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  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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Definitions

• the present invention relates to a medicine, in particular, a novel pyridine derivative or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the derivative or ester, which has a hypoglycemic effect or treats and/or prevents the onset of a disorder of carbohydrate or lipid metabolism or a disease mediated by peroxisome proliferator-activated receptor (PPAR) ⁇ .
• a medicine in particular, a novel pyridine derivative or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the derivative or ester, which has a hypoglycemic effect or treats and/or prevents the onset of a disorder of carbohydrate or lipid metabolism or a disease mediated by peroxisome proliferator-activated receptor (PPAR) ⁇ .
• PPAR peroxisome proliferator-activated receptor
• the present invention also relates to a therapeutic agent and/or prophylactic agent for diabetes (especially type II diabetes), hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired fasting glucose, cachexia, psoriasis, diabetic complications, arteriosclerosis, atherosclerosis, hypertension, pancreatitis, polycystic ovary syndrome, fatty liver, nonalcoholic steatohepatitis (NASH), gestational diabetes mellitus, inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease, hyperuricemia, metabolic syndrome, or the like, which has an effect of improving carbohydrate or lipid metabolism, an effect of improving insulin resistance, an antiinflammatory effect or an effect of inhibiting the growth of cancer cells, the therapeutic agent and/or prophylactic agent comprising a novel pyridine derivative or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the derivative or ester
• Non-Patent Document 1 Non-Patent Document 1
• Non-Patent Document 2 Ligands acting on PPAR ⁇ inhibit the production of inflammatory cytokines (Non-Patent Documents 3 and 4) and induce apoptosis to inhibit the growth of cancer cells (Non-Patent Document 5). Therefore, the ligands are also useful for the prevention or improvement of inflammatory disease or cancer.
• Non-Patent Document 6 pioglitazone
• Non-Patent Document 7 rosiglitazone
• Patent Document 8 thiazolidinedione drugs already medically used in the treatment of type II diabetes.
• These thiazolidinedione drugs have side effects such as fluid retention, body weight increase and increased risks for heart disease. Therefore, safer pharmaceuticals have been desired to be developed.
• Patent Document 8 Many researchers have now been researching and developing pharmaceuticals with an aim to prevent or improve insulin resistance, diseases caused by inflammation or the like, or metabolic syndrome through researches of ligands activating or inhibiting PPAR ⁇ , PPAR ⁇ or PPAR ⁇
• Patent Document 2 describes compounds having an alkoxy group, a (substituted) phenyloxy group, a pyridyloxy group or the like bonded to the 6-position of a benzimidazole group as derivatives having the same skeleton as in the compounds of the present invention, and use of those compounds as therapeutic agents for diabetes, hyperglycemia or the like.
• the sole pyridyloxy group at the 6-position of the benzimidazole group is an unsubstituted 3-pyridyloxy group.
• a pyridyloxy group having 1 to 3 substituent(s) is bonded to the 6-position of a benzimidazole group.
• the present inventors have conducted extensive studies to develop therapeutic agents and/or prophylactic agents for disorders of carbohydrate or lipid metabolism or diseases mediated by peroxisome proliferator-activated receptor (PPAR) ⁇ .
• PPAR peroxisome proliferator-activated receptor
• the inventors have found that pyridine derivatives having a specific chemical structure have an excellent hypoglycemic effect or have an effect of improving carbohydrate or lipid metabolism, an effect of improving insulin resistance or an effect of improving so-called metabolic syndrome such as arteriosclerosis, hypertension, cardiovascular disorder or complications derived from them or a pathology caused by various inflammations.
• the inventors have further found that the compounds are ligands acting on peroxisome proliferator-activated receptor (PPAR) ⁇ and therefore have an effect of inhibiting the growth of cancer cells.
• the present invention provides novel pyridine derivatives or pharmacologically acceptable esters thereof, or pharmacologically acceptable salts of the derivatives or esters, which are useful as therapeutic agents or prophylactic agents for metabolic syndrome, specifically, diseases such as diabetes (especially type II diabetes), hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance (IGT), insulin resistance, impaired fasting glucose (IFG), hypertension, fatty liver, nonalcoholic steatohepatitis (NASH), diabetic complications (such as retinopathy, nephropathy or neuropathy), arteriosclerosis, gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), inflammatory disease (such as osteoarthritis, pain or inflammatory enteritis), acne, sunburn, psoriasis, eczema, allergic disease, asthma, peptic ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retin
• the compounds have been found to be highly safe.
• the present invention relates to:
• R represents a pyridyl group substituted with 1 to 3 group(s) independently selected from Substituent Group A,
• Substituent Group A represents a group consisting of a halogen atom, a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group, and Me represents a methyl group]
• Substituent Group A is a group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a methoxy group;
• a pharmaceutical composition comprising the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to any one of (1) to (26) as an active ingredient;
• composition (27), wherein the pharmaceutical composition is a composition for activating peroxisome proliferator-activated receptor (PPAR) ⁇ ;
• PPAR peroxisome proliferator-activated receptor
• composition (27), wherein the pharmaceutical composition is a composition for improving carbohydrate or lipid metabolism, for improving insulin resistance, for inhibiting inflammation or for inhibiting the growth of cancer cells;
• composition (27), wherein the pharmaceutical composition is a composition for the treatment and/or prevention of a disease caused by metabolic syndrome;
• PPAR peroxisome proliferator-activated receptor
• composition (36) The pharmaceutical composition according to (27), wherein the pharmaceutical composition is a composition for the treatment and/or prevention of hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired fasting glucose, hypertension, fatty liver, nonalcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes mellitus or polycystic ovary syndrome;
• a peroxisome proliferator-activated receptor (PPAR) ⁇ activator/modulator comprising the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to any one of (1) to (26) as an active ingredient;
• composition for improving carbohydrate or lipid metabolism, for improving insulin resistance, for inhibiting inflammation or for inhibiting the growth of cancer cells;
• the pharmaceutical composition is a composition for the treatment and/or prevention of hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance, insulin resistance, impaired fasting glucose, hypertension, fatty liver, nonalcoholic steatohepatitis, diabetic complications, arteriosclerosis, atherosclerosis, gestational diabetes mellitus or polycystic ovary syndrome;
• composition for the treatment and/or prevention of inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease or hyperuricemia;
• the pharmaceutical composition is a composition for the treatment and/or prevention of acne, sunburn, psoriasis, eczema, allergic disease, asthma, peptic ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disturbance, autoimmune disease, pancreatitis, cachexia, leukemia, sarcoma or dry eyes;
• a method for lowering blood glucose comprising administering a pharmacologically effective amount of the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to any one of (1) to (26) to a warm-blooded animal;
• a method for activating peroxisome proliferator-activated receptor (PPAR) ⁇ comprising administering a pharmacologically effective amount of the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to any one of (1) to (26) to a warm-blooded animal;
• PPAR peroxisome proliferator-activated receptor
• a method for improving carbohydrate or lipid metabolism, for improving insulin resistance, for inhibiting inflammation or for inhibiting the growth of cancer cells comprising administering a pharmacologically effective amount of the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to any one of (1) to (26) to a warm-blooded animal;
• a method for the treatment and/or prevention of a disease comprising administering a pharmacologically effective amount of the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to any one of (1) to (26) to a warm-blooded animal;
• the “halogen atom” in the present invention is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
• the halogen atom is preferably a fluorine atom or a chlorine atom.
