WO2015046405A1

WO2015046405A1 - Analgesic

Info

Publication number: WO2015046405A1
Application number: PCT/JP2014/075571
Authority: WO
Inventors: 建也西; 裕西村; 祐子加藤; 新之助林; 亜衣子山崎; 将史山本; 由次浅岡; 将輝山田; 光長谷部
Original assignee: 東レ株式会社
Priority date: 2013-09-26
Filing date: 2014-09-26
Publication date: 2015-04-02
Also published as: JPWO2015046405A1

Abstract

　The purpose of the present invention is to provide a novel analgesic effective against pain, particularly nociceptive pain and neuropathic pain. The present invention provides an analgesic containing, as an active ingredient, a nipecotic acid derivative represented by the chemical formula or a pharmaceutically acceptable salt thereof.

Description

Painkiller

The present invention relates to an analgesic.

Pain is an experience with an unpleasant sensation or unpleasant emotion that occurs when tissue damage or potential damage is caused. Pain is mainly classified into nociceptive pain and neuropathic pain, depending on the cause. In the present specification, “pain” and “pain” are synonymous.

“Nociceptive pain” refers to pain caused by damage to a living tissue or the addition of a noxious stimulus having such a risk, and refers to pain via a nociceptor. For example, physiological pain and inflammatory pain are applicable.

Neuropathic pain is pathological pain caused by abnormal functioning of the peripheral or central nervous system itself, and is caused by direct damage or compression of nerve tissue even though nociceptors are not subjected to noxious stimulation. This refers to the pain that occurs. Neuropathic pain is defined as “pain caused directly by damage or disease to the somatosensory system” at the International Society of Pain (IASP) (Non-Patent Document 1), along with nociceptive pain and the like. It is positioned as one, and is classified into peripheral and central depending on the causative disease (Non-patent Document 2). Neuropathic pain is characterized by persistent spontaneous pain, allodynia (pain response to non-nociceptive stimuli) and hyperalgesia, and in patients with neuropathic pain, severe pain due to these is a long-term of several months to 10 years or more. Since QOL (Quality of life) is significantly reduced (Non-patent Document 3), active treatment is required.

Non-steroidal anti-inflammatory analgesics (NSAIDs), narcotic analgesics (opioids, etc.) are used as analgesics for nociceptive pain, and anticonvulsants and antidepressants are used as analgesics for neuropathic pain. Antiepileptic agents such as anti-anxiety agents, gabapentin and pregabalin are used.

Recently, it has been reported that epoxyeicosatrienoic acids (hereinafter referred to as EETs), which is one of endothelial cell-derived hyperpolarizing factors, exhibits an analgesic effect on nociceptive pain (Non-patent Document 4). EETs are metabolized and inactivated by a soluble epoxide hydrolase (hereinafter, sEH) to dihydroxyeicosatrienoic acids (hereinafter, DHETs), but are soluble epoxide hydrolase inhibitors (hereinafter, DHETs). sEH inhibitors) have been shown to increase the amount of EETs (Non-Patent Document 5). Recently, compounds having sEH inhibitory activity have been reported, and these compounds have been shown to have analgesic effects on nociceptive pain and neuropathic pain (Non-Patent Documents 6 and 7).

None of the compounds having sEH inhibitory activity reported so far has a nipecotic acid diamide structure, and a heteroaryl amide derivative in which a heteroarylamine is condensed with nipecotic acid as a compound having a nipecotic acid diamide structure (Patent Document 1) ), Amidine derivatives (Patent Document 2) and hydroxamic acid derivatives (Patent Document 3) have been reported, but the relationship with sEH inhibitory activity has not been disclosed or suggested.

International Publication No. 2010/096371 International Publication No. 2000/0117158 International Publication No. 2002/028829

However, non-steroidal anti-inflammatory analgesics used for nociceptive pain are associated with side effects such as gastrointestinal disorders and renal disorders, and narcotic analgesics are known to have side effects such as constipation, sleepiness, nausea and vomiting. And its use is known to be limited. Anticonvulsants, antidepressants, anxiolytics and antiepileptics used for neuropathic pain frequently involve central side effects such as dizziness, nausea and vomiting, which are difficult to discontinue for a long time or are discontinued. It has been pointed out that there are cases in which these drugs do not provide sufficient analgesic effects with these drugs (Non-patent Document 4).

Therefore, an object of the present invention is to provide a new analgesic effective for pain, particularly nociceptive pain and neuropathic pain.

As a result of intensive studies to solve the above problems, the present inventors have shown that a novel nipecotic acid derivative or a pharmacologically acceptable salt thereof exhibits sEH inhibitory activity, and pain based on its action, In particular, it has been found that it exhibits an excellent analgesic effect against nociceptive pain and neuropathic pain, and has completed the present invention.

That is, the present invention provides an analgesic containing an nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

[Wherein R ¹ represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms. A cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms, Each independently may be substituted with a halogen atom, a hydroxyl group, a cyano group, —SR ⁶ , —S (═O) —R ⁶ or —S (═O) ₂ R ⁶ ), —N (R ⁶ ) C (═O) R ⁷ , —N (R ⁶ ) S (═O) ₂ R ⁷ , —C (═O) N (R ⁶ ) R ⁷ or a heteroaryl group having 5 ring atoms, R ² and R ³ are Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkyloxyalkyl group each have 1 to 3 hydrogen atoms independently And may be substituted with a halogen atom, a hydroxyl group or a cyano group, or together, — (CH ₂ ) ₁ — or — (CH ₂ ) _m —O— (CH ₂ ) _n -Represents a hydrogen atom, but R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, 3 to 6 cycloalkyl groups or cycloalkyloxy groups (the alkyl group, alkyloxy group, cycloalkyl group and cycloalkyloxy group each have 1 to 3 hydrogen atoms independently represented by Halogen may be substituted by atoms) or -C (= O) represents the NH _2, not simultaneously represent an alkyl group, R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms , R ⁷ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, A cycloalkyl group, an alkyloxyalkyl group and a cycloalkylalkyl group each represent 1 to 3 hydrogen atoms each independently may be substituted with a halogen atom, a hydroxyl group or a cyano group, Represents an integer of 2 to 5, and m and n each independently represent 1 or 2. ]

In the above nipecotic acid derivative, R ² and R ³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent — (CH ₂ ) ₁ —. At the same time, it is preferable that R ⁴ represents a substituent at the 2-position on the benzene ring and R ⁵ represents a substituent at the 4-position on the benzene ring.

In this case, it has a stronger sEH inhibitory activity and exhibits a more excellent analgesic effect on pain.

In the above nipecotic acid derivative, R ¹ represents —N (R ⁶ ) C (═O) R ⁷ or —N (R ⁶ ) S (═O) ₂ R ⁷ , and R ⁴ represents a halogen atom. Or an alkyl group or alkyloxy group having 1 to 6 carbon atoms, R ⁵ represents a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms, and R ⁶ represents a hydrogen atom. Is more preferred, R ¹ represents —N (H) C (═O) CH ₂ CH ₃ , R ² and R ³ together represent — (CH ₂ ) ₃ —, and R ⁴ represents It is particularly preferred that it represents —OCF ₃ and R ⁵ represents a cyano group.

In this case, since it has stronger sEH inhibitory activity and excellent pharmacokinetics, a further excellent analgesic effect on pain is exhibited.

The above analgesic is preferably an analgesic for nociceptive pain and / or neuropathic pain.

The analgesic of the present invention exhibits a high therapeutic effect or preventive effect on nociceptive pain and neuropathic pain based on sEH inhibitory activity, so that it can be administered as a medicine for a wide range of pain symptoms. Become.

It is a figure which shows the effect of Example compound 1 with respect to a mouse | mouth acetate rising model (oral administration). It is a figure which shows the effect of Example compound 1 with respect to a mouse | mouth sciatic nerve partial ligation model (1 hour after oral administration). It is a figure which shows the effect of the Example compound 1 with respect to a mouse | mouth sciatic nerve partial ligation model (2 hours after oral administration).

The analgesic of the present invention is characterized by containing a nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

“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, Ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-2-propyl group (tert-butyl group), 2-methyl-1-propyl group, 2,2 -Dimethyl-1-propyl group, 1-pentyl group, 2-pentyl group or 3-pentyl 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.

“C3-C6 cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

“C3-C6 cycloalkyloxy group” means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.

“C2-C7 alkyloxyalkyl group” means a group having 2 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with an alkyloxy group. Group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, propoxymethyl group or isopropoxymethyl group.

The “cycloalkyl alkyl group having 4 to 7 carbon atoms” means a group having 4 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with a cycloalkyl group. Examples thereof include a methyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.

“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term “heteroaryl group having 5 ring atoms” means that the number of ring atoms is 5 including 1 to 4 identical or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And includes, for example, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, furanyl group and thiazolyl group.

In the above nipecotic acid derivative, in general formula (I), R ¹ may be —N (R ⁶ ) C (═O) R ⁷ or —N (R ⁶ ) S (═O) ₂ R ⁷ Preferably, it is acetylamidyl, propionamidyl group or methanesulfonylamidyl group.

R ² and R ³ are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or are preferably taken together as — (CH ₂ ) ₁ —. , A hydrogen atom or an alkyl group having 1 to 3 carbon atoms (in which the alkyl group, one hydrogen atom may be substituted with a hydroxyl group), or together, — (CH ₂ ) ₂ -Or-(CH ₂ ) _3- is more preferable, and each independently represents a hydrogen atom, a methyl group or a 2-hydroxy-2-propyl group, or together,-(CH ₂ ) ₂ -or-(CH ₂ ) _3- is more preferred, but they are not simultaneously hydrogen atoms.

R ⁴ is preferably a substituent at the 2-position on the benzene ring. R ⁴ is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, more preferably a halogen atom or an alkyloxy group, and further preferably an alkyloxy group.

R ⁵ is preferably a substituent at the 4-position on the benzene ring. R ⁵ is preferably a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms, and more preferably a halogen atom or a cyano group.

R ⁶ is preferably a hydrogen atom, and R ⁷ is preferably a methyl group or an ethyl group.

L is preferably 2 or 3, m is preferably 2, and n is preferably 2.

The nipecotic acid derivative represented by the above general formula (I) (hereinafter referred to as nipecotic acid derivative (I)) has at least one asymmetric carbon atom and has optical isomers and diastereomers. However, the nipecotic acid derivative (I) includes not only a single isomer but also a racemate and a mixture of diastereomers. Moreover, when a rotamer exists, all rotamers are included.

Examples of the pharmacologically acceptable salt of the nipecotic acid derivative (I) include, for example, hydrochloride, trifluoroacetate, sulfate, nitrate, hydrobromide, hydroiodide or methane as an acid addition salt. Examples of the sulfonate include hydrochloride, sulfate, hydrobromide, hydroiodide, and methanesulfonate.

