New nitromethyl ketones, process for preparing them and compositions containing them

Abstract

The present invention relates to the compounds of formula: in which R 1 , R 2 , R 3 , E, A, X, Z, p and n are as defined herein. These compounds are aldose reductase inhibitors.

What is claimed is:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       in which 
 A represents C 6 -C 10 -aryl or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N;  
 X represents halogen, cyano, C 1 -C 7 -alkyl, trifluoromethyl, C 2 -C 7 -alkoxy or trifluoromethoxy;  
 R 1  and R 2 , which are identical or different, represent a hydrogen atom, a C 1 -C 7 -alkyl group, a C 1 -C 12 -cycloalkyl group, a trifluoromethyl group, a C 1 -C 7 -alkoxy group or R 1  and R 2  together form an alkylene chain —(CH 2 ) r —, where r is chosen from 2, 3 and 4;  
 p is chosen from 0, 1, 2, 3, 4 and 5;  
 Z represents a bond, the divalent radical —CO—NH— in which the carbonyl function is linked to R 3 , the divalent radical —SO 2 —NH— in which the sulfonyl function is linked to R 3 , a C 2 -C 7 -alkenylene radical, a sulfur atom, the sulfinyl radical or the sulfonyl radical;  
 R 3  represents a hydrogen atom; a halogen atom; a tri-(C 1 -C 7 -alkyl)silyl group; a C 1 -C 7 -alkyl group optionally substituted with one or more identical or different Y radicals; a C 6 -C 10 -aryl group optionally substituted with one or more identical or different Y radicals; a C 6 -C 1 -aryloxy group optionally substituted with one or more identical or different Y radicals; a C 3 -C 12 -cycloalkyl group optionally substituted with one or more identical or different Y radicals; an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, the heterocycle being optionally substituted with one or more identical or different Y radicals, or R 3  represents indanyl, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-benzodioxolyl, 2-oxopiperidinyl or 2-[(4-nitromethylcarbonyl-3-chlorophenyl)aminocarbonyl]-1-(phenyl)ethyl;  
 Y represents a halogen atom, C 1 -C 7 -alkyl, C 1 -C 7 -alkoxy, trifluoromethyl, carboxy, carbamoyl, (C 1 -C 7 )alkylcarbamoyl, di-(C 2 -C 7 )alkylcarbamoyl, C-c,-alkoxycarbonyl, amino, C 1 -C 7 -alkylamino, di-(C 1 -C 7 )-alkylamino, nitro, cyano, hydroxy, trifluoromethoxy, C 3 -C 12 -cycloalkyl, sulfo, C 1 -C 7 -alkylthio, C 1 -C 7 -alkylsulfinyl, C 1 -C 7 -alkylsulfonyl, C 2 -C 8 -alkylcarbonyl, C 2 -C 8 -alkylthiocarbonyl, C 2 -C 8 -alkylcarbonylamino, or C 6 -C 10 -aryl;  
 E represents a divalent radical chosen from: 
 (i) —CO—NR 4 —, in which the carbonyl group is linked to —(CR 1 R 2 ) p — and R 4  represents the radical (CH 2 ) q —R 5  where q is chosen from 0 and 1; and where R 5  represents a hydrogen atom; a C 1 -C 7 -alkyl group, a C 6 -C 10 -aryl group or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, N and S; or R 5  and R 3  together form a bond;  
 (ii) —SO 2 —NR 4 — in which the sulfonyl group is linked to —(CR 1 R 2 ) p — and R 4  is as defined above;  
 (iii) —NR 4 — in which R 4  is as defined above;  
 (iv) —CH═N— in which the nitrogen atom is linked to A; and  
 (v) an oxygen atom;  
 
 n represents 0 or 1;  
 on the condition that -A(X)-(E), —(CR 1 R 2 ) p -Z-R 3  does not represent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl, 4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl, 2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substituted with a group X and optionally substituted 2-fluorophenyl as defined above, and  
 on the condition that when A represents pyridyl, X represents methyl and n is equal to 1, E does not represent —NR 4 —,  
 and addition salts thereof with pharmaceutically acceptable bases.  
 
