WO2013161980A1 - Cyclohexanediamide derivative and use thereof for medical purposes - Google Patents
Cyclohexanediamide derivative and use thereof for medical purposes Download PDFInfo
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- 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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- 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
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- 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
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- 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
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- 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
The purpose of the present invention is to provide: a compound having an sEH-inhibiting activity; and a medicinal agent which has an sEH-inhibiting activity and therefore can exhibit a therapeutic effect and a prophylactic effect on chronic kidney diseases and pulmonary hypertension. The present invention provides a cyclohexanediamide derivative represented by chemical formula (1).
Description
本発明は、シクロヘキサンジアミド誘導体及びその医薬用途に関する。
The present invention relates to a cyclohexanediamide derivative and its pharmaceutical use.
腎臓病患者の増加に伴い、人工透析患者が世界中で増加し続けており、その数はこの30年間で10倍以上に達している。このような状況下、慢性腎臓病という新しい疾患の概念が2002年に提唱された(非特許文献1)。慢性腎臓病とは、腎不全には至っていない腎機能低下状態から腎不全の末期までを含む大きな概念であり、腎機能の低下や腎障害を示唆する所見が持続して認められる状態であっても、放置すれば腎不全へと進行するリスクが高いことが判明したために提唱されたものである。
As the number of patients with kidney disease increases, the number of dialysis patients continues to increase all over the world, and the number has increased more than 10 times over the past 30 years. Under such circumstances, a new disease concept called chronic kidney disease was proposed in 2002 (Non-patent Document 1). 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.
慢性腎臓病の患者は、末期の腎不全にまで進行すると、人工透析や腎移植なしでは生存できなくなるため、患者のクオリティー・オブ・ライフは著しく低下する。さらに、慢性腎臓病の患者は、心血管疾患を併発することも多く、この場合には死亡リスクが一段と高まる。このため、慢性腎臓病の早期治療は極めて重要性が高く、心血管疾患の併発を抑制するという観点からも大きな意味を持つとされている。
When a patient with chronic kidney disease progresses to end-stage renal failure, it cannot survive without artificial dialysis or kidney transplantation, and the patient's quality of life is significantly reduced. Furthermore, patients with chronic kidney disease often have cardiovascular disease, which further increases the risk of death. For this reason, early treatment of chronic kidney disease is extremely important, and is considered to have great significance from the viewpoint of suppressing the concurrent occurrence of cardiovascular disease.
しかし、現在、慢性腎臓病の有効な治療剤は存在しないため、慢性腎臓病の患者には、アンジオテンシンII受容体拮抗剤やアンジオテンシン変換酵素阻害剤等のアンジオテンシン系の降圧剤が処方され、厳格な血圧管理を行うことで、慢性腎臓病の進展と心血管疾患の併発及び進展を食い止める治療がなされるのが通例である(非特許文献2)。
However, since there is currently no effective therapeutic agent for chronic kidney disease, patients with chronic kidney disease are prescribed angiotensin-based antihypertensive agents such as angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors. By performing blood pressure management, it is usual that treatment to stop the progression and progression of chronic kidney disease and cardiovascular disease is performed (Non-patent Document 2).
一方、肺高血圧症とは、肺動脈圧の上昇を認める病態の総称であり、運動耐容能を著しく低下させ、そのほとんどが進行性で予後も不良であることが知られている。健常人は、肺動脈圧が全身の血圧より低く維持されているが、肺高血圧症患者は、平均肺動脈圧が安静時に25mmHg以上あり(運動時には30mmHg以上あり)、この状態が長期間持続することで右心室肥大や右心不全が誘発され、最悪の場合には死に至ることになる。
On the other hand, 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. In healthy individuals, 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.
肺高血圧症発症の原因の一つには、肺血管攣縮が関与していると考えられているため、肺高血圧症の治療には、プロスタサイクリン誘導体、エンドセリンレセプター拮抗剤及びホスホジエステラーゼ阻害剤等の短期肺血管拡張作用を示す薬剤が使用されている(非特許文献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).
近年、内皮細胞由来の過分極因子の一つであるエポキシエイコサトリエン酸(Epoxyeicosatrienoic acids;以下、EETs)が、血圧上昇抑制作用及び血管内皮保護作用を有しており、腎臓や肺の疾患において臓器保護作用を示すことが報告された(非特許文献4及び5)。EETsは、可溶性エポキシド加水分解酵素(soluble epoxide hydrolase;以下、sEH)によってジヒドロキシエイコサトリエン酸(dihydroxyeicosatrienoic acids;以下、DHETs)に代謝され失活するが、可溶性エポキシド加水分解酵素阻害剤(以下、sEH阻害剤)は、EETsの量を増加させ、血圧上昇抑制や血管内皮保護作用を発揮することが示されている(非特許文献6~8及び特許文献1)。
In recent years, epoxyeicosatrienoic acid (hereinafter referred to as EETs), one of endothelial cell-derived hyperpolarizing factors, has an antihypertensive action and a protective action on vascular endothelium. It has been reported to show an organ protecting action (Non-patent Documents 4 and 5). EETs are metabolized to dihydroxyeicosatrienoic acids (hereinafter referred to as DHETs) by a soluble epoxide hydrolase (hereinafter referred to as sEH), but are soluble epoxide hydrolase inhibitors (hereinafter referred to as sEH). Inhibitors) have been shown to increase the amount of EETs and to exert a blood pressure increase suppression and vascular endothelial protection action (Non-Patent Documents 6 to 8 and Patent Document 1).
しかし、sEH阻害剤であっても、自然発症型高血圧(Spontaneously Hypertensive Rat)モデルに対しては治療効果を示さないことが報告されている(非特許文献9~11)。
However, it has been reported that even sEH inhibitors have no therapeutic effect on spontaneous hypertensive rat models (Non-Patent Documents 9 to 11).
一方、sEH阻害活性を示し、慢性腎臓病及び肺高血圧症の治療に有用な化合物が、報告されている(特許文献1及び2並びに非特許文献8)が、これらの化合物の構造は、いずれもシクロヘキサンジアミド構造を有するものではない。
On the other hand, 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.
また、シクロヘキサンジアミド構造を有する化合物としては、O6-アルキルグアニン誘導体(特許文献3)及びアミノメチルシクロヘキサンアミン誘導体(特許文献4)が報告されているが、これらの誘導体とsEH阻害活性との関係については一切開示されていない。
Further, as compounds having a cyclohexanediamide structure, 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.
しかしながら、慢性腎臓病の治療において、アンジオテンシン系降圧剤による血圧管理のみでは慢性腎臓病の進行を阻止するには不十分であるだけでなく、アンジオテンシン系降圧剤の使用は咳等の副作用のリスクを伴うおそれがある。また、肺高血圧症については、その治療法及び予防法は未だ確立されていないのが現状であり、肺高血圧症の治療に用いられている薬剤は、頭痛や潮紅等の副作用を高頻度で引き起こすリスクがある。中でも、プロスタサイクリン誘導体は、半減期が短いだけでなく、持続投与した場合であっても薬効が不十分であり、エンドセリンレセプター拮抗剤に至っては、肝毒性等の副作用を伴うリスクが懸念されている。
However, in the treatment of chronic kidney disease, blood pressure management with angiotensin antihypertensive drugs alone is not enough to prevent the progression of chronic kidney disease, and the use of angiotensin antihypertensive drugs increases the risk of side effects such as cough. May be accompanied. In addition, treatment and prevention methods for pulmonary hypertension have not been established yet, and drugs used for the treatment of pulmonary hypertension frequently cause side effects such as headache and flushing. There is a risk. Among them, prostacyclin derivatives not only have a short half-life, but also have inadequate efficacy even when continuously administered, and there are concerns about the risks associated with side effects such as hepatotoxicity when endothelin receptor antagonists are reached. Yes.
さらに、慢性腎臓病及び肺高血圧症は、患者のクオリティー・オブ・ライフを著しく低下させるおそれがあり、死亡リスクのある重篤な疾患であるため、発症メカニズムに基づき薬効が発揮される薬剤の早期創出が強く望まれている。
In addition, chronic kidney disease and pulmonary hypertension can seriously reduce the patient's quality of life and are serious diseases with a risk of death. Creation is strongly desired.
原因は不明であるが、sEH阻害活性を示す化合物であったとしても、高血圧に対して治療効果を示すとは限らないため(非特許文献10~12)、慢性腎不全や肺高血圧症に対して、治療効果を示すsEH阻害剤を見出すことは容易ではない。しかしながら、sEHを阻害しEETsの分解を強く抑制することにより、病態の進行に伴う腎機能低下や肺動脈圧上昇に対して抑制作用を示す化合物を見出すことができれば、sEHが過剰発現していない正常組織には影響を及ぼさない、安全性の高い医薬になり得ると考えるに至った。
The cause is unknown, but even if it is a compound showing sEH inhibitory activity, it does not always show therapeutic effects on hypertension (Non-Patent Documents 10 to 12). Thus, it is not easy to find an sEH inhibitor exhibiting a therapeutic effect. However, if sEH is inhibited and 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.
そこで本発明は、sEH阻害活性を示す化合物を提供するとともに、sEH阻害作用に基づき慢性腎臓病及び肺高血圧症に対する治療効果及び予防効果を発揮する医薬を提供することを目的とする。
Therefore, 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.
本発明者らは上記課題を解決するため鋭意検討した結果、新規なシクロヘキサンジアミド誘導体が、sEH阻害活性を示すこと、並びに、その作用メカニズムに基づき慢性腎臓病及び肺高血圧症に対し優れた治療効果を発揮することを見出し、本発明を完成させた。
As a result of intensive studies to solve the above problems, the present inventors have shown that a novel cyclohexanediamide derivative exhibits sEH inhibitory activity, and an excellent therapeutic effect on chronic kidney disease and pulmonary hypertension based on its mechanism of action. The present invention was completed.
すなわち、本発明は、以下の一般式(I)で示されるシクロヘキサンジアミド誘導体を提供する。
[式中、R1は、水酸基、シアノ基、炭素数1~6のアルキル基若しくはアルキルオキシ基、炭素数3~6のシクロアルキル基、炭素数2~7のアルキルオキシアルキル基、炭素数4~7のシクロアルキルアルキル基(該アルキル基、該アルキルオキシ基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、-SR6、-S(=O)R6又は-S(=O)2R6で置換されていてもよい)、フェニルオキシ基(該フェニルオキシ基は、ベンゼン環の1~3個の水素原子が、それぞれ独立して、炭素数1~6のアルキルオキシ基で置換されていてもよい)、-N(H)C(=O)R7、-N(H)S(=O)2R7、-C(=O)N(H)R7又は-C(=O)OR7を表し、R2及びR3は、それぞれ独立して、水素原子(ただし、R2及びR3は、同時に水素原子を表すことはない)、炭素数1~6のアルキル基又は炭素数2~7のアルキルオキシアルキル基(該アルキル基及び該アルキルオキシアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい)を表すか、一緒になって-(CH2)l-を表すか、又は、さらにR1と一緒になってアダマンチル基を表してもよく、R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基又は炭素数1~6のアルキル基若しくはアルキルオキシ基(該アルキル基及び該アルキルオキシ基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子で置換されていてもよい)を表し、R6は、炭素数1~6のアルキル基を表し、R7は、炭素数1~6のアルキル基、炭素数3~6のシクロアルキル基、炭素数2~7のアルキルオキシアルキル基又は炭素数4~7のシクロアルキルアルキル基(該アルキル基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい)を表し、lは、2~5の整数を表す。]
That is, the present invention provides a cyclohexanediamide derivative represented by the following general formula (I).
[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 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) 1 to 3 hydrogen atoms may be independently substituted with an alkyloxy group having 1 to 6 carbon atoms), —N (H) C (═O) R 7 , —N (H ) S (= O) 2 R 7 , —C (═O) N (H) R 7 or —C (═O) OR 7 , wherein R 2 and R 3 are each independently a hydrogen atom (provided that R 2 and R 3 are simultaneously hydrogen An alkyl group having 1 to 6 carbon atoms or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkyloxyalkyl group are each independently formed by 1 to 3 hydrogen atoms). And may be substituted with a halogen atom, a hydroxyl group or a cyano group), together with — (CH 2 ) 1 —, or together with R 1 to form an adamantyl group 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 A cycloalkyl group having 6 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogen atoms each independently represents a halogen atom, a hydroxyl group or a cyano group), and l represents an integer of 2 to 5. ]
上記のシクロヘキサンジアミド誘導体は、R2及びR3が、それぞれ独立して、水素原子若しくは炭素数1~6のアルキル基を表すか、又は、一緒になって-(CH2)l-を表し、R5が、ベンゼン環上の2位の置換基であることが好ましい。
In the above cyclohexanediamide derivative, R 2 and R 3 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent — (CH 2 ) 1 —, R 5 is preferably a substituent at the 2-position on the benzene ring.
この場合には、より強いsEH阻害活性が期待できる点で優れている。
In this case, it is excellent in that a stronger sEH inhibitory activity can be expected.
また、上記のシクロヘキサンジアミド誘導体は、R1が、炭素数1~6のアルキル基又は-N(H)C(=O)R7であり、R4が、ハロゲン原子、シアノ基又は炭素数1~6のアルキル基若しくはアルキルオキシ基であり、R5が、ハロゲン原子又は炭素数1~6のアルキル基若しくはアルキルオキシ基であることがより好ましい。
In the cyclohexanediamide derivative, R 1 is an alkyl group having 1 to 6 carbon atoms or —N (H) C (═O) R 7 , and R 4 is a halogen atom, a cyano group, or 1 carbon atom. It is more preferable that R 5 is a halogen atom or an alkyl group or alkyloxy group having 1 to 6 carbon atoms.
この場合には、より強いsEH阻害活性が期待でき、加えて、薬物動態も優れていることから、慢性腎臓病及び肺高血圧症におけるより優れた治療効果が期待できる。
In this case, stronger sEH inhibitory activity can be expected, and in addition, since the pharmacokinetics are also excellent, a more excellent therapeutic effect in chronic kidney disease and pulmonary hypertension can be expected.
また本発明は、上記のシクロヘキサンジアミド誘導体を有効成分として含有するsEH阻害剤を提供する。
The present invention also provides an sEH inhibitor containing the above cyclohexanediamide derivative as an active ingredient.
さらに本発明は、上記のシクロヘキサンジアミド誘導体を有効成分として含有する医薬を提供する。この医薬は、慢性腎臓病若しくは肺高血圧症の治療剤又は予防剤であることが特に好ましい。
Furthermore, 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.
本発明のシクロヘキサンジアミド誘導体は、sEH阻害活性が強いことから、その作用メカニズムに基づき慢性腎臓病及び肺高血圧症に対して高い治療効果又は予防効果を発揮でき、患者の症状に合わせて、副作用を軽減した処方を選択できる。
Since 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.
本発明のシクロヘキサンジアミド誘導体は、以下の一般式(I)で示されることを特徴としている。
[式中、R1は、水酸基、シアノ基、炭素数1~6のアルキル基若しくはアルキルオキシ基、炭素数3~6のシクロアルキル基、炭素数2~7のアルキルオキシアルキル基、炭素数4~7のシクロアルキルアルキル基(該アルキル基、該アルキルオキシ基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、-SR6、-S(=O)R6又は-S(=O)2R6で置換されていてもよい)、フェニルオキシ基(該フェニルオキシ基は、ベンゼン環の1~3個の水素原子が、それぞれ独立して、炭素数1~6のアルキルオキシ基で置換されていてもよい)、-N(H)C(=O)R7、-N(H)S(=O)2R7、-C(=O)N(H)R7又は-C(=O)OR7を表し、R2及びR3は、それぞれ独立して、水素原子(ただし、R2及びR3は、同時に水素原子を表すことはない)、炭素数1~6のアルキル基又は炭素数2~7のアルキルオキシアルキル基(該アルキル基及び該アルキルオキシアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい)を表すか、一緒になって-(CH2)l-を表すか、又は、さらにR1と一緒になってアダマンチル基を表してもよく、R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基又は炭素数1~6のアルキル基若しくはアルキルオキシ基(該アルキル基及び該アルキルオキシ基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子で置換されていてもよい)を表し、R6は、炭素数1~6のアルキル基を表し、R7は、炭素数1~6のアルキル基、炭素数3~6のシクロアルキル基、炭素数2~7のアルキルオキシアルキル基又は炭素数4~7のシクロアルキルアルキル基(該アルキル基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい)を表し、lは、2~5の整数を表す。]
The cyclohexanediamide derivative of the present invention is characterized by being represented by the following general formula (I).
[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 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) 1 to 3 hydrogen atoms may be independently substituted with an alkyloxy group having 1 to 6 carbon atoms), —N (H) C (═O) R 7 , —N (H ) S (= O) 2 R 7 , —C (═O) N (H) R 7 or —C (═O) OR 7 , wherein R 2 and R 3 are each independently a hydrogen atom (provided that R 2 and R 3 are simultaneously hydrogen An alkyl group having 1 to 6 carbon atoms or an alkyloxyalkyl group having 2 to 7 carbon atoms (the alkyl group and the alkyloxyalkyl group are each independently formed by 1 to 3 hydrogen atoms). And may be substituted with a halogen atom, a hydroxyl group or a cyano group), together with — (CH 2 ) 1 —, or together with R 1 to form an adamantyl group 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 A cycloalkyl group having 6 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, the cycloalkyl group, the alkyloxyalkyl group, and the cycloalkylalkyl group are 1 to 3 hydrogen atoms each independently represents a halogen atom, a hydroxyl group or a cyano group), and l represents an integer of 2 to 5. ]
「炭素数1~6のアルキル基」とは、炭素原子を1~6個有する直鎖状又は炭素原子を3~6個有する分岐鎖状の飽和炭化水素基を意味し、例えば、メチル基、エチル基、1-プロピル基、2-プロピル基、1-ブチル基、2-ブチル基、2-メチル-2-プロピル基(tert-ブチル基)、2-メチル-1-プロピル基、2,2-ジメチル-1-プロピル基、1-ペンチル基、2-ペンチル基又は3-ペンチル基が挙げられる。
“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.
「炭素数1~6のアルキルオキシ基」とは、上記の炭素数1~6のアルキル基が酸素原子に結合した基を意味し、例えば、メトキシ基、エトキシ基、1-プロピルオキシ基、2-プロピルオキシ基、1-ブチルオキシ基又は2-ブチルオキシ基が挙げられる。
The “C 1-6 alkyloxy group” means a group in which the above C 1-6 alkyl group is bonded to an oxygen atom, such as a methoxy group, an ethoxy group, a 1-propyloxy group, -Propyloxy group, 1-butyloxy group or 2-butyloxy group.
「炭素数3~6のシクロアルキル基」とは、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基を意味する。
“C3-C6 cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
「炭素数2~7のアルキルオキシアルキル基」とは、炭素原子を2~7個有し、アルキル基の1個の水素原子がアルキルオキシ基で置換された基を意味し、例えば、メトキシメチル基、メトキシエチル基、メトキシプロピル基、エトキシメチル基、プロポキシメチル基又はイソプロポキシメチル基が挙げられる。
“C2-C7 alkyloxyalkyl group” means a group having 2 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with an alkyloxy group. Group, methoxyethyl group, methoxypropyl group, ethoxymethyl group, propoxymethyl group or isopropoxymethyl group.