• the “C 1 -C 6 alkyl group” in the present invention is a linear or branched alkyl group having 1 to 6 carbon atom(s).
• Examples of such a group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a pentyl group, an isopentyl group and a hexyl group.
• the group is preferably a methyl group or an ethyl group.
• the “C 1 -C 6 alkoxy group” in the present invention is a group in which the above-mentioned “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 atom(s).
• Examples of such a group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, a pentyloxy group, an isopentyloxy group and a hexyloxy group.
• the group is preferably a methoxy group or an ethoxy group, and more preferably a methoxy group.
• the “Substituent Group A” in the present invention is a group consisting of the above-mentioned “halogen atom”, the above-mentioned “C 1 -C 6 alkyl group” and the above-mentioned “C 1 -C 6 alkoxy group”, and is preferably a group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a methoxy group.
• the “pyridyl group substituted with 1 to 3 group(s) independently selected from Substituent Group A” in the present invention is a 2-pyridyl group, 3-pyridyl group or 4-pyridyl group substituted with 1 to 3 group(s) independently selected from the above-mentioned “Substituent Group A”, and is preferably a 2-pyridyl group, 3-pyridyl group or 4-pyridyl group substituted with 1 to 3 group(s) independently selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a methoxy group.
• R is preferably a 2-pyridyl group, 3-pyridyl group, or 4-pyridyl group substituted with 1 to 3 group(s) independently selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a methoxy group.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention includes all isomers (such as a keto-enol isomer, a diastereomer, an optical isomer, a rotamer, etc.).
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention has various isomers because asymmetric carbon atom(s) exist in the molecule.
• These isomers and mixtures of these isomers of the present invention are all represented by a single formula, specifically, the general formula (I). Accordingly, the present invention includes all of these isomers and mixtures of these isomers in arbitrary ratios.
• the aforementioned stereoisomers can be obtained by synthesizing the compound of the present invention using an optically active raw material compound or using an asymmetric synthesis or asymmetric induction technique or by isolating the synthesized compound of the present invention by a common optical resolution or separation method if desired.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) and carbon-14 ( 14 C).
• the above-described compounds may be radiolabeled with radioisotopes such as 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 isotopic variants of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
• the “pharmacologically acceptable ester thereof” refers to an ester of the compound represented by the general formula (I), which has a carboxyl group and can therefore be esterified, wherein the ester has an ester residue that is a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.
• the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” refers to a protecting group to be cleaved in the human body by a biological method such as hydrolysis to generate a free acid or a salt thereof. Whether the ester has such a protecting group or not can be determined by administering the ester to laboratory animals such as rats or mice and then examining the body fluid of the animals to confirm if the original compound or pharmacologically acceptable salt thereof can be detected.
• Examples of the protecting group include (C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) groups such as 1-methoxyethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl and t-butoxymethyl; (C 1 -C 6 alkoxy)-(C 1 -C 6 alkoxy)-(C 1 -C 6 alkyl) groups such as 2-methoxyethoxymethyl; C 6 -C 14 aryl groups such as phenyl and naphthyl; (C 6 -C 14 aryloxy)-(C 1 -C 6 alkyl) groups such as phenoxymethyl; (C 1 -C 6 halogenated
• the “pharmacologically acceptable salt of the compound or ester” refers to a salt that does not have significant toxicity and can be used as a medicine.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof can be converted to a salt by reacting a basic group with an acid or by reacting an acidic group with a base.
• Examples of the salt based on a basic group include hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides; inorganic acid salts such as nitrates, perchlorates, sulfates and phosphates; alkyl sulfonates such as methanesulfonates and ethanesulfonates; haloalkyl sulfonates such as trifluoromethanesulfonates; aryl sulfonates such as benzenesulfonates and p-toluenesulfonates; and organic acid salts such as acetates, malates, fumarates, succinates, citrates, ascorbates, tartrates, oxalates and maleates.
• hydrohalides such as hydrofluorides, hydrochlorides, hydrobromides and hydroiodides
• inorganic acid salts such as nitrates, perchlorates,
• examples of the salt based on an acidic group include alkali metal salts such as sodium salts, potassium salts and lithium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and metal salts such as aluminum salts and iron salts.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention may incorporate water molecules to form a hydrate when left to stand in the air or recrystallized, and such a hydrate is also included in the salt of the present invention.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention may absorb some other specific solvent(s) to form a solvate, and such a solvate is also included in the salt of the present invention.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention is preferably the compound represented by the general formula (I) or pharmacologically acceptable salt thereof according to the present invention, and more preferably the compound represented by the general formula (I) according to the present invention.
• the compounds represented by the general formula (I) or pharmacologically acceptable esters thereof, or pharmacologically acceptable salts of the compounds or esters according to the present invention have been found to have an excellent hypoglycemic effect, an effect of improving carbohydrate or lipid metabolism, an effect of improving insulin resistance or an effect of improving so-called metabolic syndrome such as arteriosclerosis, hypertension, cardiovascular disorder or complications derived from them or a pathology caused by various inflammations. It has also been found that the compounds are ligands acting on peroxisome proliferator-activated receptor (PPAR) ⁇ and therefore have an effect of inhibiting the growth of cancer cells.
• PPAR peroxisome proliferator-activated receptor
• the compounds are useful in a therapeutic agent or prophylactic agent for metabolic syndrome, specifically, a disease such as diabetes, hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance (IGT), insulin resistance, impaired fasting glucose (IFG), hypertension, fatty liver, nonalcoholic steatohepatitis (NASH), diabetic complications (such as retinopathy, nephropathy or neuropathy), arteriosclerosis, gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), inflammatory disease (such as osteoarthritis, pain or inflammatory enteritis), acne, sunburn, psoriasis, eczema, allergic disease, asthma, peptic ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, atherosclerosis, diabetic retinopathy, diabetic maculopathy, macular edema, diabetic nephropathy, ischemic heart disease, cerebrovascular disorder, peripheral circulatory disturbance,
• the compounds represented by the general formula (I) or pharmacologically acceptable esters thereof, or pharmacologically acceptable salts of the compounds or esters according to the present invention are highly safe.
• the compound represented by the general formula (I) according to the present invention can be produced according to Processes A to D described below.
• the solvent used in the reaction in each step of the following Processes A to D is not particularly limited insofar as it does not inhibit the reaction and dissolves the starting material to some extent.
• the solvent is selected from the following solvent group, for example.
• the solvent group consists of hydrocarbons such as pentane, hexane, octane, petroleum ether, ligroin and cyclohexane; amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methyl-2-pyrrolidinone and hexamethylphosphoric triamide; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether and cyclopentyl methyl ether; alcohols such as methanol, ethanol, n-propanol, i-
• Examples of the base used in the reaction in each step of the following Processes A to D include inorganic bases such as alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and lithium bicarbonate; alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; and alkali metal fluorides such as sodium fluoride and potassium fluoride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide; alkali metal trialkylsilanolates such as sodium trimethylsilanolate, potassium trimethylsilanolate and lithium trimethylsilanolate; alkali metal mercapt
• the reaction temperature varies according to the solvent, the starting material, the reagent and the like
• the reaction time varies according to the solvent, the starting material, the reagent, the reaction temperature and the like.