     
     
         2 . Compound according to  claim 1 , in which A represents phenyl and n and p represent 0, Z represents a bond and R 3  represents a hydrogen atom.  
     
     
         3 . Compound according to  claim 1 , in which A represents phenyl, n is equal to 1 and E represents —CO—NR 4 —.  
     
     
         4 . Compound according to  claim 11 , in which A represents phenyl, n and p are equal to 1, E represents —CO—NR 4 —, R 1  and R 2  represent a hydrogen atom and Z represents a bond.  
     
     
         5 . Compound according to  claim 1 , in which A represents phenyl, n is equal to 1 and E represents —SO 2 —NR 4 —.  
     
     
         6 . Compound according to  claim 1 , in which A represents phenyl, n is equal to 1, E represents —CO—NR 4 —, p is equal to 0 and Z represents the divalent radical —SO 2 —NH— in which SO 2  is linked to R 3 .  
     
     
         7 . Compound according to  claim 1 , in which A represents an aromatic heterocycle.  
     
     
         8 . Compound according to  claim 1 , in which A represents naphthyl.  
     
     
         9 . Compound according to  claim 1 , in which n is 1 and E represents an oxygen atom.  
     
     
         10 . Compound according to  claim 1  chosen from: 
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-2-methylphenylacetamide,  
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-2-trifluoromethylphenylacetamide,  
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-phenylacetamide,  
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-2-chlorophenylacetamide,  
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-2-chlorophenylacetamide,  
 N-[3-chloro-4-nitromethylcarbonylphenyl)]-4-chlorobenzamide,  
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-4-chlorobenzenesulfonamide,  
 N-[4-chloro-3-(nitromethylcarbonylphenyl)]-benzenesulfonamide,  
 N-[3-chloro-4-(nitromethylcarbonylphenyl)]-benzenesulfonamide,  
 1-[3-chloro-4-(nitromethylcarbonylphenyl)]-3-(phenylsulfonyl)urea,  
 nitromethyl 2-trifluoromethoxyphenyl ketone,  
 nitromethyl 3-methyl-2-thienyl ketone,  
 4-methyl-N-[2-nitromethylcarbonyl-3-methylbenzo[b]-thien-5-yl]benzenesulfonamide,  
 nitromethyl 2-methyl-1-naphthyl ketone,  
 nitromethyl 3-chloro-2-naphthyl ketone,  
 nitromethyl 6-methoxy-5-trifluoromethyl-1-naphthyl ketone.  
 
     
     
         11 . A process for the preparation of a compound of formula (I) according to  claim 1 , comprising treating an acid of formula  
       
         
           
           
               
               
           
         
       
       in which R 1 , R 2 , R 3 , Z, E, n, p, A and X are as defined in  claim 1 , with a mixture of nitromethane and di(C 1 -C 7 )alkyl cyanophosphonate in the presence of a base.  
     
     
         12 . A process for the preparation of a compound of formula (I) according to  claim 1 , comprising: 
 (i) treating an acid of formula (II):                           in which R 1 , R 2 , R 3 , Z, E, n, p, A and X are as defined in  claim 1 , by the action of thionyl chloride or phosphoryl chloride in the presence of phenol to give the corresponding phenyl ester of formula (III):                           in which R 1 , R 2 , R 3 , Z, E, n, p, A and X are as defined above; and then    (ii) treating the phenyl ester obtained in (i) by the action of nitromethane in the presence of a base to give the compound of formula (I).    
     
     
         13 . A process for the preparation of a compound of formula (I) according to  claim 1 , in which: 
 (i) when n is equal to 1 and E represents —CO—NR 4 —: 
 reacting an acid halide of the formula R 3 -Z-(CR 1 R 2 ) p —CO-hal, where R 1 , R 2 , R 3 , Z and p are as defined in  claim 1  and hal is a halogen atom, with an amine of formula (IV):  
                     in which A and X are as defined in  claim 1;  or    
   (ii) when n is equal to 1 and E represents —SO 2 —NR 4 —: 
 reacting a sulfonyl halide of formula R 3 -Z-(CR 1 R 2 ) p —SO 2 -hal, where R 1 , R 2 , R 3 , Z and p are as defined in  claim 1  and hal is a halogen atom, with an amine of formula (IV) as defined above.  
   
