Nitromethylthiobenzene derivatives as aldose reductase inhihibitors

Abstract

The invention concerns novel compounds of general formula (1), their tautomeric forms, and their additive salts with pharmaceutically acceptable bases. The invention also concerns methods for preparing these compounds and their applications as medicines. These compounds inhibit the aldose reductase enzyme and can be used in the treatment or prevention of peripheral and autonomous neurological diabetic complications, renal and ocular disorders such as cataract and retinopathy.

1 . Compounds of the formula 1  
       
         
           
           
               
               
           
         
       
       in which: 
 P represents  
 the radical (i): —(CO—NH) m —SO 2 -R;  
 the radical (ii):  
                     
 or the radical (iii):  
                     
 R represents a radical chosen from phenyl, benzyl, diphenylmethyl, naphthyl, cycloalkylalkyl in which the alkyl part is C 1 -C 4  and the cycloalkyl part is C 3 -C 7 , and styryl, the said radical optionally being substituted with one or more groups Z which may be identical or different, or alternatively  
 R represents a C 3 -C 5  aromatic heterocyclic radical comprising 1 or 2 hetero atoms chosen from O, S and N, the said radical optionally being substituted with one or more groups Z, which may be identical or different, and optionally being fused to 1 or 2 phenyl rings which are optionally substituted with one or more groups Z, which may be identical or different; or alternatively  
 R represents C 1 -C 4  alkyl optionally substituted with one or more halogen atoms, which may be identical or different, C 3 -C 7  cycloalkyl or cyclo(C 3 -C 7 )alkyl(C 1 -C 4 )alkyl;  
 Z is chosen from a halogen atom, a C 1 -C 4  alkyl, C 1 -C 4  alkoxy, nitro, cyano, trifluoromethyl, trifluoro-methoxy, (C 2 -C 5 ) alkylamino, (C 1 -C 4 ) alkylsulphonyl, C 1 -C 4 )alkylthio and phenyl group;  
 X represents a hydrogen or halogen atom;  
 m is 0 or 1;  
 n is 0, 1 or 2;  
 T 1  and T 2  represent, independently of each other, a hydrogen atom or a C 1 -C 4  alkyl group,  
 u is 0 or 1;  
 A represents C 1 -C 8  alkylene or the group  
                     
 y being an integer chosen from 0, 1, 2, 3 and 4; it being understood that when P represents the radical (ii), A can also represent a bond;  
 the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.  
 
     
     
         2 . Compounds of formula I according to  claim 1 , characterized in that 
 P represents —(CO—NH) m SO 2 -R    R represents a radical chosen from phenyl, diphenylmethyl, naphthyl and styryl, the said radical optionally being substituted with one or more groups Z, which may be identical or different, or alternatively R represents a C 3 -C 5  aromatic heterocyclic radical comprising 1 or 2 hetero atoms chosen from O, S and N, the said radical optionally being substituted with one or more groups Z, which may be identical or different, and optionally being fused to 1 or 2 phenyl rings which are optionally substituted with one or more groups Z, which may be identical or different; or alternatively R represents C 1 -C 4  alkyl optionally substituted with one or more halogen atoms, which may be identical or different, C 3 -C 7  cycloalkyl or cyclo(C 3 -C 7 )alkyl(C 1 -C 4 )alkyl;    Z, X, m and n being as defined in  claim 1 , the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.    
     
     
         3 . Compounds of formula 1 according to  claim 1 , characterized in that: 
 P represents —(CO—NH) m —SO 2 -R;    R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; benzyl; benzyl substituted with one or more groups Z which may be identical or different; C 1 -C 4  alkyl optionally substituted with one or more halogen atoms, which may be identical or different; C 3 -C 7  cycloalkyl; cyclo(C 3 -C 7 )alkyl(C 1 -C 4 )alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; or diphenylmethyl;    Z is chosen from a halogen atom, a C 1 -C 4  alkyl, C 1 -C 4  alkoxy, nitro, trifluoromethyl, trifluoromethoxy, (C 2 -C 4 )alkylamino, (C 1 -C 4 )alkylsulphonyl and phenyl group;    X, m and n being as defined in  claim 1 , the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.    
     