• each desired compound is collected from the reaction mixture according to conventional methods after completion of the reaction.
• the desired compound is obtained as follows, for example.
• the reaction mixture is appropriately neutralized and insoluble matter, if present, is removed by filtration.
• water and an immiscible organic solvent such as ethyl acetate are added, and the organic layer containing the desired compound is separated.
• the organic layer is washed with water or the like and then dried over anhydrous magnesium sulfate, anhydrous sodium sulfate or the like and filtered. Then, the solvent is evaporated.
• the resulting desired compound may be isolated and purified if necessary by appropriately combining usual methods, for example, methods suitably used for isolation and purification of organic compounds such as recrystallization and reprecipitation and eluting with an appropriate eluent by application of chromatography.
• the desired compound insoluble in a solvent may be purified by washing the resulting solid crude product with a solvent.
• the desired compound in each step may also be used as is for the next reaction without purification.
• X represents a halogen atom (preferably a chlorine atom in the compound represented by the general formula (II) and the compound represented by the general formula (XI), and preferably a fluorine atom or a bromine atom in the compound represented by the general formula (XX)
• Y represents a protecting group for the carboxyl group (a protecting group generally used in organic synthesis chemistry, preferably a C 1 -C 6 alkyl group, and more preferably a methyl group or an ethyl group) and Z represents a C 1 -C 6 alkoxy group (preferably a methoxy group).
• the “protecting group for the carboxyl group” as defined above for Y refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis or photolysis and represents a protecting group generally used in organic synthesis chemistry (see T. W. Greene et al., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, Inc. (1999), for example).
• a protecting group is not particularly limited insofar as it is a protecting group for a carboxyl group used in the field of organic synthesis chemistry.
• Examples of the protecting group include C 1 -C 6 alkyl groups; C 2 -C 6 alkenyl groups such as ethenyl, 1-propenyl and 2-propenyl; C 2 -C 6 alkynyl groups such as ethynyl, 1-propynyl and 2-propynyl; C 1 -C 6 halogenated alkyl groups such as trifluoromethyl and trichloromethyl; C 1 -C 6 hydroxyalkyl groups such as hydroxymethyl and 2-hydroxyethyl; (C 2 -C 7 alkylcarbonyl)-(C 1 -C 6 alkyl)groups such as acetylmethyl; aralkyl groups such as benzyl, ⁇ -naphthylmethyl, ⁇ -naphthylmethyl, diphenylmethyl, triphenylmethyl, ⁇ -naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl,
• Process A is a process for producing a compound represented by the general formula (I).
• This step is a step of producing a compound represented by the general formula (IV).
• This step is carried out by 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 base.
• 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 are easily produced from known compounds as starting materials by a known method or a method similar to a known method.
• the solvent used in this step is preferably an amide, and more preferably N,N-dimethylformamide or N-methyl-2-pyrrolidone.
• the base used in this step is preferably an alkali metal carbonate or an alkali metal hydride, and more preferably cesium carbonate or sodium hydride.
• the reaction temperature in this step is usually 50° C. to 150° C., and preferably 80° C. to 120° C.
• the reaction time in this step is usually 0.5 to 48 hours, and preferably 1 to 30 hours.
• This step is a step of producing a compound represented by the general formula (V).
• This step is carried out by reacting the compound represented by the general formula (IV) with iron in a solvent in the presence of a weak acid or by reducing the compound represented by the general formula (IV) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere.
• the solvent used in this step is preferably an ether, an alcohol, water or a mixed solvent of an alcohol and water, more preferably tetrahydrofuran, methanol, ethanol, water or a mixed solvent of ethanol and water, and still more preferably ethanol or a mixed solvent of ethanol and water.
• the weak acid used in this step is preferably acetic acid or ammonium chloride, and more preferably ammonium chloride.
• the palladium catalyst used in this step is, for example, a divalent palladium catalyst or a zerovalent palladium catalyst, preferably palladium-active carbon, palladium (II) acetate, palladium (II) trifluoroacetate, palladium black, palladium (II) bromide, 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 (II) sulfide, tris(dibenzylideneacetone)dipalladium (0),
• the reaction temperature in this step is usually ⁇ 20° C. to 120° C., and preferably 0° C. to 100° C.
• the reaction time in this step is usually 1 to 48 hours, and preferably 2 to 24 hours.
• This step is a step of producing a compound represented by the general formula (VI).
• This step is carried out by reacting the compound represented by the general formula (V) with glycolic acid in a solvent in the presence of hydrochloric acid (preferably 4 N hydrochloric acid).
• the solvent used in this step is preferably an ether, water or a mixed solvent of an ether and water, more preferably dioxane, water or a mixed solvent of dioxane and water, and still more preferably a mixed solvent of dioxane and water.
• the reaction temperature in this step is usually 50° C. to 150° C., and preferably 80° C. to 120° C.
• the reaction time in this step is usually 0.5 to 48 hours, and preferably 1 to 24 hours.
• This step is a step of producing a compound represented by the general formula (VIII).
• This step is carried out by reacting the compound represented by the general formula (VI) with a compound represented by the general formula (VII) in a solvent in the presence of a condensing agent.
• the compound represented by the general formula (VII) used in this step is a known compound or is easily produced from a known compound as a starting material by a known method or a method similar to a known method.
• the solvent used in this step is preferably an aromatic hydrocarbon, and more preferably toluene.
• Examples of the condensing agent used in this step include a combination of an azodicarboxylate and a tertiary phosphine, a combination of an azodicarboxylic amide and a tertiary phosphine, and (trialkylphosphoranylidene)acetonitrile.
• the condensing agent is preferably a combination of an azodicarboxylic amide and a tertiary phosphine, and more preferably a combination of tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine.
• the reaction temperature in this step is usually ⁇ 78° C. to 120° C., and preferably 0° C. to 50° C.
• the reaction time in this step is usually 0.5 to 24 hours, and preferably 1 to 12 hours.
• This step is a step of producing a compound represented by the general formula (I).
• This step is carried out according to known methods (such as a method described in “Protective Groups in Organic Synthesis” (Theodora W. Greene, Peter G. M. Wuts, 1999, published by Wiley-Interscience Publication)).
• Y is a C 1 -C 6 alkyl group.
• This step is carried out by reacting the compound represented by the general formula (VIII) with a base in a solvent.
• 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 an alkali metal hydroxide, more preferably lithium hydroxide, potassium hydroxide or sodium hydroxide, and still more preferably sodium hydroxide.
• the reaction temperature in this step is usually 0° C. to 150° C., and preferably 20° C. to 100° C.
• the reaction time in this reaction is usually 0.5 to 24 hours, and preferably 1 to 10 hours.
• Process B is another process for producing a compound represented by the general formula (I).
• This step is a step of producing a compound represented by the general formula (X).
