WO2012173219A1 - Novel biaryl ether derivative - Google Patents

Abstract

The present invention relates to a compound having an excellent DGAT inhibitory activity and an excellent antifeeding activity or a pharmacologically acceptable salt thereof. A compound represented by general formula (I) [wherein R¹ represents a hydrogen atom, a halogen atom, a C₁-C₆ alkyl group or a C₃-C₆ cycloalkyl group; R²'s independently represent a halogen atom, a C₁-C₆ alkyl group, a C₁-C₆ alkoxy group or a hydroxy group; and n represents an integer of 0 to 2] or a pharmacologically acceptable salt thereof.

Description

New biaryl ether derivatives

The present invention relates to a compound having a specific chemical structure having an excellent acylcoenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibitory activity and an excellent feeding inhibitory activity, Relates to acceptable salts.

In obesity, triglyceride (triacylglycerol or triglyceride, hereinafter also referred to as TG) accumulates in adipocytes due to the persistence of excess energy compared to energy consumption, resulting in standard weight gain. It is in a state of significantly increasing compared to body weight (Non-Patent Document 1). Obesity is hyperlipidemia, hyperTGemia, diabetes, hypertension, lifestyle-related diseases such as arteriosclerosis, cerebrovascular disorder, coronary artery disease, respiratory abnormalities, low back pain, knee osteoarthritis, gout, cholelithiasis, etc. Any obesity that has these complications or that may cause these complications in the future is defined as obesity and is treated as a disease.

Animals and plants store lipid as insoluble TG, and decompose TG as necessary to produce energy. TG ingested by the meal is broken down into free fatty acids and monoacylglycerol by the action of bile acids and pancreatic lipase in the lumen of the small intestine. Micelles composed of free fatty acid, monoacylglycerol and bile acid are absorbed into small intestinal epithelial cells, and in the endoplasmic reticulum by the action of acylcoenzyme A synthase (hereinafter referred to as ACS), acylcoenzyme A: monoacylglycerol acyltransferase and DGAT. TG is newly synthesized. TG, in combination with phospholipids, cholesterol and apolipoprotein, is secreted into the gastrointestinal lymphatic vessels as kilomicrons. Furthermore, TG is secreted into the blood via the lymph main duct and transported to the periphery for use. On the other hand, in adipose tissue, TG is synthesized from glycerol 3-phosphate and free fatty acids by the action of ACS, glycerol 3-phosphate acyltransferase, lysophosphatidic acid acyltransferase, and DGAT (Non-patent Document 2). Thus, TG ingested excessively accumulates in adipose tissue, resulting in obesity.

DGAT is an enzyme that is present in the endoplasmic reticulum in the cell and catalyzes the most important final step reaction in the TG synthesis pathway, that is, the reaction of transferring the acyl group of acylcoenzyme A to the 3-position of 1,2-diacylglycerol. (Non-Patent Documents 3 to 5). It has been reported that DGAT has two types of isozymes DGAT1 (Non-patent document 6) and DGAT2 (Non-patent document 7). Since DGAT1 is highly expressed in the small intestine and adipose tissue, and DGAT2 is highly expressed in the liver and adipose tissue, respectively, DGAT1 is mainly used for fat absorption from the small intestine and fat accumulation, and DGAT2 is used for TG synthesis or VLDL in the liver. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue. Although the difference in the roles of DGAT1 and DGAT2 has not yet been clarified in detail, the relationship between DGAT and obesity, lipid metabolism, sugar metabolism, etc. has been suggested (Non-patent Document 8). DGAT is a key enzyme for TG synthesis in gastrointestinal epithelial cells and adipose tissue, and a drug that inhibits DGAT suppresses fat absorption in the gastrointestinal tract and fat accumulation in adipose tissue by suppressing TG synthesis, and obesity , Obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, diabetes, non-alcoholic steatohepatitis, or obesity-induced hyperlipidemia, hypertriglyceridemia, lipid metabolism It is expected to be useful as a therapeutic or prophylactic agent for abnormal diseases, insulin resistance syndrome, diabetes, nonalcoholic steatohepatitis, hypertension, arteriosclerosis, cerebrovascular disorder, coronary artery disease, etc. 9 to 13).

An appetite suppressant directly or indirectly regulates the appetite control system, but its mechanism of action is roughly divided into central and peripheral. An appetite suppressant acting centrally acts on the hypothalamic nervous system where the feeding center and satiety center exist and the monoamine nervous system in the brain that regulates the nervous system, thereby directly suppressing appetite. On the other hand, an appetite suppressant that acts on the periphery acts on a mechanism that senses and transmits the intake of nutrients and the accumulation of surplus energy, and indirectly suppresses appetite.

In recent years, gastrointestinal hormones (CCK, GLP-1, PYY, etc.) secreted in close association with the digestion and absorption of food (Non-Patent Document 14) and from fat cells according to the energy accumulation (fat mass) The mechanism by which secreted leptin (Non-patent Document 15) or the like transmits a signal that regulates appetite from the periphery to the center in a hormonal or neurological manner has been clarified. These new appetite suppressants associated with peripheral signals are expected to be more effective and less effective for the treatment of obesity.

As a compound having a DGAT inhibitory action, Patent Document 1 discloses a compound having 4- (5-carboxamido-2,3'-bipyridin-6'-yloxy) cyclohexanecarboxylic acid.

WO2011 / 031628

As a result of intensive studies on compounds having a DGAT inhibitory action and an antifeedant action, the inventors have found that a compound having a specific chemical structure has an excellent DGAT inhibitory action, particularly high for DGAT1. It was found to have an inhibitory effect. The present inventors have also found that this compound has an excellent antifeeding action. Furthermore, the present inventors have found that this compound is obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral Neuropathy, including diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic Hyperlipidemia, hypertriglyceridemia, lipid metabolism resulting from obesity or as an active ingredient of a medicament for the prevention and / or treatment of a disease selected from the group consisting of arteriosclerosis, ischemic heart disease and bulimia Abnormal diseases, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataracts, Gynecologic diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, deformity It was found useful as an active ingredient of a medicament for the treatment and / or prevention of a disease selected from the group consisting of knee arthropathy, gout, and cholelithiasis.

The present invention comprises (1) general formula (I)

[Where:
R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₃ -C ₆ cycloalkyl group,
R ² independently represents a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a hydroxy group,
n represents an integer of 0 to 2. Or a pharmacologically acceptable salt thereof.

In the present invention, preferably,
(2) In (1),
The compound or its pharmacologically acceptable salt whose general formula (I) is general formula (Ia).

(3) In (1) or (2),
A compound or a pharmacologically acceptable salt thereof, wherein R ¹ is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a cyclopropyl group.

(4) In any one item selected from (1) to (3),
A compound in which n is 0 or a pharmacologically acceptable salt thereof.

(5) In any one item selected from (1) to (3),
A compound or a pharmacologically acceptable salt thereof, wherein n is 1, and R ² is a methyl group.

(6) In (1),
A compound in which general formula (I) is general formula (Ia), R ¹ is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a cyclopropyl group, and n is 0, or a pharmacologically acceptable salt thereof. Salt.

(7) In (1),
The general formula (I) is the general formula (Ia), R ¹ is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a cyclopropyl group, n is 1, and R ² is a methyl group Or a pharmacologically acceptable salt thereof.

