Association of calpain inhibitors and reactive oxygen species trapping agents

Abstract

A pharmaceutical composition comprising, as active ingredient, at least one calpain inhibitor substance and at least one reactive oxygen species trapping substance, and optionally a pharmaceutically acceptable support.

1 . A pharmaceutical composition comprising, as active ingredient, at least one calpain inhibitor substance and at least one reactive oxygen species trapping substance, and optionally a pharmaceutically acceptable support.  
   
   
       2 . A composition of  claim 1 , comprising, as active ingredient, a calpain inhibitor substance and a reactive oxygen species trapping substance, and optionally a pharmaceutical acceptable support.  
   
   
       3 . A composition of  claim 1  wherein the calpain inhibitor has the formula  
       T-NH—CH(R 1 )—C(O)—NH—CH(R 2 )—C(O)—H—CH(R 3 )—C(O)] n —Y   (I b )  wherein    R 1 , R 2  and R 3  are, independently, selected from the group consisting of hydrogen or lower alkyl optionally substituted by at least one member selected from the group consisting of hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, aminocarbonyl, (lower alkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, amino, guanidino and optionally substituted aryl or optionally substituted heteroaryl, with the substituents of aryl and heteroaryl being selected from the group consisting of halo, hydroxy, lower alkyl and lower alkoxy;    Y is selected from the group consisting of hydrogen, —C(O)-Ry and —C(O)—O—R′y wherein 
 Ry is lower alkyl or —N(Ry 1 )(Ry 2 );  
 R′y is selected from the group consisting of hydrogen, lower alkyl and lower arylalkyl;  
 Ry 1  and Ry 2  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower arylalkyl, lower heteroarylalkyl, cycloalkyl-alkyl, heterocycloalkyl, all optionally substituted by at least one member of the group consisting of halo, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy and arylalkoxy;  
 n is 0 or 1;  
 T is selected from the group consisting of —C(O)—O-Rt 1  or —C(O)-Rt 2  wherein 
 Rt 1  is lower alkyl or lower arylalkyl;  
 Rt 2  is selected from the group consisting of lower alkyl, lower arylalkyl, aryloxy lower alkyl and heteroaryl.  
 
   
   
   
       4 . A composition of  claim 1  wherein the calpain inhibitor has the formula  
       T-NH—CH(R 1 )—C(O)—NH—CH(R 2 )—C(O)—[NH—CH(R 3 )—C(O)] n —Y   (I b )  wherein    R 1 , R 2  and R 3  are, independently, alkyl optionally substituted by at least one member selected from the group consisting of hydroxy, mercapto, lower alkylthio, carboxy, aminocarbonyl, amino, guanidino and optionally substituted phenyl, indole or imidazole, 
 the phenyl, indole and imidazole substitution being selected from the group consisting of halo, hydroxy, lower alkyl and lower alkoxy;  
   Y is selected from the group consisting of hydrogen, —C(O)-Ry and —C(O)—O—R′y wherein 
 Ry is lower alkyl or —N(Ry 1 )(Ry2);  
 R′y is lower alkyl or benzyl;  
 Ry 1  is hydrogen and Ry 2  is, independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower arylalkyl, lower heteroarylalkyl, cycloalkyl-alkyl and heterocycloalkyl, all optionally being substituted by at least one member selected from the group consisting of halo, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy and arylalkoxy;  
 n is 0 or 1;  
 T is —C(O)—O-Rt 1  or —C(O)-Rt 2  wherein 
 Rt 1  is selected from the group consisting of lower alkyl, benzyl and phenethyl;  
 Rt 2  is selected from the group consisting of lower alkyl, lower arylalkyl, aryloxy lower alkyl and heteroaryl.  
 
   
   
   
       5 . A composition of  claim 1  wherein the calpain inhibitor corresponds to formula  
       T-NH—CH(R 1 )—C(O)—NH—CH(R 2 )—C(O)—[NH—CH(R 3 )—C(O)] n —Y   (I b )  wherein    R 1  and R 2  are, independently, alkyl optionally substituted by phenyl optionally substituted by halo or hydroxy;    Y is hydrogen;    T is —(O)—O-Rt 1  wherein Rt 1  is lower alkyl or benzyl and n=0.    
   
   
       6 . A composition of  claim 1  wherein the calpain inhibitor is 3-(4-iodophenyl)-2-mercapto-2-propenoic acid.  
   
