TW201601724A - Therapeutic agent or prophylactic agent for pulmonary hypertension - Google Patents

Abstract

The purpose of the present invention is to provide a therapeutic agent or prophylactic agent for pulmonary hypertension to treat pulmonary hypertension on the basis of a dual mechanism of action consisting of a pulmonary vasodilating action and an sEH inhibiting action, and to provide a therapeutic agent or prophylactic agent for pulmonary hypertension to be used in conjunction with a pulmonary vasodilator. The present invention provides a therapeutic agent or prophylactic agent for pulmonary hypertension containing, as active ingredients, a nipecotic acid derivative shown by the formula or a pharmaceutically acceptable salt thereof, and a pulmonary vasodilator.

Description

A therapeutic or prophylactic agent for pulmonary hypertension

The present invention relates to a therapeutic or prophylactic agent for pulmonary hypertension.

Pulmonary hypertension refers to a general term for a pathological condition that is judged to be an increase in pulmonary arterial pressure, and is known to significantly reduce exercise tolerance, and most of them are progressive and have a poor prognosis. In healthy people, pulmonary artery pressure is kept lower than systemic blood pressure, but in patients with pulmonary hypertension, the average pulmonary artery pressure is 25 mmHg or more (even 30 mmHg or more during exercise). It is generally considered that this state is Long-term persistence, so right ventricular hypertrophy, right heart failure will be induced, the worst case is death.

In the case of one of the causes of pulmonary hypertension, pulmonary vasospasm is considered to be involved, and prostacyclin derivatives, phosphodiesterase inhibitors, and endothelin have been used in the treatment of pulmonary hypertension. A drug (pulmonary vasodilator) which exhibits pulmonary vasodilating action such as a receptor antagonist (Patent Documents 1 to 4 and Non-Patent Document 1) can be used in a single dose, and a sufficient antihypertensive effect cannot be obtained, and two doses or The treatment for administration of three doses of pulmonary vasodilator is administered (Patent Documents 4 and 5 and Non-Patent Documents 2 and 3).

Epoxidized eicosatrienoic acid from one of the hyperpolarizing factors of endothelial cells in recent years (Epoxyeicosatrienoic acids; hereinafter referred to as EETs) have been reported to have an inhibitory effect on blood pressure increase and a protective effect on vascular endothelium, and have a protective effect on sputum in lung diseases (Non-Patent Documents 4 and 5). Further, EETs are inactivated by the action of soluble epoxide hydrolase (hereinafter, sEH) to dihydroxyeicosatrienoic acids (hereinafter, DHETs), but soluble rings Oxide hydrolyzing enzyme inhibitors (hereinafter, sEH inhibitors) increase the amount of EETs by inhibiting the decomposition of EETs, and sEH inhibitors are suggested to be useful as therapeutic drugs for pulmonary hypertension (Patent Document 6 and Non-Patent Document 6) 7).

The use of a compound having sEH inhibitory activity as a therapeutic drug for pulmonary hypertension has been suggested (Patent Document 6 and Non-Patent Document 6), but it has been reported that even if it has sEH inhibitory activity, it also has spontaneous hypertension. An example of the therapeutic effect is not shown in the rat (Spontaneously Hypertensive Rat) (Non-Patent Documents 8 to 10).

On the other hand, in the case of a compound having a nipecotic acid diamide structure, a heteroaryl decylamine derivative in which hexahydronicotinic acid is condensed with a heteroarylamine has been reported (Patent Literature) 7) an anthracene derivative (Patent Document 8) and a hydroxamic acid derivative (Patent Document 9), but the sEH inhibitory activity is neither disclosed nor implied.

Prior technical literature Patent literature

Patent Document 1 International Publication No. 96/26721

Patent Document 2 International Publication No. 95/19978

Patent Document 3 Publication No. EP1097711

Patent Document 4 International Publication No. 2005/30187

Patent Document 5 International Publication No. 2004/17993

Patent Document 6 International Publication No. 2007/106525

Patent Document 7 International Publication No. 2010/096371

Patent Document 8 International Publication No. 2000/017158

Patent Document 9 International Publication No. 2002/028829

Non-patent literature

Non-Patent Document 1 Sato Toru, The Latest Medicine, 2010, Vol. 65, No. 8, p.1698-1702

Non-Patent Document 2 Chinese and Western Xuanwen et al. Guidelines for the treatment of pulmonary hypertension (2012 revised edition)

Non-Patent Document 3 Benza et al., The Journal of Heart and Lung Transplantation, 2007, Vol. 26, p. 437-446

Non-Patent Document 4 Lee et al., The Journal of the Federation of America Societies for Experimantal Biology, 2010, Vol. 24, p. 3770-3781

Non-Patent Document 5 Dhanasekaran et al., AJP-Heart and Circulatory Physiology, 2006, Vol. 291, H517-H531

Non-Patent Document 6 Spector et al., Progress in Lipid Research, 2004, Vol. 43, p. 55-90

Non-Patent Document 7 Larsen et al., Trends in Pharmacological Science, 2006, Vol. 28, No. 1, p. 32-38

Non-Patent Document 8 Shen et al., Bioorganic and Medicinal Chemistry Letters, 2009, Vol. 19, p. 3398-3404

Non-Patent Document 9 Shen et al., Journal of Medicinal Chemistry, 2009, Vol. 52, p.5009-5012

Non-Patent Document 10 Shen et al., Bioorganic and Medicinal Chemistry Letters, 2009, Vol. 19, p. 5314-5320

[Summary of the Invention]

However, even if the pulmonary vasodilator used in the treatment of pulmonary hypertension is effective, it has an effect on inhibiting the rise of pulmonary arterial pressure and its subsequent right ventricular hypertrophy, pulmonary hypertrophy, pulmonary hypertrophy and cardiac hypertrophy. In the treatment of pulmonary hypertension, it is imperative to create a potent drug or a combination of drugs that can treat pulmonary blood pressure with a mechanism different from pulmonary vasodilation.

In addition, even if a known compound exhibiting sEH inhibitory activity does not necessarily exert a pharmacological action such as a blood pressure lowering action in vivo, it is difficult to find an sEH inhibitor which exerts a therapeutic effect on pulmonary hypertension. However, since an sEH inhibitor having a hexahydronicotinic acid diamine structure has not been created so far, a hexahydronicotinic acid derivative capable of inhibiting an increase in pulmonary artery pressure based on sEH inhibitory activity is considered to be available for use. The possibility of treating a novel agent or a combination of drugs for pulmonary hypertension.

Accordingly, an object of the present invention is to provide a therapeutic or prophylactic agent for pulmonary hypertension for treating pulmonary hypertension based on a mechanism of action of both pulmonary vasodilatation and sEH inhibition, and a combination thereof with pulmonary vasodilator A therapeutic or prophylactic agent for pulmonary hypertension.

In order to solve the above problems, the present inventors have continually studied and found that a novel hexahydronicotinic acid derivative or a pharmacologically acceptable salt thereof exhibits strong sEH inhibitory activity and lung function based on its action. Hypertension exerts excellent therapeutic effects and preventive effects. Further, it has been found that pulmonary hypertension can be exerted by combining the above novel hexahydronicotinic acid derivatives or pharmacologically acceptable salts thereof and pulmonary vasodilators. The present invention has been accomplished by an excellent therapeutic effect and a preventive effect.

That is, the present invention provides a therapeutic or prophylactic agent for pulmonary hypertension comprising a hexahydronicotinic acid derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, and a lung Vasodilators as active ingredients:

Wherein R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group, and an alkoxy group having 2 to 7 carbon atoms; An alkyl group, a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the alkoxy group, the cycloalkyl group, the cycloalkyloxy group, the alkoxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogens) The atoms may each independently be substituted by 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 ring constituting a heteroaryl group having 5 atoms; R ² and R ³ are each independently And a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkoxyalkyl group each having 1 to 3 hydrogen atoms independently pass through a halogen atom or a hydroxyl group) Or cyano substituted), or R ² and R ³ together represent -(CH ₂ ) _l - or -(CH ₂ ) _m -O-(CH ₂ ) _n -, but not simultaneously represent a hydrogen atom; R ⁴ and R ⁵ Each independently represents a hydrogen atom, a halogen atom, a cyano group, an alkyl or alkoxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group (the alkyl group, alkoxy group, Cycloalkyl and cycloalkyloxy groups 1 to 3 hydrogen atoms can each independently be taken through a halogen atom ), Or -C (= O) NH _2, but do not simultaneously represent alkoxy; R & lt ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms of; R ⁷ represents an alkyl group having 1 to 6 carbon atoms, the carbon number of 3 - a cycloalkyl group of 6, alkoxyalkyl group having 2 to 7 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, cycloalkyl group, alkoxyalkyl group and cycloalkylalkyl group) 1 to 3 hydrogen atoms may each independently be substituted by 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].

The above-mentioned hexahydronicotinic acid derivative 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 ) _l -, but not simultaneously represent a hydrogen atom; R ⁴ It is preferred to represent 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, since the hexahydronicotinic acid derivative or its pharmacologically acceptable salt can be expected to exhibit strong sEH inhibitory activity, the therapeutic or prophylactic agent for pulmonary hypertension can be more excellent for pulmonary hypertension. Therapeutic effect and preventive effect.

In the above hexahydronicotinic 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 carbon. a number of 1 to 6 alkyl or alkoxy groups, R ⁵ represents a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms or an alkoxy group, R ⁶ represents a hydrogen atom more preferably, and R ¹ represents a -N (H) group. C(=O)CH ₂ CH ₃ , R ² and R ³ together represent -(CH ₂ ) ₃ -, R ⁴ represents -OCF ₃ , and R ⁵ represents a particularly preferred cyano group.

In this case, it is expected that the hexahydronicotinic acid derivative or its pharmacologically acceptable salt exhibits a strong sEH inhibitory activity, and besides, it is excellent in drug dynamics, and a therapeutic agent or prevention of pulmonary hypertension. The agent can further exert excellent therapeutic effects and preventive effects on pulmonary hypertension.

The above pulmonary vasodilator is preferably a prostacyclin derivative, a phosphodiesterase inhibitor and/or an endothelin receptor antagonist, and the phosphodiesterase inhibitor and/or the endothelin receptor antagonist are Better.

Further, the above phosphodiesterase inhibitor is sildenafil or a pharmacologically acceptable salt thereof, or tadalafil, and tadalafil is more preferred. An endothelin receptor antagonist is ambrisentan or a pharmacologically acceptable salt thereof, or bosentan or a hydrate thereof, preferably ambrisentan or a pharmacologically acceptable salt thereof For better.

Further, the present invention provides a therapeutic or prophylactic agent for pulmonary hypertension, which comprises the above-mentioned hexahydronicotinic acid derivative or a pharmacologically acceptable salt thereof used in combination with a pulmonary vasodilator as an active ingredient .

The therapeutic or prophylactic agent for pulmonary hypertension of the present invention is based on pulmonary vasodilatation and sEH inhibition, and can treat or prevent lung Sexual hypertension. Further, the therapeutic or prophylactic agent for pulmonary hypertension of the present invention can treat or prevent pulmonary hypertension by enhancing the pharmacological action of a pulmonary vasodilator.

Figure 1 is a graph showing the effect of Example Compound 1 on right ventricular systolic pressure in a rat model of pulmonary hypertension administered to monocrotalin.

Figure 2 is a graph showing the effect of Example Compound 1 on the right ventricular weight ratio in rat pulmonary hypertension administered to the pulmonary hypertension model.

Figure 3 is a graph showing the effect of Example Compound 1 on the lung weight of rat monocrotaline administered to a pulmonary hypertension model.

Figure 4 is a graph showing the effect of Example Compound 1 on the right ventricular weight ratio in rat pulmonary hypertension administered to the pulmonary hypertension model.

Figure 5 is a graph showing the effect of Example Compound 2 on right ventricular systolic pressure in a rat model of pulmonary hypertension administered by monocrotaline.

Figure 6 is a graph showing the effect of Example Compound 2 on the right ventricular weight ratio in rat pulmonary hypertension administered to the pulmonary hypertension model.

Figure 7 is a graph showing the effect of Example Compound 2 on the lung weight ratio in rat pulmonary hypertension administered to the pulmonary hypertension model.

Figure 8 is a graph showing the effect of Example Compound 31 on the right ventricular weight ratio in rat pulmonary hypertension administered to the pulmonary hypertension model.

Figure 9 is a graph showing the effect of the compound of Example 1 and tadalafil on the right ventricular weight ratio in a rat model of pulmonary hypertension administered with monocrotaline.

Fig. 10 is a graph showing the effect of administration of Compound Example 1 on the right ventricular weight ratio in a rat model of pulmonary hypertension administered to a pathological stage of administration of tadalafil. .

Fig. 11 is a graph showing the effect of administration of Compound Example 1 on the right ventricle weight ratio in the pulmonary hypertensive mode in which a rat is administered to abalone in a pathological stage.

Figure 12 is a graph showing the effect of administration of additional compound 31 on the ratio of right ventricle in the pulmonary hypertensive mode in the pathological stage of rat dalmatine administered with tadalafil. .

[Formation for implementing the invention]

The therapeutic or prophylactic agent for pulmonary hypertension of the present invention is characterized by comprising a hexahydronicotinic acid derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, and a pulmonary vasodilator As an active ingredient:

Wherein R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group, and an alkoxy group having 2 to 7 carbon atoms; An alkyl group or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the alkoxy group, the cycloalkyl group, the cycloalkyloxy group, the alkoxyalkyl group and the cycloalkylalkyl group are 1 to 3) The hydrogen atoms are each independently represented by a halogen atom, a hydroxyl group, a cyano group, -SR ⁶ , -S(=O)-R ⁶ or -S(=O) ₂ R ⁶ , and -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 a ring of 5; R ² and R ³ are Each independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkoxyalkyl group each having 1 to 3 hydrogen atoms independently of a halogen atom, Hydroxy or cyano substituted), or together represent -(CH ₂ ) _l - or -(CH ₂ ) _m -O-(CH ₂ ) _n -, but not simultaneously represent a hydrogen atom; R ⁴ and R ⁵ are each independently represented a hydrogen atom, a halogen atom, a cyano group, an alkyl group or alkoxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group (the alkyl group, the alkoxy group, the cycloalkyl group and Cycloalkyloxy groups 1 to 3 hydrogen atoms each independently can be taken through a halogen atom ), Or -C (= O) NH _2, but do not simultaneously represent alkoxy; R & lt ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms of; R ⁷ represents an alkyl group having 1 to 6 carbon atoms, the carbon number of 3 - a cycloalkyl group of 6, alkoxyalkyl group having 2 to 7 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, cycloalkyl group, alkoxyalkyl group and cycloalkylalkyl group) 1 to 3 hydrogen atoms may each independently be substituted by 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].

The "alkyl group having 1 to 6 carbon atoms" means a branched chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched chain having 3 to 6 carbon atoms, and examples thereof include a methyl group and an ethyl group. , 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl (tertiary butyl), 2-methyl-1-propyl, 2, 2 - dimethyl-1-propyl, 1-pentyl, 2-pentyl or 3-pentyl.

The "alkoxy group having 1 to 6 carbon atoms" means a group in which the above-mentioned alkyl group having 1 to 6 carbon atoms is bonded to an oxygen atom, and examples thereof include a methoxy group, an ethoxy group, and a 1-propoxy group. 2-propoxy, 1-butoxy or 2-butoxy.

The "cycloalkyl group having 3 to 6 carbon atoms" means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

The "cycloalkyloxy group having 3 to 6 carbon atoms" means a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group or a cyclohexyloxy group.

The "alkoxyalkyl group having 2 to 7 carbon atoms" means a group having 2 to 7 carbon atoms and one hydrogen atom of the alkyl group is substituted with an alkoxy group, and examples thereof include a methoxymethyl group. Methoxyethyl, methoxypropyl, ethoxymethyl, propoxymethyl or isopropoxymethyl.

The "cycloalkylalkyl group having 4 to 7 carbon atoms" means a group having 4 to 7 carbon atoms and one hydrogen atom of the alkyl group is substituted by a cycloalkyl group, and examples thereof include a cyclopropylmethyl group. Cyclopropylethyl, cyclopropylpropyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "heteroaryl group having a ring number of 5" means that the same or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom are used as a ring constituent atom, and the ring constitutes an atomic number. Examples of the heteroaromatic group of 5 include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, and a triazolyl group. Azolyl, different Azolyl, furyl or thiazolyl.

The above hexahydronicotinic acid derivative is in the formula (I), and the R ¹ -N(R ⁶ )C(=O)R ⁷ or -N(R ⁶ )S(=O) ₂ R ⁷ is Preferably, an acetamino group, a propylamine group or a methanesulfonamide group is more preferred.

R ² and R ³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or preferably -(CH ₂ ) _l - together, each independently being a hydrogen atom or an alkyl group having 1 to 3 carbon atoms ( The alkyl group may have one hydrogen atom substituted by a hydroxy group, or may be -(CH ₂ ) ₂ - or -(CH ₂ ) ₃ - together, more preferably each independently a hydrogen atom, a methyl group or a 2-hydroxy-2 group. The -propyl group, or a combination of -(CH ₂ ) ₂ - or -(CH ₂ ) ₃ - is more preferred, but does not simultaneously become a hydrogen atom.

The substituent at the 2-position of the R ⁴ -based benzene ring is preferred. Further, R ⁴ is a halogen atom or an alkyl group having 1 to 6 carbon atoms or an alkoxy group, more preferably a halogen atom or an alkoxy group, and still more preferably an alkoxy group.

