Novel specific caspase-10 inhibitors

Abstract

The invention relates to compounds of the general formula (I) wherein R1, R2, R3, R4, R5, R6, i and j have the meanings given in claim 1, and to the use thereof as caspase-10 inhibitors, especially for the treatment of diabetic retinopathy.

1 .- 28 . (canceled) 
     
     
         29 . A method for treating retinopathy comprising administering a compound of the formula (I): 
       
         
           
           
               
               
           
         
       
       in which:
 R1 represents a group of the formula: —X—(Y) m , in which:
 —X— represents an aryl, cycloalkyl, heteroaryl, alkyl or heterocyclyl group; 
 each of the groups Y, which may be identical or different, independently represents a halogen atom or an -alkyl, —O-alkyl, —CO-alkyl, —NO 2 , —O-perhaloalkyl, —S(O) q -alkyl or -perhaloalkyl group, or two groups Y together form an aryl or heteroaryl group fused to the phenyl nucleus to which they are attached; and 
 m represents an integer chosen from 0, 1, 2, 3, 4 and 5; 
 
 R2 and R3 together form a cycloalkyl or heterocyclyl group optionally substituted by one or more alkyl groups; 
 R4 represents OH; 
 i represents an integer greater than or equal to 2; 
 R5 represents a hydrogen atom or an alkyl group, optionally substituted by one or more cycloalkyl groups; 
 each of the groups R6, which may be identical or different, independently represents a group chosen from alkyl, O-alkyl, a halogen atom and a —CN, —NO 2 , —CO-alkyl, —CO 2 R, —NRR′, —O-perhaloalkyl or -perhaloalkyl group; 
 j represents an integer chosen between 0, 1, 2, 3 and 4; 
 R and R′, which may be identical or different, independently represent a hydrogen atom or an alkyl group; and 
 q represents an integer chosen from 0, 1 and 2;
 or a tautomeric, enantiomeric, diastereoisomeric or epimeric form thereof, or a pharmaceutically acceptable salt thereof. 
 
 
     
     
         30 . A method according to Claim  1 , in which R1 represents a phenyl group optionally substituted by one or more groups, which may be identical or different, chosen from a halogen atom and an -alkyl, —O-alkyl, —CO-alkyl, —NO 2 , —O-perhaloalkyl, —S(O) q -alkyl or -perhaloalkyl group, or two substituents together form a phenyl or pyridyl group fused to the phenyl nucleus to which they are attached; or R1 represents a cycloalkyl, heteroaryl or alkyl group. 
     
     
         31 . A method according to Claim  1 , in which R1 represents a phenyl group substituted by at least one halogen atom. 
     
     
         32 . A method according to Claim  1 , in which R2 and R3 together form a cycloalkyl group, optionally substituted by one or more alkyl groups; or R2 and R3 together form a heterocyclyl group. 
     
     
         33 . A method according to Claim  1 , in which R5 represents a hydrogen atom or an alkyl group, optionally substituted by one or more cycloalkyl groups. 
     
     
         34 . A method according to Claim  1 , in which R and R′, which may be identical or different, independently represent a hydrogen atom or an alkyl group. 
     
     
         35 . A method according to Claim  1 , in which i=2. 
     
     
         36 . A method according to Claim  1 , in which j=0. 
     
     
         37 . A method according to Claim  1 , in which the group —(CH 2 ) i R4 is in the para position. 
     
     
         38 . A method according to Claim  1 , in which the compounds are chosen from:
 N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-(methylsulfonyl)benzenesulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]-3,3-dimethylcyclobutyl}methyl)benzenesulfonamide;   4-chloro-N-({1-[3-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfon amide;   2,4-dichloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzene sulfonamide;   4-chloro-N-({4-[4-(2-hydroxyethyl)benzyl]tetrahydro-2H-pyran-4-yl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)naphthalene-2-sulfon amide;   4-cyclohexyl-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzene sulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)pyridine-3-sulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopropyl}methyl)benzenesulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)benzenesulfon amide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)-4-methylbenzenesulfon-amide;   2,3,4,5 ,6-pentafluoro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl) benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-methylbenzenesul-fonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-methylbenzenesul-fonamide;   3,4,5-trifluoro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl) benzenesulfonamide;   3,5-dichloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl} methyl)-3-methylbenzenesul-fonamide;   4-fluoro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-3-(trifluoromethyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-nitro-3-(trifluoromethyl)benzenesulfonamide;   N-(cyclopropylmethyl)-N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)4-methylbenzenesulfonamide;   
       4-chloro-N-(cyclopropylmethyl)-N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)benzenesulfonamide. 
     
     
         39 . A method according to Claim  1 , wherein the compound is administered to a newly diagnosed diabetic patient and/or a patient suffering from early retinopathy and which comprises specifically inhibiting caspase-10 in the patient. 
     
     
         40 . A compound of the formula (I) 
       
         
           
           
               
               
           
         
       
       in which:
 R1 represents a group of the formula: —X—(Y) m , in which:
 —X— represents an aryl, cycloalkyl, heteroaryl, alkyl or heterocyclyl group; 
 each of the groups Y, which may be identical or different, independently represents a halogen atom or an -alkyl, —O-alkyl, —CO-alkyl, —NO2, —O-perhaloalkyl, —S(O) q -alkyl or -perhaloalkyl group, or two groups Y together form an aryl or heteroaryl group fused to the phenyl nucleus to which they are attached; and 
 m represents an integer chosen from 0, 1, 2, 3, 4 and 5; 
 
 R2 and R3 together form a cycloalkyl or heterocyclyl group optionally substituted by one or more alkyl groups; 
 R4 represents OH; 
 i represents an integer greater than or equal to 2; 
 R5 represents a hydrogen atom or an alkyl group, optionally substituted by one or more cycloalkyl groups; 
 each of the groups R6, which may be identical or different, independently represents a group chosen from alkyl, O-alkyl, a halogen atom and a —CN, —NO 2 , —CO-alkyl, —CO 2 R, —NRR′, —O-perhaloalkyl or -perhaloalkyl group; 
 j represents an integer chosen between 0, 1, 2, 3 and 4; 
 R and R′, which may be identical or different, independently represent a hydrogen atom or an alkyl group; and 
 q represents an integer chosen from 0, 1 and 2;
 or a tautomeric, enantiomeric, diastereoisomeric or epimeric form thereof, or a pharmaceutically acceptable salt thereof. 
 
