Pyrimido[5,4-e][1,2,4]triazine-5,7-diones, processes for preparing them and their use

Abstract

The invention relates to pyrimido[5,4-e][1,2,4]triazine-5,7-diones, pharmaceutically acceptable salts thereof and physiologically functional derivatives. The invention therefore relates to compounds of the formula I, in which the radicals have the given meanings, and to their physiologically tolerated salts and processes for preparing them. The compounds are suitable for use as antidiabetics, for example.

We claim:  
     
         1 . A compound of formula I,  
       
         
           
           
               
               
           
         
       
       wherein 
 R1, R3 and R4 are each independently H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 10 )-alkyl, O—(C 1 -C 10 )-alkenyl, O—(C 2 -C 10 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl, 
 wherein said (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 10 )-alkyl, O—(C 1 -C 10 )-alkenyl, O—(C 2 -C 10 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl radicals are optionally substituted with one or more groups independently selected from F, Cl, Br, SO-phenyl, SO 2 -phenyl or phenyl, 
 wherein said SO-phenyl, SO 2 -phenyl or phenyl radicals is optionally substituted with F, Cl, Br, R13 or OR13,  
 
 COOR13, CON(R14)(R15), N(R14)(R15), CO-heteroalkyl, O—SO—(C 1 -C 6 )-alkyl, O—SO 2 —(C 1 -C 6 )-alkyl, O—SO 2 —(C 6 -C 10 )-aryl, O—(C 6 -C 10 )-aryl, 
 wherein said O—SO 2 —(C 6 -C 10 )-aryl and O—(C 6 -C 10 )-aryl radicals is optionally mono- or disubstituted with F, Cl, CN, OR13, R13, CF 3  or OCF 3 ,  
 
 SO—(C 1 -C 6 )-al kyl, SO 2 —(C 1 -C 6 )-al kyl, SO 2 —(C 6 -C 10 )-aryl, 
 wherein said SO 2 —(C 6 -C 10 )-aryl radical is optionally mono- or disubstituted with F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R15),  
 
 SO 2 —N(R14)(R15) or heteroalkyl;  
 
 R13, R14 and R15, are each independently H, (C 1 -C 6 )-alkyl or phenyl;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1  wherein: 
 R1 is H or (C 1 -C 6 )-alkyl;  
 R1, R3 and R4 are each independently H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 10 )-alkyl, O—(C 1 -C 10 )-alkenyl, O—(C 2 -C 10 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl, 
 wherein said (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, O—(C 1 -C 10 )-alkyl, O—(C 1 -C 10 )-alkenyl, O—(C 2 -C 10 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl and (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl radicals are optionally substituted with one or more groups independently selected from F, Cl, Br, SO-phenyl, SO 2 -phenyl or phenyl, 
 wherein said SO-phenyl, SO 2 -phenyl or phenyl radicals is optionally substituted with F, Cl, Br, R13 or OR13,  
 
 COOR13, CON(R14)(R15), N(R14)(R15), CO-heteroalkyl, O—SO—(C 1 -C 6 )-alkyl, O—SO 2 —(C 1 -C 6 )-alkyl, O—SO 2 —(C 6 -C 10 )-aryl, O—(C 6 -C 10 )-aryl, 
 wherein said O—SO 2 —(C 6 -C 10 )-aryl and O—(C 6 -C 10 )-aryl radicals is optionally mono- or disubstituted with F, Cl, CN, OR13, R13, CF 3  or OCF 3 ,  
 
 SO—(C 1 -C 6 )-al kyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —(C 6 -C 10 )-aryl, 
 wherein said SO 2 —(C 6 -C 10 )-aryl radical is optionally mono- or disubstituted with F, Cl, Br, CN, OR13, R13, CF 3 , OCF 3 , COOR13 or CON(R14)(R15),  
 
 SO 2 —N(R14)(R15) or heteroalkyl;  
 
 R13, R14 and R15 are, independently of each other, H, (C 1 -C 6 )-alkyl or phenyl;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The compound of  claim 2  wherein: 
 R1 is (C 1 -C 6 )-alkyl;  
 R3 is (C 1 -C 6 )-alkyl-phenyl or (C 2 -C 6 )-alkenyl-phenyl, wherein the phenyl ring of said (C 1 -C 6 )-alkyl-phenyl and (C 2 -C 6 )-alkenyl-phenyl groups is optionally substituted by F, Cl, Br, OR13 or R13;  
 R4 is (C 1 -C 6 )-alkyl or (C 1 -C 6 )-alkylene-D;  
 R13 is (C 1 -C 6 )-alkyl or phenyl;  
 and pharmaceutically acceptable salts thereof.  
 
     
     
         4 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         5 . A pharmaceutical composition comprising the composition of  claim 4  and at least one additional active compound.  
     
     
         6 . The pharmaceutical composition of  claim 5  wherein said additional active compound is selected from one or more of the following classes: antidiabetics, hypoglycaemic active compounds, HMGCOA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid absorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active compounds acting on the ATP-dependent potassium channel in beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 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, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (Bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists or amphetamines.  
     
     
         7 . A method of lowering blood sugar which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         8 . A method of treating type 2 diabetes which comprises 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 which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         10 . A method of treating arteriosclerotic symptoms which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1 .  
     
     
         11 . A method of treating insulin resistance which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of  claim 1.