Prodrugs of imidazopyridine derivatives

Abstract

Compounds of formula (1), in which the substituents have the meanings mentioned in the description are suitable for the prevention and treatment of gastrointestinal diseases.

1 . A compound of the formula 1 
       
         
           
           
               
               
           
         
       
       in which 
 R1 is hydrogen, 1-4C-alkyl or hydroxy-1-4C-alkyl,  
 R2 is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl, halogen, 2-4C-alkenyl or 2-4C-alkynyl,  
 R3 is hydrogen, halogen, trifluoromethyl, 1-4C-alkyl, 2-4C-alkenyl, 2-4C-alkynyl, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3aR3b,  
 one of the substitutents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy,  1-4 C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy or the radical R4′, or in which R4a and R4b together are O (oxygen), 
 where R4′ is a radical from which a hydroxyl group is formed under physiological conditions,  
 
 one of the substitutents R5a and R5b is hydrogen and the other is hydrogen, hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy, 1-4C-alkylcarbonyloxy or the radical R5′, or in which R5a and R5b together are O (oxygen), 
 where R5′ is a radical from which a hydroxyl group is formed under physiological conditions,  
 where  
 
 one of the substituents R4a and R4b must have the meaning R4′ and/or one of the substituents R5a and R5b must have the meaning R5′,  
 R6 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl,  
 R7 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy and  
 X is O (oxygen) or NH,  
 where 
 R3a is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  
 R3b is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,  
 or where  
 R3a and R3b together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino or morpholino radical,  
 or its salts.  
 
 
     
     
         2 . A compound of the formula 1 as claimed in  claim 1 , in which 
 R1 is 1-4C-alkyl,    R2 is 1-4C-alkyl or hydroxy-1-4C-alkyl,    R3 is hydrogen, halogen, carboxyl, —CO-1-4C-alkoxy, hydroxy-1-4C-alkyl, 1-4C-alkoxy-1-4C-alkyl, fluoro-1-4C-alkoxy-1-4C-alkyl or the radical —CO—NR3aR3b,    one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R4a and R4b together are O (oxygen),    one of the substituents R5a and R5b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R5a and R5b together are O (oxygen),    where one of the substituents R4a and R4b must have the meaning —OR′ and/or one of the substituents R5a and R5b must have the meaning —OR′,    R6 is hydrogen, halogen, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl,    R7 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy and    X is O (oxygen) or NH,    where 
 R3a is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  
 R3b is hydrogen, 1-7C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,  
 or where  
 R3a and R3b together, including the nitrogen atom to which both are bonded, are a pyrrolidino, piperidino or morpholino radical,  
 and where  
 R′ is selected from the group consisting of 
 —C(O)—NR8R9,  
 —C(O)-alk-NR8R9,  
 —C(O)-alk-C(O)—N R8R9,  
 —P(O)(OH) 2 ,  
 —S(O) 2 NR8R9,  
 —C(O)—R8,  
 —C(O)—C 6 H 3 R10R11,  
 —C(O)—OR8,  
 —C(O)-alk-C(O)—R8,  
 —C(O)-alk-C(O)—OR8,  
 —C(O)—C(O)—R8,  
 —C(O)—C(O)—OR8 and  
 —CH 2 —OR8,  
 where 
 alk is 1-7C-alkylene,  
 R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by halogen, carboxyl, hydroxyl, sulfo (—SO 3 H), sulfamoyl (—SO 2 NH 2 ), carbamoyl (—CONH 2 ), 1-4C-alkoxy or 1-4C-alkoxycarbonyl,  
 R9 is hydrogen or 1-4C-alkyl,  
 R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl und  
 R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy.  
 or its salts.  
 