The substituent at the 4-position on the R ⁵ -phenyl ring is preferred. Further, R ⁵ is a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, more preferably a halogen atom or a cyano group.

The R ⁶ -based hydrogen atom is preferred, and the R ⁷ -methyl or ethyl group is preferred.

Further, it is preferred that l is 2 or 3, m is preferably 2, and n is preferably 2.

The hexahydronicotinic acid derivative represented by the above formula (I) (hereinafter, the hexahydronicotinic acid derivative (I)) has at least one asymmetric carbon atom and an optical isomer or a non- Enantiomers, but the hexahydronicotinic acid derivative (I) is not only a single isomer but also a racemate and a mixture of diastereomers. Further, in the case where a rotamer exists, all of the rotamers are contained.

With regard to the pharmacologically acceptable salt of the hexahydronicotinic acid derivative (I), for example, a hydrochloride, a trifluoroacetate, a sulfate, a nitrate, a hydrobromide or a hydroiodide can be mentioned. Or a methanesulfonate as an acid addition salt, but a hydrochloride, a sulfate, a hydrobromide, a hydroiodide or a methanesulfonate is preferred.

Further, the therapeutic or prophylactic agent for pulmonary hypertension of the present invention is characterized by comprising a pulmonary vasodilator and a hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof for use as an active ingredient. .

The starting material and the reagent used in the production of the hexahydronicotinic acid derivative (I) can be directly used as a commercially available product or synthesized by a known method.

The hexahydronicotinic acid derivative (Ia) is, for example, as shown in the following Scheme 1, in the presence of a base and a condensing agent, by condensation reaction of the amine derivative (II) with the carboxylic acid derivative (III) Manufacturing.

Wherein R ^{1 '} represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group, and an alkoxy group having 2 to 7 carbon atoms; Alkylalkyl group, a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the alkoxy group, the cycloalkyl group, the cycloalkyloxy group, the alkoxyalkyl group and the cycloalkylalkyl group are 1 to 3) The hydrogen atoms may each independently be substituted by 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, and benzotriene. Zin-1-yloxy-shendimethylamino sulfonium salt (BOP reagent), 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide Hexafluorophosphate (HBTU) or O-(7-nonylbenzotriazol-1-yl)tetramethyluronium hexafluorophosphate (hereinafter, HATU), but HATU is preferred. The equivalent of the condensing agent is preferably from 1 to 10 equivalents, more preferably from 1 to 3 equivalents.

Examples of the solvent used in the condensation reaction include N,N-dimethylformamide (hereinafter, DMF), tetrahydrofuran (hereinafter, THF), dichloromethane, chloroform, diethyl ether or dimethyl. Alkyl ether, but DMF or THF is preferred, and DMF is more preferred.

The base to be used in the condensation reaction may, for example, be an organic base such as diisopropylethylamine (hereinafter, DIPEA), triethylamine (hereinafter, TEA), pyridine or N-methylmorpholine or An organic acid salt such as potassium carbonate, sodium carbonate or sodium hydrogencarbonate, but DIPEA or TEA is preferred. The equivalent of the base is preferably from 1 to 100 equivalents, more preferably from 1 to 10 equivalents, per equivalent of the amine derivative (II).

The equivalent 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, still more preferably 0.8 to 2 equivalents, based on the amine derivative (II).

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

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

Further, the hexahydronicotinic acid derivative (Ib) wherein R ¹ is -N(H)C(=O)R ⁷ is, for example, as shown in the following Scheme 2, in the presence of a base, by an amine derivative. (IV) It can be produced by a condensation reaction with a hydrazine derivative (V) or a condensation reaction of an amine derivative (IV) with a carboxylic acid derivative (VI) in the presence of a base and a condensing agent.

[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 hydrazine derivative (V) include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, and Alkyl, diethyl ether or 1,2-dimethoxyethane, but dichloromethane, 1,2-dichloroethane, acetonitrile or THF is preferred, dichloromethane or 1,2-dichloroethane. The alkane is better.

The equivalent of ruthenium chloride (V) used in the condensation reaction with the oxime chloro derivative (V) is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, and more preferably 1 to 1.5, based on the amine derivative (IV). The equivalent is better.

The base to be used for the condensation reaction with the hydrazine derivative (V) may, for example, be an organic base such as DIPEA, TEA, pyridine or N-methylmorpholine, but DIPEA or TEA is preferred. The equivalent of the base is preferably from 1 to 100 equivalents, more preferably from 1 to 10 equivalents, per equivalent of the amine derivative (IV).

The reaction temperature of the condensation reaction with the hydrazine derivative (V) is preferably -50 to 100 ° C, more preferably -20 to 60 ° C, and more preferably 0 to 40 ° C. Further, the reaction time for the condensation reaction with ruthenium chloride (V) is preferably from 30 minutes to 24 hours, more preferably from 30 minutes to 12 hours, and even more preferably from 30 minutes to 8 hours.

The concentration at the start of the reaction of the amine derivative (IV) in the condensation reaction with the hydrazine chloride derivative (V) is preferably 0.01 to 100 M, more preferably 0.01 to 10 M, and still more preferably 0.1 to 10 M.

On the other hand, the condensation reaction of the amine derivative (IV) with the carboxylic acid derivative (VI) can be carried out under the same conditions as in the scheme 1.

R hexahydronicotinic acid derivative (Ic) wherein R ¹ is -N(H)S(=O) ₂ R ⁷ , for example, as shown in the following Scheme 3, in the presence of a base, by an amine derivative The sulfoximation reaction with (IV) and the sulfonium chloride derivative (VII) can be produced.

[wherein R ² to R ⁵ and R ⁷ are as defined above].

Examples of the solvent used in the sulfonylation reaction include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, and Alkyl, diethyl ether or 1,2-dimethoxyethane, but dichloromethane, 1,2-dichloroethane, acetonitrile or THF is preferred, dichloromethane or 1,2-dichloroethane. The alkane is better.

The sulfonium chloride derivative (VII) used in the sulfonylation reaction is preferably equivalent to 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, and more preferably 1 to 1.5 equivalents, based on the amine derivative (IV). Better.

The base to be used in the sulfoximation reaction may, for example, be an organic base such as DIPEA, TEA, pyridine or N-methylmorpholine, but DIPEA or TEA is preferred. The equivalent of the base is preferably from 1 to 100 equivalents, more preferably from 1 to 10 equivalents, per equivalent of the amine derivative (IV).

The reaction temperature of the sulfoximation reaction is preferably -50 to 50 ° C, more preferably -30 to 30 ° C, and more preferably -20 to 20 ° C. Further, the reaction time of the sulfoximation reaction is preferably from 30 minutes to 24 hours, more preferably from 30 minutes to 12 hours, and even more preferably from 30 minutes to 8 hours.

The concentration at the start of the reaction of the amine derivative (IV) in the sulfoximation reaction is preferably 0.01 to 100 M, more preferably 0.01 to 10 M, and still more preferably 0.1 to 10 M.

The amine derivative (IV) of the starting material in the above Schemes 2 and 3 is, for example, as shown in the following Scheme 4, in the presence of a base, the amine derivative (II) and the carboxylic acid derivative (VIII). After the condensation reaction, it can be produced by removing the deprotection reaction of the protecting group.

[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) with the carboxylic acid derivative (VIII) can be carried out under the same conditions as in the scheme 1.

The deprotection reaction of the subsequent condensation reaction can be carried out 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, in the case where the protecting group is a tertiary butoxycarbonyl group, the protecting group can be removed by treatment with a strong acid such as trifluoroacetic acid.

The carboxylic acid derivative (VIII) in the above-mentioned Scheme 4 can be produced by directly using a commercially available product or by a known method.

The amine derivative (II) of the starting material in the above Schemes 1 and 4 is, for example, as shown in the following Scheme 5, in the presence of a base and a condensing agent, by a benzylamine derivative (IX) and After the condensation reaction of the hexahydronicotinic acid derivative (X), the deprotection reaction for removing the protecting group can be produced.

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

The condensation reaction of the benzylamine derivative (IX) with the hexahydronicotinic acid derivative (X) can be carried out under the same conditions as in the scheme 1.

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

The condensation reaction of Scheme 5 can also be carried out by converting the hexahydronicotinic acid derivative (X) to an acid chloride in the presence of a base.

The reagent for converting the hexahydronicotinic acid derivative (X) into an acid chloride may, for example, be chloroform or sulfinium chloride, but grass chloroform is preferred. The equivalent of the reagent is preferably 1 to 10 equivalents, more preferably 1 to 1.5 equivalents, based on the hexahydronicotinic acid derivative (X).

Examples of the solvent used for converting the hexahydronicotinic acid derivative (X) into an acid chloride include dichloromethane, chloroform, THF, 1,2-dichloroethane, acetonitrile, 1,4. -two Alkane or DMF, but dichloromethane, THF or DMF, or a mixed solvent thereof is preferred, a mixed solvent of dichloromethane and DMF or a mixed solvent of THF and DMF is more preferred. In the case of the ratio of the mixed solvent, for example, a mixed solvent of dichloromethane and DMF, dichloromethane: DMF = 1 to 1000:1 is preferred, and 1 to 100:1 is more preferred.

The reaction temperature at which the hexahydronicotinic acid derivative (X) is converted into an acid chloride is preferably -50 to 100 ° C, preferably -30 to 30 ° C, and more preferably -20 to 0 ° C. Further, the reaction time for converting the hexahydronicotinic acid derivative (X) into an acid chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and 30 minutes to 2 hours is more. good.

The concentration of the hexahydronicotinic acid derivative (X) at the start of the reaction of converting the hexahydronicotinic acid derivative (X) into an acid chloride is preferably 0.01 to 100 M, more preferably 0.01 to 10 M. 0.1~3M is even better.

The above-mentioned hexahydronicotinic acid derivative (I), a pharmacologically acceptable salt thereof, or an intermediate, a raw material compound or the use of the above-mentioned hexahydronicotinic acid derivative (I) The reagents may be isolated and purified by extraction, distillation, chromatography or recrystallization, if necessary.

The pulmonary vasodilator to be used in combination with the above-described hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof may, for example, be a prostacyclin derivative, a phosphodiesterase inhibitor, or an endothelium. A receptor antagonist or the like may also include a plurality of such species. Further, the pulmonary vasodilator refers to a medicament which reduces pulmonary artery pressure by expanding the pulmonary artery as a main mechanism of action.

As the prostacyclin derivative, for example, epoprostenol sodium ((Z)-(3aR, 4R, 5R, 6aS)-3, 3a, 4, 5, 6, 6a-hexahydrogen can be cited. -5-hydroxy-4-[(E)-(3S)-3-hydroxy-1-octenyl]-2H-cyclopenta[b]furan-Δ2, σ gypinate sodium), beraprost sodium (beraprost sodium)((1RS,2RS,3aSR,8bSR)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(1E,3SR,4RS)-3-hydroxy-4-methylxin 1-ene-6-yn-1-yl]-1H-cyclopenta[b]benzofuran-5-butyrate), iloprost ((E)-(3aS,4R, 5R,6aR)-Hexahydro-5-hydroxy-4-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octene-6-ynyl]-△(2(1H) ), △-pentalene valeric acid, treprostinil sodium ((1R, 2R, 3aS, 9aS)-[[2,3,3a,4,9, 9a-hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H benzo[f]indole-5-yl]oxy]acetate), but sodium anthemum is preferred .

As the phosphodiesterase inhibitor, for example, sildenafil (1-[[3-(6,7-dihydro-1-methyl-7-o-oxy-3-propyl-1H) can be cited. -pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylper Or a pharmacologically acceptable salt thereof, or tadalafil ((6R,12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2) ,3,6,7,12,12a-hexahydropyridyl And [1',2':1,6]pyrido[3,4-b]indole-1,4-dione), but sildenafil or its pharmacologically acceptable salt, or Tata Raf is better, and he is better.

As the endothelin receptor antagonist, for example, ambrisentan ((2S)-2[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy group) -3,3-diphenylpropionic acid) or a pharmacologically acceptable salt thereof, or bosentan (4-(1,1-dimethylethyl)-N-[6-(2-hydroxyethyl) Oxy)-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]benzenesulfonamide) or a hydrate thereof, but ampicillin or its pharmacology The above-mentioned permissible salt, or bosentan or a hydrate thereof is preferred, and amphetamine or a pharmacologically acceptable salt thereof is more preferable.

The pharmacologically acceptable salt of sildenafil or amphetamine may, for example, be a mineral acid salt such as a hydrochloride, a sulfate, a nitrate, a phosphate, a hydrobromide or a hydroiodide; or Oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate An organic acid salt such as a benzoate, an ascorbate, a methanesulfonate, a p-toluenesulfonate or a cinnamate; or an inorganic alkali salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt or an ammonium salt Or an organic base salt such as a methylamine salt, a diethylamine salt, a trimethylamine salt, a triethylamine salt, a pyridinium salt, a triethanolamine salt, an ethylenediamine salt or a phosphonium salt. The pharmacologically acceptable salt citrate of sildenafil is preferred.

The prostacyclin derivative can be obtained by a commercially available product, and can be synthesized, for example, according to the method described in the document (Japanese Patent Publication No. 1-536672).

The phosphodiesterase inhibitor can be obtained by a commercially available product, and can be synthesized, for example, according to the method described in the document (International Publication No. 95/19978).

The endothelin receptor antagonist can be obtained by a method described in the above-mentioned document (International Publication No. 96/11914).

The hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof which is an active ingredient of the therapeutic or prophylactic agent for pulmonary hypertension described above exhibits strong sEH inhibitory activity, and, based on its action, Pulmonary hypertension exerts excellent therapeutic effects and preventive effects.

"sEH" is an abbreviation of soluble epoxide hydrolase, which catalyzes the hydrolysis of epoxide and converts it into a metabolic enzyme corresponding to the diol. The most well-known matrix of sEH is EETs, one of the hyperpolarizing factors derived from endothelial cells, which has the effect of metabolizing EETs to DHETs for inactivation. "EETs" is an abbreviation for Epoxyeicosatrienoic Acid, and "DHETs" is an abbreviation for Dihydroxyeicosatrienoic Acid. As the EETs, for example, 14,15-Epoxyeicosatrienoic acid (14,15-EET) can be cited. As the DHETs, for example, 14,15-dihydroxyeicosatrienoic acid (14,15-DHETET) can be cited.

The "sEH inhibitory activity" means the activity of inhibiting the action of sEH. Accordingly, the sEH inhibitory activity comprises an activity of an enzyme reaction inhibiting sEH which hydrolyzes EETs which catalyzes one of the substrates of sEH.

The "sEH inhibitor" means a composition containing a compound exhibiting sEH inhibitory activity or the compound as an active ingredient.

The sEH inhibitory activity can be achieved, for example, by reacting human sEH with its matrix EETs in the presence of an sEH inhibitor, and the amount of DHETs produced, and the amount of DHETs produced in the absence of the sEH inhibitor. Compare and measure. Further, a commercially available measurement kit (Soluble Epoxide Hydrolase Inhibitor Screening Assay Kit; Cayman) or a well-known literature (Analytical Biochemistry, 2005, 343) is used. The method described in Vol., p. 66-75, etc., can measure the sEH inhibitory activity of the sEH inhibitor.

Further, 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- The appearance of a nitrophenolate anion, or the use of cyano (6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxydecane-2-yl) acetate as a substrate for sEH, The sEH inhibitory activity of the sEH inhibitor can also be measured by measuring the presence of 6-methoxy-2-naphthaldehyde.

sEH inhibitors inhibit the metabolism of EETs to DHETs or increase the amount of EETs, which can be confirmed by measuring EETs concentration, DHETs concentration or EETs/DHETs ratio. The EETs concentration, the DHETs concentration, and the EETs/DHETs ratio can be measured using, for example, a commercially available measurement kit (14, 15-EET/DHET ELISA Kit; Detroit R & D).

"Pulmonary hypertension" means a state in which the pulmonary artery pressure is increased from the heart to the lungs, and the average pulmonary artery pressure in the resting position is 25 mmHg or more, or the lung disease, sleepless respiratory syndrome, and In the pulmonary hypoventilation syndrome, the average pulmonary artery pressure is 20 mmHg or more (30 mmHg or more during exercise) (simplified version, guidelines for treatment of pulmonary hypertension (2006 revised edition), P2-P3.). Pulmonary hypertension was observed in right ventricular systolic pressure, right ventricular hypertrophy, pulmonary hypertrophy, pulmonary hypertrophy, cell proliferation in the lung, or cardiac hypertrophy.

The therapeutic effect of the above-mentioned therapeutic or prophylactic agent for pulmonary hypertension on pulmonary hypertension can be evaluated by artificially artificially inducing an animal model of pulmonary hypertension. In the animal model, for example, a rat model of pulmonary hypertension using a monocrotaline of a rat can be cited (Journal of Pharmacological Sciences, 2009, Vol. 111, p. 235-243). Further, the pathological progress can be confirmed by measuring the right ventricular weight ratio (right ventricular weight / (sept. weight + left ventricular weight)). Further, each of the pathological systems of right ventricular hypertrophy and pulmonary hypertrophy accompanying pulmonary hypertension can be measured by measuring the right ventricular weight ratio (right ventricular weight/(sept. weight + left ventricular weight)).