「炭素数4~7のシクロアルキルアルキル基」とは、炭素原子を4~7個有し、アルキル基の1個の水素原子がシクロアルキル基で置換された基を意味し、例えば、シクロプロピルメチル基、シクロプロピルエチル基、シクロプロピルプロピル基、シクロブチルメチル基、シクロペンチルメチル基又はシクロヘキシルメチル基が挙げられる。
The “cycloalkyl alkyl group having 4 to 7 carbon atoms” means a group having 4 to 7 carbon atoms in which one hydrogen atom of the alkyl group is substituted with a cycloalkyl group. Examples thereof include a methyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子又はヨウ素原子を意味する。
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
上記のシクロヘキサンジアミド誘導体は、一般式(I)において、R1は、水酸基、炭素数1~6のアルキル基又は-N(H)C(=O)R7であることが好ましく、炭素数1~6のアルキル基又は-N(H)C(=O)R7であることがより好ましく、メチル基又はプロピオンアミジル基であることがさらに好ましい。この場合、炭素数1~6のアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、-SR6、-S(=O)R6又は-S(=O)2R6で置換されていてもよい。
In the above-mentioned cyclohexanediamide derivative, in general formula (I), 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. In this case, in the alkyl group having 1 to 6 carbon atoms, 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.
R2及びR3は、それぞれ独立して、水素原子若しくは炭素数1~6のアルキル基であるか、又は、一緒になって-(CH2)l-であることが好ましく、それぞれ独立して、水素原子若しくは炭素数1~3のアルキル基であるか、又は、一緒になって-(CH2)2-若しくは-(CH2)3-であることがより好ましく、それぞれ独立して、水素原子、メチル基又は2-プロピル基であることがさらに好ましい。
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.
R4は、ハロゲン原子、シアノ基又は炭素数1~6のアルキル基若しくはアルキルオキシ基であることが好ましく、ハロゲン原子又はシアノ基であることがより好ましい。
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.
R5は、ベンゼン環上の2位の置換基であることが好ましい。また、R5は、ハロゲン原子又は炭素数1~6のアルキル基若しくはアルキルオキシ基であることが好ましく、ハロゲン原子又は炭素数1~6のアルキルオキシ基であることがより好ましく、トリフルオロメトキシ基であることがさらに好ましい。
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.
R6は、メチル基であることが好ましい。
R 6 is preferably a methyl group.
R7は、メチル基又はエチル基であることが好ましい。
R 7 is preferably a methyl group or an ethyl group.
lは、2又は3であることが好ましい。
L is preferably 2 or 3.
上記の一般式(I)で示されるシクロヘキサンジアミド誘導体(以下、シクロヘキサンジアミド誘導体(I))は、不斉炭素原子を有する化合物を包含している。この場合、光学異性体やジアステレオマーが存在するものであるが、シクロヘキサンジアミド誘導体(I)は単一異性体のみならず、ラセミ体及びジアステレオマー混合物も包含するものである。
The cyclohexanediamide derivative represented by the above general formula (I) (hereinafter, cyclohexanediamide derivative (I)) includes a compound having an asymmetric carbon atom. In this case, 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.
シクロヘキサンジアミド誘導体(I)の製造に使用する出発物質と試薬は、市販品をそのまま利用してもよいし、又は、公知の方法により合成しても構わない。
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.
シクロヘキサンジアミド誘導体(I-a)は、例えば、以下のスキーム1に示すように、塩基及び縮合剤存在下、アミン誘導体(II)とカルボン酸誘導体(III)との縮合反応により製造できる。
[式中、R1’は、水酸基、シアノ基、炭素数1~6のアルキル基若しくはアルキルオキシ基、炭素数3~6のシクロアルキル基、炭素数2~7のアルキルオキシアルキル基、炭素数4~7のシクロアルキルアルキル基(該アルキル基、該アルキルオキシ基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基、シアノ基、-SR6、-S(=O)-R6又は-S(=O)2R6で置換されていてもよい)、-N(H)C(=O)R7、-C(=O)N(H)R7又は-C(=O)OR7を表す。R2~R7は、上記定義に同じ。]
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.
[Wherein 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. ]
縮合反応に用いる縮合剤としては、例えば、シクロヘキシルカルボジイミド、N-エチル-N’-3-ジメチルアミノプロピルカルボジイミド塩酸塩、ベンゾトリアゾール-1-イルオキシ-トリスジメチルアミノホスホニウム塩(BOP試薬)、1-[ビス(ジメチルアミノ)メチレン]-1H-ベンゾトリアゾリウム-3-オキシドヘキサフルオロホスファート(HBTU)又はO-(7-アザベンゾトリアゾール-1-イル)テトラメチルウロニウム ヘキサフルオロホスファート(以下、HATU)が挙げられるが、HATUが好ましい。該縮合剤の当量は、アミン誘導体(II)に対して1~10当量が好ましく、1~3当量がより好ましい。
Examples of the condensing agent used in the condensation reaction include cyclohexylcarbodiimide, N-ethyl-N′-3-dimethylaminopropylcarbodiimide hydrochloride, benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent), 1- [ Bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU) or O- (7-azabenzotriazol-1-yl) tetramethyluronium hexafluorophosphate HATU), and HATU is preferred. The equivalent of the condensing agent is preferably 1 to 10 equivalents and more preferably 1 to 3 equivalents with respect to the amine derivative (II).
縮合反応に用いる溶媒としては、例えば、N,N-ジメチルホルムアミド(以下、DMF)、テトラヒドロフラン(以下、THF)、ジクロロメタン、クロロホルム、ジエチルエーテル又はジメチルエーテルが挙げられるが、DMF又はTHFが好ましく、DMFがより好ましい。
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.
縮合反応に用いる塩基としては、例えば、ジイソプロピルエチルアミン(以下、DIPEA)、トリエチルアミン(以下、TEA)、ピリジン若しくはN-メチルモルホリン等の有機塩基又は炭酸カリウム、炭酸ナトリウム若しくは炭酸水素ナトリウム等の有機酸塩が挙げられるが、DIPEA又はTEAが好ましい。該塩基の当量は、アミン誘導体(II)に対して1~100当量が好ましく、1~10当量がより好ましい。
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).
縮合反応に用いるカルボン酸誘導体(III)の当量は、アミン誘導体(II)に対して0.1~100当量が好ましく、0.1~10当量がより好ましく、0.8~2当量がさらに好ましい。
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). .
縮合反応の反応温度は、-50~100℃が好ましく、0~50℃がより好ましく、0~30℃がさらに好ましい。また、縮合反応の反応時間は、1分間~48時間が好ましく、1分間~24時間がより好ましく、10分間~24時間がさらに好ましい。
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.
縮合反応におけるアミン誘導体(II)の反応開始時の濃度は、0.01~100Mが好ましく、0.01~10Mがより好ましく、0.1~10Mがさらに好ましい。
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.
R1が、-N(H)C(=O)R7であるシクロヘキサンジアミド誘導体(I-b)は、例えば、以下のスキーム2に示すように、塩基存在下、アミン誘導体(IV)と酸クロリド誘導体(V)との縮合反応、又は、塩基及び縮合剤存在下、アミン誘導体(IV)とカルボン酸誘導体(VI)との縮合反応により製造できる。
[式中、R2~R5及びR7は、上記定義に同じ。]
Cyclohexanediamide derivative (Ib), in which R 1 is —N (H) C (═O) R 7 , is represented by, for example, amine derivative (IV) and acid in the presence of a base, as shown in Scheme 2 below. It can be produced by a condensation reaction with a 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.
[Wherein R 2 to R 5 and R 7 are the same as defined above]. ]
酸クロリド誘導体(V)との縮合反応に用いる溶媒としては、例えば、ジクロロメタン、1,2-ジクロロエタン、アセトニトリル、DMF、THF、ジオキサン、ジエチルエーテル又は1,2-ジメトキシエタンが挙げられるが、ジクロロメタン、1,2-ジクロロエタン、アセトニトリル又はTHFが好ましく、ジクロロメタン又は1,2-ジクロロエタンがより好ましい。
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.
酸クロリド誘導体(V)との縮合反応に用いる酸クロリド(V)の当量は、アミン誘導体(IV)に対して0.1~10当量が好ましく、1~3当量がより好ましく、1~1.5当量がさらに好ましい。
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.
酸クロリド誘導体(V)との縮合反応に用いる塩基としては、例えば、DIPEA、TEA、ピリジン又はN-メチルモルホリン等の有機塩基が挙げられるが、DIPEA又はTEAが好ましい。該塩基の当量は、アミン誘導体(IV)に対して1~100当量が好ましく、1~10当量がより好ましい。
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).
酸クロリド誘導体(V)との縮合反応の反応温度は、-50~100℃が好ましく、-20~60℃がより好ましく、0~40℃がさらに好ましい。また、酸クロリド(V)との縮合反応の反応時間は、30分間~24時間が好ましく、30分間~12時間がより好ましく、30分間~8時間がさらに好ましい。
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.
酸クロリド誘導体(V)との縮合反応におけるアミン誘導体(IV)の反応開始時の濃度は、0.01~100Mが好ましく、0.01~10Mがより好ましく、0.1~10Mがさらに好ましい。
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.
一方、アミン誘導体(IV)とカルボン酸誘導体(VI)との縮合反応は、スキーム1と同様の条件により行うことができる。
On the other hand, the condensation reaction between the amine derivative (IV) and the carboxylic acid derivative (VI) can be performed under the same conditions as in Scheme 1.
R1が、-N(H)S(=O)2R7であるシクロヘキサンジアミド誘導体(I-c)は、例えば、以下のスキーム3に示すように、塩基存在下、アミン誘導体(IV)とスルホン酸クロリド誘導体(VII)とのスルホンアミド化反応により製造できる。
[式中、R2~R5及びR7は、上記定義に同じ。]
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]. ]
スルホンアミド化反応に用いる溶媒としては、例えば、ジクロロメタン、1,2-ジクロロエタン、アセトニトリル、DMF、THF、ジオキサン、ジエチルエーテル又は1,2-ジメトキシエタンが挙げられるが、ジクロロメタン、1,2-ジクロロエタン、アセトニトリル又はTHFが好ましく、ジクロロメタン又は1,2-ジクロロエタンがより好ましい。
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.
スルホンアミド化反応に用いるスルホン酸クロリド誘導体(VII)の当量は、アミン誘導体(IV)に対して0.1~10当量が好ましく、1~3当量がより好ましく、1~1.5当量がさらに好ましい。
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.
スルホンアミド化反応に用いる塩基としては、例えば、DIPEA、TEA、ピリジン又はN-メチルモルホリン等の有機塩基が挙げられるが、DIPEA又はTEAが好ましい。該塩基の当量は、アミン誘導体(IV)に対して1~100当量が好ましく、1~10当量がより好ましい。
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).
スルホンアミド化反応の反応温度は、-50~50℃が好ましく、-30~30℃がより好ましく、-20~20℃がさらに好ましい。また、スルホンアミド化反応の反応時間は、30分間~24時間が好ましく、30分間~12時間がより好ましく、30分間~8時間がさらに好ましい。
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.
スルホンアミド化反応におけるアミン誘導体(IV)の反応開始時の濃度は、0.01~100Mが好ましく、0.01~10Mがより好ましく、0.1~10Mがさらに好ましい。
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.
上記のスキーム2及び3における出発物質であるアミン誘導体(IV)は、例えば、以下のスキーム4に示すように、塩基存在下、アミン誘導体(II)とカルボン酸誘導体(VIII)との縮合反応後、保護基を除去する脱保護反応により製造できる。
[式中、R2~R5は、上記定義に同じであり、R8は、保護基を表す。]
The amine derivative (IV) which is the starting material in the above-mentioned schemes 2 and 3 is, for example, after the condensation reaction between the amine derivative (II) and the carboxylic acid derivative (VIII) in the presence of a base, as shown in the following scheme 4. Can be produced by a deprotection reaction to remove the protecting group.
[Wherein R 2 to R 5 are the same as defined above, and R 8 represents a protecting group. ]
アミン誘導体(II)とカルボン酸誘導体(VIII)との縮合反応は、スキーム1と同様の条件により行うことができる。
The condensation reaction of the amine derivative (II) and the carboxylic acid derivative (VIII) can be performed under the same conditions as in Scheme 1.
縮合反応に続く脱保護反応は、例えば、Protective Groups in Organic Synthesis第3版(Greenら著、1999年、John Wiley & Sons,Inc.)に記されている公知の方法により行うことができる。例えば、保護基が、tert-ブトキシカルボニル基である場合には、トリフルオロ酢酸(以下、TFA)等の強酸で処理することで保護基を除去することができる。
The deprotection reaction following the condensation reaction can be performed by a known method described in, for example, Protective Groups in Organic Synthesis 3rd Edition (Green et al., 1999, John Wiley & Sons, Inc.). For example, when the protecting group is a tert-butoxycarbonyl group, the protecting group can be removed by treatment with a strong acid such as trifluoroacetic acid (hereinafter, TFA).
上記のスキーム4におけるカルボン酸誘導体(VIII)は、市販品をそのまま利用してもよいし、又は、公知の方法により製造しても構わない。
As the carboxylic acid derivative (VIII) in the above scheme 4, a commercially available product may be used as it is, or it may be produced by a known method.
上記のスキーム1及び4における出発物質であるアミン誘導体(II)は、例えば、以下のスキーム5に示すように、塩基及び縮合剤存在下、ベンジルアミン誘導体(IX)とシクロヘキサン誘導体(X)との縮合反応後、保護基を除去する脱保護反応により製造できる。
[式中、R4、R5及びR8は、上記定義に同じ。]
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. ]
ベンジルアミン誘導体(IX)とシクロヘキサン誘導体(X)との縮合反応は、スキーム1と同様の条件により行うことができる。
The condensation reaction of the benzylamine derivative (IX) and the cyclohexane derivative (X) can be performed under the same conditions as in Scheme 1.
脱保護反応は、スキーム4記載の方法と同様の条件にて行うことができる。
The deprotection reaction can be carried out under the same conditions as in the method described in Scheme 4.
スキーム5の縮合反応は、シクロヘキサン誘導体(X)を酸クロリドへ変換し、塩基存在下にて行うこともできる。
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.
シクロヘキサン誘導体(X)を酸クロリドへ変換する試薬としては、オキサリルクロリド又は塩化チオニルが挙げられるが、オキサリルクロリドが好ましい。該試薬の当量は、シクロヘキサン誘導体(X)に対して1~10当量が好ましく、1~1.5当量がより好ましい。
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).
シクロヘキサン誘導体(X)を酸クロリドへ変換する際に用いる溶媒としては、ジクロロメタン、クロロホルム、THF、1,2-ジクロロエタン、アセトニトリル、1,4-ジオキサン若しくはDMF、または、これらの混合溶媒が挙げられるが、ジクロロメタン、THF若しくはDMF、又は、これらの混合溶媒が好ましく、ジクロロメタンとDMFとの混合溶媒又はTHFとDMFとの混合溶媒がより好ましい。混合溶媒の比率としては、例えば、ジクロロメタンとDMFとの混合溶媒の場合、ジクロロメタン:DMF=1~1000:1が好ましく、1~100:1がより好ましい。
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. As a ratio of the mixed solvent, for example, in the case of a mixed solvent of dichloromethane and DMF, dichloromethane: DMF = 1 to 1000: 1 is preferable, and 1 to 100: 1 is more preferable.
シクロヘキサン誘導体(X)を酸クロリドへ変換する際の反応温度は、-50~100℃が好ましく、-30~30℃が好ましく、-20~0℃がさらに好ましい。また、シクロヘキサン誘導体(X)を酸クロリドへ変換する際の反応時間は、30分間~24時間が好ましく、30分間~12時間がより好ましく、30分間~2時間がさらに好ましい。
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.
シクロヘキサン誘導体(X)を酸クロリドへ変換する際の反応開始時のシクロヘキサン誘導体(X)の濃度は、0.01~100Mが好ましく、0.01~10Mがより好ましく、0.1~3Mがさらに好ましい。
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.
上記のスキーム5におけるベンジルアミン誘導体(IX)は、市販品をそのまま利用してもよいし、又は、公知の方法により製造しても構わない。
As the 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.
また、シクロヘキサンジアミド誘導体(I-b)は、例えば、以下のスキーム6に示すように、塩基及び縮合剤存在下、ベンジルアミン誘導体(IX)とカルボン酸誘導体(XI)との縮合反応によっても製造できる。
[式中、R2~R5及びR7は、上記定義に同じ。]
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]. ]
ベンジルアミン誘導体(IX)とカルボン酸誘導体(XI)との縮合反応は、スキーム1と同様の条件により行うことができる。
The condensation reaction of the benzylamine derivative (IX) and the carboxylic acid derivative (XI) can be performed under the same conditions as in Scheme 1.
上記のスキーム6における出発物質であるカルボン酸誘導体(XI)は、例えば、以下のスキーム7に示すように、塩基存在下、アミン誘導体(XII)と酸クロリド誘導体(V)との縮合反応、又は、塩基及び縮合剤存在下、アミン誘導体(XII)とカルボン酸誘導体(VI)との縮合反応後、保護基を除去する脱保護反応により製造できる。
[式中、R2、R3及びR7は、上記定義に同じであり、R9は、保護基を表す。]
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.
[Wherein R 2 , R 3 and R 7 are the same as defined above, and R 9 represents a protecting group. ]
アミン誘導体(XII)と酸クロリド誘導体(V)との縮合反応、又は、アミン誘導体(XII)とカルボン酸誘導体(VI)との縮合反応は、スキーム2と同様の条件により行うことができる。
The 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.
縮合反応に続く脱保護反応は、例えば、Protective Groups in Organic Synthesis第3版(Greenら著、1999年、John Wiley & Sons,Inc.)に記されている公知の方法により行うことができる。例えば、保護基が、メチル基である場合には、水酸化ナトリウム等の強塩基で処理することで保護基を除去することができる。
The deprotection reaction following the condensation reaction can be performed by a known method described in, for example, Protective Groups in Organic Synthesis 3rd Edition (Green et al., 1999, John Wiley & Sons, Inc.). For example, when the protecting group is a methyl group, the protecting group can be removed by treatment with a strong base such as sodium hydroxide.
上記のスキーム7における出発物質であるアミン誘導体(XII)は、例えば、以下のスキーム8に示すように、塩基及び縮合剤存在下、アミン誘導体(XIII)とカルボン酸誘導体(VIII)との縮合反応後、保護基を除去する脱保護反応により製造できる。
[式中、R2、R3、R8及びR9は、上記定義に同じ。]
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.
[Wherein R 2 , R 3 , R 8 and R 9 are the same as defined above. ]
アミン誘導体(XIII)とカルボン酸誘導体(VIII)との縮合反応は、スキーム1と同様の条件により行うことができる。
The condensation reaction of the amine derivative (XIII) and the carboxylic acid derivative (VIII) can be performed under the same conditions as in Scheme 1.
