WO2013161980A1 - Dérivé de cyclohexanediamide et son utilisation à des fins médicales - Google Patents

Dérivé de cyclohexanediamide et son utilisation à des fins médicales Download PDF

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WO2013161980A1
WO2013161980A1 PCT/JP2013/062335 JP2013062335W WO2013161980A1 WO 2013161980 A1 WO2013161980 A1 WO 2013161980A1 JP 2013062335 W JP2013062335 W JP 2013062335W WO 2013161980 A1 WO2013161980 A1 WO 2013161980A1
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聡 黒澤
裕 西村
祐子 加藤
信寛 渕
拓実 青木
将輝 山田
尚弘 山田
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東レ株式会社
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/06—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/52—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • the present invention relates to a cyclohexanediamide derivative and its pharmaceutical use.
  • Chronic kidney disease is a major concept that includes a state of renal function that does not lead to renal failure to the end stage of renal failure. Is proposed because it has been found that the risk of progression to renal failure is high if left untreated.
  • Non-patent Document 2 Treatment to stop the progression and progression of chronic kidney disease and cardiovascular disease is performed.
  • 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 prognosis is poor.
  • pulmonary arterial pressure is maintained lower than systemic blood pressure, but in patients with pulmonary hypertension, mean pulmonary arterial pressure is 25 mmHg or more at rest (30 mmHg or more during exercise), and this state persists for a long time.
  • Right ventricular hypertrophy and right heart failure are induced, and in the worst case, death.
  • Non-patent Document 3 As one of the causes of pulmonary hypertension is considered to involve pulmonary vasospasm, short-term treatment of pulmonary hypertension such as prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase inhibitors Drugs that exhibit pulmonary vasodilatory effects have been used (Non-patent Document 3).
  • EETs epoxyeicosatrienoic acid
  • DHETs dihydroxyeicosatrienoic acids
  • sEH soluble epoxide hydrolase
  • sEH soluble epoxide hydrolase inhibitors
  • Non-Patent Documents 9 to 11 it has been reported that even sEH inhibitors have no therapeutic effect on spontaneous hypertensive rat models.
  • Patent Documents 1 and 2 and Non-Patent Document 8 compounds showing sEH inhibitory activity and useful for the treatment of chronic kidney disease and pulmonary hypertension have been reported (Patent Documents 1 and 2 and Non-Patent Document 8). It does not have a cyclohexanediamide structure.
  • Patent Document 3 O6-alkylguanine derivatives (Patent Document 3) and aminomethylcyclohexaneamine derivatives (Patent Document 4) have been reported. Regarding the relationship between these derivatives and sEH inhibitory activity Is not disclosed at all.
  • Non-Patent Documents 10 to 12 Non-Patent Documents 10 to 12
  • EETs decomposition is strongly suppressed to find a compound exhibiting an inhibitory action against a decrease in renal function and an increase in pulmonary artery pressure associated with the progression of the disease state
  • sEH is not overexpressed. I came to think that it can be a highly safe medicine that does not affect the organization.
  • an object of the present invention is to provide a compound exhibiting sEH inhibitory activity, and to provide a medicament that exhibits therapeutic and preventive effects on chronic kidney disease and pulmonary hypertension based on the sEH inhibitory action.
  • the present invention provides a cyclohexanediamide derivative represented by the following general formula (I).
  • R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a carbon number of 4 To 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group each have 1 to 3 hydrogen atoms, independently An atom, a hydroxyl group, a cyano group, —SR 6 , optionally substituted with —S ( ⁇ O) R 6 or —S ( ⁇ O) 2 R 6 ), a phenyloxy group (the phenyloxy group is a benzene ring
  • R 4 and R 5 each independently represents a hydrogen atom, a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms (the alkyl group and the alkyloxy group are each 1 ⁇ 3 hydrogen atoms Each independently may be substituted with a halogen atom),
  • R 6 represents an alkyl group having 1 to 6 carbon atoms
  • R 7 represents an alkyl group having 1 to 6 carbon atoms, 3 carbon atoms
  • 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 5 is preferably a substituent at the 2-position on the benzene ring.
  • R 1 is an alkyl group having 1 to 6 carbon atoms or —N (H) C ( ⁇ O) R 7
  • R 4 is a halogen atom, a cyano group, or 1 carbon atom.
  • R 5 is a halogen atom or an alkyl group or alkyloxy group having 1 to 6 carbon atoms.
  • the present invention also provides an sEH inhibitor containing the above cyclohexanediamide derivative as an active ingredient.
  • the present invention provides a medicine containing the above cyclohexanediamide derivative as an active ingredient.
  • This medicament is particularly preferably a therapeutic or prophylactic agent for chronic kidney disease or pulmonary hypertension.
  • the cyclohexanediamide derivative of the present invention has a strong sEH inhibitory activity, it can exert a high therapeutic effect or preventive effect on chronic kidney disease and pulmonary hypertension based on its action mechanism, and has side effects according to the patient's symptoms.
  • a reduced prescription can be selected.
  • the cyclohexanediamide derivative of the present invention is characterized by being represented by the following general formula (I).