The starting materials and reagents used for the production of the nipecotic acid derivative (I) may be commercially available products or may be synthesized by known methods.

The nipecotic acid derivative (Ia) can be produced, for example, by a condensation reaction of an amine derivative (II) and a carboxylic acid derivative (III) in the presence of a base and a condensing agent as shown in the following scheme 1.
(Scheme 1)

[Wherein R ¹ ′ represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxy group having 2 to 7 carbon atoms. An alkyl group, a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms) Each independently represents a halogen atom, a hydroxyl group, a cyano group, —SR ⁶ , —S (═O) —R ⁶ or —S (═O) ₂ R ⁶ . R ² to R ⁶ are the same as defined above. ]

Examples of the condensing agent used in the condensation reaction include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 1- [ Bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate HATU), and HATU is preferred. The equivalent of the condensing agent is preferably 1 to 10 equivalents, and more preferably 1 to 3 equivalents.

Examples of the solvent used in the condensation reaction include N, N-dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), dichloromethane, chloroform, diethyl ether or dimethyl ether, with DMF or THF being preferred, and DMF being More preferred.

Examples of the base used in the condensation reaction include organic bases such as diisopropylethylamine (hereinafter DIPEA), triethylamine (hereinafter TEA), pyridine or N-methylmorpholine, or organic acid salts such as potassium carbonate, sodium carbonate or sodium bicarbonate. DIPEA or TEA is preferable. The equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (II).

The equivalent amount of the carboxylic acid derivative (III) used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.1 to 10 equivalents, and even more preferably 0.8 to 2 equivalents with respect to the amine derivative (II). .

The reaction temperature of the condensation reaction is preferably −50 to 100 ° C., more preferably 0 to 50 ° C., and further preferably 0 to 30 ° C. The reaction time for the condensation reaction is preferably 1 minute to 48 hours, more preferably 1 minute to 24 hours, and even more preferably 10 minutes to 24 hours.

The concentration of the amine derivative (II) at the start of the condensation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and even more preferably 0.1 to 10M.

In addition, the nipecotic acid derivative (Ib) in which R ¹ is —N (H) C (═O) R ⁷ is represented by, for example, an amine derivative (IV) in the presence of a base as shown in Scheme 2 below. And an acid chloride derivative (V), or a condensation reaction between an amine derivative (IV) and a carboxylic acid derivative (VI) in the presence of a base and a condensing agent.
(Scheme 2)

[Wherein R ² to R ⁵ and R ⁷ are the same as defined above]. ]

Examples of the solvent used for the condensation reaction with the acid chloride derivative (V) 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.

The equivalent amount of the acid chloride (V) used in the condensation reaction with the acid chloride derivative (V) is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the amine derivative (IV). 5 equivalents are more preferred.

Examples of the base used for the condensation reaction with the acid chloride derivative (V) include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred. The equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (IV).

The reaction temperature of the condensation reaction with the acid chloride derivative (V) 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 acid chloride (V) 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 amine derivative (IV) in the condensation reaction with the acid chloride derivative (V) is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.

On the other hand, the condensation reaction between the amine derivative (IV) and the carboxylic acid derivative (VI) can be performed under the same conditions as in Scheme 1.

The nipecotic acid derivative (Ic) in which R ¹ is —N (H) S (═O) ₂ R ⁷ can be synthesized, for example, with an amine derivative (IV) in the presence of a base as shown in Scheme 3 below. It can be produced by a sulfonamidation reaction with a sulfonic acid chloride derivative (VII).
(Scheme 3)

[Wherein R ² to R ⁵ and R ⁷ are the same as defined above]. ]

Examples of the solvent used in the sulfonamidation reaction include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether, or 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 sulfonic acid chloride derivative (VII) used in the sulfonamidation reaction is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, and further preferably 1 to 1.5 equivalents with respect to the amine derivative (IV). preferable.

Examples of the base used in the sulfonamidation reaction include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred. The equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (IV).

The reaction temperature of the sulfonamidation reaction is preferably −50 to 50 ° C., more preferably −30 to 30 ° C., and further preferably −20 to 20 ° C. The reaction time of the sulfonamidation reaction 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 amine derivative (IV) at the start of the reaction in the sulfonamidation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.

The amine derivative (IV), which is the starting material in the above-mentioned schemes 2 and 3, is, for example, after the condensation reaction between the amine derivative (II) and the carboxylic acid derivative (VIII) in the presence of a base, as shown in the following scheme 4. Can be produced by a deprotection reaction to remove the protecting group.
(Scheme 4)

[Wherein R ² to R ⁵ are the same as defined above, and R ⁸ represents a protecting group. ]

The condensation reaction of the amine derivative (II) and the carboxylic acid derivative (VIII) can be performed under the same conditions as in Scheme 1.

The deprotection reaction following the condensation reaction can be performed by a known method described in, for example, Protective Groups in Organic Synthesis 3rd Edition (Green et al., 1999, John Wiley & Sons, Inc.). For example, when the protecting group is a tert-butoxycarbonyl group, the protecting group can be removed by treatment with a strong acid such as trifluoroacetic acid.

As the carboxylic acid derivative (VIII) in the above scheme 4, a commercially available product may be used as it is, or it may be produced by a known method.

The amine derivative (II) which is the starting material in the above-mentioned schemes 1 and 4 is, for example, as shown in the following scheme 5, in the presence of a base and a condensing agent, benzylamine derivative (IX), nipecotic acid derivative (X) and After the condensation reaction, a deprotection reaction for removing the protecting group can be used.
(Scheme 5)

[Wherein R ⁴ , R ⁵ and R ⁸ are the same as defined above. ]

The condensation reaction of the benzylamine derivative (IX) and the nipecotic acid derivative (X) can be carried out under the same conditions as in Scheme 1.

The deprotection reaction can be carried out under the same conditions as in the method described in Scheme 4.

The condensation reaction of Scheme 5 can also be performed in the presence of a base by converting the nipecotic acid derivative (X) into an acid chloride.

Examples of the reagent for converting the nipecotic acid derivative (X) into acid chloride include oxalyl chloride and thionyl chloride, with oxalyl chloride being preferred. The equivalent amount of the reagent is preferably 1 to 10 equivalents, more preferably 1 to 1.5 equivalents, relative to the nipecotic acid derivative (X).

Examples of the solvent used for converting the nipecotic acid derivative (X) into the acid chloride include dichloromethane, chloroform, THF, 1,2-dichloroethane, acetonitrile, 1,4-dioxane, and DMF, and dichloromethane, THF, or DMF. Alternatively, a mixed solvent thereof is preferable, and a mixed solvent of dichloromethane and DMF or a mixed solvent of THF and DMF is more preferable. As a ratio of the mixed solvent, for example, in the case of a mixed solvent of dichloromethane and DMF, dichloromethane: DMF = 1 to 1000: 1 is preferable, and 1 to 100: 1 is more preferable.

The reaction temperature for converting the nipecotic acid derivative (X) to acid chloride is preferably -50 to 100 ° C, more preferably -30 to 30 ° C, and further preferably -20 to 0 ° C. The reaction time for converting the nipecotic acid derivative (X) to acid chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 2 hours.

The concentration of the nipecotic acid derivative (X) at the start of the reaction when converting the nipecotic acid derivative (X) to acid chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and more preferably 0.1 to 3M. Is more preferable.

The nipecotic acid derivative (I) obtained as described above, a pharmacologically acceptable salt thereof, or an intermediate, a raw material compound or a reagent used for the production of the nipecotic acid derivative (I) is necessary. Depending on the method, it may be isolated and purified by a method such as extraction, distillation, chromatography or recrystallization.

The above analgesic is characterized by containing the above nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient, and is based on sEH inhibitory activity, and in particular, nociceptive pain In addition, it can exert a high analgesic effect on neuropathic pain.

“SEH” is an abbreviation for soluble epoxide hydrolase, which is a metabolic enzyme that catalyzes the hydrolysis of epoxide and converts it to the corresponding diol. The most known substrate of sEH is EETs, which is one of endothelial cell-derived hyperpolarizing factors, and sEH has an action of metabolizing EETs to DHETs and inactivating them. “EETs” is an abbreviation for Epoxyeicosatrienoic acids, and “DHETs” is an abbreviation for Dihydroxyeicosatrienoic acids. Examples of the EETs include 14,15-epoxyeicosatrienoic acid (hereinafter, 14,15-EET). Examples of DHETs include 14,15-dihydroxyeicosatrienoic acid (14,15-DHET).

“SEH inhibitory activity” means an activity that inhibits the action of sEH. Therefore, the sEH inhibitory activity includes the activity of inhibiting the enzymatic reaction of sEH to catalyze the hydrolysis of EETs, which is one of sEH substrates.

“SEH inhibitor” means a compound showing sEH inhibitory activity or a composition containing the compound as an active ingredient.

The sEH inhibitory activity is, for example, that human sEH and its substrate EETs are reacted in the presence of an sEH inhibitor, and the amount of DHETs produced is compared with the amount of DHETs produced in the absence of the sEH inhibitor. Can be measured. In addition, a commercially available measurement kit (Soluable Epoxide Hydrose Inhibitor Screening Assay Kit; Cayman) is used, or is described in a publicly known document (Analytical Biochemistry, 2005, Vol. 343, p. 66-75, E, etc.). The sEH inhibitory activity of the inhibitor can be measured.

In addition, in the presence and absence of an sEH inhibitor, racemic 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate was used as a substrate for sEH, and 4-nitrophenolate anion was used. The appearance of 6-methoxy-2-naphthaldehyde is measured using cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate as a substrate for sEH. The sEH inhibitory activity of the sEH inhibitor can also be measured by measuring the appearance.

“Nociceptive pain” refers to pain caused by damage to biological tissue or the addition of a noxious stimulus having such a risk, and refers to pain via nociceptors.

Examples of nociceptive pain include pain caused by injuries such as fractures and cuts, postoperative pain, sprain pain, bruise pain, joint pain, low back pain, muscle pain, post-extraction pain, toothache, appendicitis, rheumatoid arthritis. Pain due to inflammatory diseases such as rheumatic fever, osteoarthritis, ankylosing spondylitis, osteoarthritis, cervical shoulder arm syndrome, periarthritis, connective tissue inflammation, acute otitis media, prostatitis, alveolar periosteitis, vaginitis Can be mentioned. In addition, the nociceptive pain includes deep pain and visceral pain (for example, headache, abdominal pain, back and back pain, chronic pelvic pain syndrome, pain associated with endometriosis, pain associated with urolithiasis and urethral stones, Pain associated with gastrointestinal lesions, pelvic pain, pain associated with urological disorders). More preferable target diseases of the above analgesic include rheumatoid arthritis, osteoarthritis, postoperative pain, joint pain, low back pain, muscle pain or toothache.