脱保護反応は、スキーム4記載の方法と同様の条件にて行うことができる。
The deprotection reaction can be carried out under the same conditions as in the method described in Scheme 4.
以上のようにして得られる上記のシクロヘキサンジアミド誘導体(I)、又は、上記のシクロヘキサンジアミド誘導体(I)の製造に用いる中間体、原料化合物若しくは試薬は、必要に応じて、抽出、蒸留、クロマトグラフィー又は再結晶等の方法で単離、精製してもよい。
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.
また、本発明の医薬、sEH阻害剤並びに慢性腎臓病若しくは肺高血圧症の治療剤及び予防剤は、シクロヘキサンジアミド誘導体(I)を有効成分として含有することを特徴としている。
Further, 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.
上記のシクロヘキサンジアミド誘導体(I)は、強力なsEH阻害活性を示すことから、医薬及びsEH阻害剤として用いることができ、特に、過剰なsEHによるEETs存在量の減少に起因する疾患である、慢性腎臓病及び肺高血圧症の治療剤又は予防剤として、好ましく用いられる。
Since 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」は、基質であるエポキシドの加水分解を触媒し、対応するジオールに変換する、生体内において重要な代謝酵素である。sEHの最も知られた基質は、内皮細胞由来の過分極因子の一つであるEETsであり、sEHは、EETsをDHETsに代謝し、失活させる。EETsは、血圧上昇抑制作用及び血管内皮保護作用を有しており、腎臓や肺の疾患において臓器保護作用を示すことが知られている(The Journal of the Federation of America Societies for Experimantal Biology、2010年、第24巻、P.3770-3781及びAJP-Heart and Circulatory Physiology、2006年、第291巻、H517-H531)。
“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阻害活性」とは、sEHの作用を阻害する活性を意味する。したがって、sEH阻害活性とは、sEHの基質の一つであるEETsの加水分解を触媒するというsEHの酵素反応を阻害する活性を包含する。
“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阻害剤」とは、sEH阻害活性を示す化合物又は該化合物を有効成分として含有する組成物を意味する。
“SEH inhibitor” means a compound showing sEH inhibitory activity or a composition containing the compound as an active ingredient.
sEH阻害活性は、例えば、ヒトsEHと、その基質であるEETsとをsEH阻害剤の存在下で反応させ、産生されるDHETsの量を、sEH阻害剤非存在下におけるDHETs産生量と比較することで測定できる。また、市販の測定キット(Soluble Epoxide Hydrolase Inhibitor Screening Assay Kit;Cayman社)を用いるか、公知文献(Analytical Biochemistry、2005年、第343巻、p.66-75、等)に記載の方法によっても、sEH阻害剤のsEH阻害活性を測定できる。
The sEH inhibitory activity is, for example, that human sEH and its substrate EETs are reacted in the presence of an sEH inhibitor, and the amount of DHETs produced is compared with the amount of DHETs produced in the absence of the sEH inhibitor. Can be measured. In addition, a commercially available measurement kit (Soluable Epoxide Hydrose Inhibitor Screening Assay Kit; Cayman) is used, or is described in a publicly known document (Analytical Biochemistry, 2005, Vol. 343, p. 66-75, etc.). The sEH inhibitory activity of the sEH inhibitor can be measured.
また、sEH阻害剤存在下及び非存在下で、sEHの基質としてラセミ性4-ニトロフェニル-トランス-2,3-エポキシ-3-フェニルプロピルカルボナートを用いて、4-ニトロフェノラート陰イオンの出現を測定するか、又は、sEHの基質としてシアノ(6-メトキシナフタレン-2-イル)メチル 2-(3-フェニルオキシラン-2-イル)アセタートを用いて、6-メトキシ-2-ナフトアルデヒドの出現を測定することによっても、sEH阻害剤のsEH阻害活性を測定できる。
In addition, in the presence and absence of an sEH inhibitor, racemic 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate was used as a substrate for sEH, and 4-nitrophenolate anion was used. The appearance of 6-methoxy-2-naphthaldehyde is measured using cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate as a substrate for sEH. The sEH inhibitory activity of the sEH inhibitor can also be measured by measuring the appearance.
「慢性腎臓病」とは、米国腎臓病財団―腎臓病患者の予後改善機構(The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative;K/DOQI)により定義された疾病を意味する。すなわち、(1)糸球体濾過量(Glomerular filtration rate;GFR)の減少の有無に関わらず、腎臓の構造上又は機能上の異常により定義される腎臓の障害を3ヶ月間以上にわたり有する疾病、又は、(2)腎臓の障害の有無に関わらず、糸球体濾過量が3ヶ月間以上にわたり60mL/分/1.73m2未満である疾病を意味する。
The term “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.
「肺高血圧症」とは、血液を心臓から肺に送る肺動脈圧の上昇を認める病態のうち、安静臥位での平均肺動脈圧が25mmHg以上の状態、又は、肺疾患、睡眠時無呼吸症候群及び肺胞低換気症候群では、平均肺動脈圧が安静時で20mmHg以上の状態(運動時では、30mmHg以上)、を意味する(ダイジェスト版 肺高血圧症治療ガイドライン(2006年改訂版)、P2-P3.)。
“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.) .
シクロヘキサンジアミド誘導体(I)の、慢性腎臓病に対する治療効果は、人為的に慢性腎臓病を誘発させた動物モデルを用いて評価することができる。そのような動物モデルとしては、例えば、マウスやラットを用いた抗糸球体基底膜抗血清(抗GBM抗血清)投与腎炎モデル(Kidney Internatinal、2003年、第64巻、p.1241-1252、等)又は5/6腎摘出による腎不全モデル(Journal of the American Society of Nephrology、2002年、第13巻、p.2909-2915、等)が挙げられる。なお、腎臓の機能上の異常は、血清クレアチニン値を測定することで確認できる。
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. As such 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.
また、シクロヘキサンジアミド誘導体(I)の、肺高血圧症に対する治療効果は、人為的に肺高血圧症を誘発させた動物モデルを用いて評価することができる。そのような動物モデルとしては、例えば、ラットを用いたモノクロタリン投与肺高血圧症モデル(Journal of Pharmacological Sciences、2009年、第111巻、p.235-243)が挙げられる。なお、肺動脈圧の上昇は、右心室収縮期圧を測定することで確認できる。また、肺高血圧症に伴う右心室肥大及び肺肥大の病態は、それぞれ、右心室重量比(右心室重量/(中隔重量+左心室重量))及び肺重量比(肺重量/体重)を測定することで確認できる。
Also, 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.
シクロヘキサンジアミド誘導体(I)を、医薬として用いる場合は、そのまま、又は、適当な剤形の医薬組成物として、哺乳動物(例えば、マウス、ラット、ハムスター、ウサギ、イヌ、サル、ウシ、ヒツジ又はヒト)に対して、経口的又は非経口的(例えば、経皮投与、静脈投与、直腸内投与、吸入投与、点鼻投与又は点眼投与)に投与することができる。
When the cyclohexanediamide derivative (I) is 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).
哺乳動物への投与のための剤形としては、例えば、錠剤、散剤、丸剤、カプセル剤、顆粒剤、シロップ剤、液剤、注射剤、乳剤、懸濁剤若しくは坐剤、又は公知の持続型製剤が挙げられる。これら剤形は、公知の方法によって製造でき、製剤分野において一般的に用いられる担体を含有するものである。そのような担体としては、例えば、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、あるいは、液状製剤における溶剤、溶解補助剤、懸濁化剤又は無痛化剤が挙げられる。また必要に応じて、等張化剤、緩衝剤、防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤又は湿潤剤等の添加物を用いても構わない。
Examples of the dosage form for administration to mammals include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions or suppositories, or known continuous forms. A formulation is mentioned. These dosage forms can be produced by a known method and contain a carrier generally used in the pharmaceutical field. Examples of such carriers include excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizers, suspending agents, or soothing agents in liquid preparations. Moreover, you may use additives, such as a tonicity agent, a buffering agent, antiseptic | preservative, an antioxidant, a coloring agent, a sweetener, an adsorbent, or a wetting agent, as needed.
賦形剤としては、例えば、乳糖、D-マンニトール、澱粉、ショ糖、コーンスターチ、結晶セルロース又は軽質無水ケイ酸が挙げられる。
Examples of the excipient include lactose, D-mannitol, starch, sucrose, corn starch, crystalline cellulose, and light anhydrous silicic acid.
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク又はコロイドシリカが挙げられる。
Examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.
結合剤としては、例えば、結晶セルロース、D-マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、澱粉、ショ糖、ゼラチン、メチルセルロース又はカルボキシメチルセルロースナトリウムが挙げられる。
Examples of the binder include crystalline cellulose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose or sodium carboxymethylcellulose.
崩壊剤としては、例えば、澱粉、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム又はL-ヒドロキシプロピルセルロースが挙げられる。
Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
溶剤としては、例えば、注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油又はトウモロコシ油が挙げられる。
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil or corn oil.
溶解補助剤としては、例えば、ポリエチレングリコール、プロピレングリコール、D-マンニトール、安息香酸ベンジル、エタノール、コレステロール、トリエタノールアミン、炭酸ナトリウム又はクエン酸ナトリウムが挙げられる。
Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, or sodium citrate.
懸濁化剤としては、例えば、ステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム若しくはモノステアリン酸グリセリン等の界面活性剤又はポリビニルアルコール、ポリビニルピロリドン、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース若しくはヒドロキシプロピルセルロース等の親水性高分子が挙げられる。
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride or glyceryl monostearate, or polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose. , Hydrophilic polymers such as hydroxymethylcellulose, hydroxyethylcellulose or hydroxypropylcellulose.
無痛化剤としては、例えば、ベンジルアルコールが挙げられる。
Examples of soothing agents include benzyl alcohol.
等張化剤としては、例えば、ブドウ糖、塩化ナトリウム、D-ソルビトール又はD-マンニトールが挙げられる。
Examples of the isotonic agent include glucose, sodium chloride, D-sorbitol, and D-mannitol.
緩衝剤としては、例えば、リン酸塩、酢酸塩、炭酸塩又はクエン酸塩等の緩衝液が挙げられる。
Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate or citrate.
防腐剤としては、例えば、パラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸又はソルビン酸が挙げられる。
Examples of the preservative include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
抗酸化剤としては、例えば、亜硫酸塩又はアスコルビン酸が挙げられる。
Examples of the antioxidant include sulfite and ascorbic acid.
上記の医薬は、シクロヘキサンジアミド誘導体(I)を、0.001~99重量%含有することが好ましく、0.01~99重量%含有することがより好ましい。シクロヘキサンジアミド誘導体(I)の、有効投与量及び投与回数は、投与形態、患者の年齢、体重又は治療すべき症状の性質若しくは重篤度によっても異なるが、通常成人1日当り1~1000mgを、好ましくは1~300mgを、1回又は数回に分けて投与することができる。
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.
なお、上記の医薬は、単独で投与してもよいが、疾患の予防効果若しくは治療効果の補完又は増強、あるいは投与量の低減のために、他の薬剤と配合するか、他の薬剤と併用して使用することもできる。
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.
配合又は併用し得る他の薬剤(以下、併用薬剤)としては、例えば、糖尿病治療剤、糖尿病性合併症治療剤、高脂血症治療剤、降圧剤、肺高血圧症治療剤、抗肥満剤、利尿剤、化学療法剤、免疫療法剤、抗血栓剤又は悪液質改善剤が挙げられる。
Examples of other drugs that can be combined or used together (hereinafter referred to as combination drugs) 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.
上記の医薬を併用薬剤と併用して使用する場合には、上記の医薬及び併用薬剤の投与時期は特に限定されず、これらを投与対象に対して同時に投与してもよいし、時間差をおいて投与しても構わない。また、併用薬剤は低分子化合物であってもよいし、タンパク質、ポリペプチド若しくは抗体等の高分子又はワクチン等であっても構わない。併用薬剤の投与量は、臨床上用いられている投与量を基準として、適宜選択することができる。上記の医薬と併用薬剤との配合比は、投与対象、投与ルート、対象疾患、症状又は、上記の医薬と併用薬剤の組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合には、シクロヘキサンジアミド誘導体(I)に対し、併用薬剤を0.01~99.99の配合比で用いればよい。
When using the above medicines in combination with a concomitant drug, the administration timing of the above medicine and the concomitant drug is not particularly limited, and these may be administered simultaneously to the administration subject, with a time difference. May be administered. 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).
糖尿病治療剤としては、例えば、ウシ若しくはブタの膵臓から抽出された動物インスリン製剤、大腸菌若しくは酵母を用いて遺伝子工学的に合成したヒトインスリン製剤、インスリン亜鉛、プロタミンインスリン亜鉛、インスリンのフラグメント若しくは誘導体等のインスリン製剤、塩酸ピオグリタゾン、トログリタゾン、ロシグリタゾン若しくはそのマレイン酸塩等のインスリン抵抗性改善剤、ボグリボース、アカルボース、ミグリトール若しくはエミグリテート等のα-グルコシダーゼ阻害剤、フェンホルミン、メトホルミン若しくはブホルミン等のビグアナイド剤、トルブタミド、グリベンクラミド、グリクラジド、クロルプロパミド、トラザミド、アセトヘキサミド、グリクロピラミド、グリメピリド、グリピザイド、グリブゾール、レパグリニド、ナテグリニド、ミチグリニド若しくはそのカルシウム塩水和物等のインスリン分泌促進剤、プラムリンチド等のアミリンアゴニスト、バナジン酸等のホスホチロシンホスファターゼ阻害剤、シタグリプチン、ビルダグリプチン、アログリプチン等のDPP-IV阻害剤、エクセナチド、リラグルチド等のGLP-1様作用物質、グリコーゲンホスホリラーゼ阻害剤、グルコース-6-ホスファターゼ阻害剤、グルカゴン拮抗剤又はSGLUT阻害剤が挙げられる。
Examples of diabetes therapeutic agents include animal insulin preparations extracted from bovine or porcine pancreas, human insulin preparations synthesized by genetic engineering using Escherichia coli or yeast, insulin zinc, protamine insulin zinc, insulin fragments or derivatives, etc. Insulin preparations, insulin resistance improvers such as pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, α-glucosidase inhibitors such as voglibose, acarbose, miglitol or emiglitate, biguanides such as phenformin, metformin or buformin, Tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide, acetohexamide, glyclopyramide, glimepiride, glipizide, glybzo Insulin secretion promoters such as repaglinide, nateglinide, mitiglinide or calcium salt hydrate thereof, amylin agonists such as pramlintide, phosphotyrosine phosphatase inhibitors such as vanadic acid, DPP-IV inhibitors such as sitagliptin, vildagliptin and alogliptin, exenatide, liraglutide GLP-1-like agents such as glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists or SGLUT inhibitors.
糖尿病性合併症治療剤としては、例えば、トルレスタット、エパルレスタット、ゼナレスタット、ゾポルレスタット、ミナルレスタット若しくはフィダレスタット等のアルドース還元酵素阻害剤、NGF、NT-3若しくはBDNF等の神経栄養因子、神経栄養因子産生・分泌促進剤、PKC阻害剤、AGE阻害剤、チオクト酸等の活性酸素消去剤又はチアプリド若しくはメキシレチン等の脳血管拡張剤が挙げられる。
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.
高脂血症治療剤としては、例えば、プラバスタチン、シンバスタチン、ロバスタチン、アトルバスタチン、フルバスタチン、リパンチル、セリバスタチン若しくはイタバスタチン等のHMG-CoA還元酵素阻害剤、ベザフィブラート、ベクロブラート、ビニフィブラート、シプロフィブラート、クリノフィブラート、クロフィブラート、クロフィブリン酸、エトフィブラート、フェノフィブラート、ゲムフィブロジル、ニコフィブラート、ピリフィブラート、ロニフィブラート、シムフィブラート若しくはテオフィブラート等のフィブラート系化合物、スクアレン合成酵素阻害剤、アバシマイブ若しくはエフルシマイブ等のACAT阻害剤、コレスチラミン等の陰イオン交換樹脂、プロブコール、ニコモール若しくはニセリトロール等のニコチン酸系薬剤又はイコサペント酸エチル、ソイステロール若しくはガンマオリザノール等の植物ステロールが挙げられる。
Examples of the therapeutic agent for hyperlipidemia include HMG-CoA reductase inhibitors such as pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, ripanstat, cerivastatin, and itavastatin, bezafibrate, beclobrate, vinifibrate, ciprofibrate, clinofibrate , Clofibrate, clofibric acid, etofibrate, fenofibrate, gemfibrozil, nicofibrate, pilifibrate, lonifibrate, fibrate compounds such as simfibrate or theofibrate, squalene synthase inhibitors, ACAT inhibitors such as avasimib or eflucimate , Anion exchange resins such as cholestyramine, probucol, nicomol or niceritrol Cochin acid drugs or ethyl icosapentate, plant sterols such as soysterol or gamma oryzanol.
降圧剤としては、例えば、カプトプリル、エナラプリル若しくはデラプリル等のアンジオテンシン変換酵素阻害剤、カンデサルタンシレキセチル、ロサルタン、エプロサルタン、バルサンタン、テルミサルタン、イルベサルタン若しくはタソサルタン等のアンジオテンシンII拮抗剤、マニジピン、ニフェジピン、ニカルジピン、アムロジピン若しくはエホニジピン等のカルシウム拮抗剤、レブクロマカリム等のカリウムチャンネル開口剤、クロニジン又はアリスキレンが挙げられる。
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.
肺高血圧症治療剤としては、例えば、ボセンタン、アンブリセンタン、シタキセンタン若しくはマシテンタン等のエンドセリン受容体拮抗剤、シルデナフィル、タダラフィル若しくはバルデナフィル等のPDE-5阻害剤、ベラプロスト、イロプロスト、エポプロステノール若しくはトレプロスチニル等のプロスタサイクリン製剤、PGI2アゴニストであるセレキシパグ又はファスジル、イマチニブ、ソラフェニブ若しくはバフェチニブ等のキナーゼ阻害剤が挙げられる。
Examples of 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. Examples include prostacyclin preparations, PEI2 agonists selexipag or kinase inhibitors such as fasudil, imatinib, sorafenib or bafetinib.
抗肥満剤としては、例えば、デキスフェンフルラミン、フェンフルラミン、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、マジンドール、フェニルプロパノールアミン若しくはクロベンゾレックス等の中枢性抗肥満剤、オルリスタット等の膵リパーゼ阻害剤、β3アゴニスト、レプチン若しくはCNTF(毛様体神経栄養因子)等のペプチド性食欲抑制剤又はリンチトリプト等のコレシストキニンアゴニストが挙げられる。
Examples of anti-obesity agents include central anti-obesity agents such as dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine or clobenzorex, pancreatic lipase such as orlistat Peptide appetite suppressants such as inhibitors, β3 agonists, leptin or CNTF (ciliary neurotrophic factor) or cholecystokinin agonists such as lynchtripto.
