WO2015046404A1 - Agent thérapeutique ou agent prophylactique pour l'hypertension pulmonaire - Google Patents

Agent thérapeutique ou agent prophylactique pour l'hypertension pulmonaire Download PDF

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WO2015046404A1
WO2015046404A1 PCT/JP2014/075570 JP2014075570W WO2015046404A1 WO 2015046404 A1 WO2015046404 A1 WO 2015046404A1 JP 2014075570 W JP2014075570 W JP 2014075570W WO 2015046404 A1 WO2015046404 A1 WO 2015046404A1
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carbon atoms
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pulmonary hypertension
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裕 西村
祐子 加藤
新之助 林
亜衣子 山崎
将史 山本
由次 浅岡
将輝 山田
尚弘 山田
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東レ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a therapeutic or preventive agent for pulmonary hypertension.
  • Pulmonary hypertension is a general term for pathological conditions in which an increase in pulmonary arterial pressure is observed, and it is known that exercise tolerance is significantly reduced, most of which is progressive and has a poor prognosis.
  • the pulmonary artery pressure is maintained lower than the systemic blood pressure, but in patients with pulmonary hypertension, the average pulmonary artery pressure is 25 mmHg or more even at rest (30 mmHg or more when exercising), and this state persists for a long time. Doing so induces right ventricular hypertrophy and right heart failure, and in the worst case, death.
  • pulmonary vasospasm One of the causes of pulmonary hypertension is considered to be pulmonary vasospasm, and pulmonary vasodilators such as prostacyclin derivatives, phosphodiesterase inhibitors and endothelin receptor antagonists are used to treat pulmonary hypertension.
  • the drugs shown are used (Patent Documents 1 to 4 and Non-patent Document 1), and when a single agent does not provide sufficient antihypertensive action, two or three pulmonary vasodilators The treatment which administers a medicine in combination is performed (Patent Documents 4 and 5 and Non-Patent Documents 2 and 3).
  • EETs epoxyeicosatrienoic acids
  • DHETs dihydroxyeicosatrienoic acids
  • sEH soluble epoxide hydrolase
  • sEH inhibitor suppresses the degradation of EETs and increases the amount of EETs, suggesting that the sEH inhibitor is useful as a therapeutic agent for pulmonary hypertension (Patent Document 6 and non-patent document) References 6 and 7).
  • Non-Patent Document 6 Although compounds having sEH inhibitory activity have been found and use as therapeutic agents for pulmonary hypertension has been suggested (Patent Document 6 and Non-Patent Document 6), spontaneously hypertensive rats even though they have sEH inhibitory activity Examples that do not show therapeutic effects against (Spontaneously Hypertensive Rat) have also been reported (Non-Patent Documents 8 to 10).
  • pulmonary vasodilators used in the treatment of pulmonary hypertension can effectively suppress pulmonary artery pressure rise and subsequent right ventricular hypertrophy, pulmonary hypertrophy, pulmonary artery thickening and myocardial hypertrophy
  • pulmonary hypertension it is urgent to create a drug or a combination drug having a strong medicinal effect that can treat pulmonary blood pressure by a mechanism different from the pulmonary vasodilatory action.
  • the present invention provides a therapeutic or preventive agent for pulmonary hypertension that treats pulmonary hypertension based on both action mechanisms of pulmonary vasodilatory action and sEH inhibitory action, and pulmonary hypertension used in combination with a pulmonary vasodilator It aims at providing the therapeutic agent or preventive agent of a disease.
  • a novel nipecotic acid derivative or a pharmacologically acceptable salt thereof exhibits a strong sEH inhibitory activity and its action.
  • the present invention was also completed by finding out that it exhibits excellent therapeutic and preventive effects on pulmonary hypertension.
  • the present invention provides a therapeutic agent for pulmonary hypertension comprising a nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof and a pulmonary vasodilator as an active ingredient:
  • Prophylactic agents are provided.
  • R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms.
  • a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms, Each independently may be substituted with a halogen atom, a hydroxyl group, a cyano group, —SR 6 , —S ( ⁇ O) —R 6 or —S ( ⁇ O) 2 R 6 ), —N (R 6 ) C ( ⁇ O) R 7 , —N (R 6 ) S ( ⁇ O) 2 R 7 , —C ( ⁇ O) N (R 6 ) R 7 or a heteroaryl group having 5 ring atoms, R 2 and R 3 are Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent — (CH 2 ) 1 —.
  • R 4 represents a substituent at the 2-position on the benzene ring
  • R 5 represents a substituent at the 4-position on the benzene ring.
  • the nipecotic acid derivative or a pharmacologically acceptable salt thereof can be expected to exhibit stronger sEH inhibitory activity, the therapeutic or preventive agent for pulmonary hypertension is more effective against pulmonary hypertension. Excellent therapeutic and preventive effects can be exhibited.
  • R 1 represents —N (R 6 ) C ( ⁇ O) R 7 or —N (R 6 ) S ( ⁇ O) 2 R 7
  • R 4 represents a halogen atom or carbon More preferably an alkyl group or alkyloxy group having 1 to 6 carbon atoms
  • R 5 represents a halogen atom, a cyano group or an alkyl group or alkyloxy group having 1 to 6 carbon atoms
  • R 6 represents a hydrogen atom.
  • R 1 represents —N (H) C ( ⁇ O) CH 2 CH 3
  • R 2 and R 3 together represent — (CH 2 ) 3 —
  • R 4 represents —OCF 3 and R 5 particularly preferably represents a cyano group.
  • the nipecotic acid derivative or a pharmacologically acceptable salt thereof can be expected to exhibit a stronger sEH inhibitory activity, and in addition, its pharmacokinetics are also excellent, so a therapeutic agent for pulmonary hypertension Or a preventive agent can exhibit the further superior therapeutic effect and preventive effect with respect to pulmonary hypertension.
  • the pulmonary vasodilator is preferably a prostacyclin derivative, a phosphodiesterase inhibitor and / or an endothelin receptor antagonist, and more preferably a phosphodiesterase inhibitor and / or an endothelin receptor antagonist.
  • the phosphodiesterase inhibitor is preferably sildenafil or a pharmacologically acceptable salt thereof, or tadalafil, more preferably tadalafil, and the endothelin receptor antagonist is ambrisentan or a pharmacologically acceptable salt thereof. Or bosentan or a hydrate thereof, and ambrisentan or a pharmacologically acceptable salt thereof is more preferable.
  • the present invention also provides a therapeutic or prophylactic agent for pulmonary hypertension, comprising as an active ingredient the above-mentioned nipecotic acid derivative or a pharmacologically acceptable salt thereof used in combination with a pulmonary vasodilator. .
  • the therapeutic or preventive agent for pulmonary hypertension of the present invention can treat or prevent pulmonary hypertension based on the pulmonary vasodilatory action and sEH inhibitory action.
  • the therapeutic or preventive agent for pulmonary hypertension of the present invention can treat or prevent pulmonary hypertension by enhancing the pharmacological action of the pulmonary vasodilator.
  • the therapeutic or prophylactic agent for pulmonary hypertension of the present invention contains a nipecotic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof, and a pulmonary vasodilator as active ingredients. It is characterized by doing.
  • R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms.
  • a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms, Each independently may be substituted with a halogen atom, a hydroxyl group, a cyano group, —SR 6 , —S ( ⁇ O) —R 6 or —S ( ⁇ O) 2 R 6 ), —N (R 6 ) C ( ⁇ O) R 7 , —N (R 6 ) S ( ⁇ O) 2 R 7 , —C ( ⁇ O) N (R 6 ) R 7 or a heteroaryl group having 5 ring atoms, R 2 and R 3 are Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group
  • C1-C6 alkyl group means a straight-chain saturated hydrocarbon group having 1 to 6 carbon atoms or a branched saturated hydrocarbon group having 3 to 6 carbon atoms, such as a methyl group, Ethyl group, 1-propyl group, 2-propyl group, 1-butyl group, 2-butyl group, 2-methyl-2-propyl group (tert-butyl group), 2-methyl-1-propyl group, 2,2 -Dimethyl-1-propyl group, 1-pentyl group, 2-pentyl group or 3-pentyl group.
  • C 1-6 alkyloxy group means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, -Propyloxy group, 1-butyloxy group or 2-butyloxy group.
  • C3-C6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • C3-C6 cycloalkyloxy group means a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.
  • C2-C7 alkyloxyalkyl group means a group having 2 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with an alkyloxy group.
  • cycloalkyl alkyl group having 4 to 7 carbon atoms means a group having 4 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with a cycloalkyl group. Examples thereof include a methyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • heteroaryl group having 5 ring atoms means that the number of ring atoms is 5 including 1 to 4 identical or different atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. And includes, for example, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, oxazolyl group, isoxazolyl group, furanyl group and thiazolyl group.
  • R 1 may be —N (R 6 ) C ( ⁇ O) R 7 or —N (R 6 ) S ( ⁇ O) 2 R 7
  • R 1 is acetylamidyl, propionamidyl group or methanesulfonylamidyl group.
  • R 2 and R 3 are each independently a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or are preferably taken together as — (CH 2 ) 1 —.
  • R 4 is preferably a substituent at the 2-position on the benzene ring.
  • R 4 is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, more preferably a halogen atom or an alkyloxy group, and further preferably an alkyloxy group.
  • R 5 is preferably a substituent at the 4-position on the benzene ring.
  • R 5 is preferably a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, or an alkyloxy group having 1 to 6 carbon atoms, and more preferably a halogen atom or a cyano group.