     
         4 . Compounds of formula 1 according to any one of claims  1  to 3, characterized in that: 
 P represents —(CO—NH) m SO 2 -R,  
 R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; benzyl; benzyl substituted with one or more groups Z which may be identical or different; methyl; C 3 -C 7  cycloalkyl; cyclo(C 3 -C 7 )alkyl(C 1 -C 4 )alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl;  
 Z is chosen from fluoro, chloro, bromo, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulphonyl and phenyl;  
 X represents hydrogen or chlorine;  
 m and n being as defined in  claim 1 ,  
 the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.  
 
     
     
         5 . Compounds of formula 1 according to any one of claims  1 ,  3  and  4 , characterized in that: 
 P represents —(CO—NH) m —SO 2 -R;  
 R represents phenyl; phenyl substituted with one or more groups Z, which may be identical or different; methyl; C 3 -C 7  cycloalkyl; cyclo (C 3 -C 7 ) alkyl(C 1 -C 4 )alkyl; styryl; thienyl; pyridyl; naphthyl; dibenzofuryl; diphenylmethyl or 2,2,2-trifluoroethyl;  
 Z is chosen from fluoro, chloro, bromo, methyl, methoxy, nitro, trifluoromethyl, trifluoromethoxy, acetamido, methylsulphonyl and phenyl;  
 X represents hydrogen or chlorine;  
 m and n being as defined,  
 the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.  
 
     
     
         6 . Compounds of formula 1 according to any one of claims  1 ,  3  and  4 , chosen from: 
 N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide;  
 3,4-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)-sulphonyl]phenyl]benzenesulphonamide;  
 3-bromo-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]benzenesulphonamide;  
 N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-2-(trifluoromethyl)benzenesulphonamide;  
 N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-fluorobenzenesulphonamide;  
 N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-fluorobenzenesulphonamide;  
 N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-phenylmethanesulphonamide;  
 2,3-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]benzenesulphonamide;  
 3,5-difluoro-N-[3,5-dimethyl-4-[(nitromethyl)-sulphonyl]phenyl]benzenesulphonamide; and  
 N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-2-fluorobenzenesulphonamide.  
 
     
     
         7 . Compounds of formula (1) according to  claim 1 , characterized in that: 
 P represents                          A represents a bond or C1-C8 alkylene;    u, n, X, T 1  and T 2  being as defined in  claim 1;     the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.    
     
     
         8 . Compounds of formula 1 according to  claim 1 , characterized in that: 
 P represents:                          A represents the group                          n, X, y, T 1  and T 2  being as defined in  claim 1 ,    the tautomeric forms thereof and the addition salts thereof with pharmaceutically acceptable bases.    
     
     
         9 . Compounds of formula 1 according to  claim 1 , chosen from the compounds: 
 N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-1,5-pentanediamide;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-1,8-octanediamide;    N,N′-bis[4-[(nitromethyl)sulphonyl]phenyl]-1,5-pentane-diamide;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-ethanediamide;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-urea;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-1,4-butanediamide;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-1,3-propanediamide;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-1,3-benzenedisulphonamide;    N,N′-bis[3,5-dimethyl-4-[(nitromethyl)sulphonyl]-phenyl]-1,3-benzenedimethane sulphonamide.    
     
     
         10 . Process for preparing the compounds of formula 1 according to any one of  claims 1  to  6 , in which P represents —(CO—NH) m —SO 2 -R, X is a hydrogen atom, m is zero and n is equal to 2, characterized in that the compound of formula 2  
       
         
           
           
               
               
           
         
       
       in which T 1  and T 2  are as defined in  claim 1 , is treated with a sulphonyl chloride of formula RSO 2 Cl in which R is as defined in  claim 1 , in the presence of a base.  
     
     
         11 . Process for preparing the compounds of formula 1 according to any one of  claims 1  to  5 , in which P represents —(CO—NH) m —SO 2 -R, X represents a halogen atom, preferably chlorine, m is zero and n is equal to 2, characterized in that a compound of formula 3  
       
         
           
           
               
               
           
         
       
       in which R, T 1  and T 2  are as defined in  claim 1 , is treated with the appropriate N-halosuccinimide in the presence of a free-radical generator, for example 2,2′-azobisisobutyronitrile.  
     