利尿剤としては、例えば、サリチル酸ナトリウムテオブロミン若しくはサリチル酸カルシウムテオブロミン等のキサンチン誘導体、エチアジド、シクロペンチアジド、トリクロルメチアジド、ヒドロクロロチアジド、ヒドロフルメチアジド、ベンチルヒドロクロロチアジド、ペンフルチジド、ポリチアジド若しくはメチクロチアジド等のチアジド系製剤、スピロノラクトン若しくはトリアムテレン等の抗アルドステロン製剤、アセタゾラミド等の炭酸脱水酵素阻害剤、クロルタリドン、メフルシド若しくはインダパミド等のクロルベンゼンスルホンアミド系製剤、アゾセミド、イソソルビド、エタクリン酸、ピレタニド、ブメタニド又はフロセミドが挙げられる。
Examples of the diuretic include xanthine derivatives such as sodium theobromide salicylate or calcium theobromide, ethiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, thiazide preparations such as benchylhydrochlorothiazide, penflutide, polythiazide or methycrothiazide. , Antialdosterone preparations such as spironolactone or triamterene, carbonic anhydrase inhibitors such as acetazolamide, chlorbenzenesulfonamide preparations such as chlorthalidone, mefluside or indapamide, azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide or furosemide.
化学療法剤としては、例えば、サイクロフォスファミド若しくはイフォスファミド等のアルキル化剤、メソトレキセート若しくは5-フルオロウラシル等の代謝拮抗剤、マイトマイシン若しくはアドリアマイシン等の抗癌性抗生物質、ビンクリスチン、ビンデシン若しくはタキソール等の植物由来抗癌剤、シスプラチン、オキサロプラチン、カルボプラチン又はエトポキシド等が挙げられる。
Examples of 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.
免疫療法剤としては、例えば、ムラミルジペプチド誘導体、ピシバニール、レンチナン、シゾフィラン、クレスチン、インターフェロン、インターロイキン(IL)、顆粒球コロニー刺激因子又はエリスロポエチン等が挙げられる。
Examples of the immunotherapeutic agent include muramyl dipeptide derivatives, picibanil, lentinan, schizophyllan, krestin, interferon, interleukin (IL), granulocyte colony stimulating factor or erythropoietin.
抗血栓剤としては、例えば、ヘパリンナトリウム、ヘパリンカルシウム若しくはダルテパリンナトリウム等のヘパリン、ワルファリンカリウム等のワルファリン、アルガトロバン等の抗トロンビン剤、ウロキナーゼ、チソキナーゼ、アルテプラーゼ、ナテプラーゼ、モンテプラーゼ若しくはパミテプラーゼ等の血栓溶解剤、塩酸チクロピジン、シロスタゾール、イコサペント酸エチル、ベラプロストナトリウム若しくは塩酸サルポグレラート等の血小板凝集抑制剤が挙げられる。
Examples of the antithrombotic agent 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, alteplase, nateplase, monteplase or pamiteplase. And platelet aggregation inhibitors such as ticlopidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium or sarpogrelate hydrochloride.
悪液質改善剤としては、例えば、インドメタシン若しくはジクロフェナック等のシクロオキシゲナーゼ阻害剤、メゲステロールアセテート等のプロゲステロン誘導体、デキサメサゾン等の糖質ステロイド、メトクロプラミド系薬剤、テトラヒドロカンナビノール系薬剤若しくはエイコサペンタエン酸等の脂肪代謝改善剤、成長ホルモン、IGF-1又は悪液質を誘導する因子であるTNF-α、LIF、IL-6若しくはオンコスタチンMに対する抗体が挙げられる。
Examples of cachexia-improving agents include cyclooxygenase inhibitors such as indomethacin or diclofenac, progesterone derivatives such as megesterol acetate, carbohydrate steroids such as dexamethasone, metoclopramide drugs, tetrahydrocannabinol drugs, and fats such as eicosapentaenoic acid. Examples thereof include antibodies to TNF-α, LIF, IL-6, or oncostatin M, which are agents that induce metabolism, growth hormone, IGF-1, or cachexia.
以下、実施例を挙げて本発明を具体的に説明するが、本発明はこれらに限定されるものではない。シリカゲルカラムクロマトグラフィーによる精製は、特に記述のない場合、「HI-FLASH」カラム(山善社製)又はPurif-α2(昭光サイエンティフィックス社製)を用いて行った。
Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited thereto. Purification by silica gel column chromatography was carried out using a “HI-FLASH” column (manufactured by Yamazen Co.) or Purif-α2 (manufactured by Shoko Scientific Co., Ltd.) unless otherwise specified.
(実施例1)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
4-ブロモ-2-(トリフルオロメトキシ)ベンズアルデヒド(以下、参考例化合物1)の合成:
-78℃下、4-ブロモ-1-ヨード-2-(トリフルオロメトキシ)ベンゼン(25g、68mmol)のTHF(0.40L)溶液に、n-ブチルリチウムヘキサン溶液(1.6規定、86mL、0.14mol)を1.5時間かけて滴下した。-78℃下で1時間撹拌した後、反応溶液に、DMF(11mL、0.14mmol)を10分間かけて滴下した。-78℃下で2時間撹拌した後、反応溶液に、クエン酸水溶液(0.25M、0.25L、63mmol)を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物1を16g(87%)得た。 Example 1
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of 4-bromo-2- (trifluoromethoxy) benzaldehyde (hereinafter referred to as Reference Example Compound 1):
To a THF (0.40 L) solution of 4-bromo-1-iodo-2- (trifluoromethoxy) benzene (25 g, 68 mmol) at −78 ° C., an n-butyllithium hexane solution (1.6 N, 86 mL, 0.14 mol) was added dropwise over 1.5 hours. After stirring at −78 ° C. for 1 hour, DMF (11 mL, 0.14 mmol) was added dropwise to the reaction solution over 10 minutes. After stirring at −78 ° C. for 2 hours, an aqueous citric acid solution (0.25 M, 0.25 L, 63 mmol) was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 16 g (87%) of Reference Example Compound 1.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
4-ブロモ-2-(トリフルオロメトキシ)ベンズアルデヒド(以下、参考例化合物1)の合成:
-78℃下、4-ブロモ-1-ヨード-2-(トリフルオロメトキシ)ベンゼン(25g、68mmol)のTHF(0.40L)溶液に、n-ブチルリチウムヘキサン溶液(1.6規定、86mL、0.14mol)を1.5時間かけて滴下した。-78℃下で1時間撹拌した後、反応溶液に、DMF(11mL、0.14mmol)を10分間かけて滴下した。-78℃下で2時間撹拌した後、反応溶液に、クエン酸水溶液(0.25M、0.25L、63mmol)を加え、ジエチルエーテルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物1を16g(87%)得た。 Example 1
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of 4-bromo-2- (trifluoromethoxy) benzaldehyde (hereinafter referred to as Reference Example Compound 1):
To a THF (0.40 L) solution of 4-bromo-1-iodo-2- (trifluoromethoxy) benzene (25 g, 68 mmol) at −78 ° C., an n-butyllithium hexane solution (1.6 N, 86 mL, 0.14 mol) was added dropwise over 1.5 hours. After stirring at −78 ° C. for 1 hour, DMF (11 mL, 0.14 mmol) was added dropwise to the reaction solution over 10 minutes. After stirring at −78 ° C. for 2 hours, an aqueous citric acid solution (0.25 M, 0.25 L, 63 mmol) was added to the reaction solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 16 g (87%) of Reference Example Compound 1.
〔ステップ2〕
(4-ブロモ-2-(トリフルオロメトキシ)フェニル)メタノール(以下、参考例化合物2)の合成:
-10℃下、参考例化合物1(16g、59mmol)のメタノール(0.23L)溶液に、水素化ホウ素ナトリウム(2.4g、63mmol)を加えた。-10℃下で10分間撹拌した後、反応溶液に、アセトン(10mL)及び1規定塩酸(10mL)を加えた。反応溶液を減圧濃縮し、得られた粗生成物に、水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:1→1:1)で精製し、参考例化合物2を15g(91%)得た。 [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. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 1 → 1: 1) to giveReference Example Compound 2 Of 15 g (91%).
(4-ブロモ-2-(トリフルオロメトキシ)フェニル)メタノール(以下、参考例化合物2)の合成:
-10℃下、参考例化合物1(16g、59mmol)のメタノール(0.23L)溶液に、水素化ホウ素ナトリウム(2.4g、63mmol)を加えた。-10℃下で10分間撹拌した後、反応溶液に、アセトン(10mL)及び1規定塩酸(10mL)を加えた。反応溶液を減圧濃縮し、得られた粗生成物に、水を加え、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:1→1:1)で精製し、参考例化合物2を15g(91%)得た。 [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. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 1 → 1: 1) to give
〔ステップ3〕
4-ブロモ-2-(トリフルオロメトキシ)ベンジル メタンスルホナート(以下、参考例化合物3)の合成:
室温下、参考例化合物2(0.63mL、7.4mmol)及びTEA(1.2mL、8.9mmol)のジクロロメタン(20mL)溶液に、メタンスルホニルクロリド(0.63mL、8.1mmol)を加えた。室温下で3時間撹拌した後、反応溶液に水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物3を2.6g(定量的)得た。 [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.
4-ブロモ-2-(トリフルオロメトキシ)ベンジル メタンスルホナート(以下、参考例化合物3)の合成:
室温下、参考例化合物2(0.63mL、7.4mmol)及びTEA(1.2mL、8.9mmol)のジクロロメタン(20mL)溶液に、メタンスルホニルクロリド(0.63mL、8.1mmol)を加えた。室温下で3時間撹拌した後、反応溶液に水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物3を2.6g(定量的)得た。 [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.
〔ステップ4〕
2-(4-ブロモ-2-(トリフルオロメトキシ)ベンジル)イソインドリン-1,3-ジオン(以下、参考例化合物4)の合成:
氷冷下、参考例化合物3(2.6g、7.4mmol)のDMF(20mL)溶液に、フタルイミドカリウム(2.1g、11mmol)を加えた。室温下で一晩撹拌した後、水を加えた。生じた固体をろ取した後、水で洗浄し、乾燥後、参考例化合物4を2.7g(91%)得た。 [Step 4]
Synthesis of 2- (4-bromo-2- (trifluoromethoxy) benzyl) isoindoline-1,3-dione (hereinafter referred to as Reference Example Compound 4):
Under ice cooling, potassium phthalimide (2.1 g, 11 mmol) was added to a DMF (20 mL) solution of Reference Example compound 3 (2.6 g, 7.4 mmol). After stirring overnight at room temperature, water was added. The resulting solid was collected by filtration, washed with water, and dried to obtain 2.7 g (91%) ofReference Example Compound 4.
2-(4-ブロモ-2-(トリフルオロメトキシ)ベンジル)イソインドリン-1,3-ジオン(以下、参考例化合物4)の合成:
氷冷下、参考例化合物3(2.6g、7.4mmol)のDMF(20mL)溶液に、フタルイミドカリウム(2.1g、11mmol)を加えた。室温下で一晩撹拌した後、水を加えた。生じた固体をろ取した後、水で洗浄し、乾燥後、参考例化合物4を2.7g(91%)得た。 [Step 4]
Synthesis of 2- (4-bromo-2- (trifluoromethoxy) benzyl) isoindoline-1,3-dione (hereinafter referred to as Reference Example Compound 4):
Under ice cooling, potassium phthalimide (2.1 g, 11 mmol) was added to a DMF (20 mL) solution of Reference Example compound 3 (2.6 g, 7.4 mmol). After stirring overnight at room temperature, water was added. The resulting solid was collected by filtration, washed with water, and dried to obtain 2.7 g (91%) of
〔ステップ5〕
(4-ブロモ-2-(トリフルオロメトキシ)フェニル)メタンアミン(以下、参考例化合物5)の合成:
室温下、参考例化合物4(2.6g、6.5mmol)のメタノール(40mL)溶液に、ヒドラジン一水和物(0.98g、19mmol)を加えた。60℃下で2時間撹拌した後、室温に冷却し、固体をろ別した。ろ液を減圧濃縮し、得られた粗生成物を酢酸エチルに溶解し、水及び飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物5を1.5g(85%)得た。 [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.
(4-ブロモ-2-(トリフルオロメトキシ)フェニル)メタンアミン(以下、参考例化合物5)の合成:
室温下、参考例化合物4(2.6g、6.5mmol)のメタノール(40mL)溶液に、ヒドラジン一水和物(0.98g、19mmol)を加えた。60℃下で2時間撹拌した後、室温に冷却し、固体をろ別した。ろ液を減圧濃縮し、得られた粗生成物を酢酸エチルに溶解し、水及び飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物5を1.5g(85%)得た。 [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.
〔ステップ6〕
tert-ブチル (cis-4-((4-ブロモ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)カルバメート(以下、参考例化合物6)の合成:
室温下、cis-4-((tert-ブトキシカルボニル)アミノ)シクロヘキサンカルボン酸(0.27g、1.1mmol)、参考例化合物5(0.30g、1.1mmol)及びDIPEA(0.48mL、2.7mmol)のDMF(3.0mL)溶液に、HATU(0.41g、1.1mmol)を加えた。室温下で4時間撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=90:10→40:60)で精製し、参考例化合物6を0.37g(68%)得た。 [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). After stirring at room temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 40: 60) to obtain 0.37 g (68%) of Reference Example Compound 6.
tert-ブチル (cis-4-((4-ブロモ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)カルバメート(以下、参考例化合物6)の合成:
室温下、cis-4-((tert-ブトキシカルボニル)アミノ)シクロヘキサンカルボン酸(0.27g、1.1mmol)、参考例化合物5(0.30g、1.1mmol)及びDIPEA(0.48mL、2.7mmol)のDMF(3.0mL)溶液に、HATU(0.41g、1.1mmol)を加えた。室温下で4時間撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=90:10→40:60)で精製し、参考例化合物6を0.37g(68%)得た。 [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). After stirring at room temperature for 4 hours, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 90: 10 → 40: 60) to obtain 0.37 g (68%) of Reference Example Compound 6.
〔ステップ7〕
tert-ブチル (cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)カルバメート(以下、参考例化合物7)の合成:
150度下、参考例化合物6(0.050g、0.10mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0.035g、0.030mmol)及びシアン化亜鉛(0.018g、0.15mmol)の1-メチル-2-ピロリドン(1.0mL)溶液をマイクロウェーブ反応装置(MONOWAVE300;アントンパール社製)にて、1時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=80:20→30:70)で精製し、参考例化合物7を0.015g(34%)得た。 [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). Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20 → 30: 70) to obtain 0.015 g (34%) of Reference Example Compound 7.
tert-ブチル (cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)カルバメート(以下、参考例化合物7)の合成:
150度下、参考例化合物6(0.050g、0.10mmol)、テトラキス(トリフェニルホスフィン)パラジウム(0.035g、0.030mmol)及びシアン化亜鉛(0.018g、0.15mmol)の1-メチル-2-ピロリドン(1.0mL)溶液をマイクロウェーブ反応装置(MONOWAVE300;アントンパール社製)にて、1時間撹拌した。反応溶液に水を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=80:20→30:70)で精製し、参考例化合物7を0.015g(34%)得た。 [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). Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20 → 30: 70) to obtain 0.015 g (34%) of Reference Example Compound 7.
〔ステップ8〕
cis-4-アミノ-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物8)の合成:
氷冷下、参考例化合物7(1.8g、4.2mmol)のジクロロメタン(40mL)溶液に、TFA(6.4mL、83mmol)を加えた。室温下で3時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をジクロロメタンに溶解させ、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物8を1.3g(93%)得た。 [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.
cis-4-アミノ-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物8)の合成:
氷冷下、参考例化合物7(1.8g、4.2mmol)のジクロロメタン(40mL)溶液に、TFA(6.4mL、83mmol)を加えた。室温下で3時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をジクロロメタンに溶解させ、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物8を1.3g(93%)得た。 [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.
〔ステップ9〕
(S)-3-メチル-2-プロピオナミドブタン酸メチル(以下、参考例化合物9)の合成:
氷冷下、L-バリンメチルエステル塩酸塩(10g、60mmol)及びピリジン(17mL、210mmol)のジクロロメタン(100mL)溶液に、プロピオニルクロリド(7.8mL、89mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に、水及び1規定塩酸を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=70:30→20:80)で精製し、参考例化合物9を12g(定量的)得た。 [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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 20: 80) to obtain 12 g (quantitative) of Reference Example Compound 9.
(S)-3-メチル-2-プロピオナミドブタン酸メチル(以下、参考例化合物9)の合成:
氷冷下、L-バリンメチルエステル塩酸塩(10g、60mmol)及びピリジン(17mL、210mmol)のジクロロメタン(100mL)溶液に、プロピオニルクロリド(7.8mL、89mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に、水及び1規定塩酸を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=70:30→20:80)で精製し、参考例化合物9を12g(定量的)得た。 [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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 20: 80) to obtain 12 g (quantitative) of Reference Example Compound 9.
〔ステップ10〕
(S)-3-メチル-2-プロピオナミドブタン酸(以下、参考例化合物10)の合成:
室温下、参考例化合物9(11g、60mmol)のメタノール(100mL)溶液に、1規定水酸化ナトリウム水溶液(90mL、90mmol)を加えた。室温下で3時間撹拌した後、反応溶液に1規定塩酸を加えて中和し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物10を8.5g(82%)得た。 [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.
(S)-3-メチル-2-プロピオナミドブタン酸(以下、参考例化合物10)の合成:
室温下、参考例化合物9(11g、60mmol)のメタノール(100mL)溶液に、1規定水酸化ナトリウム水溶液(90mL、90mmol)を加えた。室温下で3時間撹拌した後、反応溶液に1規定塩酸を加えて中和し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物10を8.5g(82%)得た。 [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.
〔ステップ11〕
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物1)の合成:
室温下、参考例化合物8(0.70g、2.1mmol)、参考例化合物10(0.34g、2.0mmol)及びDIPEA(0.85mL、4.9mmol)のDMF(20mL)溶液に、HATU(0.97g、2.5mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=90:10)で精製し、実施例化合物1を0.63g(65%)得た。 [Step 11]
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. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.63 g (65%) of Example Compound 1.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物1)の合成:
室温下、参考例化合物8(0.70g、2.1mmol)、参考例化合物10(0.34g、2.0mmol)及びDIPEA(0.85mL、4.9mmol)のDMF(20mL)溶液に、HATU(0.97g、2.5mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=90:10)で精製し、実施例化合物1を0.63g(65%)得た。 [Step 11]
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. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.63 g (65%) of Example Compound 1.