  • R 6 is preferably a hydrogen atom
  • R 7 is preferably a methyl group or an ethyl group.
  • L is preferably 2 or 3
  • m is preferably 2
  • n is preferably 2.
  • nipecotic acid derivative (I) has at least one asymmetric carbon atom and has optical isomers and diastereomers.
  • the nipecotic acid derivative (I) includes not only a single isomer but also a racemate and a mixture of diastereomers.
  • all rotamers are included.
  • Examples of the pharmacologically acceptable salt of the nipecotic acid derivative (I) include, for example, hydrochloride, trifluoroacetate, sulfate, nitrate, hydrobromide, hydroiodide or methane as an acid addition salt.
  • Examples of the sulfonate include hydrochloride, sulfate, hydrobromide, hydroiodide, and methanesulfonate.
  • the therapeutic or preventive agent for pulmonary hypertension contains the nipecotic acid derivative (I) used in combination with a pulmonary vasodilator or a pharmacologically acceptable salt thereof as an active ingredient. It is a feature.
  • the starting materials and reagents used for the production of the nipecotic acid derivative (I) may be commercially available products or may be synthesized by known methods.
  • the nipecotic acid derivative (Ia) can be produced, for example, by a condensation reaction of an amine derivative (II) and a carboxylic acid derivative (III) in the presence of a base and a condensing agent as shown in the following scheme 1.
  • Scheme 1 [Wherein R 1 ′ represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group or cycloalkyloxy group having 3 to 6 carbon atoms, or an alkyloxy group having 2 to 7 carbon atoms.
  • alkyl group, a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, alkyloxy group, cycloalkyl group, cycloalkyloxy group, alkyloxyalkyl group and cycloalkylalkyl group have 1 to 3 hydrogen atoms)
  • R 2 to R 6 are the same as defined above. ]
  • condensing agent used in the condensation reaction examples include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 1- [ Bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate HATU), and HATU is preferred.
  • the equivalent of the condensing agent is preferably 1 to 10 equivalents, and more preferably 1 to 3 equivalents.
  • Examples of the solvent used in the condensation reaction include N, N-dimethylformamide (hereinafter referred to as DMF), tetrahydrofuran (hereinafter referred to as THF), dichloromethane, chloroform, diethyl ether or dimethyl ether, with DMF or THF being preferred, and DMF being More preferred.
  • DMF N, N-dimethylformamide
  • THF tetrahydrofuran
  • dichloromethane dichloromethane
  • chloroform chloroform
  • diethyl ether or dimethyl ether dimethyl ether
  • Examples of the base used in the condensation reaction include organic bases such as diisopropylethylamine (hereinafter DIPEA), triethylamine (hereinafter TEA), pyridine or N-methylmorpholine, or organic acid salts such as potassium carbonate, sodium carbonate or sodium bicarbonate. DIPEA or TEA is preferable.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (II).
  • the equivalent amount of the carboxylic acid derivative (III) used in the condensation reaction is preferably 0.1 to 100 equivalents, more preferably 0.1 to 10 equivalents, and even more preferably 0.8 to 2 equivalents with respect to the amine derivative (II). .
  • the reaction temperature of the condensation reaction is preferably ⁇ 50 to 100 ° C., more preferably 0 to 50 ° C., and further preferably 0 to 30 ° C.
  • the reaction time for the condensation reaction is preferably 1 minute to 48 hours, more preferably 1 minute to 24 hours, and even more preferably 10 minutes to 24 hours.
  • the concentration of the amine derivative (II) at the start of the condensation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and even more preferably 0.1 to 10M.
  • nipecotic acid derivative (Ib) in which R 1 is —N (H) C ( ⁇ O) R 7 is represented by, for example, an amine derivative (IV) in the presence of a base as shown in Scheme 2 below.
  • an acid chloride derivative (V), or a condensation reaction between an amine derivative (IV) and a carboxylic acid derivative (VI) in the presence of a base and a condensing agent. Scheme 2 [Wherein R 2 to R 5 and R 7 are the same as defined above]. ]
  • Examples of the solvent used for the condensation reaction with the acid chloride derivative (V) include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether or 1,2-dimethoxyethane. 1,2-dichloroethane, acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the acid chloride (V) used in the condensation reaction with the acid chloride derivative (V) is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the amine derivative (IV). 5 equivalents are more preferred.
  • Examples of the base used for the condensation reaction with the acid chloride derivative (V) include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (IV).
  • the reaction temperature of the condensation reaction with the acid chloride derivative (V) is preferably ⁇ 50 to 100 ° C., more preferably ⁇ 20 to 60 ° C., and further preferably 0 to 40 ° C.
  • the reaction time for the condensation reaction with acid chloride (V) is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 8 hours.
  • the concentration at the start of the reaction of the amine derivative (IV) in the condensation reaction with the acid chloride derivative (V) is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.
  • nipecotic acid derivative (Ic) in which R 1 is —N (H) S ( ⁇ O) 2 R 7 can be synthesized, for example, with an amine derivative (IV) in the presence of a base as shown in Scheme 3 below. It can be produced by a sulfonamidation reaction with a sulfonic acid chloride derivative (VII). (Scheme 3) [Wherein R 2 to R 5 and R 7 are the same as defined above]. ]
  • Examples of the solvent used in the sulfonamidation reaction include dichloromethane, 1,2-dichloroethane, acetonitrile, DMF, THF, dioxane, diethyl ether, or 1,2-dimethoxyethane, but dichloromethane, 1,2-dichloroethane, Acetonitrile or THF is preferred, and dichloromethane or 1,2-dichloroethane is more preferred.
  • the equivalent amount of the sulfonic acid chloride derivative (VII) used in the sulfonamidation reaction is preferably 0.1 to 10 equivalents, more preferably 1 to 3 equivalents, and further preferably 1 to 1.5 equivalents with respect to the amine derivative (IV). preferable.
  • Examples of the base used in the sulfonamidation reaction include organic bases such as DIPEA, TEA, pyridine and N-methylmorpholine, with DIPEA or TEA being preferred.
  • the equivalent of the base is preferably 1 to 100 equivalents and more preferably 1 to 10 equivalents with respect to the amine derivative (IV).
  • the reaction temperature of the sulfonamidation reaction is preferably ⁇ 50 to 50 ° C., more preferably ⁇ 30 to 30 ° C., and further preferably ⁇ 20 to 20 ° C.
  • the reaction time of the sulfonamidation reaction is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and further preferably 30 minutes to 8 hours.
  • the concentration of the amine derivative (IV) at the start of the reaction in the sulfonamidation reaction is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 10M.
  • the amine derivative (IV) which is the starting material in the above-mentioned schemes 2 and 3, is, for example, after the condensation reaction between the amine derivative (II) and the carboxylic acid derivative (VIII) in the presence of a base, as shown in the following scheme 4.
  • the deprotection reaction following the condensation reaction can be performed by a known method described in, for example, Protective Groups in Organic Synthesis 3rd Edition (Green et al., 1999, John Wiley & Sons, Inc.).
  • the protecting group is a tert-butoxycarbonyl group
  • the protecting group can be removed by treatment with a strong acid such as trifluoroacetic acid.
  • the amine derivative (II) which is the starting material in the above-mentioned schemes 1 and 4 is, for example, as shown in the following scheme 5, in the presence of a base and a condensing agent, benzylamine derivative (IX), nipecotic acid derivative (X) and After the condensation reaction, a deprotection reaction for removing the protecting group can be used.
  • Scheme 5 [Wherein R 4 , R 5 and R 8 are the same as defined above. ]
  • the deprotection reaction can be carried out under the same conditions as in the method described in Scheme 4.
  • the condensation reaction of Scheme 5 can also be performed in the presence of a base by converting the nipecotic acid derivative (X) into an acid chloride.
  • Examples of the reagent for converting the nipecotic acid derivative (X) into acid chloride include oxalyl chloride and thionyl chloride, with oxalyl chloride being preferred.
  • the equivalent amount of the reagent is preferably 1 to 10 equivalents, more preferably 1 to 1.5 equivalents, relative to the nipecotic acid derivative (X).
  • Examples of the solvent used for converting the nipecotic acid derivative (X) into the acid chloride include dichloromethane, chloroform, THF, 1,2-dichloroethane, acetonitrile, 1,4-dioxane, and DMF, and dichloromethane, THF, or DMF.
  • a mixed solvent thereof is preferable, and a mixed solvent of dichloromethane and DMF or a mixed solvent of THF and DMF is more preferable.
  • the reaction temperature for converting the nipecotic acid derivative (X) to acid chloride is preferably -50 to 100 ° C, more preferably -30 to 30 ° C, and further preferably -20 to 0 ° C.
  • the reaction time for converting the nipecotic acid derivative (X) to acid chloride is preferably 30 minutes to 24 hours, more preferably 30 minutes to 12 hours, and even more preferably 30 minutes to 2 hours.
  • the concentration of the nipecotic acid derivative (X) at the start of the reaction when converting the nipecotic acid derivative (X) to acid chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and more preferably 0.1 to 3M. Is more preferable.
  • nipecotic acid derivative (I) obtained as described above, a pharmacologically acceptable salt thereof, or an intermediate, a raw material compound or a reagent used for the production of the nipecotic acid derivative (I) is necessary. Depending on the method, it may be isolated and purified by a method such as extraction, distillation, chromatography or recrystallization.
  • a pulmonary vasodilator is a drug whose main mechanism of action is to lower pulmonary artery pressure by dilating the pulmonary artery.
