Pyridine derivative

Abstract

The present invention relates to a novel pyridine derivative or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the derivative or ester, which has an excellent 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) γ. A compound represented by the general formula (I): [wherein R represents a pyridyl group substituted with 1 to 3 group(s) independently selected from Substituent Group A, and Substituent Group A represents a halogen atom, a C 1 -C 6 alkyl group and a C 1 -C 6 alkoxy group] or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the compound or ester.

1 . A compound represented by general formula (I): 
       
         
           
           
               
               
           
         
         wherein
 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 
 
         or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the compound or ester. 
       
     
     
         2 . The compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to  claim 1 , wherein Substituent Group A is a group consisting of a fluorine atom, a chlorine atom, a methyl group, an ethyl group and a methoxy group. 
     
     
         3 . The compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to  claim 1 , wherein R is a 2-pyridyl group substituted with 1 to 3 group(s) independently selected from Substituent Group A. 
     
     
         4 . The compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to  claim 1 , wherein R is a 3-pyridyl group substituted with 1 to 3 group(s) independently selected from Substituent Group A. 
     
     
         5 . The compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to  claim 1 , wherein R is a 4-pyridyl group substituted with 1 to 3 group(s) independently selected from Substituent Group A. 
     
     
         6 . The compound according to  claim 1  that is:
 3-({6-[(3-chloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-ethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(6-methoxy-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5,6-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-chloro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3,5-dichloropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-fluoro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-ethyl-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-ethyl-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3,6-difluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(4-methoxy-3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({1-methyl-6-[(3,5,6-trimethylpyridin-2-yl)oxy]-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(2-methoxypyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(2-methoxy-6-methylpyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(6-methoxypyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid or 
 3-({6-[(5-ethylpyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid 
 
       or a pharmacologically acceptable ester thereof, or a pharmacologically acceptable salt of the compound or ester. 
     
     
         7 . The compound according to  claim 1  that is:
 3-({6-[(3-ethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5,6-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-fluoro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-ethyl-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-ethyl-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(4-methoxy-3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({1-methyl-6-[(3,5,6-trimethylpyridin-2-yl)oxy]-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(2-methoxypyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(2-methoxy-6-methylpyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid or 
 3-({6-[(6-methoxypyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid 
 
       or a pharmacologically acceptable salt thereof. 
     
     
         8 . The compound according to  claim 1  that is:
 3-({6-[(3-ethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5,6-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-fluoro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(5-ethyl-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(3-ethyl-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(4-methoxy-3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({1-methyl-6-[(3,5,6-trimethylpyridin-2-yl)oxy]-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(2-methoxypyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid, 
 3-({6-[(2-methoxy-6-methylpyridin-4-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid or 
 3-({6-[(6-methoxypyridin-3-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
 
     
     
         9 . A compound that is:
 3-({6-[(5-Chloro-3-fluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid.   
     
     
         10 . A compound that is:
 3-({6-[(5-Chloro-3-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid.   
     
     
         11 . A compound that is:
 3-({6-[(3-Fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid.   
     
     
         12 . A compound that is:
 3-({6-[(3,5-Dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid.   
     
     
         13 . A compound that is:
 3-({6-[(3,6-Difluoropyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid.   
     
     
         14 . A pharmaceutical composition comprising the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to  claim 1  as an active ingredient. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for lowering blood glucose. 
     
     
         16 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for the treatment and/or prevention of diabetes. 
     
     
         17 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for the treatment and/or prevention of type II diabetes. 
     
     
         18 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for activating peroxisome proliferator-activated receptor (PPAR) γ. 
     
     
         19 . The pharmaceutical composition according to  claim 14 , 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. 
     
     
         20 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for the treatment and/or prevention of a disease caused by metabolic syndrome. 
     
     
         21 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for the treatment and/or prevention of a disease mediated by peroxisome proliferator-activated receptor (PPAR) γ. 
     
     
         22 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition activates peroxisome proliferator-activated receptor (PPAR) γ and improves insulin resistance to treat, improve, relieve and/or prevent symptoms. 
     
     
         23 . The pharmaceutical composition according to  claim 14 , 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. 
     
     
         24 . The pharmaceutical composition according to  claim 14 , wherein the pharmaceutical composition is a composition for the treatment and/or prevention of inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease or hyperuricemia. 
     
     
         25 . The pharmaceutical composition according to  claim 14 , wherein 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. 
     
     
         26 . A peroxisome proliferator-activated receptor (PPAR) γ activator/modulator comprising the compound or pharmacologically acceptable ester thereof, or pharmacologically acceptable salt of the compound or ester according to  claim 1  as an active ingredient. 
     