(実施例2)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-ピバルアミドシクロヘキサンカルボキサミド(以下、実施例化合物2)の合成:
氷冷下、参考例化合物8(0.15g、0.44mmol)及びピリジン(0.11mL、1.3mmol)のジクロロメタン(5.0mL)溶液に、ピバロイルクロリド(0.070mL、0.57mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=60:40→10:90)で精製し、実施例化合物2を0.13g(68%)得た。 (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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 60: 40 → 10: 90) to obtain 0.13 g (68%) ofExample Compound 2.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-ピバルアミドシクロヘキサンカルボキサミド(以下、実施例化合物2)の合成:
氷冷下、参考例化合物8(0.15g、0.44mmol)及びピリジン(0.11mL、1.3mmol)のジクロロメタン(5.0mL)溶液に、ピバロイルクロリド(0.070mL、0.57mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=60:40→10:90)で精製し、実施例化合物2を0.13g(68%)得た。 (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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 60: 40 → 10: 90) to obtain 0.13 g (68%) of
(実施例3)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-メチル-2-(メチルスルホナミド)プロパナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
2-メチル-2-(メチルスルホナミド)プロパン酸エチル(以下、参考例化合物11)の合成:
氷冷下、2-アミノ-2-メチルプロパン酸エチル塩酸塩(4.0g、24mmol)及びDIPEA(13mL、72mmol)のジクロロメタン溶液に、メタンスルホニルクロリド(1.9mL、25mmol)を加えた。室温下で2時間撹拌後、反応溶液に1規定塩酸を加え、クロロホルムで抽出した。有機層を水及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物を、シリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=10:1→1:1)にて精製し、参考例化合物11を4.3g(86%)得た。 (Example 3)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methyl-2- (methylsulfonamido) propanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of ethyl 2-methyl-2- (methylsulfonamide) propanoate (hereinafter referred to as Reference Example Compound 11):
Under ice-cooling, methanesulfonyl chloride (1.9 mL, 25 mmol) was added to a dichloromethane solution of ethyl 2-amino-2-methylpropanoate hydrochloride (4.0 g, 24 mmol) and DIPEA (13 mL, 72 mmol). After stirring at room temperature for 2 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1 → 1: 1) to obtain 4.3 g (86%) of Reference Example Compound 11.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-メチル-2-(メチルスルホナミド)プロパナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
2-メチル-2-(メチルスルホナミド)プロパン酸エチル(以下、参考例化合物11)の合成:
氷冷下、2-アミノ-2-メチルプロパン酸エチル塩酸塩(4.0g、24mmol)及びDIPEA(13mL、72mmol)のジクロロメタン溶液に、メタンスルホニルクロリド(1.9mL、25mmol)を加えた。室温下で2時間撹拌後、反応溶液に1規定塩酸を加え、クロロホルムで抽出した。有機層を水及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物を、シリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=10:1→1:1)にて精製し、参考例化合物11を4.3g(86%)得た。 (Example 3)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (2-methyl-2- (methylsulfonamido) propanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of ethyl 2-methyl-2- (methylsulfonamide) propanoate (hereinafter referred to as Reference Example Compound 11):
Under ice-cooling, methanesulfonyl chloride (1.9 mL, 25 mmol) was added to a dichloromethane solution of ethyl 2-amino-2-methylpropanoate hydrochloride (4.0 g, 24 mmol) and DIPEA (13 mL, 72 mmol). After stirring at room temperature for 2 hours, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1 → 1: 1) to obtain 4.3 g (86%) of Reference Example Compound 11.
〔ステップ2〕
2-メチル-2-(メチルスルホナミド)プロパン酸(以下、参考例化合物12)の合成:
室温下、参考例化合物11(4.0g、19mmol)のメタノール(35mL)溶液に、水酸化ナトリウム水溶液(1規定、29mL、29mmol)を加えた。室温下で8時間撹拌後、反応溶液を減圧濃縮した。得られた粗生成物を1規定塩酸に溶解させた後、クロロホルム:メタノール混合溶媒(10:1)にて抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物12を2.5g(72%)得た。 [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.
2-メチル-2-(メチルスルホナミド)プロパン酸(以下、参考例化合物12)の合成:
室温下、参考例化合物11(4.0g、19mmol)のメタノール(35mL)溶液に、水酸化ナトリウム水溶液(1規定、29mL、29mmol)を加えた。室温下で8時間撹拌後、反応溶液を減圧濃縮した。得られた粗生成物を1規定塩酸に溶解させた後、クロロホルム:メタノール混合溶媒(10:1)にて抽出した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物12を2.5g(72%)得た。 [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.
〔ステップ3〕
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-メチル-2-(メチルスルホナミド)プロパナミド)シクロヘキサンカルルボキサミド(以下、実施例化合物3)の合成:
氷冷下、参考例化合物12(0.074g、0.41mmol)及びDMF(1mL)のジクロロメタン(5mL)溶液に、オキザリルクロリド(0.037mL、0.43mmol)を加えた。室温下で30分撹拌後、氷冷下、参考例化合物8(0.10g、0.29mmol)及びDIPEA(0.015mL、0.88mmol)のジクロロメタン(10mL)溶液に、反応液を加えた。室温下で30分撹拌後、反応液に水を加え、ジエチルエーテルで抽出した。有機層を0.1規定塩酸、水及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物を、シリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製し、実施例化合物3を0.11g(75%)を得た。 [Step 3]
of 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). After stirring at room temperature for 30 minutes, the reaction solution was added to a dichloromethane (10 mL) solution of Reference Example Compound 8 (0.10 g, 0.29 mmol) and DIPEA (0.015 mL, 0.88 mmol) under ice cooling. After stirring at room temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) to obtain 0.11 g (75%) of Example Compound 3.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-メチル-2-(メチルスルホナミド)プロパナミド)シクロヘキサンカルルボキサミド(以下、実施例化合物3)の合成:
氷冷下、参考例化合物12(0.074g、0.41mmol)及びDMF(1mL)のジクロロメタン(5mL)溶液に、オキザリルクロリド(0.037mL、0.43mmol)を加えた。室温下で30分撹拌後、氷冷下、参考例化合物8(0.10g、0.29mmol)及びDIPEA(0.015mL、0.88mmol)のジクロロメタン(10mL)溶液に、反応液を加えた。室温下で30分撹拌後、反応液に水を加え、ジエチルエーテルで抽出した。有機層を0.1規定塩酸、水及び飽和食塩水で洗浄後、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物を、シリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製し、実施例化合物3を0.11g(75%)を得た。 [Step 3]
of 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). After stirring at room temperature for 30 minutes, the reaction solution was added to a dichloromethane (10 mL) solution of Reference Example Compound 8 (0.10 g, 0.29 mmol) and DIPEA (0.015 mL, 0.88 mmol) under ice cooling. After stirring at room temperature for 30 minutes, water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 0.1N hydrochloric acid, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) to obtain 0.11 g (75%) of Example Compound 3.
(実施例4)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-2,3-ジメチル-2-(メチルスルホナミド)ブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
(9H-フルオレン-9-イル)メチル ((S)-1-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アミノ)-2,3-ジメチル-1-オキソブタン-2-イル)カルバメート(以下、参考例化合物13)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、((S)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)アミノ)-2,3-ジメチルブタン酸(0.10g、0.28mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(10mL)溶液にHATU(0.14g、0.36mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→20:80)で精製し、参考例化合物13を0.16g(84%)得た。 (Example 4)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2- (methylsulfonamido) butanamide) cyclohexanecarboxamide:
[Step 1]
(9H-Fluoren-9-yl) methyl ((S) -1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,3-dimethyl Synthesis of -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 13):
At room temperature, Reference Compound 8 (0.10 g, 0.29 mmol), ((S) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,3-dimethylbutanoic acid HATU (0.14 g, 0.36 mmol) was added to a DMF (10 mL) solution of (0.10 g, 0.28 mmol) and DIPEA (0.12 mL, 0.70 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 a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 50: 50 → 20: 80) gave 0.16 g (84%) of Reference Example Compound 13.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-2,3-ジメチル-2-(メチルスルホナミド)ブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
(9H-フルオレン-9-イル)メチル ((S)-1-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アミノ)-2,3-ジメチル-1-オキソブタン-2-イル)カルバメート(以下、参考例化合物13)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、((S)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)アミノ)-2,3-ジメチルブタン酸(0.10g、0.28mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(10mL)溶液にHATU(0.14g、0.36mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→20:80)で精製し、参考例化合物13を0.16g(84%)得た。 (Example 4)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((S) -2,3-dimethyl-2- (methylsulfonamido) butanamide) cyclohexanecarboxamide:
[Step 1]
(9H-Fluoren-9-yl) methyl ((S) -1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,3-dimethyl Synthesis of -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 13):
At room temperature, Reference Compound 8 (0.10 g, 0.29 mmol), ((S) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,3-dimethylbutanoic acid HATU (0.14 g, 0.36 mmol) was added to a DMF (10 mL) solution of (0.10 g, 0.28 mmol) and DIPEA (0.12 mL, 0.70 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 a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 50: 50 → 20: 80) gave 0.16 g (84%) of Reference Example Compound 13.
〔ステップ2〕
cis-4-((S)-2-アミノ-2,3-ジメチルブタナミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物14)の合成:
氷冷下、参考例化合物13(0.16g、0.24mmol)のDMF(4.0mL)溶液に、モルホリン(1.0mL、11mmol)を加えた。室温下で5時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、参考例化合物14を0.072g(69%)得た。 [Step 2]
Synthesis of cis-4-((S) -2-amino-2,3-dimethylbutanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 14) :
Morpholine (1.0 mL, 11 mmol) was added to a DMF (4.0 mL) solution of Reference Example Compound 13 (0.16 g, 0.24 mmol) under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.072 g (69%) of Reference Example Compound 14.
cis-4-((S)-2-アミノ-2,3-ジメチルブタナミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物14)の合成:
氷冷下、参考例化合物13(0.16g、0.24mmol)のDMF(4.0mL)溶液に、モルホリン(1.0mL、11mmol)を加えた。室温下で5時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、参考例化合物14を0.072g(69%)得た。 [Step 2]
Synthesis of cis-4-((S) -2-amino-2,3-dimethylbutanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 14) :
Morpholine (1.0 mL, 11 mmol) was added to a DMF (4.0 mL) solution of Reference Example Compound 13 (0.16 g, 0.24 mmol) under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.072 g (69%) of Reference Example Compound 14.
〔ステップ3〕
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-2,3-ジメチル-2-(メチルスルホナミド)ブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物4)の合成:
氷冷下、参考例化合物14(0.035g、0.077mmol)及びピリジン(0.019mL、0.23mmol)のジクロロメタン(2.0mL)溶液に、メタンスルホニルクロリド(0.0072mL、0.092mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、実施例化合物4を0.0042g(10%)得た。 [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. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0042 g (10%) ofExample Compound 4.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-2,3-ジメチル-2-(メチルスルホナミド)ブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物4)の合成:
氷冷下、参考例化合物14(0.035g、0.077mmol)及びピリジン(0.019mL、0.23mmol)のジクロロメタン(2.0mL)溶液に、メタンスルホニルクロリド(0.0072mL、0.092mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、実施例化合物4を0.0042g(10%)得た。 [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. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0042 g (10%) of
(実施例5)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-2,3-ジメチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物5)の合成:
氷冷下、参考例化合物14(0.035g、0.077mmol)及びピリジン(0.019mL、0.23mmol)のジクロロメタン(2.0mL)溶液に、プロピオニルクロリド(0.0080mL、0.092mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、実施例化合物5を0.0052g(13%)得た。 (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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0052 g (13%) of Example Compound 5.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((S)-2,3-ジメチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物5)の合成:
氷冷下、参考例化合物14(0.035g、0.077mmol)及びピリジン(0.019mL、0.23mmol)のジクロロメタン(2.0mL)溶液に、プロピオニルクロリド(0.0080mL、0.092mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、実施例化合物5を0.0052g(13%)得た。 (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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0052 g (13%) of Example Compound 5.
(実施例6)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-2,3-ジメチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
(9H-フルオレン-9-イル)メチル ((R)-1-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アミノ)-2,3-ジメチル-1-オキソブタン-2-イル)カルバメート(以下、参考例化合物15)の合成:
室温下、参考例化合物8(0.50g、1.3mmol)、((R)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)アミノ)-2,3-ジメチルブタン酸(0.47g、1.3mmol)及びDIPEA(0.90mL、5.2mmol)のDMF(10mL)溶液にHATU(0.65g、1.7mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→20:80)で精製し、参考例化合物15を0.55g(61%)得た。 (Example 6)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
(9H-Fluoren-9-yl) methyl ((R) -1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,3-dimethyl Synthesis of -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 15):
Reference Example Compound 8 (0.50 g, 1.3 mmol), ((R) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,3-dimethylbutanoic acid at room temperature HATU (0.65 g, 1.7 mmol) was added to a DMF (10 mL) solution of (0.47 g, 1.3 mmol) and DIPEA (0.90 mL, 5.2 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 a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 50: 50 → 20: 80) gave 0.55 g (61%) of Reference Example Compound 15.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-2,3-ジメチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
(9H-フルオレン-9-イル)メチル ((R)-1-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アミノ)-2,3-ジメチル-1-オキソブタン-2-イル)カルバメート(以下、参考例化合物15)の合成:
室温下、参考例化合物8(0.50g、1.3mmol)、((R)-2-((((9H-フルオレン-9-イル)メトキシ)カルボニル)アミノ)-2,3-ジメチルブタン酸(0.47g、1.3mmol)及びDIPEA(0.90mL、5.2mmol)のDMF(10mL)溶液にHATU(0.65g、1.7mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→20:80)で精製し、参考例化合物15を0.55g(61%)得た。 (Example 6)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
(9H-Fluoren-9-yl) methyl ((R) -1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) amino) -2,3-dimethyl Synthesis of -1-oxobutan-2-yl) carbamate (hereinafter referred to as Reference Example Compound 15):
Reference Example Compound 8 (0.50 g, 1.3 mmol), ((R) -2-((((9H-fluoren-9-yl) methoxy) carbonyl) amino) -2,3-dimethylbutanoic acid at room temperature HATU (0.65 g, 1.7 mmol) was added to a DMF (10 mL) solution of (0.47 g, 1.3 mmol) and DIPEA (0.90 mL, 5.2 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 a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (eluent; hexane: ethyl acetate = 50: 50 → 20: 80) gave 0.55 g (61%) of Reference Example Compound 15.
〔ステップ2〕
cis-4-((R)-2-アミノ-2,3-ジメチルブタナミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物16)の合成:
氷冷下、参考例化合物15(0.16g、0.24mmol)のDMF(4.0mL)溶液に、モルホリン(1.0mL、11mmol)を加えた。室温下で5時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、参考例化合物16を0.10g(94%)得た。 [Step 2]
Synthesis of cis-4-((R) -2-amino-2,3-dimethylbutanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (Reference Example Compound 16) :
Morpholine (1.0 mL, 11 mmol) was added to a DMF (4.0 mL) solution of Reference Example Compound 15 (0.16 g, 0.24 mmol) under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.10 g (94%) of Reference Example Compound 16.
cis-4-((R)-2-アミノ-2,3-ジメチルブタナミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物16)の合成:
氷冷下、参考例化合物15(0.16g、0.24mmol)のDMF(4.0mL)溶液に、モルホリン(1.0mL、11mmol)を加えた。室温下で5時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、参考例化合物16を0.10g(94%)得た。 [Step 2]
Synthesis of cis-4-((R) -2-amino-2,3-dimethylbutanamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (Reference Example Compound 16) :
Morpholine (1.0 mL, 11 mmol) was added to a DMF (4.0 mL) solution of Reference Example Compound 15 (0.16 g, 0.24 mmol) under ice cooling. After stirring at room temperature for 5 hours, the reaction solution was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.10 g (94%) of Reference Example Compound 16.
〔ステップ3〕
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-2,3-ジメチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物6)の合成:
氷冷下、参考例化合物16(0.050g、0.11mmol)及びピリジン(0.027mL、0.33mmol)のジクロロメタン(2.0mL)溶液に、プロピオニルクロリド(0.011mL、0.13mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、実施例化合物6を0.0068g(12%)得た。 [Step 3]
cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 6) Synthesis of:
Under ice-cooling, propionyl chloride (0.011 mL, 0.13 mmol) was added to a solution of Reference Compound 16 (0.050 g, 0.11 mmol) and pyridine (0.027 mL, 0.33 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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0068 g (12%) of Example Compound 6.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-2,3-ジメチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物6)の合成:
氷冷下、参考例化合物16(0.050g、0.11mmol)及びピリジン(0.027mL、0.33mmol)のジクロロメタン(2.0mL)溶液に、プロピオニルクロリド(0.011mL、0.13mmol)を加えた。室温下で一晩撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=95:5)で精製し、実施例化合物6を0.0068g(12%)得た。 [Step 3]
cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -2,3-dimethyl-2-propionamidobutanamide) cyclohexanecarboxamide (hereinafter, Example Compound 6) Synthesis of:
Under ice-cooling, propionyl chloride (0.011 mL, 0.13 mmol) was added to a solution of Reference Compound 16 (0.050 g, 0.11 mmol) and pyridine (0.027 mL, 0.33 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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 95: 5) to obtain 0.0068 g (12%) of Example Compound 6.
(実施例7)
N-(cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アダマンタン-1-カルボキサミド(以下、実施例化合物7)の合成:
氷冷下、参考例化合物8(0.10g、0.29mmol)及びTEA(0.20mL、1.5mmol)のジクロロメタン(2.0mL)溶液に、アダマンタン-1-カルボニルクロリド(0.064g、0.32mmol)を加えた。室温下で一晩撹拌した後、減圧濃縮した。粗生成物を飽和炭酸水素ナトリウム水溶液で洗浄した後、エタノール-水で再結晶し、実施例化合物7を0.11g(72%)得た。 (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.
N-(cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アダマンタン-1-カルボキサミド(以下、実施例化合物7)の合成:
氷冷下、参考例化合物8(0.10g、0.29mmol)及びTEA(0.20mL、1.5mmol)のジクロロメタン(2.0mL)溶液に、アダマンタン-1-カルボニルクロリド(0.064g、0.32mmol)を加えた。室温下で一晩撹拌した後、減圧濃縮した。粗生成物を飽和炭酸水素ナトリウム水溶液で洗浄した後、エタノール-水で再結晶し、実施例化合物7を0.11g(72%)得た。 (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.
(実施例8)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(1-(トリフルオロメチル)シクロプロパンカルボキサミド)シクロヘキサンカルボキサミド(以下、実施例化合物8)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、1-(トリフルオロメチル)シクロプロパンカルボン酸(0.045g、0.29mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(1.0mL)溶液にHATU(0.13g、0.35mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製し、ヘキサン-酢酸エチルから再結晶し、実施例化合物8を0.10g(72%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) and recrystallized from hexane-ethyl acetate to obtain 0.10 g of Example Compound 8 ( 72%).
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(1-(トリフルオロメチル)シクロプロパンカルボキサミド)シクロヘキサンカルボキサミド(以下、実施例化合物8)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、1-(トリフルオロメチル)シクロプロパンカルボン酸(0.045g、0.29mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(1.0mL)溶液にHATU(0.13g、0.35mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製し、ヘキサン-酢酸エチルから再結晶し、実施例化合物8を0.10g(72%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) and recrystallized from hexane-ethyl acetate to obtain 0.10 g of Example Compound 8 ( 72%).
