Carboxamide-substituted phenylurea derivatives, process for their preparation and their use as medicaments

Abstract

The invention relates to carboxamide-substituted phenylurea derivatives and their physiologically tolerated salts and physiologically functional derivatives. Compounds of the formula I in which the radicals have the stated meanings, and the physiologically tolerated salts thereof and process for their preparation are described. The compounds are suitable, for example, for treating type II diabetes.

1 . A compound of the formula I,  
       
         
           
           
               
               
           
         
       
       in which 
 A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, (C 0 -C 6 )-alkylene-COOH, (C 0 -C 6 )-alkylene-COO—(C 1 -C 7 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 2 -C 7 )-alkenyl, CONH 2 , CONH—(C 1 -C 6 )-alkyl, CON—[(C 1 -C 6 )-alkyl] 2 , CONH—(C 3 -C 6 )-cycloalkyl, (C 0 -C 6 )-alkylene-NH 2 , (C 0 -C 6 )-alkylene-NH—(C 2 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, and NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CONH 2 ;  
 R1, R2 are, independently of one another, H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, or COO—(C 1 -C 6 )-alkyl;  
 R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , CO—NH—(C 1 -C 6 )-alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CO—NH—(C 3 -C 7 )-cycloalkyl, NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, or NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CO—NH 2 ;  
 R7 is H, (C 1 -C 6 )-alkyl, or CO(C 1 -C 6 )-alkyl;  
 R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl and NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )— aryl; or  
  (CH 2 ) m -aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;  
 R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl;  
 or a physiologically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.  
 
     
     
         2 . The compound as claimed in  claim 1 , in which 
 A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;    R1, R2 are H;    R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO 2 , O—(C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;    R7 is H, or CH 3 ;    R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl or NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl; or     (CH2)m-aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;    R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl;    or a pharmaceutically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.    
     
     
         3 . The compound as claimed in  claim 1 , in which 
 A is phenyl, where the phenyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, and Br;    R1, R2 are H;    R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, NO 2 , O—(C 1 -C 6 )-alkyl, or (C 1 -C 6 )-alkyl;    R7 is H, or CH 3 ;    R8 is (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl or NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )-aryl; or     (CH 2 ) m -aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;    R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl;    or a pharmaceutically tolerable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio.    
     
     
         4 . A medicament, comprising at least one compound as claimed  claim 1  and at least one pharmaceutically acceptable carrier.  
     
     
         5 . A medicament, comprising at least one compound as claimed  claim 1 , at least one additional blood glucose-lowering active ingredient, and at least one pharmaceutically acceptable carrier.  
     
     
         6 . A method for treating type II diabetes comprising, administering to a patient in need thereof at least one compound as claimed  claim 1  and at least one additional blood glucose-lowering active ingredients.  
     
     
         7 . The method of treating type II diabetes of  claim 6 , wherein the at least, one compound as claimed  claim 1  and the at least one additional blood glucose-lowering active ingredients are administered sequentially.  
     
     
         8 . A method for lowering blood glucose comprising, administering to a patient in need thereof at least one compound as claimed  claim 1  and at least one additional blood glucose-lowering active ingredients.  
     
     
         9 . The method for lowering blood glucose of  claim 8 , wherein the at least one compound as claimed  claim 1  and the at least one additional blood glucose-lowering active ingredients are administered sequentially.  
     
     
         10 . A process for producing a medicament comprising at least one compound as claimed  claim 1 , which comprises mixing the at least one compound as claimed  claim 1  with a pharmaceutically-suitable carrier and converting this mixture into a form suitable for administration.  
     
     
         11 . A method of lowering blood glucose comprising administering to a patient in need thereof at least one compound chosen from compounds of the formula I,  
       
         
           
           
               
               
           
         
       
       in which 
 A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, (C 0 -C 6 )-alkylene-COOH, (C 0 -C 6 )-alkylene-COO—(C 1 -C 7 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 2 -C 7 )-alkenyl, CONH 2 , CONH—(C 1 -C 6 )-alkyl, CON—[(C 1 -C 6 )-alkyl] 2 , CONH—(C 3 -C 6 )-cycloalkyl, (C 0 -C 6 )-alkylene-NH 2 , (C 0 -C 6 )-alkylene-NH—(C 2 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, and NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CONH 2 ;  
 R1, R2 are, independently of one another, H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, or COO—(C 1 -C 6 )-alkyl;  
 R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkyl-(C 1 -C 4 )-alkylene, COOH, COO—(C 1 -C 6 )alkyl, CO—NH 2 , CO—NH—(C 1 -C 6 )-alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CO—NH—(C 3 -C 7 )cycloalkyl, NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, or NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CO—NH 2 ;  
 R7 is H, (C 1 -C 6 )-alkyl, or CO(C 1 -C 6 )-alkyl;  
 R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl and NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )— aryl; or  
  (CH 2 ) m -aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;  
 R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl;  
 and physiologically tolerable salts thereof, in any stereoisomeric form, and any mixture of any such compounds in any ratio.  
 