“Neuropathic pain” is pathological pain caused by abnormalities in the function of the peripheral or central nervous system itself, and direct damage or compression of nerve tissue even though nociceptors are not subjected to noxious stimuli. This refers to pain caused by the like.

Examples of neuropathic pain include cancer pain, herpes zoster pain, postherpetic neuralgia, painful diabetic neuropathic pain, AIDS-related neuralgia, neuropathic back pain, phantom limb pain, anticancer Neuropathic pain caused by administration of agents, pain after spinal cord injury, pain due to strangulated neuropathy such as carpal trunk syndrome and spinal canal stenosis, pain due to Guillain-Barre syndrome, or trigeminal neuralgia.

The analgesic effect on nociceptive pain and neuropathic pain of nipecotic acid derivative (I), which is an active ingredient of the above-mentioned analgesic agent, or a pharmacologically acceptable salt thereof should be evaluated using an appropriate animal model. Can do. Suitable animal models for nociceptive pain include, for example, the mouse acetate rising model, the rat formalin test, the rat carrageenan-induced inflammation model, the mouse or rat hot plate test for acute pain, or the tail flick test.

Also, suitable animal models of neuropathic pain include, for example, a mouse or rat partial sciatic nerve ligation model or a mouse or rat spinal nerve ligation model, or a mouse or rat streptozotocin-induced diabetic neuropathy model.

The above analgesics are also useful for acute and chronic pain. Acute pain is usually short-term, but includes acute postoperative pain, herpes zoster pain, post-extraction pain, or trigeminal neuralgia. Chronic pain is usually defined as pain lasting for 3-6 months and includes somatic and psychogenic pain, such as rheumatoid arthritis, osteoarthritis, painful diabetic neuropathic pain Chronic postoperative neuropathic pain or postherpetic neuralgia.

The above-mentioned analgesic is prepared by using a nipecotic acid derivative (I), which is an active ingredient, or a pharmacologically acceptable salt thereof as it is or as a pharmaceutical composition in an appropriate dosage form for mammals (eg, mice, rats, etc.). , Hamsters, rabbits, dogs, monkeys, cows, sheep or humans) orally or parenterally (eg, transdermal, intravenous, rectal, inhalation, nasal or ophthalmic) Can be administered.

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 forms. A formulation 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 in solid preparations, and solvents, solubilizers, suspending agents, or soothing agents in liquid 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 analgesic preferably contains 0.001 to 99% by weight, more preferably 0.01 to 99% by weight, of the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof. . The effective dosage and frequency of administration of the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof vary depending on the dosage form, patient age, body weight, or the nature or severity of the symptoms to be treated / prevented. However, usually 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 analgesics may be administered alone, but may be combined with other drugs or combined with other drugs to supplement or enhance the preventive or therapeutic effect of the disease or reduce the dose. It can also be used in combination.

Examples of other drugs that can be combined or used together (hereinafter referred to as combined drugs) include antitussives, expectorants, antitussive expectorants, bronchodilators, peptic ulcers, antibiotics, or narcotic analgesics.

When the analgesic is used in combination with a concomitant drug, the timing of administration of the analgesic and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, May be administered. The concomitant drug may be a low molecular compound, a polymer such as a protein, polypeptide or antibody, or a vaccine. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the analgesic and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination of the above analgesic and concomitant drug, and the like. For example, when the administration subject is a human, the concomitant drug may be used in a mixing ratio of 0.01 to 99.99 with respect to the above analgesic.

Antitussives, expectorants and antitussive expectorants include, for example, dextromethorphan, benproperine, dimemorphan, clofedanol, ephedrine, decoben, minc ), Methylephedrine, acetylcysteine, ambroxol, carbocysteine, bromhexine, epradinone, incode, indehyde Ydrocodeine) or tipepidine (tipepidine) and the like.

Examples of bronchodilators include clenbuterol, cromoglycate, salbutamol, salmeterol, tulobuterol, and theophylline.

Examples of peptic ulcer agents include azulene, aldioxa, irsogladine, ecabet, omeprazole, ornoprostil, cimetidine, cimetidine, cimetidine. , Sulpiride, cetraxate or famotidine.

Antibiotics include, for example, amoxicillin, azithromycin, erythromycin, clarithromycin, tetracycline, and doxycycline (doxycycline).

Examples of narcotic analgesics include opium alkaloids, ethyl morphine, oxycodone, morphine, cocaine, fentanyl, and pethidine.

Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. Purification by silica gel column chromatography was performed using a “HI-FLASH” column (Yamazen Co., Ltd.) and Purif-α2 (Shoko Scientific Co., Ltd.) unless otherwise specified.

Example 1 Synthesis of (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-propionamidocyclobutanecarbonyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of 4-bromo-2- (trifluoromethoxy) benzaldehyde:
To a THF (0.40 L) solution of 4-bromo-1-iodo-2- (trifluoromethoxy) benzene (25 g, 68 mmol) at −78 ° C., an n-butyllithium hexane solution (1.6 N, 86 mL, 0.14 mol) was added dropwise over 1.5 hours. After stirring at −78 ° C. for 1 hour, DMF (11 mL, 0.14 mmol) was added dropwise to the reaction solution over 10 minutes. After stirring at −78 ° C. for 2 hours, an aqueous citric acid solution (0.25 M, 0.25 L, 63 mmol) was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 16 g (87%) of 4-bromo-2- (trifluoromethoxy) benzaldehyde (hereinafter referred to as Reference Example Compound 1).

[Step 2]
Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanol:
At −10 ° C., sodium borohydride (2.4 g, 63 mmol) was added to a methanol (0.23 L) solution of Reference Example compound 1 (16 g, 59 mmol). After stirring at −10 ° C. for 10 minutes, acetone (10 mL) and 1N hydrochloric acid (10 mL) were added to the reaction solution. The reaction solution was concentrated under reduced pressure, water was added to the obtained crude product, and the mixture was extracted with ethyl acetate. 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 = 50: 1 → 1: 1), and (4-bromo 15 g (91%) of -2- (trifluoromethoxy) phenyl) methanol (hereinafter referred to as Reference Example Compound 2) was obtained.

[Step 3]
Synthesis of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate:
Methanesulfonyl chloride (0.93 g, 8.1 mmol) was added to a solution of Reference Example Compound 2 (2.0 g, 7.4 mmol) and TEA (1.2 mL, 8.9 mmol) in dichloromethane (20 mL) under ice cooling. It was. After stirring at room temperature for 3 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 2.6 g of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate (hereinafter referred to as Reference Example Compound 3) ( (Quantitative).

[Step 4]
Synthesis of 2- (4-bromo-2- (trifluoromethoxy) benzyl) isoindoline-1,3-dione:
Under ice-cooling, potassium phthalimide (2.1 g, 11 mmol) was added to a DMF (20 mL) solution of Reference Example compound 3 (2.6 g, 7.4 mmol). After stirring at room temperature for 14 hours, water was added to the reaction solution. The precipitated solid was collected by filtration, washed with water, and dried to give 2- (4-bromo-2- (trifluoromethoxy) benzyl) isoindoline-1,3-dione (hereinafter referred to as Reference Example Compound 4). 0.7 g (91%) was obtained.

[Step 5]
Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanamine:
Hydrazine monohydrate (0.98 g, 19 mmol) was added to a methanol (40 mL) solution of Reference Example compound 4 (2.6 g, 6.5 mmol) at room temperature. After stirring at 60 ° C. for 2 hours, the solid precipitated at room temperature was filtered off. The filtrate was concentrated under reduced pressure, and the resulting crude product was dissolved in ethyl acetate and washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.5 g (85%) of (4-bromo-2- (trifluoromethoxy) phenyl) methanamine (hereinafter referred to as Reference Example Compound 5).

[Step 6]
Synthesis of (R) -tert-butyl 3-((4-bromo-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carboxylate:
Reference temperature compound 5 (0.50 g, 1.9 mmol), (R) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (0.43 g, 1.9 mmol), DIPEA (0.53 g) at room temperature 4.1 mmol) in DMF (3.0 mL) was added HATU (0.77 g, 2.0 mmol). After stirring at room temperature for 15 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and a saturated aqueous sodium chloride solution. 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 = 9: 1 → 1: 1), and (R) — As a result, 0.89 g (quantitative) of tert-butyl 3-((4-bromo-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carboxylate (hereinafter referred to as Reference Example Compound 6) was obtained.

[Step 7]
Synthesis of (R) -tert-butyl 3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carboxylate:
At room temperature, a solution of Reference Compound 6 (0.050 g, 0.10 mmol) and zinc cyanide (0.012 g, 0.10 mmol) in DMF (2.0 mL) was added to tetrakistriphenylphosphine palladium (0) (0. 030 g, 0.026 mmol) was added. After stirring at 150 ° C. for 30 minutes, water was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, 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 = 20: 1 → 1: 2), and (R) -tert-butyl 3-((4-cyano-2- ( 0.017 g (39%) of trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carboxylate (hereinafter referred to as Reference Example Compound 7) was obtained.

[Step 8]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
Under ice-cooling, trifluoroacetic acid (hereinafter TFA) (35 mL, 0.45 mol) was added to a solution of Reference Example Compound 7 (6.9 g, 16 mmol) in dichloromethane (0.16 L). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 8). 2 g (98%) were obtained.

[Step 9]
Synthesis of (R) -tert-butyl (1- (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carbonyl) cyclobutyl) carbamate:
Reference Example Compound 8 (0.20 g, 0.67 mmol), 1-((tert-butoxycarbonyl) amino) cyclobutanecarboxylic acid (0.15 g, 0.67 mmol), DIPEA (0.24 mL, 1. To a solution of 3 mmol) in DMF (0.70 mL) was added HATU (0.28 g, 0.73 mmol). After stirring at room temperature for 86 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 7: 3 → 4: 6), and (R) -tert-butyl (1 0.25 g (78%) of — (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carbonyl) cyclobutyl) carbamate (hereinafter referred to as Reference Example Compound 9) was obtained.

[Step 10]
Synthesis of (R) -1- (1-aminocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
TFA (0.70 mL, 9.1 mmol) was added to a dichloromethane (1.4 mL) solution of Reference Example compound 9 (0.25 g, 0.47 mmol) under ice cooling. 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 a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and (R) -1- (1-aminocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide ( Hereinafter, 0.18 g (90%) of Reference Example Compound 10) was obtained.

[Step 11]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-propionamidocyclobutanecarbonyl) piperidine-3-carboxamide:
Under ice-cooling, propionyl chloride (1.8 g, 20 mmol) was added to a solution of Reference Example Compound 10 (7.6 g, 18 mmol) and TEA (5.5 mL, 40 mmol) in dichloromethane (54 mL). After stirring for 1 hour under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 → 95: 5), and (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl was obtained. ) -1- (1-propionamidocyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 1) was obtained in an amount of 6.2 g (71%).