(実施例9)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(1-プロピオナミドシクロブタンカルボキサミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
tert-ブチル (1-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)カルバモイル)シクロブチル)カルバメート(以下、参考例化合物17)の合成:
室温下、参考例化合物8(0.30g、0.88mmol)、1-((tert-ブトキシカルボニル)アミノ)シクロブタンカルボン酸(0.18g、0.84mmol)及びDIPEA(0.37mL、2.1mmol)のDMF(10mL)溶液にHATU(0.41g、1.1mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=40:60→酢酸エチルのみ)で精製し、参考例化合物17を0.50g(定量的)得た。 Example 9
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1-propionamidocyclobutanecarboxamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of tert-butyl (1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamoyl) cyclobutyl) carbamate (hereinafter referred to as Reference Example Compound 17):
At room temperature, Reference Compound 8 (0.30 g, 0.88 mmol), 1-((tert-butoxycarbonyl) amino) cyclobutanecarboxylic acid (0.18 g, 0.84 mmol) and DIPEA (0.37 mL, 2.1 mmol) ) In DMF (10 mL) was added HATU (0.41 g, 1.1 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 aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 40: 60 → ethyl acetate only) to obtain 0.50 g (quantitative) of Reference Example Compound 17.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(1-プロピオナミドシクロブタンカルボキサミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
tert-ブチル (1-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)カルバモイル)シクロブチル)カルバメート(以下、参考例化合物17)の合成:
室温下、参考例化合物8(0.30g、0.88mmol)、1-((tert-ブトキシカルボニル)アミノ)シクロブタンカルボン酸(0.18g、0.84mmol)及びDIPEA(0.37mL、2.1mmol)のDMF(10mL)溶液にHATU(0.41g、1.1mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=40:60→酢酸エチルのみ)で精製し、参考例化合物17を0.50g(定量的)得た。 Example 9
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4- (1-propionamidocyclobutanecarboxamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of tert-butyl (1-((cis-4-((4-cyano-2- (trifluoromethoxy) benzyl) carbamoyl) cyclohexyl) carbamoyl) cyclobutyl) carbamate (hereinafter referred to as Reference Example Compound 17):
At room temperature, Reference Compound 8 (0.30 g, 0.88 mmol), 1-((tert-butoxycarbonyl) amino) cyclobutanecarboxylic acid (0.18 g, 0.84 mmol) and DIPEA (0.37 mL, 2.1 mmol) ) In DMF (10 mL) was added HATU (0.41 g, 1.1 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 aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 40: 60 → ethyl acetate only) to obtain 0.50 g (quantitative) of Reference Example Compound 17.
〔ステップ2〕
cis-4-(1-アミノシクロブタンカルボキサミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物18)の合成:
氷冷下、参考例化合物17(0.050g、0.93mmol)のジクロロメタン(15mL)溶液に、TFA(1.4mL、19mmol)を加えた。室温下で3時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をジクロロメタンに溶解させ、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物18を0.41g(定量的)得た。 [Step 2]
Synthesis of cis-4- (1-aminocyclobutanecarboxamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 18):
TFA (1.4 mL, 19 mmol) was added to a dichloromethane (15 mL) solution of Reference Example compound 17 (0.050 g, 0.93 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 0.41 g (quantitative) of Reference Example Compound 18.
cis-4-(1-アミノシクロブタンカルボキサミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、参考例化合物18)の合成:
氷冷下、参考例化合物17(0.050g、0.93mmol)のジクロロメタン(15mL)溶液に、TFA(1.4mL、19mmol)を加えた。室温下で3時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をジクロロメタンに溶解させ、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物18を0.41g(定量的)得た。 [Step 2]
Synthesis of cis-4- (1-aminocyclobutanecarboxamide) -N- (4-cyano-2- (trifluoromethoxy) benzyl) cyclohexanecarboxamide (hereinafter referred to as Reference Example Compound 18):
TFA (1.4 mL, 19 mmol) was added to a dichloromethane (15 mL) solution of Reference Example compound 17 (0.050 g, 0.93 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 0.41 g (quantitative) of Reference Example Compound 18.
〔ステップ3〕
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(1-プロピオナミドシクロブタンカルボキサミド)シクロヘキサンカルボキサミド(以下、実施例化合物9)の合成:
氷冷下、参考例化合物18(0.20g、0.46mmol)及びDIPEA(0.24mL、1.4mmol)のジクロロメタン(5.0mL)溶液に、プロピオニルクロリド(0.048mL、0.55mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=90:10)で精製し、実施例化合物9を0.19g(85%)得た。 [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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.19 g (85%) of Example Compound 9.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(1-プロピオナミドシクロブタンカルボキサミド)シクロヘキサンカルボキサミド(以下、実施例化合物9)の合成:
氷冷下、参考例化合物18(0.20g、0.46mmol)及びDIPEA(0.24mL、1.4mmol)のジクロロメタン(5.0mL)溶液に、プロピオニルクロリド(0.048mL、0.55mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=90:10)で精製し、実施例化合物9を0.19g(85%)得た。 [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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.19 g (85%) of Example Compound 9.
(実施例10)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-ヒドロキシ-2-メチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物10)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、2-ヒドロキシ-2-メチルプロパン酸(0.031g、0.29mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(1.0mL)溶液にHATU(0.13g、0.35mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製し、実施例化合物10を0.040g(32%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only → ethyl acetate: methanol = 90: 10), and 0.040 g of Example Compound 10 ( 32%).
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-ヒドロキシ-2-メチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物10)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、2-ヒドロキシ-2-メチルプロパン酸(0.031g、0.29mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(1.0mL)溶液にHATU(0.13g、0.35mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製し、実施例化合物10を0.040g(32%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only → ethyl acetate: methanol = 90: 10), and 0.040 g of Example Compound 10 ( 32%).
(実施例11)
3-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アミノ)-2,2-ジメチル-3-オキソプロパン酸エチル(以下、実施例化合物11)の合成:
室温下、参考例化合物8(0.50g、1.5mmol)、3-エトキシ-2,2-ジメチル3-オキソプロパン酸(0.26g、1.6mmol)及びDIPEA(0.61mL、3.5mmol)のDMF(3.0mL)溶液にHATU(0.67g、1.8mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製し、実施例化合物11を0.65g(91%)得た。 (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). 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 aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) to obtain 0.65 g (91%) of Example Compound 11.
3-((cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)アミノ)-2,2-ジメチル-3-オキソプロパン酸エチル(以下、実施例化合物11)の合成:
室温下、参考例化合物8(0.50g、1.5mmol)、3-エトキシ-2,2-ジメチル3-オキソプロパン酸(0.26g、1.6mmol)及びDIPEA(0.61mL、3.5mmol)のDMF(3.0mL)溶液にHATU(0.67g、1.8mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄し、硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製し、実施例化合物11を0.65g(91%)得た。 (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). 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 aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) to obtain 0.65 g (91%) of Example Compound 11.
(実施例12)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-メトキシ-2-メチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物12)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、2-メトキシ-2-メチルプロパン酸(0.038g、0.32mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(1.0mL)溶液にHATU(0.13g、0.35mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した。得られた生成物をヘキサン中に懸濁させ、生じた固体をろ取し、実施例化合物12を0.063g(49%)得た。 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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.063 g (49%) of Example Compound 12.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-メトキシ-2-メチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物12)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、2-メトキシ-2-メチルプロパン酸(0.038g、0.32mmol)及びDIPEA(0.12mL、0.70mmol)のDMF(1.0mL)溶液にHATU(0.13g、0.35mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した。得られた生成物をヘキサン中に懸濁させ、生じた固体をろ取し、実施例化合物12を0.063g(49%)得た。 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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.063 g (49%) of Example Compound 12.
(実施例13)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-(4-メトキシフェノキシ)-2-メチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物13)の合成:
室温下、参考例化合物8(0.080g、0.23mmol)、2-(4-メトキシフェノキシ)-2-メチルプロパン酸(0.054g、0.26mmol)及びDIPEA(0.098mL、0.56mmol)のDMF(1.0mL)溶液にHATU(0.11g、0.28mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した後、ヘキサン-酢酸エチルから再結晶し、実施例化合物13を0.080g(64%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) and recrystallized from hexane-ethyl acetate to obtain 0.080 g of Example Compound 13. (64%) was obtained.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2-(4-メトキシフェノキシ)-2-メチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物13)の合成:
室温下、参考例化合物8(0.080g、0.23mmol)、2-(4-メトキシフェノキシ)-2-メチルプロパン酸(0.054g、0.26mmol)及びDIPEA(0.098mL、0.56mmol)のDMF(1.0mL)溶液にHATU(0.11g、0.28mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した後、ヘキサン-酢酸エチルから再結晶し、実施例化合物13を0.080g(64%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only) and recrystallized from hexane-ethyl acetate to obtain 0.080 g of Example Compound 13. (64%) was obtained.
(実施例14)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(3-ヒドロキシ-2,2-ジメチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物14)の合成:
氷冷下、実施例化合物11(0.59g、1.2mmol)のTHF(5.0mL)溶液にテトラヒドロホウ酸リチウム(0.080g、3.7mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製し、実施例化合物14を0.35g(64%)得た。 (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. The resulting crude product was purified by silica gel column chromatography (eluent; ethyl acetate only → ethyl acetate: methanol = 90: 10) to obtain 0.35 g (64%) of Example Compound 14.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(3-ヒドロキシ-2,2-ジメチルプロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物14)の合成:
氷冷下、実施例化合物11(0.59g、1.2mmol)のTHF(5.0mL)溶液にテトラヒドロホウ酸リチウム(0.080g、3.7mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製し、実施例化合物14を0.35g(64%)得た。 (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. The resulting crude product was purified by silica gel column chromatography (eluent; ethyl acetate only → ethyl acetate: methanol = 90: 10) to obtain 0.35 g (64%) of Example Compound 14.
(実施例15)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2,2-ジメチル-3-(メチルチオ)プロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物15)の合成:
室温下、参考例化合物8(0.30g、0.89mmol)、2,2-ジメチル-3-(メチルチオ)プロパン酸(0.14g、0.97mmol)及びDIPEA(0.37mL、2.1mmol)のDMF(1.0mL)溶液にHATU(0.40g、1.1mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した。得られた生成物をヘキサン中に懸濁させ、生じた固体をろ取し、実施例化合物15を0.31g(75%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.31 g (75%) of Example Compound 15.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2,2-ジメチル-3-(メチルチオ)プロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物15)の合成:
室温下、参考例化合物8(0.30g、0.89mmol)、2,2-ジメチル-3-(メチルチオ)プロパン酸(0.14g、0.97mmol)及びDIPEA(0.37mL、2.1mmol)のDMF(1.0mL)溶液にHATU(0.40g、1.1mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した。得られた生成物をヘキサン中に懸濁させ、生じた固体をろ取し、実施例化合物15を0.31g(75%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.31 g (75%) of Example Compound 15.
(実施例16)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2,2-ジメチル-3-(メチルスルフィニル)プロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物16)の合成:
氷冷下、実施例化合物15(0.10g、0.21mmol)のジクロロメタン(1.0mL)溶液に、3-クロロ過安息香酸(70%、0.055g、0.22mmol)を加えた。室温下で4時間撹拌した後、反応溶液をシリカゲルカラムクロマトグラフィー(富士シリシア化学社製アミンシリカゲルDM1020、溶離液;酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製し、実施例化合物16を0.097g(94%)得た。 (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). After stirring at room temperature for 4 hours, the reaction solution was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent: ethyl acetate only → ethyl acetate: methanol = 90: 10), and Example Compound 16 Of 0.097 g (94%) was obtained.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2,2-ジメチル-3-(メチルスルフィニル)プロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物16)の合成:
氷冷下、実施例化合物15(0.10g、0.21mmol)のジクロロメタン(1.0mL)溶液に、3-クロロ過安息香酸(70%、0.055g、0.22mmol)を加えた。室温下で4時間撹拌した後、反応溶液をシリカゲルカラムクロマトグラフィー(富士シリシア化学社製アミンシリカゲルDM1020、溶離液;酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製し、実施例化合物16を0.097g(94%)得た。 (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). After stirring at room temperature for 4 hours, the reaction solution was purified by silica gel column chromatography (amine silica gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent: ethyl acetate only → ethyl acetate: methanol = 90: 10), and Example Compound 16 Of 0.097 g (94%) was obtained.
(実施例17)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2,2-ジメチル-3-(メチルスルホニル)プロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物17)の合成:
氷冷下、実施例化合物15(0.10g、0.21mmol)のジクロロメタン(1.0mL)溶液に、3-クロロ過安息香酸(70%、0.13g、0.51mmol)を加えた。室温下で4時間撹拌した後、反応溶液をシリカゲルカラムクロマトグラフィー(富士シリシア化学社製アミンシリカゲルDM1020、溶離液;酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製した。得られた生成物をヘキサン-酢酸エチルから再結晶し、実施例化合物17を0.091g(85%)得た。 (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). After stirring at room temperature for 4 hours, the reaction solution was purified by silica gel column chromatography (Amine Silica Gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; ethyl acetate only → ethyl acetate: methanol = 90: 10). The obtained product was recrystallized from hexane-ethyl acetate to obtain 0.091 g (85%) of Example Compound 17.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-(2,2-ジメチル-3-(メチルスルホニル)プロパナミド)シクロヘキサンカルボキサミド(以下、実施例化合物17)の合成:
氷冷下、実施例化合物15(0.10g、0.21mmol)のジクロロメタン(1.0mL)溶液に、3-クロロ過安息香酸(70%、0.13g、0.51mmol)を加えた。室温下で4時間撹拌した後、反応溶液をシリカゲルカラムクロマトグラフィー(富士シリシア化学社製アミンシリカゲルDM1020、溶離液;酢酸エチルのみ→酢酸エチル:メタノール=90:10)で精製した。得られた生成物をヘキサン-酢酸エチルから再結晶し、実施例化合物17を0.091g(85%)得た。 (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). After stirring at room temperature for 4 hours, the reaction solution was purified by silica gel column chromatography (Amine Silica Gel DM1020, manufactured by Fuji Silysia Chemical Ltd., eluent; ethyl acetate only → ethyl acetate: methanol = 90: 10). The obtained product was recrystallized from hexane-ethyl acetate to obtain 0.091 g (85%) of Example Compound 17.
(実施例18)
cis-4-(3-シアノ-2,2-ジメチルプロパナミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、実施例化合物18)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、3-シアノ-2,2-ジメチルプロパン酸(0.056g、0.44mmol)及びDIPEA(0.15mL、0.88mmol)のDMF(1.0mL)溶液にHATU(0.17g、0.44mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した。得られた生成物をヘキサン中に懸濁させ、生じた固体をろ取し、実施例化合物18を0.077g(58%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.077 g (58%) of Example Compound 18.
cis-4-(3-シアノ-2,2-ジメチルプロパナミド)-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)シクロヘキサンカルボキサミド(以下、実施例化合物18)の合成:
室温下、参考例化合物8(0.10g、0.29mmol)、3-シアノ-2,2-ジメチルプロパン酸(0.056g、0.44mmol)及びDIPEA(0.15mL、0.88mmol)のDMF(1.0mL)溶液にHATU(0.17g、0.44mmol)を加えた。室温下で一晩撹拌した後、反応溶液に酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液、水及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=50:50→酢酸エチルのみ)で精製した。得られた生成物をヘキサン中に懸濁させ、生じた固体をろ取し、実施例化合物18を0.077g(58%)得た。 (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). After stirring overnight at room temperature, ethyl acetate was added to the reaction solution, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 50: 50 → ethyl acetate only). The obtained product was suspended in hexane, and the resulting solid was collected by filtration to obtain 0.077 g (58%) of Example Compound 18.
(実施例19)
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
(R)-3-メチル-2-プロピオナミドブタン酸メチル(以下、参考例化合物19)の合成:
氷冷下、D-バリンメチルエステル塩酸塩(1.0g、6.0mmol)及びピリジン(1.7mL、21mmol)のジクロロメタン(10mL)溶液に、プロピオニルクロリド(0.78mL、8.9mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に水及び1規定塩酸を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=70:30→20:80)で精製し、参考例化合物19を1.2g(定量的)得た。 (Example 19)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of methyl (R) -3-methyl-2-propionamidobutanoate (hereinafter referred to as Reference Example Compound 19):
Under ice-cooling, propionyl chloride (0.78 mL, 8.9 mmol) was added to a solution of D-valine methyl ester hydrochloride (1.0 g, 6.0 mmol) and pyridine (1.7 mL, 21 mmol) in dichloromethane (10 mL). It was. 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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 20: 80) to obtain 1.2 g (quantitative) of Reference Example Compound 19.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
(R)-3-メチル-2-プロピオナミドブタン酸メチル(以下、参考例化合物19)の合成:
氷冷下、D-バリンメチルエステル塩酸塩(1.0g、6.0mmol)及びピリジン(1.7mL、21mmol)のジクロロメタン(10mL)溶液に、プロピオニルクロリド(0.78mL、8.9mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に水及び1規定塩酸を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=70:30→20:80)で精製し、参考例化合物19を1.2g(定量的)得た。 (Example 19)
Synthesis of cis-N- (4-cyano-2- (trifluoromethoxy) benzyl) -4-((R) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of methyl (R) -3-methyl-2-propionamidobutanoate (hereinafter referred to as Reference Example Compound 19):
Under ice-cooling, propionyl chloride (0.78 mL, 8.9 mmol) was added to a solution of D-valine methyl ester hydrochloride (1.0 g, 6.0 mmol) and pyridine (1.7 mL, 21 mmol) in dichloromethane (10 mL). It was. 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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 20: 80) to obtain 1.2 g (quantitative) of Reference Example Compound 19.
〔ステップ2〕
(R)-3-メチル-2-プロピオナミドブタン酸(以下、参考例化合物20)の合成:
室温下、参考例化合物19(1.0g、5.3mmol)のメタノール(10mL)溶液に、1規定水酸化ナトリウム水溶液(8.0mL、8.0mmol)を加えた。室温下で3時間撹拌した後、反応溶液に1規定塩酸を加えて中和し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物20を0.68g(73%)得た。 [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.
(R)-3-メチル-2-プロピオナミドブタン酸(以下、参考例化合物20)の合成:
室温下、参考例化合物19(1.0g、5.3mmol)のメタノール(10mL)溶液に、1規定水酸化ナトリウム水溶液(8.0mL、8.0mmol)を加えた。室温下で3時間撹拌した後、反応溶液に1規定塩酸を加えて中和し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物20を0.68g(73%)得た。 [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.
〔ステップ3〕
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物19)の合成:
室温下、参考例化合物8(0.30g、0.88mmol)、参考例化合物20(0.15g、0.84mmol)及びDIPEA(0.37mL、2.1mmol)のDMF(15mL)溶液にHATU(0.41g、1.1mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=90:10)で精製し、実施例化合物19を0.31g(75%)得た。 [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. 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 aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.31 g (75%) of Example Compound 19.
cis-N-(4-シアノ-2-(トリフルオロメトキシ)ベンジル)-4-((R)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物19)の合成:
室温下、参考例化合物8(0.30g、0.88mmol)、参考例化合物20(0.15g、0.84mmol)及びDIPEA(0.37mL、2.1mmol)のDMF(15mL)溶液にHATU(0.41g、1.1mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;クロロホルムのみ→クロロホルム:メタノール=90:10)で精製し、実施例化合物19を0.31g(75%)得た。 [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. 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 aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; chloroform only → chloroform: methanol = 90: 10) to obtain 0.31 g (75%) of Example Compound 19.