• This step is carried out by reacting a compound represented by the general formula (V) with a compound represented by the general formula (IX) in a solvent in the presence of a condensing agent and a base.
• the compound represented by the general formula (IX) used in this step is a known compound or is easily produced from a known compound as a starting material by a known method or a method similar to a known method.
• the solvent used in this step is preferably an ether, an amide or a halogenated hydrocarbon, and more preferably tetrahydrofuran, N,N-dimethylformamide or dichloromethane.
• condensing agent used in this step examples include O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 1-propanephosphonic acid cyclic anhydride (T3P), dicyclohexylcarbodiimide (DCCD), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC), isobutyl chloroformate (IBCF), 1,1′-carbonylbis-1H-imidazole (CDI), diethyl cyanophosphonate (DEPC), diphenylphosphoryl azide (DPPA), N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboxylmide and dipyridyl disulfide
• the base used in this step is preferably triethylamine, N-methylmorpholine or 4-(N,N-dimethylamino)pyridine.
• the reaction temperature in this step is usually ⁇ 50° C. to 100° C., and preferably ⁇ 20° C. to 60° C.
• the reaction time in this step is usually 0.1 to 24 hours, and preferably 0.5 to 10 hours.
• This step is a step of producing a compound represented by the general formula (VIII).
• This step is carried out by reacting the compound represented by the general formula (X) with an acid in a solvent.
• the solvent used in this step is preferably an ether, an amide or an alcohol, and more preferably 1,4-dioxane, N,N-dimethylformamide or ethanol.
• the acid used in this step is preferably hydrochloric acid, sulfuric acid, nitric acid or benzenesulfonic acid, and more preferably hydrochloric acid.
• the reaction temperature in this step is usually ⁇ 20° C. to 150° C., and preferably 0° C. to 100° C.
• the reaction time in this step is usually 0.5 to 150 hours, and preferably 1 to 72 hours.
• This step is a step of producing a compound represented by the general formula (I).
• This step is carried out in the same manner as in Step A5 of the above Process A.
• Process C is another process for producing a compound represented by the general formula (I).
• This step is a step of producing a compound represented by the general formula (XII).
• This step is carried out by reacting a compound represented by the general formula (XI) with a compound represented by the general formula (III) in a solvent in the presence of a base.
• the compound represented by the general formula (XI) used in this step is a known compound or is easily produced from a known compound as a starting material by a known method or a method similar to a known method.
• the solvent used in this step is preferably an amide, and more preferably N,N-dimethylformamide or N-methyl-2-pyrrolidone.
• the base used in this step is preferably an alkali metal hydride, and more preferably sodium hydride.
• the reaction temperature in this step is usually ⁇ 78° C. to 150° C., and preferably 0° C. to 100° C.
• the reaction time in this step is usually 0.5 to 48 hours, and preferably 1 to 24 hours.
• This step is a step of producing a compound represented by the general formula (XIII).
• This step is carried out in the same manner as in Step A2 of the above Process A by reacting the compound represented by the general formula (XII) with iron in a solvent in the presence of a weak acid or by reducing the compound represented by the general formula (XII) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere.
• This step is a step of producing a compound represented by the general formula (XIV).
• This step is carried out in the same manner as in Step B1 of the above Process B by reacting the compound represented by the general formula (XIII) with a compound represented by the general formula (IX) in a solvent in the presence of a condensing agent and a base.
• This step is a step of producing a compound represented by the general formula (VIII).
• This step is carried out in the same manner as in Step B2 of the above Process B by reacting the compound represented by the general formula (XIV) with acetic acid.
• This step is a step of producing a compound represented by the general formula (I).
• This step is carried out in the same manner as in Step A5 of the above Process A.
• Process D is another process for producing a compound represented by the general formula (I).
• This step is a step of producing a compound represented by the general formula (XVI).
• This step is carried out by reacting a compound represented by the general formula (II) with a compound represented by the general formula (XV) in a solvent in the presence of a base.
• the compound represented by the general formula (XV) used in this step is a known compound or is easily produced from a known compound as a starting material by a known method or a method similar to a known method.
• the solvent used in this step is preferably an amide, and more preferably N,N-dimethylformamide or N-methyl-2-pyrrolidone.
• the base used in this step is preferably an alkali metal carbonate or an alkali metal hydride, and more preferably cesium carbonate or sodium hydride.
• the reaction temperature in this step is usually 50° C. to 150° C., and preferably 80° C. to 120° C.
• the reaction time in this reaction is usually 0.5 to 48 hours, and preferably 1 to 30 hours.
• This step is a step of producing a compound represented by the general formula (XVII).
• This step is carried out in the same manner as in Step A2 of the above Process A by reacting the compound represented by the general formula (XVI) with iron in a solvent in the presence of a weak acid or by reducing the compound represented by the general formula (XVI) in a solvent in the presence of a palladium catalyst in a hydrogen atmosphere.
• This step is a step of producing a compound represented by the general formula (XVIII).
• This step is carried out in the same manner as in Step B1 of the above Process B by reacting the compound represented by the general formula (XVII) with a compound represented by the general formula (IX) in a solvent in the presence of a condensing agent and a base.
• This step is a step of producing a compound represented by the general formula (XIX).
• This step is carried out by reacting the compound represented by the general formula (XVIII) with an acid in a solvent.
• the solvent used in this step is preferably an ether or an alcohol, and more preferably dioxane or methanol.
• Examples of the acid used in this step include hydrogen halides such as hydrogen chloride gas and hydrogen bromide gas; mineral acids such as sulfuric acid, hydrobromic acid and hydrochloric acid; organic sulfonic acids such as methanesulfonic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate (PPTS), camphorsulfonic acid and trifluoromethanesulfonic acid; carboxylic acids such as acetic acid, formic acid and trifluoroacetic acid; methyl sulfate; Lewis acids such as aluminum chloride, zinc chloride, tin tetrachloride, titanium trichloride, titanium tetrachloride, boron trifluoride, boron trifluoride-diethyl ether and boron tribromide; and acidic ion exchange resins.
• the acid is preferably a mineral acid, more preferably sulfuric acid or hydrochloric acid
• the reaction temperature in this step is usually 0° C. to 150° C., and preferably 20° C. to 120° C.
• the reaction time in this reaction is usually 0.5 to 24 hours, and preferably 1 to 10 hours.
• This step is a step of producing a compound represented by the general formula (VIII).
• This step is carried out by reacting the compound represented by the general formula (XIX) with a compound represented by the general formula (XX) in a solvent in the presence of copper and its ligand(s).
• the compound represented by the general formula (XX) used in this step is a known compound or is easily produced from a known compound as a starting material by a known method or a method similar to a known method.
• the solvent used in this step is preferably an ether or an amide, and more preferably tetrahydrofuran, N,N-dimethylformamide or N-methyl-2-pyrrolidone.
• Examples of the copper used in this step include zerovalent copper and complexes thereof; monovalent copper salts such as copper (I) chloride, copper (I) bromide, copper (I) iodide and copper (I) trifluoromethanesulfonate, and complexes thereof; and divalent copper salts such as copper (II) bromide, copper (II) acetate and copper (II) sulfate, and complexes thereof.