  • prostacyclin derivatives include epoprostenol sodium ((Z)-(3aR, 4R, 5R, 6aS) -3,3a, 4,5,6,6a-hexahydro-5-hydroxy-4-[(E )-(3S) -3-hydroxy-1-octenyl] -2H-cyclopenta [b] furan- ⁇ 2, ⁇ sodium valerate), beraprost sodium ((1RS, 2RS, 3aSR, 8bSR) -2,3,3a, 8b-Tetrahydro-2-hydroxy-1-[(1E, 3SR, 4RS) -3-hydroxy-4-methyloct-1-en-6-in-1-yl] -1H-cyclopenta [b] benzofuran-5 Sodium butanoate), iloprost ((E)-(3aS, 4R, 5R, 6aR) -hexahydro-5-hydroxy-4-[(E)-(3 S, 4RS) -3-Hyl
  • Examples of the phosphodiesterase inhibitor include sildenafil (1-[[3- (6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d] pyrimidin-5-yl).
  • tadalafil ((6R, 12aR) -6- (1,3-benzodioxol-5- Yl) -2-methyl-2,3,6,7,12,12a-hexahydropyrazino [1 ′, 2 ′: 1,6] pyrido [3,4-b] indole-1,4-dione)
  • sildenafil or a pharmacologically acceptable salt thereof or tadalafil is preferable, and tadalafil is more preferable.
  • Examples of the endothelin receptor antagonist include ambrisentan ((2S) -2 [(4,6-dimethylpyrimidin-2-yl) oxy] -3-methoxy-3,3-diphenylpropanoic acid) or its pharmacology Or bosentan (4- (1,1-dimethylethyl) -N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) ) Pyrimidin-4-yl] benzenesulfonamide) or a hydrate thereof, but ambrisentan or a pharmacologically acceptable salt thereof, bosentan or a hydrate thereof is preferable, and ambrisentan or a drug thereof Physiologically acceptable salts are more preferred.
  • ambrisentan ((2S) -2 [(4,6-dimethylpyrimidin-2-yl) oxy] -3-methoxy-3,3-diphenylpropanoic acid) or
  • the pharmacologically acceptable salt of sildenafil or ambrisentan is, for example, an inorganic acid salt such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide or hydroiodide, or Acid salt, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbine Acid salt, organic acid salt such as methanesulfonate, p-toluenesulfonate or cinnamate, or inorganic base salt such as sodium salt, potassium salt, calcium salt, magnesium salt or ammonium salt, or methyl Amine salt, diethylamine salt, trimethylamine salt, triethylamine salt, pyridinium salt, triethanolamine salt, ethylenediamine salt or Organic base salts such as guanidine salts.
  • the pharmacologically acceptable salt of sildenafil is
  • the prostacyclin derivative can be obtained as a commercial product, and can also be synthesized, for example, according to a method described in known literature (Japanese Patent Publication No. 1-53672).
  • the phosphodiesterase inhibitor can be obtained as a commercial product, and can also be synthesized, for example, according to a method described in known literature (International Publication No. 95/19978).
  • the endothelin receptor antagonist is not only commercially available, but also can be synthesized according to the method described in known literature (International Publication No. 96/11914), for example.
  • nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof which is an active ingredient of the therapeutic or preventive agent for pulmonary hypertension described above, exhibits a strong sEH inhibitory activity. Demonstrates excellent therapeutic and prophylactic effects for the disease.
  • SEH is an abbreviation for soluble epoxide hydrolase, which is a metabolic enzyme that catalyzes the hydrolysis of epoxide and converts it to the corresponding diol.
  • the most known substrate of sEH is EETs, which is one of endothelial cell-derived hyperpolarizing factors, and sEH has an action of metabolizing EETs to DHETs and inactivating them.
  • EETs is an abbreviation for Epoxyeicosatrienoic acids
  • DHETs is an abbreviation for Dihydroxyeicosatrienoic acids. Examples of the EETs include 14,15-epoxyeicosatrienoic acid (hereinafter, 14,15-EET). Examples of DHETs include 14,15-dihydroxyeicosatrienoic acid (14,15-DHET).
  • SEH inhibitory activity means an activity that inhibits the action of sEH. Therefore, the sEH inhibitory activity includes the activity of inhibiting the enzymatic reaction of sEH to catalyze the hydrolysis of EETs, which is one of sEH substrates.
  • SEH inhibitor means a compound showing sEH inhibitory activity or a composition containing the compound as an active ingredient.
  • the sEH inhibitory activity is, for example, that human sEH and its substrate EETs are reacted in the presence of an sEH inhibitor, and the amount of DHETs produced is compared with the amount of DHETs produced in the absence of the sEH inhibitor. Can be measured.
  • a commercially available measurement kit Soluable Epoxide Hydrose Inhibitor Screening Assay Kit; Cayman
  • the sEH inhibitory activity of the inhibitor can be measured.
  • racemic 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate was used as a substrate for sEH, and 4-nitrophenolate anion was used.
  • the appearance of 6-methoxy-2-naphthaldehyde is measured using cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate as a substrate for sEH.
  • the sEH inhibitory activity of the sEH inhibitor can also be measured by measuring the appearance.
  • EETs concentration, the DHETs concentration, or 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” is a condition in which an increase in pulmonary arterial pressure in which blood is sent from the heart to the lung is observed, the mean pulmonary artery pressure in a resting position is 25 mmHg or more, or pulmonary disease, sleep apnea syndrome and In alveolar hypoventilation syndrome, mean pulmonary artery pressure is 20 mmHg or more at rest (30 mmHg or more when exercising) (digest version, pulmonary hypertension treatment guideline (2006 revision), P2-P3.). In pulmonary hypertension, increased right ventricular systolic pressure, right ventricular hypertrophy, pulmonary hypertrophy, pulmonary artery thickening, cell proliferation or myocardial hypertrophy in the lung are observed.
  • the therapeutic effect on pulmonary hypertension of the pulmonary hypertension therapeutic agent or preventive agent can be evaluated using an animal model in which pulmonary hypertension is artificially induced.
  • An example of such an animal model is a monocrotaline-administered pulmonary hypertension model using rats (Journal of Pharmacological Sciences, 2009, Vol. 111, p. 235-243).
  • the progression of the disease state can be confirmed by measuring the right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)).
  • the right ventricular hypertrophy and pulmonary hypertrophy associated with pulmonary hypertension can be confirmed by measuring the right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)).
  • sEH in the pulmonary hypertension lesion site can be confirmed by immunohistochemical staining of lung tissue using an anti-sEH antibody.
  • Pulmonary arterial thickening due to pulmonary hypertension can be confirmed by staining the lung tissue with Elastica-Wangieson and observing the stained image or measuring the pulmonary artery median thickness ratio ((pulmonary artery median thickness ⁇ 2 / pulmonary artery diameter) ⁇ 100).
  • Cell proliferation in lungs with pulmonary hypertension can be confirmed by immunostaining lung tissue with an antiproliferative cell nuclear antigen (hereinafter, PCNA) antibody.
  • PCNA antiproliferative cell nuclear antigen
  • Myocardial hypertrophy of pulmonary hypertension can be confirmed by staining the right ventricle with HE.
  • the systemic blood pressure in pulmonary hypertension can be confirmed by the method described in the examples. By confirming these, pulmonary arterial hypertension, pulmonary vein occlusive disease, pulmonary capillary hemangiomatosis, pulmonary hypertension due to left heart disease, pulmonary hypertension due to pulmonary disease and hypoxia, chronic thromboembolism pulmonary hypertension Moreover, the therapeutic effect with respect to the pulmonary hypertension by the complex factor of unknown cause can be evaluated.
  • the above therapeutic or preventive agent for pulmonary hypertension exhibits an excellent therapeutic or preventive effect on pulmonary hypertension when administered to humans.
  • mammals other than humans it exhibits an excellent therapeutic or preventive effect on pulmonary hypertension.
  • mammals other than humans include mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, and monkeys.
  • Examples of the administration form of the therapeutic or preventive agent for pulmonary hypertension include nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof, and pulmonary vasodilators (for example, prostacyclin derivatives, phosphodiesterase inhibitors and (Or endothelin receptor antagonist) can be administered orally or parenterally as a mixture of both, ie, a combination of the same or a pharmaceutically acceptable carrier.
  • both may be prepared alone, that is, as a single agent, not as a compounding agent, and these may be administered as they are or in combination with a pharmaceutically acceptable carrier.
  • dosage forms for oral administration as a single agent or combination agent include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), Syrups, emulsions or suspensions are exemplified, and dosage forms for parenteral administration include, for example, injections, infusions, drops, and suppositories.
  • a suitable base for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester
  • a suitable base for example, a polymer of butyric acid, a polymer of glycolic acid, a copolymer of butyric acid-glycolic acid, a mixture of a polymer of butyric acid and a polymer of glycolic acid, or a polyglycerol fatty acid ester
  • Preparation of a single agent or a compounding agent in the above dosage form can be performed according to a known production method generally used in the pharmaceutical field. In this case, if necessary, it is produced by containing excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers and the like generally used in the pharmaceutical field. be able to.
  • Preparation as a single agent or combination tablet can be carried out by adding excipients, binders, disintegrants or lubricants, etc., and preparations as pills and granules are as excipients, binders It can be carried out by containing an agent or a disintegrant.
  • preparations as powders and capsules include excipients
  • preparations as syrups include sweeteners
  • preparations as emulsions and suspensions include surfactants, suspending agents or emulsifiers, respectively. It can be made to contain.