The sEH findings in the lesions of the lungs of pulmonary hypertension can be confirmed by immunological tissue staining of lung tissue using an anti-sEH antibody. Pulmonary hypertrophy of pulmonary hypertension can be performed by Elastica van Gieson staining of the lung tissue, and the ratio of the thickness of the pulmonary artery is observed or measured by the stained image ((pulmonary media thickness × 2 / pulmonary artery diameter) × 100) ) and confirm it. The cell proliferation in the lungs of pulmonary hypertension can be confirmed by immunostaining lung tissue using a proliferation cell nuclear antigen (PCNA) antibody. Cardiac hypertrophy of pulmonary hypertension can be confirmed by HE staining the right ventricle. Systemic blood pressure in pulmonary hypertension can be confirmed by the method described in the examples. By confirming this, pulmonary hypertension caused by pulmonary hypertension, pulmonary venous obstructive disease, pulmonary capillary angiogenesis, left heart disease, pulmonary disease, and hypoxia can be evaluated. Therapeutic effect of pulmonary hypertension caused by chronic thromboembolism and pulmonary hypertension and a compound cause of unknown cause.

The therapeutic or prophylactic agent for pulmonary hypertension described above exhibits an excellent therapeutic effect or preventive effect of pulmonary hypertension in the case of administration to humans. Moreover, the case of administration to mammals other than humans also shows the therapeutic effect or preventive effect of excellent pulmonary hypertension. Among them, in the case of mammals other than humans, for example, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep or monkeys can be cited.

The hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof, and a pulmonary vasodilator (for example, in the administration form of the therapeutic or prophylactic agent for pulmonary hypertension described above) a mixture of prostacyclin derivatives, phosphodiesterase inhibitors and/or endothelin receptor antagonists, ie, a complexing agent, directly or further blended into a pharmaceutically acceptable carrier, orally or non-performed Oral vote. Alternatively, the two may not be formulated as a compounding agent, but may be prepared separately as a single agent, and these may be directly or further blended into a pharmaceutically acceptable carrier, and administered simultaneously. Further, each of the individual agents may be administered at appropriate intervals. In these cases, there is no need to have the same dosage form and the same route for each single dose. Moreover, the above "appropriate interval" can be confirmed by clinical or animal experiments.

In the case of a single dose or a dosage form for oral administration as a compounding agent, for example, a tablet (including a sugar-coated tablet, a film-coated tablet), a pill, a granule, a powder, a capsule (including a soft capsule, a micro-particle) may be mentioned. In the case of a dosage form which is not administered orally, for example, an injection, an injection, a drip or a suppository may be mentioned. Further, with a suitable base (for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a polymer of butyric acid and a hydroxyl group) Combination of a polymer of acetic acid or a polyglycerol fatty acid ester or the like is also effective as a sustained release preparation.

The preparation of a single agent or a complexing agent of the above dosage form can be carried out according to a known production method generally used in the field of preparation. In this case, if necessary, an excipient, a binder, a lubricant, a disintegrator, a sweetener, a surfactant, a suspending agent or an emulsifier which are generally used in the field of preparation can be produced.

The preparation of a tablet or a compounding agent may be carried out by using an excipient, a binding agent, a disintegrating agent or a lubricant, and the preparation of the tablet and the granule may be carried out by containing an excipient or a binder. Or a disintegrator or the like. Further, each of the preparations may be carried out as a powder and a capsule, and an excipient or the like may be contained as a syrup preparation, and a sucrose preparation containing a sweetener or the like may be used as an emulsion and a suspending agent, and a surfactant and a suspension may be contained. a emulsifier or an emulsifier.

Examples of the above excipients include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice, mannitol, sodium hydrogencarbonate, calcium phosphate or calcium sulfate.

Examples of the above-mentioned binder include a starch paste solution, an acacia gum, a gelatin solution, a tragacanth solution, a carboxymethylcellulose solution, a sodium alginate solution, or glycerin.

The above-mentioned disintegrator may, for example, be starch or calcium carbonate.

Examples of the lubricant described above include magnesium stearate, stearic acid, calcium stearate, and purified talc.

As the above-mentioned sweetener, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or a monosaccharide syrup can be cited.

The above surfactant may, for example, be sodium lauryl sulfate, polysorbate 80, sorbitan mono-fatty acid ester or polyoxyl stearate 40.

As the above-mentioned suspending agent, for example, gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose or bentonite can be cited.

As the emulsifier described above, for example, gum arabic, tragacanth, gelatin or polysorbate 80 can be cited.

Further, a single agent or a compounding agent of the above dosage form may be added with a coloring agent, a preservative, a fragrance, a flavoring agent, a stabilizer or a thickener which are generally used in the field of preparation.

Hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof, and a pulmonary vasodilator (for example, a prostacyclin derivative, a phosphodiesterase inhibitor, and/or an endothelin receptor antagonist) The dose ratio or blend ratio may be appropriately selected depending on the administration target, the administration route, the target disease, the symptom, or a combination of blending.

The dosage per day of the preparation containing the prostacyclin derivative varies depending on the state or body weight of the patient, the type of prostacyclin derivative, the administration route, and the like, but for example, oral administration of beniprosal sodium In the case where an adult (weight: about 60 kg) is 0.1 μg/kg to 100 mg/kg, preferably 1 μg/kg to 50 mg/kg, it is preferred to divide it into 1 to 4 times a day.

The dosage per day of the preparation containing the phosphodiesterase inhibitor depends on the state or body weight of the patient, the species of the phosphodiesterase inhibitor The class, the route of administration, etc. vary, but for example, in the case of oral administration of tadalafil, if it is an adult (body weight of about 60 kg), it is preferable to divide the range of 5 to 80 mg into 1 to 3 times. In the case of oral administration of sildenafil or a pharmacologically acceptable salt thereof, in the case of an adult (weight of about 60 kg), it is preferred to divide the range of 5 to 90 mg into 1 to 3 administrations.

The dosage per day of the preparation containing the endothelin receptor antagonist is, for example, oral administration of ambrisentan, and if it is an adult (weight: about 60 kg), it is divided into 1 to 3 times in the range of 1 to 20 mg. In the case of administration, it is preferred to administer bosentan or a hydrate thereof orally. In the case of an adult (weight: about 60 kg), it is preferred to divide it into 1 to 3 doses in the range of 10 to 400 mg.

The dosage per one day of the preparation containing the hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof, for example, in the case of oral administration, if it is an adult (weight: about 60 kg), The range of 1 to 1000 mg is preferably divided into 1 to 3 administrations, and in the case of non-oral administration, if it is an injection, it is preferably administered by intravenous injection in a range of 0.01 to 100 mg per 1 kg of body weight.

[Examples]

Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these examples. Purification by a ruthenium column chromatography method was carried out using a "HI-FLASH" column (Shanshan Society) and Purif-α2 (Shoko Scientific Co., Ltd.), unless otherwise specified.

(Example 1)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-propionamidocyclobutanecarbonyl)piperidine-3-carboxamide (carboxamide) Synthesis:

[step 1]

Synthesis of 4-bromo-2-(trifluoromethoxy)benzaldehyde:

N-butyllithium hexane was added dropwise over 1.5 hours in a solution of 4-bromo-1-iodo-2-(trifluoromethoxy)benzene (25 g, 68 mmol) in THF (0.40 L). Solution (1.6 N, 86 mL, 0.14 mol). After stirring at -78 ° C for 1 hour, DMF (11 mL, 0.14 mmol) was added dropwise over 10 min. 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 extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and evaporated to drynessielielielielielielielielielielielielielielielielielielielielieliel

[Step 2]

Synthesis of (4-bromo-2-(trifluoromethoxy)phenyl)methanol:

Sodium borohydride (2.4 g, 63 mmol) was added to a solution of the title compound 1 (16 g, 59 mmol) in methanol (0.23 L). After stirring at -10 ° C for 10 minutes, acetone (10 mL) and 1N hydrochloric acid (10 mL) were added to the reaction mixture. The reaction solution was concentrated under reduced pressure, and water was added to the obtained crude product, and 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 (hexanes: ethyl acetate = 50:1 → 1:1) to obtain (4- Bromo-2-(trifluoromethoxy)phenyl)methanol (hereinafter, Reference Example Compound 2) 15 g (91%).

[Step 3]

Synthesis of 4-bromo-2-(trifluoromethoxy)benzyl methanesulfonate:

Add to a solution of Reference Example Compound 2 (2.0 g, 7.4 mmol), TEA (1.2 mL, 8.9 mmol) in dichloromethane (20 mL) Methanesulfonium chloride (0.93 g, 8.1 mmol). After stirring at room temperature for 3 hours, water was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. 2.6 g (quantitative).

[Step 4]

Synthesis of 2-(4-bromo-2-(trifluoromethoxy)benzyl)isoindoline-1,3-dione:

Under ice cooling, a solution of the compound of Example 3 (2.6 g, 7.4 mmol) in DMF (20 mL). 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, reference compound) 4) 2.7 g (91%).

[Step 5]

Synthesis of (4-bromo-2-(trifluoromethoxy)phenyl)methanamine:

To a solution of the title compound 4 (2.6 g, 6.5 mmol) in methanol (40 mL), m. After stirring at 60 ° C for 2 hours, the precipitated solid was filtered off at room temperature. The filtrate was concentrated under reduced pressure, and the obtained crude product was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated to drynessielielielielielielielielielielielielielielielielielielielielielielielieliel

[Step 6]

Synthesis of (R)-tertiary butyl 3-((4-bromo-2-(trifluoromethoxy)benzyl)aminemethanyl)piperidine-1-carboxylate:

Reference Example Compound 5 (0.50 g, 1.9 mmol), (R)-1-(tertiary butoxycarbonyl)piperidine-3-carboxylic acid (0.43 g, 1.9 mmol), DIPEA (0.53 g) In a solution of 4.1 mmol) of DMF (3.0 mL), HATU (0.77 g, 2.0 mmol) was added. After stirring at room temperature for 15 hours, ethyl acetate was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and saturated aqueous sodium chloride. 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 (hexanes: ethyl acetate = 9:1 → 1:1) to obtain (R) - Tert-butyl 3-((4-bromo-2-(trifluoromethoxy)benzyl)amine-carbamoyl)piperidine-1-carboxylate (hereinafter, Reference Example Compound 6) 0.89 g (quantification of).

[Step 7]

Synthesis of (R)-tertiary butyl 3-((4-cyano-2-(trifluoromethoxy)benzyl)aminemethanyl)piperidine-1-carboxylate:

To a solution of the compound of Reference Example 6 (0.050 g, 0.10 mmol), zinc cyanide (0.012 g, 0.10 mmol) in DMF (2.0 mL) was added to the triphenylphosphine palladium (0) (0.030 g, 0.026) Mm). After stirring at 150 ° C for 30 minutes, water was added to the reaction solution at room temperature, and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=20:1→1:2) to obtain (R)-tertiary butyl 3-((4-cyano) Benzyl-2-(trifluoromethoxy)benzyl)amine-carbazyl)piperidine-1-carboxylate (hereinafter referred to as Reference Compound 7) was 0.017 g (39%).

[Step 8]

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide:

Trifluoroacetic acid (hereinafter, TFA) (35 mL, 0.45 mol) was added to a solution of the title 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 saturated aqueous sodium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (D)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 8) 5.2 g (98%).

[Step 9]

(R)-tertiary butyl (1-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidine-1-carbonyl)cyclobutyl)amine Synthesis of formate:

Under ice cooling, reference compound 8 (0.20 g, 0.67 mmol), 1-((tertiary butoxycarbonyl)amino)cyclobutanecarboxylic acid (0.15 g, 0.67 mmol), DIPEA (0.24 mL, 1.3 mmol) HATU (0.28 g, 0.73 mmol) was added to a solution of DMF (0.70 mL). After stirring at room temperature for 86 hours, 1N hydrochloric acid was added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was purified by ruthenium column chromatography (Amine DM1020, a solvent obtained by FUJI SILYSIA CHEMICAL CO., LTD; hexane: ethyl acetate = 7:3 → 4:6) to obtain (R)- Tert-butyl (1-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidine-1-carbonyl)cyclobutyl)carbamate ( Hereinafter, Reference Example Compound 9) 0.25 g (78%).

[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 solution of the title compound 9 (0.25 g, 0.4. 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 saturated aqueous sodium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (D)-1-(1-aminocyclobutanecarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl Piperidine-3-carboxamide (hereinafter, Reference Example Compound 10) 0.18 g (90%).

[Step 11]

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-propionamidocyclobutanecarbonyl)piperidine-3-carboxamide:

Under ice cooling, a solution of the compound of Example 10 (7.6 g, 18 mmol), TEA (5.5 mL, 40 mmol) in dichloromethane (54 mL) was added to hexane (1.8 g, 20 mmol). After stirring for 1 hour under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→95:5) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy) Benzyl)-1-(1-propionylaminocyclobutanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 1) 6.2 g (71%).

(Example 2)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl)piperidine-3 - Synthesis of carboxamide:

[step 1]

(R)-tertiary butyl (1-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidin-1-yl)-2-methyl Synthesis of 1-acetoxypropan-2-yl)amine formate:

Under ice cooling, reference compound 8 (3.5 g, 11 mmol), 2-((tertiary butoxycarbonyl)amino)-2-methylpropanoic acid (2.6 g, 13 mmol), DIPEA (4.1 mL, 24 mmol) After adding HATU (4.9 g, 13 mmol) to a solution of DMF (40 mL), and stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was purified by ruthenium column chromatography (Amine DM1020, a solvent, hexane: ethyl acetate = 9:1 → 4:6, manufactured by FUJI SILYSIA CHEMICAL CO., LTD) to obtain (R)- Tert-butyl butyl (1-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidin-1-yl)-2-methyl-1- side Oxypropan-2-yl)carbamate (hereinafter, Reference Example Compound 11) 5.2 g (95%).

[Step 2]

(R)-1-(2-Amino-2-methylpropenyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide synthesis:

TFA (25 mL, 0.32 mol) was added to a solution of the title compound 11 (5.2 g, 10 mmol) in dichloromethane (0.10 L). 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 saturated aqueous sodium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (D)-1-(2-amino-2-methylpropenyl)-N-(4-cyano-2-(trifluoromethoxy) Benzyl)piperidine-3-carboxamide (hereinafter, Reference Example Compound 12) 3.4 g (82%).

[Step 3]

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl)piperidine-3 - Synthesis of carboxamide:

Under ice cooling, to a solution of the title compound 12 (2.3 g, 5.6 mmol), TEA (1.6 mL, 11 mmol) in dichloromethane (15 mL) was added methanesulfonium chloride (0.97 g, 8.5 mmol). After stirring for 5 minutes under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→95:5) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy) Benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl)piperidine-3-carboxamide (hereinafter, Example Compound 2) 2.4 g (87%).

(Example 3)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(methylsulfonamide)cyclopropanecarbonyl)piperidine-3-carboxamide synthesis:

[step 1]

(R)-tertiary butyl (1-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidine-1-carbonyl)cyclopropyl)amine Synthesis of formate:

Under ice cooling, reference compound 8 (0.67 g, 2.0 mmol), 1-((tertiary butoxycarbonyl)amino)cyclopropanecarboxylic acid (0.49 g, 2.4 mmol), DIPEA (1.1 mL, 6.1 mmol) In a solution of DMF (5.0 mL), HATU (1.1 g, 2.5 mmol) was added. After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was obtained by capillary column chromatography (FUJI SILYSIA). Chemical CO., LTD. Amine phthalocyanine DM1020, dissolving solution; hexane: ethyl acetate = 9:1 → 4:6) purification, obtaining (R)-tertiary butyl (1-(3-((4-cyanide)) Benzyl-2-(trifluoromethoxy)benzyl)amine carbhydryl)piperidine-1-carbonyl)cyclopropyl)carbamate (hereinafter, Reference Compound 13) 0.92 g (88%).

[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 solution of the title compound 13 (0.92 g, 1.8 mmol) in dichloromethane (20 mL). 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 saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (D)-1-(1-aminocyclopropanecarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl) Piperidine-3-carboxamide (hereinafter, Reference Example Compound 14) 0.63 g (87%).

[Step 3]

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(methylsulfonamide)cyclopropanecarbonyl)piperidine-3-carboxamide synthesis:

Under ice cooling, to a solution of the title compound 14 (0.63 g, 1.5 mmol) and TEA (1.1 mL, 7.7 mmol) in dichloromethane (5.0 mL), methanesulfonium chloride (0.27 g, 2.3 mmol) was added. After stirring for 1.5 hours under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→95:5) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy) Benzyl)-1-(1-(methyl) Sulfonamide) cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 3) 0.56 g (74%).

(Example 4)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)piperidine-3-carboxamide :

(R)-N-(4-cyano-2-) was obtained by the same reaction as in Example 1 [Step 9] using 1-(trifluoromethyl)cyclopropanecarboxylic acid (0.054 g, 0.17 mmol). (Trifluoromethoxy)benzyl)-1-(1-(trifluoromethyl)cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 4) 0.044 g (58%).

(Example 5)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(methylsulfonamide)cyclobutanecarbonyl)piperidine-3-carboxamide Synthesis:

Using the same reference compound 10 (0.020 g, 0.047 mmol), the same reaction as in Example 2 [Step 3] was carried out to obtain (R)-N-(4-cyano-2-(trifluoromethoxy). Benzyl)-1-(1-(methylsulfonamide)cyclobutanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 5) 0.017 g (71%).

(Example 6)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-isobutylguanamine cyclobutanecarbonyl)piperidine-3-carboxamide :

(R)-N-(4-cyano-2-(trifluoromethoxy)benzylidene was obtained by the same reaction as in Example 1 [Step 11] using isobutylphosphonium chloride (0.0055 g, 0.052 mmol). 1-(1-Isobutylguanamine cyclobutanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 6) was 0.022 g (95%).