Example 2 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide:
[Step 1]
(R) -tert-butyl (1- (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-yl) -2-methyl-1-oxopropan-2-yl) Synthesis of carbamate:
Under ice-cooling, Reference Example Compound 8 (3.5 g, 11 mmol), 2-((tert-butoxycarbonyl) amino) -2-methylpropanoic acid (2.6 g, 13 mmol), DIPEA (4.1 mL, 24 mmol) To a DMF (40 mL) solution, HATU (4.9 g, 13 mmol) was added. After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 9: 1 → 4: 6), and (R) -tert-butyl (1 -(3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-yl) -2-methyl-1-oxopropan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 11) Of 5.2 g (95%).

[Step 2]
Synthesis of (R) -1- (2-amino-2-methylpropanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
TFA (25 mL, 0.32 mol) was added to a solution of Reference Example Compound 11 (5.2 g, 10 mmol) in dichloromethane (0.10 L) under ice cooling. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and (R) -1- (2-amino-2-methylpropanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine- 3.4 g (82%) of 3-carboxamide (hereinafter referred to as Reference Example Compound 12) was obtained.

[Step 3]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide:
Methanesulfonyl chloride (0.97 g, 8.5 mmol) was added to a solution of Reference Example Compound 12 (2.3 g, 5.6 mmol) and TEA (1.6 mL, 11 mmol) in dichloromethane (15 mL) under ice cooling. After stirring for 5 minutes under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 → 95: 5), and (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl was obtained. ) -1- (2-Methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 2) was obtained in an amount of 2.4 g (87%).

Example 3 Synthesis of (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of (R) -tert-butyl (1- (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carbonyl) cyclopropyl) carbamate:
Under ice-cooling, Reference Compound 8 (0.67 g, 2.0 mmol), 1-((tert-butoxycarbonyl) amino) cyclopropanecarboxylic acid (0.49 g, 2.4 mmol), DIPEA (1.1 mL, 6 mmol) .1 mmol) in DMF (5.0 mL) was added HATU (1.1 g, 2.5 mmol). After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 9: 1 → 4: 6), and (R) -tert-butyl (1 0.92 g (88%) of — (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carbonyl) cyclopropyl) carbamate (hereinafter referred to as Reference Example Compound 13) was obtained.

[Step 2]
Synthesis of (R) -1- (1-aminocyclopropanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
TFA (4.7 mL, 61 mmol) was added to a dichloromethane (20 mL) solution of Reference Example Compound 13 (0.92 g, 1.8 mmol) under ice cooling. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (R) -1- (1-aminocyclopropanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide. As a result, 0.63 g (87%) of Reference Example Compound 14 was obtained.

[Step 3]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide:
Under ice cooling, methanesulfonyl chloride (0.27 g, 2.3 mmol) was added to a solution of Reference Compound 14 (0.63 g, 1.5 mmol) and TEA (1.1 mL, 7.7 mmol) in dichloromethane (5.0 mL). Was added. After stirring for 1.5 hours under ice cooling, water and 1N hydrochloric acid were 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 → 95: 5), and (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl was obtained. ) -1- (1- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 3) was obtained in an amount of 0.56 g (74%).

Example 4 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) piperidine-3-carboxamide:
The same reaction as in Example 1 [Step 9] was carried out using 1- (trifluoromethyl) cyclopropanecarboxylic acid (0.054 g, 0.17 mmol) to give (R) -N- (4-cyano- 0.044 g (58%) of 2- (trifluoromethoxy) benzyl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 4) was obtained.

Example 5 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (methylsulfonamido) cyclobutanecarbonyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 10 (0.020 g, 0.047 mmol). 0.017 g (71%) of benzyl) -1- (1- (methylsulfonamido) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 5) was obtained.

Example 6 Synthesis of (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclobutanecarbonyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using isobutyryl chloride (0.0055 g, 0.052 mmol). 0.022 g (95%) of (benzyl) -1- (1-isobutyramidecyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 6) was obtained.

Example 7 Synthesis of (R) —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclobutanecarbonyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using pivaloyl chloride (0.0063 g, 0.052 mmol). 0.017 g (72%) of (benzyl) -1- (1-pivalamidocyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 7) was obtained.

Example 8 Synthesis of (R) -1- (1-acetamidocyclopentanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of (R) -tert-butyl (1- (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carbonyl) cyclopentyl) carbamate:
(R) -tert-butyl was prepared by carrying out the same reaction as in Example 1 [Step 9] using 1-((tert-butoxycarbonyl) amino) cyclopentanecarboxylic acid (0.078 g, 0.34 mmol). 0.13 g (77%) of (1- (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carbonyl) cyclopentyl) carbamate (hereinafter referred to as Reference Example Compound 15) was obtained. .

[Step 2]
Synthesis of (R) -1- (1-aminocyclopentanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1- (1-aminocyclopentanecarbonyl) -N— (R) -1- (1-aminocyclopentanecarbonyl) -N— (Reference Example Compound 15 (0.13 g, 0.24 mmol) was used for the same reaction as in Example 1 [Step 10]. 0.051 g (49%) of 4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 16) was obtained.

[Step 3]
Synthesis of (R) -1- (1-acetamidocyclopentanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
Under ice-cooling, acetic anhydride (0.0070 g, 0.068 mmol) was added to a solution of Reference Example Compound 16 (0.020 g, 0.046 mmol) and TEA (0.019 mL, 0.14 mmol) in dichloromethane (0.20 mL). added. After stirring for 1 hour under ice cooling, water and 1N hydrochloric acid were 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 → 95: 5), and (R) -1- (1-acetamidocyclopentanecarbonyl) -N- (4 0.014 g (62%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 8) was obtained.

Example 9 Synthesis of (R) -1- (1-acetamidocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1- (1-acetamidocyclobutanecarbonyl) -N- (4) was prepared by performing the same reaction as in Example 8 [Step 3] using Reference compound 10 (0.020 g, 0.047 mmol). 0.013 g (60%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 9) was obtained.

Example 10 (R) -N- (4-Chloro-2- (2,2,2-trifluoroethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) propanoyl) piperidine- Synthesis of 3-carboxamide:
[Step 1]
Synthesis of 4-chloro-2- (2,2,2-trifluoroethoxy) benzonitrile:
Sodium hydride (55 wt%, 0.67 g, 15 mmol) was added to a solution of 2,2,2-trifluoroethanol (1.5 g, 15 mmol) in THF (50 mL) under ice cooling. The mixture was stirred for 10 minutes under ice cooling, and then stirred for 30 minutes at room temperature. 4-Chloro-2-fluorobenzonitrile (2.0 g, 13 mmol) was added to the reaction solution under ice cooling. After stirring at room temperature for 1 hour, 0.1N hydrochloric acid was added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, 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 = 10: 0 → 3: 1), and 4-chloro-2- (2,2,2-trifluoroethoxy) benzo 2.6 g (86%) of nitrile (hereinafter referred to as Reference Example Compound 17) was obtained.

[Step 2]
Synthesis of (4-chloro-2- (2,2,2-trifluoroethoxy) phenyl) methanamine:
Under ice cooling, lithium aluminum hydride (1.0 g, 27 mmol) was added to a solution of Reference Example Compound 17 (2.5 g, 11 mmol) in diethyl ether (30 mL). After stirring at room temperature for 4 hours, THF (20 mL), water (1.0 mL), 1N aqueous sodium hydroxide solution (1.0 mL), and water (3.0 mL) were added to the reaction solution under ice cooling. . After the reaction solution was filtered, the filtrate was concentrated under reduced pressure to obtain 2.4 g (94%) of (4-chloro-2- (2,2,2-trifluoroethoxy) phenyl) methanamine (hereinafter referred to as Reference Example Compound 18). Obtained.

[Step 3]
Synthesis of (R) -tert-butyl 3-((4-chloro-2- (2,2,2-trifluoroethoxy) benzyl) carbamoyl) piperidine-1-carboxylate:
(R) -tert-butyl 3-((4-chloro-2- (2,4 g, 10 mmol) was used in the same manner as in Example 1 [Step 6] using Compound 18 (2.4 g, 10 mmol). 4.5 g (quantitative) of 2,2-trifluoroethoxy) benzyl) carbamoyl) piperidine-1-carboxylate (hereinafter referred to as Reference Example Compound 19) was obtained.

[Step 4]
Synthesis of (R) -N- (4-chloro-2- (2,2,2-trifluoroethoxy) benzyl) piperidine-3-carboxamide:
Concentrated hydrochloric acid (10 mL, 0.12 mol) was added to Reference Example Compound 19 (2.0 g, 4.4 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (10 mL), and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added. 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 washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (R) -N- (4-chloro-2- (2,2,2-trifluoroethoxy) benzyl) piperidine-3-carboxamide. 1.4 g (87%) of Reference Example Compound 20 was obtained.

[Step 5]
(R) -tert-butyl (1-3-((4-chloro-2- (2,2,2-trifluoroethoxy) benzyl) carbamoyl) piperidin-1-yl) -2-methyl-1-oxopropane Synthesis of -2-yl) carbamate:
(R) -tert-butyl (1-3-((4-chloro-) was obtained by conducting the same reaction as in Example 2 [Step 1] using Reference Example Compound 20 (0.60 g, 1.7 mmol). 0.77 g of 2- (2,2,2-trifluoroethoxy) benzyl) carbamoyl) piperidin-1-yl) -2-methyl-1-oxopropan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 21) (84%) obtained.

[Step 6]
Synthesis of (R) -1- (2-amino-2-methylpropanoyl) -N- (4-chloro-2- (2,2,2-trifluoroethoxy) benzyl) piperidine-3-carboxamide:
TFA (10 mL) was added to Reference Example Compound 21 (0.83 g, 1.5 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (10 mL), and saturated aqueous sodium hydrogen carbonate solution (10 mL) was added. 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 washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (R) -1- (2-amino-2-methylpropanoyl) -N- (4-chloro-2- (2,2 , 2-trifluoroethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Reference Example Compound 22) was obtained in an amount of 0.65 g (96%).

[Step 7]
Synthesis of (R) -N- (4-chloro-2- (2,2,2-trifluoroethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide :
Under ice cooling, a solution of Reference Compound 22 (0.080 g, 0.18 mmol) and pyridine (0.030 mL, 0.37 mmol) in dichloromethane (2.0 mL) was added to methanesulfonyl chloride (0.023 g, 0.20 mmol). Was added. After stirring at room temperature for 10 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with 0.1N hydrochloric acid, water, and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform: methanol = 100: 1 → 10: 1), and (R) -N- (4-chloro-2- (2,2,2 -Trifluoroethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 10) was obtained in an amount of 0.030 g (32%).