 
   
     
     
         3 . A compound as claimed in  claim 1 , having the formula 1*  
       
         
           
           
               
               
           
         
       
       in which 
 R1 is 1-4C-alkyl,  
 R2 is 1-4C-alkyl,  
 R3 is hydrogen, chlorine, fluorine, hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b,  
 one of the substituents R4a and R4b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R4a and R4b together are O (oxygen),  
 one of the substituents R5a and R5b is hydrogen and the other is hydroxyl, 1-4C-alkoxy, 1-4C-alkoxy-1-4C-alkoxy or the radical —OR′, or in which R5a and R5b together are O (oxygen),  
 where one of the substituents R4a and R4b must have the meaning —OR′ and/or one of the substituents R5a and R5b must have the meaning —OR′,  
 R6 is hydrogen,  
 R7 is hydrogen and  
 X is O (oxygen) or NH,  
 where 
 R3a is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl and  
 R3b is hydrogen, 1-4C-alkyl, hydroxy-1-4C-alkyl or 1-4C-alkoxy-1-4C-alkyl,  
 and where  
 R′ is selected from the group consisting of 
 —C(O)—NR8R9,  
 —C(O)-alk-NR8R9,  
 —C(O)-alk-C(O)—NR8R9,  
 —P(O)(OH) 2 ,  
 —S(O) 2 NR8R9,  
 —C(O)—R8,  
 —C(O)—C 6 H 3 R10R11,  
 —C(O)—OR8 ,  
 —C(O)-alk-C(O)—OR8,  
 —C(O)—C(O)—OR8 and  
 —CH 2 —OR8,  
 where 
 alk is 1-7C-alkylene,  
 R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by carboxyl or sulfo (—SO 3 H),  
 R9 is hydrogen or 1-4C-alkyl,  
 R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkoxycarbonylamino, 1-4C-alkoxy-1-4C-alkoxycarbonylamino or trifluoromethyl and  
 R11 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,  
 or its salts of the compounds.  
 
 
 
 
     
     
         4 . A compound as claimed in  claim 1 , which has the formula 1* in  claim 3 , in which 
 R1 is methyl,    R2 is methyl,    R3 is hydrogen, chlorine, fluorine, hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b,    one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,    one of the substituents R5a and R5b is hydrogen and the other is the radical —OR′,    R6 is hydrogen,    R7 is hydrogen and    X is O (oxygen) or NH,    where 
 R3a is hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 2-methoxyethyl and  
 R3b is hydrogen, methyl or ethyl,  
 and where  
 R′ is selected from the group consisting of 
 —C(O)—NR8R9,  
 —C(O)-alk-NR8R9,  
 —C(O)-alk-C(O)—NR8R9,  
 —P(O)(OH) 2 ,  
 —S(O) 2 NR8R9,  
 —C(O)—R8,  
 —C(O)—C 6 H 3 R10R11,  
 —C(O)—OR8,  
 —C(O)-alk-C(O)—OR8,  
 —C(O)—C(O)—OR8 and  
 —CH 2 —OR8,  
 where 
 alk is 1-7C-alkylene,  
 R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by carboxyl or sulfo (— 3 H),  
 R9 is hydrogen or 1-4C-alkyl,  
 R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or trifluoromethyl and  
 R11 is hydrogen or halogen,  
 or the salts of the compound.  
 
 
   
     
     
         5 . A compound as claimed in  claim 4 , in which R′ has the meaning —C(O)—N(CH 3 ) 2 , —C(O)—N(C 2 H 5 ) 2 , —C(O)—NHC 2 H 5 , —C(O)—CH 2 CH 2 NH 2 , —C(O)—(CH 2 ) 3 NH 2 , —C(O)—C(CH 3 ) 2 NH 2 , —C(O)—CH 2 N(CH 3 ) 2 , —C(O)—CH(NH 2 )—CH(CH 3 ) 2 , —C(O)—CH(NH 2 )CH(CH 3 )C 2 H 5 , —C(O)—(CH 2 ) 6 C(O)N(CH 3 )CH 2 CH 2 SO 3 H, —P(O)(OH) 2 , —S(O) 2 NH 2 , —C(O)—H, —C(O)—C(CH 3 ) 3 , —C(O)—CH 2 CH 2 COOH, —C(O)—CH 3 , —C(O)—C 2 H 5 , —C(O)—CH 2 OCH 3 , —C(O)—C 6 H 5 , —C(O)—C 6 H 4 —4—NO 2 , —C(O)—C 6 H 4 —3—NO 2 , —C(O)—C 6 H 4 —4—OCH 3 , —C(O)—C 6 H 4 —4—C(O)—OCH 3 , —C(O)—OCH 3 , —C(O)—O-menthyl, —C(O)—CH 2 —C(O)—OCH 3 , —C(O)—CH 2 CH 2 —C(O)—OCH 3 , —C(O)—C(O)—OCH 3 , —C(O)—C(O)—OC 2 H 5  or —CH 2 O CH(CH 3 ) 2 .  
     