(Example 7)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-trimethylacetamide cyclobutanecarbonyl)piperidine-3-carboxamide synthesis:

The same reaction as in Example 1 [Step 11] was carried out by using trimethylethyl sulfonium chloride (0.0063 g, 0.052 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy). Benzyl)-1-(1-trimethylacetamide cyclobutanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 7) was 0.017 g (72%).

(Example 8)

Synthesis of (R)-1-(1-acetamidocyclopentanecarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide:

[step 1]

(R)-tertiary butyl (1-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidin-1-carbonyl)cyclopentyl)amine Synthesis of formate:

The same reaction as in Example 1 [Step 9] was carried out by using 1-((tertiary butoxycarbonyl)amino)cyclopentanecarboxylic acid (0.078 g, 0.34 mmol) to obtain (R)-tertiary (1-(3-((4-Cyano-2-(trifluoromethoxy)benzyl)amine)indolyl)piperidine-1-carbonyl)cyclopentyl)amine formate (hereinafter, reference Example Compound 15) 0.13 g (77%).

[Step 2]

Synthesis of (R)-1-(1-aminocyclopentanecarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

The same reaction as in Example 1 [Step 10] was carried out by using Reference Example Compound 15 (0.13 g, 0.24 mmol) to obtain (R)-1-(1-aminocyclopentanecarbonyl)-N-(4- Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Example Compound 16) was 0.051 g (49%).

[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 the title compound 16 (0.020 g, 0.046 mmol) and TEA (0.019 mL, 0.14 mmol) in dichloromethane (0.20 mL). After stirring for 1 hour under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform: methanol = 99:1 → 95:5) to obtain (R)-1-(1-acetamidocyclopentanecarbonyl)- N-(4-Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 8) was 0.014 g (62%).

(Example 9)

Synthesis of (R)-1-(1-acetamidocyclobutanecarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

The same reaction as in Example 8 [Step 3] was carried out by using Reference Example Compound 10 (0.020 g, 0.047 mmol) to obtain (R)-1-(1-ethylindenylcyclobutanecarbonyl)-N-( 4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 9) was 0.013 g (60%).

(Embodiment 10)

(R)-N-(4-chloro-2-(2,2,2-trifluoroethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl Synthesis of piperidine-3-carboxyguanamine:

[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). After stirring for 10 minutes under ice cooling, the mixture was stirred at room temperature for 30 minutes. 4-chloro-2-fluorobenzonitrile (2.0 g, added to the reaction solution under ice cooling 13mmol). After stirring at room temperature for 1 hour, 0.1 N hydrochloric acid was added to the reaction solution under ice cooling, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=10:0→3:1) to give 4-chloro-2-(2,2,2-trifluoroethyl) Oxy)benzonitrile (hereinafter, Reference Example Compound 17) 2.6 g (86%).

[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 the title 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 sodium hydroxide aqueous solution (1.0 mL), and water (3.0 mL) were added to the reaction mixture under ice cooling. After filtering the reaction solution, the filtrate was concentrated under reduced pressure to give (4-chloro-2-(2,2,2-trifluoroethoxy)phenyl)methylamine (hereinafter, Reference Compound 18) 2.4 g (94%) ).

[Step 3]

Synthesis of (R)-tertiary butyl 3-((4-chloro-2-(2,2,2-trifluoroethoxy)benzyl)aminecarboxamido)piperidine-1-carboxylate:

The same reaction as in Example 1 [Step 6] was carried out by using Reference Example Compound 18 (2.4 g, 10 mmol) to obtain (R)-tertiary butyl 3-((4-chloro-2-(2,2, 2-trifluoroethoxy)benzyl)amine-mercapto)piperidine-1-carboxylate (hereinafter, Reference Example Compound 19) 4.5 g (quantitative).

[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 the title 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 sulfate (10 mL). After stirring at room temperature for 30 minutes, water was added to the reaction solution, and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. 3-carboxycarboxamide (hereinafter, Reference Example Compound 20) 1.4 g (87%).

[Step 5]

(R)-tertiary butyl (1-3-((4-chloro-2-(2,2,2-trifluoroethoxy)benzyl)aminecarboxamido)piperidin-1-yl)- Synthesis of 2-methyl-1-oxopropan-2-yl)carbamate:

The same reaction as in Example 2 [Step 1] was carried out by using Reference Example Compound 20 (0.60 g, 1.7 mmol) to obtain (R)-tertiary butyl (1-3-((4-chloro-2-) 2,2,2-Trifluoroethoxy)benzyl)amine-carbamoyl)piperidin-1-yl)-2-methyl-1-oxopropan-2-yl)carbamate (below) Reference compound 21) 0.77 g (84%).

[Step 6]

(R)-1-(2-Amino-2-methylpropenyl)-N-(4-chloro-2-(2,2,2-trifluoroethoxy)benzyl)piperidine-3 - Synthesis of carboxamide:

TFA (10 mL) was added to the title compound 21 (0.83 g, 1.5 mmol). After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (10 mL), and saturated aqueous sodium hydrogen sulfate (10 mL). After stirring at room temperature for 30 minutes, water was added to the reaction solution, and extracted with dichloromethane. Organic layer with water After washing, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (R)-1-(2-amino-2-methylpropenyl)-N-(4-chloro-2-(2,2, 2-Trifluoroethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Example Compound 22) 0.65 g (96%).

[Step 7]

(R)-N-(4-chloro-2-(2,2,2-trifluoroethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl Synthesis of piperidine-3-carboxyguanamine:

Under ice cooling, to a solution of the title compound 22 (0.080 g, 0.18 mmol), pyridine (0.030 mL, 0.37 mmol) in dichloromethane (2.0 mL), methanesulfonium 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 extracted with dichloromethane. The organic layer was washed with aq. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=100:1→10:1) to obtain (R)-N-(4-chloro-2-(2,2,2) -trifluoroethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl)piperidine-3-carboxamide (hereinafter, Example Compound 10) 0.030 g (32%).

(Example 11)

(R)-1-((R)-2-Ethylamino-3-methylbutanyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidin-3- Synthesis of carboxyguanamine:

[step 1]

(R)-1-((R)-2-amino-3-methylbutanyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxyindole Synthesis of amines:

Under ice cooling, in Reference Example Compound 8 (0.21 g, 0.65 mmol), (R)-2-(((9H-indol-9-yl)methoxy)carbonyl)amino)-3-methylbutyric acid (0.24 g, 0.72 mmol), DIPEA (0.14 mL, 0.78 mmol) In a solution of DMF (3.5 mL), HATU (0.30 g, 0.78 mmol) was added. After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 9:1 to 1:9) to give a crude product (0.30 g). 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 extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→90:10) to obtain (R)-1-((R)-2-amino-3-methyl -N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Example Compound 23) 0.18 g (2 stage yield 65%) .

[Step 2]

(R)-1-((R)-2-Ethylamino-3-methylbutanyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidin-3- Synthesis of carboxyguanamine:

The same reaction as in Example 8 [Step 3] was carried out by using Reference Example Compound 23 (0.020 g, 0.047 mmol) to obtain (R)-1-((R)-2-ethinylamino-3-methyl. Butylmethyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 11), 0.018 g (83%).

(Embodiment 12)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-3-methyl-2-(methylsulfonamide)butanyl)piperidine Synthesis of -3-carboxyguanamine:

The same reaction as in Example 2 [Step 3] was carried out by using Reference Example Compound 23 (0.020 g, 0.047 mmol) to obtain (R)-N-(4-cyano). -2-(Trifluoromethoxy)benzyl)-1-((R)-3-methyl-2-(methylsulfonamide)butanyl)piperidine-3-carboxamide (hereinafter, examples Compound 12) 0.020 g (83%).

(Example 13)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(ethylsulfonamide)cyclopropanecarbonyl)piperidine-3-carboxamide synthesis:

Under ice cooling, ethane sulfonyl chloride (0.017 g, 0.13) was added to a solution of the title compound 14 (0.050 g, 0.12 mmol), DIPEA (0.043 mL, 0.24 mmol) in dichloromethane (3.0 mL). Mm). 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 extracted with dichloromethane. The organic layer was washed with aq. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=100:1→10:1) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy) Benzyl)-1-(1-(ethylsulfonamide)cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 13) was 0.0080 g (13%).

(Example 14)

(R)-N-(4-Aminomethyl-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl)piperidine Synthesis of -3-carboxyguanamine:

Hydrogen peroxide water (30% by weight, 0.021 mL) was added to a solution of Example Compound 2 (0.020 g, 0.041 mmol) and potassium carbonate (0.0028 g, 0.020 mmol) in DMF (0.38 mL). After stirring at room temperature for 18 hours, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium thiosulfate solution and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol = 99:1 to 85:15) to obtain (R)-N-(4-amine-carbamoyl-2-(trifluoro) Methoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)propanyl)piperidine-3-carboxamide (hereinafter, Example Compound 14) 0.013 g (63% ).

(Example 15)

(R)-N-(4-Aminomethyl-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(methylsulfonamide)cyclopropanecarbonyl)piperidine Synthesis of -3-carboxyguanamine:

The same reaction as in Example 14 was carried out by using Example Compound 3 (0.025 g, 0.051 mmol) to give (R)-N-(4-amine-carbamoyl-2-(trifluoromethoxy)benzyl)- 1-(2-Methyl-2-(methylsulfonamide)cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 15) 0.020 g (77%).

(Embodiment 16)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-hydroxy-2-methylpropenyl)piperidine-3-carboxamide :

The same reaction as in Example 1 [Step 9] was carried out by using 2-hydroxy-2-methylpropionic acid (0.15 g, 0.46 mmol) to obtain (R)-N-(4-cyano-2-(3) Fluoromethoxy)benzyl)-1-(2-hydroxy-2-methylpropenyl)piperidine-3-carboxamide (hereinafter, Example Compound 16) 0.12 g (62%).

(Example 17)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-trimethylethenylpiperidine-3-carboxamide

The same reaction as in Example 1 [Step 11] was carried out by using Reference Example Compound 8 (0.15 g, 0.46 mmol), trimethylethylhydrazine chloride (0.066 g, 0.55 mmol) to obtain (R)-N-(4). -Cyano-2-(trifluoromethoxy)benzyl)-1-trimethylethenylpiperidine-3-carboxamide (hereinafter, Example Compound 17) 0.19 g (quantitative).

(Embodiment 18)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(N-methylmethylsulfonamide)cyclopropanecarbonyl)piperidin-3- Synthesis of carboxyguanamine:

[step 1]

Synthesis of 1-(methylsulfonamide) cyclopropanecarboxylate:

Add methanesulfonium chloride (1.4 g, 12 mmol) to a solution of 1-aminocyclopropanecarboxylate hydrochloride (2.0 g, 12 mmol), DIPEA (6.3 mL, 36 mmol) in dichloromethane (35 mL) . After stirring for 3 hours under ice cooling, 1N hydrochloric acid was added to the reaction solution to make it acidic, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 10:1 to 1:2) to obtain 1-(methylsulfonamide) cyclopropanecarboxylate (hereinafter , Reference Example Compound 24) 2.3 g (60%).

[Step 2]

Synthesis of 1-(N-methylmethylsulfonamide) cyclopropanecarboxylate:

Sodium hydride (55 wt%, 0.51 g, 12 mmol) was added to a solution of the title compound 24 (2.0 g, 9.7 mmol) in DMF (10 mL). After stirring for 10 minutes under ice cooling, the mixture was stirred at room temperature for 30 minutes. 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 hexane:ethyl acetate mixture (hexane: ethyl acetate = 1:2). The organic layer was washed with water and a saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 10:1 → 1:1). 1.8 g (84%) of 1-(N-methylmethylsulfonamide) cyclopropanecarboxylate (hereinafter, Reference Example Compound 25) was obtained.

[Step 3]

Synthesis of 1-(N-methylmethylsulfonamide) cyclopropanecarboxylic acid:

A 1 N aqueous sodium hydroxide solution (12 mL, 12 mmol) was added to a solution of the title compound 25 (1.8 g, 7.9 mmol) in methanol (20 mL). After stirring at 50 ° C for 3 hours, 1 N hydrochloric acid was added to the reaction solution at room temperature, and extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. 58%).

[Step 4]

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(N-methylmethylsulfonamide)cyclopropanecarbonyl)piperidin-3- Synthesis of carboxyguanamine:

The same reaction as in Example 1 [Step 9] was carried out by using Reference Example Compound 26 (0.13 g, 0.67 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. 1-(1-(N-methylmethylsulfonamide)cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 18) 0.17 g (60%).

(Embodiment 19)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(3-hydroxy-2,2-dimethylpropionyl)piperidine-3-carboxyindole Synthesis of amines:

A solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1.0 g, 7.6 mmol) in methanol (7.5 mL) was evaporated. 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 concentrated under reduced pressure. Icy Next, HATU (0.35 g, 0.93 mmol) was added to a solution of the obtained crude product (0.10 g), DIPEA (0.30 mL, 1.7 mmol) in DMF (1.6 mL). After stirring under ice cooling for 15 minutes, the title compound 8 (0.28 g, 0.85 mmol) was added to the reaction solution. After stirring at room temperature for one night, water was added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 8:2: ethyl acetate) to obtain (R)-N-(4-cyano-2-( Trifluoromethoxy)benzyl)-1-(3-hydroxy-2,2-dimethylpropenyl)piperidine-3-carboxamide (hereinafter, Example Compound 19) 0.24 g (2 stage production) Rate 65%).

(Embodiment 20)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-hydroxycyclohexanecarbonyl)piperidine-3-carboxamide:

Under ice cooling, a solution of sulfuric acid (40% by weight, 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 extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. 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 give a crude product (4.0 g). HATU (0.45 g, 0.60) was added to a solution of the obtained crude product (0.16 g), Reference Compound 8 (0.15 g, 0.46 mmol), DIPEA (0.24 mL, 1.4 mmol) in DMF (1.0 mL). Mm). After stirring at room temperature for 2 hours, water and 1N hydrochloric acid were added to the reaction solution, and extracted with diethyl ether. The organic layer is washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. After drying over sodium sulfate, it was concentrated under reduced pressure. The obtained crude product was purified by ruthenium column chromatography (Amine DM1020, a solvent obtained by FUJI SILYSIA CHEMICAL CO., LTD; hexane: ethyl acetate = 7:3 → 4:6) to obtain (R)- N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-hydroxycyclohexanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 20) 0.061 g (2 stage yield 29%).

(Example 21)

Synthesis of (R)-1-((R)-2-acetamidobutyryl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide :

[step 1]

Synthesis of (R)-2-((tertiary butoxycarbonyl)amino)butyric acid:

Under ice cooling, 1,4-di(R)-2-aminobutyric acid (2.0 g, 19 mmol), sodium hydrogencarbonate (1.6 g, 19 mmol) Alkane: water (1,4-two Alkane: water = 3:10, 26 mL) In the mixed solution, di-tertiary butyl dicarbonate (4.7 g, 21 mmol) was added. 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 extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (t)-2-((tris-butoxycarbonyl)amino)butyric acid (hereinafter referred to as Reference Compound 27) 2.0 g (quant.).

[Step 2]

Tert-butyl butyl ((R)-1-((R)-3-((4-cyano-2-(trifluoromethoxy)benzyl))aminomethyl)piperidin-1-yl)- Synthesis of 1-oxobutan-2-yl)carbamate:

The same reaction as in Example 1 [Step 9] was carried out by using Reference Example Compound 27 (0.20 g, 1.0 mmol) to obtain a tributyl group. ((R)-1-((R)-3-((4-Cyano-2-(trifluoromethoxy)benzyl))aminomethane)piperidin-1-yl)-1-oxyloxy The butyral-2-yl)carbamate (hereinafter, Reference Example Compound 28) was 0.47 g (quantitative).

[Step 3]

Synthesis of (R)-1-((R)-2-aminobutylidene)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

The same reaction as in Example 1 [Step 10] was carried out by using Reference Example Compound 28 (0.47 g, 0.91 mmol) to obtain (R)-1-((R)-2-aminodinyl)-N-(4) -Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Compound 29) 0.38 g (quantitative).

[Step 4]

Synthesis of (R)-1-((R)-2-acetamidobutyryl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide :

The same reaction as in Example 8 [Step 3] was carried out by using Reference Example Compound 29 (0.091 g, 0.22 mmol) to obtain (R)-1-((R)-2-acetamidobutyryl)-N- (4-Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 21) was 0.085 g (85%).

(Example 22)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-2-(methylsulfonamide)butanyl)piperidine-3-carboxyindole Synthesis of amines:

The same reaction as in Example 2 [Step 3] was carried out by using Reference Example Compound 29 (0.096 g, 0.23 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. (1)-((R)-2-(methylsulfonamide)butanyl)piperidine-3-carboxamide (hereinafter, Example Compound 22) 0.090 g (79%).

(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 carried out by using 1-cyanocyclopropanecarboxylic acid (0.034 g, 0.31 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy) 0.087 g (63%) of benzyl)-1-(1-cyanocyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 23).