Example 11 Synthesis of (R) -1-((R) -2-acetamido-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide :
[Step 1]
Synthesis of (R) -1-((R) -2-amino-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
Reference Example Compound 8 (0.21 g, 0.65 mmol), (R) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -3-methylbutanoic acid (0. HATU (0.30 g, 0.78 mmol) was added to a DMF (3.5 mL) solution of 24 g, 0.72 mmol), DIPEA (0.14 mL, 0.78 mmol). After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 → 1: 9) to obtain 0.30 g of a crude product. Under ice-cooling, morpholine (0.20 mL, 2.3 mmol) was added to a solution of the obtained crude product (0.30 g) in DMF (2.0 mL). After stirring at room temperature for 2.5 hours, water 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: chloroform: methanol = 99: 1 → 90: 10) to give (R) -1-((R) -2-amino-3-methylbutaline. Noyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 23) (0.18 g, 2-step yield 65%) was obtained.

[Step 2]
Synthesis of (R) -1-((R) -2-acetamido-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1-((R) -2-acetamido-3-methyl) was prepared by performing the same reaction as in Example 8 [Step 3] using Reference compound 23 (0.020 g, 0.047 mmol). 0.018 g (83%) of butanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 11) was obtained.

Example 12 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3- Synthesis of carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by conducting the same reaction as in Example 2 [Step 3] using Reference Example Compound 23 (0.020 g, 0.047 mmol). 0.020 g (83%) of benzyl) -1-((R) -3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 12) was obtained.

Example 13 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (ethylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide:
Under ice-cooling, ethanesulfonyl chloride (0.017 g, 0.13 mmol) was added to a solution of Reference Example Compound 14 (0.050 g, 0.12 mmol) and DIPEA (0.043 mL, 0.24 mmol) in dichloromethane (3.0 mL). Was added. After stirring at room temperature for 3 hours, pyridine (0.30 mL, 3.7 mmol) was added. After stirring at room temperature for 3 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with 0.1N hydrochloric acid, water, and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform: methanol = 100: 1 → 10: 1), and (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl was obtained. ) -1- (1- (ethylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 13) was obtained in an amount of 0.0080 g (13%).

Example 14 Synthesis of (R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide:
Under ice-cooling, a hydrogen peroxide solution (30% by weight, 0.0. 021 mL) was added. After stirring at room temperature for 18 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution, 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 → 85: 15), and (R) —N- (4-carbamoyl-2- (trifluoromethoxy) benzyl was obtained. ) -1- (2-Methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 14) was obtained in an amount of 0.013 g (63%).

Example 15 (R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide Synthesis:
(R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1 was prepared by carrying out the same reaction as in Example 14 using Example Compound 3 (0.025 g, 0.051 mmol). As a result, 0.020 g (77%) of — (2-methyl-2- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 15) was obtained.

Example 16 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-hydroxy-2-methylpropanoyl) piperidine-3-carboxamide:
The same reaction as in Example 1 [Step 9] was performed using 2-hydroxy-2-methylpropanoic acid (0.15 g, 0.46 mmol) to give (R) -N- (4-cyano-2- 0.12 g (62%) of (trifluoromethoxy) benzyl) -1- (2-hydroxy-2-methylpropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 16) was obtained.

Example 17 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-pivaloylpiperidine-3-carboxamide:
By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 8 (0.15 g, 0.46 mmol) and pivaloyl chloride (0.066 g, 0.55 mmol), (R) — 0.19 g (quantitative) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-pivaloylpiperidine-3-carboxamide (hereinafter, Example Compound 17) was obtained.

Example 18 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (N-methylmethylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide :
[Step 1]
Synthesis of ethyl 1- (methylsulfonamido) cyclopropanecarboxylate:
Methanesulfonyl chloride (1.4 g, 12 mmol) was added to a solution of ethyl 1-aminocyclopropanecarboxylic acid hydrochloride (2.0 g, 12 mmol) and DIPEA (6.3 mL, 36 mmol) in dichloromethane (35 mL) under ice cooling. It was. After stirring for 3 hours under ice cooling, 1N hydrochloric acid was added to the reaction solution to make it acidic, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 = 10: 1 → 1: 2) to give ethyl 1- (methylsulfonamido) cyclopropanecarboxylate (hereinafter referred to as Reference Example Compound). 24) 2.3 g (60%) was obtained.

[Step 2]
Synthesis of ethyl 1- (N-methylmethylsulfonamido) cyclopropanecarboxylate:
Sodium hydride (55 wt%, 0.51 g, 12 mmol) was added to a DMF (10 mL) solution of Reference Example Compound 24 (2.0 g, 9.7 mmol) under ice cooling. The mixture was stirred for 10 minutes under ice cooling, and then stirred for 30 minutes at room temperature. Methyl iodide (0.78 mL, 13 mmol) was added to the reaction solution under ice cooling. After stirring at room temperature for 14 hours, 0.1N hydrochloric acid was added to the reaction solution under ice cooling, and the mixture was extracted with a mixed solvent of hexane: ethyl acetate (hexane: ethyl acetate = 1: 2). The organic layer was washed with water and a saturated aqueous sodium chloride solution, 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 = 10: 1 → 1: 1), and ethyl 1- (N-methylmethylsulfonamido) cyclopropanecarboxylate (hereinafter referred to as “eluent”). 1.8 g (84%) of Reference Example Compound 25) was obtained.

[Step 3]
Synthesis of 1- (N-methylmethylsulfonamido) cyclopropanecarboxylic acid:
A 1N aqueous sodium hydroxide solution (12 mL, 12 mmol) was added to a methanol (20 mL) solution of Reference Example Compound 25 (1.8 g, 7.9 mmol) at room temperature. After stirring at 50 ° C. for 3 hours, 1N hydrochloric acid was added to the reaction solution at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.88 g (58 %)Obtained.

[Step 4]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (N-methylmethylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 1 [Step 9] using Reference Example Compound 26 (0.13 g, 0.67 mmol). 0.17 g (60%) of benzyl) -1- (1- (N-methylmethylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 18) was obtained.

Example 19 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (3-hydroxy-2,2-dimethylpropanoyl) piperidine-3-carboxamide:
A 1N aqueous sodium hydroxide solution (9.1 mL) was added to a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1.0 g, 7.6 mmol) in methanol (7.5 mL) at room temperature. After stirring at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure. 1N Hydrochloric acid was added to the obtained crude product, and the mixture was concentrated under reduced pressure. HATU (0.35 g, 0.93 mmol) was added to a DMF (1.6 mL) solution of the obtained crude product (0.10 g) and DIPEA (0.30 mL, 1.7 mmol) under ice cooling. After stirring for 15 minutes under ice cooling, Reference Example Compound 8 (0.28 g, 0.85 mmol) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, 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 = 8: 2 → ethyl acetate only), and (R) -N- (4-cyano-2- (trifluoromethoxy) 0.24 g (2-step yield 65%) of benzyl) -1- (3-hydroxy-2,2-dimethylpropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 19) was obtained.

Example 20 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide:
Under ice-cooling, an aqueous sulfuric acid solution (40 wt%, 5.6 mL) was added to a solution of cyclohexanone (3.0 g, 31 mmol) and potassium cyanide (2.2 g, 34 mmol) in water (5.6 mL). After stirring at room temperature for 1 hour, water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Concentrated hydrochloric acid (60 mL) was added to the obtained crude product. After stirring at 80 ° C. for 16 hours, the reaction solution was concentrated under reduced pressure to obtain 4.0 g of a crude product. Under ice cooling, the obtained crude product (0.16 g), Reference Example Compound 8 (0.15 g, 0.46 mmol), DIPEA (0.24 mL, 1.4 mmol) in DMF (1.0 mL) solution, HATU (0.45 g, 0.60 mmol) was added. After stirring at room temperature for 2 hours, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 7: 3 → 4: 6), and (R) -N- (4- 0.061 g (2-step yield 29%) of cyano-2- (trifluoromethoxy) benzyl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 20) was obtained.

Example 21 Synthesis of (R) -1-((R) -2-acetamidobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of (R) -2-((tert-butoxycarbonyl) amino) butanoic acid:
Under ice-cooling, (R) -2-aminobutanoic acid (2.0 g, 19 mmol), sodium bicarbonate (1.6 g, 19 mmol) in 1,4-dioxane: water (1,4-dioxane: water = 3: 10) , 26 mL) di-tert-butyl dicarbonate (4.7 g, 21 mmol) was added to the mixed solution. After stirring at room temperature for 120 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, 1N hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.0 g (quantitative) of (R) -2-((tert-butoxycarbonyl) amino) butanoic acid (hereinafter referred to as Reference Example Compound 27).

[Step 2]
tert-Butyl ((R) -1-((R) -3-((4-Cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-yl) -1-oxobutan-2-yl) carbamate Synthesis of:
The same reaction as in Example 1 [Step 9] was carried out using Reference Compound 27 (0.20 g, 1.0 mmol) to give tert-butyl ((R) -1-((R) -3- ( 0.47 g (quantitative) of (4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-yl) -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 28) was obtained. .

[Step 3]
Synthesis of (R) -1-((R) -2-aminobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1-((R) -2-aminobutanoyl)-was prepared by carrying out the same reaction as in Example 1 [Step 10] using Reference Example Compound 28 (0.47 g, 0.91 mmol). 0.38 g (quantitative) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 29) was obtained.

[Step 4]
Synthesis of (R) -1-((R) -2-acetamidobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1-((R) -2-acetamidobutanoyl)-was prepared by conducting the same reaction as in Example 8 [Step 3] using Reference compound 29 (0.091 g, 0.22 mmol). 0.085 g (85%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 21) was obtained.

Example 22 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 29 (0.096 g, 0.23 mmol). 0.090 g (79%) of (benzyl) -1-((R) -2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 22) was obtained.

Example 23 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-cyanocyclopropanecarbonyl) piperidine-3-carboxamide:
The same reaction as in Example 1 [Step 9] was performed using 1-cyanocyclopropanecarboxylic acid (0.034 g, 0.31 mmol) to give (R) -N- (4-cyano-2- (tri 0.081 g (63%) of fluoromethoxy) benzyl) -1- (1-cyanocyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 23) was obtained.