     
     
         12 . A method for treating type II diabetes comprising administering to a patient in need thereof at least one compound chosen from compounds of the formula I,  
       
         
           
           
               
               
           
         
       
       in which 
 A is phenyl or naphthyl, where the phenyl or naphthyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, (C 0 -C 6 )-alkylene-COOH, (C 0 -C 6 )-alkylene-COO—(C 1 -C 7 )-alkyl, (C 0 -C 6 )-alkylene-COO—(C 2 -C 7 )-alkenyl, CONH 2 , CONH—(C 1 -C 6 )-alkyl, CON—[(C 1 -C 6 )-alkyl] 2 , CONH—(C 3 -C 6 )-cycloalkyl, (C 0 -C 6 )-alkylene-NH 2 , (C 0 -C 6 )-alkylene-NH—(C 2 -C 6 )-alkyl, (C 0 -C 6 )-alkylene-N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, and NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO—(C 1 -C 6 )-alkyl and CONH 2 ;  
 R1, R2 are, independently of one another, H, (C 1 -C 6 )-alkyl, O—(C 1 -C 6 )-alkyl, CO—(C 1 -C 6 )-alkyl, or COO—(C 1 -C 6 )-alkyl;  
 R3, R4, R5, R6 are, independently of one another, H, F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF 3 , O—(C 1 -C 6 )-alkyl, O—(C 2 -C 6 )-alkenyl, O—(C 2 -C 6 )-alkynyl, S—(C 1 -C 6 )-alkyl, S—(C 2 -C 6 )-alkenyl, S—(C 2 -C 6 )-alkynyl, SO—(C 1 -C 6 )-alkyl, SO 2 —(C 1 -C 6 )-alkyl, SO 2 —NH 2 , (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 2 -C 6 )-alkynyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkylene, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , CO—NH—(C 1 -C 6 )alkyl, CO—N—[(C 1 -C 6 )-alkyl] 2 , CO—NH—(C 3 -C 7 )cycloalkyl, NH 2 , NH—(C 1 -C 6 )alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NH—CO—(C 1 -C 6 )-alkyl, NH—CO-phenyl, or NH—SO 2 -phenyl, wherein the phenyl of NH—CO-phenyl and NH—SO 2 -phenyl is unsubstituted or substituted 1 or 2 times wherein each substituent is independently chosen from F, Cl, CN, OH, (C1-C6)-alkyl, O—(C1-C 6 )-alkyl, CF 3 , OCF 3 , COOH, COO(C 1 -C 6 )-alkyl and CO—NH 2 ;  
 R7 is H, (C 1 -C 6 )-alkyl, or CO(C 1 -C 6 )-alkyl;  
 R8 is H, (C 1 -C 10 )-alkyl, where the alkyl is unsubstituted or substituted 1, 2, or 3 times wherein each substituent is independently chosen from OH, CF 3 , CN, COOH, COO—(C 1 -C 6 )-alkyl, CO—NH 2 , NH 2 , NH—(C 1 -C 6 )-alkyl, N—[(C 1 -C 6 )-alkyl] 2 , NCO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkyl, NCOO—(C 1 -C 6 )-alkenyl, NCOO—(C 1 -C 6 )-alkynyl and NCOO—(C 1 -C 4 )-alkylene-(C 6 -C 10 )—aryl; or  
  (CH 2 ) m -aryl, where m ranges from 0-6, and aryl is phenyl, O-phenyl, CO-phenyl, benzo[1,3]dioxolyl, heterocycloalkyl, pyridyl, indolyl, piperidinyl, tetrahydronaphthyl, naphthyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,5]thiadiazolyl, pyrrolidinyl, or morpholinyl, where the aryl is unsubstituted or substituted by at least one R9;  
 R9 is F, Cl, Br; OH, NO 2 , CF 3 , OCF 3 , (C 1 -C 6 )-alkyl, (C 1 -C 6 )-alkyl-OH, O—(C 1 -C 6 )-alkyl, S—(C 1 -C 6 )-alkyl, (C 1 -C 4 )-alkylphenyl, COOH, or COO—(C 1 -C 6 )-alkyl;  
 and physiologically tolerable salts thereof, in any stereoisomeric form, and any mixture of any such compounds in any ratio.