(実施例20)
cis-N-(4-クロロ-2-メチルベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
cis-4-((S)-2-(tert-ブトキシカルボニル)アミノ)-3-メチルブタナミド)シクロヘキサンカルボン酸メチル(以下、参考例化合物21)の合成:
室温下、cis-4-アミノシクロヘキサンカルボン酸メチル塩酸塩(2.0g、10mmol)、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-メチルブタン酸(2.2g、10mmol)及びDIPEA(7.0mL、40mmol)のDMF(40mL)溶液にHATU(5.1g、13mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=70:30→40:60)で精製し、参考例化合物21を4.0g(定量的)得た。 (Example 20)
Synthesis of cis-N- (4-Chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of methyl cis-4-((S) -2- (tert-butoxycarbonyl) amino) -3-methylbutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 21):
At room temperature, cis-4-aminocyclohexanecarboxylic acid methyl hydrochloride (2.0 g, 10 mmol), (S) -2-((tert-butoxycarbonyl) amino) -3-methylbutanoic acid (2.2 g, 10 mmol) and HATU (5.1 g, 13 mmol) was added to a solution of DIPEA (7.0 mL, 40 mmol) in DMF (40 mL). 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 aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 40: 60) to obtain 4.0 g (quantitative) of Reference Example Compound 21.
cis-N-(4-クロロ-2-メチルベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミドの合成:
〔ステップ1〕
cis-4-((S)-2-(tert-ブトキシカルボニル)アミノ)-3-メチルブタナミド)シクロヘキサンカルボン酸メチル(以下、参考例化合物21)の合成:
室温下、cis-4-アミノシクロヘキサンカルボン酸メチル塩酸塩(2.0g、10mmol)、(S)-2-((tert-ブトキシカルボニル)アミノ)-3-メチルブタン酸(2.2g、10mmol)及びDIPEA(7.0mL、40mmol)のDMF(40mL)溶液にHATU(5.1g、13mmol)を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、減圧濃縮した。粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=70:30→40:60)で精製し、参考例化合物21を4.0g(定量的)得た。 (Example 20)
Synthesis of cis-N- (4-Chloro-2-methylbenzyl) -4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxamide:
[Step 1]
Synthesis of methyl cis-4-((S) -2- (tert-butoxycarbonyl) amino) -3-methylbutanamide) cyclohexanecarboxylate (hereinafter referred to as Reference Example Compound 21):
At room temperature, cis-4-aminocyclohexanecarboxylic acid methyl hydrochloride (2.0 g, 10 mmol), (S) -2-((tert-butoxycarbonyl) amino) -3-methylbutanoic acid (2.2 g, 10 mmol) and HATU (5.1 g, 13 mmol) was added to a solution of DIPEA (7.0 mL, 40 mmol) in DMF (40 mL). 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 aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 70: 30 → 40: 60) to obtain 4.0 g (quantitative) of Reference Example Compound 21.
〔ステップ2〕
cis-4-((S)-2-アミノ-3-メチルブタナミド)シクロヘキサンカルボン酸メチル(以下、参考例化合物22)の合成:
氷冷下、参考例化合物21(3.7g、10mmol)のジクロロメタン(100mL)溶液に、TFA(16mL、210mmol)を加えた。室温下で3時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をジクロロメタンに溶解させ、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物22を2.4g(89%)得た。 [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.
cis-4-((S)-2-アミノ-3-メチルブタナミド)シクロヘキサンカルボン酸メチル(以下、参考例化合物22)の合成:
氷冷下、参考例化合物21(3.7g、10mmol)のジクロロメタン(100mL)溶液に、TFA(16mL、210mmol)を加えた。室温下で3時間撹拌した後、反応溶液を減圧濃縮した。得られた粗生成物をジクロロメタンに溶解させ、飽和炭酸ナトリウム水溶液で中和し、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物22を2.4g(89%)得た。 [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.
〔ステップ3〕
cis-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボン酸メチル(以下、参考例化合物23)の合成:
氷冷下、参考例化合物22(2.3g、9.1mmol)及びTEA(2.8mL、20mmol)のジクロロメタン(30mL)溶液に、プロピオニルクロリド(0.87mL、10mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=60:40→30:70)で精製し、参考例化合物23を2.1g(75%)得た。 [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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 60: 40 → 30: 70) to obtain 2.1 g (75%) of Reference Example Compound 23.
cis-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボン酸メチル(以下、参考例化合物23)の合成:
氷冷下、参考例化合物22(2.3g、9.1mmol)及びTEA(2.8mL、20mmol)のジクロロメタン(30mL)溶液に、プロピオニルクロリド(0.87mL、10mmol)を加えた。氷冷下で3時間撹拌した後、反応溶液に、水を加え、ジクロロメタンで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=60:40→30:70)で精製し、参考例化合物23を2.1g(75%)得た。 [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. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 60: 40 → 30: 70) to obtain 2.1 g (75%) of Reference Example Compound 23.
〔ステップ4〕
cis-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボン酸(以下、参考例化合物24)の合成:
室温下、参考例化合物23(1.0g、3.2mmol)のメタノール(10mL)溶液に、1規定水酸化ナトリウム水溶液(4.8mL、4.8mmol)を加えた。室温下で3時間撹拌した後、反応溶液に1規定塩酸を加えて中和し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物24を1.0g(定量的)得た。 [Step 4]
Synthesis of cis-4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxylic acid (hereinafter referred to as Reference Example Compound 24):
A 1N aqueous sodium hydroxide solution (4.8 mL, 4.8 mmol) was added to a methanol (10 mL) solution of Reference Example Compound 23 (1.0 g, 3.2 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 1.0 g (quantitative) of Reference Example Compound 24.
cis-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボン酸(以下、参考例化合物24)の合成:
室温下、参考例化合物23(1.0g、3.2mmol)のメタノール(10mL)溶液に、1規定水酸化ナトリウム水溶液(4.8mL、4.8mmol)を加えた。室温下で3時間撹拌した後、反応溶液に1規定塩酸を加えて中和し、クロロホルムで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮し、参考例化合物24を1.0g(定量的)得た。 [Step 4]
Synthesis of cis-4-((S) -3-methyl-2-propionamidobutanamide) cyclohexanecarboxylic acid (hereinafter referred to as Reference Example Compound 24):
A 1N aqueous sodium hydroxide solution (4.8 mL, 4.8 mmol) was added to a methanol (10 mL) solution of Reference Example Compound 23 (1.0 g, 3.2 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 1.0 g (quantitative) of Reference Example Compound 24.
〔ステップ5〕
cis-N-(4-クロロ-2-メチルベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物20)の合成:
室温下、MiniBlock(登録商標)-XT(48-position;Mettler Toledo Bohdan社)反応管に、参考例化合物24(0.010g、0.034mmol)及びHATU(0.017g、0.044mmol)のDMF(0.50mL)溶液並びにDIPEA(0.015mL、0.084mmol)のDMF(0.10mL)溶液を加えた。室温下で5分間撹拌した後、反応溶液に、4-クロロ-2-メチルベンジルアミン(0.0052g、0.034mmol)のDMF(0.10mL)溶液を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、窒素を吹き付けて濃縮した。得られた粗生成物をLC-MS逆相分取精製(LC-MS装置:Agilent System 1100、カラム:Zorbax(登録商標)Extend-C18 9.4mm×50mm 5.0μm、移動相:10mM炭酸水素アンモニウム水溶液-アセトニトリル)することで実施例化合物20を0.0022g(15%)得た。 [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. After stirring at room temperature for 5 minutes, a solution of 4-chloro-2-methylbenzylamine (0.0052 g, 0.034 mmol) in DMF (0.10 mL) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was purified by LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extended-C18 9.4 mm x 50 mm 5.0 µm, mobile phase: 10 mM hydrogen carbonate. Aqueous ammonium solution-acetonitrile) gave 0.0022 g (15%) of Example Compound 20.
cis-N-(4-クロロ-2-メチルベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、実施例化合物20)の合成:
室温下、MiniBlock(登録商標)-XT(48-position;Mettler Toledo Bohdan社)反応管に、参考例化合物24(0.010g、0.034mmol)及びHATU(0.017g、0.044mmol)のDMF(0.50mL)溶液並びにDIPEA(0.015mL、0.084mmol)のDMF(0.10mL)溶液を加えた。室温下で5分間撹拌した後、反応溶液に、4-クロロ-2-メチルベンジルアミン(0.0052g、0.034mmol)のDMF(0.10mL)溶液を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、窒素を吹き付けて濃縮した。得られた粗生成物をLC-MS逆相分取精製(LC-MS装置:Agilent System 1100、カラム:Zorbax(登録商標)Extend-C18 9.4mm×50mm 5.0μm、移動相:10mM炭酸水素アンモニウム水溶液-アセトニトリル)することで実施例化合物20を0.0022g(15%)得た。 [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. After stirring at room temperature for 5 minutes, a solution of 4-chloro-2-methylbenzylamine (0.0052 g, 0.034 mmol) in DMF (0.10 mL) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was purified by LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extended-C18 9.4 mm x 50 mm 5.0 µm, mobile phase: 10 mM hydrogen carbonate. Aqueous ammonium solution-acetonitrile) gave 0.0022 g (15%) of Example Compound 20.
実施例化合物20について、以下に記載の分析方法を用いてLC保持時間及び[M+H]+又は[M-H]-を計測した。分析方法とは、LC-MS装置:Agilent System 1100、カラム:Zorbax(登録商標)Extend-C18 9.4mm×50mm 5.0μm、移動相:A=アセトニトリル B=10mM炭酸水素アンモニウム水溶液、グラジェント:A/B=5/95→80/20(6分間)、流速:4mL/分、で示される分析方法である。
For Example Compound 20, the LC retention time and [M + H] + or [M−H] − were measured using the analysis method described below. The analysis method is as follows: LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extend-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: A = acetonitrile B = 10 mM aqueous ammonium hydrogen carbonate, gradient: A / B = 5/95 → 80/20 (6 minutes), flow rate: 4 mL / min.
(比較例1)
(S)-N-(cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキサミド(以下、比較例化合物1)の合成:
氷冷下、参考例化合物8(0.10g、0.29mmol)及びトリホスゲン(30 mg、0.35 mmol)のジクロロメタン(3.0 mL)溶液にTEA(0.16 mL、1.2 mmol)を加えた。氷冷下で5分間撹拌した後、氷冷下、L-プロリノール(0.030g、0.29 mmol)を加えた。室温下で5時間撹拌した後、反応溶液にメタノールを加え、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=80:20→酢酸エチルのみ)で精製し、比較例化合物1を0.12g(83%)得た。 (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. After stirring for 5 minutes under ice cooling, L-prolinol (0.030 g, 0.29 mmol) was added under ice cooling. After stirring at room temperature for 5 hours, methanol was added to the reaction solution, followed by concentration under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20 → ethyl acetate only) to obtain 0.12 g (83%) of Comparative Compound 1.
(S)-N-(cis-4-((4-シアノ-2-(トリフルオロメトキシ)ベンジル)カルバモイル)シクロヘキシル)-2-(ヒドロキシメチル)ピロリジン-1-カルボキサミド(以下、比較例化合物1)の合成:
氷冷下、参考例化合物8(0.10g、0.29mmol)及びトリホスゲン(30 mg、0.35 mmol)のジクロロメタン(3.0 mL)溶液にTEA(0.16 mL、1.2 mmol)を加えた。氷冷下で5分間撹拌した後、氷冷下、L-プロリノール(0.030g、0.29 mmol)を加えた。室温下で5時間撹拌した後、反応溶液にメタノールを加え、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー(溶離液;ヘキサン:酢酸エチル=80:20→酢酸エチルのみ)で精製し、比較例化合物1を0.12g(83%)得た。 (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. After stirring for 5 minutes under ice cooling, L-prolinol (0.030 g, 0.29 mmol) was added under ice cooling. After stirring at room temperature for 5 hours, methanol was added to the reaction solution, followed by concentration under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 80: 20 → ethyl acetate only) to obtain 0.12 g (83%) of Comparative Compound 1.
(比較例2)
cis-N-(5-クロロ-2-メチルベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、比較例化合物2)の合成:
室温下、MiniBlock(登録商標)-XT(48-position;Mettler Toledo Bohdan社)反応管に、参考例化合物24(0.010g、0.034mmol)及びHATU(0.017g、0.044mmol)のDMF(0.50mL)溶液並びにDIPEA(0.015mL、0.084mmol)のDMF(0.10mL)溶液を加えた。室温下で5分間撹拌した後、反応溶液に、5-クロロ-2-メチルベンジルアミン(0.0052g、0.034mmol)のDMF(0.10mL)溶液を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、窒素を吹き付けて濃縮した。得られた粗生成物をLC-MS逆相分取精製(LC-MS装置:Agilent System 1100、カラム:Zorbax(登録商標)Extend-C18 9.4mm×50mm 5.0μm、移動相:10mM炭酸水素アンモニウム水溶液-アセトニトリル)することで比較例化合物2を0.0039g(26%)得た。 (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. After stirring at room temperature for 5 minutes, a solution of 5-chloro-2-methylbenzylamine (0.0052 g, 0.034 mmol) in DMF (0.10 mL) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was purified by LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extended-C18 9.4 mm x 50 mm 5.0 µm, mobile phase: 10 mM hydrogen carbonate. Aqueous ammonium solution-acetonitrile) gave 0.0039 g (26%) ofComparative Compound 2.
cis-N-(5-クロロ-2-メチルベンジル)-4-((S)-3-メチル-2-プロピオナミドブタナミド)シクロヘキサンカルボキサミド(以下、比較例化合物2)の合成:
室温下、MiniBlock(登録商標)-XT(48-position;Mettler Toledo Bohdan社)反応管に、参考例化合物24(0.010g、0.034mmol)及びHATU(0.017g、0.044mmol)のDMF(0.50mL)溶液並びにDIPEA(0.015mL、0.084mmol)のDMF(0.10mL)溶液を加えた。室温下で5分間撹拌した後、反応溶液に、5-クロロ-2-メチルベンジルアミン(0.0052g、0.034mmol)のDMF(0.10mL)溶液を加えた。室温下で一晩撹拌した後、反応溶液に水を加え、窒素を吹き付けて濃縮した。得られた粗生成物をLC-MS逆相分取精製(LC-MS装置:Agilent System 1100、カラム:Zorbax(登録商標)Extend-C18 9.4mm×50mm 5.0μm、移動相:10mM炭酸水素アンモニウム水溶液-アセトニトリル)することで比較例化合物2を0.0039g(26%)得た。 (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. After stirring at room temperature for 5 minutes, a solution of 5-chloro-2-methylbenzylamine (0.0052 g, 0.034 mmol) in DMF (0.10 mL) was added to the reaction solution. After stirring overnight at room temperature, water was added to the reaction solution, and the mixture was concentrated by blowing nitrogen. The obtained crude product was purified by LC-MS reverse phase preparative purification (LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extended-C18 9.4 mm x 50 mm 5.0 µm, mobile phase: 10 mM hydrogen carbonate. Aqueous ammonium solution-acetonitrile) gave 0.0039 g (26%) of
比較例化合物2について、以下に記載の分析方法を用いてLC保持時間及び[M+H]+又は[M-H]-を計測した。分析方法とは、LC-MS装置:Agilent System 1100、カラム:Zorbax(登録商標)Extend-C18 9.4mm×50mm 5.0μm、移動相:A=アセトニトリル B=10mM炭酸水素アンモニウム水溶液、グラジェント:A/B=5/95→80/20(6分間)、流速:4mL/分、で示される分析方法である。
For Comparative Compound 2, the LC retention time and [M + H] + or [M−H] − were measured using the analysis method described below. The analysis method is as follows: LC-MS apparatus: Agilent System 1100, column: Zorbax (registered trademark) Extend-C18 9.4 mm × 50 mm 5.0 μm, mobile phase: A = acetonitrile B = 10 mM aqueous ammonium hydrogen carbonate, gradient: A / B = 5/95 → 80/20 (6 minutes), flow rate: 4 mL / min.
以上の実施例で挙げた本発明の化合物の物性データを表1-1~表1-3、比較例化合物の物性データを表2-1~表2-2、及び参考例で挙げた化合物の物性データを表3-1~表3-3に示す。なお、表中のN.D.は「データなし」を表す。
The physical property data of the compounds of the present invention listed in the above Examples are shown in Table 1-1 to Table 1-3, the physical property data of the Comparative Example compounds are shown in Table 2-1 to Table 2-2, and the compounds listed in Reference Examples. Physical property data are shown in Tables 3-1 to 3-3. In the table, N.I. D. Represents “no data”.
1H-NMRデータ中の溶媒名は、測定に使用した溶媒を示している。また、400 MHzNMRスペクトルは、JNM-AL400型核磁気共鳴装置(日本電子製)を用いて測定した。ケミカルシフトは、テトラメチルシランを基準としてδ(単位:ppm)で表し、シグナルはそれぞれs(一重線)、d(二重線)、t(三重線)、q(四重線)、m(多重線)、brs(幅広)、brd(幅広二重線)、brt(幅広三重線)、dd(二重二重線)、dt(二重三重線)、ddd(二重二重二重線)又はddt(二重二重三重線)で表した。溶媒は全て市販のものを用いた。ESI-MSスペクトルは、Agilent Technologies 1200 Series、G6130A(AgilentTechnology製)を用いて測定した。
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 δ (unit: ppm) based on tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), m ( Multiple line), brs (wide), 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).
(実施例21)
In vitroにおけるsEH阻害活性の評価試験:
公知文献(Analytical Biochemistry、2005年、第343巻、p.66-75)記載の方法に基づき、ヒトsEHを用いて、シクロヘキサンジアミド誘導体(I)のsEH阻害活性を評価した。 (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.
In vitroにおけるsEH阻害活性の評価試験:
公知文献(Analytical Biochemistry、2005年、第343巻、p.66-75)記載の方法に基づき、ヒトsEHを用いて、シクロヘキサンジアミド誘導体(I)のsEH阻害活性を評価した。 (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.