(8) (cis-4-{[5- (4-{[(3-Methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] Oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(3-Cyclopropyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} (Cyclohexyl) acetic acid,
(cis-4-{[5- (2-Methyl-4-{[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl ] Oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (4-{[(3-Ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid,
(cis-4-{[5- (4-{[(1-Pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
(cis-4-{[5- (2-Methyl-4-{[(1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid, or
(cis-4-{[5- (4-{[(3-Chloro-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl ) A compound which is acetic acid or a pharmacologically acceptable salt thereof.

(9) A compound described in (8) or a pharmacologically acceptable salt thereof.

(10) An acyl coenzyme A: diacylglycerol acyltransferase inhibitor comprising the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof as an active ingredient.

(11) An antifeedant and / or an appetite suppressant containing the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof as an active ingredient.

(12) A pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof.

(13) The pharmaceutical composition according to (12), wherein the pharmaceutical composition has an inhibitory action on acylcoenzyme A: diacylglycerol acyltransferase.

(14) The pharmaceutical composition according to (12), wherein the pharmaceutical composition has an antifeedant action and / or an appetite suppressive action.

(15) The pharmaceutical composition according to (12), for treating and / or preventing a disease wherein the pharmaceutical composition is treated and / or prevented by acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.

(16) The pharmaceutical composition according to (12), wherein the pharmaceutical composition is used for treatment and / or prevention of a disease caused by an increase in acylcoenzyme A: diacylglycerol acyltransferase activity.

(17) The pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase, inhibits synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby treating, improving, reducing and / or preventing symptoms. The pharmaceutical composition according to (12) for the treatment and / or prevention of certain diseases.

(18) The pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase and inhibits the synthesis of triglyceride, thereby treating and / or treating diseases in which symptoms are treated, ameliorated, reduced and / or prevented. The pharmaceutical composition according to (12) for prevention.

(19) The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridosis, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The pharmaceutical composition according to (12) for the treatment and / or prevention of blood heart disease or bulimia.

(20) The pharmaceutical composition according to (12), wherein the pharmaceutical composition is for the treatment and / or prevention of obesity or obesity.

(21) The pharmaceutical composition according to (12), wherein the pharmaceutical composition is for the treatment and / or prevention of diabetes.

(22) When the pharmaceutical composition is obesity-induced hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension (12) The pharmaceutical composition for treatment and / or prevention of symptom, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormality, low back pain, knee osteoarthritis, gout or cholelithiasis.

(23) The pharmaceutical composition according to (12), wherein the pharmaceutical composition is for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(24) The pharmaceutical composition according to (12), wherein the pharmaceutical composition suppresses fat absorption from the small intestine.

(25) Obesity, obesity, hyperlipidemia, hypertriglyceridemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetes Retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, non-alcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or The compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of bulimia.

(26) The compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of obesity or obesity.

(27) The compound according to any one of (1) to (9) or a pharmacologically acceptable salt thereof for use in the treatment and / or prevention of diabetes.

(28) Use of the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.

(29) The use according to (28), wherein the pharmaceutical composition is a pharmaceutical composition for inhibiting acylcoenzyme A: diacylglycerol acyltransferase.

(30) Use according to (28), wherein the pharmaceutical composition is a pharmaceutical composition for suppressing eating and / or appetite.

(31) The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic Nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, false The use according to (28), which is a pharmaceutical composition for the treatment and / or prevention of blood heart disease or bulimia.

(32) The use according to (28), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and / or prevention of obesity or obesity.

(33) Use according to (28), wherein the pharmaceutical composition is a pharmaceutical composition for the treatment and / or prevention of diabetes.

(34) Hyperlipidemia due to obesity, hypertriglyceridemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic kidney) , Including diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension The use according to (28), which is a pharmaceutical composition for the treatment and / or prevention of cerebrovascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or cholelithiasis.

(35) The use according to (28), wherein the pharmaceutical composition is a therapeutic composition for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity. .

(36) The use according to (28), wherein the pharmaceutical composition is a pharmaceutical composition for suppressing fat absorption from the small intestine.

(37) Acyl coenzyme A: diacylglycerol for administering to a warm-blooded animal a pharmacologically effective amount of the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof Acyltransferase inhibition method.

(38) Feeding suppression and / or administration of a pharmacologically effective amount of the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof to a warm-blooded animal Appetite suppression method.

(39) Treatment of a disease in which a pharmacologically effective amount of the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal and / or Prevention method.

(40) Diseases are obesity, obesity, hyperlipidemia, hypertriglycerideemia, lipid metabolism disorders, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy , Including diabetic retinopathy, diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart The method according to (39), which is a disease or bulimia.

(41) The method according to (39), wherein the disease is obesity or obesity.

(42) The method according to (39), wherein the disease is diabetes.

(43) Hyperlipidemia due to obesity, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, hypertension, brain (39) The method according to (39), which is vascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or cholelithiasis.

(44) The method according to (39), wherein the disease is hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.

(45) Absorption of fat from the small intestine in which a pharmacologically effective amount of the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof is administered to a warm-blooded animal. How to suppress.

(46) The method according to any one of (37) to (45), wherein the warm-blooded animal is a human.

In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferred is a fluorine atom or a chlorine atom, and more preferred is a chlorine atom.

In the present invention, the “C ₁ -C ₆ alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, hexyl, isohexyl or 4-methylpentyl group. Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms (C ₁ -C ₄ alkyl group), and more preferred is a methyl group or an ethyl group (C ₁ -C ₂ alkyl group). And even more preferably a methyl group.

In the present invention, the “C ₁ -C ₆ alkoxy group” is a group in which the “C ₁ -C ₆ alkyl group” is bonded to an oxygen atom, and is a linear or branched alkoxy group having 1 to 6 carbon atoms. It is. For example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, pentoxy or hexyloxy group. Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms (C ₁ -C ₄ alkoxy group), and more preferred is a methoxy group or an ethoxy group (C ₁ -C ₂ alkoxy group). And even more preferably a methoxy group.

In the present invention, the “C ₃ -C ₆ cycloalkyl group” is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, and preferably a cyclopropyl group.

In the present invention, preferred general formula (I) is general formula (Ia).

In the present invention, preferred R ¹ is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a cyclopropyl group.

In the present invention, preferred R ² is a methyl group.

In the present invention, n is preferably 0.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has all isomers (diastereoisomers, optical isomers, rotational isomers, etc.).

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom exists in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.

For the stereoisomer as described above, an optically active raw material compound is used, or a compound according to the present invention is synthesized using an asymmetric synthesis or asymmetric induction method, or a synthesized compound according to the present invention is synthesized. If desired, it can be obtained by isolation using a conventional optical resolution method or separation method.

The compound represented by the general formula (Ia) or a pharmacologically acceptable salt thereof is more preferable than the compound represented by the general formula (Ib) or a pharmacologically acceptable salt thereof.

The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of the atomic isotope include deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), carbon-14 ( ¹⁴ C), and the like. The compound can also be radiolabeled with a radioisotope such as, for example, tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.

“The pharmacologically acceptable salt” refers to a salt that has no significant toxicity and can be used as a medicine. The compound represented by the general formula (I) of the present invention can be converted into a salt by reacting with an acid when it has a basic group, or by reacting with a base when it has an acidic group. can do.

Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonates such as benzenesulfonate and p-toluenesulfonate Organic acids such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate; and glycine salt, lysine salt, Examples thereof include amino acid salts such as arginine salt, ornithine salt, glutamate salt and aspartate salt.