  • R 1 represents a hydroxyl group, a cyano group, an alkyl group or alkyloxy group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a carbon number of 4 To 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group each have 1 to 3 hydrogen atoms, independently An atom, a hydroxyl group, a cyano group, —SR 6 , optionally substituted with —S ( ⁇ O) R 6 or —S ( ⁇ O) 2 R 6 ), a phenyloxy group (the phenyloxy group is a benzene
  • R 4 and R 5 each independently represents a hydrogen atom, a halogen atom, a cyano group, or an alkyl group or alkyloxy group having 1 to 6 carbon atoms (the alkyl group and the alkyloxy group are each 1 ⁇ 3 hydrogen atoms Each independently may be substituted with a halogen atom),
  • R 6 represents an alkyl group having 1 to 6 carbon atoms
  • R 7 represents an alkyl group having 1 to 6 carbon atoms, 3 carbon atoms
  • 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.
  • 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.
  • R 1 is preferably a hydroxyl group, an alkyl group having 1 to 6 carbon atoms, or —N (H) C ( ⁇ O) R 7. It is more preferably an alkyl group of ⁇ 6 or —N (H) C ( ⁇ O) R 7 , and further preferably a methyl group or a propionamidyl group.
  • 1 to 3 hydrogen atoms are each independently a halogen atom, a hydroxyl group, a cyano group, —SR 6 , —S ( ⁇ O) R 6 or —S. ( ⁇ O) 2 R 6 may be substituted.
  • 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 —. More preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or together, — (CH 2 ) 2 — or — (CH 2 ) 3 —, each independently More preferred is an atom, a methyl group or a 2-propyl group.
  • R 4 is preferably a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, and more preferably a halogen atom or a cyano group.
  • R 5 is preferably a substituent at the 2-position on the benzene ring.
  • R 5 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 having 1 to 6 carbon atoms, and a trifluoromethoxy group. More preferably.
  • R 6 is preferably a methyl group.
  • R 7 is preferably a methyl group or an ethyl group.
  • L is preferably 2 or 3.
  • cyclohexanediamide derivative (I) includes a compound having an asymmetric carbon atom.
  • optical isomers and diastereomers are present, but the cyclohexanediamide derivative (I) includes not only a single isomer but also a racemate and a diastereomeric mixture.
  • the starting materials and reagents used for the production of the cyclohexanediamide derivative (I) may be commercially available products or may be synthesized by known methods.
  • the cyclohexanediamide derivative (Ia) can be produced, for example, by a condensation reaction between an amine derivative (II) and a carboxylic acid derivative (III) in the presence of a base and a condensing agent, as shown in Scheme 1 below.
  • R 1 ′ represents a hydroxyl group, a cyano group, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, 4 to 7 cycloalkylalkyl groups (the alkyl group, the alkyloxy group, the cycloalkyl group, the alkyloxyalkyl group and the cycloalkylalkyl group each independently have 1 to 3 hydrogen atoms, Halogen atom, hydroxyl group, cyano group, —SR 6 , —S ( ⁇ O) —R 6 or —S ( ⁇ O) 2 R 6 may be substituted), —N (H) C ( ⁇ O) R 7 , —C ( ⁇ O) N (H) R 7 or —C ( ⁇ O) OR 7 is represented.
  • R 2 to R 7 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 with respect to the amine derivative (II).
  • 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.
  • 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.
  • the cyclohexanediamide derivative (Ic) in which R 1 is —N (H) S ( ⁇ O) 2 R 7 can be synthesized with an amine derivative (IV) in the presence of a base, for example, as shown in Scheme 3 below. It can be produced by a sulfonamidation reaction with a sulfonic acid chloride derivative (VII). [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.
  • R 2 to R 5 are the same as defined above, and R 8 represents a protecting group.
  • 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 (hereinafter, TFA).
  • the amine derivative (II) which is a 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, between a benzylamine derivative (IX) and a cyclohexane derivative (X). After the condensation reaction, it can be produced by a deprotection reaction to remove the protecting group. [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 cyclohexane derivative (X) to an acid chloride.
  • Examples of the reagent for converting the cyclohexane derivative (X) to 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 cyclohexane derivative (X).
  • Examples of the solvent used for converting the cyclohexane derivative (X) to the acid chloride include dichloromethane, chloroform, THF, 1,2-dichloroethane, acetonitrile, 1,4-dioxane, DMF, or a mixed solvent thereof.
  • Dichloromethane, THF or DMF, or 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 cyclohexane 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 cyclohexane derivative (X) to the 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 cyclohexane derivative (X) at the start of the reaction when the cyclohexane derivative (X) is converted to an acid chloride is preferably 0.01 to 100M, more preferably 0.01 to 10M, and further preferably 0.1 to 3M. preferable.
  • benzylamine derivative (IX) in the above scheme 5 a commercially available product may be used as it is, or it may be produced by a known method.
  • the cyclohexanediamide derivative (Ib) can also be produced, for example, by a condensation reaction between a benzylamine derivative (IX) and a carboxylic acid derivative (XI) in the presence of a base and a condensing agent as shown in Scheme 6 below. it can. [Wherein R 2 to R 5 and R 7 are the same as defined above]. ]
  • the carboxylic acid derivative (XI), which is the starting material in Scheme 6 above, is, for example, a condensation reaction between an amine derivative (XII) and an acid chloride derivative (V) in the presence of a base, as shown in Scheme 7 below, or In the presence of a base and a condensing agent, after the condensation reaction of the amine derivative (XII) and the carboxylic acid derivative (VI), it can be produced by a deprotection reaction to remove the protecting group.
