WO2012173219A1 - Nouveau dérivé de biaryle-éther - Google Patents

Nouveau dérivé de biaryle-éther Download PDF

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Publication number
WO2012173219A1
WO2012173219A1 PCT/JP2012/065315 JP2012065315W WO2012173219A1 WO 2012173219 A1 WO2012173219 A1 WO 2012173219A1 JP 2012065315 W JP2012065315 W JP 2012065315W WO 2012173219 A1 WO2012173219 A1 WO 2012173219A1
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Prior art keywords
diabetic
pharmaceutical composition
compound
obesity
acceptable salt
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PCT/JP2012/065315
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English (en)
Japanese (ja)
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芳一 宇都
鈴木　敬子
悠子 上野
隆之 北澤
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第一三共株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • 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.
  • DGAT diacylglycerol acyltransferase
  • triglyceride triacylglycerol or triglyceride, hereinafter also referred to as TG
  • TG triglyceride
  • 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.
  • ACS acylcoenzyme A synthase
  • 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.
  • 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).
  • ACS glycerol 3-phosphate acyltransferase
  • DGAT Non-patent Document 2
  • 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).
  • DGAT1 is highly expressed in the small intestine and adipose tissue
  • 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
  • DGAT2 is used for TG synthesis or VLDL in the liver. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue.
  • 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.
  • 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.
  • Non-patent Document 14 gastrointestinal hormones 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)
  • Non-patent Document 15 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.
  • Patent Document 1 discloses a compound having 4- (5-carboxamido-2,3'-bipyridin-6'-yloxy) cyclohexanecarboxylic acid.
  • 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 ova
  • the present invention comprises (1) general formula (I)
  • 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.
  • a pharmacologically acceptable salt thereof thereof.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition comprising as an active ingredient the compound described in any one of (1) to (9) or a pharmacologically acceptable salt thereof.
  • 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 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 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 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)
  • 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.
  • 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.
  • composition is a therapeutic composition for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity. .
  • (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.
  • the method according to (39) which is vascular disorder, coronary artery disease, fatty liver, respiratory disorder, low back pain, knee osteoarthritis, gout or cholelithiasis.
  • 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.
  • the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • 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.
  • 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.
  • 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.
  • preferred general formula (I) is general formula (Ia).
  • preferred R 1 is a hydrogen atom, a chlorine atom, a methyl group, an ethyl group or a cyclopropyl group.
  • preferred R 2 is a methyl group.
  • 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.
  • 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.
  • 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.
  • 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.
  • hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide
  • 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 salt
  • 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
  • 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.
  • 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
  • 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, triethyl
  • reaction temperature varies depending on the solvent, starting material, reagent, etc.
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
  • 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.
  • an immiscible organic solvent such as ethyl acetate
  • 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.
  • a target compound insoluble in a solvent the obtained solid crude product can be purified by washing with a solvent.
  • the target compound in each step can be directly used in the next reaction without purification.
  • 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 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).
  • DEAD diethyl azodicarboxylate
  • DIAD diisopropyl azodicarboxylate
  • CMBP Cyanomethylene tributylphosphorane
  • 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) ferrocen
  • 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 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 hexafluoro
  • 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.
  • Y 1 is a C 1 -C 6 alkyl group.
  • 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).
  • 1 such as copper (I) chloride, copper (I) bromide, copper (I) iodide, copper (I) trifluoromethanesulfonate.
  • 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.
  • 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.
  • 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.
  • 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)).
  • 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.
  • alkylcarbonyl group such as an unsaturated alkylcarbonyl group such as benzoyl, ⁇ -naphthoyl, ⁇ -naphthoyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E) -2
  • 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
  • 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 “Tetrahydro
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be administered in various forms.
  • 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.
  • 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
  • the tablet which gave the normal coating 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.
  • 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.
  • 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.
  • solutions, emulsions or suspensions 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.
  • water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isoforms are used. Examples include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • 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.
  • 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.
  • 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.
  • 1 H NMR nuclear magnetic resonance
  • MS Mass spectrometry
  • Example (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.
  • Example (1e) (cis-4- ⁇ [5- (4- ⁇ [(3-Ethyl-1-pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino ⁇ phenyl) pyrimidin-2-yl] Oxy ⁇ cyclohexyl) acetic acid
  • 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.
  • the amide compound (92 mg) was hydrolyzed to obtain 31 mg (22%, 2 steps) of the title compound as a yellow solid.
  • Example (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.
  • Example (1e) (cis-4- ⁇ [5- (4- ⁇ [(1-Pyridin-2-yl-1H-pyrazol-4-yl) carbonyl] amino ⁇ phenyl) pyrimidin-2-yl] oxy ⁇ cyclohexyl) Acetic acid
  • 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.
  • the amide compound (100 mg) was hydrolyzed to obtain 81 mg (84%) of the title compound as a pale yellow solid.
  • Example (1e) 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.
  • 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). .
  • Example (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
  • the compound (101 mg) obtained in Example (7a) was hydrolyzed to obtain 82 mg (84%) of the title compound as a pale yellow solid.
  • reaction stop solution 70 ⁇ l
  • isopropanol / 1-heptane / water 80: 20: 2, v / v / v
  • water 30 ⁇ l
  • 1-heptane 100 ⁇ l
  • a 1-heptane layer 50 ⁇ l 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 ⁇ g / ml.
  • the DGAT inhibitory activity test is not limited to the above method.
  • microsomes prepared from the small intestine, adipose tissue, or liver of animals such as rats and mice may be used as the DGAT enzyme.
  • 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.
  • a flash plate PerkinElmer in which the extraction operation is omitted can be used.
  • the compound of the present invention has excellent DGAT1 inhibitory biological activity.
  • 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.
  • 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.
  • the compound of the present invention has excellent neutral fat absorption inhibitory activity.
  • mice 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.
  • the compound of the present invention has an excellent antifeedant action.
  • 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.