Example 24 Synthesis of (R) -1-((R) -2-acetamidopropanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of (R) -1-((R) -2-aminopropanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
Reference Example Compound 8 (0.35 g, 1.1 mmol), (R) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) propanoic acid (0.37 g, 1. 2 mmol), DIPEA (0.56 mL, 3.2 mmol) in DMF (2.0 mL) was added HATU (0.53 g, 1.4 mmol). After stirring at room temperature for 30 minutes, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Amine silica gel DM1020 manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 9: 1 → 1: 9) to obtain 0.53 g of the crude product. . Morpholine (0.36 mL, 4.1 mmol) was added to a solution of the obtained crude product (0.53 g) in DMF (4.0 mL) at room temperature. After stirring at room temperature for 6 hours, water 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 (amine silica gel DM1020 manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform: methanol = 99: 1 → 95: 5), and (R) -1-((R) -2-Aminopropanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 30) (0.29 g, 2-step yield 67%) was obtained. It was.

[Step 2]
Synthesis of (R) -1-((R) -2-acetamidopropanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
Acetic anhydride (0.032 g, 0.32 mmol) was added to a dichloromethane (1.0 mL) solution of Reference Example Compound 30 (0.10 g, 0.25 mmol) and TEA (0.11 mL, 0.14 mmol) under ice cooling. added. After stirring for 5 minutes under ice cooling, water and 1N hydrochloric acid were 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), and (R) -1-((R) -2-acetamidopropanoyl) -N 0.11 g (quantitative) of-(4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 24) was obtained.

Example 25 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 30 (0.10 g, 0.25 mmol). 0.099 g (83%) of benzyl) -1-((R) -2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 25) was obtained.

Example 26 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclopropanecarbonyl) piperidine-3-carboxamide:
By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and isobutyryl chloride (0.0062 g, 0.058 mmol), (R) — 0.017 g (71%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 26) was obtained. It was.

Example 27 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclopropanecarbonyl) piperidine-3-carboxamide:
By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and pivaloyl chloride (0.0064 g, 0.058 mmol), (R) — 0.018 g (73%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 27) Obtained.

Example 28 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (4- (methylsulfonamido) tetrahydro-2H-pyran-4-carbonyl) piperidine-3- Synthesis of carboxamide:
[Step 1]
Synthesis of 8-oxa-1,3-diazaspiro [4.5] decane-2,4-dione:
Dihydro-2H-pyran 4 (3H) -one (2.0 g, 20 mmol), ammonium carbonate (9.6 g, 0.10 mol), TEA (2.8 mL, 20 mmol) in water: methanol (water: methanol) at room temperature. = 1: 1, 60 mL) Potassium cyanide (3.9 g, 60 mmol) was added to the mixed solution. After stirring for 48 hours under reflux with heating, the reaction solution is concentrated under reduced pressure, the solvent is distilled off by about half, the precipitated solid is collected by filtration, washed with water and dried, and then 8-oxa-1,3-diazaspiro. [4.5] 1.4 g (41%) of decane-2,4-dione (hereinafter referred to as Reference Example Compound 31) was obtained. Concentrated hydrochloric acid was added to the filtrate until acidic, and the precipitated solid was collected by filtration, washed with water and dried to obtain 0.80 g (24%) of Reference Example Compound 31.

[Step 2]
Synthesis of 4-((tert-butoxycarbonyl) amino) tetrahydro-2H-pyran-4-carboxylic acid:
Calcium hydroxide (3.0 g, 41 mmol) was added to a solution of Reference Example Compound 31 (2.2 g, 13 mmol) in water (30 mL) at room temperature. After stirring for 48 hours under heating reflux, the reaction solution was filtered through Celite, and the residue was washed with hot water. The filtrate was concentrated under reduced pressure, and the resulting crude product was dissolved in a mixed solution of water: 1,4-dioxane: methanol (water: 1,4-dioxane: methanol = 10: 10: 3, 23 mL). Di-tert-butyl dicarbonate (3.4 g, 16 mmol) and sodium hydroxide (0.50 g, 13 mmol) were added to the reaction solution at room temperature. After stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure. Dilute hydrochloric acid (15 mL) was added to the resulting crude product, and the mixture was extracted with a mixed solution of chloroform: methanol (chloroform: methanol = 10: 1). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.6 g (82%) of 4-((tert-butoxycarbonyl) amino) tetrahydro-2H-pyran-4-carboxylic acid (hereinafter referred to as Reference Example Compound 32). )Obtained.

[Step 3]
Synthesis of (R) -tert-butyl (4- (3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-carbonyl) tetrahydro-2H-pyran-4-yl) carbamate:
(R) -tert-butyl (4- (3-((4-cyano) was obtained by conducting the same reaction as in Example 9 [Step 9] using Reference Example Compound 32 (0.082 g, 0.34 mmol). 0.10 g (62%) of -2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-carbonyl) tetrahydro-2H-pyran-4-yl) carbamate (hereinafter referred to as Reference Example Compound 33) was obtained.

[Step 4]
Synthesis of (R) -1- (4-aminotetrahydro-2H-pyrancarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1- (4-Aminotetrahydro-2H-pyrancarbonyl)-was prepared by carrying out the same reaction as in Example 1 [Step 10] using Reference Example Compound 33 (0.10 g, 0.19 mmol). 0.050 g (58%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 34) was obtained.

[Step 5]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (4- (methylsulfonamido) tetrahydro-2H-pyran-4-carbonyl) piperidine-3-carboxamide:
The same reaction as in Example 2 [Step 3] was carried out using Reference Example Compound 34 (0.040 g, 0.088 mmol) under ice cooling to give (R) -N- (4-cyano-2- ( 0.024 g (5.1%) of (trifluoromethoxy) benzyl) -1- (4- (methylsulfonamido) tetrahydro-2H-pyran-4-carbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 28) Obtained.

Example 29 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (cyclopropanecarboxamido) cyclobutanecarbonyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using cyclopropanecarbonyl chloride (0.0059 g, 0.057 mmol). 0.012 g (52%) of benzyl) -1- (1- (cyclopropanecarboxamide) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 29) was obtained.

Example 30 (R) -1-((R) -2-Acetamido-3-hydroxy-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3 -Synthesis of carboxamide:
[Step 1]
Synthesis of methyl (R) -2-((tert-butoxycarbonyl) amino) -3-hydroxypropanoate:
Under ice-cooling, a solution of methyl (R) -2-amino-3-hydroxypropanoate (3.0 g, 19 mmol) and TEA (8.1 mL, 58 mmol) in methanol (50 mL) was added to di-tert-butyl dicarbonate. (4.6 g, 21 mmol) was added. After stirring for 14 hours at room temperature, dilute hydrochloric acid was added to the reaction solution. After stirring at room temperature for 1 hour, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, 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 = 20: 1 → 2: 1), and (R) -2-((tert-butoxycarbonyl) amino) -3- 4.1 g (97%) of methyl hydroxypropanoate (hereinafter referred to as Reference Example Compound 35) was obtained.

[Step 2]
Synthesis of (S) -tert-butyl (1,3-dihydroxy-3-methylbutan-2-yl) carbamate:
Methyl magnesium bromide diethyl ether solution (3N, 30 mL, 91 mmol) was added to a diethyl ether (0.12 L) solution of Reference Example compound 35 (4.0 g, 18 mmol) at −78 ° C. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution and water were added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with 0.1N dilute hydrochloric acid and water, 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 = 10: 1 → 3: 1), and (S) -tert-butyl (1,3-dihydroxy-3-methylbutane- 2.8 g (84%) of 2-yl) carbamate (hereinafter referred to as Reference Example Compound 36) was obtained.

[Step 3]
Synthesis of (R) -2-((tert-butoxycarbonyl) amino) -3-hydroxy-3-methylbutanoic acid:
Reference compound 36 (2.8 g, 13 mmol), 2,2,6,6, -tetramethylpiperidine 1-oxyl (0.40 g, 2.6 mmol), standard neutral phosphate buffer (45 mL) at 35 ° C. ) In acetonitrile (50 mL), a solution of sodium hypochlorite (0.8 g, 0.64 mmol) in water (5.0 mL), chlorous acid (2.4 g, 27 mmol) in water (10 mL), Slowly added separately at the same time. After stirring at 35 ° C. for 3 hours, acetic acid (1.0 mL) was added to the reaction solution. After stirring at 35 ° C. for 3 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in a saturated aqueous sodium hydrogen carbonate solution and washed with ethyl acetate. The aqueous layer was acidified with 3N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (R) -2-((tert-butoxycarbonyl) amino) -3-hydroxy-3-methylbutanoic acid (hereinafter referred to as “R”). Then, 2.5 g (84%) of Reference Example Compound 37) was obtained.

[Step 4]
tert-butyl ((R) -1-((R) -3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-yl) -3-hydroxy-3-methyl-1 Synthesis of -oxobutan-2-yl) carbamate:
To a DMF (2.0 mL) solution of Reference Example Compound 8 (0.30 g, 0.92 mmol), Reference Example Compound 37 (0.24 g, 1.0 mmol) and DIPEA (0.35 mL, 2.0 mmol) at room temperature. , HATU (0.42 g, 1.1 mmol) was added. After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Amine Silica DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane: ethyl acetate = 7: 3 → 4: 6), and tert-butyl ((R) -1 -((R) -3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidin-1-yl) -3-hydroxy-3-methyl-1-oxobutan-2-yl) carbamate ( In the following, 0.44 g (89%) of Reference Example Compound 38) was obtained.

[Step 5]
Synthesis of (R) -1-((R) -2-amino-3-hydroxy-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
TFA (1.8 mL, 23 mmol) was added to a solution of Reference Example Compound 38 (0.44 g, 0.82 mmol) in dichloromethane (8.0 mL) under ice cooling. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and (R) -1-((R) -2-amino-3-hydroxy-3-methylbutanoyl) -N- (4-cyano-2- ( 0.20 g (58%) of (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 39) was obtained.

[Step 6]
Synthesis of ((R) -1-((R) -2-acetamido-3-hydroxy-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide :
Under ice cooling, acetic anhydride (0.010 g, 0.10 mmol) was added to a solution of Reference Example Compound 39 (0.040 g, 0.090 mmol) and DIPEA (0.035 mL, 0.20 mmol) in dichloromethane (0.30 mL). added. After stirring for 10 minutes under ice cooling, water and 1N hydrochloric acid were 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: chloroform: methanol = 99: 1 → 95: 5) to obtain ((R) -1-((R) -2-acetamido-3-hydroxy 0.029 g (66%) of -3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 30) was obtained.

Example 31 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine- Synthesis of 3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by conducting the same reaction as in Example 1 [Step 11] using Reference Example Compound 39 (0.0083 g, 0.019 mmol). As a result, 0.0065 g (70%) of benzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 31) was obtained.

Example 32 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) Synthesis of piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference Example Compound 39 (0.040 g, 0.090 mmol). 0.038 g (81%) of (benzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 32) was obtained. .

Example 33 Synthesis of (R) -1- (1-butylamidocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
(R) -1- (1-Butylamidocyclobutanecarbonyl) -N— (4) was prepared by performing the same reaction as in Example 1 [Step 11] using butyryl chloride (0.0060 g, 0.057 mmol). 0.018 g (79%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 33) was obtained.