(Example 24)

(R)-1-((R)-2-acetamidopropyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide Synthesis:

[step 1]

Synthesis of (R)-1-((R)-2-aminopropionyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide :

Reference Example Compound 8 (0.35 g, 1.1 mmol), (R)-2-(((9H-indol-9-yl)methoxy)carbonyl)amino)propanoic acid (0.37 g, In a solution of 1.2 mmol) and DIPEA (0.56 mL, 3.2 mmol) in DMF (2.0 mL), HATU (0.53 g, 1.4 mmol) was added. After stirring at room temperature for 30 minutes, water and 1N hydrochloric acid were added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was purified by silica gel column chromatography (amine phthalocyanine DM1020, eluted liquid; hexane: ethyl acetate = 9:1 → 1:9) from FUJI SILYSIA CHEMICAL CO., LTD. to obtain a crude product 0.53. g. 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). After stirring at room temperature for 6 hours, water was added to the reaction solution, and extracted with ethyl acetate. Organic layer After drying over anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (Amine DM1020, lysate; chloroform:methanol=99:1→95:5, manufactured by FUJI SILYSIA CHEMICAL CO., LTD) to obtain (R)-1-( (R)-2-aminopropionyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Example Compound 30) 0.29 g (stage 2 yield 67%).

[Step 2]

(R)-1-((R)-2-acetamidopropyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide Synthesis:

Acetic anhydride (0.032 g, 0.32 mmol) was added to a solution of the title compound 30 (0.10 g, 0.25 mmol) and TEA (0.11 mL, 0.14 mmol) in dichloromethane. After stirring for 5 minutes under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→90:10) to obtain (R)-1-((R)-2-acetamidopropyl hydrazine. -N-(4-Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 24) 0.11 g (quantitative).

(Embodiment 25)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-2-(methylsulfonamide)propanyl)piperidin-3- Synthesis of carboxyguanamine:

The same reaction as in Example 2 [Step 3] was carried out by using Reference Example Compound 30 (0.10 g, 0.25 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. (1)-((R)-2-(methylsulfonamide)propanyl)piperidine-3-carboxamide (hereinafter, Example Compound 25) 0.099 g (83%).

(Example 26)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-isobutylguanamine cyclopropanecarbonyl)piperidine-3-carboxamide

The same reaction as in Example 1 [Step 11] was carried out by using Reference Example Compound 14 (0.020 g, 0.049 mmol), isobutylphosphonium chloride (0.0062 g, 0.058 mmol) to obtain (R)-N-(4-cyanide). Benzyl-2-(trifluoromethoxy)benzyl)-1-(1-isobutylguanamine cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 26) 0.017 g (71% ).

(Example 27)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-trimethylacetamide cyclopropanecarbonyl)piperidine-3-carboxamide :

The same reaction as in Example 1 [Step 11] was carried out by using Reference Example Compound 14 (0.020 g, 0.049 mmol), trimethylethyl sulfonium chloride (0.0064 g, 0.058 mmol) to obtain (R)-N-(4) -Cyano-2-(trifluoromethoxy)benzyl)-1-(1-trimethylacetamide cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, Example Compound 27) 0.018 g (73%).

(Embodiment 28)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-(methylsulfonamide)tetrahydro-2H-pyran-4-carbonyl)per Synthesis of pyridine-3-carboxyguanamine:

[step 1]

Synthesis of 8-oxo-1,3-dioxaspiro[4.5]indole-2,4-dione:

Water at room temperature in 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): methanol (water: methanol) = 1:1, 60 mL) In the mixed solution, potassium cyanide (3.9 g, 60 mmol) was added. After stirring under heating circulation for 48 hours, the reaction solution was concentrated under reduced pressure. In the liquid, the solvent is distilled off by about half, and the precipitated solid is collected by filtration, washed with water, and dried to obtain 8-oxo-1,3-dioxaspiro[4.5]indole-2,4-dione (hereinafter, reference Example Compound 31) 1.4 g (41%). Further, concentrated hydrochloric acid was added to the filtrate to make it acidic, and the precipitated solid was collected by filtration, washed with water, and then dried to obtain 0.80 g (24%) of the reference compound 31.

[Step 2]

Synthesis of 4-((tertiary butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid:

Calcium hydroxide (3.0 g, 41 mmol) was added to a solution of the title compound 31 (2.2 g, 13 mmol) in water (30 mL). After stirring under a heating loop for 48 hours, the reaction solution was filtered through celite, and the filtrate was washed with hot water. The filtrate was concentrated under reduced pressure, and the obtained crude product was dissolved in water: 1,4- Alkane: methanol (water: 1,4-two Alkane: methanol = 10:10:3, 23 mL) mixed solution. Di-tertiary 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 obtained crude product, and 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 give 4-((tris-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (hereinafter, Reference Compound 32) 2.6 g (82%).

[Step 3]

(R)-tertiary butyl (4-(3-((4-cyano-2-(trifluoromethoxy)benzyl))carbamoyl)piperidine-1-carbonyl)tetrahydro-2H- Synthesis of piperidin-4-yl)carbamate:

The same reaction as in Example 1 [Step 9] was carried out by using Reference Example Compound 32 (0.082 g, 0.34 mmol) to obtain (R)-tertiary butyl (4-(3-((4-cyano-2)). -(Trifluoromethoxy)benzyl)amine-carbazyl)piperidine-1-carbonyl)tetrahydro-2H-piperidin-4-yl)carbamate (hereinafter, Reference Compound 33) 0.10 g ( 62%).

[Step 4]

(R)-1-(4-Aminotetrahydro-2H-piperanylcarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide synthesis:

The same reaction as in Example 1 [Step 10] was carried out by using Reference Example Compound 33 (0.10 g, 0.19 mmol) to obtain (R)-1-(4-aminotetrahydro-2H-pyranylcarbonyl)-N. -(4-Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Compound 34) 0.050 g (58%).

[Step 5]

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(4-(methylsulfonamide)tetrahydro-2H-pyran-4-carbonyl)per Synthesis of pyridine-3-carboxyguanamine:

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

(Example 29)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(cyclopropanecarboxamide)(cyclobutanecarbonyl)piperidin-3- Synthesis of carboxyguanamine:

By using cyclopropane carbonyl chloride (0.0059 g, 0.057 mmol) and Example 1 [Step 11] In the same reaction, (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(cyclopropanecarboxamide)cyclobutanecarbonyl)piperidine- 3-carboxyguanamine (hereinafter, Example Compound 29) was 0.012 g (52%).

(Embodiment 30)

(R)-1-((R)-2-acetamido-3-hydroxy-3-methylbutanyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)per Synthesis of pyridine-3-carboxyguanamine:

[step 1]

Synthesis of (R)-2-((tertiary butoxycarbonyl)amino)-3-hydroxypropionate methyl ester:

Add a di-tertiary butyl group to a solution of methyl (R)-2-amino-3-hydroxypropanoate (3.0 g, 19 mmol), TEA (8.1 mL, 58 mmol) in methanol (50 mL) Carbonate (4.6 g, 21 mmol). After stirring at room temperature for 14 hours, 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 extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium The obtained crude product was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 20:1 → 2:1) to obtain (R)-2-((tris-butoxycarbonyl)amine. Methyl 3-hydroxypropionate (hereinafter, Reference Example 35) 4.1 g (97%).

[Step 2]

Synthesis of (S)-tertiary butyl (1,3-dihydroxy-3-methylbutan-2-yl)carbamate:

Add methyl bromide diethyl ether solution to a solution of the reference compound 35 (4.0 g, 18 mmol) in diethyl ether (0.12 L) at -78 °C (3N, 30 mL, 91 mmol). After stirring at room temperature for 1 hour, a saturated aqueous solution of ammonium chloride and water were added to the mixture, and the mixture was evaporated. The organic layer was washed with aq. The obtained crude product was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 10:1 → 3:1) to obtain (S)-tris-butyl (1,3-dihydroxy-) 3-methylbutan-2-yl)carbamate (hereinafter, Reference Example Compound 36) 2.8 g (84%).

[Step 3]

Synthesis of (R)-2-((tertiary butoxycarbonyl)amino)-3-hydroxy-3-methylbutyric acid:

Reference compound 36 (2.8 g, 13 mmol), 2,2,6,6-tetramethylpiperidine 1-oxide (0.40 g, 2.6 mmol), standard neutral phosphate buffer (45 mL) at 35 ° C A solution of sodium hypochlorite (0.8 g, 0.64 mmol) in water (5.0 mL) and a solution of chlorous acid (2.4 g, 27 mmol) in water (10 mL) were gradually added to a solution of acetonitrile (50 mL). 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 extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous The obtained crude product was dissolved in saturated aqueous sodium hydrogencarbonate and washed with ethyl acetate. 3N hydrochloric acid was added to the aqueous layer to make it acidic, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Methyl butyric acid (hereinafter, Reference Example Compound 37) 2.5 g (84%).

[Step 4]

Tert-butyl butyl ((R)-1-((R)-3-((4-cyano-2-(trifluoromethoxy)benzyl))aminomethyl)piperidin-1-yl)- Synthesis of 3-hydroxy-3-methyl-1-oxobutan-2-yl)carbamate:

HATU (0.42) was added to a solution of Reference Example Compound 8 (0.30 g, 0.92 mmol), Reference Compound 37 (0.24 g, 1.0 mmol), DIPEA (0.35 mL, 2.0 mmol) in DMF (2.0 mL) g, 1.1 mmol). After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with a saturated aqueous The obtained crude product was purified by silica gel column chromatography (Amine DM1020, a solvent, hexane: ethyl acetate = 7:3 → 4:6, manufactured by FUJI SILYSIA CHEMICAL CO., LTD) to obtain a tertiary butyl group. ((R)-1-((R)-3-((4-Cyano-2-(trifluoromethoxy)benzyl))aminomethyl)piperidin-1-yl)-3-hydroxy- 3-methyl-1-oxobutan-2-yl)carbamate (hereinafter, Reference Example 38) 0.44 g (89%).

[Step 5]

(R)-1-((R)-2-amino-3-hydroxy-3-methylbutanyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine- Synthesis of 3-carboxyguanamine:

TFA (1.8 mL, 23 mmol) was added to a solution of the title compound 38 (0.44 g, 0.82 mmol 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 saturated aqueous sodium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (R)-1-((R)-2-amino-3-hydroxy-3-methylbutanyl)-N-(4- Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Reference Compound 39) 0.20 g (58%).

[Step 6]

((R)-1-((R)-2-Ethylamino-3-hydroxy-3-methylbutanyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl) Synthesis of piperidine-3-carboxyguanamine:

Under ice cooling, acetic anhydride (0.010 g, 0.10 mmol) was added to a solution of the title compound 39 (0.040 g, 0.090 mmol), DIPEA (0.035 mL, 0.20 mmol) in dichloromethane (0.30 mL). After stirring for 10 minutes under ice cooling, water and 1N hydrochloric acid were added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→95:5) to obtain ((R)-1-((R)-2-acetamidoamine- 3-hydroxy-3-methylbutylidene)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 30) 0.029 g ( 66%).

(Example 31)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-3-hydroxy-3-methyl-2-propanylaminobutanyl) piperidine Synthesis of pyridine-3-carboxyguanamine:

The same reaction as in Example 1 [Step 11] was carried out by using Reference Example Compound 39 (0.0083 g, 0.019 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. ))-1-((R)-3-hydroxy-3-methyl-2-propanylaminobutanyl)piperidine-3-carboxamide (hereinafter, Example Compound 31) 0.0065 g (70%).

(Example 32)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-3-hydroxy-3-methyl-2-(methylsulfonamide) Synthesis of piperidine-3-carboxyguanamine:

The same reaction as in Example 2 [Step 3] was carried out by using Reference Example Compound 39 (0.040 g, 0.090 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. -1((R)-3-hydroxy-3-methyl-2-(methylsulfonamide)butanyl)piperidine-3-carboxamide (hereinafter, Example Compound 32) 0.038 g (81 %).

(Example 33)

Synthesis of (R)-1-(1-butylguanamine cyclobutanecarbonyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide

The same reaction as in Example 1 [Step 11] was carried out by using butyl sulfonium chloride (0.0060 g, 0.057 mmol) to obtain (R)-1-(1-butylguanamine cyclobutanecarbonyl)-N-(4) -Cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxamide (hereinafter, Example Compound 33) 0.018 g (79%).

(Example 34)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(2-cyclopropylethylamino)cyclobutanecarbonyl)piperidine-3 - Synthesis of carboxamide:

The same reaction as in Example 1 [Step 9] was carried out by using Reference Example Compound 10 (0.021 g, 0.049 mmol), 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol) to obtain (R)-N-(4). -Cyano-2-(trifluoromethoxy)benzyl)-1-(1-(2-cyclopropylethylguanidinium)cyclobutanecarbonyl)piperidine-3-carboxamide (hereinafter, carried out Example Compound 34) 0.0065 g (26%).

(Example 35)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(1-(2-cyclopropylethylguanidino)cyclopropanecarbonyl)piperidin-3- Synthesis of carboxyguanamine:

The same reaction as in Example 1 [Step 9] was carried out by using Reference Example Compound 14 (0.020 g, 0.049 mmol), 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol) to obtain (R)-N-(4). -Cyano-2-(trifluoromethoxy)benzyl)-1-(1-(2-cyclopropylethylguanidino)cyclopropanecarbonyl)piperidine-3-carboxamide (hereinafter, examples) Compound 35) 0.0083 g (35%).

(Example 36)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(1H-1,2,4-triazol-1-yl) Synthesis of propionyl) piperidine-3-carboxamide:

[step 1]

Synthesis of ethyl 2-methyl-2-(1H-1,2,4-triazol-1-yl)propanoate:

Add cesium carbonate (5.0 g, 15 mmol), 1,2,4-triazole to a solution of ethyl 2-bromo-2-methylpropanoate (1.0 g, 5.1 mmol) in DMF (25 mL). Sodium (1,2,4-triazol-1-ide sodium) (0.58 g, 6.2 mmol). 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 obtained crude product was purified by silica gel column chromatography (hexanes: ethyl acetate=7:3→4:6) to obtain 2-A Ethyl 2-(1H-1,2,4-triazol-1-yl)propanoate (hereinafter, Reference Compound 40) was 0.84 g (89%).

[Step 2]

Synthesis of sodium 2-methyl-2-(1H-1,2,4-triazol-1-yl)propionate:

Under ice cooling, a solution of the title compound 40 (0.65 g, 3.6 mmol) in ethanol (18 mL) 3.9 mmol). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure to give sodium 2-methyl-2-(1H-1,2,4-triazol-1-yl)propanoate (hereinafter, reference compound 41) 0.67 g (quantitative).

[Step 3]

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(1H-1,2,4-triazol-1-yl) Synthesis of propionyl) piperidine-3-carboxamide:

The same reaction as in Example 1 [Step 6] was carried out by using Reference Example Compound 41 (0.090 g, 0.51 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. 1-(2-methyl-2-(1H-1,2,4-triazol-1-yl)propanyl)piperidine-3 (hereinafter, Example Compound 36) 0.12 g (54% ).

(Example 37)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(1H-pyrazol-1-yl)propanyl)per Synthesis of pyridine-3-carboxyguanamine:

[step 1]

Synthesis of ethyl 2-methyl-2-(1H-pyrazol-1-yl)propanoate:

The same reaction as in Example 36 [Step 1] was carried out by using 1H-pyrazole (0.42 g, 6.2 mmol) to obtain ethyl 2-methyl-2-(1H-pyrazol-1-yl)propanoate ( Hereinafter, reference compound 42) 0.81 g (87%).

[Step 2]

Synthesis of sodium 2-methyl-2-(1H-pyrazol-1-yl)propionate:

The same reaction as in Example 36 [Step 2] was carried out by using Reference Example Compound 42 (0.81 g, 4.5 mmol) to obtain sodium 2-methyl-2-(1H-pyrazol-1-yl)propionate (hereinafter , Reference Example Compound 43) 0.80 g.

[Step 3]

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-(2-methyl-2-(1H-pyrazol-1-yl)propanyl)per Synthesis of pyridine-3-carboxyguanamine:

The same reaction as in Example 1 [Step 9] was carried out by using Reference Example Compound 43 (0.090 g, 0.51 mmol) to obtain (R)-N-(4-cyano-2-(trifluoromethoxy)benzylbenzene. 1-(2-methyl-2-(1H-pyrazol-1-yl)propanyl)piperidine-3-carboxamide (hereinafter, Example Compound 37) 0.16 g (68%).

(Example 38)

Synthesis of (R)-N-(2,4-dichlorobenzyl)-1-(1-hydroxycyclohexanecarbonyl)piperidine-3-carboxamide:

[step 1]

Synthesis of (R)-tertiary butyl 3-((2,4-dichlorobenzyl)aminemethanyl)piperidine-1-carboxylate:

The same reaction as in Example 1 [Step 6] was carried out by using 2,4-dichlorobenzylamine (1.5 g, 8.5 mmol) to obtain (R)-tertiary butyl 3-((2,4-di) Chlorobenzyl)amine-mercapto)piperidine-1-carboxylate (hereinafter, Reference Example Compound 44) was 2.6 g (quantitative).

[Step 2]

Synthesis of (R)-N-(2,4-dichlorobenzyl)piperidine-3-carboxamide:

The same reaction as in Example 1 [Step 8] was carried out by using Reference Example Compound 44 (2.6 g, 6.7 mmol) to obtain (R)-N-(2,4-dichlorobenzyl)piperidine-3-carboxylate. Indoleamine (hereinafter, Reference Example Compound 45) 1.8 g (95%).

[Step 3]

Synthesis of (R)-N-(2,4-dichlorobenzyl)-1-(1-hydroxycyclohexanecarbonyl)piperidine-3-carboxamide:

The same reaction as in Example 20 was carried out by using Reference Example Compound 45 (0.10 g, 0.35 mmol) to obtain (R)-N-(2,4-dichlorobenzyl)-1-(1-hydroxycyclohexane). Carbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 38) was 0.030 g (24%).