     
         27 . 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  claim 1  to a warm-blooded animal. 
     
     
         28 . The method according to  claim 27 , wherein the disease is diabetes. 
     
     
         29 . The method according to  claim 27 , wherein the disease is 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. 
     
     
         30 . The method according to  claim 27 , wherein the disease is inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease or hyperuricemia. 
     
     
         31 . The method according to  claim 27 , wherein the disease is 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. 
     
     
         32 . The method according to  claim 27 , wherein the warm-blooded animal is a human. 
     
     
         33 . A compound represented by general formula (XIX): 
       
         
           
           
               
               
           
         
         wherein
 Y represents a C 1 -C 6  alkyl group or aralkyl group. 
 
       
     
     
         34 . The compound according to  claim 33 , wherein the compound represented by the general formula (XIX) is:
 Methyl 3-[(6-hydroxy-1-methyl-1H-benzimidazol-2-yl)methoxy]benzoate.   
     
     
         35 . A pharmacologically acceptable salt of 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         36 . The pharmacologically acceptable salt according to  claim 35 , wherein the pharmacologically acceptable salt is a calcium salt of 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         37 . The pharmacologically acceptable salt according to  claim 35 , wherein the pharmacologically acceptable salt is a sodium salt of 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         38 . The pharmacologically acceptable salt according to  claim 35 , wherein the pharmacologically acceptable salt is a hydrochloride salt of 3-({6-[(3-fluoro-5-methylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         39 . A pharmacologically acceptable salt of 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         40 . The pharmacologically acceptable salt according to  claim 39 , wherein the pharmacologically acceptable salt is a calcium salt of 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         41 . The pharmacologically acceptable salt according to  claim 39 , wherein the pharmacologically acceptable salt is a sodium salt of 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         42 . The pharmacologically acceptable salt according to  claim 39 , wherein the pharmacologically acceptable salt is a hydrochloride salt of 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         43 . The calcium salt according to  claim 40 , wherein the calcium salt is a calcium salt hydrate of 3-({6-[(3,5-dimethylpyridin-2-yl)oxy]-1-methyl-1H-benzimidazol-2-yl}methoxy)benzoic acid. 
     
     
         44 . A pharmaceutical composition comprising the compound according to  claim 11  as an active ingredient. 
     
     
         45 . A pharmaceutical composition comprising the compound according to  claim 12  as an active ingredient. 
     
     
         46 . A pharmaceutical composition comprising the calcium salt according to  claim 36  as an active ingredient. 
     
     
         47 . A pharmaceutical composition comprising the calcium salt according to  claim 40  as an active ingredient. 
     
     
         48 . A pharmaceutical composition comprising the calcium salt hydrate according to  claim 43  as an active ingredient. 
     
     
         49 . A method for the treatment of a diabetes, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 36  to a human. 
     
     
         50 . A method for the treatment of a type II diabetes, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 36  to a human. 
     
     
         51 . A method for the treatment of a 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, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 36  to a human. 
     
     
         52 . A method for the treatment of an inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease or hyperuricemia, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 36  to a human. 
     
     
         53 . A method for the treatment of an 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, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 36  to a human. 
     
     
         54 . A method for the treatment of a diabetes, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 40  to a human. 
     
     
         55 . A method for the treatment of a type II diabetes, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 40  to a human. 
     
     
         56 . A method for the treatment of a 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, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 40  to a human. 
     
     
         57 . A method for the treatment of an inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease or hyperuricemia, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 40  to a human. 
     
     
         58 . A method for the treatment of an 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, comprising administering a pharmacologically effective amount of the calcium salt according to  claim 40  to a human. 
     
     
         59 . A method for the treatment of a diabetes, comprising administering a pharmacologically effective amount of the calcium salt hydrate according to  claim 43  to a human. 
     
     
         60 . A method for the treatment of a type II diabetes, comprising administering a pharmacologically effective amount of the calcium salt hydrate according to  claim 43  to a human. 
     
     
         61 . A method for the treatment of a 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, comprising administering a pharmacologically effective amount of the calcium salt hydrate according to  claim 43  to a human. 
     
     
         62 . A method for the treatment of an inflammatory disease, cancer, osteoporosis, involutional osteoporosis, neurodegenerative disease, Alzheimer's disease or hyperuricemia, comprising administering a pharmacologically effective amount of the calcium salt hydrate according to  claim 43  to a human. 
     
     
         63 . A method for the treatment of an 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, comprising administering a pharmacologically effective amount of the calcium salt hydrate according to  claim 43  to a human.