 
     
     
         41 . A compound of the formula (I) according to Claim  40 , for which R1 represents a phenyl group optionally substituted by one or more groups, which may be identical or different, chosen from a halogen atom and an -alkyl, —O-alkyl, —CO-alkyl, —NO 2 , —S(O) 2 -alkyl, —O-perhaloalkyl or -perhaloalkyl group, or two substituents together form a phenyl or pyridyl group fused to the phenyl nucleus to which they are attached; or R1 represents a cycloalkyl, heteroaryl or alkyl group. 
     
     
         42 . A compound of the formula (I) according to Claim  40 , for which R2 and R3 together form a cycloalkyl group, optionally substituted by one or more alkyl groups; or R2 and R3 together form a heterocyclyl group. 
     
     
         43 . A compound of the formula (I) according to Claim  40 , for which i=2. 
     
     
         44 . A compound of the formula (I) according to Claim  40 , for which R5 represents a hydrogen atom or an alkyl group, optionally substituted by one or more cycloalkyl groups. 
     
     
         45 . A compound of the formula (I) according to Claim  40 , for which j=0. 
     
     
         46 . A compound of the formula (I) according to Claim  40 , for which R and R′, which may be identical or different, independently represent a hydrogen atom or an alkyl group. 
     
     
         47 . A compound of the formula (I) according to Claim  40 , for which q represents an integer chosen from 0, 1 and 2. 
     
     
         48 . A compound of the formula (I) according to Claim  40 , chosen from:
 N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-(methylsulfonyl)benzenesulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]-3,3-dimethylcyclobutyl}methyl)benzenesulfonamide;   4-chloro-N-({1-[3-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   2,4-dichloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   4-chloro-N-({4-[4-(2-hydroxyethyl)benzyl]tetrahydro-2H-pyran-4-yl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)naphthalene-2-sulfonamide;   4-cyclohexyl-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)pyridine-3-sulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopropyl}methyl)benzenesulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)-4-methylbenzenesulfon-amide;   2,3,4,5 ,6-pentafluoro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-methylbenzenesul-fonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-methylbenzenesul-fonamide;   3,4,5-trifluoro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl) benzenesulfonamide;   3,5-dichloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-3-methylbenzenesul-fonamide;   4-fluoro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)benzenesulfonamide;   4-chloro-N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-3-(trifluoromethyl)benzenesulfonamide;   N-({1-[4-(2-hydroxyethyl)benzyl]cyclopentyl}methyl)-4-nitro-3-(trifluoromethyl)benzenesulfonamide;   N-(cyclopropylmethyl)-N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)4-methylbenzenesulfonamide; and   4-chloro-N-(cyclopropylmethyl)-N-({1-[4-(2-hydroxyethyl)benzyl]cyclobutyl}methyl)benzene sulfonamide.   
     
     
         49 . A process for the preparation of a compound of the formula(I) of  claim 40 , comprising the step of preparing a compound of the corresponding formula(I′): 
       
         
           
           
               
               
           
         
       
       in which R2, R3, R6 and j are as defined in  claim 40 , i′ represents 0 or i as defined in formula (I) in Claim  15  and R 4 ′ represents OH or a group —Z-Gp in which Z represents —O- and Gp represents a leaving group, comprising:
 reacting a compound of the formula (III): 
 
       
         
           
           
               
               
           
         
       
       with a compound of the formula (IV):
   R1-SO 2 -Hal  (IV)
 
 
       in which R1 is as defined in  claim 40  and Hal represents a halogen atom, optionally followed, if R5 is other than H in formula(I′), by alkylation of the nitrogen atom. 
     
     
         50 . A process according to Claim  49 , in which the compound of the formula (III) is obtained from a compound of the coffesponding formula (V) 
       
         
           
           
               
               
           
         
       
       in which,
 R2 and R3 together form a cycloalkyl or heterocyclyl group optionally substituted by one or more alkyl groups; 
 each of the groups R6, which may be identical or different, independently represents a group chosen from alkyl, O-alkyl and a halogen atom, or a —CN, —NO 2 , —CO-alkyl, —CO 2 R, —NRR′, —O-perhaloalkyl or-perhaloalkyl group; 
 j represents an integer chosen between 0, 1, 2, 3 and 4; 
 R and R′, which may be identical or different, independently represent a hydrogen atom or an alkyl group; 
 and i′ and R4′ are as defined in formula (I′), via reduction of the nitrile function using any suitable reducing agent. 
 
     
     
         51 . A process according to Claim  50 , in which the compound of the formula (V) is obtained from a compound of the corresponding formula (VI): 
       
         
           
           
               
               
           
         
       
       in which i′ and R4′ are as defined in formula (I′) and Hal represents a halogen atom, by reacting with a compound of the formula (VII): 
       
         
           
           
               
               
           
         
       
       in which R2 and R3 are as defined in formula (I′). 
     
     
         52 . A pharmaceutical composition comprising a compound of the formula (I) of  claim 40  and a pharmaceutically acceptable excipient.