(Example 39)

((R)-1-((R)-2-Ethylamino-3-hydroxy-3-methylbutanyl)-N-(2,4-dichlorobenzyl)piperidine-3-carboxamide Synthesis:

[step 1]

Tert-butyl ((R)-1-((R)-3-(2,4-dichlorobenzyl)aminemethanyl)piperidin-1-yl)-3-hydroxy-3-methyl- Synthesis of 1-oxobutan-2-yl)carbamate:

HATU (0.16 g) was added to a solution of Reference Example Compound 37 (0.089 g, 0.38 mmol), Reference Compound 45 (0.10 g, 0.35 mmol), DIPEA (0.20 mL, 1.1 mmol) in DMF (0.70 mL) , 0.42 mmol). After stirring at room temperature for 1 hour, 1N hydrochloric acid was added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=7:3→4:6) to obtain a tri-butyl group ((R)-1-((R)- 3-(2,4-Dichlorobenzyl)amine-carbamoyl)piperidin-1-yl)-3-hydroxy-3-methyl-1-oxobutan-2-yl)carbamate ( Hereinafter, Reference Example Compound 46) 0.15 g (82%).

[Step 2]

TFA (1.0 mL, 13 mmol) was added to a solution of the title compound 46 (0.70 g, 1.7 mmol). After stirring at room temperature for 2.5 hours, TFA (1.0 mL, 13mmol). 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 saturated aqueous sodium carbonate, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (R)-1-((R)-2-amino-3-hydroxy-3-methylbutanyl)-N-(2,4-dichloro Benzyl)piperidine-3-carboxamide (hereinafter, reference compound 47) 0.47 g (84%).

[Step 3]

((R)-1-((R)-2-Ethylamino-3-hydroxy-3-methylbutanyl)-N-(2,4-dichlorobenzyl)piperidine-3-carboxamide Synthesis:

Under ice cooling, acetic anhydride (0.0056 g, 0.055 mmol) was added to a solution of the title compound 47 (0.020 g, 0.050 mmol), TEA (0.014 mL, 0.099 mmol) in dichloromethane (0.15 mL). After stirring for 10 minutes under ice cooling, water and 1N hydrochloric acid were added to the reaction mixture, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and evaporated. The obtained crude product was purified by silica gel column chromatography (solvent; chloroform:methanol=99:1→95:5) to obtain ((R)-1-((R)-2-acetamidoamine- 3-hydroxy-3-methylbutanyl)-N-(2,4-dichlorobenzyl)piperidine-3-carboxamide (hereinafter, Example Compound 39) was obtained (yield: 0.02 g).

(Embodiment 40)

(R)-N-(2,4-dichlorobenzyl)-1-((R)-3-hydroxy-3-methyl-2-propanylaminobutanyl)piperidine-3-carboxamide synthesis:

The same reaction as in Example 1 [Step 11] was carried out by using Reference Example Compound 47 (0.020 g, 0.050 mmol) to obtain (R)-N-(2,4-dichlorobenzyl)-1-((R). -3-hydroxy-3-methyl-2-propionylaminobutanyl)piperidine-3-carboxamide (hereinafter, Example Compound 40) was 0.018 g (77%).

(Example 41)

(R)-N-(2,4-dichlorobenzyl)-1-((R)-3-hydroxy-3-methyl-2-(methylsulfonamide)butanyl)piperidine-3-carboxylate Synthesis of guanamine:

The same reaction as in Example 2 [Step 3] was carried out by using Reference Example Compound 47 (0.020 g, 0.050 mmol) to obtain (R)-N-(2,4-dichlorobenzyl)-1-((R). -3-hydroxy-3-methyl-2-(methylsulfonamide)butanyl)piperidine-3-carboxamide (hereinafter, Example Compound 41) 0.020 g (85%).

(Example 42)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-2-hydroxypropionyl)piperidine-3-carboxamide:

The same reaction as in Example 1 [Step 9] was carried out by using sodium (R)-2-hydroxypropionate (0.019 g, 0.17 mmol) to obtain (R)-N-(4-cyano-2-(3) Fluoromethoxy)benzyl)-1-((R)-2-hydroxypropionyl)piperidine-3-carboxamide (hereinafter, Example Compound 42), 0.045 g (74%).

(Example 43)

Synthesis of (R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-2-hydroxybutanyl)piperidine-3-carboxamide:

The same reaction as in Example 1 [Step 9] was carried out by using (R)-2-hydroxybutyric acid (0.017 g, 0.17 mmol) to obtain (R)-N-(4-cyano-2-(trifluoro). Methoxy)benzyl)-1-((R)-2-hydroxybutanyl)piperidine-3-carboxamide (hereinafter, Example Compound 43) was 0.056 g (89%).

(Example 44)

(R)-N-(4-cyano-2-(trifluoromethoxy)benzyl)-1-((R)-2-hydroxy-3-methylbutanyl)piperidine-3-carboxamide Synthesis:

The same reaction as in Example 1 [Step 9] was carried out by using (R)-2-hydroxy-3-methylbutyric acid (0.018 g, 0.15 mmol) to obtain (R)-N-(4-cyano- 2-(Trifluoromethoxy)benzyl)-1-((R)-2-hydroxy-3-methylbutanyl)piperidine-3-carboxamide (hereinafter, Example Compound 44) 0.042 g (64 %).

(Comparative Example 1) Synthesis of (R)-1-(1-hydroxycyclohexanecarbonyl)-N-(5-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide:

[step 1]

Synthesis of (R)-tertiary butyl 3-((5-(trifluoromethyl)pyridin-2-yl)aminecarboxamido)piperidine-1-carboxylate:

DMF was added to a solution of (R)-1-(tertiary butoxycarbonyl)piperidine-3-carboxylic acid (20 g, 87 mmol) in THF (1.0 L) under ice-cooling so that the internal temperature did not exceed 5 °C. (0.68 mL, 8.7 mmol), grass chloroform (8.0 mL, 92 mmol). After stirring for 30 minutes under ice cooling, 2-amino-5-(trifluoromethyl)pyridine (15 g, 92 mmol) and pyridine (15 mL) were added to the reaction solution at -25 ° C at an internal temperature of not more than -20 ° C. , 0.18 mmol) in THF (0.10 L). After stirring for 3 hours under ice cooling, a saturated aqueous solution of sodium chloride was added to the reaction solution so that the internal temperature did not exceed 5 ° C, and extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Hexane was added to the obtained crude product. The precipitated solid was collected by filtration, and the filtrate was concentrated under reduced pressure. The same purification operation was repeated twice. The obtained solid was combined to obtain (R)-tertiary butyl 3-((5-(trifluoromethyl)pyridin-2-yl)aminemethanyl)piperidine-1-carboxylate (hereinafter, reference example) Compound 48) 26 g (80%).

[Step 2]

Synthesis of (R)-N-(5-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide:

To a solution of the title compound 48 (1.5 g, 4.0 mmol) in dichloromethane (10 mL), EtOAc. After 2 hours, a saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction mixture, and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated The amine (hereinafter, Reference Example Compound 49) was 0.95 g (87%).

[Step 3]

Synthesis of (R)-1-(1-hydroxycyclohexanecarbonyl)-N-(5-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide

Add to a solution of the title compound 49 (0.13 g, 0.46 mmol), 1-hydroxycyclohexanecarboxylic acid (0.079 g, 0.55 mmol), DIPEA (0.24 mL, 1.4 mmol) in DMF (1.0 mL) HATU (0.23 g, 0.60 mmol). After stirring at room temperature for 1 hour, water and 1N hydrochloric acid were added to the reaction solution, and extracted with diethyl ether. The organic layer was washed with saturated aqueous The obtained crude product was purified by ruthenium column chromatography (Amine DM1020, Eluent: hexane: ethyl acetate = 9:1 → 3:7, manufactured by FUJI SILYSIA CHEMICAL CO., LTD) to obtain (R)- 1-(1-Hydroxycyclohexanecarbonyl)-N-(5-(trifluoromethyl)pyridin-2-yl)piperidine-3-carboxamide (hereinafter, Comparative Example Compound 1) 0.058 g (32%) ).

(Comparative Example 2) (R)-1-(2-acetamidoethyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine-3-carboxyindole Synthesis of amines:

Add HATU to a solution of Reference Example Compound 8 (0.10 g, 0.31 mmol), N-ethylglycylglycine (0.036 g, 0.31 mmol), DIPEA (0.16 mL, 0.92 mmol) in DMF (5 mL) (0.14 g, 0.37 mmol). After stirring at room temperature for 14 hours, 1 N of dilute hydrochloric acid was added to the reaction solution, and the mixture was extracted with hexane: ethyl acetate (hexane: ethyl acetate = 1:2). The organic layer was washed with water and a saturated aqueous The obtained crude product was dissolved in diethyl ether (1.0 mL), and hexane (4.0 mL) was added. The precipitated colloidal substance was collected by filtration to give (R)-1-(2-acetamidoethyl)-N-(4-cyano-2-(trifluoromethoxy)benzyl)piperidine- 3-Carboxylimine (hereinafter, Comparative Example Compound 2) was 0.040 g (31%).

Table 1-1 to Table 1-6 show the physical properties of the compounds of Examples 1 to 44, Table 2 shows the physical properties of the comparative compounds 1 to 2, and Tables 3-1 to 3-5 show the reference compounds 1 to 49. Physical information. Also, N.D. in the table indicates "no data".

In the 1H-NMR data, the proton integral value is a non-integer due to the presence of a rotamer or the like.

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

(Example 45) In vitro sEH inhibitory activity of hexahydronicotinic acid derivative (I):

Evaluation of hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof using human sEH based on the method described in the literature (Analytical Biochemistry, 2005, Vol. 343, p. 66-75) sEH inhibits activity.

Recombinant human sEH (final concentration 0.026 μg/mL; Cayman) was incubated with the test compound in 25 mM Bis-Tris-HCl buffer (pH 7.0) containing 0.1 mg/mL BSA at room temperature. minute. Thereafter, cyano (6-methoxynaphthalen-2-yl)methyl 2-(3-phenyloxy) was added. -2-yl)acetate (final concentration 6.25 μmol/L; Cayman) was used as a fluorescent substrate, and then incubated at room temperature for 20 minutes, ZnSO ₄ (final concentration 0.2 mol/L) was added to stop the reaction, and fluorescence was measured. Strength (Fusion α (Packard); excitation: 330 nm, emission: 485 nm).

The sEH is not added and the fluorescence intensity of the test compound is not added as the 0% sEH enzyme reaction rate, the sEH is added and the fluorescence intensity of the test compound is not added as the 100% sEH enzyme reaction rate, from the obtained fluorescence intensity, The sEH enzyme reaction rate of each test compound was calculated to obtain an IC ₅₀ . The results are shown in Table 4.

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

From this, it is known that the hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof exhibits a very strong inhibitory activity against the enzyme reaction of human sEH.

(Example 46) Effect of hexahydronicotinic acid derivative (I) in the administration of rat monocrotaline to pulmonary hypertension model:

In the rat model of pulmonary hypertension administered by the monocrotaline (Journal of Pharmacological Sciences, 2009, Vol. 111, p. 235-243), the compound of Example 1, 2 or 31 was administered to evaluate hexahydronicotine. The therapeutic effect of the acid derivative (I) or a pharmacologically acceptable salt thereof on pulmonary hypertension.

1) The effect of the compound of Example 1 on the cardiopulmonary function, right ventricular hypertrophy, pulmonary hypertrophy, pulmonary hypertrophy, cell proliferation and cardiac hypertrophy in the pulmonary hypertensive mode of rat monocrotaline:

In the back of rats (Wistar, male, 5 weeks old, Japan SLC Co., Ltd.), an aqueous solution of wild lily (Sigma) (60 mg/kg) was administered, and the group induced by pulmonary hypertension was regarded as "lung. Sexual hypertension induced group. On the other hand, the administration group that injected water for injection was similarly referred to as a "normal group".

In the rats in the pulmonary hypertension-inducing group, the compound of the example 1 (3, 10, and 30 mg/kg) or the positive control compound tadalafil was orally administered once a day from the 24th day after the administration of the monocrotaline. (10 mg/kg). Example Compound 1 and tadalafil were suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80. Each of the groups of Example Compound 1 administered at a dose of 3, 10, and 30 mg/kg was administered as "Example Compound 1 (3 mg/kg) in the administration group" and "Example Compound 1 (10 mg/kg). "Administration group" and "Example compound 1 (30 mg/kg) administration group". In addition, the administration group of Tadalafei at a dose of 10 mg/kg was used as the "Tadala Affordable Group". On the other hand, as a comparative control, in the lungs In the rats in the hypertensive-induced group, a group containing 0.5% Tween 80 in 0.5% methylcellulose aqueous solution was also administered as a "pulmonary hypertension control group". Further, a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was also administered to the normal group.

Right ventricular systolic pressure, systemic systolic blood pressure, and heart rate were measured on the day following the final administration of the test compound. The right ventricular systolic pressure and the systemic systolic blood pressure were measured using a blood pressure measuring amplifier (Japan Photoelectric Industries Co., Ltd.), and the heart rate was measured using an instantaneous heart rate unit (Japan Opto-Industry Co., Ltd.). On the same day, the body weight, lung wet weight, and wet weight of the right ventricle, left ventricle, and septum were measured to determine the right ventricular weight ratio (right ventricular weight / (sept. weight + left ventricular weight)) and lung weight ratio. (lung weight/weight).

Further, the lungs were immersed in the formalin solution after the wet weight measurement and stored. The lungs fixed with the formalin solution were embedded in paraffin, and sections were prepared, and immunostained tissue samples were prepared using the anti-sEH antibody, and the sEH expression was examined. In addition, pathological tissue specimens stained with elastic fibers were prepared, and pulmonary artery hypertrophy was reviewed. Further, immunostained tissue specimens were prepared using an anti-PCNA antibody, and cell proliferation was examined. Further, the right ventricle was immersed in the formalin solution after the wet weight measurement and stored. The right ventricle fixed with the formalin solution was embedded in paraffin, and sections were prepared to prepare HE-stained pathological tissue specimens, and myocardial hypertrophy was examined.

Further, after the extracted lungs were disrupted in a buffer, 14,15-EET and 14,15-DHET were extracted. The extracted 14,15-EET was hydrolyzed and converted to 14,15-DHET, and the 14,15-DHET concentration was measured using an ELISA method. The 14,15-DHET concentration increased after the hydrolysis reaction was used as the 14,15-EET concentration to determine the 14,15-EET/14,15-DHET ratio.

The results of sEH in pulmonary hypertension were reviewed. In the lungs of the pulmonary hypertension-induced group, sEH was observed in the lesions compared with the lungs in the normal group. Accordingly, the performance of sEH is hyperactive in the lung lesions of pulmonary hypertension.

The right ventricular systolic pressure, right ventricular weight ratio, and lung weight ratio of the next day after the test compound was finally administered, the results are shown in Figures 1 to 3. The horizontal axis of the graph indicates each group, and the vertical axis indicates each measurement value (mean value ± standard error, n = 10). The * mark in the figure indicates statistically significant comparison with the pulmonary hypertension control group (Dunnett's test, p < 0.05).

The right ventricular systolic pressure in the pulmonary hypertension control group was statistically significant compared with the right ventricular systolic pressure in the normal group (Aspin-Welch t test, p<0.05), indicating a high lung height. The morbidity of blood pressure. Further, in the Example Compound 1 (10 mg/kg) administration group and the Example Compound 1 (30 mg/kg) administration group, the right ventricular systolic pressure was compared with the right ventricular systolic pressure of the pulmonary hypertension control group, and statistics were presented. Learn to be meaningfully low (Dunnett's test, p < 0.05) (Figure 1). From this, it is understood that the compound of the example 1 has a therapeutic effect on the pathological condition of pulmonary hypertension in which pulmonary artery pressure is observed to rise.

The right ventricular weight ratio of the pulmonary hypertension control group was statistically significant compared with the right ventricular weight ratio of the normal group (Aspin-Welch t test, p<0.05), indicating the pathology of right ventricular hypertrophy. Further, the right ventricular weight ratio of the Example Compound 1 (10 mg/kg) administration group and the Example Compound 1 (30 mg/kg) administration group was compared with the right ventricular weight ratio of the pulmonary hypertension control group, and statistically Significantly low values (Dunnett's test, p<0.05) (Fig. 2). According to this, the implementation Example Compound 1 also has a therapeutic effect on the pathology of pulmonary hypertension in which right ventricular hypertrophy is observed.

The lung weight ratio of the pulmonary hypertension control group was statistically significant compared with the lung weight ratio of the normal group (Aspin-Welch t test, p<0.05), indicating that the lung hypertrophy was present. Further, the lung weight ratio of the Example Compound 1 (10 mg/kg) administration group was compared with the lung weight ratio of the pulmonary hypertension control group, and showed a statistically significant low value (Dunnett's test, p<0.05) (No. 3)). From this, it is understood that the compound of the example 1 has a therapeutic effect on the pathological condition of pulmonary hypertension in which pulmonary hypertrophy is observed.

On the other hand, in the Example Compound 1 (3 mg/kg) administration group, the Example Compound 1 (10 mg/kg) administration group, and the Example Compound 1 (30 mg/kg) administration group, the heart rate and systemic contraction The blood pressure was compared with the heart rate of the pulmonary hypertension control group and the systemic systolic blood pressure. No significant difference was observed (Dunnett's test, p<0.05). From this, it can be seen that Example Compound 1 has no effect on heart rate and systemic blood pressure in pulmonary hypertension.