• Preferred examples include monovalent copper salts and complexes thereof, and divalent copper salts.
• More preferred examples include copper (I) chloride, a copper (I) bromide-dimethyl sulfide complex, copper (I) iodide, copper (I) trifluoromethanesulfonate and copper (II) acetate. Still more preferred examples include copper (I) iodide.
• the ligand used in this step is preferably N,N′-dimethylethylenediamine, trans-N,N′-dimethylcyclohexane-1,2-diamine, 2-(diphenylphosphino)-2′-(N,N-dimethylamino)biphenyl or 1,10-phenanthroline, and more preferably 1,10-phenanthroline.
• the reaction temperature in this step is usually 0° C. to 150° C., and preferably 20° C. to 100° C.
• the reaction time in this reaction is usually 0.5 to 24 hours, and preferably 1 to 10 hours.
• This step is a step of producing a compound represented by the general formula (I).
• This step is carried out in the same manner as in Step A5 of the above Process A.
• the compound represented by the general formula (I) or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to the present invention used as a medicine can be orally administered as tablets, capsules, granules, powder or syrup or parenterally administered as an injection or suppository, for example, alone or in a mixture with an appropriate pharmacologically acceptable excipient, diluent or the like.
• excipients whose examples include organic excipients such as sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; and pullulan; and inorganic excipients such as silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, calcium silicate and magnesium aluminometasilicate; phosphates such as calcium hydrogenphosphate; carbonates such as calcium carbonate; and sulfates such as calcium sulfate), lubricants (whose examples include stearic acid and stearic acid metal salts such as calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and spermaceti; boric acid; adipic excipients (whose examples include organic excipient
• the dose of the preparation varies according to the symptoms, the age and the like of the patient (a warm-blooded animal, in particular, a human).
• the preparation is preferably orally administered at 0.0015 mg/kg body weight (preferably 0.008 mg/kg body weight) per dose per day at the lower limit to 70 mg/kg body weight (preferably 7 mg/kg body weight) per dose per day at the upper limit or intravenously administered at 0.00015 mg/kg body weight (preferably 0.0008 mg/kg body weight) per dose per day at the lower limit to 8.5 mg/kg body weight (preferably 5 mg/kg body weight) per dose per day at the upper limit to an adult once to six times per day according to the symptoms.
• MS Mass spectrometry
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10 mmol), 3-bromo-2-fluoropyridine (1.94 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol), cesium carbonate (9.77 g, 30 mmol) and DMF (50 mL) to obtain the title compound (2.19 g, 47%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(3-ethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (2b) (0.55 g, 1.32 mmol), a 2 M sodium hydroxide aqueous solution (5 mL) and 1,4-dioxane (10 mL) to obtain the title compound (0.44 g, 89%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (1.56 g, 5.0 mmol), 3-bromo-2-chloro-6-fluoropyridine (1.16 g, 5.50 mmol), copper iodide (0.10 g, 0.50 mmol), 1,10-phenanthroline (0.09 g, 0.50 mmol), cesium carbonate (4.89 g, 15 mmol) and DMF (30 mL) to obtain the title compound (1.70 g, 68%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(6-methoxy-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (3c) (0.26 g, 0.61 mmol), a 1 M sodium hydroxide aqueous solution (20 mL) and 1,4-dioxane (40 mL) to obtain the title compound (0.22 g, 87%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10 mmol), 3-bromo-6-fluoro-2-methylpyridine (2.09 g, 11 mmol), copper iodide (0.19 g, 1.0 mmol), 1,10-phenanthroline (0.18 g, 1.0 mmol), cesium carbonate (9.77 g, 30 mmol) and DMF (50 mL) to obtain the title compound (0.68 g, 14%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(5,6-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (4b) (0.17 g, 0.41 mmol), a 2 M sodium hydroxide aqueous solution (5 mL) and 1,4-dioxane (10 mL) to obtain the title compound (0.16 g, 99%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (15.6 g, 50.0 mmol), 5-chloro-2,3-difluoropyridine (8.22 g, 55.0 mmol), copper iodide (0.95 g, 5.00 mmol), 1,10-phenanthroline (0.90 g, 5.00 mmol), cesium carbonate (48.9 g, 150 mmol) and DMF (200 mL) to obtain the title compound (15.4 g, 70%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (5a) (15.4 g, 34.9 mmol), a 2 M sodium hydroxide aqueous solution (100 mL) and THF (200 mL) to obtain the title compound (14.0 g, 94%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (9.40 g, 30.0 mmol), 3-bromo-5-chloro-2-fluoropyridine (6.90 g, 33.0 mmol), copper iodide (0.57 g, 3.00 mmol), 1,10-phenanthroline (0.54 g, 3.00 mmol), cesium carbonate (29.3 g, 90 mmol) and DMF (90 mL) to obtain the title compound (13.7 g, 91%) as a white solid.
• Example (2b) The reaction and post-treatment were carried out according to Example (2b) using methyl 3-( ⁇ 6-[(5-chloro-3-bromopyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (6a) (10.1 g, 20.0 mmol), trimethylboroxine (50% solution in THF, 6.2 mL, 44.0 mmol), a [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)-dichloromethane mixture (0.82 g, 1.00 mmol), potassium carbonate (8.29 g, 60.0 mmol) and DMF (80 mL) to obtain the title compound (6.60 g, 75%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(5-chloro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (6b) (465 mg, 1.06 mmol), a 1 M sodium hydroxide aqueous solution (2.1 mL), THF (10 mL) and methanol (10 mL) to obtain the title compound (230 mg, 51%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (7.81 g, 25.0 mmol), 3,5-dichloro-2-fluoropyridine (4.57 g, 27.5 mmol), copper iodide (0.48 g, 2.50 mmol), 1,10-phenanthroline (0.45 g, 2.50 mmol), cesium carbonate (24.44 g, 75.0 mmol) and DMF (100 mL) to obtain the title compound (5.90 g, 53%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(3,5-dichloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (7a) (5.90 g, 12.9 mmol), a 2 M sodium hydroxide aqueous solution (50 mL) and 1,4-dioxane (100 mL) to obtain the title compound (5.30 g, 93%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (2.28 g, 7.30 mmol), 3-bromo-2,5-difluoropyridine produced in Example (8a) (1.56 g, 8.03 mmol), copper iodide (0.14 g, 0.73 mmol), 1,10-phenanthroline (0.13 g, 0.73 mmol), cesium carbonate (7.14 g, 21.9 mmol) and DMF (40 mL) to obtain the title compound (1.92 g, 54%) as a white solid.
