WO2011078102A1 - Nouveau dérivé de phénoxypyrimidine - Google Patents

Nouveau dérivé de phénoxypyrimidine Download PDF

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WO2011078102A1
WO2011078102A1 PCT/JP2010/072848 JP2010072848W WO2011078102A1 WO 2011078102 A1 WO2011078102 A1 WO 2011078102A1 JP 2010072848 W JP2010072848 W JP 2010072848W WO 2011078102 A1 WO2011078102 A1 WO 2011078102A1
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group
diabetic
pharmaceutical composition
phenyl
compound
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Japanese (ja)
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芳一 宇都
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第一三共株式会社
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    • 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
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to a compound having a specific chemical structure having an excellent acyl coenzyme A: diacylglycerol acyltransferase (hereinafter also referred to as DGAT) inhibitory action and an excellent antifeedant action, or a pharmacologically 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
  • DGAT1 is mainly used for fat absorption from the small intestine and fat accumulation in the adipose tissue
  • DGAT2 is used for TG synthesis or VLDL in the liver. (Very low density lipoproteins) secretion and fat accumulation in adipose tissue.
  • 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 cyclohexyl having a substituent on (1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group.
  • a compound in which a carbonylamino group is bonded via an ethylene bond (Example E150) etc. and their use as DGAT inhibitors are described.
  • a phenyl group having a substituent is directly bonded to the (1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group.
  • Patent Document 2 a phenyl group is substituted on the pyrazole ring side of the 3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group, and a carboxyl group is formed on the amino group side through two aromatic rings. Bound compounds (compound no. 70) etc. and their use as DGAT inhibitors are described.
  • a pyridyl group is substituted on the pyrazole ring side of the 3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino group, and two amino rings and phenoxy ether are introduced on the amino group side. And a substituent such as a carboxyl group is bonded.
  • Patent Document 2 discloses a compound having a substituted piperidine ring at the 4-position of the benzene ring of [(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] phenyl group ( Compound No. 75) etc. and their use as DGAT inhibitors are described.
  • the compound of the present invention has a substituted pyrimidine ring at the 4-position of the benzene ring of the [(1-pyridin-2-yl-3-trifluoromethyl-1H-pyrazole-4-carbonyl) amino] phenyl group. Yes.
  • Patent Document 3 a cycloalkylmethyl group having a carboxyl group is substituted on the oxygen atom side of the 5- [4- (carbonylamino) phenyl] pyrimidin-2-yloxy group, and the carbonyl group side has a substituent.
  • Compounds with substituted phenyl groups Compound No. 405 and their use as DGAT inhibitors are described.
  • a phenyl group having a substituent on the oxygen atom side of the 5- [4- (carbonylamino) phenyl] pyrimidin-2-yloxy group is substituted, and 1-pyridine-2- The yl-3-trifluoromethyl-1H-pyrazole group is substituted.
  • 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 represents a halogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 halogenated alkyl group, a hydroxymethyl group, a cyano group, a carboxyl group, a carboxymethyl group, a C 2 -C 7 alkoxycarbonyl group and a C 2- group.
  • a phenyl group which may be independently substituted with 1 to 3 groups independently selected from a C 7 hydroxyalkoxycarbonyl group. Or a pharmacologically acceptable salt thereof.
  • R is a phenyl group independently substituted with one or two groups selected from a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, a carboxyl group, and a carboxymethyl group, or a pharmacologically acceptable salt thereof.
  • R is 4-carboxylphenyl group, 4-carboxyl-2-fluorophenyl group, 4-carboxyl-2-chlorophenyl group, 4-carboxyl-2-methylphenyl group, 4-carboxyl-2-trifluoromethylphenyl group or A compound having a 4-carboxymethyl-2-chlorophenyl group or a pharmacologically acceptable salt thereof.
  • An acyl coenzyme A diacylglycerol acyltransferase inhibitor containing the compound described in any one of (1) to (5) 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 (5) or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition inhibits acyl coenzyme A: diacylglycerol acyltransferase, inhibits the synthesis of triglyceride, and suppresses the absorption of triglyceride, thereby treating, improving, reducing and / or preventing symptoms.
  • the pharmaceutical composition for treatment and / or prevention of a disease.
  • 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, hypertriglyceride disease, 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 (8)
  • composition according to (8) wherein the pharmaceutical composition is for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.
  • 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
  • Hyperlipidemia hypertriglycerideemia, 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