On the other hand, examples of the salt based on the acidic group include alkali metal salts such as sodium salt, potassium salt and lithium salt, alkaline earth metal salts such as calcium salt and magnesium salt, metal salts such as aluminum salt and iron salt. Inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane salt Amine salts such as organic salts; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is taken in the air or recrystallized to take in water molecules, Such hydrates are also encompassed by the salts of the present invention.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present. Included in the salts of the invention.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and feeding inhibitory action, and is a warm-blooded animal (preferably a mammal, Diseases (including humans): obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, Diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis , A disease selected from the group consisting of ischemic heart disease and bulimia, or hyperlipidemia, hypertriglycerideemia, lipid metabolism disorder, insulin resistance syndrome, impaired glucose tolerance, sugar caused by obesity Urinary disease, diabetic complications (including diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis Disease selected from the group consisting of infectious disease, atherosclerosis, diabetic arteriosclerosis, hypertension, cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout, and cholelithiasis It is useful as a medicament for the prevention and / or treatment. Further, the novel compound represented by the general formula (I) provided by the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action, and is a warm-blooded animal (preferably a mammalian animal). And is useful as an active ingredient of a medicament for the prevention and / or treatment of the above-mentioned diseases (including humans). Suitably, it can be used as a medicament for the treatment of the above-mentioned diseases.

The compound represented by the general formula (I) of the present invention can be produced according to Method A and Method B described below.

The solvent used in the reaction of each step of the following method A and method B is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, and is selected from the following solvent group, for example. Solvent groups include hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin, cyclohexane; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl Amides such as -2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; methanol, ethanol, n-propanol, i -Propanol, n-butanol, 2-butanol, 2-methyl-1-propanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, Alcohols such as methyl cellosolve; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane; nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ketones such as acetone, methyl ethyl ketone, 4-methyl-2-pentanone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; dichloromethane, 1, Halogenated hydrocarbons such as 2-dichloroethane, chlorobenzene, dichlorobenzene, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; N-methylmorpholine, tri Tylamine, tripropylamine, tributylamine, diisopropylethylamine, N-methylpiperidine, pyridine, 2,6-lutidine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (T-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1, 4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), amines such as piperidine; water; and mixtures thereof It consists of a solvent.

The base used in the reaction of each step of the following method A and B is, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate Alkali metal bicarbonates such as sodium acetate, potassium acetate, lithium acetate, alkali metal acetates such as cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; Alkali metal hydroxides such as sodium, potassium hydroxide and lithium hydroxide; alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium Alkali metal alcohols such as t-butoxide Cids; alkali metal trialkylsiloxides such as sodium trimethylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N- Methylpiperidine, pyridine, 2,6-lutidine, collidine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane ( DABCO), 1,8-diazabicyclo [5 4.0] organic bases such as undec-7-ene (DBU); organometallic bases such as n-butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide; or amino acids such as proline is there.

In the reaction of each step of Method A and Method B below, the reaction temperature varies depending on the solvent, starting material, reagent, etc., and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.

In the reaction of each step of the following method A and method B, after completion of the reaction, each target compound is collected from the reaction mixture according to a conventional method. For example, neutralize the reaction mixture as appropriate, or remove insoluble matter by filtration, add water and an immiscible organic solvent such as ethyl acetate, and separate the organic layer containing the target compound, It can be obtained by washing with water, drying over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtering, and then distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., usually using methods commonly used for separation and purification of organic compounds, applying chromatography, and the like. Can be separated and purified. For a target compound insoluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. In addition, the target compound in each step can be directly used in the next reaction without purification.

In the reaction of each step of the following method A and method B, R ¹ , R ² and n have the same meaning as described above. X ¹ and X ^{2 each} represent a halogen atom (preferably a bromine atom or an iodine atom, and more preferably a bromine atom), and Y ¹ and Y ² are used in the field of synthetic organic chemistry. A protecting group for carboxy group (preferably a C ₁ -C ₆ alkyl group or an aralkyl group. Y ¹ is more preferably a methyl group, and Y ² is more preferably An ethyl group). R ^2a is a hydroxy group contained in the group R ² is other is protected may be hydroxy groups include the same groups as in the definition of group R ^2.

Method A is a method for producing a compound represented by the general formula (I).
(Method A)

Step AI This step comprises reacting a compound represented by the general formula (II) with a compound represented by the general formula (III) in a solvent in the presence of a Mitsunobu reagent. It is a process of manufacturing the compound represented by these.

The compound represented by the general formula (II) and the compound represented by the general formula (III) used in this step are known compounds, or a known method using a known compound as a starting material or a method similar thereto. Easily manufactured according to.

The solvent used in this step is preferably aromatic hydrocarbons or ethers, and more preferably toluene or tetrahydrofuran.

The Mitsunobu reagent used in this step is preferably an azodicarboxylic acid diester or (cyanomethylene) phosphorane reagent, more preferably diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or ( Cyanomethylene) tributylphosphorane (CMBP).

The reaction temperature in this step is usually −20 ° C. to 180 ° C., preferably 0 ° C. to 120 ° C.

The reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.

Step A-II In this step, the compound represented by the general formula (IV) is reacted with the compound represented by the general formula (V) in the presence of a palladium catalyst and a base in a solvent, to thereby obtain a compound represented by the general formula (V). This is a process for producing a compound represented by VI).

The compound represented by the general formula (V) used in this step is a known compound, or can be easily produced according to a known method or a similar method using the known compound as a starting material.

The solvent used in this step is preferably a mixed solvent of ethers or amides and water, more preferably a mixed solvent of tetrahydrofuran, dioxane or N, N-dimethylacetamide and water.

The palladium catalyst used in this step is, for example, tetrakis (triphenylphosphine) palladium (0), palladium-activated carbon, palladium acetate (II), palladium trifluoroacetate (II), palladium black, palladium bromide (II ), Palladium (II) chloride, palladium (II) iodide, palladium (II) cyanide, palladium (II) nitrate, palladium (II) oxide, palladium (II) sulfate, dichlorobis (acetonitrile) palladium (II), dichlorobis (Benzonitrile) palladium (II), dichloro (1,5-cyclooctadiene) palladium (II), acetylacetone palladium (II), palladium sulfide (II), [1,1'-bis (diphenylphosphino) ferrocene] Palladium (II) dichroic A divalent palladium catalyst such as Lido, tris (dibenzylideneacetone) dipalladium (0), tetrakis (acetonitrile) palladium (II) tetrafluoroborate or arylpalladium chloride dimer, preferably a zerovalent palladium catalyst, , A zero-valent palladium catalyst, and more preferably tetrakis (triphenylphosphine) palladium (0).

The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.

The reaction temperature in this step is usually 20 ° C. to 180 ° C., preferably 60 ° C. to 120 ° C.

The reaction time in this step is usually 0.5 hours to 72 hours, preferably 2 hours to 24 hours.

Step A-III In this step, the compound represented by the general formula (VI) is converted into the general formula (VII) in a solvent in the presence of a condensing agent, in the presence or absence of a base (preferably in the presence). ) To produce a compound represented by the general formula (VIII).

The solvent used in this step is preferably an amide, and more preferably N, N-dimethylacetamide.

The condensing agent used in this step is, for example, azodicarboxylic acid dilower alkyl ester-triphenylphosphine such as azodicarboxylic acid diethyl ester-triphenylphosphine; N, N′-dicyclohexylcarbodiimide (DCC), 1- Carbodiimide derivatives such as ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI); 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; diphenylphosphoryl azide ( Diarylphosphoryl azides such as DPPA; phosphoryl chlorides such as diethyl phosphoryl chloride; imidazole derivatives such as N, N′-carbodiimidazole (CDI); benzotriazol-1-yloxy-to (Dimethylamino) phosphonium hexafluorophosphate (BOP), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (HATU), (1H -Benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), a benzotriazole derivative, preferably a benzotriazole derivative, more preferably BOP.