• Example 8b The reaction and post-treatment were carried out according to Example (2b) using methyl 3-( ⁇ 6-[(3-bromo-5-fluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (8b) (1.92 g, 3.95 mmol), trimethylboroxine (50% solution in THF, 2.23 mL, 7.90 mmol), a [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)-dichloromethane mixture (0.32 g, 0.39 mmol), potassium carbonate (1.09 g, 7.90 mmol) and DMF (40 mL) to obtain the title compound (0.99 g, 60%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(5-fluoro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (8c) (0.99 g, 2.35 mmol), a 1 M sodium hydroxide aqueous solution (10 mL), 1,4-dioxane (10 mL) and methanol (10 mL) to obtain the title compound (0.91 g, 95%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (4.06 g, 13.0 mmol), 5-Bromo-2,3-difluoropyridine produced in Example (9a) (2.77 g, 14.3 mmol), copper iodide (0.25 g, 1.30 mmol), 1,10-phenanthroline (0.23 g, 1.30 mmol), cesium carbonate (12.71 g, 39.0 mmol) and DMF (65 mL) to obtain the title compound (4.14 g, 66%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (9c) (2.02 g, 4.79 mmol), a 1 M sodium hydroxide aqueous solution (25 mL) and methanol (50 mL) to obtain the title compound (1.98 g, 98%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (2.50 g, 8.00 mmol), 3,5-dibromo-2-fluoropyridine (2.24 g, 8.81 mmol), copper iodide (0.15 g, 0.80 mmol), 1,10-phenanthroline (0.14 g, 0.80 mmol), cesium carbonate (7.82 g, 24.0 mmol) and DMF (40 mL) to obtain the title compound (3.24 g, 74%) as a white solid.
• Example 2b The reaction and post-treatment were carried out according to Example (2b) using methyl 3-( ⁇ 6-[(3,5-dibromopyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (10a) (5.47 g, 10.0 mmol), trimethylboroxine (50% solution in THF, 11.28 mL, 40.0 mmol), a [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)-dichloromethane mixture (0.82 g, 1.00 mmol), potassium carbonate (5.53 g, 40.0 mmol) and DMF (100 mL) to obtain the title compound (3.80 g, 91%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (10b) (0.96 g, 2.30 mmol), a 1 M sodium hydroxide aqueous solution (50 mL) and methanol (50 mL) to obtain the title compound (0.85 g, 92%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10.0 mmol), 5-bromo-2-fluoro-3-methylpyridine (2.09 g, 11.0 mmol), copper iodide (0.19 g, 1.00 mmol), 1,10-phenanthroline (0.18 g, 1.00 mmol), cesium carbonate (9.77 g, 30.0 mmol) and DMF (50 mL) to obtain the title compound (0.65 g, 14%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(5-ethyl-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (11b) (0.58 g, 1.34 mmol), a 1 M sodium hydroxide aqueous solution (5 mL) and methanol (10 mL) to obtain the title compound (0.43 g, 77%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10.0 mmol), 3-bromo-2-fluoro-5-methylpyridine (2.09 g, 11.0 mmol), copper iodide (0.19 g, 1.00 mmol), 1,10-phenanthroline (0.18 g, 1.00 mmol), cesium carbonate (9.77 g, 30.0 mmol) and DMF (50 mL) to obtain the title compound (0.65 g, 14%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(3-ethyl-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (12b) (0.23 g, 0.53 mmol), a 1 M sodium hydroxide aqueous solution (5 mL) and methanol (10 mL) to obtain the title compound (0.15 g, 68%) as a white solid.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (3.12 g, 10.0 mmol), 2,3,6-trifluoropyridine (1.46 g, 11.0 mmol), copper iodide (0.19 g, 1.00 mmol), 1,10-phenanthroline (0.18 g, 1.00 mmol), cesium carbonate (9.77 g, 30.0 mmol) and DMF (50 mL) to obtain the title compound (3.02 g, 71%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(3,6-difluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (13a) (3.02 g, 7.10 mmol), a 2 M sodium hydroxide aqueous solution (10 mL) and 1,4-dioxane (20 mL) to obtain the title compound (2.52 g, 86%) as a white solid.
• Example (8a) The reaction and post-treatment were carried out according to Example (8a) using 3,5-dibromo-4-chloropyridin-2-amine produced in Example (14a) (10.1 g, 35.4 mmol), sodium nitrite (3.66 g, 53.1 mmol) and hydrogen fluoride-pyridine (50 mL) to obtain the title compound (8.50 g, 83%) as a pale yellow oil.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (1.69 g, 5.00 mmol), 3,5-dibromo-4-chloro-2-fluoropyridine produced in Example (14b) (1.59 g, 5.50 mmol), copper iodide (0.10 g, 0.50 mmol), 1,10-phenanthroline (0.09 g, 0.50 mmol), cesium carbonate (4.89 g, 15.0 mmol) and DMF (30 mL) to obtain the title compound (1.56 g, 54%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(4-methoxy-3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (14e) (57 mg, 0.13 mmol), a 1 M sodium hydroxide aqueous solution (2 mL) and methanol (2 mL) to obtain the title compound (37 mg, 67%) as a white solid.
• Example 8a The reaction and post-treatment were carried out according to Example (8a) using 3,5,6-tribromopyridin-2-amine produced in Example (15a) (2.34 g, 7.07 mmol), sodium nitrite (0.73 g, 10.6 mmol) and hydrogen fluoride-pyridine (5 mL) to obtain the title compound (1.98 g, 84%) as a pale yellow oil.
• Example (1f) The reaction and post-treatment were carried out according to Example (1f) using methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate produced in Example (1e) (1.69 g, 5.40 mmol), 2,3,5-tribromo-6-fluoropyridine produced in Example (15b) (1.98 g, 5.94 mmol), copper iodide (0.10 g, 0.54 mmol), 1,10-phenanthroline (0.10 g, 0.54 mmol), cesium carbonate (5.28 g, 16.2 mmol) and DMF (30 mL) to obtain the title compound (2.92 g, 86%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 1-methyl-6-[(3,5,6-trimethylpyridin-2-yl)oxy]-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (15d) (1.30 g, 3.01 mmol), a 1 M sodium hydroxide aqueous solution (100 mL), 1,4-dioxane (100 mL) and methanol (100 mL) to obtain the title compound (1.13 g, 93%) as a white solid.
• Example (1b) The reaction and post-treatment were carried out according to Example (1b) using 5-[(2-methoxypyridin-4-yl)oxy]-N-methyl-2-nitroaniline produced in Example (16c) (3.90 g, 14.2 mmol), iron powder (3.96 g, 70.8 mmol), ammonium chloride (0.38 g, 7.08 mmol), ethanol (80 mL) and water (40 mL) to obtain the title compound (3.46 g, 99%) as a brown oil.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(2-methoxypyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (16f) (3.10 g, 7.39 mmol), a 1 M sodium hydroxide aqueous solution (25 mL) and methanol (50 mL) to obtain the title compound (2.65 g, 88%) as a white solid.
• Example (1b) The reaction and post-treatment were carried out according to Example (1b) using 5-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N-methyl-2-nitroaniline produced in Example (17b) (4.87 g, 16.8 mmol), iron powder (4.70 g, 84.2 mmol), ammonium chloride (0.45 g, 8.42 mmol), ethanol (80 mL) and water (40 mL) to obtain the title compound (4.37 g, 99%) as a brown oil.