     
         6 . A compound as claimed in  claim 1 , which has the formula 1* in  claim 3 , in which 
 R1 is methyl,    R2 is methyl,    R3 is hydrogen, chlorine, fluorine, hydroxymethyl, difluoromethoxymethyl or the radical —CO—NR3aR3b,    one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,    R5a is the radical —OR′,    R5b is hydrogen,    R6 is hydrogen,    R7 is hydrogen and    X is O (oxygen) or NH,    where 
 R3a is hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl or 2-methoxyethyl and  
 R3b is hydrogen, methyl or ethyl,  
 and where  
 R′ is selected from the group consisting of 
 —C(O)—NR8R9,  
 —C(O)-alk-NR8R9,  
 —C(O)—R8  
 —C(O)—C 6 H 3 R10R11,  
 —C(O)—OR8,  
 —C(O)-alk-C(O)—OR8, and  
 —C(O)—C(O)—OR8,  
 where 
 alk is 1-4C-alkylene,  
 R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by 1-4C-alkoxy,  
 R9 is hydrogen or 1-4C-alkyl,  
 R10 is hydrogen, halogen, nitro, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or trifluoromethyl and  
 R11 is hydrogen or halogen,  
 or its salts.  
 
 
   
     
     
         7 . A compound as claimed in  claim 1 , which has the formula 1* in  claim 3 , in which 
 R1 is methyl,    R2 is methyl,    R3 is hydrogen,    one of the substituents R4a and R4b is hydrogen and the other is 1-4C-alkoxy or 1-4C-alkoxy-1-4C-alkoxy,    R5a is the radical —OR′,    R5b is hydrogen,    R6 is hydrogen,    R7 is hydrogen and    X is O (oxygen) or NH,    where 
 R′ is selected from the group consisting of 
 —C(O)—NR8R9,  
 —C(O)-alk-NR8R9,  
 —C(O)—R8  
 —C(O)—C 6 H 3 R10R11,  
 —C(O)—OR8,  
 —C(O)-alk-C(O)—OR8, and  
 —C(O)—C(O)—OR8,  
 where 
 alk is 1-4C-alkylene,  
 R8 is hydrogen, 1-10C-alkyl or 1-4C-alkyl substituted by 1-4C-alkoxy,  
 R9 is hydrogen or 1-4C-alkyl,  
 R10 is hydrogen, nitro, 1-4C-alkoxy or 1-4C-alkoxycarbonyl and  
 R11 is hydrogen,  
 or its salts.  
 
 
   
     
     
         8 . A compound as claimed in  claim 7 , in which R′ has the meaning —C(O)—N(CH 3 ) 2 , —C(O)—N(C 2 H 5 ) 2 , —C(O)—NHC 2 H 5 , —C(O)—CH 2 N(CH 3 ) 2 , —C(O)—H, —C(O)—CH 3 , —C(O)—C 2 H 5 , —C(O)—CH 2 OCH 3 , —C(O)—C 6 H 5 , —C(O)—C 6 H 4 —4—NO 2 , —C(O)—C 6 H 4 —3—NO 2 , —C(O)—C 6 H 4 —4—OCH 3 , —C(O)—C 6 H 4 —4—C(O)—OCH 3 , —C(O)—OCH 3 , —C(O)—O-menthyl, —C(O)—CH 2 —C(O)—OCH 3 , —C(O)—CH 2 CH 2 —C(O)—OCH 3 , —C(O)—C(O)—OCH 3  or —C(O)—C(O)—OC 2 H 5 .  
     
     
         9 . A medicament comprising a compound as claimed in  claim 1  and/or a pharmacologically tolerable salt thereof together with customary pharmaceutical excipients and/or vehicles.  
     
     
         10 . The use of compounds as claimed in  claim 1  and their pharmacologically tolerable salts for the prevention and treatment of gastrointestinal diseases.