The base used in this step is preferably an organic base, and more preferably triethylamine.

The reaction temperature in this step is usually -20 ° C to 160 ° C, preferably 0 ° C to 100 ° C.

The reaction time in this step is usually 0.1 hour to 120 hours, preferably 1 hour to 24 hours.

Step A-IV This step is based on a known method (for example, “Protective Groups in Organic Synthesis” (the method described in Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication), etc.). Done. For example, the case where Y ¹ is a C ₁ -C ₆ alkyl group is shown below.

This step is represented by the general formula (I) by reacting the compound represented by the general formula (VIII) with a base in a solvent and then removing the hydroxy protecting group in R ^{2a as} required. This is a process for producing a compound.

The solvent used in this step is preferably an ether or an alcohol, and more preferably tetrahydrofuran, dioxane or methanol.

The base used in this step is preferably a quaternary ammonium salt, and more preferably tetrabutylammonium hydroxide.

The reaction temperature in this step is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

The reaction time in this reaction is usually 0.5 to 24 hours, preferably 1 to 10 hours.

Method B is a method for producing a compound represented by the general formula (VII) used in Step A-III of Method A.
(Method B)

Step BI This step is performed by reacting a compound represented by the general formula (IX) with a compound represented by the general formula (X) in a solvent in the presence of a copper catalyst, a base and a ligand. In this step, the compound represented by formula (XI) is produced.

The compound represented by the general formula (IX) and the compound represented by the general formula (X) used in this step are known compounds, or a known method using a known compound as a starting material or a method similar thereto. Easily manufactured according to.

The solvent used in this step is preferably an aromatic hydrocarbon, and more preferably toluene.

The copper catalyst used in this step is 0-valent copper or a complex thereof; 1 such as copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) trifluoromethanesulfonate. Or a divalent copper salt such as copper (II) bromide, copper (II) acetate, or copper (II) sulfate, preferably a monovalent copper salt, more preferably Is copper iodide (I).

The base used in this step is preferably an alkali metal carbonate, and more preferably potassium carbonate.

The ligand used in this step is, for example, an amine compound, preferably a diamine, and more preferably 1,2-di (methylamino) cyclohexane.

The reaction temperature in this step is usually 0 ° C to 200 ° C, preferably 80 ° C to 130 ° C.

The reaction time in this step is usually 0.5 hours to 96 hours, preferably 2 hours to 48 hours.

Step B-II This step is based on a known method (for example, the method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter GMWuts, 1999, published by Wiley-Interscience Publication), etc.) Done. For example, the case where Y ² is a C ₁ -C ₆ alkyl group is shown below.

This step is a step of producing the compound represented by the general formula (VII) by reacting the compound represented by the general formula (XI) with a base in a solvent.

The solvent used in this step is preferably ethers, alcohols, water or a mixed solvent thereof, more preferably a mixed solvent of tetrahydrofuran, ethanol and water.

The base used in this step is preferably an alkali metal hydroxide, and more preferably sodium hydroxide.

The reaction temperature in this step is usually 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C.

The reaction time in this reaction is usually 0.5 to 24 hours, preferably 1 to 10 hours.

In the above, the protecting group of the “optionally protected hydroxy group” in the definition of R ^2a refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis, Protective groups commonly used in organic synthetic chemistry are shown (see, for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)).

In the above, the “protecting group” of the “hydroxy group that may be protected” in the definition of R ^2a is not particularly limited as long as it is a protecting group for a hydroxy group used in the field of synthetic organic chemistry. Groups, alkylcarbonyl groups such as acetyl, propionyl, isobutyryl, pivaloyl, valeryl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl An “alkylcarbonyl group” such as an unsaturated alkylcarbonyl group such as benzoyl, α-naphthoyl, β-naphthoyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E) -2-methyl-2-butenoyl; Reel carbonyl group, halogenated arylcarbonyl group such as 2-bromobenzoyl, 4-chlorobenzoyl, alkylated arylcarbonyl group such as 2,4,6-trimethylbenzoyl, 4-toluoyl, 4-anisoyl, etc. Alkoxylated arylcarbonyl groups such as 4-nitrobenzoyl, nitrated arylcarbonyl groups such as 2-nitrobenzoyl, alkoxycarbonylated arylcarbonyl groups such as 2- (methoxycarbonyl) benzoyl, aryls such as 4-phenylbenzoyl An “arylcarbonyl group” such as an arylcarbonyl group; an alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, An “alkoxycarbonyl group” such as an alkoxycarbonyl group substituted with a halogen or trialkylsilyl group such as 2-trimethylsilylethoxycarbonyl; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydro “Tetrahydropyranyl or tetrahydrothiopyranyl groups” such as pyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydrothiofuran-2 A “tetrahydrofuranyl or tetrahydrothiofuranyl group” such as -yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl A “silyl group” such as a trialkylsilyl group such as triisopropylsilyl, an alkyldiarylsilyl or dialkylarylsilyl group such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl; 1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, alkoxymethyl groups such as t-butoxymethyl, alkoxyalkoxymethyl groups such as 2-methoxyethoxymethyl, 2,2, “Alkoxymethyl groups” such as halogenated alkoxymethyl such as 2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; such as 1-ethoxyethyl and 1- (isopropoxy) ethyl “Substituted ethyl groups” such as alkoxyethyl groups and ethyl halide groups such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl Alkyl groups substituted with 1 to 3 aryl groups such as 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl , 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl (alkyl, alkoxy, nitro, halogen, cyano groups with an aryl ring Substituted alkyl groups substituted with 1 to 3 aryl groups) Kill group ";" alkenyloxycarbonyl group "such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4- An “aralkyloxycarbonyl group” in which the aryl ring may be substituted with one or two alkoxy or nitro groups, such as nitrobenzyloxycarbonyl, preferably an alkylcarbonyl group, a silyl group or an aralkyl group. is there.

Processes that require protection / deprotection are described in known methods (for example, “Protective Groups in Organic Synthesis” (written by Theodora W. Greene, Peter G. M.Wuts, 1999, published by Wiley-Interscience Publication)). Method).

The compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms. Examples of the administration form include oral administration by tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), etc., or injections (intravenous, intramuscular, subcutaneous or intraperitoneal administration), Examples include parenteral administration such as instillation and suppository (rectal administration). These various preparations are usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. as main ingredients in accordance with conventional methods. It can be formulated with the resulting adjuvant.

When used as a tablet, as a carrier, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegrators such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary ammonium salts, sodium lauryl sulfate Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; Use of lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol can do. Moreover, it can be set as the tablet which gave the normal coating as needed, for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.

When used as pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol; laminaran, Disintegrants such as agar can be used.

When used as a suppository, a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cocoa butter, higher alcohol, esters of higher alcohol, gelatin, semi-synthetic glyceride and the like.

When used as an injection, it can be used as a solution, emulsion or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the preparation to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. may be included. You may go out.

In addition, the above-mentioned preparation may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as required, and may further contain other medicines.

The amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.

The amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animal, particularly human), but in the case of oral administration, the upper limit is 2000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg ( Preferably 1 mg, more preferably 10 mg) is administered to adults 1 to 6 times per day depending on the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but the scope of the present invention is not limited thereto.

Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). In TLC observation, silica gel 60F ₂₅₄ manufactured by Merck was used as a TLC plate, a solvent used as an elution solvent in column chromatography was used as a developing solvent, and a UV detector was used as a detection method. As silica gel for the column, silica gel SK-85 (230-400 mesh) manufactured by Merck Co., Ltd. or Fuji Silysia Chemical Chromatorex NH (200-350 mesh) was used. In addition to ordinary column chromatography, an automatic chromatography apparatus (Purif-α2 or Purif-espoir2) manufactured by Shoko Scientific was used as appropriate. As the elution solvent, the solvent specified in each example was used at the specified ratio. (Or, the ratio was changed as necessary.) The abbreviations used in the examples have the following significance.
mg: milligram, g: gram, mL: milliliter, MHz: megahertz.

In the following examples, nuclear magnetic resonance (hereinafter, ¹ H NMR) spectra are described with chemical shift values expressed as δ values (ppm) using tetramethylsilane as a standard substance. The splitting pattern is indicated by s for single lines, d for double lines, t for triple lines, q for quadruple lines, m for multiple lines, and br for broad lines.

Mass spectrometry (hereinafter referred to as MS) was performed by ESI (Electron Spray Ionization) method.

Example 1
(cis-4-{[5- (4-{[(3-Methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid

(1a) 3-methyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester solution of 3-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (7.86 g) in toluene (100 mL) 2-bromopyridine (5.9 mL), potassium carbonate (14.8 g), copper (I) iodide (486 mg), and N, N'-dimethylcyclohexane-1,2-diamine (725 mg) at room temperature It was. The reaction mixture was heated to reflux for 15 hours, cooled to room temperature, filtered through celite, and concentrated. The residue was purified by chromatography (dichloromethane / ethyl acetate 100: 0 → 80: 20) to give 4.36 g (37%) of the title compound as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.97 (1H, s), 8.44 (1H, d, J = 5.8Hz), 7.97 (1H, d, J = 8.2Hz), 7.84 (1H, ddd, J = 7.5,7.5,2.0Hz), 7.23 (1H, dd, J = 8.4,4.9Hz), 4.32 (2H, q, J = 7.0Hz), 2.57 (3H, s), 1.37 (3H, t , J = 7.2Hz).

(1b) 3-methyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid 1N water was added to a solution of the compound obtained in Example (1a) 4.36 g in tetrahydrofuran / ethanol (1: 1, 80 mL). Aqueous sodium oxide was added at room temperature. The reaction mixture was stirred for 24 hours, diluted with water and neutralized with 1N hydrochloric acid (40 mL). The precipitated solid was collected by filtration and dried under reduced pressure to obtain 3.78 g (99%) of the title compound as a white solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.07 (1H, s), 8.47-8.45 (1H, m), 7.99 (1H, d, J = 8.2 Hz), 7.85 (1H, ddd, J = 7.2,7.2,1.8Hz), 7.26-7.24 (1H, m), 2.59 (3H, s), 1.8-1.4 (1H, brs).

(1c) {cis-4-[(5-Bromopyrimidin-2-yl) oxy] cyclohexyl} acetic acid methyl ester (trans-4-hydroxycyclohexyl) acetic acid methyl ester (WO2009119534) (2.58 g) and 5-bromopyrimidine- Cyanomethylenetributylphosphorane (CMBP) (3.93 mL) was added to a toluene (30 mL) solution of 2-ol (1.74 g) at room temperature. The reaction mixture was heated at 120 ° C. for 9 hours, cooled to room temperature, diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with water and concentrated. The residue was purified by chromatography (automatic chromatography apparatus, hexane / ethyl acetate 100: 0 → 80: 20) to give 1.67 g (51%) of the title compound as a pale yellow oil.
_{^{1 H NMR (500MHz, CDCl 3}} ): δ (ppm) = 8.51 (2H, s), 5.23-5.18 (1H, m), 3.67 (3H, s), 2.28 (2H, d, J = 6.8 Hz), 2.09-1.89 (3H, m), 1.69-1.43 (6H, m).

(1d) (cis-4-{[5- (4-Aminophenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid methyl ester Compound (1.67 g) obtained in Example (1c), 4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.11 g), tetrakis (triphenylphosphine) palladium (0) (295 mg), and potassium carbonate (1.41 g) A 1,4-dioxane / water (7: 3, 30 mL) solution was heated at 80 ° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and concentrated. The residue was purified by chromatography (automatic chromatography apparatus, dichloromethane / ethyl acetate 100: 0 → 85: 15) to obtain 1.59 g (92%) of the title compound as a yellow solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.64 (2H, s), 7.32 (2H, d, J = 8.6Hz), 6.79 (2H, d, J = 8.2Hz), 5.29 (1H, brs), 3.80 (2H, brs), 3.68 (3H, s), 2.29 (2H, d, J = 7.0Hz), 2.13-2.09 (2H, m), 1.97-1.91 (1H, m), 1.72-1.55 (6H, m).

(1e) (cis-4-{[5- (4-{[(3-Methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] Oxy} cyclohexyl) acetic acid methyl ester Compound (3.78 g) obtained in Example (1b), Compound (6.35 g) obtained in Example (1d), Triethylamine (3.1 mL) and BOP reagent (9.05 g) in dimethylacetamide The solution (100 mL) was stirred at room temperature for 3 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and further diluted with ethyl acetate and water. The resulting mixture was stirred. The precipitated solid was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure. This gave 6.93 g (71%) of the title compound as an off-white solid.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 10.2 (1H, s), 9.50 (1H, s), 8.91 (2H, s), 8.55 (1H, dd, J = 4.9 and 1.8 Hz ), 8.07-8.03 (1H, m), 7.96 (1H, d, J = 8.2Hz), 7.90 (2H, d, J = 9.0Hz), 7.72 (2H, d, J = 9.0Hz), 7.44 (1H , dd, J = 7.3, 4.9Hz), 5.24-5.20 (1H, m), 3.61 (3H, s), 2.53 (3H, s), 2.30 (2H, d, J = 7.0Hz), 1.99-1.92 ( 2H, m), 1.91-1.81 (1H, m), 1.72-1.64 (2H, m), 1.60-1.54 (2H, m), 1.44-1.33 (2H, m).

(1f) (cis-4-{[5- (4-{[(3-Methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] Oxy} cyclohexyl) acetic acid A dioxane solution (70 mL) of the compound (6.93 g) obtained in Example (1e) and a tetrabutylammonium aqueous solution (1 mol / L, 27 mL) was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, diluted with water and acidified with 1 N hydrochloric acid (150 mL). Diisopropyl ether was added to the resulting suspension and stirred vigorously for 3 hours. The precipitated solid was collected by filtration and dried under reduced pressure. This gave 6.63 g (98%) of the title compound as a white solid.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 10.2 (1H, s), 9.50 (1H, s), 8.91 (2H, s), 8.55 (1H, d, J = 5.9 Hz), 8.05 (1H, dd, J = 9.8 and 7.9Hz), 7.96 (1H, d, J = 8.2Hz), 7.90 (2H, d, J = 9.0Hz), 7.72 (2H, d, J = 8.6Hz), 7.44 (1H, dd, J = 7.2 and 4.9Hz), 5.24-5.19 (1H, m), 2.53 (3H, s), 2.18 (2H, d, J = 7.1Hz), 1.99-1.92 (2H, m) , 1.89-1.76 (1H, m), 1.71-1.55 (4H, m), 1.43-1.35 (2H, m).
MS (ESI) m / z: 513 (M + H) ^<+> .

(Example 2)
(cis-4-{[5- (4-{[(3-Cyclopropyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} (Cyclohexyl) acetic acid

(2a) 3-Cyclopropyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid In the same manner as in Example (1a), 5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (500 mg) and 2-bromopyridine (0.29 mL) gave 501 mg of a light orange oil. This pale orange oil (500 mg) was hydrolyzed in the same manner as in Example (1b) to obtain 164 mg (24%, 2 steps) of the title compound as a colorless solid.