  • R 2 , R 3 and R 7 are the same as defined above, and R 9 represents a protecting group.
  • condensation reaction between the amine derivative (XII) and the acid chloride derivative (V), or the condensation reaction between the amine derivative (XII) and the carboxylic acid derivative (VI) can be performed under the same conditions as in Scheme 2.
  • 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 methyl group
  • the protecting group can be removed by treatment with a strong base such as sodium hydroxide.
  • the amine derivative (XII) which is the starting material in the above-mentioned scheme 7 is a condensation reaction between an amine derivative (XIII) and a carboxylic acid derivative (VIII) in the presence of a base and a condensing agent, for example, as shown in the following scheme 8. Then, it can manufacture by the deprotection reaction which removes a protecting group.
  • R 2 , R 3 , R 8 and R 9 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 cyclohexanediamide derivative (I) obtained as described above, or the intermediate, raw material compound or reagent used in the production of the cyclohexanediamide derivative (I) is extracted, distilled, or chromatographed as necessary. Alternatively, it may be isolated and purified by a method such as recrystallization.
  • the medicament, sEH inhibitor and the therapeutic and prophylactic agent for chronic kidney disease or pulmonary hypertension of the present invention are characterized by containing cyclohexanediamide derivative (I) as an active ingredient.
  • the above cyclohexanediamide derivative (I) exhibits a potent sEH inhibitory activity, it can be used as a pharmaceutical and an sEH inhibitor, and is particularly a chronic disease that is caused by a decrease in the amount of EETs present due to excessive sEH. It is preferably used as a therapeutic or prophylactic agent for kidney disease and pulmonary hypertension.
  • SEH is an important metabolic enzyme in vivo that catalyzes the hydrolysis of the substrate epoxide and converts it to the corresponding diol.
  • the best known substrate of sEH is EETs, one of endothelial cell-derived hyperpolarizing factors, which metabolizes EETs into DHETs and inactivates them.
  • EETs have a blood pressure increase inhibitory effect and a vascular endothelial protective effect, and are known to show an organ protective effect in kidney and lung diseases (The Journal of the Federation of American Society for Experimental Biology, 2010). 24, P.3770-3781 and AJP-Heart and Circuit Physiology, 2006, Vol. 291, H517-H531).
  • 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 sEH 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.
  • chronic kidney disease means a disease defined by The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K / DOQI). That is, (1) a disease having a renal disorder defined by a structural or functional abnormality of the kidney for 3 months or more, regardless of the presence or absence of a glomerular filtration rate (GFR), or (2) It means a disease whose glomerular filtration rate is less than 60 mL / min / 1.73 m 2 for 3 months or more regardless of the presence or absence of kidney damage.
  • K / DOQI National Kidney Foundation-Kidney Disease Outcomes Quality Initiative
  • “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 arterial pressure is at least 20 mmHg at rest (more than 30 mmHg at exercise) (digest version, pulmonary hypertension treatment guidelines (2006 revision), P2-P3.) .
  • the therapeutic effect of cyclohexanediamide derivative (I) on chronic kidney disease can be evaluated using an animal model that has artificially induced chronic kidney disease.
  • an animal model for example, an anti-glomerular basement membrane antiserum (anti-GBM antiserum) -administered nephritis model (Kidney International, 2003, Vol. 64, p.1241-1252, etc.) using mice and rats, etc. ) Or 5/6 nephrectomy (Journal of the American Society of Nephrology, 2002, Vol. 13, p. 2909-2915, etc.). Abnormalities in kidney function can be confirmed by measuring serum creatinine levels.
  • the therapeutic effect of cyclohexanediamide derivative (I) on pulmonary hypertension can be evaluated using an animal model that artificially induces pulmonary hypertension.
  • 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).
  • An increase in pulmonary artery pressure can be confirmed by measuring right ventricular systolic pressure.
  • the right ventricular hypertrophy and pulmonary hypertrophy associated with pulmonary hypertension were measured by measuring the right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)) and lung weight ratio (lung weight / body weight), respectively. This can be confirmed.
  • cyclohexanediamide derivative (I) When used as a medicine, a mammal (eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human as it is or as a pharmaceutical composition in an appropriate dosage form. ) Can be administered orally or parenterally (for example, transdermal administration, intravenous administration, rectal administration, inhalation administration, nasal administration or ophthalmic administration).
  • a mammal eg, mouse, rat, hamster, rabbit, dog, monkey, cow, sheep or human as it is or as a pharmaceutical composition in an appropriate dosage form.
  • Can be administered orally or parenterally for example, transdermal administration, intravenous administration, rectal administration, inhalation administration, nasal administration or ophthalmic administration).
  • Examples of the dosage form for administration to mammals include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions or suppositories, or known continuous forms.
  • a formulation is mentioned.
  • These dosage forms can be produced by a known method and contain a carrier generally used in the pharmaceutical field. Examples of such carriers include excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizers, suspending agents, or soothing agents in liquid preparations.
  • excipient examples include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • lubricant examples include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • binder examples include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose or sodium carboxymethylcellulose.
  • disintegrant examples include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
  • solvent examples include water for injection, alcohol, propylene glycol, macrogol, sesame oil or corn oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, or sodium citrate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose. , Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose.
  • Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the isotonic agent include glucose, sodium chloride, D-sorbitol, and D-mannitol.
  • buffer solutions such as phosphate, acetate, carbonate or citrate.
