxamide (Example Compound 59):
Under ice-cooling, tert-butyl 2- (2,6-difluorobenzoyl) -2,9-diazaspiro [5.5] undecane-9-carboxylate (Reference Example Compound 17) (0.017 g, 0.043 mmol) To a dichloromethane (1.0 mL) solution was added TFA (0.50 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the resulting crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Under ice cooling, a solution of the obtained crude product in chloroform (1.0 mL) was added to triethylamine (0.0078 mL, 0.056 mmol), 2,4- (trifluoromethoxy) phenyl isocyanate (0.0060 mL,. 041 mmol) was added. After stirring at room temperature for 5 minutes, the reaction solution was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 3: 7) to obtain 0.014 g (76%) of Example Compound 59.

(Comparative Example 1)
Synthesis of N- (adamantan-1-yl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (hereinafter, Comparative Compound 1):
[Step 1]
Synthesis of 1-tert-butyl 4-ethyl 4- (2-methoxy-2-oxoethyl) piperidine-1,4-dicarboxylate (Reference Example Compound 18):
A 1.57N n-butyllithium / n-hexane solution (11 mL, 17 mmol) was added dropwise to a tetrahydrofuran solution (30 mL) of DIPEA (2.4 mL, 17 mmol) at −78 ° C. under an argon atmosphere. After stirring at −78 ° C. for 30 minutes, a solution of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (4.0 g, 16 mmol) in THF (15 mL) was added dropwise to the reaction solution. After stirring at −78 ° C. for 1 hour, methyl bromoacetate (2.2 mL, 24 mmol) was added to the reaction solution. After stirring at −78 ° C. for 1 hour, the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 3: 7) to obtain 0.82 g (16%) of Reference Example Compound 18.

[Step 2]
Synthesis of tert-butyl 2-benzyl-1,3-dioxo-2,8-diazaspiro [4.5] decane-8-carboxylate (Reference Example Compound 19):
1-tert-butyl 4-ethyl 4- (2-methoxy-2-oxoethyl) piperidine-1,4-dicarboxylate (Reference Example Compound 18) (0.82 g, 2.5 mmol) was added to benzylamine (2. 7 mL, 25 mmol) was added. After stirring at 160 ° C. for 18 hours, 3N hydrochloric acid was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 3: 7) to obtain 0.51 g (58%) of Reference Example Compound 19.

[Step 3]
Synthesis of 2-benzyl-2,8-diazaspiro [4.5] decane-1,3-dione (Reference Example Compound 20):
tert-Butyl 2-benzyl-1,3-dioxo-2,8-diazaspiro [4.5] decane-8-carboxylate (Reference Example Compound 19) (0.51 g, 1.4 mmol) in methanol (4.0 mL) ) To the solution was added 10% hydrogen chloride / methanol solution (6.0 mL). After stirring at room temperature for 4 hours, the reaction solution was neutralized with 1N aqueous sodium hydroxide solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.33 g (88%) of Reference Example Compound 20.

[Step 4]
Synthesis of 2-benzyl-2,8-diazaspiro [4.5] decane (Reference Example Compound 21):
To a solution of 2-benzyl-2,8-diazaspiro [4.5] decane-1,3-dione (Reference Example Compound 20) (0.28 g, 1.1 mmol) in THF (5.0 mL) was added lithium aluminum hydride. (0.21 g, 5.4 mmol) was added. After stirring at room temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.22 g (87%) of Reference Example Compound 21.

[Step 5]
Synthesis of (2-benzyl-2,8-diazaspiro [4.5] decan-8-yl) (2,6-difluorophenyl) methanone (Reference Example Compound 22):
2-Benzyl-2,8-diazaspiro [4.5] decane (0.12 g, 0.52 mmol), 2,6-difluorobenzoyl chloride (Reference Example Compound 21) (0.11 g, 0.62 mmol) in dichloromethane ( To the 3.0 mL) solution, DIPEA (0.15 mL, 1.0 mmol) was added. After stirring at room temperature for 2 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 1: 9) to obtain 0.15 g (76%) of Reference Example Compound 22.

[Step 6]
Synthesis of (2,6-difluorophenyl) (2,8-diazaspiro [4.5] decan-8-yl) methanone (Reference Example Compound 23):
(2-Benzyl-2,8-diazaspiro [4.5] decan-8-yl) (2,6-difluorophenyl) methanone (Reference Example Compound 22) (0.15 g, 0.40 mmol) in methanol (3. 0%) solution was added 10 wt% palladium hydroxide / carbon (0.045 g). After stirring for 18 hours at room temperature under a hydrogen atmosphere, the reaction solution was filtered through Celite, and the resulting filtrate was concentrated under reduced pressure to obtain 0.11 g (quantitative) of Reference Example Compound 23.

[Step 7]
Synthesis of N- (adamantan-1-yl) -8- (2,6-difluorobenzoyl) -2,8-diazaspiro [4.5] decane-2-carboxamide (Comparative Example Compound 1):
(2-Benzyl-2,8-diazaspiro [4.5] decan-8-yl) (2,6-difluorophenyl) methanone (Reference Example Compound 23) (0.025 g, 0.089 mmol), 1-isocyanate To a solution of adamantane (0.019 g, 0.11 mmol) in dichloromethane (1.0 mL) was added DIPEA (0.023 mL, 0.13 mmol). After stirring at room temperature for 30 minutes, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 9: 1 → 3: 7) to obtain 0.033 g (81%) of Comparative Compound 1.

