Phenylamino-benzoxazole substituted carboxylic acids, method for their production and use thereof as medicaments

Abstract

This invention relates to a compound of formula I, wherein R1, R2, R6, R7, R8, R9, R10, m and X are as defined herein, or a physiologically tolerated salt thereof, its pharmaceutical composition and use for lowering blood glucose, treating diabetes, or increasing insulin release.

1 . A compound of formula I, 
     
       
         
         
             
             
         
       
       wherein: 
       R1 is H or (C 1 -C 6 )-alkyl; 
       R6, R7, R8, R9 and R10 are, independently of one another, H, F, Cl, Br, CN, CF 3 , OH, OCF 3 , OCHF 2 , SCH 3 , SCF 3 , phenyl, O-phenyl, COOH, COO—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, OBn, SO 3 H, SO 2 NR3R4, NR3R4 or SO 2 —N-piperidinyl, wherein the alkyl and phenyl moieties are optionally substituted one or more times by R2, or 
       two of the radicals R6, R7, R8, R9 and R10, in adjacent position on the phenyl ring may together form a radical —O—CH 2 —O—, —O—(CH 2 ) 2 —O— or —CH═CH—CH═CH—; 
       m is 0, 1, 2 or 3; 
       X is bond, (C 2 -C 10 )-alkylene, (C 3 -C 12 )-cycloalkyl, (C 1 -C 8 )-alkylene-(C 3 -C 12 )-cycloalkyl-(C 1 -C 8 )-alkylene, (C 1 -C 8 )-alkylene-(C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyl-(C 1 -C 8 )-alkylene, (C 2 -C 8 )-alkenylene-(C 3 -C 12 )-cycloalkyl-(C 1 -C 8 )-alkylene, (C 1 -C 8 )-alkylene-(C 3 -C 12 )-cycloalkyl-(C 2 -C 8 )-alkenylene, (C 2 -C 8 )-alkenylene-(C 3 -C 12 )-cycloalkyl, (C 3 -C 12 )-cycloalkyl-(C 2 -C 8 )-alkenylene, (C 2 -C 10 )-alkenylene or (C 2 -C 10 )-alkynylene, wherein the alkylene, cycloalkyl, alkenylene and alkynylene moieties are optionally substituted one or more times by R5; 
       R2 is OH, F, Cl, Br, CN, OCH 3 , OCF 3 , CH 3 , CF 3 , (C 1 -C 6 )-alkyl or O—(C 1 -C 6 )-alkyl, wherein the alkyl moiety is optionally substituted one or more times by OH, F, Cl, Br or CN; 
       R3 and R4 are, independently of one another, H or (C 1 -C 6 )-alkyl, wherein the alkyl is optionally substituted one or more times by OH, F, Cl or Br; and 
       R5 is NH 2 , NH(C 1 -C 4 )-alkyl, N[(C 1 -C 4 )-alkyl] 2 , F, Cl, Br, CN, OH, O—(C 1 -C 6 )-alkyl, (C 1-6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 2 -C 6 )-alkynyl; 
       or a physiologically tolerated salt thereof. 
     
   
   
       2 . The compound according to  claim 1 , wherein:
 R6, R7, R8, R9 and R10 are, independently of one another, H, F, Cl, Br, CF 3 , OCH 3 , OCF 3 , OCHF 2 , SCH 3 , SCF 3 , phenyl, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl or NR3R4, wherein the alkyl and phenyl moieties are optionally substituted one or more times by R2, or   two of the radicals R6, R7, R8, R9 and R10 in adjacent position on the phenyl ring may together form a radical —CH═CH—CH═CH—;   X is (C 2 -C 10 )-alkylene, which is optionally substituted one or more times by R5;   R2 is F, Cl, Br, CN, OCH 3 , OCF 3 , CH 3 , CF 3 , (C 1 -C 6 )-alkyl or O—(C 1 -C 6 )-alkyl, wherein the alkyl moiety is optionally substituted one or more times by OH, F, Cl, Br or CN; and   R3 and R4 are, independently of one another, H or (C 1 -C 6 )-alkyl;   or a physiologically tolerated salt thereof.   
   