  • excipient examples include lactose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate or calcium sulfate.
  • binder examples include starch paste, gum arabic solution, gelatin solution, tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, and glycerin.
  • disintegrant examples include starch and calcium carbonate.
  • Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • sweetener examples include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, and simple syrup.
  • surfactant examples include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agent examples include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, and bentonite.
  • emulsifier examples include gum arabic, tragacanth, gelatin, and polysorbate 80.
  • a coloring agent, a preservative, a fragrance, a corrigent, a stabilizer, a thickener and the like that are generally used in the pharmaceutical field can be added.
  • the dose ratio or compounding ratio of the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof and a pulmonary vasodilator is: It can be appropriately selected depending on the administration subject, administration route, target disease, symptom or combination of the combination.
  • the daily dose of a preparation containing a prostacyclin derivative varies depending on the condition and body weight of the patient, the type of prostacyclin derivative, the route of administration, etc.
  • a preparation containing a prostacyclin derivative varies depending on the condition and body weight of the patient, the type of prostacyclin derivative, the route of administration, etc.
  • the daily dose of a preparation containing a phosphodiesterase inhibitor varies depending on the patient's condition and body weight, the type of phosphodiesterase inhibitor, the route of administration, etc.
  • a preparation containing a phosphodiesterase inhibitor varies depending on the patient's condition and body weight, the type of phosphodiesterase inhibitor, the route of administration, etc.
  • body weight of about 60 kg.
  • a pharmacologically acceptable salt thereof is administered orally, it should be an adult (body weight of about 60 kg). It is preferable to administer 1 to 3 times in the range of 5 to 90 mg.
  • the daily dose of the preparation containing an endothelin receptor antagonist is, for example, in the case of an oral administration of ambrisentan divided into 1 to 3 times in the range of 1 to 20 mg for an adult (body weight of about 60 kg).
  • an oral administration of ambrisentan or a hydrate thereof it is preferable to administer in 1 to 3 divided doses in the range of 10 to 400 mg for an adult (body weight of about 60 kg).
  • the daily dosage of the preparation containing the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof is, for example, 1 to 1000 mg for an adult (body weight of about 60 kg) when orally administered. It is preferable to administer in 1 to 3 divided doses in the range. In the case of parenteral administration, it is desirable to administer by intravenous injection in the range of 0.01 to 100 mg / kg body weight for injections.
  • Step 2 Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanol: Sodium borohydride (2.4 g, 63 mmol) was added to a methanol (0.23 L) solution of Reference Example Compound 1 (16 g, 59 mmol) at ⁇ 10 ° C. After stirring at ⁇ 10 ° C. for 10 minutes, acetone (10 mL) and 1N hydrochloric acid (10 mL) were added to the reaction solution. The reaction solution was concentrated under reduced pressure, water was added to the obtained crude product, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Step 3 Synthesis of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate: Methanesulfonyl chloride (0.93 g, 8.1 mmol) was added to a solution of Reference Example Compound 2 (2.0 g, 7.4 mmol) and TEA (1.2 mL, 8.9 mmol) in dichloromethane (20 mL) under ice cooling. It was. After stirring at room temperature for 3 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 2.6 g of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate (hereinafter referred to as Reference Example Compound 3) ( (Quantitative).
  • Step 5 Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanamine: Hydrazine monohydrate (0.98 g, 19 mmol) was added to a methanol (40 mL) solution of Reference Example compound 4 (2.6 g, 6.5 mmol) at room temperature. After stirring at 60 ° C. for 2 hours, the solid precipitated at room temperature was filtered off. The filtrate was concentrated under reduced pressure, and the resulting crude product was dissolved in ethyl acetate and washed with water and a saturated aqueous sodium chloride solution.
  • Step 7 Synthesis of (R) -tert-butyl 3-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) piperidine-1-carboxylate: At room temperature, a solution of Reference Compound 6 (0.050 g, 0.10 mmol) and zinc cyanide (0.012 g, 0.10 mmol) in DMF (2.0 mL) was added to tetrakistriphenylphosphine palladium (0) (0. 030 g, 0.026 mmol) was added. After stirring at 150 ° C. for 30 minutes, water was added to the reaction solution at room temperature, and the mixture was extracted with diethyl ether.
  • Step 8 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: Under ice-cooling, trifluoroacetic acid (hereinafter TFA) (35 mL, 0.45 mol) was added to a solution of Reference Example Compound 7 (6.9 g, 16 mmol) in dichloromethane (0.16 L). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane.
  • TFA trifluoroacetic acid
  • Example Compound 1 (1-propionamidocyclobutanecarbonyl) piperidine-3-carboxamide was obtained in an amount of 6.2 g (71%).
  • Example Compound 2 (2-Methyl-2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 2) was obtained in an amount of 2.4 g (87%).
  • Example Compound 3 (1- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 3) was obtained in an amount of 0.56 g (74%).
  • Example 4 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) piperidine-3-carboxamide: The same reaction as in Example 1 [Step 9] was carried out using 1- (trifluoromethyl) cyclopropanecarboxylic acid (0.054 g, 0.17 mmol) to give (R) -N- (4-cyano- 0.044 g (58%) of 2- (trifluoromethoxy) benzyl) -1- (1- (trifluoromethyl) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 4) was obtained.
  • Example 5 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (methylsulfonamido) cyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 10 (0.020 g, 0.047 mmol). 0.017 g (71%) of benzyl) -1- (1- (methylsulfonamido) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 5) was obtained.
  • Example 6 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutylamidocyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using isobutyryl chloride (0.0055 g, 0.052 mmol). 0.022 g (95%) of (benzyl) -1- (1-isobutyramidecyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 6) was obtained.
  • Example 7 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using pivaloyl chloride (0.0063 g, 0.052 mmol). 0.017 g (72%) of (benzyl) -1- (1-pivalamidocyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 7) was obtained.
  • Example 9 Synthesis of (R) -1- (1-acetamidocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1- (1-acetamidocyclobutanecarbonyl) -N- (4) was prepared by performing the same reaction as in Example 8 [Step 3] using Reference compound 10 (0.020 g, 0.047 mmol). 0.013 g (60%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 9) was obtained.
  • Step 2 Synthesis of (R) -1-((R) -2-acetamido-3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1-((R) -2-acetamido-3-methyl) was prepared by performing the same reaction as in Example 8 [Step 3] using Reference compound 23 (0.020 g, 0.047 mmol). 0.018 g (83%) of butanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 11) was obtained.
  • Example 12 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by conducting the same reaction as in Example 2 [Step 3] using Reference Example Compound 23 (0.020 g, 0.047 mmol). 0.020 g (83%) of benzyl) -1-((R) -3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 12) was obtained.
  • Example Compound 13 was obtained in an amount of 0.0080 g (13%).
  • Example Compound 14 was obtained in an amount of 0.013 g (63%).
  • Example 15 Synthesis of (R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1- (2-methyl-2- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-carbamoyl-2- (trifluoromethoxy) benzyl) -1 was prepared by carrying out the same reaction as in Example 14 using Example Compound 3 (0.025 g, 0.051 mmol). As a result, 0.020 g (77%) of — (2-methyl-2- (methylsulfonamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 15) was obtained.
  • Example 16 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (2-hydroxy-2-methylpropanoyl) piperidine-3-carboxamide: The same reaction as in Example 1 [Step 9] was performed using 2-hydroxy-2-methylpropanoic acid (0.15 g, 0.46 mmol) to give (R) -N- (4-cyano-2- 0.12 g (62%) of (trifluoromethoxy) benzyl) -1- (2-hydroxy-2-methylpropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 16) was obtained.
  • Example 17 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-pivaloylpiperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 8 (0.15 g, 0.46 mmol) and pivaloyl chloride (0.066 g, 0.55 mmol), (R) — 0.19 g (quantitative) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-pivaloylpiperidine-3-carboxamide (hereinafter, Example Compound 17) was obtained.
  • Step 2 Synthesis of ethyl 1- (N-methylmethylsulfonamido) cyclopropanecarboxylate: Sodium hydride (55 wt%, 0.51 g, 12 mmol) was added to a DMF (10 mL) solution of Reference Example Compound 24 (2.0 g, 9.7 mmol) under ice cooling. The mixture was stirred for 10 minutes under ice cooling, and then stirred for 30 minutes at room temperature. Methyl iodide (0.78 mL, 13 mmol) was added to the reaction solution under ice cooling.
  • Step 3 Synthesis of 1- (N-methylmethylsulfonamido) cyclopropanecarboxylic acid: A 1N aqueous sodium hydroxide solution (12 mL, 12 mmol) was added to a methanol (20 mL) solution of Reference Example Compound 25 (1.8 g, 7.9 mmol) at room temperature. After stirring at 50 ° C. for 3 hours, 1N hydrochloric acid was added to the reaction solution at room temperature, and the mixture was extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.88 g (58 %)Obtained.
  • HATU (0.35 g, 0.93 mmol) was added to a DMF (1.6 mL) solution of the obtained crude product (0.10 g) and DIPEA (0.30 mL, 1.7 mmol) under ice cooling. After stirring for 15 minutes under ice cooling, Reference Example Compound 8 (0.28 g, 0.85 mmol) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 3 Synthesis of (R) -1-((R) -2-aminobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1-((R) -2-aminobutanoyl)-was prepared by carrying out the same reaction as in Example 1 [Step 10] using Reference Example Compound 28 (0.47 g, 0.91 mmol). 0.38 g (quantitative) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter referred to as Reference Example Compound 29) was obtained.