     
         12 . Process for preparing the compounds of formula 1 according to any one of  claims 1  to  5 , in which P represents —(CO—NH) m —SO 2 -R, X is a hydrogen atom, m is 1 and n is equal to 2, characterized in that the compound of formula 2  
       
         
           
           
               
               
           
         
       
       in which T 1  and T 2  are as defined in  claim 1 , is treated with a sulphonyl isocyanate of formula RSO 2 NCO, in which R is as defined in  claim 1 .  
     
     
         13 . Process for preparing the compounds of formula 1 according to any one of  claims 1  to  5 , in which P represents —(CO—NH) m —SO 2 -R, X is a hydrogen atom and m and n are equal to zero, characterized in that the compound of formula 10  
       
         
           
           
               
               
           
         
       
       in which T 1  and T 2  are as defined in  claim 1 , is treated with a sulphonyl chloride of formula RSO 2 Cl, in which R is as defined in  claim 1 , in the presence of a base.  
     
     
         14 . Process for preparing the compounds of formula 1 according to any one of  claims 1  to  5 , in which P represents —(CO—NH) m —SO 2 -R, X is a hydrogen atom, m is zero and n is equal to 1, characterized in that a compound of formula 4  
       
         
           
           
               
               
           
         
       
       in which R, T 1  and T 2  are as defined in  claim 1 , is treated with an oxidizing agent such as m-chlorobenzoic acid.  
     
     
         15 . Process for preparing 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline by basic hydrolysis of N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]acetamide, characterized in that the N-[3,5-dimethyl-4-[(nitromethyl)thio]phenyl]acetamide is obtained by reacting nitromethanesodium of formula NaCH 2 NO 2  with 4-acetamido-2,6-dimethylphenyl thiocyanate.  
     
     
         16 . Process for preparing the compounds of formula (1) according to any one of claims  1 ,  7  and  9 , in which P represents the radical (ii):  
       
         
           
           
               
               
           
         
         u is 1, X represents a hydrogen atom and n is equal to 2, characterized in that a compound of formula 2  
         
           
             
             
                 
                 
             
           
         
         in which T 1  and T 2  are as defined in  claim 1 , is treated with a dichloride of formula 5:  
         Cl—(CO-A) u —COCl  5   
         in which A and u have the same meanings as in  claim 1 , in the presence of a base, the molar ratio of the compound of formula 2 to the compound of formula 5 being at least equal to 2.  
       
     
     
         17 . Process for preparing the compounds of formula (1) according to any one of claims  1 ,  8  and  9 , in which P represents the radical (iii)  
       
         
           
           
               
               
           
         
         X represents a hydrogen atom and n is equal to 2, characterized in that a compound of formula 2  
         
           
             
             
                 
                 
             
           
         
         in which T 1  and T 2  are as defined in  claim 1 , is treated with a dichloride of formula  
         Cl—SO 2 -A—SO 2 —Cl  6   
         in the presence of a base, the molar ratio of the compound of formula 2 to the compound of formula 6 being at least equal to 2.  
       
     
     
         18 . Process for preparing the compounds of formula (1) according to either of claims  1  and  7 , in which P represents the radical (ii)  
       
         
           
           
               
               
           
         
         X represents a hydrogen atom, n is equal to 2 and u is equal to zero, characterized in that a compound of formula 2  
         
           
             
             
                 
                 
             
           
         
         in which T 1  and T 2  are as defined in  claim 1 , is treated with trichloromethyl chloroformate in the presence of a base, the molar ratio of the compound of formula 2 to the trichloromethyl chloroformate being at least equal to 2.  
       
     
     
         19 . Pharmaceutical composition comprising, as active principle, an effective amount of at least one compound according to any one of  claims 1  to  9 , in combination with one or more pharmaceutically acceptable vehicles.  
     
     
         20 . Pharmaceutical composition according to  claim 18 , characterized in that it is in the form of immediate-release tablets, controlled-release tablets, gelatin capsules, injectable solutions, creams or eyedrops.  
     
     
         21 . Use of a compound according to one of  claims 1  to  9  for the preparation of a medicinal product intended to inhibit aldose reductase.  
     
     
         22 . Use of a compound according to one of  claims 1  to  9  for the preparation of a medicinal product intended for the treatment of diabetic complications such as cataracts, retinopathies, neuropathies, nephropathies and vascular diseases.