• Example (16e) The reaction and post-treatment were carried out according to Example (16e) using 4-[(2-methoxy-6-methylpyridin-4-yl)oxy]-N 2 -methylbenzene-1,2-diamine produced in Example (17c) (4.13 g, 15.9 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (3.68 g, 17.5 mmol), triethylamine (4.44 mL, 31.8 mmol), pivaloyl chloride (1.96 mL, 15.9 mmol) and dichloromethane (80 mL) to obtain the title compound (4.44 g, 64%) as a white powder.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(2-Methoxy-6-methylpyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (17e) (4.12 g, 9.50 mmol), a 1 M sodium hydroxide aqueous solution (25 mL) and methanol (50 mL) to obtain the title compound (3.85 g, 99%) as a white solid.
• Example (1b) The reaction and post-treatment were carried out according to Example (1b) using tert-butyl ⁇ 5-[(6-chloropyridin-3-yl)oxy]-2-nitrophenyl ⁇ methylcarbamate produced in Example (18a) (8.0 g, 21 mmol), iron powder (5.6 g, 105 mmol), ammonium chloride (0.56 g, 11 mmol), ethanol (40 mL) and water (20 mL) to obtain the title compound (7.4 g, 99%) as a brown oil.
• Example (1d) The reaction and post-treatment were carried out according to Example (1d) using tert-butyl ⁇ 2-amino-5-[(6-chloropyridin-3-yl)oxy]phenyl ⁇ methylcarbamate produced in Example (18b) (7.4 g, 21 mmol), [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (4.4 g, 21 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.8 g, 25 mmol) and dichloromethane (80 mL) to obtain the title compound (8.0 g, 70%).
• Example (1e) The reaction and post-treatment were carried out according to Example (1e) using methyl 3-[2-( ⁇ 2-[(tert-butoxycarbonyl)(methyl)amino]-4-[(6-chloropyridin-3-yl)oxy]phenyl ⁇ amino)-2-oxoethoxybenzoate produced in Example (18c) (8.0 g, 14 mmol) and a 4 M hydrochloric acid/ethyl acetate solution (40 mL) to obtain the title compound (4.9 g, 78%) as a white solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(6-chloropyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (18d) (4.9 g, 12 mmol), a 1 M sodium hydroxide aqueous solution (17 mL) and 1,4-dioxane (20 mL) to obtain the title compound (4.6 g, 97%) as a white solid.
• Example (1b) The reaction and post-treatment were carried out according to Example (1b) using tert-butyl ⁇ 5-[(5-bromopyridin-3-yl)oxy]-2-nitrophenyl ⁇ methylcarbamate produced in Example (19a) (11.1 g, 26.2 mmol), iron powder (4.38 g, 78.5 mol), ammonium chloride (0.70 g, 13.1 mmol), ethanol (87 mL) and water (40 mL) to obtain the title compound (9.63 g, 94%) as a brown solid.
• Example (1d) The reaction and post-treatment were carried out according to Example (1d) using [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (5.65 g, 26.9 mmol), tert-butyl ⁇ 2-amino-5-[(5-bromopyridin-3-yl)oxy]phenyl ⁇ methylcarbamate produced in Example (19b) (9.63 g, 24.4 mmol), 1-hydroxybenzotriazole (0.33 g, 2.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.15 g, 26.9 mmol) and methylene chloride (81 mL) to obtain the title compound (14.3 g, 99%) as a brown solid.
• Example (1e) The reaction and post-treatment were carried out according to Example (1e) using methyl 3-[2-( ⁇ 4-[(5-bromopyridin-3-yl)oxy]-2-[(tert-butoxycarbonyl)(methyl)amino)-2-oxoethoxy]benzoate produced in Example (19c) (14.3 g, 24.4 mmol), a 4 M hydrochloric acid/1,4-dioxane solution (24 mL) and 1,4-dioxane (12 mL) to obtain the title compound (10.9 g, 96%) as a pale brown solid.
• Example (1g) The reaction and post-treatment were carried out according to Example (1g) using methyl 3-( ⁇ 6-[(5-ethylpyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl ⁇ methoxy)benzoate produced in Example (19e) (0.590 g, 1.41 mmol), a 1 M sodium hydroxide aqueous solution (2.12 mL) and 1,4-dioxane (7.1 mL) to obtain the title compound (0.551 g, 97%) as a white solid.
• mice Six-week-old male KK mice were purchased from CLEA Japan, Inc. and then were fed until 15 to 20 weeks old to develop diabetes. The mice were individually fed during the adaptation period and the test period, and water and feed (FR2, Funabashi Farm) were freely ingested.
• FR2 Funabashi Farm
• mice blood was collected from the tail vein of the mice into a heparin-coated glass tube and centrifuged, and then plasma was separated.
• the glucose level in the plasma was measured by Glucoloader GXT (A&T Corp.), and individuals having a plasma glucose level of about 350 mg/dl or more were selected.
• the mice were grouped, each group having 3 to 4 mice, to make the average body weight and the average plasma glucose level similar.
• Each compound was administered to a compound group with a diet admixture containing 0.03% of the compound.
• a separate group in which the mice were fed only with diet was a control group.
• the experiment period was three days.
• the grouping day was the 0th day.
• the body weight was measured and blood was collected from the tail vein to measure the plasma glucose level.
• the glucose lowering rate was determined by the following formula.
• Glucose lowering rate [(Control group plasma glucose level ⁇ Compound-administered group plasma glucose level)/Control group plasma glucose level] ⁇ 100
• the compounds of the present invention have a hypoglycemic effect equal to or greater than that of Compound A described in WO 2008/126732. Accordingly, the compounds of the present invention are assumed to be useful as therapeutic agents for diabetes (especially therapeutic agents for type II diabetes).
• Rosiglitazone used in Examples is a commercially available PPAR ⁇ activator and is a compound described in U.S. Pat. No. 5,002,953, and can be produced according to the method described therein.
• the ligand-binding domain of human PPAR ⁇ (corresponding to about 300 amino acids at the carboxy end) was bound to the DNA-binding domain of the yeast transcription factor GAL4 (corresponding to 147 amino acids at the amino end) with reference to the report by Kliewer et al. to prepare a gene expressing a GAL4-PPAR ⁇ receptor.
• the base sequence of the human PPAR ⁇ gene is described in the gene database GenBank under Accession No. X90563.
• the cell line HepG2 (American Type Culture Collection HB-8065) was purchased from Dainippon Pharmaceutical Co., Ltd. and cultured in a tissue culture flask having a culture area of 75 cm 2 (manufactured by BD Biosciences). Dulbecco's modified Eagle's medium (Gibco D-MEM, manufactured by Invitrogen Corporation) supplemented with fetal bovine serum (manufactured by HyClone) at a volume ratio of 10% and an antibiotic solution [Antibiotic Antimycotic Solution, stabilized (100 ⁇ ), manufactured by Sigma] at a volume ratio of 1% was used as a medium.
• Dulbecco's modified Eagle's medium Gibco D-MEM, manufactured by Invitrogen Corporation
• fetal bovine serum manufactured by HyClone
• an antibiotic solution [Antibiotic Antimycotic Solution, stabilized (100 ⁇ ), manufactured by Sigma] at a volume ratio of 1% was used as a medium.