  • Step 4 Synthesis of (R) -1-((R) -2-acetamidobutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1-((R) -2-acetamidobutanoyl)-was prepared by conducting the same reaction as in Example 8 [Step 3] using Reference compound 29 (0.091 g, 0.22 mmol). 0.085 g (85%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 21) was obtained.
  • Example 22 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 29 (0.096 g, 0.23 mmol). 0.090 g (79%) of (benzyl) -1-((R) -2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 22) was obtained.
  • Example 23 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-cyanocyclopropanecarbonyl) piperidine-3-carboxamide: The same reaction as in Example 1 [Step 9] was performed using 1-cyanocyclopropanecarboxylic acid (0.034 g, 0.31 mmol) to give (R) -N- (4-cyano-2- (tri 0.081 g (63%) of fluoromethoxy) benzyl) -1- (1-cyanocyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 23) was obtained.
  • Morpholine (0.36 mL, 4.1 mmol) was added to a solution of the obtained crude product (0.53 g) in DMF (4.0 mL) at room temperature. After stirring at room temperature for 6 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example Compound 24 The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Example 25 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was obtained by conducting the same reaction as in Example 2 [Step 3] using Reference compound 30 (0.10 g, 0.25 mmol). 0.099 g (83%) of benzyl) -1-((R) -2- (methylsulfonamido) propanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 25) was obtained.
  • Example 26 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclopropanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and isobutyryl chloride (0.0062 g, 0.058 mmol), (R) — 0.017 g (71%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-isobutyramidecyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 26) was obtained. It was.
  • Example 27 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclopropanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and pivaloyl chloride (0.0064 g, 0.058 mmol), (R) — 0.018 g (73%) of N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1-pivalamidocyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 27) Obtained.
  • Example 29 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (cyclopropanecarboxamido) cyclobutanecarbonyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2- (trifluoromethoxy) was prepared by carrying out the same reaction as in Example 1 [Step 11] using cyclopropanecarbonyl chloride (0.0059 g, 0.057 mmol). 0.012 g (52%) of benzyl) -1- (1- (cyclopropanecarboxamide) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 29) was obtained.
  • Step 2 Synthesis of (S) -tert-butyl (1,3-dihydroxy-3-methylbutan-2-yl) carbamate: Methyl magnesium bromide diethyl ether solution (3N, 30 mL, 91 mmol) was added to a diethyl ether (0.12 L) solution of Reference Example compound 35 (4.0 g, 18 mmol) at ⁇ 78 ° C. After stirring at room temperature for 1 hour, a saturated aqueous ammonium chloride solution and water were added to the reaction solution under ice cooling, and the mixture was extracted with ethyl acetate.
  • Example Compound 30 ((R) -1-((R) -2-acetamido-3-hydroxy 0.029 g (66%) of -3-methylbutanoyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 30) was obtained.
  • Example Compound 31 benzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide
  • Example Compound 32 0.038 g (81%) of (benzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 32) was obtained. .
  • Example 33 Synthesis of (R) -1- (1-Butylamidocyclobutanecarbonyl) -N- (4-cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide: (R) -1- (1-Butylamidocyclobutanecarbonyl) -N— (4) was prepared by performing the same reaction as in Example 1 [Step 11] using butyryl chloride (0.0060 g, 0.057 mmol). 0.018 g (79%) of -cyano-2- (trifluoromethoxy) benzyl) piperidine-3-carboxamide (hereinafter, Example Compound 33) was obtained.
  • Example 34 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclobutanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 9] using Reference Example Compound 10 (0.021 g, 0.049 mmol) and 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol), (R) 0.0065 g of —N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclobutanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 34) (26%) obtained.
  • Example 35 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclopropanecarbonyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 9] using Reference Example Compound 14 (0.020 g, 0.049 mmol) and 2-cyclopropylacetic acid (0.0059 g, 0.058 mmol), (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1- (1- (2-cyclopropylacetamido) cyclopropanecarbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 35) 0083 g (35%) was obtained.
  • Step 2 Synthesis of sodium 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate: Under ice-cooling, 1N aqueous sodium hydroxide solution (3.9 mL, 3.9 mmol) was added to a solution of Reference Example Compound 40 (0.65 g, 3.6 mmol) in ethanol (18 mL). After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and sodium 2-methyl-2- (1H-1,2,4-triazol-1-yl) propanoate (hereinafter referred to as Reference Example Compound 41) was reduced to 0. Obtained .67 g (quantitative).
  • Step 2 Synthesis of sodium 2-methyl-2- (1H-pyrazol-1-yl) propanoate: By performing the same reaction as in Example 36 [Step 2] using Reference Example Compound 42 (0.81 g, 4.5 mmol), sodium 2-methyl-2- (1H-pyrazol-1-yl) propanoate 0.80 g of Reference Example Compound 43 was obtained.
  • Step 3 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexanecarbonyl) piperidine-3-carboxamide: (R) -N- (2,4-dichlorobenzyl) -1- (1-hydroxycyclohexane) was prepared by performing the same reaction as in Example 20 using Reference Example Compound 45 (0.10 g, 0.35 mmol). 0.030 g (24%) of carbonyl) piperidine-3-carboxamide (hereinafter, Example Compound 38) was obtained.
  • Example Compound 39 ((R) -1-((R) -2-acetamido-3-hydroxy 0.021 g (96%) of -3-methylbutanoyl) -N- (2,4-dichlorobenzyl) piperidine-3-carboxamide (hereinafter, Example Compound 39) was obtained.
  • Example 40 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1-((R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide: By performing the same reaction as in Example 1 [Step 11] using Reference Compound 47 (0.020 g, 0.050 mmol), (R) -N- (2,4-dichlorobenzyl) -1- ( 0.018 g (77%) of (R) -3-hydroxy-3-methyl-2-propionamidobutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 40) was obtained.
  • Example 41 Synthesis of (R) -N- (2,4-dichlorobenzyl) -1-((R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide: The same reaction as in Example 2 [Step 3] was carried out using Reference Compound 47 (0.020 g, 0.050 mmol) to give (R) -N- (2,4-dichlorobenzyl) -1- ( 0.020 g (85%) of (R) -3-hydroxy-3-methyl-2- (methylsulfonamido) butanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 41) was obtained.
  • Example 42 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxypropanoyl) piperidine-3-carboxamide: (R) -N- (4-cyano-2) was obtained by carrying out the same reaction as in Example 1 [Step 9] using (R) -2-hydroxypropanoic acid sodium salt (0.019 g, 0.17 mmol). 0.045 g (74%) of-(trifluoromethoxy) benzyl) -1-((R) -2-hydroxypropanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 42) was obtained.
  • Example 43 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxybutanoyl) piperidine-3-carboxamide: (R) -2-N- (4-cyano-2-) is prepared by carrying out the same reaction as in Example 1 [Step 9] using (R) -2-hydroxybutanoic acid (0.017 g, 0.17 mmol). 0.056 g (89%) of (trifluoromethoxy) benzyl) -1-((R) -2-hydroxybutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 43) was obtained.
  • Example 44 Synthesis of (R) -N- (4-cyano-2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxy-3-methylbutanoyl) piperidine-3-carboxamide: (R) -2-Hydroxy-3-methylbutanoic acid (0.018 g, 0.15 mmol) was used for the same reaction as in Example 1 [Step 9] to give (R) -N- (4-cyano 0.042 g (64%) of 2- (trifluoromethoxy) benzyl) -1-((R) -2-hydroxy-3-methylbutanoyl) piperidine-3-carboxamide (hereinafter, Example Compound 44) was obtained. It was.
  • Tables 1-1 to 1-6 show physical property data of Example compounds 1 to 44
  • Table 2 shows physical property data of Comparative compounds 1 to 2
  • Tables 3-1 to 3-5 The physical property data of Reference Example compounds 1 to 49 are shown in FIG. In the table, N.I. D. Represents “no data”.
  • the solvent name in the 1H-NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (JEOL Ltd.). The chemical shift is represented by ⁇ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), m ( Multiple line), brs (wide), dd (double double line), dt (double triple line), ddd (double double line), dq (double quadruple line), td (triple double line) (Multiple line) or tt (triple triple line). All solvents were commercially available.
  • the ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technology).
  • Example 45 sEH inhibitory activity of nipecotic acid derivative (I) in vitro: Inhibition of sEH of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof using human sEH based on the method described in known literature (Analytical Biochemistry, 2005, 343, p. 66-75) Activity was evaluated.
  • Example compounds 1 to 44 showed a very strong inhibitory activity against the enzymatic reaction of human sEH, as compared with Comparative compounds 1 and 2.
  • nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof exhibits a very strong inhibitory activity on the enzyme reaction of human sEH.
  • Example 46 Effect of nipecotic acid derivative (I) in rat monocrotaline-administered pulmonary hypertension model: Example compound 1, 2 or 31 was administered to rat monocrotaline-administered pulmonary hypertension model (Journal of Pharmaceutical Sciences, 2009, Vol. 111, p. 235-243), and nipecotic acid derivative (I) or a drug thereof The therapeutic effect of physically acceptable salt on pulmonary hypertension was evaluated.
  • Example Compound 1 Effects of Example Compound 1 on cardiopulmonary function, right ventricular hypertrophy, pulmonary hypertrophy, pulmonary artery thickening, lung cell proliferation and myocardial hypertrophy in a rat pulmonary hypertension model administered with monocrotaline in rats:
  • a group to which water for injection was similarly administered was defined as a “normal group”.