  • preservative examples include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidant examples include sulfite and ascorbic acid.
  • the above medicament preferably contains 0.001 to 99% by weight of cyclohexanediamide derivative (I), more preferably 0.01 to 99% by weight.
  • the effective dose and frequency of administration of the cyclohexanediamide derivative (I) vary depending on the administration form, patient age, body weight, or the nature or severity of symptoms to be treated, but usually 1 to 1000 mg per day for adults is preferable. 1 to 300 mg can be administered once or divided into several times.
  • the above medicines may be administered alone, but may be combined with other drugs or used in combination with other drugs in order to supplement or enhance the preventive or therapeutic effect of the disease or reduce the dose. Can also be used.
  • combination drugs examples include, for example, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, a hypotensive agent, a therapeutic agent for pulmonary hypertension, an anti-obesity agent, A diuretic, a chemotherapeutic agent, an immunotherapeutic agent, an antithrombotic agent or a cachexia improving agent is mentioned.
  • the administration timing of the above medicine and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, with a time difference. May be administered.
  • the concomitant drug may be a low molecular compound, a polymer such as a protein, polypeptide or antibody, or a vaccine.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the above medicine and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination of the above medicine and concomitant drug, and the like. For example, when the administration subject is a human, the concomitant drug may be used at a compounding ratio of 0.01 to 99.99 with respect to the cyclohexanediamide derivative (I).
  • diabetes therapeutic agents include animal insulin preparations extracted from bovine or porcine pancreas, human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast, insulin zinc, protamine insulin zinc, insulin fragments or derivatives, etc.
  • Insulin preparations insulin resistance improvers such as pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, ⁇ -glucosidase inhibitors such as voglibose, acarbose, miglitol or emiglitate, biguanides such as phenformin, metformin or buformin, Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybzo Insulin secretion promoters such as repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof, am
  • Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat or fidarestat, neurotrophic factors such as NGF, NT-3 or BDNF, neurotrophic factors Examples include production / secretion promoters, PKC inhibitors, AGE inhibitors, active oxygen scavengers such as thioctic acid, and cerebral vasodilators such as thioprid or mexiletine.
  • aldose reductase inhibitors such as tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat or fidarestat
  • neurotrophic factors such as NGF, NT-3 or BDNF
  • neurotrophic factors include production / secretion promoters, PKC inhibitors, AGE inhibitors, active oxygen scavengers such as thioctic acid, and cerebral vasodilators such as thi
  • HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripanstat, cerivastatin, and itavastatin, bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate , Clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pilifibrate, lonifibrate, fibrate compounds such as simfibrate or theofibrate, squalene synthase inhibitors, ACAT inhibitors such as avasimib or eflucimate , Anion exchange resins such as cholestyramine, probucol, nicomol or niceritrol Cochin acid drugs or ethyl icosapentate,
  • Antihypertensive agents include, for example, angiotensin converting enzyme inhibitors such as captopril, enalapril or delapril, candesartan cilexetil, losartan, eprosartan, valsantan, telmisartan, irbesartan or tasosartan and other angiotensin II antagonists, manidipine, nifedipine, nicardipine, Calcium antagonists such as amlodipine or efonidipine, potassium channel openers such as lebuchromacalim, clonidine or aliskiren.
  • angiotensin converting enzyme inhibitors such as captopril, enalapril or delapril
  • candesartan cilexetil losartan
  • eprosartan valsantan
  • telmisartan telmisartan
  • therapeutic agents for pulmonary hypertension include endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, and macitentan, PDE-5 inhibitors such as sildenafil, tadalafil, or vardenafil, beraprost, iloprost, epoprostenol, or treprostinil.
  • endothelin receptor antagonists such as bosentan, ambrisentan, sitaxsentan, and macitentan
  • PDE-5 inhibitors such as sildenafil, tadalafil, or vardenafil, beraprost, iloprost, epoprostenol, or treprostinil.
  • prostacyclin preparations PEI2 agonists selexipag or kinase inhibitors such as fasudil, imatinib, sorafenib or bafetinib.
  • anti-obesity agents include central anti-obesity agents such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine or clobenzorex, pancreatic lipase such as orlistat Peptide appetite suppressants such as inhibitors, ⁇ 3 agonists, leptin or CNTF (ciliary neurotrophic factor) or cholecystokinin agonists such as lynchtripto.
  • central anti-obesity agents such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine or clobenzorex, pancreatic lipase such as orlistat Peptide appetite suppressants such as inhibitors, ⁇ 3 agonists, leptin or CNTF (
  • diuretic examples include xanthine derivatives such as sodium theobromide salicylate or calcium theobromide, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, thiazide preparations such as benchylhydrochlorothiazide, penflutide, polythiazide or methycrothiazide.
  • xanthine derivatives such as sodium theobromide salicylate or calcium theobromide
  • ethiazide cyclopenthiazide
  • trichloromethiazide hydrochlorothiazide
  • hydroflumethiazide hydroflumethiazide
  • thiazide preparations such as benchylhydrochlorothiazide, penflutide, polythiazide or methycrothiazide.
  • Antialdosterone preparations such as spironolactone or triamterene, carbonic anhydrase inhibitors such as acetazolamide, chlorbenzenesulfonamide preparations such as chlorthalidone, mefluside or indapamide, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide or furosemide.
