Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments

Abstract

Carboxyalkoxy-substituted acyl-carboxyphenylurea derivatives and their use as medicaments The invention relates to acyl-carboxyphenylurea derivatives and to their physiologically tolerated salts and physiologically functional derivatives. Compounds of the formula I, in which the radicals have the stated meanings, and the physiological tolerated salts thereof and processes for preparing them are described. The compounds are suitable for example for the treatment of type II diabetes.

1 . A compound of the formula I,  
       
         
           
           
               
               
           
         
       
       in which 
 R1 is H, (C 1 -C 6 )-alkyl or (C 0 -C 6 )-alkyl-phenyl wherein the phenyl ring is optionally mono- or disubstituted with F, Cl, Br, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 -C 6 )-alkyl or CONH 2 ;  
 R2 is H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, COO—(C 1 -C 6 )-alkyl or (C 0 -C 6 )-alkylene-COOH;  
 R3 is H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl; and  
 n is 1, 2, 3, 4, 5, 6, 7 or 8;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1  wherein 
 R1 is H or (C 1 -C 6 )-alkyl;  
 R2 is H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, COO—(C 1 -C 6 )-alkyl or (C 0 -C 6 )-alkylene-COOH;  
 R3 is H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkyl; and  
 n is 1, 2, 3, 4, 5, 6, 7 or 8;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The compound of  claim 2 , wherein 
 R1 is H or (C 1 -C 6 )-alkyl;    R2 is H, COO—(C 1 -C6)-alkyl or —COOH;    R3 is H or F; and    n is 1, 2, 3 or 4;    and pharmaceutically acceptable salts thereof.    
     
     
         4 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds of  claim 1 .  
     
     
         5 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, one or more compounds of  claim 1 , and at least one other active ingredient.  
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the other active ingredient comprises one or more antidiabetics, hypoglycemic active ingredients, antiobesics, anorexia, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, cholesterol absorption inhibitors (ezetimibe), ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, ACC inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, glitinides, thiazolidinediones, α-glucosidase inhibitors, glucagon-receptor antagonists, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, GLP1 agonists, GIP agonists, MC4 agonists, MCH antagonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 is agonists, MSH (melanocyte-stimulating hormone) 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, LXR modulators, FXR modulators, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β agonists or amphetamines.  
     
     
         7 . A method of reducing blood glucose comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         8 . A method of treating type II diabetes comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         9 . A method of treating disturbances of lipid and carbohydrate metabolism comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         10 . A method of treating symptoms associated with arteriosclerosis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         11 . A method of treating insulin resistance comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         12 . A process for producing a pharmaceutical composition comprising one or more of the compounds of  claim 1  comprising mixing said compound of  claim 1  with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration.  
     
     
         13 . A method of treating or preventing acute and chronic damage and disorders of the heart, peripheral organs and limbs which are caused by ischemic events or by reperfusion events comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         14 . A method of treating or preventing diseases caused by ischemic states comprising administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         15 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment or prophylaxis of acute and chronic damage and disorders of the heart which are caused by ischemic events or by reperfusion events, and for the treatment or prevention of myocardial infarction.  
     
     
         16 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment or prophylaxis of angina pectoris.  
     
     
         17 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment or prophylaxis of ischemic states of the heart.  
     
     
         18 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment or prevention of ischemic states of the peripheral and central nervous system and of stroke.  
     
     
         19 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment or prevention of ischemic states of the peripheral organs and limbs.  
     
     
         20 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment of oncosis.  
     
     
         21 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment of oncosis in which the tumor growth is dependent on glycogen phosphorylase activity.  
     
     
         22 . The use of a compound of  claim 1  for producing a pharmaceutical composition for the treatment of cancer of the lung, breast and bowel.