  • Example compound 1 (3, 10 and 30 mg / kg) or positive control compound tadalafil (10 mg / kg) was orally administered once daily to rats in the pulmonary hypertension induction group for 24 days from the day of monocrotaline administration.
  • Example compound 1 and tadalafil were used suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • Groups in which Example Compound 1 was administered at doses of 3, 10 and 30 mg / kg were “Example Compound 1 (3 mg / kg) administration group” and “Example Compound 1 (10 mg / kg) administration group”, respectively. And “Example Compound 1 (30 mg / kg) administration group”.
  • tadalafil administration group a group in which tadalafil was administered at a dose of 10 mg / kg was referred to as a “tadalafil administration group”.
  • a comparative control a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • the normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • body weight, lung wet weight, and wet weight of right ventricle, left ventricle and septum were measured, right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)) and lung weight. The ratio (lung weight / body weight) was determined.
  • the lungs were immersed in a formalin solution after wet weight measurement and stored.
  • Lungs fixed with formalin solution were embedded in paraffin, sections were prepared, immunostained tissue specimens were prepared using anti-sEH antibodies, and sEH expression was examined.
  • an immunostained tissue specimen was prepared using an anti-PCNA antibody, and cell proliferation was examined.
  • the right ventricle was immersed in a formalin solution after wet weight measurement and stored.
  • the right ventricle fixed with formalin solution was embedded in paraffin, a section was prepared, a pathological tissue specimen was prepared by HE staining, and myocardial hypertrophy was examined.
  • 14,15-EET and 14,15-DHET were extracted after the excised lung was crushed in a buffer solution.
  • 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 before and after the hydrolysis reaction was taken as the 14,15-EET concentration, and the 14,15-EET / 14,15-DHET ratio was determined.
  • the * mark in the figure indicates statistical significance in comparison with the pulmonary hypertension control group (Dunnett's test, p ⁇ 0.05).
  • the right ventricular systolic pressure of the pulmonary hypertension control group is statistically significantly higher than the right ventricular systolic pressure of the normal group (Aspin-Welch t test, p ⁇ 0.05), It was shown to have a pathological condition of pulmonary hypertension.
  • the right ventricular systolic pressure in the group administered with Example Compound 1 (10 mg / kg) and the group administered with Example Compound 1 (30 mg / kg) were statistically compared with those in the pulmonary hypertension control group. Scientifically significantly lower values (Dunnett's test, p ⁇ 0.05) (FIG. 1). Therefore, it was shown that Example Compound 1 has a therapeutic effect on the pathological condition of pulmonary hypertension in which an increase in pulmonary artery pressure is observed.
  • the right ventricular weight ratio of the pulmonary hypertension control group was statistically significantly higher than the right ventricular weight ratio of the normal group (Aspin-Welch t test, p ⁇ 0.05). It was shown that he had a hypertrophic condition.
  • 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 statistically compared with the right ventricular weight ratio of the pulmonary hypertension control group. (Dunnett's test, p ⁇ 0.05) (FIG. 2). Therefore, it was shown that Example Compound 1 has a therapeutic effect also on the pathological condition of pulmonary hypertension in which right ventricular hypertrophy is observed.
  • the lung weight ratio of the pulmonary hypertension control group was statistically significantly higher than the lung weight ratio of the normal group (Aspin-Welch t test, p ⁇ 0.05), and the pathological condition of lung hypertrophy Was shown.
  • the lung weight ratio of the Example Compound 1 (10 mg / kg) administration group was statistically significantly lower than the lung weight ratio of the pulmonary hypertension control group (Dunnett's test, p ⁇ 0.05) (FIG. 3). Therefore, it was shown that Example Compound 1 has a therapeutic effect also on the pathological condition of pulmonary hypertension in which pulmonary hypertrophy is observed.
  • Example Compound 1 has no effect on heart rate and systemic blood pressure in pulmonary hypertension.
  • Example Compound 1 As a result of examining pulmonary artery thickening in pulmonary hypertension, pulmonary artery thickening was observed in the lungs of the pulmonary hypertension control group compared to the lungs of the normal group. On the other hand, in the lungs of Example Compound 1 (3 mg / kg) administration group, pulmonary artery thickening was not observed as compared with the lungs of the pulmonary hypertension control group. Therefore, it was shown that Example Compound 1 has a therapeutic effect also on the pathological condition of pulmonary hypertension in which pulmonary artery thickening is observed.
  • Example Compound 1 has a therapeutic effect also on the pathological condition of pulmonary hypertension in which cell proliferation in the lung is observed.
  • Example Compound 1 has a therapeutic effect also on the pathological condition of pulmonary hypertension in which myocardial hypertrophy is observed.
  • the 14,15-EET / 14,15-DHET ratio in the lung of the pulmonary hypertension control group was Compared with the 15-EET / 14,15-DHET ratio, a low value was shown. Therefore, it was shown that the 14,15-EET / 14,15-DHET ratio decreased in the lungs with pulmonary hypertension.
  • the 14,15-EET / 14,15-DHET ratio in the lung of the Example Compound 1 (10 mg / kg) administration group is the 14,15-EET / 14,15-DHET ratio in the lung of the pulmonary hypertension control group. High value was shown in comparison with. Thus, Example Compound 1 was shown to increase the 14,15-EET / 14,15-DHET ratio in lungs with pulmonary hypertension.
  • Example Compound 1 Effect of Example Compound 1 on right ventricular hypertrophy by administration from the advanced stage of pulmonary hypertension in rat monocrotaline administration model: A group in which pulmonary hypertension was induced by administering a monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 5 weeks old; Nippon SLC Co., Ltd.) Pulmonary hypertension induction group. On the other hand, a group to which water for injection was similarly administered was defined as a “normal group”.
  • Example compound 1 (3 and 10 mg / kg) or positive control compound tadalafil (10 mg / kg) was orally administered to rats in the pulmonary hypertension induction group once a day.
  • Example compound 1 (3 and 10 mg / kg) was administered for 18 or 19 days from 10 days after the administration of monocrotaline.
  • Tadalafil (10 mg / kg) was administered for 28 or 29 days from the day of monocrotaline administration.
  • Example compound 1 and tadalafil were used suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • Example Compound 1 The groups administered with Example Compound 1 at doses of 3 and 10 mg / kg were referred to as “Example Compound 1 (3 mg / kg) administration group” and “Example Compound 1 (10 mg / kg) administration group”, respectively. Further, a group in which tadalafil was administered at a dose of 10 mg / kg was referred to as a “tadalafil administration group”. On the other hand, as a comparative control, a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”. The normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • the 14,15-DHET concentration and sEH activity in the blood of the pulmonary hypertension control group were higher than the 14,15-DHET concentration and sEH activity in the blood of the normal group. Therefore, in pulmonary hypertension, it was shown that the 14,15-DHET concentration increased and the sEH activity increased.
  • results are shown in FIG. 4 for the right ventricular weight ratio on the last administration day of the test compound.
  • the * mark in the figure indicates that it is statistically significant in comparison with the pulmonary hypertension control group (t test, p ⁇ 0.05).
  • the right ventricular weight ratio of the pulmonary hypertension control group was statistically significantly higher than the right ventricular weight ratio of the normal group (t test, p ⁇ 0.05). Therefore, it was shown that the control group for pulmonary hypertension exhibits a pathological condition of right ventricular hypertrophy.
  • the right ventricular weight ratio of the Example Compound 1 (10 mg / kg) administration group was statistically significantly lower than the right ventricular weight ratio of the pulmonary hypertension control group (t test, p ⁇ 0.05) (FIG. 4). Therefore, Example Compound 1 was shown to have a therapeutic effect on the pathophysiology of pulmonary hypertension in which right ventricular hypertrophy is observed even when administered from the stage of pathophysiology of pulmonary hypertension.
  • Example Compound 1 Effect of Example Compound 1 on systemic blood pressure in a pulmonary hypertension model administered with rat monocrotaline: Monocrotaline-administered pulmonary hypertension model rats were administered Example Compound 1 once, and the effect on systemic blood pressure immediately after administration of nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof was evaluated.
  • Monocrotaline (Sigma) aqueous solution 60 mg / kg was administered subcutaneously to the back of rats (SD system, male, 11 weeks old; Nippon Charles River Co., Ltd.) to induce pulmonary hypertension.
  • Example Compound 1 was orally administered once at a dose of 10 mg / kg. In addition, Example compound 1 was used suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80. The group to which Example Compound 1 was administered was referred to as “Example Compound 1 Administration Group”.
  • pulmonary hypertension control group a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats in which pulmonary hypertension was induced was referred to as “pulmonary hypertension control group”.
  • Systemic mean blood pressure was measured immediately after administration of Example Compound 1 or 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 until 1, 2, 3, 4, 5 and 6 hours after administration.
  • Example Compound 1 does not affect systemic blood pressure immediately after administration in pulmonary hypertension.
  • Example Compound 2 Effect of Example Compound 2 on cardiopulmonary function and right ventricular hypertrophy in rat monocrotaline-administered pulmonary hypertension model: The effect of Example Compound 2 on rat monocrotaline-administered pulmonary hypertension model was evaluated in the same manner as in Example 46 1) except that the test compound was different.
  • Rats of the “pulmonary hypertension induction group” produced by the same method as in Example 46 1) were treated with Example Compound 2 (10 mg / kg) or positive control compound Tadalafil (10 mg / kg) for 24 days from the day of monocrotaline administration. ) was orally administered once a day.
  • Example compound 2 and tadalafil were suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80.