  • chemotherapeutic agents include alkylating agents such as cyclophosphamide or ifosfamide, antimetabolite agents such as methotrexate or 5-fluorouracil, anticancer antibiotics such as mitomycin or adriamycin, plants such as vincristine, vindesine or taxol. Derived anticancer agents, cisplatin, oxaloplatin, carboplatin, etopoxide and the like.
  • immunotherapeutic agent examples include muramyl dipeptide derivatives, picibanil, lentinan, schizophyllan, krestin, interferon, interleukin (IL), granulocyte colony stimulating factor or erythropoietin.
  • antithrombotic agent examples include heparin such as heparin sodium, heparin calcium or sodium dalteparin, warfarin such as warfarin potassium, antithrombin agent such as argatroban, thrombolytic agent such as urokinase, tisokinase,reteplase, nateplase, monteplase or pamiteplase.
  • platelet aggregation inhibitors such as ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium or sarpogrelate hydrochloride.
  • cachexia-improving agents examples include cyclooxygenase inhibitors such as indomethacin or diclofenac, progesterone derivatives such as megesterol acetate, carbohydrate steroids such as dexamethasone, metoclopramide drugs, tetrahydrocannabinol drugs, and fats such as eicosapentaenoic acid.
  • cyclooxygenase inhibitors such as indomethacin or diclofenac
  • progesterone derivatives such as megesterol acetate
  • carbohydrate steroids such as dexamethasone
  • metoclopramide drugs tetrahydrocannabinol drugs
  • fats such as eicosapentaenoic acid.
  • examples thereof include antibodies to TNF- ⁇ , LIF, IL-6, or oncostatin M, which are agents that induce metabolism, growth hormone, IGF-1, or cachexia.
  • Step 2 Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanol (hereinafter referred to as Reference Example Compound 2): At ⁇ 10 ° C., sodium borohydride (2.4 g, 63 mmol) was added to a methanol (0.23 L) solution of Reference Example compound 1 (16 g, 59 mmol). After stirring at ⁇ 10 ° C. for 10 minutes, acetone (10 mL) and 1N hydrochloric acid (10 mL) were added to the reaction solution. The reaction solution was concentrated under reduced pressure, water was added to the obtained crude product, and the mixture was extracted with ethyl acetate.
  • Reference Example Compound 2 4-bromo-2- (trifluoromethoxy) phenyl) methanol
  • Step 3 Synthesis of 4-bromo-2- (trifluoromethoxy) benzyl methanesulfonate (hereinafter referred to as Reference Example Compound 3): Methanesulfonyl chloride (0.63 mL, 8.1 mmol) was added to a solution of Reference Example Compound 2 (0.63 mL, 7.4 mmol) and TEA (1.2 mL, 8.9 mmol) in dichloromethane (20 mL) at room temperature. . 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 saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2.6 g (quantitative) of Reference Example Compound 3.
  • Step 5 Synthesis of (4-bromo-2- (trifluoromethoxy) phenyl) methanamine (hereinafter referred to as Reference Example Compound 5): 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 mixture was cooled to room temperature and the solid 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 saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.5 g (85%) of Reference Example Compound 5.
  • Step 6 Synthesis of tert-butyl (cis-4-((4-bromo-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamate (hereinafter referred to as Reference Example Compound 6): At room temperature, cis-4-((tert-butoxycarbonyl) amino) cyclohexanecarboxylic acid (0.27 g, 1.1 mmol), Reference Example Compound 5 (0.30 g, 1.1 mmol) and DIPEA (0.48 mL, 2 .7 mmol) in DMF (3.0 mL) was added HATU (0.41 g, 1.1 mmol).
  • Step 7 Synthesis of tert-butyl (cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamate (hereinafter referred to as Reference Example Compound 7): Under 150 degrees, reference compound 6 (0.050 g, 0.10 mmol), tetrakis (triphenylphosphine) palladium (0.035 g, 0.030 mmol) and zinc cyanide (0.018 g, 0.15 mmol) 1- The methyl-2-pyrrolidone (1.0 mL) solution was stirred for 1 hour in a microwave reactor (MONOWAVE 300; manufactured by Anton Paar).
  • Step 8 Synthesis of cis-4-amino-N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 8): TFA (6.4 mL, 83 mmol) was added to a dichloromethane (40 mL) solution of Reference Example compound 7 (1.8 g, 4.2 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1.3 g (93%) of Reference Example Compound 8.
  • Step 9 Synthesis of methyl (S) -3-methyl-2-propionamidobutanoate (hereinafter referred to as Reference Example Compound 9): Under ice cooling, propionyl chloride (7.8 mL, 89 mmol) was added to a solution of L-valine methyl ester hydrochloride (10 g, 60 mmol) and pyridine (17 mL, 210 mmol) in dichloromethane (100 mL). After stirring for 3 hours under ice cooling, water and 1N hydrochloric acid were added to the reaction solution, and the mixture was extracted with dichloromethane.
  • Step 10 Synthesis of (S) -3-methyl-2-propionamidobutanoic acid (hereinafter referred to as Reference Example Compound 10): A 1N aqueous sodium hydroxide solution (90 mL, 90 mmol) was added to a methanol (100 mL) solution of Reference Example Compound 9 (11 g, 60 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction solution was neutralized with 1N hydrochloric acid, and 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 8.5 g (82%) of Reference Example Compound 10.