   
       7 . A composition of  claim 1  wherein the reactive oxygen species trap is selected from the group consisting of ascorbic acid, ethoxyquin, N-acetyl-cysteine, β-carotene, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid, the Q10 coenzyme, captodative compounds, nitrones, phenolic compounds, indole derivatives, indolines, imidazoles, phenothiazines, phenoxazines, phenazines, diphenylamines and carbazoles.  
   
   
       8 . A composition of  claim 1  wherein the reactive oxygen species trap is selected from the group consisting of ascorbic acid, ethoxyquin, tempol, N-tert-butyl-α-phenyl-nitrone, N-acetyl-cysteine, β-carotene, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid, the Q10 coenzyme, captodative compounds, probucol, NDGA, α-, β-, γ-, ε-, τ- or δ-tocopherol, 3,5-di-tert-butyl-4-hydrobenzoic acid, 2,3,6-trimethyl-2-hexyloxyphenol, 2,6-di-tert-butyl-4-methoxyphenol, 2,6-di-tert-butyl-4-methylphenol, trolox, n-propyl gallate, eugenol, cafeic acid, sinapinic, gallic acid, propofol, melatonin, 5-hydroxy-tryptamine, 5-hydroxy-indole-2-carboxylic acid, 5-amino-indoline, N-methyl-indoline, imidazole, cimetidine, 4-hydroxy-carbazole, carvedilol, 2-methoxy-10H-phenothiazine, 4-hydroxydiphenylamine, 4-aminodiphenylamine, 4-methoxy-N-(4-methoxyphenyl) aniline and 9-[2-(4-morpholinyl)ethyl]-2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b]indole.  
   
   
       9 . A composition of  claim 1  wherein the reactive oxygen species trap is selected from the group consisting of phenolic compounds, phenothiazines and diphenylamines.  
   
   
       10 . A composition of  claim 1  wherein the reactive oxygen species trap is selected from the group consisting of 3-5-di-tert-butyl-4-hydroxybenzoic acid (BHT), 2-methoxy-10H-phenothiazine or 4-hydroxydiphenylamine; and 
 the compound which inhibits calpains is selected from the group consisting of benzyl (1S)-1-({[(1S)-1 formyl-3-methylbutyl]amino } carbonyl)-3-methylbutylcarbamate, benzyl (1S)-1-{[(1-benzyl-2-oxoethyl)amino]carbonyl}-3-methylbutylcarbamate, benzyl ester of [1-[[1-formylpentyl)amino]carbonyl-3-methylbutyl]carbamic (calpeptin) and 3-(4-iodophenyl)-2-mercapto-2-propenoic acid.    
   
   
       11 . A product comprising at least one substance which inhibits calpains and at least one reactive oxygen species trapping substance as a combination product, in separated form, for simultaneous or sequential use in the treatment of pathologies in which calpains and the reactive oxygen species are involved, pathologies characterized by an excessive production of ROS's and/or an activation of calpains.  
   
   
       12 . (canceled)  
   
   
       13 . A product of  claim 11  wherein the calpain inhibitor has the formula  
       T-NH—CH(R 1 )—C(O)—NH—CH(R 2 )—C(O)—[NH—CH(R 3 )—C(O)] n —Y   (I b )  wherein    R 1 , R 2  and R 3  are, independently, hydrogen or lower alkyl optionally substituted by at least one member selected from the group consisting of hydroxy, lower alkoxy, mercapto, lower alkylthio, carboxy, aminocarbonyl, (lower alkyl)aminocarbonyl, di(lower alkyl)aminocarbonyl, amino, guanidino, optionally substituted aryl or optionally substituted heteroaryl, with the substituents aryl and heteroaryl being at least one member selected from the group consisting of halo, hydroxy, lower alkyl and lower alkoxy;    Y is selected from the group consisting of hydrogen, —C(O)-Ry and —C(O)—O—R′y wherein 
 Ry is lower alkyl or —N(Ry 1 )(Ry 2 );  
 R′y is hydrogen, lower alkyl and lower arylalkyl;  
 Ry 1  and Ry 2  are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower arylalkyl, lower heteroarylalkyl, cycloalkyl-alkyl and heterocycloalkyl, all optionally substituted by at least one member selected from the group consisting of halo, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy and arylalkoxy;  
 n is 0 or 1;  
 T is —C(O)—O-Rt 1  or —C(O)-Rt 2  wherein 
 Rt 1  is lower alkyl or lower arylalkyl;  
 Rt 2  is selected from the group consisting of lower alkyl, lower arylalkyl, aryloxy lower alkyl and heteroaryl.  
 