(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.

The physical property data of the compounds of the present invention mentioned in the above Examples and the compounds mentioned in Comparative Examples are shown in Table 1-1 to Table 1-9, and the physical property data of the compounds mentioned in Reference Examples are shown in Table 2-1 to Table 2- 3 shows. In the table, N.I. D. Represents “no data”.

(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.

Human recombinant sEH (Cayman) was incubated with test compound in Bis-Tris-HCl buffer (25 mM, pH 7.0, containing 0.1 mg / mL BSA) for 30 minutes at room temperature. Thereafter, cyano (6-methoxy-naphthalen-2-yl) methyltrans-[(3-phenyloxiran-2-yl) methyl] carbonate (Cayman) is added as a fluorescent substrate, and further incubated at room temperature for 20 to 45 minutes. ZnSO ₄ was added to stop the reaction, and the fluorescence intensity (Excitation: 330 nm, Emission: 485 nm) was measured. 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 results are shown in Table 3.

From this result, it was revealed that 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.

After anesthetizing SHR (SHR system, male, 23-29 weeks old; Charles River Japan Co., Ltd.), the crotch and back neck were removed and the surgical field was disinfected using isodine solution. 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.

After the blood pressure was stabilized,

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.

In the Example Compound 1 administration group, the Example Compound 2 administration group, the Example Compound 3 administration group, and the Example Compound 4 administration group, it was shown that the blood pressure was reduced as compared with the solvent administration group. On the other hand, 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):
In this example, 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.

After the blood pressure was stabilized, 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.

There was no change in blood pressure in the Example Compound 1 administration group and the solvent administration group. On the other hand, it was shown that blood pressure was significantly reduced in the telmisartan administration group. * Mark in a figure shows that it is statistically significant compared with a solvent administration group (t test, p <0.05).

From the above results, it was clarified that the diaza spiro urea derivative (I) and its pharmacologically acceptable salt are effective for the treatment of hypertension.

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.

Claims

The diaza spiro urea derivative or its pharmaceutically acceptable salt shown with the following general formula (I).

[Wherein X is —C (═O) NHR 1 , —C (═O) —ML or —S (═O) 2 —ML;
Y is —C (═O) —ML or —S (═O) 2 —ML when X is —C (═O) NHR 1 and X is —C (═O) -C (= O) NHR 1 when -ML or -S (= O) 2 -ML;
L represents 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, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 10 carbon atoms, a ring structure A heterocyclyl group having 4 to 6 atoms, —C (═O) NHR 2 , —NHC (═O) R 2 , a phenyl group or a heteroaryl group having 5 to 10 ring atoms (the alkyl group and the alkyl In the oxy group, a hydrogen atom may be independently substituted with 1 to 3 halogen atoms, and the phenyl group and the heteroaryl group may be independently substituted with 1 to 3 halogen atoms. Substituted with an atom or an alkyl group having 1 to 6 carbon atoms, and a heterocyclyl group may be condensed),
M is an alkylene group having 1 to 8 carbon atoms, a cycloalkylene group having 3 to 6 carbon atoms, 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, a hydrogen atom may be independently substituted with 1 to 3 halogen atoms, and the heterocyclylene group constitutes a ring. One methylene group may be replaced by —C (═O) —, and the phenylene group and the heteroarylene group may be condensed with a heterocyclyl group),
R 1 is a phenyl group or a benzyl group (the phenyl group and the benzyl group each independently represent a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, or an alkyloxy group on the benzene ring. A hydrogen atom in each of the alkyl group and the alkyloxy group 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 represents at least a hydrogen atom at the 4-position on the benzene ring, 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 each have a hydrogen atom, Independently substituted with 1 to 3 halogen atoms), a phenyl group or a benzyl group substituted with
The diaza spiro urea derivative or pharmaceutically acceptable salt thereof according to claim 1.
R 1 represents at least a 4-position hydrogen atom on the benzene ring having an alkyl group or alkyloxy group having 1 to 6 carbon atoms (the alkyl group and the alkyloxy group each independently have 1 to 3 hydrogen atoms). A phenyl group which may be substituted with a halogen atom of
A is an oxygen atom,
The diaza spiro urea derivative of Claim 2, or its pharmaceutically acceptable salt.
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 which may be condensed with a heterocyclyl group or a heteroarylene group having 5 to 10 ring atoms,
R 1 is a phenyl group in which at least a 4-position hydrogen atom on the benzene ring is substituted with a trifluoromethyl group or a trifluoromethoxy group.
The diaza spiro urea derivative of Claim 3, or its pharmaceutically acceptable salt.
A pharmaceutical comprising the diazaspirourea derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
A soluble epoxide hydrolase inhibitor comprising the diazaspiroura derivative according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
A therapeutic or prophylactic agent for hypertension, comprising the diazaspirourea derivative or the pharmacologically acceptable salt thereof according to any one of claims 1 to 4 as an active ingredient.