  • Example Compound 1 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 1) : To a DMF (20 mL) solution of Reference Example Compound 8 (0.70 g, 2.1 mmol), Reference Example Compound 10 (0.34 g, 2.0 mmol) and DIPEA (0.85 mL, 4.9 mmol) at room temperature, HATU (0.97 g, 2.5 mmol) was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Example 2 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-pivalamidocyclohexanecarboxamide (hereinafter, Example Compound 2): Under ice cooling, pivaloyl chloride (0.070 mL, 0.57 mmol) was added to a solution of Reference Example Compound 8 (0.15 g, 0.44 mmol) and pyridine (0.11 mL, 1.3 mmol) in dichloromethane (5.0 mL). ) was added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane.
  • Step 2 Synthesis of 2-methyl-2- (methylsulfonamido) propanoic acid (hereinafter referred to as Reference Example Compound 12): A sodium hydroxide aqueous solution (1N, 29 mL, 29 mmol) was added to a methanol (35 mL) solution of Reference Example Compound 11 (4.0 g, 19 mmol) at room temperature. After stirring at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in 1N hydrochloric acid and then extracted with a chloroform: methanol mixed solvent (10: 1). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 2.5 g (72%) of Reference Example Compound 12.
  • Example Compound 3 cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methyl-2- (methylsulfonamido) propanamide) cyclohexanecarboxamide (hereinafter referred to as Example Compound 3) Synthesis: Under ice-cooling, oxalyl chloride (0.037 mL, 0.43 mmol) was added to a solution of Reference Example Compound 12 (0.074 g, 0.41 mmol) and DMF (1 mL) in dichloromethane (5 mL).
  • Step 3 cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2- (methylsulfonamide) butanamide) cyclohexanecarboxamide (hereinafter referred to as Example compound) 4) Synthesis: Under ice cooling, a solution of Reference Compound 14 (0.035 g, 0.077 mmol) and pyridine (0.019 mL, 0.23 mmol) in dichloromethane (2.0 mL) was added to methanesulfonyl chloride (0.0072 mL, 0.092 mmol). Was added.
  • Example 5 cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 5) Synthesis of: Under ice cooling, propionyl chloride (0.0080 mL, 0.092 mmol) was added to a solution of Reference Example Compound 14 (0.035 g, 0.077 mmol) and pyridine (0.019 mL, 0.23 mmol) in dichloromethane (2.0 mL). added. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane.
  • Example 7 Synthesis of N- (cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) adamantane-1-carboxamide (hereinafter Example Compound 7): Under ice cooling, a solution of Reference Example Compound 8 (0.10 g, 0.29 mmol) and TEA (0.20 mL, 1.5 mmol) in dichloromethane (2.0 mL) was added to adamantane-1-carbonyl chloride (0.064 g, 0 .32 mmol) was added. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The crude product was washed with a saturated aqueous sodium bicarbonate solution and then recrystallized from ethanol-water to obtain 0.11 g (72%) of Example Compound 7.
  • Example 8 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1- (trifluoromethyl) cyclopropanecarboxamide) cyclohexanecarboxamide (hereinafter, Example Compound 8): DMF of Reference Example Compound 8 (0.10 g, 0.29 mmol), 1- (trifluoromethyl) cyclopropanecarboxylic acid (0.045 g, 0.29 mmol) and DIPEA (0.12 mL, 0.70 mmol) at room temperature To the (1.0 mL) solution was added HATU (0.13 g, 0.35 mmol).
  • Step 3 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1-propionamidocyclobutanecarboxamide) cyclohexanecarboxamide (hereinafter, Example Compound 9): Under ice cooling, propionyl chloride (0.048 mL, 0.55 mmol) was added to a solution of Reference Compound 18 (0.20 g, 0.46 mmol) and DIPEA (0.24 mL, 1.4 mmol) in dichloromethane (5.0 mL). added. After stirring for 3 hours under ice cooling, water was added to the reaction solution, and the mixture was extracted with dichloromethane.
  • Example 10 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-hydroxy-2-methylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 10): DMF (1) of Reference Example Compound 8 (0.10 g, 0.29 mmol), 2-hydroxy-2-methylpropanoic acid (0.031 g, 0.29 mmol) and DIPEA (0.12 mL, 0.70 mmol) at room temperature. .0 mL) solution was added HATU (0.13 g, 0.35 mmol).
  • Example 11 Ethyl 3-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,2-dimethyl-3-oxopropanoate (hereinafter, Example Compound 11) Synthesis of: At room temperature, Reference Compound 8 (0.50 g, 1.5 mmol), 3-ethoxy-2,2-dimethyl-3-oxopropanoic acid (0.26 g, 1.6 mmol) and DIPEA (0.61 mL, 3.5 mmol) ) In DMF (3.0 mL) was added HATU (0.67 g, 1.8 mmol).
  • Example 12 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methoxy-2-methylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 12): At room temperature, DMF (1) of Reference Example Compound 8 (0.10 g, 0.29 mmol), 2-methoxy-2-methylpropanoic acid (0.038 g, 0.32 mmol) and DIPEA (0.12 mL, 0.70 mmol) .0 mL) solution was added HATU (0.13 g, 0.35 mmol).
  • Example 13 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2- (4-methoxyphenoxy) -2-methylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 13) : At room temperature, Reference Compound 8 (0.080 g, 0.23 mmol), 2- (4-methoxyphenoxy) -2-methylpropanoic acid (0.054 g, 0.26 mmol) and DIPEA (0.098 mL, 0.56 mmol) ) In DMF (1.0 mL) was added HATU (0.11 g, 0.28 mmol).