Abstract

L'invention concerne un composé présentant une excellente activité d'inhibition de DGAT et une excellente activité anti-appétante, ou un sel pharmacologiquement acceptable de celui-ci. L'invention concerne en particulier un composé de formule générale (I) [dans laquelle R1 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle C1-C6 ou un groupe cycloaklyle C3-C6 ; R2 représentent indépendamment un atome d'halogène, un groupe alkyle C1-C6, un groupe alcoxy C1-C6 ou un groupe hydroxy ; et n représente un entier compris entre 0 et 2] ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2012/065315 2011-06-17 2012-06-15 Nouveau dérivé de biaryle-éther WO2012173219A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093497A1 (en) * 2007-05-22 2009-04-09 David Robert Bolin Diacylglycerol Acyltransferase Inhibitors
JP2010132590A (ja) * 2008-12-03 2010-06-17 Astellas Pharma Inc オキサジアゾール化合物
WO2010077861A1 (fr) * 2008-12-17 2010-07-08 Via Pharmaceuticals, Inc Inhibiteurs de la diacylglycérol acyltransférase
WO2011078102A1 (fr) * 2009-12-22 2011-06-30 第一三共株式会社 Nouveau dérivé de phénoxypyrimidine
WO2012063896A1 (fr) * 2010-11-11 2012-05-18 第一三共株式会社 Nouveau dérivé de pyrazole amide

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093497A1 (en) * 2007-05-22 2009-04-09 David Robert Bolin Diacylglycerol Acyltransferase Inhibitors
JP2010132590A (ja) * 2008-12-03 2010-06-17 Astellas Pharma Inc オキサジアゾール化合物
WO2010077861A1 (fr) * 2008-12-17 2010-07-08 Via Pharmaceuticals, Inc Inhibiteurs de la diacylglycérol acyltransférase
WO2011078102A1 (fr) * 2009-12-22 2011-06-30 第一三共株式会社 Nouveau dérivé de phénoxypyrimidine
WO2012063896A1 (fr) * 2010-11-11 2012-05-18 第一三共株式会社 Nouveau dérivé de pyrazole amide

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