  • diabetes 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 which is a composition for the treatment and / or prevention of cerebrovascular disorder, coronary artery disease, fatty liver, respiratory abnormalities, low back pain, knee osteoarthritis, gout or cholelithiasis.
  • composition for the treatment and / or prevention of hyperlipidemia, hypertriglyceridemia, diabetes, arteriosclerosis or hypertension caused by obesity.
  • 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 (5) or a pharmacologically acceptable salt thereof Acyltransferase inhibition method.
  • the disease is obesity, obesity, hyperlipidemia, hypertriglyceridemia, dyslipidemia, 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 (32) which is a disease or bulimia.
  • the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • a fluorine atom or a chlorine atom is preferable.
  • the “C 1 -C 6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms.
  • a methyl group is a linear or branched alkyl group having 1 to 4 carbon atoms.
  • the “C 1 -C 6 halogenated alkyl group” is a group in which the same or different 1 to 5 “halogen atoms” are bonded to the “C 1 -C 6 alkyl group”.
  • the same or different 1 to 5 “halogen atoms” are groups (C 1 -C 2 halogenated alkyl groups) bonded to the “C 1 -C 2 alkyl group”, More preferably, it is a trifluoromethyl group.
  • the “C 2 -C 7 alkoxycarbonyl group” is a group in which one oxygen atom bonded to the “C 1 -C 6 alkyl group” is bonded to a carbonyl group.
  • methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl or t-butoxycarbonyl group preferably one of the above-mentioned “C 1 -C 4 alkyl”
  • the “C 2 -C 7 hydroxyalkoxycarbonyl group” is a group in which one hydroxy group is bonded to the “C 1 -C 6 alkyl group” of the “C 2 -C 7 alkoxycarbonyl group”.
  • 1-hydroxymethoxycarbonyl, 2-hydroxyethoxycarbonyl, 1-hydroxyethoxycarbonyl or 3-hydroxypropoxycarbonyl group, preferably “C 1 -C 3 ” of the above “C 2 -C 3 alkoxycarbonyl group” 2 alkyl group ” is a group in which one hydroxy group is bonded (C 2 -C 3 hydroxyalkoxycarbonyl group), more preferably a 2-hydroxyethoxycarbonyl group.
  • a phenyl group preferably a fluorine atom, a chlorine atom, a methyl group, a trifluoromethyl group, A phenyl group independently substituted with one or two groups selected from a ruboxyl group and a carboxymethyl group, more preferably a 4-carboxylphenyl group, a 4-carboxyl-2-fluorophenyl group, 4- A carboxyl-2-chlorophenyl group, a 4-carboxyl-2-methylphenyl group, a 4-carboxyl-2-trifluoromethylphenyl group or a 4-carboxymethyl-2-chlorophenyl group;
  • the compound having 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 having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has various isomers because an asymmetric carbon atom is present 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 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 having the general formula (I) of the present invention has a basic group, it is reacted with an acid, and when it has an acidic group, it is reacted with a base to form a salt. Can do.
  • Examples of the salt based on the basic group include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfate, Inorganic acid salts such as phosphates; C 1 -C 6 alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • Organic acid salts such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, succinate, maleate; and glycine salt And amino acid salts such as lysine salt, arginine salt, ornithine salt, glutamate and aspartate.
  • 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 having 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 a solvate of the present invention. Included in the salt.
  • 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 having the general formula (I) of the present invention can be produced according to Method A described below.
  • 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-but
  • the base used in the reaction of each step of the following method A 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, etc.
  • Alkali metal bicarbonates alkali metal acetates such as sodium acetate, potassium acetate, lithium acetate, cesium acetate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, water Alkali metal hydroxides such as potassium oxide, barium hydroxide and lithium hydroxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium-t-butoxide, potassium-t -Alkali metal alkoxides such as butoxide; Alkali metal trialkylsiloxides such as methylsiloxide, potassium trimethylsiloxide, lithium trimethylsiloxide; N-methylmorpholine, trie
  • reaction temperature varies depending on the solvent, starting material, reagent, and the like
  • 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.
  • Method A is a method for producing a compound having the general formula (I).
  • R represents the same meaning as described above, and R a represents a hydroxy group and / or carboxyl group in which a hydroxy group and / or carboxyl group contained as a substituent in the R group may be protected.
  • R a represents a hydroxy group and / or carboxyl group in which a hydroxy group and / or carboxyl group contained as a substituent in the R group may be protected.
  • the same groups as those in the definition of the R group are shown.
  • Step A1 This step is a step of producing a compound having the general formula (IV).
  • This step is performed by reacting the compound having the general formula (II) with the compound (III) in the presence of a base in a solvent.