  • Example 14 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (3-hydroxy-2,2-dimethylpropanamide) cyclohexanecarboxamide (hereinafter, Example Compound 14): Under ice cooling, lithium tetrahydroborate (0.080 g, 3.7 mmol) was added to a THF (5.0 mL) solution of Example Compound 11 (0.59 g, 1.2 mmol). After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • Example 15 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2,2-dimethyl-3- (methylthio) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 15): Reference Example Compound 8 (0.30 g, 0.89 mmol), 2,2-dimethyl-3- (methylthio) propanoic acid (0.14 g, 0.97 mmol) and DIPEA (0.37 mL, 2.1 mmol) at room temperature HATU (0.40 g, 1.1 mmol) was added to a solution of DMF (1.0 mL).
  • Example 16 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2,2-dimethyl-3- (methylsulfinyl) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 16): Under ice cooling, 3-chloroperbenzoic acid (70%, 0.055 g, 0.22 mmol) was added to a solution of Example Compound 15 (0.10 g, 0.21 mmol) in dichloromethane (1.0 mL).
  • Example 17 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2,2-dimethyl-3- (methylsulfonyl) propanamide) cyclohexanecarboxamide (hereinafter, Example Compound 17): Under ice-cooling, 3-chloroperbenzoic acid (70%, 0.13 g, 0.51 mmol) was added to a solution of Example Compound 15 (0.10 g, 0.21 mmol) in dichloromethane (1.0 mL).
  • Example 18 Synthesis of cis-4- (3-cyano-2,2-dimethylpropanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter, Example Compound 18): DMF of Reference Example Compound 8 (0.10 g, 0.29 mmol), 3-cyano-2,2-dimethylpropanoic acid (0.056 g, 0.44 mmol) and DIPEA (0.15 mL, 0.88 mmol) at room temperature To the (1.0 mL) solution was added HATU (0.17 g, 0.44 mmol).
  • Step 2 Synthesis of (R) -3-methyl-2-propionamidobutanoic acid (hereinafter referred to as Reference Example Compound 20): A 1N aqueous sodium hydroxide solution (8.0 mL, 8.0 mmol) was added to a methanol (10 mL) solution of Reference Example Compound 19 (1.0 g, 5.3 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction solution was neutralized with 1N hydrochloric acid, and 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 0.68 g (73%) of Reference Example Compound 20.
  • Step 3 Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 19) : At room temperature, HATU (15 mL) was added to a solution of Reference Example Compound 8 (0.30 g, 0.88 mmol), Reference Example Compound 20 (0.15 g, 0.84 mmol) and DIPEA (0.37 mL, 2.1 mmol) in DMF (15 mL). 0.41 g, 1.1 mmol) was added.
  • Step 2 Synthesis of methyl cis-4-((S) -2-amino-3-methylbutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 22): TFA (16 mL, 210 mmol) was added to a dichloromethane (100 mL) solution of Reference Example compound 21 (3.7 g, 10 mmol) under ice cooling. After stirring at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane, neutralized with a saturated aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.4 g (89%) of Reference Example Compound 22.
  • Step 3 Synthesis of methyl cis-4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 23): Under ice cooling, propionyl chloride (0.87 mL, 10 mmol) was added to a solution of Reference Example Compound 22 (2.3 g, 9.1 mmol) and TEA (2.8 mL, 20 mmol) in dichloromethane (30 mL). After stirring for 3 hours under ice cooling, water was added to the reaction solution, and the mixture was extracted with dichloromethane.
  • Step 5 Synthesis of cis-N- (4-Chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 20): At room temperature, MiniBlock®-XT (48-position; Mettler Toledo Bohdan) reaction tube was charged with DMF of Reference Compound 24 (0.010 g, 0.034 mmol) and HATU (0.017 g, 0.044 mmol). (0.50 mL) solution as well as DIPEA (0.015 mL, 0.084 mmol) in DMF (0.10 mL) was added.
  • Example Compound 20 the LC retention time and [M + H] + or [M ⁇ H] ⁇ were measured using the analysis method described below.
  • Comparative Example 1 (S) -N- (cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) -2- (hydroxymethyl) pyrrolidine-1-carboxamide (hereinafter referred to as Comparative Example Compound 1) Synthesis of: Under ice-cooling, TEA (0.16 mL, 1.2 mmol) was added to a solution of Reference Example Compound 8 (0.10 g, 0.29 mmol) and triphosgene (30 mg, 0.35 mmol) in dichloromethane (3.0 mL). Was added.
  • Comparative Example 2 Synthesis of cis-N- (5-chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Comparative Compound 2): At room temperature, MiniBlock®-XT (48-position; Mettler Toledo Bohdan) reaction tube was charged with DMF of Reference Compound 24 (0.010 g, 0.034 mmol) and HATU (0.017 g, 0.044 mmol). (0.50 mL) solution as well as DIPEA (0.015 mL, 0.084 mmol) in DMF (0.10 mL) was added.
  • 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 (manufactured by JEOL).
  • 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), brd (wide double line), brt (wide triple line), dd (double double line), dt (double triple line), ddd (double double line) ) Or ddt (double double triple line). All solvents were commercially available.
  • the ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technology).