     
     
         14 . A process for the preparation of a compound of formula (I) according to  claim 1 , in which Z represents —SO 2 —NH—, p is equal to 0, n is equal to 1 and E represents —CO—NR 4 —, comprising: 
 (a) reacting an isocyanate of formula R 3 —SO 2 —N═C=O, where R 3  is as defined in  claim 1 , with an amine of formula:  
                     
  in which A and X are as defined in  claim 1;  and then  
 (b) treating the phenyl ester obtained in (a) by the action of nitromethane in the presence of a base to give the compound of formula (I).  
 
     
     
         15 . A process for the preparation of a compound of formula (I) according to  claim 1 , comprising: 
 (a) preparing a phenyl ester of formula (III):                           according to one of the following steps (i) to (v): 
 (i) when n is equal to 1 and E represents —CO—NR 4 —: 
 reacting an acid halide of formula R 3 -Z-(CR 1 R 2 ) p —CO-hal, where R 1 , R 2 , R 3 , Z and p are as defined in  claim 1  and hal is a halogen atom, with an amine of formula (V):  
                     in which A and X are as defined in  claim 1;  or    
 
 (ii) when n is equal to 1 and E represents —SO 2 —NR 4 —, 
 reacting a sulfonyl halide of formula R 3 -Z-(CR 1 R 2 ) p —SO 2 -hal, where R 1 , R 2 , R 3 , Z and p are as defined in  claim 1  and hal is a halogen atom, with an amine of formula (V) as defined above; or  
 
 (iii) when n is equal to 1 and E represents —NR 4 —: 
 reacting a compound of formula R 3 -Z-(CR 1 R 2 ) p -hal, where R 1 , R 2 , R 3 , Z and p are as defined in  claim 1  and hal is a halogen atom, with an amine of formula (V) as defined above; or  
 
 (iv) when n is equal to 1 and E represents —CH═N—: 
 reacting an aldehyde of formula R 3 -Z-(CR 1 R 2 ) p —CHO, where R 1 , R 2 , R 31  Z and p are as defined in  claim 1 , with an amine of formula (V) as defined above; or  
 
 (v) when n is equal to 1 and E represents —O—: 
 reacting a compound of formula R 3 -Z-(CR 1 R 2 ) p -hal, where R 1 , R 2 , R 3 , Z and p are as defined in  claim 1  and hal is a halogen-atom, with an alcohol of formula (VI):  
                     in which A and X are as defined in  claim 1;     
 
 (vi) when n is equal to 1 and E represents —CO—NR 4 —: 
 reacting an acid of formula R 3 -Z-(CR 1 R 2 ) p —COOH where R 1 , R 2 , R 3 , Z and p are as defined above, with an amine of formula (V) as defined above; and then  
 
   (b) treating the phenyl ester obtained in (a) above by the action of nitromethane in the presence of a base to give the compound of formula (I).    
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of formula (I) according to  claim 1 , in combination with at least one pharmaceutically acceptable vehicle.  
     
     
         17 . Composition according to  claim 16 , in the form of an immediate-release tablet, a controlled-release tablet, a gelatin capsule, an injectable solution, a cream or a collyrium.  
     
     
         18 . A medicament for treating a condition by inhibition of aldose reductase which comprises an aldose reductase inhibiting amount of a compound of  claim 1  or addition salt thereof with a pharmaceutically acceptable base.  
     
     
         19 . A method for treating a condition by inhibition of aldose reductase which comprises administering to a patient in need thereof an aldose reductase inhibiting amount of a compound of  claim 1  or addition salt thereof with a pharmaceutically acceptable base.  
     
     
         20 . The method of  claim 19 , wherein the condition is a complication from diabetes.  
     
     
         21 . The method of  claim 20 , wherein the complication is cataract, retinopathy, neuropathy, nephropathy and/or a vascular disease.