Example 34 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclobutanecarbonyl) piperidine-3-carboxamide:
By performing the same reaction as in Example 1 [Step 9] using Reference Example Compound 10 (0.021 g, 0.049 mmol) and 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol), (R) 0.0065 g of —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 34) (26%) obtained.

Example 35 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclopropanecarbonyl) piperidine-3-carboxamide:
By performing the same reaction as in Example 1 [Step 9] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol), (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 35) 0083 g (35%) was obtained.

Example 36 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (1H-1,2,4-triazol-1-yl) Synthesis of propanoyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of ethyl 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate:
At room temperature, a solution of ethyl 2-bromo-2-methylpropanoate (1.0 g, 5.1 mmol) in DMF (25 mL) was added to cesium carbonate (5.0 g, 15 mmol), 1,2,4-triazole-1- Id sodium (0.58 g, 6.2 mmol) was added. After stirring at 50 ° C. for 24 hours, the reaction solution was concentrated under reduced pressure. Water was added to the obtained crude product and extracted with chloroform. 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 → 4: 6) to give 2-methyl- 0.84 g (89%) of ethyl 2- (1H-1,2,4-triazol-1-yl) propanoate (hereinafter referred to as Reference Example Compound 40) was obtained.

[Step 2]
Synthesis of sodium 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate:
Under ice-cooling, 1N aqueous sodium hydroxide solution (3.9 mL, 3.9 mmol) was added to a solution of Reference Example Compound 40 (0.65 g, 3.6 mmol) in ethanol (18 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and sodium 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate (hereinafter referred to as Reference Example Compound 41) was reduced to 0. Obtained .67 g (quantitative).

[Step 3]
(R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoyl) piperidine-3 -Synthesis of carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 1 [Step 6] using Reference compound 41 (0.090 g, 0.51 mmol). 0.12 g (54%) of (benzyl) -1- (2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoyl) piperidine-3 (hereinafter, Example Compound 36) was obtained. .

Example 37 (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (1H-pyrazol-1-yl) propanoyl) piperidine-3- Synthesis of carboxamide:
[Step 1]
Synthesis of ethyl 2-methyl-2- (1H-pyrazol-1-yl) propanoate:
The same reaction as in Example 36 [Step 1] was performed using 1H-pyrazole (0.42 g, 6.2 mmol) to give ethyl 2-methyl-2- (1H-pyrazol-1-yl) propanoate ( In the following, 0.81 g (87%) of Reference Example Compound 42) was obtained.

[Step 2]
Synthesis of sodium 2-methyl-2- (1H-pyrazol-1-yl) propanoate:
By performing the same reaction as in Example 36 [Step 2] using Reference Example Compound 42 (0.81 g, 4.5 mmol), sodium 2-methyl-2- (1H-pyrazol-1-yl) propanoate 0.80 g of Reference Example Compound 43 was obtained.

[Step 3]
Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (1H-pyrazol-1-yl) propanoyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 1 [Step 9] using Reference Example Compound 43 (0.090 g, 0.51 mmol). 0.16 g (68%) of benzyl) -1- (2-methyl-2- (1H-pyrazol-1-yl) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 37) was obtained.

Example 38 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of (R) -tert-butyl 3-((2,4-dichlorobenzyl) carbamoyl) piperidine-1-carboxylate:
The same reaction as in Example 1 [Step 6] was performed using 2,4-dichlorobenzylamine (1.5 g, 8.5 mmol) to give (R) -tert-butyl 3-((2,4- 2.6 g (quantitative) of dichlorobenzyl) carbamoyl) piperidine-1-carboxylate (hereinafter referred to as Reference Example Compound 44) was obtained.

[Step 2]
Synthesis of (R) -N- (2,4-dichlorobenzyl) piperidine-3-carboxamide:
(R) -N- (2,4-dichlorobenzyl) piperidine-3-reaction was carried out in the same manner as in Example 1 [Step 8] using Reference Compound 44 (2.6 g, 6.7 mmol). 1.8 g (95%) of carboxamide (hereinafter referred to as Reference Example Compound 45) was obtained.

[Step 3]
Synthesis of (R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide:
(R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexane) was prepared by performing the same reaction as in Example 20 using Reference Example Compound 45 (0.10 g, 0.35 mmol). 0.030 g (24%) of carbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 38) was obtained.

Example 39 Synthesis of ((R) -1-((R) -2-acetamido-3-hydroxy-3-methylbutanoyl) -N- (2,4-dichlorobenzyl) piperidine-3-carboxamide:
[Step 1]
tert-butyl ((R) -1-((R) -3- (2,4-dichlorobenzyl) carbamoyl) piperidin-1-yl) -3-hydroxy-3-methyl-1-oxobutan-2-yl) Synthesis of carbamate:
Reference Example Compound 37 (0.089 g, 0.38 mmol), Reference Example Compound 45 (0.10 g, 0.35 mmol), DIPEA (0.20 mL, 1.1 mmol) in DMF (0.70 mL) under ice cooling Was added HATU (0.16 g, 0.42 mmol). After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 → 4: 6), and tert-butyl ((R) -1-((R) -3- ( 0.15 g (82%) of 2,4-dichlorobenzyl) carbamoyl) piperidin-1-yl) -3-hydroxy-3-methyl-1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 46) was obtained. It was.

[Step 2]
TFA (1.0 mL, 13 mmol) was added to a dichloromethane (2.0 mL) solution of Reference Example compound 46 (0.70 g, 1.7 mmol) under ice cooling. After stirring at room temperature for 2.5 hours, TFA (1.0 mL, 13 mmol) was added to the reaction solution. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and (R) -1-((R) -2-amino-3-hydroxy-3-methylbutanoyl) -N- (2,4-dichlorobenzyl) 0.47 g (84%) of piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 47) was obtained.

[Step 3]
Synthesis of ((R) -1-((R) -2-acetamido-3-hydroxy-3-methylbutanoyl) -N- (2,4-dichlorobenzyl) piperidine-3-carboxamide:
Acetic anhydride (0.0056 g, 0.055 mmol) was added to a dichloromethane (0.15 mL) solution of Reference Example Compound 47 (0.020 g, 0.050 mmol) and TEA (0.014 mL, 0.099 mmol) under ice cooling. added. After stirring for 10 minutes under ice cooling, water and 1N hydrochloric acid were 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: chloroform: methanol = 99: 1 → 95: 5) to obtain ((R) -1-((R) -2-acetamido-3-hydroxy 0.021 g (96%) of -3-methylbutanoyl) -N- (2,4-dichlorobenzyl) piperidine-3-carboxamide (hereinafter, Example Compound 39) was obtained.

Example 40 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide:
By performing the same reaction as in Example 1 [Step 11] using Reference Compound 47 (0.020 g, 0.050 mmol), (R) -N- (2,4-dichlorobenzyl) -1- ( 0.018 g (77%) of (R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 40) was obtained.

Example 41 (R) -N- (2,4-dichlorobenzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide Synthesis:
The same reaction as in Example 2 [Step 3] was carried out using Reference Compound 47 (0.020 g, 0.050 mmol) to give (R) -N- (2,4-dichlorobenzyl) -1- ( 0.020 g (85%) of (R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 41) was obtained.

Example 42 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxypropanoyl) piperidine-3-carboxamide:
(R) -N- (4-cyano-2) was obtained by carrying out the same reaction as in Example 1 [Step 9] using (R) -2-hydroxypropanoic acid sodium salt (0.019 g, 0.17 mmol). 0.045 g (74%) of-(trifluoromethoxy) benzyl) -1-((R) -2-hydroxypropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 42) was obtained.

Example 43 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxybutanoyl) piperidine-3-carboxamide:
(R) -2-N- (4-cyano-2-) is prepared by carrying out the same reaction as in Example 1 [Step 9] using (R) -2-hydroxybutanoic acid (0.017 g, 0.17 mmol). 0.056 g (89%) of (trifluoromethoxy) benzyl) -1-((R) -2-hydroxybutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 43) was obtained.

Example 44 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxy-3-methylbutanoyl) piperidine-3-carboxamide :
(R) -2-Hydroxy-3-methylbutanoic acid (0.018 g, 0.15 mmol) was used for the same reaction as in Example 1 [Step 9] to give (R) -N- (4-cyano 0.042 g (64%) of 2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxy-3-methylbutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 44) was obtained. It was.

Comparative Example 1 Synthesis of (R) —N- (5- (tert-butyl) isoxazol-3-yl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide:
[Step 1]
Synthesis of (R) -tert-butyl 3-((5- (tert-butyl) isoxazol-3-yl) carbamoyl) piperidine-1-carboxylate:
Under ice cooling, a solution of (R) -1- (tert-butoxycarbonyl) piperidine-3-carboxylic acid (0.80 g, 3.5 mmol) in THF (12 mL) was added to DMF (2.0 mL, 26 mmol), oxalyl chloride. (0.33 mL, 3.7 mmol) was added so that the internal temperature did not exceed 5 ° C. After stirring for 30 minutes under ice cooling, the reaction solution was added to 5- (tert-butyl) isoxazol-3-amine (0.49 g, 3.5 mmol), pyridine (0.71 mL, 8.7 mmol) at −25 ° C. ) In THF (5 mL) was added so that the internal temperature did not exceed -20 ° C. After stirring for 3 hours under ice cooling, a saturated aqueous sodium chloride solution was added to the reaction solution so that the internal temperature did not exceed 5 ° C., and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, 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 = 20: 1 → 1: 1), and (R) -tert-butyl 3-((5- (tert-butyl) 0.93 g (76%) of isoxazol-3-yl) carbamoyl) piperidine-1-carboxylate (hereinafter referred to as Reference Example Compound 48) was obtained.

[Step 2]
Synthesis of (R) -N- (5- (tert-butyl) isoxazol-3-yl) piperidine-3-carboxamide hydrochloride:
Under ice-cooling, 4N hydrogen chloride ethyl acetate solution (5 mL, 20 mmol) was added to Reference Example compound 48 (0.85 g, 2.4 mmol). After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure to give (R) -N- (5- (tert-butyl) isoxazol-3-yl) piperidine-3-carboxamide hydrochloride (hereinafter referred to as Reference Example Compound 49). ) Was obtained 0.69 g (100%).

[Step 3]
Synthesis of (R) -N- (5- (tert-butyl) isoxazol-3-yl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide:
DMF (7.0 mL) of Reference Example Compound 49 (0.30 g, 1.0 mmol), 1-hydroxycyclohexanecarboxylic acid (0.14 g, 0.95 mmol), DIPEA (0.50 mL, 2.8 mmol) under ice-cooling. ) To the solution was added HATU (0.43 g, 1.1 mmol). After stirring at room temperature for 14 hours, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, 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 = 5: 1 → 1: 2), and (R) -N- (5- (tert-butyl) isoxazole-3- Yl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide (hereinafter, Comparative Compound 1) was obtained in an amount of 0.29 g (80%).