The results of pulmonary hypertrophy in pulmonary hypertension were reviewed. Pulmonary hypertrophy was observed in the lungs of the pulmonary hypertension control group compared with the lungs of the normal group. On the other hand, Example Compound 1 (3 mg/kg) was administered to the lungs of the group, and no pulmonary hypertrophy was observed as compared with the lungs of the pulmonary hypertension control group. From this, it is understood that the compound of the example 1 has a therapeutic effect on the pathological condition of pulmonary hypertension in which pulmonary artery hypertrophy is observed.

The results of cell proliferation in pulmonary hypertension were reviewed. The lungs of the pulmonary hypertension control group were observed to have increased cells compared with the lungs of the normal group. Colonization. On the other hand, Example Compound 1 (3 mg/kg) was administered to the lungs of the group, and no cell proliferation was observed as compared with the lungs of the pulmonary hypertension control group. From this, it is understood that the compound of the example 1 has a therapeutic effect on the pathological condition of pulmonary hypertension in which cell proliferation in the lung is observed.

The results of cardiac hypertrophy in pulmonary hypertension were reviewed. Cardiac hypertrophy was observed in the right ventricle of the pulmonary hypertension control group compared with the right ventricle of the normal group. On the other hand, in the right ventricle of the Example Compound 1 (3 mg/kg) administered to the group, no cardiac hypertrophy was observed as compared with the right ventricle of the pulmonary hypertension control group. From this, it is understood that the compound of the example 1 has a therapeutic effect on the pathological condition of pulmonary hypertension in which cardiac hypertrophy is observed.

To review the results of 14,15-EET/14,15-DHET ratio in pulmonary hypertension, the lungs in the lung hypertension control group were compared with the 14,15-EET/14,15-DHET ratio in the lungs of the normal group. The comparison of 14,15-EET/14, 15-DHET showed a low value. It can be seen that in the lungs of pulmonary hypertension, the ratio of 14,15-EET/14, 15-DHET is decreased. On the other hand, the ratio of 14,15-EET/14,15-DHET in the lung of the compound of Example 1 (10 mg/kg) was compared with that of the lung of the pulmonary hypertension control group, 14,15-EET/ 14,15-DHET is compared to a high value. From this, it was found that Example Compound 1 exhibited an increase in the ratio of 14,15-EET/14, 15-DHET in the lungs of pulmonary hypertension.

2) Effect of Example Compound 1 on right ventricular hypertrophy caused by the administration of the pathological phase of the pulmonary hypertension model administered by the rat monocrotaline:

An aqueous solution of monocrotaline (Sigma) was administered subcutaneously in the back of rats (Wistar, male, 5 weeks old; Japan SLC Co., Ltd.). (60 mg/kg), the group induced by pulmonary hypertension was referred to as "pulmonary hypertension-induced group". On the other hand, the group in which the water for injection was administered in the same manner was referred to as a "normal group".

In the rats in the pulmonary hypertension-inducing group, the compound of Example 1 (3 and 10 mg/kg) or the positive control compound tadalafil (10 mg/kg) was orally administered once a day. Example Compound 1 (3 and 10 mg/kg) was administered from 10 days after the administration of wild lily liquid to 18 or 19 days. Tadalafil (10 mg/kg) was administered from wild lily to the day of 28 or 29 days. Example Compound 1 and tadalafil were suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80. Each of the groups to which the Example Compound 1 was administered at a dose of 3 and 10 mg/kg was used as the "Example Compound 1 (3 mg/kg) administration group" and the "Example Compound 1 (10 mg/kg) administration group. "." In addition, the group to which Tadara is administered at a dose of 10 mg/kg was referred to as the "Tadala Affordable Group". On the other hand, as a comparative control, a group containing a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to a rat in the pulmonary hypertension-inducing group as a "pulmonary hypertension control group". Further, a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was also administered in the same manner in the normal group.

On the day of the final administration of the test compound, the rats were bled from the abdominal aorta under anesthesia, and then euthanized, the palpitations were removed, and the wet weight of the right ventricle, left ventricle and septum was measured to obtain the right ventricular weight ratio (right ventricle). Weight / (separate weight + left ventricular weight)). Further, the concentration of 14,15-DHET in the blood taken was measured by an ELISA method. Further, a certain amount of 14,15-EET was added to the blood taken, and the reaction was allowed to proceed at 37 ° C for 30 minutes, and the amount of 14,15-DHET produced was measured by an ELISA method to determine the sEH activity in the blood.

The 14,15-DHET concentration and sEH activity in the blood of the pulmonary hypertension control group showed a high value compared with the 14,15-DHET concentration and sEH activity in the blood of the normal group. According to this, pulmonary hypertension showed an increase in the concentration of 14,15-DHET and an increase in sEH activity.

The right ventricular weight ratio of the test compound was finally administered to the day, and the results are shown in Fig. 4. The horizontal axis of the graph represents each group, and the vertical axis represents the right ventricular weight ratio (mean ± standard error, n = 10). The * mark in the figure indicates statistically significant comparison with the pulmonary hypertension control group (t assay, p < 0.05).

The right ventricular weight ratio of the pulmonary hypertension control group showed a statistically significant high value compared with the right ventricular weight ratio of the normal group (t assay, p<0.05). According to this, the pulmonary hypertension control group showed a pathological state of right ventricular hypertrophy. On the other hand, the right ventricular weight ratio of the Example Compound 1 (10 mg/kg) administration group was compared with the right ventricular weight ratio of the pulmonary hypertension control group, showing a statistically significant low value (t assay, p< 0.05) (Fig. 4). From this, it can be seen that the compound of the example 1 has a therapeutic effect on the pathological condition of the observed pulmonary hypertension of right ventricular hypertrophy even if it is administered from the pathological stage of pulmonary hypertension.

3) Effect of Example Compound 1 on systemic blood pressure of rat monocrotaline administered to pulmonary hypertension model:

The rats in the pulmonary hypertension model were administered with monocrotaline, and the compound of Example 1 was administered in a single administration, and the whole body immediately after administration of the hexahydronicotinic acid derivative (I) or its pharmacologically acceptable salt was evaluated. The role of blood pressure.

An aqueous solution of wild lily (Sigma) (60 mg/kg) was administered subcutaneously to the back of rats (SD line, male, 11 weeks old; Charles River, Japan) to induce pulmonary hypertension.

After 7 days of administration of monocrotaline, the rats triggered by pulmonary hypertension were anesthetized, the thighs and the back neck were depilated, and the surgery was disinfected with Isodine solution. After cutting the skin of the thigh and the back of the neck, the small muscles were used to bluntly cut the muscle layer of the thigh, and the thigh artery was peeled off, and then the small incision was made and the indwelling polyethylene tube was inserted. After 9 days of administration of monocrotaline, the blood pressure transducer was connected to the tube inserted into the thigh artery, and the blood pressure was increased by the Blood Pressure Amplifier. The heart rate was induced by the heart rate counter, and the heart rate counter (Heart Rate Counter) was used. Get waveforms from any Power Lab system. Confirm that the whole body blood pressure and heart rate are stable. After confirming that the systemic blood pressure was stable, Example Compound 1 was administered orally in a single oral dose of 10 mg/kg. Further, Example Compound 1 was suspended in a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 and used. The group to which Example Compound 1 was administered was designated as "Example Compound 1 administration group". On the other hand, as a comparative control, a group in which pulmonary hypertension was induced was similarly administered to a group containing 0.5% Tween 80 in a 0.5% methylcellulose aqueous solution as a "pulmonary hypertension control group". The whole body mean blood pressure of Example 1 or 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was measured immediately after administration for 1, 2, 3, 4, 5 and 6 hours after administration.

As a result, the systemic mean blood pressure of the Example Compound 1 administration group was compared with the systemic mean blood pressure of the pulmonary hypertension control group, and no significant difference was observed. From this, it was found that the compound of the example 1 showed no effect on systemic blood pressure immediately after administration of pulmonary hypertension.

4) The effect of the compound of Example 2 on the cardiopulmonary function and right ventricular hypertrophy of the rat hemorrhoids administered with pulmonary hypertension model:

The effect of the Example Compound 2 which administered the pulmonary hypertension model to the rat monocrotaline was evaluated in the same manner as in Example 46 (1) except that the test compound was different.

The rats in the "pulmonary hypertension-inducing group" prepared in the same manner as in Example 46 (1) were administered with monocrotaline 24 hours a day, and once a day, the compound of Example 2 was administered orally (10 mg/ Kg) or positive control compound tadalafil (10 mg/kg). Example Compound 2 and tadalafil were suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80 for use. The group of Example Compound 2 administered at a dose of 10 mg/kg was administered as the "Example Compound 2 administration group", and the group administered with the dose of 10 mg/kg of tadalafil was referred to as "Tadala". Non-submission group." On the other hand, as a comparative control, a group in which a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was administered in the same manner as a "pulmonary hypertension control group" was used in the rats in the pulmonary hypertension-inducing group. Further, a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to the "normal group" to which no wild lily base was administered.

In the same manner as in 1) of Example 46, right ventricular systolic pressure, systemic systolic blood pressure, and heart rate were measured on the day following the final administration of the test compound. Also, on the same day, the body weight, lung wet weight, and wet weight of the right ventricle, left ventricle, and septum were measured to determine the right ventricular weight ratio (right ventricular weight / (sept. weight + left ventricular weight)) and lung weight ratio ( Lung weight / weight).

The results are shown in Figures 5-7. The horizontal axis of the graph indicates each group, and the vertical axis indicates each measurement value (mean value ± standard error, n = 10). The * mark in the figure is statistically significant in comparison with the pulmonary hypertension control group (Dunnett's test, p < 0.05).

The right ventricular systolic pressure in the pulmonary hypertension control group was compared with the right ventricular systolic pressure in the normal group, showing a statistically significant high value (Aspin-Welch t test, p<0.05), showing high lung height. The morbidity of blood pressure. Further, the right ventricular systolic pressure of the Example Compound 2 administration group was compared with the right ventricular systolic pressure of the pulmonary hypertension control group, and a statistically significant low value was obtained (Dunnett's test, p<0.05) (5th Figure). From this, it is understood that the compound of the example 2 has a therapeutic effect on the pathological condition of pulmonary hypertension in which pulmonary artery pressure is observed to rise.

The right ventricular weight ratio of the pulmonary hypertension control group was compared with the right ventricular weight ratio of the normal group, showing a statistically significant high value (Aspin-Welch t test, p<0.05), showing the pathology of right ventricular hypertrophy. Further, the right ventricular weight ratio of the Example Compound 2 administration group was compared with the right ventricular weight ratio of the pulmonary hypertension control group, and a statistically significant low value was obtained (Dunnett's test, p < 0.05) (Fig. 6) . From this, it is understood that the compound of the example 2 has a therapeutic effect on the pathology of pulmonary hypertension in which right ventricular hypertrophy is observed.

The lung weight ratio of the pulmonary hypertension control group was compared with the lung weight ratio of the normal group, and a statistically significant high value (Aspin-Welch t test, p<0.05) was shown, indicating a pathological state of pulmonary hypertrophy. Further, the lung weight ratio of the Example Compound 2 administration group was compared with the lung weight ratio of the pulmonary hypertension control group, and showed a low value (Fig. 7). From this, it is understood that the compound of the example 2 has a therapeutic effect on the pathological condition of pulmonary hypertension in which pulmonary hypertrophy is observed.

On the other hand, in the Example Compound 2 administration group, the heart rate and systemic systolic blood pressure, and the heart rate of the pulmonary hypertension control group and No significant difference was observed in either systemic systolic blood pressure (Dunnett's test, p < 0.05). From this, it is understood that the compound of the example 2 has no effect on the heart rate of pulmonary hypertension and systemic blood pressure.

5) Effect of Example Compound 31 on right ventricular hypertrophy in a rat model of pulmonary hypertension administered by monocrotaline:

A solution of monocrotaline (Sigma) (60 mg/kg) was administered subcutaneously to the back of rats (Wistar, male, 6 weeks old, Japan SLC Co., Ltd.), and the group induced by pulmonary hypertension was regarded as "pulmonary". Hypertensive induced group." On the other hand, the group in which the water for injection was administered in the same manner was referred to as a "normal group".

In the rats in the pulmonary hypertension-inducing group, the compound of Example 31 (3 mg/kg and 10 mg/kg) was orally administered once a day from the day of the 29th or 30th day. The compound of Example 31 was suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80. Each of the groups of Example Compound 31 administered at a dose of 3 mg/kg and 10 mg/kg was administered as "Example Compound 31 (3 mg/kg) administration group" and "Example Compound 31 (10 mg/kg). group". On the other hand, as a comparative control, a group in which a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was administered in a rat in the pulmonary hypertension-inducing group was referred to as a "pulmonary hypertension control group". Further, a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was also administered in the normal group.

On the day of the final administration of the test compound, the wet weight of the right ventricle, left ventricle and septum was measured, and the right ventricular weight ratio (right ventricular weight / (sept. weight + left ventricular weight)) was obtained.

The results of the right ventricular weight ratio survey on the final dose of the test compound are shown in Fig. 8. The horizontal axis of the graph represents each group, and the vertical axis represents the right ventricular weight ratio (mean ± standard error, n = 7 to 18). The # mark in the figure indicates statistically significant comparison with the normal group (t assay, p < 0.05).

The right ventricular weight ratio of the pulmonary hypertension control group was compared with the normal group right ventricular weight ratio, showing a statistically significant high value (t test, p < 0.05), showing a pathological state of right ventricular hypertrophy. Further, the right ventricular weight ratio of the Example Compound 31 (3 mg/kg) administration group and the Example Compound 31 (10 mg/kg) administration group was compared with the right ventricular weight ratio of the pulmonary hypertension control group, showing a low value. (Figure 8). From this, it is understood that the compound of the example 31 has a therapeutic effect on the pathological state of pulmonary hypertension in which right ventricular hypertrophy is observed.

From the results of 1), 2), 3), 4) and 5) of Example 46, it is understood that the hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof has a therapeutic effect on pulmonary hypertension. .

(Example 47) A combination of a hexahydronicotinic acid derivative (I) and a phosphodiesterase inhibitor or an endothelin receptor antagonist of a pulmonary vasodilator in a rat model of pulmonary hypertension administered with monocrotaline effect:

In the rat model of pulmonary hypertension administered by the monocrotaline (Journal of Pharmacological Sciences, 2009, Vol. 111, p. 235-243), evaluation and administration of hexahydronicotinic acid derivative (I) or its pharmacology The therapeutic effect of a tolerable salt and pulmonary vasodilator phosphodiesterase inhibitor or an endothelin receptor antagonist on pulmonary hypertension.

For the hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof, Example Compound 1 and Example Compound 31 were selected. Also, in the case of a phosphodiesterase inhibitor, tadalafil is selected. For endothelin receptor antagonists, ambrisin is selected.

1) The effect of the combination of the compound of Example 1 and tadalafil on the right ventricular hypertrophy of the rat hemorrhoids administered with pulmonary hypertension mode (simultaneous administration):

A solution of monocrotaline (Sigma) (60 mg/kg) was administered subcutaneously to the back of rats (Wistar, male, 5 weeks old, Japan SLC Co., Ltd.), and the group induced by pulmonary hypertension was regarded as "pulmonary". Hypertensive induced group." On the other hand, the group that also administered the water for injection was referred to as a "normal group".

For rats in the pulmonary hypertension-inducing group, Example Compound 1 (10 mg/kg) or tadalafil (10 mg/kg) alone or Example Compound 1 (10 mg/kg) and tadalafil (10 mg) /kg) Combined use, from the wild lily liquid for the next 24 days, once a day orally. Each of the administration solutions of the compound of Example 1 or tadalafil was suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80 to prepare. Further, the compound of Example 1 and tadalafil were mixed and suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80 in the form of a solution for administration.

The group of Example Compound 1 administered at a dose of 10 mg/kg was administered as "Example Compound 1 (10 mg/kg) administration group". The administration group of tadalafil at a dose of 10 mg/kg was referred to as the "Tadalafil (10 mg/kg) administration group". Example compound 1 of 10 mg/kg will be used in combination The group administered with 10 mg/kg of tadalafil was administered as "Example Compound 1 (10 mg/kg) + tadalafil (10 mg/kg)." On the other hand, as a comparative control, rats in the pulmonary hypertension-inducing group were also administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 as a "pulmonary hypertension control group". Further, a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to the normal group.

On the day of the final administration of the test compound, the rats were anesthetized with isoflurane and lethaled to death. After euthanasia, the heart palpitations were removed, and the wet weight of the right ventricle, left ventricle and septum was measured to obtain the right ventricular weight. Ratio (right ventricular weight / (median weight + left ventricular weight)).

The right ventricular weight ratio of the test compound was finally administered to the day, and the results are shown in Fig. 9. The horizontal axis of the graph represents each group, and the vertical axis represents the right ventricular weight ratio (mean ± standard error, n = 5 to 6). The # mark in the figure shows statistically significant compared with the normal group (t test, p < 0.05), and the * mark indicates statistically significant comparison with the pulmonary hypertension control group (t assay, p<0.05).

The right ventricular weight ratio of the pulmonary hypertension control group was compared with the right ventricular weight ratio of the normal group, showing a statistically significant high value (t test, P < 0.05), showing a pathological state of right ventricular hypertrophy. Further, the right ventricular weight ratio of the compound of Example 1 (10 mg/kg) + tadalafil (10 mg/kg) was administered to the group of Example Compound 1 (10 mg/kg) and tadalafil (10 mg/). The kg group was compared for a low value, and compared with the right ventricular weight ratio of the pulmonary hypertension control group, a statistically significant low value was observed (t test, p<0.05) (Fig. 9) ). From this, it was found that administration of the compound of Example 1 and tadalafil showed an excellent therapeutic effect on the pathology of pulmonary hypertension.