リコンビナント・ヒトsEH(最終濃度0.026μg/mL;Cayman社)を、被験化合物とともに、0.1mg/mL BSAを含む25mM Bis-Tris-HCl緩衝液(pH7.0)中にて室温で30分間インキュベートした。その後、蛍光基質としてシアノ(6-メトキシナフタレン-2-イル)メチル 2-(3-フェニルオキシラン-2-イル)アセタート(最終濃度6.25μmol/L;Cayman社)を加え、さらに室温で20分間インキュベートし、ZnSO4(最終濃度0.2mol/L)を加え反応を停止させ、蛍光強度(Fusionα(パッカード社);Excitation:330nm、Emission:485nm)を測定した。
Recombinant human sEH (final concentration 0.026 μg / mL; Cayman) together with the test compound in 25 mM Bis-Tris-HCl buffer (pH 7.0) containing 0.1 mg / mL BSA for 30 minutes at room temperature Incubated. Thereafter, cyano (6-methoxynaphthalen-2-yl) methyl 2- (3-phenyloxiran-2-yl) acetate (final concentration 6.25 μmol / L; Cayman) was added as a fluorescent substrate, and further at room temperature for 20 minutes. After incubation, ZnSO 4 (final concentration 0.2 mol / L) was added to stop the reaction, and fluorescence intensity (Fusion α (Packard); Excitation: 330 nm, Emission: 485 nm) was measured.
sEH非添加かつ被験化合物非添加の蛍光強度を0%sEH酵素反応率とし、sEH添加かつ被験化合物非添加の蛍光強度を100%sEH酵素反応率として、得られた蛍光強度から、各被験化合物の各sEH酵素反応率を算出し、IC50を求めた。その結果を表4に示す。
The fluorescence intensity with no sEH added and no test compound added was defined as 0% sEH enzyme reaction rate, and the fluorescence intensity with sEH added and no test compound added was defined as 100% sEH enzyme reaction rate. Each sEH enzyme reaction rate was calculated and IC 50 was determined. The results are shown in Table 4.
その結果、実施例化合物1~20は、比較例化合物1及び2と比較して、ヒトsEHの酵素反応に対して非常に強い阻害活性を示した。
As a result, 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.
したがって、シクロヘキサンジアミド誘導体(I)が、ヒトsEHの酵素反応に対して非常に強い阻害活性を示すことが明らかとなった。
Therefore, it was revealed that the cyclohexanediamide derivative (I) exhibits a very strong inhibitory activity on the enzyme reaction of human sEH.
(実施例22)
ラット抗糸球体基底膜抗血清(抗GBM抗血清)投与腎炎モデルでの薬効評価試験:
ラット抗糸球体基底膜抗血清(抗GBM抗血清)投与腎炎モデル(Proceedings of the National Academy of Sciences of the United States of America、2005年、第102巻、p.7736-7741;European journal of pharmacology、2002年、第449巻、p.167-176)に実施例化合物1又は2を投与し、シクロヘキサンジアミド誘導体(I)の慢性腎臓病に対する治療効果を評価した。 (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 administeredExample Compound 1 or 2, and the therapeutic effect of cyclohexanediamide derivative (I) on chronic kidney disease was evaluated.
ラット抗糸球体基底膜抗血清(抗GBM抗血清)投与腎炎モデルでの薬効評価試験:
ラット抗糸球体基底膜抗血清(抗GBM抗血清)投与腎炎モデル(Proceedings of the National Academy of Sciences of the United States of America、2005年、第102巻、p.7736-7741;European journal of pharmacology、2002年、第449巻、p.167-176)に実施例化合物1又は2を投与し、シクロヘキサンジアミド誘導体(I)の慢性腎臓病に対する治療効果を評価した。 (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
ラット(Wistar-Kyoto系、雄性、8週齢;日本チャールス・リバー株式会社)の尾静脈内に、文献記載の方法(Proceedings of the National Academy of Sciences of the United States of America、2005年、第102巻、p.7736-7741;European journal of pharmacology、2002年、第449巻、p.167-176)にて作成したウサギの抗糸球体基底膜抗血清(以下、抗GBM抗血清)を投与して、腎炎を誘発させた群を「腎炎誘発群」とした。一方で、抗GBM抗血清を投与しない群を、「正常群」とした。
In the tail vein of rats (Wistar-Kyoto strain, male, 8 weeks old; Charles River Japan Co., Ltd.), the method described in the literature (Proceedings of the National Academy of Sciences of United States of America, 5th Amer 102th Amer. Vol., P. 7736-7741; European journal of pharmacology, 2002, vol. 449, p. 167-176) was administered rabbit anti-glomerular basement membrane antiserum (hereinafter referred to as anti-GBM antiserum). The group in which nephritis was induced was referred to as “nephritis induction group”. On the other hand, the group not administered with anti-GBM antiserum was designated as the “normal group”.
抗GBM抗血清投与の2週間後に、ラットの尾静脈又は頚静脈から採血し、血清クレアチニン(以下、sCre)を測定した。sCreは酵素法を用いて測定した。
Two weeks after administration of the anti-GBM antiserum, blood was collected from the tail vein or jugular vein of the rat, and serum creatinine (hereinafter referred to as sCre) was measured. sCre was measured using an enzymatic method.
腎炎誘発群における抗GBM抗血清投与の2週間後のsCre値(平均値±標準誤差、n=18)は0.47±0.01mg/dLであった。正常群におけるsCre値(0.27±0.01mg/dL(平均値±標準誤差、n=3))に比べて、統計学的に有意に上昇していた(t検定、p<0.05)。すなわち、腎炎誘発群では、抗GBM抗血清投与の2週間後に腎不全の病態を呈していることが示された。
The sCre value (mean value ± standard error, n = 18) 2 weeks after administration of anti-GBM antiserum in the nephritis induction group was 0.47 ± 0.01 mg / dL. Compared to the sCre value in the normal group (0.27 ± 0.01 mg / dL (mean ± standard error, n = 3)), it was statistically significantly increased (t test, p <0.05). ). That is, in the nephritis induction group, it was shown that two weeks after administration of anti-GBM antiserum, a pathological condition of renal failure was exhibited.
腎不全の病態を呈した腎炎誘発群のラットに、抗GBM抗血清投与の2週間後から実験終了時まで、実施例化合物1又は2を0.5%Tween80含有0.5%メチルセルロース水溶液に懸濁して、3mg/kgの投与量で、1日1回経口投与した。実施例化合物1又は2を投与した群をそれぞれ、「実施例化合物1(3mg/kg)投与群」又は「実施例化合物2(3mg/kg)投与群」とした。また、比較対照として、腎炎誘発群のラットに、0.5%Tween80含有0.5%メチルセルロース水溶液を同様に投与した群を、「腎炎対照群」とした。なお、正常群にも0.5%Tween80含有0.5%メチルセルロース水溶液を同様に投与した。また、抗GBM抗血清投与の4週間後にも、上記と同じ方法で、sCreを測定した。
From the 2nd week after administration of anti-GBM antiserum to the end of the experiment, 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. In addition, as a comparative control, 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. In addition, sCre was measured by the same method as described above also 4 weeks after administration of anti-GBM antiserum.
抗GBM抗血清投与の2及び4週間後のsCre値の測定結果を、図1に示す。図の横軸は、抗GBM抗血清投与後の週数を示し、縦軸は各測定値(平均値±標準誤差、n=6)を示す。
The measurement results of sCre values after 2 and 4 weeks after administration of anti-GBM antiserum are shown in FIG. The horizontal axis of the figure indicates the number of weeks after administration of anti-GBM antiserum, and the vertical axis indicates each measured value (mean value ± standard error, n = 6).
腎炎対照群における、抗GBM抗血清投与の2及び4週間後のsCre値は、抗GBM抗血清投与の2週間後から持続的に高値を示した。したがって、腎炎対照群は、慢性の腎炎及び腎不全の病態を呈していることが示された。
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.
また、抗GBM抗血清投与の4週間後の、実施例化合物1(3mg/kg)投与群及び実施例化合物2(3mg/kg)投与群におけるsCre値は、腎炎対照群におけるsCre値に比べて、それぞれ顕著に低値を示した(図1)。したがって、実施例化合物1及び2は、慢性の腎炎及び腎不全の病態に対して治療効果を有することが示された。
In addition, the sCre value in the Example Compound 1 (3 mg / kg) administration group and the Example Compound 2 (3 mg / kg) administration group 4 weeks after the anti-GBM antiserum administration was compared with the sCre value in the nephritis control group. The values were remarkably low (FIG. 1). Therefore, it was shown that Example compounds 1 and 2 have a therapeutic effect on the pathological conditions of chronic nephritis and renal failure.
この結果から、シクロヘキサンジアミド誘導体(I)が、慢性の腎炎及び腎不全の病態に対して治療効果を示すことが明らかとなった。
From this result, it was revealed that cyclohexanediamide derivative (I) has a therapeutic effect on the pathological conditions of chronic nephritis and renal failure.
(実施例23)
ラットモノクロタリン投与肺高血圧症モデルでの薬効評価試験:
ラットモノクロタリン投与肺高血圧症モデル(Journal of Pharmacological Sciences、2009年、第111巻、p.235-243)に、実施例化合物1又は2を投与し、シクロヘキサンジアミド誘導体(I)の肺高血圧症に対する治療効果を評価した。 (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.
ラットモノクロタリン投与肺高血圧症モデルでの薬効評価試験:
ラットモノクロタリン投与肺高血圧症モデル(Journal of Pharmacological Sciences、2009年、第111巻、p.235-243)に、実施例化合物1又は2を投与し、シクロヘキサンジアミド誘導体(I)の肺高血圧症に対する治療効果を評価した。 (Example 23)
Evaluation of drug efficacy in rat monocrotaline-treated pulmonary hypertension model:
ラット(Wistar系、雄性、5週齢;日本エスエルシー株式会社)の背部皮下に、モノクロタリン(シグマ社)水溶液(60mg/kg)を投与して、肺高血圧症を誘発させた群を、「肺高血圧症誘発群」とした。一方で、注射用水を同様に投与した群を、「正常群」とした。
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”.
肺高血圧症誘発群のラットに、モノクロタリン投与日から24日間、実施例化合物1(3及び10mg/kg)又は実施例化合物2(10mg/kg)を1日1回経口投与した。実施例化合物1及び2は、0.5%Tween80含有0.5%メチルセルロース水溶液に懸濁して用いた。実施例化合物1を、3又は10mg/kgの投与量で投与した群をそれぞれ、「実施例化合物1(3mg/kg)投与群」又は「実施例化合物1(10mg/kg)投与群」とした。また、実施例化合物2を10mg/kgの投与量で投与した群を、「実施例化合物2投与群」とした。一方で、比較対照として、肺高血圧症誘発群のラットに、0.5%Tween80含有0.5%メチルセルロース水溶液を同様に投与した群を、「肺高血圧症対照群」とした。正常群にも0.5%Tween80含有0.5%メチルセルロース水溶液を同様に投与した。なお、各群n=10とした。
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. . In addition, a group in which Example Compound 2 was administered at a dose of 10 mg / kg was designated as “Example Compound 2 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. Each group n = 10.
被験化合物最終投与の翌日に、右心室収縮期圧、全身収縮期血圧及び心拍数を測定した。右心室収縮期圧及び全身収縮期血圧は、血圧測定用アンプ(日本光電工業株式会社)を用いて測定し、心拍数は、瞬時心拍計ユニット(日本光電工業株式会社)を用いて測定した。また、同日に、右心室、左心室及び中隔の湿重量を測定し、右心室重量比(右心室重量/(中隔重量+左心室重量))を求めた。
The day after the final administration of the test compound, the right ventricular systolic pressure, systemic systolic blood pressure, and heart rate were measured. The right ventricular systolic pressure and systemic systolic blood pressure were measured using a blood pressure measurement amplifier (Nihon Koden Kogyo Co., Ltd.), and the heart rate was measured using an instantaneous heart rate monitor unit (Nihon Koden Kogyo Co., Ltd.). On the same day, 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.
その結果を表5及び6に示す。
The results are shown in Tables 5 and 6.
肺高血圧症対照群の右心室収縮期圧(平均値±標準誤差、n=10)は123±5mmHgであり、正常群の右心室収縮期圧(31±2mmHg(平均値±標準誤差、n=10))と比較して、統計学的に有意に高値を示し(Aspin-Welchのt検定、p<0.05)、肺高血圧症の病態を呈していることが示された。また、実施例化合物1(3mg/kg)投与群及び実施例化合物2投与群の右心室収縮期圧は、肺高血圧症対照群の右心室収縮期圧と比較して、統計学的に有意に低値を示した(Dunnett’s検定、p<0.05)(表5)。したがって、実施例化合物1及び2が、肺高血圧症の病態に対して治療効果を有することが示された。
The right ventricular systolic pressure (mean ± standard error, n = 10) of the pulmonary hypertension control group is 123 ± 5 mmHg, and the right ventricular systolic pressure (31 ± 2 mmHg (mean ± standard error, n = 10) of the normal group. Compared with 10)), the value was statistically significantly higher (Aspin-Welch t test, p <0.05), indicating that the patient had a pathological condition of pulmonary hypertension. In addition, the right ventricular systolic pressure in the group administered with Example Compound 1 (3 mg / kg) and the group administered with Example Compound 2 were statistically significant compared to the right ventricular systolic pressure in the pulmonary hypertension control group. A low value was shown (Dunnett's test, p <0.05) (Table 5). Therefore, it was shown that Example compounds 1 and 2 have a therapeutic effect on the pathology of pulmonary hypertension.
肺高血圧症対照群の右心室重量比(平均値±標準誤差、n=10)は0.54±0.02であり、正常群の右心室重量比(0.27±0.01(平均値±標準誤差、n=10))と比較して、統計学的に有意に高値を示し(Aspin-Welchのt検定、p<0.05)、右心室肥大の病態を呈していることが示された。また、実施例化合物2投与群の右心室重量比は、肺高血圧症対照群の右心室重量比と比較して、統計学的に有意に低値を示した(Dunnett’s検定、p<0.05)(表6)。また、実施例化合物1(3mg/kg)投与群及び実施例化合物1(10mg/kg)投与群の右心室重量比は、肺高血圧症対照群の右心室重量比と比較して、低値を示した(表6)。したがって、実施例化合物1及び2が、右心室肥大の病態に対しても治療効果を有することが示された。
The right ventricular weight ratio (mean value ± standard error, n = 10) of the pulmonary hypertension control group is 0.54 ± 0.02, and the right ventricular weight ratio (0.27 ± 0.01 (mean value) of the normal group Compared with ± standard error, n = 10)), it is statistically significantly higher (Aspin-Welch t-test, p <0.05), indicating that the disease state of right ventricular hypertrophy is exhibited. It was done. In addition, 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). Further, the right ventricular weight ratio of the Example Compound 1 (3 mg / kg) administration group and the Example Compound 1 (10 mg / kg) administration group is lower than the right ventricular weight ratio of the pulmonary hypertension control group. (Table 6). Therefore, it was shown that Example compounds 1 and 2 have a therapeutic effect also on the pathophysiology of right ventricular hypertrophy.
一方、実施例化合物1(3mg/kg)投与群、実施例化合物1(10mg/kg)投与群及び実施例化合物2投与群の、心拍数及び全身収縮期血圧については、肺高血圧症対照群の心拍数及び全身収縮期血圧と比較して、いずれも有意な差は認められなかった(Dunnett’s検定、p<0.05)。
On the other hand, 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).
この結果から、シクロヘキサンジアミド誘導体(I)が、肺高血圧症に対して治療効果を示すことが明らかとなった。
From this result, it was revealed that cyclohexanediamide derivative (I) has a therapeutic effect on pulmonary hypertension.
本発明のシクロヘキサンジアミド誘導体は、強力なsEH阻害活性を示し、医薬の分野において慢性腎臓病及び肺高血圧症の治療剤又は予防剤として用いることができる。
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.
Claims (6)
- 以下の一般式(I)で示される、シクロヘキサンジアミド誘導体。
R2及びR3は、それぞれ独立して、水素原子(ただし、R2及びR3は、同時に水素原子を表すことはない)、炭素数1~6のアルキル基又は炭素数2~7のアルキルオキシアルキル基(該アルキル基及び該アルキルオキシアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい)を表すか、一緒になって-(CH2)l-を表すか、又は、さらにR1と一緒になってアダマンチル基を表してもよく、
R4及びR5は、それぞれ独立して、水素原子、ハロゲン原子、シアノ基又は炭素数1~6のアルキル基若しくはアルキルオキシ基(該アルキル基及び該アルキルオキシ基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子で置換されていてもよい)を表し、
R6は、炭素数1~6のアルキル基を表し、
R7は、炭素数1~6のアルキル基、炭素数3~6のシクロアルキル基、炭素数2~7のアルキルオキシアルキル基又は炭素数4~7のシクロアルキルアルキル基(該アルキル基、該シクロアルキル基、該アルキルオキシアルキル基及び該シクロアルキルアルキル基は、1~3個の水素原子が、それぞれ独立して、ハロゲン原子、水酸基又はシアノ基で置換されていてもよい)を表し、
lは、2~5の整数を表す。] A cyclohexanediamide derivative represented by the following general formula (I):
R 2 and R 3 are each independently a hydrogen atom (wherein R 2 and R 3 do not represent a hydrogen atom at the same time), an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 2 to 7 carbon atoms. An oxyalkyl group (the alkyl group and the alkyloxyalkyl group each represent 1 to 3 hydrogen atoms each independently may be substituted with a halogen atom, a hydroxyl group or a cyano group), or together And represents-(CH 2 ) 1- or may be further combined with R 1 to represent an adamantyl group,
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 represented by 1 to 3 hydrogen atoms) Each atom may be independently 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, a cycloalkyl group having 3 to 6 carbon atoms, an alkyloxyalkyl group having 2 to 7 carbon atoms, or a cycloalkylalkyl group having 4 to 7 carbon atoms (the alkyl group, A cycloalkyl group, the alkyloxyalkyl group and the cycloalkylalkyl group each represent 1 to 3 hydrogen atoms may be independently substituted with a halogen atom, a hydroxyl group or a cyano group),
l represents an integer of 2 to 5. ] - R2及びR3は、それぞれ独立して、水素原子若しくは炭素数1~6のアルキル基を表すか、又は、一緒になって-(CH2)l-を表し、
R5は、ベンゼン環上の2位の置換基である、請求項1記載のシクロヘキサンジアミド誘導体。 R 2 and R 3 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, or together represent-(CH 2 ) l- ,
The cyclohexanediamide derivative according to claim 1, wherein R 5 is a substituent at the 2-position on the benzene ring. - R1は、炭素数1~6のアルキル基又は-N(H)C(=O)R7であり、
R4は、ハロゲン原子、シアノ基又は炭素数1~6のアルキル基若しくはアルキルオキシ基であり、
R5は、ハロゲン原子又は炭素数1~6のアルキル基若しくはアルキルオキシ基である、請求項2記載のシクロヘキサンジアミド誘導体。 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, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group,
The cyclohexanediamide derivative according to claim 2, wherein R 5 is a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyloxy group. - 請求項1~3のいずれか一項記載のシクロヘキサンジアミド誘導体を有効成分として含有する、医薬。 A pharmaceutical comprising the cyclohexanediamide derivative according to any one of claims 1 to 3 as an active ingredient.
- 請求項1~3のいずれか一項記載のシクロヘキサンジアミド誘導体を有効成分として含有する、可溶性エポキシド加水分解酵素阻害剤。 A soluble epoxide hydrolase inhibitor comprising the cyclohexanediamide derivative according to any one of claims 1 to 3 as an active ingredient.
- 請求項1~3のいずれか一項記載のシクロヘキサンジアミド誘導体を有効成分として含有する、慢性腎臓病若しくは肺高血圧症の治療剤又は予防剤。 A therapeutic or prophylactic agent for chronic kidney disease or pulmonary hypertension, comprising the cyclohexanediamide derivative according to any one of claims 1 to 3 as an active ingredient.
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