  • Example 21 Evaluation test of sEH inhibitory activity in vitro: Based on a method described in a publicly known document (Analytical Biochemistry, 2005, 343, p. 66-75), sEH inhibitory activity of cyclohexanediamide derivative (I) was evaluated using human sEH.
  • Example compounds 1 to 20 showed a very strong inhibitory activity against the enzymatic reaction of human sEH, as compared with Comparative compounds 1 and 2.
  • Example 22 Evaluation of drug efficacy in a rat anti-glomerular basement membrane antiserum (anti-GBM antiserum) -administered nephritis model: Rat anti-glomerular basement membrane antiserum (anti-GBM antiserum) -administered nephritis model (Proceedings of the National Academy of Sciences of United States of America, vol. 102, 77, 1977, vol. In Example 2002, Vol. 449, pp. 167-176) was administered Example Compound 1 or 2, and the therapeutic effect of cyclohexanediamide derivative (I) on chronic kidney disease was evaluated.
  • anti-GBM antiserum rabbit anti-glomerular basement membrane antiserum
  • sCre serum creatinine
  • Example Compound 1 or 2 was suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80 to rats in the nephritis-inducing group showing a pathological condition of renal failure. It became cloudy and was orally administered once a day at a dose of 3 mg / kg.
  • the groups to which Example Compound 1 or 2 was administered were designated as “Example Compound 1 (3 mg / kg) administration group” or “Example Compound 2 (3 mg / kg) administration group”, respectively.
  • nephritis control group a group in which 0.5% Tween 80-containing 0.5% methylcellulose aqueous solution was similarly administered to rats in the nephritis induction group was designated as a “nephritis control group”.
  • the normal group was similarly administered with a 0.5% methylcellulose aqueous solution containing 0.5% Tween80.
  • sCre was measured by the same method as described above also 4 weeks after administration of anti-GBM antiserum.
  • the measurement results of sCre values after 2 and 4 weeks after administration of anti-GBM antiserum are shown in FIG.
  • the nephritis control group In the nephritis control group, the sCre value 2 and 4 weeks after administration of anti-GBM antiserum showed a high value continuously after 2 weeks of administration of anti-GBM antiserum. Therefore, the nephritis control group was shown to exhibit chronic nephritis and renal failure.
  • Example compounds 1 and 2 have a therapeutic effect on the pathological conditions of chronic nephritis and renal failure.
  • cyclohexanediamide derivative (I) has a therapeutic effect on the pathological conditions of chronic nephritis and renal failure.
  • Example 23 Evaluation of drug efficacy in rat monocrotaline-treated pulmonary hypertension model:
  • Example Compound 1 or 2 was administered to rat monocrotaline-administered pulmonary hypertension model (Journal of Pharmaceutical Sciences, 2009, Vol. 111, p. 235-243), and cyclohexanediamide derivative (I) against pulmonary hypertension The therapeutic effect was evaluated.
  • 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 Example Compound 2 (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 compounds 1 and 2 were suspended in a 0.5% aqueous solution of methylcellulose containing 0.5% Tween 80.
  • Groups in which Example Compound 1 was administered at a dose of 3 or 10 mg / kg were referred to as “Example Compound 1 (3 mg / kg) administration group” or “Example Compound 1 (10 mg / kg) administration group”, respectively.
  • a group in which Example Compound 2 was administered at a dose of 10 mg / kg was designated as “Example Compound 2 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.
  • Each group n 10.
  • the wet weights of the right ventricle, left ventricle and septum were measured, and the right ventricular weight ratio (right ventricular weight / (septal weight + left ventricular weight)) was determined.
  • Example compounds 1 and 2 have a therapeutic effect on the pathology of pulmonary hypertension.
  • 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) (Table 6).
  • Example compounds 1 and 2 have a therapeutic effect also on the pathophysiology of right ventricular hypertrophy.
  • the heart rate and systemic systolic blood pressure of the Example Compound 1 (3 mg / kg) administration group, the Example Compound 1 (10 mg / kg) administration group and the Example Compound 2 administration group were the same as those of the pulmonary hypertension control group. There was no significant difference in both heart rate and systemic systolic blood pressure (Dunnett's test, p ⁇ 0.05).
  • the cyclohexanediamide derivative of the present invention exhibits potent sEH inhibitory activity and can be used as a therapeutic or prophylactic agent for chronic kidney disease and pulmonary hypertension in the pharmaceutical field.

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Abstract

L'invention concerne un composé et un agent médicinal présentant tous deux une activité d'inhibition de sEH, et pouvant ainsi avoir un effet thérapeutique et un effet prophylactique sur les maladies rénales chroniques et l'hypertension pulmonaire. L'invention concerne également un dérivé de cyclohexanediamide représenté par la formule (1).
PCT/JP2013/062335 2012-04-27 2013-04-26 Dérivé de cyclohexanediamide et son utilisation à des fins médicales WO2013161980A1 (fr)

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WO2019090088A1 (fr) * 2017-11-02 2019-05-09 Calico Life Sciences Llc Modulateurs de la voie de réponse intégrée au stress
US11149043B2 (en) 2018-10-11 2021-10-19 Calico Life Sciences Llc Prodrug modulators of the integrated stress pathway
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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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019090088A1 (fr) * 2017-11-02 2019-05-09 Calico Life Sciences Llc Modulateurs de la voie de réponse intégrée au stress
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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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