(2b) (cis-4-{[5- (4-{[(3-Cyclopropyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl ] Oxy} cyclohexyl) acetic acid In the same manner as in Example (1e), from the compound obtained in Example (2a) and the compound obtained in Example (1d), 135 mg (93%) of the amide compound was converted to a pale yellow amorphous product. Obtained. This amide compound (130 mg) was hydrolyzed in the same manner as in Example (1f) to obtain 90 mg (72%) of the title compound as a colorless solid.
1H NMR (500 MHz, DMSO-d ₆ ): δ (ppm) = 12.0 (1H, s), 10.2 (1H, s), 9.43 (1H, s), 8.91 (2H, s), 8.52 (1H, d, J = 4.3Hz), 8.02 (1H, t, J = 7.8Hz), 7.91-7.86 (3H, m), 7.72 (2H, d, J = 8.3Hz), 7.41 (1H, t, J = 6.1Hz) , 5.22 (1H, brs), 2.81-2.76 (1H, m), 2.19 (2H, d, J = 7.4Hz), 1.99-1.94 (2H, m), 1.86-1.80 (1H, m), 1.71-1.65 (2H, m), 1.60-1.57 (2H, m), 1.42-1.34 (2H, m), 1.01-0.98 (4H, m).

(Example 3)
(cis-4-{[5- (2-Methyl-4-{[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl ] Oxy} cyclohexyl) acetic acid

(3a) (cis-4-{[5- (4-Amino-2-methylphenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid methyl ester In the same manner as in Example (1d), Example (1c ) And 3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (466 mg) to give the title compound 501 mg (71%) was obtained as a brown solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.44 (2H, s), 6.99 (1H, d, J = 8.2Hz), 6.65-6.60 (2H, m), 5.30-5.28 (1H, m ), 3.68 (3H, s), 2.29 (2H, d, J = 7.4Hz), 2.22 (3H, s), 2.14-2.10 (2H, m), 1.98-1.92 (1H, m), 1.73-1.53 ( 6H, m).

(3b) (cis-4-{[5- (2-Methyl-4-{[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidine- 2-yl] oxy} cyclohexyl) acetic acid In the same manner as in Example (1e), from the compound (178 mg) obtained in Example (3a) and the compound (102 mg) obtained in Example (1b), amide 213 mg (79%) of body was obtained as a light brown solid.

In the same manner as in Example (1f), 181 mg (88%) of the title compound was obtained as a white solid from the amide compound (212 mg).
¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 12.1 (1H, brs), 10.1 (1H, s), 9.51 (1H, s), 8.62 (2H, s), 8.56-8.54 (1H , m), 8.07-8.03 (1H, m), 7.96 (1H, d, J = 8.2Hz), 7.77 (1H, d, J = 1.9Hz), 7.70 (1H, dd, J = 8.2 and 2.3Hz) , 7.45-7.42 (1H, m), 7.26 (1H, d, J = 8.2Hz), 5.23-5.22 (1H, m), 2.53 (3H, s), 2.28 (3H, s), 2.19 (2H, d , J = 7.0Hz), 1.99-1.94 (2H, m), 1.87-1.82 (1H, m), 1.72-1.65 (2H, m), 1.62-1.58 (2H, m), 1.44-1.34 (2H, m ).
MS (ESI) m / z: 527 (M + H) ^<+> .

Example 4
(cis-4-{[5- (4-{[(3-Ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid

(4a) 3-Ethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid methyl ester In the same manner as in Example (1a), methyl 5-ethyl-1H-pyrazole-4-carboxylic acid ( WO 2009110520) (256 mg) and 2-bromopyridine (0.147 mL) gave 76 mg (21%) of the title compound as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.98 (1H, s), 8.43 (1H, d, J = 5.1 Hz), 7.99 (1H, d, J = 8.2 Hz), 7.84 (1H, dd, J = 8.8 and 6.9Hz), 7.23 (1H, dd, J = 7.4 and 4.7Hz), 3.86 (3H, s), 3.00 (2H, q, J = 7.7Hz), 1.33 (3H, t, J = 7.4Hz).

(4b) 3-ethyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid The compound (75 mg) obtained in Example (4a) was hydrolyzed in the same manner as in Example (1b). The title compound 59 mg (90%) was obtained as a colorless solid.
¹ H NMR (500 MHz, CDCl ₃ ): δ (ppm) = 9.06 (1H, s), 8.45 (1H, d, J = 4.3 Hz), 8.00 (1H, d, J = 8.3 Hz), 7.85 (1H, dd, J = 7.8 and 7.8Hz), 7.27-7.24 (1H, m), 3.02 (2H, q, J = 7.3Hz), 1.85-1.40 (1H, brs), 1.36 (3H, t, J = 8.3Hz ).

(4c) (cis-4-{[5- (4-{[(3-Ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] Oxy} cyclohexyl) acetic acid In the same manner as in Example (1e), from the compound (57 mg) obtained in Example (4b) and the compound (90 mg) obtained in Example (1d), 92 mg of the amide compound was obtained. Obtained as an off-white amorphous. In the same manner as in Example (1f), the amide compound (92 mg) was hydrolyzed to obtain 31 mg (22%, 2 steps) of the title compound as a yellow solid.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 12.2-12.0 (1H, brs), 10.2 (1H, s), 9.49 (1H, s), 8.91 (2H, s), 8.56-8.54 (1H, m), 8.07-8.03 (1H, m), 7.97 (1H, d, J = 8.2Hz), 7.90 (2H, d, J = 8.6Hz), 7.72 (2H, d, J = 9.0Hz) , 7.45-7.42 (1H, m), 5.24-5.21 (1H, m), 2.99 (2H, q, J = 7.5Hz), 2.19 (2H, d, J = 7.0Hz), 1.98-1.93 (2H, m ), 1.86-1.80 (1H, m), 1.72-1.64 (2H, m), 1.62-1.56 (2H, m), 1.43-1.34 (2H, m), 1.28 (3H, t, J = 7.5Hz).

(Example 5)
(cis-4-{[5- (4-{[(1-Pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid

(5a) 1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester In the same manner as in Example (1a), 1H-pyrazole-4-carboxylic acid ethyl ester (1.4 g) and 2-bromo The title compound (1.56 g, 72%) was obtained as a colorless solid from pyridine (0.955 mL).
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.05 (1H, s), 8.45 (1H, d, J = 5.0 Hz), 8.11 (1H, s), 8.01 (1H, d, J = 8.2 Hz), 7.82 (1H, dd, J = 8.2 and 7.5Hz), 7.25 (1H, dd, J = 7.4 and 5.1Hz), 4.35 (2H, q, J = 7Hz), 1.47 (3H, t, J = 7Hz).

(5b) 1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid The compound (1.06 g) obtained in Example (5a) was hydrolyzed in the same manner as in Example (1b) to give the title compound 595 mg (64%) was obtained as a colorless solid.
¹ H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 9.15 (1H, s), 8.48 (1H, d, J = 5.0 Hz), 8.18 (1H, s), 8.04 (1H, d, J = 8.2 Hz), 7.89 (1H, dd, J = 8.2 and 7.5 Hz), 7.30 (1H, dd, J = 7.4 and 5.1 Hz), 2.02-1.40 (1H, brs).