  • the compound having the general formula (II) is a known compound (for example, WO2006 / 004200, J. Med. Chem. 1987, 30, 1887, etc.) or a known method using a known compound as a starting material (for example, , WO2006 / 004200, J. Med. Chem. 1987, 30, 1887, etc.) or similar methods.
  • the solvent used in this step is preferably an amide, and more preferably N, N-dimethylacetamide.
  • 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 0 ° 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 A2 This step is a step of producing a compound having the general formula (I).
  • a compound having the general formula (IV) is reacted with the compound (V) in a solvent in the presence of a palladium catalyst and a base, and then, optionally, a protective group for a hydroxy group and / or a carboxyl group in Ra . This is done by removing.
  • the solvent used in this step is preferably a mixed solvent of amides and water, and more preferably a mixed solvent of 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.
  • the protecting group of “optionally protected hydroxy group” and “optionally protected carboxyl group” in the definition of R a is a chemical group such as hydrogenolysis, hydrolysis, electrolysis or photolysis. This refers to a protecting group that can be cleaved by a method, and shows a protecting group commonly used in organic synthetic chemistry (for example, TW Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999)). reference).
  • the “protecting group” of the “hydroxy group that may be protected” in the definition of R a 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, C 2 -C 7 alkylcarbonyl groups such as acetyl, propionyl, butyryl, pentanoyl, valeryl, halogenated alkylcarbonyl groups such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, alkoxy such as methoxyacetyl
  • Alkylcarbonyl groups such as alkylcarbonyl groups, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, unsaturated alkylcarbonyl groups such as (E) -2-methyl-2-butenoyl; benzoyl, ⁇ -naphtho
  • the “protecting group” of the “optionally protected carboxyl group” in the definition of R a is not particularly limited as long as it is a protecting group for a carboxyl group used in the field of synthetic organic chemistry.
  • 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. 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 to prepare an isotonic solution may be included in the preparation, and a normal solubilizing agent, buffering agent, 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
  • reaction mixture was concentrated, acidified with 1 N aqueous hydrochloric acid (10 mL), diluted with ethyl acetate, and stirred vigorously for 1 hour.
  • the precipitated solid was collected by filtration and dried under reduced pressure to obtain 277 mg (98%) of the title compound as a white solid.
  • Example 4 4- (5- ⁇ 4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl ⁇ pyrimidin-2-yloxy) benzoic acid
  • Example (1c) 4- (5-bromopyrimidin-2-yloxy) benzoic acid methyl ester (Org. Lett., 2009, 11, 2511.) (311 mg) and Example (1a) From the compound (462 mg) obtained in 1 above, 385 mg (68%) of a biaryl compound was obtained as a white solid. In the same manner as in Example (1d), 210 mg (56%) of the title compound was obtained as a white solid from this biaryl compound (385 mg).
  • Example (1d) methyl 3- (5-bromopyrimidin-2-yloxy) benzoate (Org. Lett., 2009, 11, 2511.) (148 mg) and Example (1a) From the compound obtained in (220 mg), 222 mg (83%) of a biaryl compound was obtained as a white solid. From this biaryl compound (222 mg), 99 mg (45%) of the title compound was obtained as a white solid in the same manner as in Example (1d).
  • Example (1c) 5-bromo-2-phenoxypyrimidine (Org. Lett., 2009, 11, 2511) (127 mg) and the compound (231 mg) obtained in Example (1a) were used. 191 mg (75%) of the title compound were obtained as a white solid.
  • Example 9 4- (5- ⁇ 4-[(1-Pyridin-2-yl-3-trifluoromethyl-1H-pyrazol-4-carbonyl) amino] phenyl ⁇ pyrimidin-2-yloxy) -3-trifluoromethylbenzoic acid
  • Example (1c) In the same manner as in Example (1c), obtained in 4- (5-bromo-pyrimidin-2-yloxy) benzonitrile (Org. Lett., 2009, 11, 2511) (139 mg) and Example (1a). The title compound (150 mg, 57%) was obtained as a light brown solid from the obtained compound (229 mg).
  • 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 10 and 12 to 18 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 suppression of neutral fat absorption after loading with neutral fat.
  • 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, 3, 4, 6, 7, 9, and 18 exhibited a neutral fat absorption inhibitory activity of 60% or more at a dose of 3 mg / kg or less.
  • mice Male C57BL / 6N mice (7-12 weeks old, body weight 17-25 g, Nippon Charles River) are reared 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 animals evenly to the experimental groups based on the amount of food consumed during the period, fast overnight, and then add vehicle (0.5% Methylcellulose) or test compound suspended in vehicle (10 mg / kg) to each group. Oral administration (10 mL / kg) was performed. 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.
  • 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 having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent DGAT inhibitory action and antifeeding action, and is useful as a medicine.