  • the group in which Example Compound 2 was administered at a dose of 10 mg / kg was designated as “Example Compound 2 Administration Group”, and the group in which tadalafil was administered at a dose of 10 mg / kg was designated as “Tadalafil Administration Group”.
  • a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to the “normal group” to which monocrotaline was not administered.
  • Example 46 1 the right ventricular systolic pressure, systemic systolic blood pressure, and heart rate were measured the day after the final administration of the test compound. On the same day, body weight, lung wet weight, and wet weight of right ventricle, left ventricle and septum were measured, right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)) and lung weight. The ratio (lung weight / body weight) was determined.
  • the * mark in the figure indicates statistical significance in comparison with the pulmonary hypertension control group (Dunnett's test, p ⁇ 0.05).
  • the right ventricular systolic pressure of the pulmonary hypertension control group is statistically significantly higher than the right ventricular systolic pressure of the normal group (Aspin-Welch t test, p ⁇ 0.05), It was shown to have a pathological condition of pulmonary hypertension.
  • the right ventricular systolic pressure of the Example Compound 2 administration group was statistically significantly lower than the right ventricular systolic pressure of the pulmonary hypertension control group (Dunnett's test, p. ⁇ 0.05) (FIG. 5). Therefore, it was shown that Example Compound 2 has a therapeutic effect on the pathological condition of pulmonary hypertension in which an increase in pulmonary artery pressure is observed.
  • the right ventricular weight ratio of the pulmonary hypertension control group was statistically significantly higher than the right ventricular weight ratio of the normal group (Aspin-Welch t test, p ⁇ 0.05). It was shown that he had a hypertrophic condition.
  • the right ventricular weight ratio of the Example Compound 2 administration group was statistically significantly lower than the right ventricular weight ratio of the pulmonary hypertension control group (Dunnett's test, p ⁇ 0). .05) (FIG. 6). Therefore, Example Compound 2 was shown to have a therapeutic effect also on the pathological condition of pulmonary hypertension in which right ventricular hypertrophy is observed.
  • the lung weight ratio of the pulmonary hypertension control group was statistically significantly higher than the lung weight ratio of the normal group (Aspin-Welch t test, p ⁇ 0.05), and the pathological condition of lung hypertrophy was shown. Moreover, the lung weight ratio of the Example Compound 2 administration group showed a low value compared with the lung weight ratio of the pulmonary hypertension control group (FIG. 7). Therefore, it was shown that Example Compound 2 has a therapeutic effect also on the pathological condition of pulmonary hypertension in which pulmonary hypertrophy is observed.
  • Example Compound 2 was shown not to affect heart rate and systemic blood pressure in pulmonary hypertension.
  • Example Compound 31 on right ventricular hypertrophy in rat monocrotaline-administered pulmonary hypertension model: A group in which pulmonary hypertension was induced by administering monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 6 weeks old; Japan SLC Co., Ltd.) The hypertension induction group. On the other hand, a group to which water for injection was similarly administered was designated as a “normal group”.
  • Example Compound 31 (3 mg / kg and 10 mg / kg) was orally administered once a day for 29 days or 30 days from the day of monocrotaline administration to rats in the pulmonary hypertension induction group.
  • Example compound 31 was suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • Groups in which Example Compound 31 was administered at doses of 3 mg / kg and 10 mg / kg were referred to as “Example Compound 31 (3 mg / kg) administration group” and “Example Compound 31 (10 mg / kg) administration group”, respectively. did.
  • a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • the normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • the wet weight of the right ventricle, left ventricle and septum was measured on the last test compound administration day, and the right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)) was determined.
  • FIG. 1 The results of examining the right ventricular weight ratio on the last administration day of the test compound are shown in FIG.
  • the # mark in the figure indicates that the comparison with the normal group is statistically significant (t test, p ⁇ 0.05).
  • the right ventricular weight ratio of the pulmonary hypertension control group is statistically significantly higher than the right ventricular weight ratio of the normal group (t test, p ⁇ 0.05). It was shown to be presenting. In addition, 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 is lower than the right ventricular weight ratio of the pulmonary hypertension control group. (FIG. 8). Therefore, it was shown that Example Compound 31 has a therapeutic effect on the pathological condition of pulmonary hypertension in which right ventricular hypertrophy is observed.
  • Example 46 From the results of Example 46 1), 2), 3), 4) and 5), the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof has a therapeutic effect on pulmonary hypertension. It became clear.
  • Example 47 Combined effect of nipecotic acid derivative (I) and pulmonary vasodilator phosphodiesterase inhibitor or endothelin receptor antagonist in rat monocrotaline-administered pulmonary hypertension model: Rat monocrotaline-administered pulmonary hypertension model (Journal of Pharmacological Sciences, 2009, Vol. 111, p. 235-243), nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof, and pulmonary vasodilation The therapeutic effect on pulmonary hypertension by administering a phosphodiesterase inhibitor or endothelin receptor antagonist as a drug in combination was evaluated.
  • Example Compound 1 and Example Compound 31 were selected as the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof.
  • Tadalafil was selected as the phosphodiesterase inhibitor.
  • Ambrisentan was selected as the endothelin receptor antagonist.
  • Example Compound 1 Effect of combined administration (simultaneous administration) of Example Compound 1 and tadalafil on right ventricular hypertrophy in rat monocrotaline-administered pulmonary hypertension model: A group in which pulmonary hypertension was induced by administering a monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 5 weeks old; Nippon SLC Co., Ltd.) Pulmonary hypertension induction group. On the other hand, a group to which water for injection was similarly administered was defined as a “normal group”.
  • Example Compound 1 (10 mg / kg) or Tadalafil (10 mg / kg) alone or in combination with Example Compound 1 (10 mg / kg) and Tadalafil (10 mg / kg) for rats in the pulmonary hypertension induction group Then, it was orally administered once a day for 24 days from the day of monocrotaline administration.
  • the administration liquid for single administration of Example Compound 1 or tadalafil was prepared by suspending each in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • An administration liquid for combined administration was prepared by mixing and suspending Example Compound 1 and tadalafil in a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • Example Compound 1 The group in which Example Compound 1 was administered at a dose of 10 mg / kg was referred to as “Example Compound 1 (10 mg / kg) administration group”.
  • the group to which tadalafil was administered at a dose of 10 mg / kg was referred to as “tadalafil (10 mg / kg) administration group”.
  • a group in which 10 mg / kg of Example Compound 1 and 10 mg / kg of tadalafil were administered in combination was referred to as “Example Compound 1 (10 mg / kg) + tadalafil (10 mg / kg) administration group”.
  • a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • the normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • results are shown in FIG. 9 for the right ventricular weight ratio on the last administration day of the test compound.
  • the symbol # indicates that the comparison with the normal group is statistically significant (t test, p ⁇ 0.05), and the symbol * indicates that the comparison with the pulmonary hypertension control group is statistical. Is significant (t test, p ⁇ 0.05).
  • the right ventricular weight ratio of the pulmonary hypertension control group is statistically significantly higher than the right ventricular weight ratio of the normal group (t test, P ⁇ 0.05). It was shown to be presenting. Further, the right ventricular weight ratio of the group administered with Example Compound 1 (10 mg / kg) + tadalafil (10 mg / kg) was compared with the group administered with Example Compound 1 (10 mg / kg) and the group administered with tadalafil (10 mg / kg). Furthermore, it was statistically significantly lower than the right ventricular weight ratio of the pulmonary hypertension control group (t test, p ⁇ 0.05) (FIG. 9). Therefore, it was shown that the therapeutic effect excellent with respect to the pathological condition of pulmonary hypertension can be obtained by administering Example Compound 1 and tadalafil in combination.
  • Example Compound 1 Effect of combined administration (additional administration) of Example Compound 1 from the stage of disease state progression in a rat monocrotaline-administered pulmonary hypertension model receiving tadalafil: A group in which pulmonary hypertension was induced by administering a monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 6 weeks old; Nippon SLC Co., Ltd.) Pulmonary hypertension induction group. On the other hand, a group to which water for injection was similarly administered was defined as a “normal group”.
  • Example Compound 1 (3 mg / kg) or Tadalafil (10 mg / kg) alone or in combination with Example Compound 1 (3 mg / kg) and Tadalafil (10 mg / kg) for rats in the pulmonary hypertension induction group (Tadalafil was started in advance, and Example Compound 1 was additionally administered).
  • Example compound 1 (3 mg / kg) alone was orally administered once a day for 18 days or 19 days from 10 days after the administration of monocrotaline.
  • Tadalafil (10 mg / kg) was administered orally once a day for 28 or 29 days from the day of monocrotaline administration.
  • Example Compound 1 (3 mg / kg) and tadalafil (10 mg / kg) were administered in combination for Example Compound 1 (3 mg / kg) once a day for 18 days or 19 days from 10 days after the administration of monocrotaline. Oral administration was conducted, and tadalafil (10 mg / kg) was orally administered once a day for 28 days or 29 days from the day of monocrotaline administration.
  • the groups administered with Example Compound 1 (3 mg / kg) or Tadalafil (10 mg / kg) alone were designated as “Example Compound 1 (3 mg / kg) administration group” and “Tadalafil (10 mg / kg) administration group”, respectively. .
  • Example Compound 1 3 mg / kg
  • Tadalafil (10 mg / kg) administration group the combination administration group of Example Compound 1 (3 mg / kg) and Tadalafil (10 mg / kg) was referred to as “Example Compound 1 (3 mg / kg) + Tadalafil (10 mg / kg) administration group”.