Comparative Example 2 Synthesis of (R) -1- (2-acetamidoacetyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide:
At room temperature, HATU (5 mL) was added to a solution of Reference Example Compound 8 (0.10 g, 0.31 mmol), N-acetylglycine (0.036 g, 0.31 mmol), DIPEA (0.16 mL, 0.92 mmol). 0.14 g, 0.37 mmol) was added. After stirring at room temperature for 14 hours, 1N dilute hydrochloric acid was added to the reaction solution under ice cooling, and the mixture was extracted with a mixed solvent of hexane: ethyl acetate (hexane: ethyl acetate = 1: 2). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in diethyl ether (1.0 mL), and hexane (4.0 mL) was added. The precipitated gel substance was collected by filtration, and (R) -1- (2-acetamidoacetyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Comparative Example Compound) 0.040 g (31%) of 2) was obtained.

Tables 1-1 to 1-6 show physical property data of Example compounds 1 to 44, Table 2 shows physical property data of Comparative compounds 1 and 2, and Tables 3-1 to 3-5 The physical property data of Reference Example compounds 1 to 49 are shown in FIG. In the table, N.I. D. Represents “no data”.

In the 1H-NMR data, the proton integral value that is not an integer is due to the presence of a rotational isomer.

The solvent name in the 1H-NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), m ( Multiple line), brs (wide), dd (double double line), dt (double triple line), ddd (double double line), dq (double quadruple line), td (triple double line) (Multiple line) or tt (triple triple line). All solvents were commercially available. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technology).

(Example 45) Evaluation test of sEH inhibitory activity in vitro:
Inhibition of sEH of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof using human sEH based on the method described in known literature (Analytical Biochemistry, 2005, 343, p. 66-75) Activity was evaluated.

Recombinant human sEH (final concentration 0.026 μg / mL; Cayman) together with the test compound in 25 mM Bis-Tris-HCl buffer (pH 7.0) containing 0.1 mg / mL BSA for 30 minutes at room temperature Incubated. Thereafter, cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate (final concentration 6.25 μmol / L; Cayman) was added as a fluorescent substrate, and further at room temperature for 20 minutes. After incubation, ZnSO ₄ (final concentration 0.2 mol / L) was added to stop the reaction, and the fluorescence intensity (Fusion α (Packard); 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 4.

As a result, Example compounds 1 to 44 showed a very strong inhibitory activity against the enzymatic reaction of human sEH, as compared with Comparative compounds 1 and 2.

Therefore, it has been clarified that the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof exhibits a very strong inhibitory activity on the enzyme reaction of human sEH.

(Example 46) Drug efficacy evaluation test in mouse acetate rising model:
The analgesic action of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was examined using a mouse acetate rising method capable of evaluating nociceptive pain.

The mouse acetate rising method was performed according to an existing method (Endoh et al., Life Science, 1999, Vol. 65, p. 1685-1694). ddY male mice, 5-6 weeks old (Japan SLC) were bred under free drinking, and the test compound solution or its solvent (Vehicle) was orally administered (10 mL / kg). Tween 80: methyl cellulose (hereinafter referred to as MC): distilled water (0.5: 0.5: 99) was used as a solvent for the test compound solution. One hour and 45 minutes after administration of the test compound solution or its solvent, a 0.6% acetic acid solution (10 mL / kg) was administered intraperitoneally to induce a rising reaction (behavior to stretch or warp the body). Rising reactions that occurred 10 minutes after administration of the acetic acid solution were counted, and the number of times was used as an index of pain. The result is shown in FIG. It should be noted that the group administered with the solvent was the “solvent administered group”, the group administered with Example Compound 1 at a dose of 30 mg / kg was the “Example Compound 1 administered group”, and the comparative compound 1 was administered at a dose of 30 mg / kg. The group administered in 1) was designated as “Comparative Example Compound 1 Administration Group”, and the group administered with Comparative Compound 2 at a dose of 30 mg / kg was designated as “Comparative Example Compound 2 Administration Group”.

In the figure, the horizontal axis represents each group, and the vertical axis represents the number of rising reactions (average value ± standard error, n = 8). The higher the value, the more painful. The * mark in the figure indicates that it is statistically significant in comparison with the solvent administration group (Student's t test, p <0.05).

When the Example Compound 1 was orally administered at 30 mg / kg, a significant decrease in the number of rising reactions was observed as compared with the solvent administration group. On the other hand, when 30 mg / kg of Comparative Example Compound 1 or Comparative Example Compound 2 was orally administered, no significant reduction in the number of rising reactions was observed compared to the solvent administration group. From the above results, Example Compound 1 was shown to have an analgesic effect on nociceptive pain, and nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was effective against nociceptive pain. It was shown to have analgesic action.

(Example 47) Drug efficacy evaluation test in mouse sciatic nerve partial ligation model:
Using a mouse partial sciatic nerve ligation model (Seltzer model) that can evaluate neuropathic pain, the analgesic action of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was examined.

The mouse partial sciatic nerve ligation model was prepared according to the method of Seltzer et al. (Malberg et al., Pain, 1998, Vol. 76, p. 215-222). An ICR male mouse, 5 weeks old (Japan SLC), is inhaled by anesthesia with isoflurane to expose the sciatic nerve of the right hind leg thigh, and sciatic nerve using 8-0 silk thread (Natsume Seisakusho) under the microscope A group that was ligated three times in half-strength was called a “ligation group”, and a group that only exposed the sciatic nerve but did not ligate was called a “sham surgery group”.

Evaluation of neuropathic pain (hereinafter referred to as von Frey test) was performed by acclimating a mouse for at least 1 hour in a measurement acrylic cage (Natsume Seisakusho) installed on a wire mesh and then applying a filament (0.16 g pressure) Using North Coast Medical, Inc. CA, USA), mechanical tactile stimulation that repeatedly presses the filament against the sole of both hind limbs for 3 seconds is repeated 3 times at intervals of 3 seconds, and escape behavior when mechanical tactile stimulation is applied (0: no response, 1: slow and slight escape behavior to the stimulus, 2: quick response to the stimulus without flinching (behavior to shake the foot quickly) or licking (foot licking behavior) Escape behavior, 3: Fast escape behavior with flinching or licking), and the total of the three scores (below) The von Frey test total score) was used as an indicator of pain. In the von Frey test, the pre value was measured before oral administration of the test compound 7 days after the sciatic nerve ligation operation, and the mice in the ligation group were divided into the solvent administration group and the test compound administration group so that the total score of the von Frey test was uniform. Divided.

Seven days after the sciatic nerve ligation surgery, the test compound solution or its solvent (Vehicle) was orally administered (10 mL / kg) to mice in the ligation group, and von Frey tests were performed 1 hour and 2 hours after oral administration, respectively. The value was used as an index of analgesic action. Tween 80: MC: distilled water (0.5: 0.5: 99) was used as a solvent for the test compound solution. The results are shown in FIGS. It should be noted that the group administered with the solvent was the “solvent administered group”, the group administered with Example Compound 1 at a dose of 30 mg / kg was the “Example Compound 1 administered group”, and the comparative compound 1 was administered at a dose of 30 mg / kg. The group administered in 1) was designated as “Comparative Example Compound 1 Administration Group”, and the group administered with Comparative Compound 2 at a dose of 30 mg / kg was designated as “Comparative Example Compound 2 Administration Group”.

In the figure, the horizontal axis shows each group, and the vertical axis shows the von Frey test total score (mean ± standard error, n = 4 to 6). The higher the value, the stronger the pain. The * mark in the figure indicates that it is statistically significant in comparison with the solvent administration group (Student's t test, p <0.05).

The oral administration of Example Compound 1 at 30 mg / kg showed a statistically significant von Frey test total score reduction effect 1 hour and 2 hours after oral administration compared to the solvent administration group. On the other hand, when 30 mg / kg of Comparative Example Compound 1 or Comparative Example Compound 2 was orally administered, no significant von Frey test total score reduction effect was observed compared to the solvent administration group. From the above results, Example Compound 1 was shown to have an analgesic effect on neuropathic pain, and nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was effective against neuropathic pain. It was shown to have analgesic action.

The analgesic of the present invention comprises a nipecotic acid derivative or a pharmacologically acceptable salt thereof as an active ingredient, and exhibits a medicinal effect based on sEH inhibitory activity, in particular nociceptive pain and / or neuropathy. It can be used as an analgesic for pain.

Claims

An analgesic comprising, as an active ingredient, a nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
[Wherein R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms. A cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms, Each independently may be substituted with a halogen atom, a hydroxyl group, a cyano group, —SR 6 , —S (═O) —R 6 or —S (═O) 2 R 6 ), —N (R 6 ) C (═O) R 7 , —N (R 6 ) S (═O) 2 R 7 , —C (═O) N (R 6 ) R 7 or a heteroaryl group having 5 ring atoms,
R 2 and R 3 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkyloxyalkyl group have 1 to 3 carbon atoms) Each independently represents a halogen atom, a hydroxyl group or a cyano group, or together, — (CH 2 ) 1 — or — (CH 2 ) m —O — (CH 2 ) n —, but not simultaneously representing a hydrogen atom,
R 4 and R 5 each independently represents a hydrogen atom, a halogen atom, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms In the alkyl group, alkyloxy group, cycloalkyl group and cycloalkyloxy group, 1 to 3 hydrogen atoms may be each independently substituted with a halogen atom) or —C (═O) NH 2 Represents an alkyloxy group at the same time,
R 6 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
R 7 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, An alkyl group, an alkyloxyalkyl group and a cycloalkylalkyl group each represents 1 to 3 hydrogen atoms, each of which may be independently substituted with a halogen atom, a hydroxyl group or a cyano group;
l represents an integer of 2 to 5;
m and n each independently represent 1 or 2. ]
R 2 and R 3 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent — (CH 2 ) 1 —, but simultaneously represent a hydrogen atom. Not,
R 4 represents a substituent at the 2-position on the benzene ring;
The analgesic according to claim 1, wherein R 5 represents a substituent at the 4-position on the benzene ring.
R 1 represents —N (R 6 ) C (═O) R 7 or —N (R 6 ) S (═O) 2 R 7 ,
R 4 represents a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group,
R 5 represents a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group,
The analgesic according to claim 1 or 2, wherein R 6 represents a hydrogen atom.
The analgesic according to any one of claims 1 to 3, which is an analgesic for nociceptive pain.
The analgesic according to any one of claims 1 to 3, which is an analgesic for neuropathic pain.