   
       3 . The compound according to  claim 1 , wherein:
 R1 is H;   R6, R7, R8, R9 and R10 are, independently of one another, H, F, Cl, Br, CF 3 , OCH 3 , OCF 3 , OCHF 2 , SCH 3 , SCF 3 , phenyl, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl or NR3R4, wherein the alkyl and phenyl moieties are optionally substituted one or more times by R2, or   two of the radicals R6, R7, R8, R9 and R10 in adjacent position on the phenyl ring may together form a radical —CH═CH—CH═CH—;   X is —(CH 2 ) 2 —;   R2 is F, Cl, Br, CN, OCH 3 , OCF 3 , CH 3 , CF 3 , (C 1 -C 6 )-alkyl or O—(C 1 -C 6 )-alkyl, wherein the alkyl moiety is optionally substituted one or more times by OH, F, Cl, Br or CN; and   R3 and R4 are, independently of one another, H or (C 1 -C 6 )-alkyl;   or a physiologically tolerated salt thereof.   
   
   
       4 . A pharmaceutical composition comprising the compound according to  claim 1  or a physiologically tolerated salt thereof, in combination with a pharmaceutically acceptable excipient. 
   
   
       5 . A pharmaceutical composition comprising the compound according to  claim 2  or a physiologically tolerated salt thereof, in combination with a pharmaceutically acceptable excipient. 
   
   
       6 . A pharmaceutical composition comprising the compound according to  claim 3  or a physiologically tolerated salt thereof, in combination with a pharmaceutically acceptable excipient. 
   
   
       7 . The pharmaceutical composition according to  claim 4 , further comprising at least one additional active ingredient. 
   
   
       8 . The pharmaceutical composition according to  claim 5 , further comprising at least one additional active ingredient. 
   
   
       9 . The pharmaceutical composition according to  claim 6 , further comprising at least one additional active ingredient. 
   
   
       10 . The pharmaceutical composition according to  claim 7 , wherein the additional active ingredient is selected from the group consisting of antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose-1,6-bisphosphatase, modulators of glucose transporter 4, inhibitors of glutamine-fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of the sodium-dependent glucose transporter 1 or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists and amphetamines. 
   
   
       11 . The pharmaceutical composition according to  claim 8 , wherein the additional active ingredient is selected from the group consisting of antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose-1,6-bisphosphatase, modulators of glucose transporter 4, inhibitors of glutamine-fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of the sodium-dependent glucose transporter 1 or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists and amphetamines. 
   
   
       12 . The pharmaceutical composition according to  claim 9 , wherein the additional active ingredient is selected from the group consisting of antidiabetics, hypoglycemic active ingredients, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha and gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein (a) antagonists, HM74A receptor agonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, glycogen phosphorylase inhibitors, glucagon receptor antagonists, activators of glucokinase, inhibitors of gluconeogenesis, inhibitors of fructose-1,6-bisphosphatase, modulators of glucose transporter 4, inhibitors of glutamine-fructose-6-phosphate amidotransferase, inhibitors of dipeptidylpeptidase IV, inhibitors of 11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosine phosphatase 1B, modulators of the sodium-dependent glucose transporter 1 or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoA carboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta, endothelin-A receptor antagonists, inhibitors of I kappaB kinase, modulators of the glucocorticoid receptor, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptor antagonists, MSH agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists, lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists and amphetamines. 
   
   
       13 . A method for lowering blood glucose, treating diabetes, or increasing insulin release, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 1 , or a physiologically tolerated salt thereof. 
   
   
       14 . A method for lowering blood glucose, treating diabetes, or increasing insulin release, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 2 , or a physiologically tolerated salt thereof. 
   
   
       15 . A method for lowering blood glucose, treating diabetes, or increasing insulin release, in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of the compound according to  claim 3 , or a physiologically tolerated salt thereof. 
   
   
       16 . A process for manufacturing a pharmaceutical composition comprising the compound according to  claim 1  or a physiologically tolerated salt thereof, in combination with a pharmaceutically acceptable excipient, which comprises mixing the compound according to  claim 1  or the physiologically tolerated salt thereof, with the pharmaceutically acceptable excipient, and converting this mixture into a form suitable for administration. 
   
   
       17 . A process for manufacturing a pharmaceutical composition comprising the compound according to  claim 2  or a physiologically tolerated salt thereof, in combination with a pharmaceutically acceptable excipient, which comprises mixing the compound according to  claim 2  or the physiologically tolerated salt thereof, with the pharmaceutically acceptable excipient, and converting this mixture into a form suitable for administration. 
   
   
       18 . A process for manufacturing a pharmaceutical composition comprising the compound according to  claim 3  or a physiologically tolerated salt thereof, in combination with a pharmaceutically acceptable excipient, which comprises mixing the compound according to  claim 3  or the physiologically tolerated salt thereof, with the pharmaceutically acceptable excipient, and converting this mixture into a form suitable for administration.