  • Example compound 1 and tadalafil were used suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • a comparative control a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to the administration group of Example Compound 1 (3 mg / kg) and to the normal group.
  • the lungs were also removed on the last administration day of the test compound, and the lungs were immersed in a formalin solution after wet weight measurement and stored. After embedding the lungs fixed in formalin solution in paraffin, preparing a histopathological specimen by Elastica-Wangieson staining, measuring the pulmonary artery median thickness, and the pulmonary artery median thickness ratio ((pulmonary artery median thickness x 2 / pulmonary artery diameter) ⁇ 100) was determined.
  • results are shown in FIG. 10 for the right ventricular weight ratio on the last administration day of the test compound.
  • the symbol # indicates that the comparison with the normal group is statistically significant (t test, p ⁇ 0.05), and the symbol * indicates that the comparison with the pulmonary hypertension control group is statistical. Is significant (t test, p ⁇ 0.05).
  • the right ventricular weight ratio of the pulmonary hypertension control group is statistically significantly higher than the right ventricular weight ratio of the normal group (t test, P ⁇ 0.05). It was shown to be presenting. Further, the right ventricular weight ratio of the Example Compound 1 (3 mg / kg) + tadalafil (10 mg / kg) administration group is the right ventricular weight ratio of the Example Compound 1 (3 mg / kg) administration group and the tadalafil (10 mg / kg). It showed a low value compared to the right ventricular weight ratio of the administration group, and further showed a statistically significantly low value compared to the right ventricular weight ratio of the pulmonary hypertension control group (t test, p ⁇ 0.05) (FIG. 10).
  • the pulmonary arterial media thickness ratio in the pulmonary hypertension control group is statistically significantly higher than that in the normal group (t test, p ⁇ 0.01). It was confirmed that it was presenting.
  • the pulmonary artery median thickness ratio of the Example Compound 1 (3 mg / kg) + tadalafil (10 mg / kg) administration group is the same as that of the Example Compound 1 (3 mg / kg) administration group and the tadalafil (10 mg / kg). kg) showed a low value compared to the pulmonary arterial media thickness ratio of the administration group, and further showed a statistically significantly lower value compared to the pulmonary arterial media thickness ratio of the pulmonary hypertension control group (steel). Test, p ⁇ 0.01) (Table 5).
  • Example Compound 1 Effect of combined administration (additional administration) of Example Compound 1 from the stage of disease state progression in a rat monocrotaline-administered pulmonary hypertension model administered ambrisentan: A group in which pulmonary hypertension was induced by administering a monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 6 weeks old; Nippon SLC Co., Ltd.) Pulmonary hypertension induction group. On the other hand, a group to which water for injection was similarly administered was defined as a “normal 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) were added to rats in the pulmonary hypertension induction group. In combination (beginning with ambrisentan prior to administration of Example Compound 1).
  • Example compound 1 (3 mg / kg) alone was orally administered once a day for 18 days or 19 days from 10 days after the administration of monocrotaline.
  • Ambrisentan (35 mg / kg) was administered orally once a day for 28 or 29 days from the day of monocrotaline administration.
  • Example Compound 1 (3 mg / kg) and ambrisentan (35 mg / kg) were administered in combination for Example Compound 1 (3 mg / kg) for 18 days or 19 days from the 10th day after monocrotaline administration. Orbrisentan was orally administered once a day for 28 days or 29 days from the day of monocrotaline administration.
  • the groups to which Example Compound 1 (3 mg / kg) or Ambrisentan (35 mg / kg) was administered alone were respectively referred to as “Example Compound 1 (3 mg / kg) administration group” and “Ambrisentan (35 mg / kg) administration group”. It was.
  • Example Compound 1 3 mg / kg
  • ambrisentan 35 mg / kg
  • Example compound 1 and ambrisentan were used suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • 0.5% methylcellulose aqueous solution containing 0.5% Tween 80 was similarly administered to the administration group of Example Compound 1 (3 mg / kg) and to the normal group.
  • FIG. 11 The results are shown in FIG. 11 for the right ventricular weight ratio on the last administration day of the test compound.
  • the # mark in the figure indicates statistical significance in comparison with the normal group (t test, p ⁇ 0.05), and the * mark and the ** mark indicate a comparison with the pulmonary hypertension control group. Indicates statistical significance (t test, * mark: p ⁇ 0.05, ** mark: p ⁇ 0.01).
  • the right ventricular weight ratio of the pulmonary hypertension control group is statistically significantly higher than the right ventricular weight ratio of the normal group (t test, P ⁇ 0.05). It was shown to be presenting.
  • the right ventricular weight ratio of the Example Compound 1 (3 mg / kg) + ambrisentan (35 mg / kg) administration group is the right ventricular weight ratio of the Example Compound 1 (3 mg / kg) administration group and the ambrisentan (35 mg / kg). kg) showed a low value compared with the right ventricular weight ratio of the administration group, and further showed a statistically significantly low value compared with the right ventricular weight ratio of the pulmonary hypertension control group (t test, p ⁇ 0.01) (FIG. 11). Therefore, it was shown that an excellent therapeutic effect can be obtained for the pathological condition of pulmonary hypertension by administering ambrisentan in advance and administering Example Compound 1 in combination with ambrisentan from the pathological stage.
  • Example Compound 31 Effect of combined administration (additional administration) of Example Compound 31 from the stage of disease state progression in a rat monocrotaline-administered pulmonary hypertension model receiving tadalafil: A group in which pulmonary hypertension was induced by administering a monocrotaline (Sigma) aqueous solution (60 mg / kg) subcutaneously to the back of a rat (Wistar strain, male, 6 weeks old; Nippon SLC Co., Ltd.) Pulmonary hypertension induction group. On the other hand, a group to which water for injection was similarly administered was defined as a “normal group”.
  • Rats in the pulmonary hypertension induction group were treated with tadalafil (10 mg / kg) alone or in combination with Example Compound 31 (10 mg / kg) and tadalafil (10 mg / kg). Compound 31 was additionally administered).
  • Tadalafil (10 mg / kg) was administered orally once a day for 28 or 29 days from the day of monocrotaline administration.
  • Example compound 31 (10 mg / kg) and tadalafil (10 mg / kg) were administered in combination for example compound 31 (10 mg / kg) once a day for 18 days or 19 days from the 10th day after the administration of monocrotaline.
  • Example Compound 31 10 mg / kg
  • Tadalafil 10 mg / kg
  • Example Compound 31 + Tadalafil 10 mg / kg
  • Example compound 31 and tadalafil were each used by being suspended in 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats of the pulmonary hypertension induction group was designated as a “pulmonary hypertension control group”.
  • the normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • results are shown in FIG. 12 for the right ventricular weight ratio on the last administration day of the test compound.
  • the symbol # indicates that the comparison with the normal group is statistically significant (t test, p ⁇ 0.05), and the symbol * indicates that the comparison with the pulmonary hypertension control group is statistical. Is significant (t test, p ⁇ 0.05).
  • the right ventricular weight ratio of the pulmonary hypertension control group is statistically significantly higher than the right ventricular weight ratio of the normal group (t test, P ⁇ 0.05). It was shown to be presenting. Further, the right ventricular weight ratio of the group administered with Example Compound 31 (10 mg / kg) + tadalafil (10 mg / kg) showed a low value compared with the right ventricular weight ratio of the tadalafil (10 mg / kg) administration group, Compared with the right ventricular weight ratio of the pulmonary hypertension control group, the value was statistically significantly lower (t test, p ⁇ 0.05) (FIG. 12).
  • Example 47 From the results of 1), 2), 3) and 4) of Example 47, the nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof, and a phosphodiesterase inhibitor or endothelin receptor antagonist which is a pulmonary vasodilator. It has been clarified that, when the agent is administered in combination, it exhibits an excellent therapeutic effect on pulmonary hypertension.
  • the present invention comprises nipecotic acid derivative (I) or a pharmacologically acceptable salt thereof and a pulmonary vasodilator as active ingredients and can be used as a therapeutic or preventive agent for pulmonary hypertension.

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Abstract

　L'objet de la présente invention est de pourvoir à un agent thérapeutique ou à un agent prophylactique pour l'hypertension pulmonaire permettant de traiter l'hypertension pulmonaire sur la base d'un double mécanisme d'action comprenant une action vasodilatatrice pulmonaire et une action d'inhibition de la sEH, et de pourvoir à un agent thérapeutique ou à un agent prophylactique pour l'hypertension pulmonaire destiné à être utilisé conjointement à un vasodilatateur pulmonaire. La présente invention porte sur un agent thérapeutique ou un agent prophylactique pour l'hypertension pulmonaire contenant, comme principes actifs, un dérivé d'acide nipécotique représenté par la formule ou un sel associé pharmaceutiquement acceptable, et un vasodilatateur pulmonaire.
PCT/JP2014/075570 2013-09-26 2014-09-26 Agent thérapeutique ou agent prophylactique pour l'hypertension pulmonaire WO2015046404A1 (fr)

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CN109305927A (zh) * 2018-10-31 2019-02-05 抚顺顺能化工有限公司 环己酮氰醇的制备方法

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Publication number Priority date Publication date Assignee Title
WO2024105225A1 (fr) 2022-11-18 2024-05-23 Universitat De Barcelona Combinaisons synergiques d'un antagoniste du récepteur sigma 1 (s1r) et d'un inhibiteur d'époxyde hydrolase soluble (sehi) et leur utilisation dans le traitement de la douleur

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