(5c) (cis-4-{[5- (4-{[(1-Pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) Acetic acid In the same manner as in Example (1e), 104 mg (78%) of the amide compound was obtained from the compound (50 mg) obtained in Example (5b) and the compound (90 mg) obtained in Example (1d). Obtained as an off-white solid. In the same manner as in Example (1f), the amide compound (100 mg) was hydrolyzed to obtain 81 mg (84%) of the title compound as a pale yellow solid.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 12.7-11.8 (1H, brs), 10.2 (1H, s), 9.46 (1H, d, J = 0.8 Hz), 8.91 (2H, s ), 8.59-8.57 (1H, m), 8.33 (1H, d, J = 0.7Hz), 8.11-8.06 (1H, m), 8.02 (1H, d, J = 8.3Hz), 7.90 (2H, d, J = 9.0Hz), 7.74 (2H, d, J = 8.6Hz), 7.49-7.46 (1H, m), 5.24-5.20 (1H, m), 2.19 (2H, d, J = 7.1Hz), 1.99- 1.92 (2H, m), 1.87-1.80 (1H, m), 1.72-1.55 (4H, m), 1.43-1.33 (2H, m).

(Example 6)
(cis-4-{[5- (2-Methyl-4-{[(1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid

In the same manner as in Example (1e), 104 mg (78%) of the amide compound was turned off from the compound (50 mg) obtained in Example (5b) and the compound (90 mg) obtained in Example (3a). Obtained as a white solid. In the same manner as in Example (1f), the amide compound (100 mg) was hydrolyzed to obtain 81 mg (84%) of the title compound as a pale yellow solid.
¹ H NMR (400 MHz, DMSO-d ₆ ): δ (ppm) = 12.2-12.0 (1H, brs), 10.2 (1H, s), 9.45 (1H, s), 8.62 (2H, s), 8.58-8.57 (1H, m), 8.32 (1H, s), 8.08 (1H, dt, J = 11.1 and 3.9Hz), 8.01 (1H, d, J = 8.2Hz), 7.75-7.73 (1H, m), 7.49- 7.46 (1H, m), 7.29-7.27 (1H, m), 5.24-5.19 (1H, m), 2.29 (3H, s), 2.19 (2H, d, J = 7.1Hz), 1.99-1.95 (2H, m), 1.87-1.81 (1H, m), 1.72-1.58 (4H, m), 1.44-1.35 (2H, m).

(Example 7)
(cis-4-{[5- (4-{[(3-Chloro-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid

(7a) (cis-4-{[5- (4-{[(3-Chloro-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] Oxy} cyclohexyl) acetic acid methyl ester 3-chloro-1- (4-methoxybenzyl) -1H-pyrazole-4-carboxylic acid ethyl ester (WO2010079239) (173 mg) in trifluoroacetic acid (10 mL) heated for 6 hours Refluxed. The reaction mixture was concentrated, diluted with dichloromethane and saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated.

This residue (3-chloro-1H-pyrazole-4-carboxylic acid ethyl ester, 102 mg), 2-bromopyridine (0.063 mL), copper (I) iodide (8.9 mg), N, N'-dimethylcyclohexane A suspension of -1,2-diamine (13 mg), potassium carbonate (242 mg), and toluene (10 mL) was heated to reflux for 8.5 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was purified by chromatography (hexane / ethyl acetate 5% → 10%) to give 123 mg of crude product (3-chloro-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester) Got.

This biaryl compound (123 mg) was hydrolyzed in the same manner as in Example (1b) to obtain a carboxylic acid compound (3-chloro-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid). .

In the same manner as in Example (1e), from this carboxylic acid form (109 mg) and the compound (178 mg) obtained in Example (1d), 101 mg (31%, 4 steps) of amide form was obtained as a pale yellow solid. Got as.
¹ H NMR (500MHz, CDCl3): δ (ppm) = 9.21 (1H, s), 8.70 (2H, s), 8.48 (1H, d, J = 4.9 Hz), 8.40 (1H, brs), 7.96 (1H , d, J = 8.3 Hz), 7.89 (1H, t, J = 8.3 Hz), 7.78 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.31 (1H, t , J = 5.9 Hz), 5.33-5.29 (1H, m), 3.68 (3H, s), 2.30 (2H, d, J = 6.8 Hz), 2.14-2.09 (2H, m), 1.98-1.92 (1H, m), 1.73-1.53 (6H, m).

(7b) (cis-4-{[5- (4-{[(3-Chloro-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] Oxy} cyclohexyl) acetic acid In the same manner as in Example (1f), the compound (101 mg) obtained in Example (7a) was hydrolyzed to obtain 82 mg (84%) of the title compound as a pale yellow solid.
¹ H-NMR (500 MHz, DMSO-d ₆ ): δ (ppm) = 12.04 (1H, brs), 10.31 (1H, s), 9.54 (1H, s), 8.91 (2H, s), 8.59 (1H , d, J = 3.9 Hz), 8.10 (1H, t, J = 7.3 Hz), 7.95 (1H, d, J = 7.4 Hz), 7.87 (2H, d, J = 8.8 Hz), 7.74 (2H, d , J = 8.8 Hz), 7.52-7.50 (1H, m), 5.24-5.20 (1H, m), 2.20 (2H, d, J = 6.8 Hz), 1.99-1.93 (3H, m), 1.71-1.56 ( 4H, m), 1.42-1.35 (2H, m).

(Test Example 1)
(1) Preparation of DGAT1 enzyme The DGAT1 enzyme was prepared and stored in accordance with the method described in US2007 / 0249620.
(2) DGAT1 inhibitory activity test Reaction solution [175 mM Tris-HCl (pH 8.0), 8 mM MgCl ₂ , 1 mg / ml BSA, 0.3 mM 1,2-dioleoyl-sn-glycerol (10-fold concentration) 10% EtOH solution), 10 μM [ ¹⁴ C] -oleoyl-CoA (about 50 mCi / mmol), 0.5% triton X-100, DGAT1 enzyme (10 μg) obtained in Test Example 1 (1), test compound Or a vehicle (DMSO / MeOH, 7: 3 solution, 5% added), total volume 50 μl] was incubated at room temperature (23 ° C.) for 30 minutes. To the reaction mixture was added a reaction stop solution (70 μl) consisting of isopropanol / 1-heptane / water (80: 20: 2, v / v / v) and stirred, then water (30 μl) and 1-heptane (100 μl) Was added and stirred. A 1-heptane layer (50 μl) was spotted on a TLC plate and developed with a developing solvent consisting of 1-hexane / diethyl ether / acetic acid (85: 15: 1, v / v / v). The radioactivity of the triglyceride fraction was quantified with a BAS2000 bioimage analyzer (Fuji Film), and the inhibitory activity of the test compound was calculated by the following formula by comparing with the control. The unreacted (0 minute incubation) radioactivity was used as the background.

Inhibition rate = 100 − [(radioactivity at the time of addition of test compound) − (background)] / [(radioactivity of control) − (background)] × 100
The compounds of Examples 1 to 7 showed an inhibition rate of 50% or more at a test compound concentration of 1 μg / ml.

The DGAT inhibitory activity test is not limited to the above method. For example, microsomes prepared from the small intestine, adipose tissue, or liver of animals such as rats and mice may be used as the DGAT enzyme. Alternatively, microsomes prepared from cultured cells (3T3-L1 adipocytes, primary cultured adipocytes, Caco2 cells, HepG2 cells, etc.) or cultured cells highly expressing DGAT can also be used as the DGAT enzyme. Furthermore, in order to efficiently evaluate a large number of test compounds in a short time, a flash plate (PerkinElmer) in which the extraction operation is omitted can be used.