• the cells were cultured in a carbon dioxide incubator at 37° C. under 5% carbon dioxide for three days. When the cells were grown to an approximately semiconfluent state, the medium in the flask was removed by aspiration. The cells were washed by adding 10 ml of ice-cooled phosphate-buffered saline (Gibco Dulbecco's Phosphate-Buffered Saline, manufactured by Invitrogen Corporation), and then the saline was removed by aspiration. Thereafter, 7.5 ml of Trizol reagent (Gibco TRIZOL reagent, manufactured by Invitrogen Corporation) was added to the cells in the flask, and repeatedly pipetted. The cells were lysed by incubating at room temperature for about five minutes.
• Trizol reagent Gibco TRIZOL reagent
• the cell lysate was subjected to precipitation with isopropyl alcohol according to the instructions of the Trizol reagent.
• the resulting RNA precipitate was dissolved in pure water and stored in a freezer at about ⁇ 20° C.
• the volume of the RNA solution was 0.22 ml.
• a sample obtained by diluting a part of the RNA solution 100-fold with pure water had an absorbance at 260 nm of 0.562.
• oligonucleotides represented by SEQ ID NOS: 1 and 2 in the later-described Sequence Listing were chemically synthesized as primers for amplification by reverse transcript polymerase chain reaction (hereinafter RT-PCR) of cDNA of the PPAR ⁇ ligand-binding domain using Beckman Oligo 1000 (manufactured by Beckman).
• RT-PCR reverse transcript polymerase chain reaction
• cDNA of PPAR ⁇ was amplified by RT-PCR using Ready-To-Go RT-PCR Beads (manufactured by Amersham Pharmacia Biotech, Inc.) with the HepG2 total RNA previously obtained as a template and the two oligonucleotides as primers.
• the reaction product was subjected to 1.5% agarose electrophoresis.
• the amplified band of about 900 base pairs was cut out, purified, and cloned to the plasmid pCRII (manufactured by Invitrogen Corporation).
• the amplified DNA fragment is assumed to have the nucleotide sequence represented by SEQ ID NO: 3 of the Sequence Listing which includes a sequence encoding the ligand-binding domain, specifically, amino acids 175 to 475, of human PPAR ⁇ , and to which a restriction enzyme BamHI cleavage site and a restriction enzyme HindIII site are added on the 5′-terminal and 3′-terminal, respectively.
• the plasmid clone correctly containing the sequence represented by SEQ ID NO: 3 was selected by confirming the nucleotide sequence.
• the selected plasmid was treated with restriction enzymes BamHI and HindIII to obtain a 900-base-pair fragment containing the gene of the PPAR ⁇ ligand-binding domain. This was inserted into the BamHI-HindIII site of the plasmid pM having the gene of the DNA-binding domain of the yeast transcription factor GAL4 (manufactured by Clontech Laboratories, Inc.) and cloned.
• the plasmid pM-PPAR ⁇ obtained by the above operation includes the nucleotide sequence represented by SEQ ID NO: 4 of the Sequence Listing and encodes an amino acid sequence represented by SEQ ID NO: 5 of the Sequence Listing containing amino acids 1 to 147 of the yeast transcription factor GAL4 at the amino end and containing amino acids 175 to 475 of human PPAR ⁇ and a stop codon at the carboxy end.
• the plasmid is a gene that can express a GAL4-PPAR ⁇ chimeric receptor in mammalian cells.
• the previously acquired plasmid pM-PPAR ⁇ and the plasmid pFR-Luc purchased from Stratagene Cloning Systems, Inc. were dissolved in deionised water at a concentration of 1 mg/mL each.
• the monkey kidney-derived cell line COS-7 (American Type Culture Collection CRL-1651) was seeded into a 75 cm 2 culture flask and cultured using Dulbecco's modified Eagle's medium containing 10% fetal bovine serum (hereinafter medium) under the conditions of 37° C. and 5% carbon dioxide gas until an approximately 80% confluent state was obtained.
• medium Dulbecco's modified Eagle's medium containing 10% fetal bovine serum
• COS-7 cells were transfected with 4.8 micrograms per flask of the plasmid pM-PPAR ⁇ and 19.2 ⁇ g per flask of the plasmid pFR-Luc using Lipofectamine 2000 transfection reagent (manufactured by Invitrogen Corporation), and the cells were cultured overnight.
• the cells were harvested by trypsin treatment, suspended in 75 mL of phenol red-free Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, seeded into a white 96-well plate (manufactured by Costar) using the medium in a volume of 95 ⁇ L per well, and cultured overnight.
• the test compound was dissolved in dimethyl sulfoxide at a concentration of 4 mM.
• the solution was serially diluted 3.3-fold with dimethyl sulfoxide to prepare solutions of the compound at concentrations up to 400 nM.
• Dimethyl sulfoxide was prepared for the control group.
• Rosiglitazone dissolved in dimethyl sulfoxide at a concentration of 4 mM was prepared for the positive control group. They were diluted 20-fold with the medium, and 5 ⁇ L of the dilution was added to the wells in which the cells were grown.
• the concentrations of the test compound treating the cells ranged from 10 ⁇ M to 1 nM. After the addition, the cells were cultured overnight.
• Luc Lite manufactured by PerkinElmer Inc.
• the plate with cells in the Luc Lite was stirred for about 30 minutes.
• the amount of luminescence in each well was measured as luciferase activity using Analyst (Molecular Devices) for 0.5 second. A dose-dependent curve was drawn.
• the maximum luciferase activity exhibited by the test compound alone was calculated as Emax (%) and the concentration of the test compound represented by Emax/2 was calculated as EC50.
• Compound A used in Test Example 1 was used as a comparative compound.
• the compounds of the present invention have PPAR ⁇ activation effect/modulator activity equal to or greater than that of Compound A described in WO 2008/126732. Accordingly, the compounds of the present invention are assumed to be useful as therapeutic agents or prophylactic agents for a disease based on dyslipidemia, arteriosclerosis, hyperlipidemia, diabetes, involutional osteoporosis, adiposis, cancer, or the like.
• the above-formulated powder is mixed and allowed to pass through a 60-mesh sieve. Then, the powder is put in 250 mg gelatin capsules to prepare capsules.
• the above-formulated powder is mixed, granulated using a corn starch paste, dried, and then tableted using a tableting machine to prepare tablets each having a weight of 200 mg.
• the tablets may be sugar-coated as necessary.
• the compounds represented by the general formula (I) or pharmacologically acceptable esters thereof, or pharmacologically acceptable salts of the compounds or esters according to the present invention have excellent hypoglycemic effects and are useful as therapeutic agents and/or prophylactic agents for metabolic syndrome, specifically, a disease such as diabetes, hyperglycemia, hyperlipidemia, adiposity, impaired glucose tolerance (IGT), insulin resistance, impaired fasting glucose (IFG), hypertension, fatty liver, nonalcoholic steatohepatitis (NASH), diabetic complications (such as retinopathy, nephropathy or neuropathy), arteriosclerosis, gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS), inflammatory disease (such as osteoarthritis, pain or inflammatory enteritis), acne, sunburn, psoriasis, eczema, allergic disease, asthma, peptic ulcer, ulcerative colitis, Crohn's disease, coronary artery disease, arteriosclerosis, at

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• 2010
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