2) The effect of administration of the self-morbid phase of the compound of the compound of the tadalafil administered to the patient of the tadalafil in the pulmonary hypertension mode (additional administration):

In the back of the rat (Wistar, male, 6 weeks old; Japan SLC Co., Ltd.), an aqueous solution of wild lily (Sigma) (60 mg/kg) was administered, and the group induced by pulmonary hypertension was regarded as "lung. Sexual hypertension induced group. On the other hand, the group that also administered the water for injection was referred to as a "normal group".

For rats in the pulmonary hypertension-inducing group, Example Compound 1 (3 mg/kg) or tadalafil (10 mg/kg) alone or Example Compound 1 (3 mg/kg) and tadalafil ( 10 mg/kg) was administered in combination (starting with the administration of tadalafil and administration of the compound of Example 1). Example Compound 1 (3 mg/kg) was administered alone from the 10th day to the 18th day or the 19th day of the administration of the wild lily lily, once orally once a day. Tadalafil (10 mg/kg) was administered alone from the wild lily liquid to the 28th or 29th day, and was administered orally once a day. Example Compound 1 (3 mg/kg) and tadalafil (10 mg/kg) were combined with the administration of Example Compound 1 (3 mg/kg) from wild lily liquid for 10 days to 18 days or 19 days. On the 1st, oral administration was carried out, and tadalafil (10mg/kg) was administered from wild lily to the day between 28th and 29th, and was administered orally once a day. Each of the groups of Example Compound 1 (3 mg/kg) or tadalafil (10 mg/kg) administered separately as "Example Compound 1 (3 mg/kg) administration group" and "Tadalafil (10 mg/) Kg) to the group." Further, the compound of Example 1 (3 mg/kg) and tadalafil (10 mg/kg) were administered in the administration group as "Example Compound 1 (3 mg/kg) + tadalafil (10 mg/kg). group". Further, Example Compound 1 and tadalafil were suspended in a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 and used. On the other hand, as a comparative control, a group in which a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was administered in a rat in the pulmonary hypertension-inducing group was referred to as a "pulmonary hypertension control group". Further, in the case of the Example Compound 1 (3 mg/kg), the 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was administered in the same manner as in the case of the start of the administration of the Example Compound 1, and in the normal group.

On the day of the final administration of the test compound, the rats were euthanized by lethal bleeding under isoflurane anesthesia, the palpitations were removed, and the wet weight of the right ventricle, left ventricle and septum were measured to determine the right ventricular weight ratio. (right ventricular weight / (median weight + left ventricular weight)).

Further, the test compound was finally administered, and the lungs were also taken out, and the lung wet weight was measured, and then immersed in the formalin solution and stored. After the lungs fixed with the formalin solution were embedded in paraffin, the pathological tissue specimens stained with elastic fibers were prepared, and the thickness of the pulmonary artery was measured, and the ratio of the medial thickness of the pulmonary artery (the thickness of the pulmonary artery × 2 / the diameter of the pulmonary artery) was obtained. 100).

The right ventricular weight ratio of the test compound was finally administered to the day, and the results are shown in Fig. 10. The horizontal axis of the graph represents each group, and the vertical axis represents the right ventricular weight ratio (mean ± standard error, n = 6 to 12). The # mark in the figure indicates statistically significant compared with the normal group (t test, p < 0.05), and the * mark indicates statistically significant comparison with the pulmonary hypertension control group (t assay, p <0.05).

The right ventricular weight ratio of the pulmonary hypertension control group was compared with the right ventricular weight ratio of the normal group, showing a statistically significant high value (t Verification, P < 0.05), showing the pathology of right ventricular hypertrophy. Further, the right ventricular weight ratio of the Example Compound 1 (3 mg/kg) + tadalafil (10 mg/kg) administration group, and the right ventricular weight ratio of the Example Compound 1 (3 mg/kg) administration group and him The ratio of right ventricle weight in the Dalafi (10 mg/kg)-administered group was low, and in comparison with the right ventricular weight ratio of the pulmonary hypertension control group, a statistically significant low value was shown ( t test, p < 0.05) (Fig. 10).

The ratio of the film thickness of the pulmonary artery to the test compound was finally administered, and the results are shown in Table 5. The values in the table indicate the ratio of the medial thickness of the pulmonary artery (%) (mean ± standard deviation, n = 6 to 12). The ## marker in the figure indicates that the comparison with the normal group is statistically significant (t assay, p<0.01), and the ** marker indicates that the comparison with the pulmonary hypertension control group is statistically significant (steel assay, p<0.01).

The pulmonary artery median thickness ratio of the pulmonary hypertension control group showed a statistically significant high value (t-test, p<0.01) compared with the pulmonary artery in the normal group, and the pathological manifestation of pulmonary hypertrophy was observed. . Further, the ratio of the pulmonary mesenteric thickness ratio of the compound of Example 1 (3 mg/kg) + tadalafil (10 mg/kg) was compared with that of the compound of Example 1 (3 mg/kg). And tadalafil (10mg/kg) administered to the group The median thickness of the pulse was compared, showing a low value. Furthermore, compared with the pulmonary artery thickness ratio of the pulmonary hypertension control group, the statistically significant low value (steel test, p<0.01) was shown (Table 5). ).

According to this, it is known that by administering Tadalafil first, and the compound of Example 1 is administered in combination with tadalafil for the pathological phase of pulmonary hypertension, excellent treatment for the pathological condition of pulmonary hypertension is obtained. effect.

3) The effect of administration of the self-morbid phase of the compound of the compound of the amphetamine administered with amphetamine in the pulmonary hypertension mode (additional administration):

In the back of the rat (Wistar, male, 6 weeks old; Japan SLC Co., Ltd.), an aqueous solution of wild lily (Sigma) (60 mg/kg) was administered, and the group induced by pulmonary hypertension was regarded as "lung. Sexual hypertension induced group. On the other hand, the group that also administered the water for injection was referred to as a "normal group".

For rats in the pulmonary hypertension-inducing group, Example Compound 1 (3 mg/kg) or ambrisentan (35 mg/kg) alone, or Example Compound 1 (3 mg/kg) and ambrisentan (35 mg/) Kg) was administered in combination (Abeshengtan was started first, and Example Compound 1 was additionally administered). Example Compound 1 (3 mg/kg) was administered alone for 10 days to 18 days or 19 days after the administration of monocrotaline, and oral administration was performed once a day. Abeshengtan (35mg/kg) was administered alone from wild lily to the day of 28th or 29th, and was administered orally once a day. Example Compound 1 (3 mg/kg) and absentan (35 mg/kg) were combined with the administration system. Example compound 1 (3 mg/kg) was administered from wild lily liquid for 10 days to 18 days or 19 days. On the 1st, oral administration of A. sinensis In the next 28 days or 29 days, one or two oral injections will be made on the 1st. Each of the groups of Example Compound 1 (3 mg/kg) or ambrisentan (35 mg/kg) administered separately as "Example Compound 1 (3 mg/kg) administration group" and "Ambendan (35 mg/kg) To the group." Further, the compound of Example 1 (3 mg/kg) and ambrisentan (35 mg/kg) were administered in the administration group as "Example Compound 1 (3 mg/kg) + ambrisentan (35 mg/kg)." . Further, Example Compound 1 and amphetamine were suspended in a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 and used. On the other hand, as a comparative control, a group containing a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to a rat in the pulmonary hypertension-inducing group as a "pulmonary hypertension control group". Further, in the case of the Example Compound 1 (3 mg/kg), the 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was administered in the same manner as in the case of the start of the administration of the Example Compound 1, and in the normal group. .

On the day of the final administration of the test compound, the rats were euthanized by lethal bleeding under isoflurane anesthesia, the palpitations were removed, and the wet weight of the right ventricle, left ventricle and septum were measured to determine the right ventricular weight ratio. (right ventricular weight / (median weight + left ventricular weight)).

The right ventricular weight ratio of the test compound was finally administered to the day, and the results are shown in Fig. 11. The horizontal axis of the graph represents each group, and the vertical axis represents the right ventricular weight ratio (mean ± standard error, n = 6 to 12). The # mark in the figure indicates that the comparison with the normal group is statistically significant (t test, p < 0.05), and the * mark and ** mark indicate that the comparison with the pulmonary hypertension control group is statistically significant (t Verification, * mark: p < 0.05, ** mark: p < 0.01).

The right ventricular weight ratio of the pulmonary hypertension control group was compared with the right ventricular weight ratio of the normal group, showing a statistically significant high value (t test, P < 0.05), indicating the pathological state of right ventricular hypertrophy. Further, the right ventricular weight ratio of the compound of Example Compound 1 (3 mg/kg) + ambrisentan (35 mg/kg) was compared with that of Example Compound 1 (3 mg/kg), and the right ventricle weight ratio and Abe The ratio of right ventricle weight in the group (35 mg/kg) was compared, showing a low value. Furthermore, compared with the right ventricular weight ratio of the pulmonary hypertension control group, a statistically significant low value was shown (t-test , p < 0.01) (Fig. 11). From this, it can be seen that the compound of the example 1 is self-medicated by the prior administration of abalone, and is administered in combination with amphetamine to obtain an excellent therapeutic effect on the pathological state of pulmonary hypertension.

4) Effect of co-administered (additional administration) of the compound phase 31 of the compound of the tadalafil administered to the patient of the patient in the pulmonary hypertension mode:

In the back of the rat (Wistar, male, 6 weeks old; Japan SLC Co., Ltd.), an aqueous solution of wild lily (Sigma) (60 mg/kg) was administered, and the group induced by pulmonary hypertension was regarded as "lung. Sexual hypertension induced group. On the other hand, the group that also administered the water for injection was referred to as a "normal group".

In rats in the pulmonary hypertension-inducing group, tadalafil (10 mg/kg) alone or the compound of Example 31 (10 mg/kg) was combined with tadalafil (10 mg/kg) (Tendala) The administration of the compound of Example 31 was carried out without prior administration. Tadalafil (10 mg/kg) was administered alone from the wild lily liquid to the 28th or 29th day, and was administered orally once a day. Example Compound 31 (10 mg/kg) and tadalafil (10 mg/kg) combined with the administration of the compound of Example 31 (10 mg/kg) from the wild lily liquid for 10 days to 18 days or 19 days, once a day orally, the Tada Non-(10mg/kg) is administered orally from wild lily to the day of the 28th or 29th, once a day. The group administered with tadalafil (10 mg/kg) alone was referred to as the "Tadalafil (10 mg/kg) administration group". Further, the compound of Example 31 (10 mg/kg) and tadalafil (10 mg/kg) were administered in the administration group as "Example Compound 31 (10 mg/kg) + tadalafil (10 mg/kg). group". Further, each of Example Compound 31 and Tadalafil was suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80 and used. On the other hand, as a comparative control, a group in which a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was administered in a rat in the pulmonary hypertension-inducing group was referred to as a "pulmonary hypertension control group". Further, a 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was also administered in the same manner in the normal group.

On the day after the final administration of the test compound, the rats were euthanized by lethal bleeding under isoflurane anesthesia, the heart palpitations were removed, and the wet weight of the right ventricle, left ventricle and septum was measured to obtain the right ventricular weight. Ratio (right ventricular weight / (median weight + left ventricular weight)).

The right ventricular weight ratio of the test compound was finally administered to the day, and the results are shown in Fig. 12. The horizontal axis of the graph represents each group, and the vertical axis represents the right ventricular weight ratio (mean ± standard error, n = 9 to 18). The # mark in the figure indicates that the comparison with the normal group is statistically significant (t test, p < 0.05), and the * mark indicates that the comparison with the pulmonary hypertension control group is statistically significant (t assay, p <0.05).

The right ventricular weight ratio of the pulmonary hypertension control group was compared with the right ventricular weight ratio of the normal group, showing a statistically significant high value (t test, P < 0.05), showing a pathological state of right ventricular hypertrophy. Further, the right ventricular weight ratio of the compound of Example 31 (10 mg/kg) + tadalafil (10 mg/kg) was compared with the right ventricular weight ratio of the tadalafil (10 mg/kg) administration group. A low value was obtained, which was compared with the right ventricular weight ratio of the pulmonary hypertension control group, showing a statistically significant low value (t assay, p < 0.05) (Fig. 12).

From this, it can be seen that the administration of the compound of Example 31 from the pathological stage of pulmonary hypertension and tadalafil was carried out in advance, and it was shown that the pathological condition of pulmonary hypertension was excellent.

From the results of 1), 2), 3) and 4) of Example 47, it is known that the hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof, and the pulmonary vasodilator phosphate II Esterase inhibitors or endothelin receptor antagonists are administered in combination to show an excellent therapeutic effect on pulmonary hypertension.

[Industry use possibility]

The present invention can be used as a therapeutic or prophylactic agent for pulmonary hypertension which contains hexahydronicotinic acid derivative (I) or a pharmacologically acceptable salt thereof, and a pulmonary vasodilator as an active ingredient.

Claims (7)

A therapeutic or prophylactic agent for pulmonary hypertension, which comprises a hexahydronicotinic acid derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof, and a pulmonary vasodilator as an active ingredient, In the formula, R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group, and an alkoxyalkyl group having 2 to 7 carbon atoms. a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the alkoxy group, the cycloalkyl group, the cycloalkyloxy group, the alkoxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogen atoms) Each independently may be substituted by 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 ring constituting a heteroaryl group having an atomic number of 5; R ² and R ³ are each independently represented a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkoxyalkyl group each having 1 to 3 hydrogen atoms independently of a halogen atom, a hydroxyl group or a cyanogen group) a group substituted), or together represent -(CH ₂ ) _l - or -(CH ₂ ) _m -O-(CH ₂ ) _n -, but not simultaneously represent a hydrogen atom; R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, a cyano group, an alkyl group or alkoxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group (the alkyl group, the alkoxy group, the cycloalkyl group and the cycloalkyl group) The oxy group is 1 to 3 hydrogen atoms each independently substituted by a halogen atom) or -C(=O NH ₂ , but not simultaneously, alkoxy; 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, and carbon Alkoxyalkyl group having 2 to 7 or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the cycloalkyl group, the alkoxyalkyl group and the cycloalkylalkyl group each having 1 to 3 hydrogen atoms) Independently substituted by 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. The therapeutic or prophylactic agent according to claim 1, wherein 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 ) _l -, but not simultaneously represent a hydrogen atom. ; 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. The therapeutic or prophylactic agent according to claim 1 or 2, wherein R ¹ represents -N(R ⁶ )C(=O)R ⁷ or -N(R ⁶ )S(=O) ₂ R ⁷ ; R ⁴ represents halogen An atom or an alkyl group having 1 to 6 carbon atoms or an alkoxy group; R ⁵ represents a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms or an alkoxy group; and R ⁶ represents a hydrogen atom. A therapeutic or prophylactic agent for pulmonary hypertension, which is used in combination with a pulmonary vasodilator, and which comprises a hexahydronicotinic acid derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof as effective ingredient, In the formula, R ¹ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkoxy group, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group, and an alkoxyalkyl group having 2 to 7 carbon atoms. a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the alkoxy group, the cycloalkyl group, the cycloalkyloxy group, the alkoxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogen atoms) Each independently may be substituted by 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 ring constituting a heteroaryl group having an atomic number of 5; R ² and R ³ are each independently represented a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkoxyalkyl group each having 1 to 3 hydrogen atoms independently of a halogen atom, a hydroxyl group or a cyanogen group) a group substituted), or together represent -(CH ₂ ) _l - or -(CH ₂ ) _m -O-(CH ₂ ) _n -, but not simultaneously represent a hydrogen atom; R ⁴ and R ⁵ each independently represent a hydrogen atom, a halogen atom, a cyano group, an alkyl group or alkoxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a cycloalkyloxy group (the alkyl group, the alkoxy group, the cycloalkyl group and the cycloalkyl group) The oxy group is 1 to 3 hydrogen atoms each independently substituted by a halogen atom) or -C(= O) NH ₂ , but not simultaneously represents an alkoxy group; R ⁶ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and R ⁷ represents an alkyl group having 1 to 6 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms; Alkoxyalkyl group having 2 to 7 carbon atoms or cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, cycloalkyl group, alkoxyalkyl group and cycloalkylalkyl group are 1 to 3 hydrogen atoms) Each of them may be independently substituted by a halogen atom, a hydroxyl group or a cyano group, and l represents an integer of 2 to 5, and m and n each independently represent 1 or 2. The therapeutic or prophylactic agent according to claim 4, wherein 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 ) _l -, but not simultaneously represent a hydrogen atom ; 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. The therapeutic or prophylactic agent according to claim 4 or 5, wherein R ¹ represents -N(R ⁶ )C(=O)R ⁷ or -N(R ⁶ )S(=O) ₂ R ⁷ ; R ⁴ represents halogen An atom or an alkyl group having 1 to 6 carbon atoms or an alkoxy group; R ⁵ represents a halogen atom, a cyano group or an alkyl group having 1 to 6 carbon atoms or an alkoxy group; and R ⁶ represents a hydrogen atom. The therapeutic or prophylactic agent according to any one of claims 1 to 6, wherein the pulmonary vasodilator is a prostacyclin derivative, a phosphodiesterase inhibitor, and/or an endothelin receptor antagonist.