From the above results, the compound of the present invention has excellent DGAT1 inhibitory biological activity.

(Test Example 2)
The DGAT1 enzyme is important for digestion and absorption of neutral fat, and when small intestine DGAT1 is inhibited, the absorption of neutral fat is suppressed. The biological activity of the DGAT1 inhibitory action was evaluated using as an index the inhibition of neutral fat absorption after neutral fat loading. Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) fasted overnight were assigned to Vehicle Group 1, Vehicle Group 2 and each test compound group, respectively vehicle (0.5% Methylcellulose) Alternatively, each test compound (1 to 10 mg / kg) suspended in the vehicle was orally administered (5 mL / kg). Lipoprotein lipase inhibitor (Pluronic-F127: Sigma-Aldrich Co., Ltd., 1 g / kg, dissolved in physiological saline at 20% by weight) was intraperitoneally administered (5 mL / kg) Distilled water was orally administered to Vehicle Group 1 and 20% neutral fat-containing emulsion (Intralipid 20%: Terumo Corporation) was orally administered (0.2 mL / mouse) to Vehicle Group 2 and Compound Group. After 1 to 4 hours after administration, blood is collected from the tail vein or right ventricle, and plasma is promptly separated and collected, and then the neutral fat concentration in the plasma is measured using a commercially available kit (Triglyceride E Test Wako: Wako Pure Chemical Industries, Ltd.) (Industry Co., Ltd.). In this method, the administration of lipoprotein lipase inhibitor suppresses the degradation of neutral fat flowing into the blood, and neutral fat accumulates in the blood, but its origin is exogenous absorbed in the digestive tract And it is divided into endogenous ones released from the liver. The neutral fat absorption inhibitory activity of each test compound was calculated based on the following formula, excluding the influence of endogenous neutral fat. It has been separately confirmed that each test compound does not affect the endogenous triglyceride concentration.

Neutral fat absorption inhibitory activity (%) = 100-[(Neutral fat concentration of each test compound group)-(Neutral fat concentration of Vehicle group 1)] / [(Neutral fat concentration of Vehicle group 2)-( Vehicle group 1 neutral fat concentration)] × 100
The compounds of Examples 1 to 6 showed neutral fat absorption inhibitory activity of 60% or more at a dose of 3 mg / kg or less.

From the above results, the compound of the present invention has excellent neutral fat absorption inhibitory activity.

(Test Example 3)
Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) are bred individually and fed with a high fat diet (fat content 45 kcal%: Research Diet D12451) for over a week. I got used to it. Allocate the animals evenly to the experimental groups based on the amount of food consumed during the period, fast overnight and then each vehicle (0.5% Methylcellulose) or test compound (1-10 mg / kg) suspended in the vehicle. The group was orally administered (10 mL / kg). A high fat diet was fed 30 minutes after the administration, and the amount of food intake was measured 6 hours after the start of feeding. The feeding inhibitory activity of each test compound was calculated based on the following formula.

Feeding inhibitory activity (%) = [(food consumption of vehicle group) − (food consumption of each test compound group)] / [(food consumption of vehicle group)] × 100
The compound of Example 1 showed an antifeedant activity of 25% or more at a dose of 10 mg / kg or less.

From the above results, the compound of the present invention has an excellent antifeedant action.

Note that the high-fat diet used for the feed is not limited to the above-mentioned high-fat diet, and for example, a rodent feed containing 45 to 60% neutral fat as calories can be used.

Formulation Example 1: Capsule 50 mg of the compound of Example 1 or 2
Lactose 128mg
Corn starch 70mg
Magnesium stearate 2mg
------------------
250mg
After mixing the powder of the above formulation and passing through a 60 mesh sieve, this powder is put into a 250 mg gelatin capsule to form a capsule.

Formulation Example 2: Tablet Example 1 or 2 compound 50 mg
Lactose 126mg
Corn starch 23mg
Magnesium stearate 1mg
------------------
200mg
The powder of the above formulation is mixed, granulated and dried using corn starch paste, and then tableted by a tableting machine to make one tablet of 200 mg. This tablet can be sugar-coated if necessary.

The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent DGAT inhibitory action and antifeeding action and is useful as a medicine.

Claims (20)

1. Formula (I)
   

   

   
   [Where:
   R ¹ represents a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkyl group or a C ₃ -C ₆ cycloalkyl group,
   R ² independently represents a halogen atom, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a hydroxy group,
   n represents an integer of 0 to 2. Or a pharmacologically acceptable salt thereof.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the general formula (I) is the general formula (Ia).
   

   
3. 3. The compound or a pharmacologically acceptable salt thereof according to claim 1 or 2, wherein n is 0.
4. (cis-4-{[5- (4-{[(3-Methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid,
   (cis-4-{[5- (4-{[(3-Cyclopropyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} (Cyclohexyl) acetic acid,
   (cis-4-{[5- (2-Methyl-4-{[(3-methyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl ] Oxy} cyclohexyl) acetic acid,
   (cis-4-{[5- (4-{[(3-Ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid,
   (cis-4-{[5- (4-{[(1-Pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl) acetic acid,
   (cis-4-{[5- (2-Methyl-4-{[(1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl Acetic acid, or
   (cis-4-{[5- (4-{[(3-Chloro-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino} phenyl) pyrimidin-2-yl] oxy} cyclohexyl ) Acetic acid or a pharmacologically acceptable salt thereof.
5. An acyl coenzyme A: diacylglycerol acyltransferase inhibitor containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
6. An antifeedant and / or an appetite suppressant containing the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
7. A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof as an active ingredient.
8. The pharmaceutical composition according to claim 7, which has an acylcoenzyme A: diacylglycerol acyltransferase inhibitory action.
9. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition has an antifeedant action and / or an appetite suppressive action.
10. The pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby preventing the treatment, amelioration, reduction and / or prevention of symptoms. 8. A pharmaceutical composition according to claim 7 for treatment and / or prevention.
11. For the treatment and / or prevention of a disease in which the pharmaceutical composition inhibits acylcoenzyme A: diacylglycerol acyltransferase and the synthesis of triglyceride is inhibited, thereby treating, ameliorating, reducing and / or preventing symptoms. The pharmaceutical composition according to claim 7.
12. The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceride disease, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease Or the pharmaceutical composition of Claim 7 for the treatment and / or prevention of bulimia.
13. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is for the treatment and / or prevention of obesity or obesity.
14. The pharmaceutical composition according to claim 7, which is used for the treatment and / or prevention of diabetes.
15. Obesity, obesity, hyperlipidemia, hypertriglycerideemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy Cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or bulimia The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4 for use in therapy and / or prevention.
16. Use of the compound according to any one of claims 1 to 4 or a pharmacologically acceptable salt thereof for producing a pharmaceutical composition.
17. The pharmaceutical composition is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, Diabetic retinopathy, including diabetic macroangiopathy), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease The use according to claim 16, which is a pharmaceutical composition for the treatment and / or prevention of bulimia.
18. A method for treating and / or preventing a disease, wherein a pharmacologically effective amount of the compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 4 is administered to a warm-blooded animal.
19. Diseases are obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, insulin resistance syndrome, impaired glucose tolerance, diabetes, diabetic complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic Retinopathy, including diabetic macrovascular disease), cataract, gestational diabetes, nonalcoholic steatohepatitis, polycystic ovary syndrome, arteriosclerosis, atherosclerosis, diabetic arteriosclerosis, ischemic heart disease or binge eating The method according to claim 18, which is a symptom.
20. The method according to claim 18 or 19, wherein the warm-blooded animal is a human.