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Abstract

La présente invention concerne un composé ayant une excellente activité inhibitrice de DGAT et une excellente activité anorexigène, ou un sel pharmacologiquement acceptable de celui-ci. La présente invention concerne spécifiquement un composé représenté par la formule générale (I) [dans laquelle R représente un groupe phényle qui peut être substitué par 1 à 3 groupes indépendamment choisis parmi un atome d'halogène, un groupe alkyle en C1-C6, un groupe alkyle halogéné en C1-C6, un groupe hydroxyméthyle, un groupe cyano, un groupe carboxyle, un groupe carboxyméthyle, un groupe (alcoxy en C2-C7)carbonyle et un groupe hydroxy(alcoxy en C2-C7)carbonyle] ou un sel pharmacologiquement acceptable de celui-ci.
PCT/JP2010/072848 2009-12-22 2010-12-20 Nouveau dérivé de phénoxypyrimidine WO2011078102A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012063896A1 (fr) * 2010-11-11 2012-05-18 第一三共株式会社 Nouveau dérivé de pyrazole amide
WO2012173219A1 (fr) * 2011-06-17 2012-12-20 第一三共株式会社 Nouveau dérivé de biaryle-éther
WO2015077299A1 (fr) * 2013-11-25 2015-05-28 Eli Lilly And Company Nouveaux inhibiteurs de la dgat2
WO2016187384A1 (fr) * 2015-05-20 2016-11-24 Eli Lilly And Company Nouveaux inhibiteurs de la dgat2

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011130A2 (fr) * 2006-07-21 2008-01-24 Takeda Pharmaceutical Company Limited Composés amidés
WO2008141976A1 (fr) * 2007-05-22 2008-11-27 Via Pharmaceuticals, Inc. Inhibiteurs de diacylglycérol acyltransférase
WO2009011285A1 (fr) * 2007-07-13 2009-01-22 Taisho Pharmaceutical Co., Ltd. Composés hétéroarylbenzènes

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008011130A2 (fr) * 2006-07-21 2008-01-24 Takeda Pharmaceutical Company Limited Composés amidés
WO2008141976A1 (fr) * 2007-05-22 2008-11-27 Via Pharmaceuticals, Inc. Inhibiteurs de diacylglycérol acyltransférase
WO2009011285A1 (fr) * 2007-07-13 2009-01-22 Taisho Pharmaceutical Co., Ltd. Composés hétéroarylbenzènes

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012063896A1 (fr) * 2010-11-11 2012-05-18 第一三共株式会社 Nouveau dérivé de pyrazole amide
WO2012173219A1 (fr) * 2011-06-17 2012-12-20 第一三共株式会社 Nouveau dérivé de biaryle-éther
WO2015077299A1 (fr) * 2013-11-25 2015-05-28 Eli Lilly And Company Nouveaux inhibiteurs de la dgat2
CN105764889A (zh) * 2013-11-25 2016-07-13 伊莱利利公司 新型dgat2抑制剂
JP2016539115A (ja) * 2013-11-25 2016-12-15 イーライ リリー アンド カンパニー 新規ｄｇａｔ２阻害剤
WO2016187384A1 (fr) * 2015-05-20 2016-11-24 Eli Lilly And Company Nouveaux inhibiteurs de la dgat2
CN107635975A (zh) * 2015-05-20 2018-01-26 伊莱利利公司 新的dgat2抑制剂
JP2018515554A (ja) * 2015-05-20 2018-06-14 イーライ リリー アンド カンパニー 新規ｄｇａｔ２阻害剤
US10053429B2 (en) 2015-05-20 2018-08-21 Eli Lilly And Company DGAT2 inhibitors
CN107635975B (zh) * 2015-05-20 2020-07-24 伊莱利利公司 Dgat2抑制剂

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