   
   
   
       14 . A product of  claim 11  wherein the calpain inhibitor has the formula  
       T-NH—CH(R 1 )—C(O)—NH—CH(R 2 )—C(O)—[NH—CH(R 3 )—C(O)] n —Y   (I b )  wherein    R 1 , R 2  and R 3  are, independently, alkyl optionally substituted by at least one member selected from the group consisting of hydroxy, mercapto, lower alkylthio, carboxy, aminocarbonyl, amino, guanidino and optionally substituted phenyl, indole or imidazole, 
 the phenyl, indole and imidazole being optionally substituted with a member selected from the group consisting of halo, hydroxy, lower alkyl and lower alkoxy;  
   Y is selected from the group consisting of hydrogen, —C(O)-Ry and —C(O)—O—R′y wherein 
 Ry is lower alkyl or —N(Ry 1 )(Ry 2 );  
 R′y is lower alkyl or benzyl;  
 Ry 1  is hydrogen and Ry 2  is, independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, lower arylalkyl, lower heteroarylalkyl, cycloalkyl-alkyl and heterocycloalkyl, all optionally substituted by at least one member selected from the group consisting of halo, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, amino, (lower alkyl)amino, di(lower alkyl)amino, aryloxy and arylalkoxy;  
 n is 0 or 1;  
 T is —C(O)—O-Rt 1  or —C(O)-Rt 2  wherein 
 Rt 1  is selected from the group consisting of lower alkyl, benzyl and phenethyl;  
 Rt 2  is selected from the group consisting of lower alkyl, lower arylalkyl, aryloxy lower alkyl and a heteroaryl.  
 
   
   
   
       15 . A product of  claim 11  wherein the calpain inhibitor has the formula  
       T-NH—CH(R 1 )—C(O)—NH—CH(R 2 )—C(O)—[NH—CH(R 3 )—C(O)] n —Y   (I b )  wherein    R 1  and R 2  are, independently, alkyl optionally substituted by phenyl optionally substituted by halo or hydroxy;    Y is hydrogen;    T is —C(O)—O-Rt 1  wherein Rt 1  is lower alkyl or benzyl, and n=0.    
   
   
       16 . A product of  claim 11  wherein the calpain inhibitor is 3-(4-iodophenyl)-2-mercapto-2-propenoic acid.  
   
   
       17 . A product of  claim 11  wherein the reactive oxygen species trap is selected from the group consisting of ascorbic acid, ethoxyquin, N-acetyl-cysteine, β-carotene, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid, the Q10 coenzyme, captodative compounds, nitrones, phenolic compounds, indole derivatives, indolines, imidazoles, phenothiazines, phenoxazines, phenazines, diphenylamines and carbazoles.  
   
   
       18 . A product of  claim 11  wherein the reactive oxygen species trap is selected from the group consisting of ascorbic acid, ethoxyquin, tempol, N-tert-butyl-α-phenyl-nitrone, N-acetyl-cysteine, β-carotene, 2,2,5,5-tetramethyl-3-pyrroline-1-oxyl-3-carboxylic acid, the Q10 coenzyme, captodative compounds, probucol, NDGA, α-, β-, γ-, ε-, τ- or δ-tocopherol, 3,5-di-tert-butyl-4-hydrobenzoic acid, 2,3,6-trimethyl-2-hexyloxyphenol, 2,6-di-tert-butyl4-methoxyphenol, 2,6-di-tert-butyl-4-methylphenol, trolox, n-propyl gallate, eugenol, cafeic acid, sinapinic, gallic acid, propofol, melatonin, 5-hydroxy-tryptamine, 5-hydroxy-indole-2-carboxylic acid, 5-amino-indoline, N-methyl-indoline, imidazole, cimetidine, 4-hydroxy-carbazole, carvedilol, 2-methoxy-10H-phenothiazine, 4-hydroxydiphenylamine, 4-aminodiphenylamine, 4-methoxy-N-(4-methoxyphenyl) aniline and 9-[2-(4-morpholinyl)ethyl]-2,4-di-1-pyrrolidinyl-9H-pyrimido [4,5-b]indole.  
   
   
       19 . A product of  claim 11  wherein the reactive oxygen species trap is selected from the group consisting of phenolic compounds, phenothiazines and diphenylamines.  
   
   
       20 . A product of  claim 11  wherein the reactive oxygen species trap is selected from the group consisting of 3-5-di-tert-butyl-4-hydroxybenzoic acid (BHT), 2-methoxy-10H-phenothiazine and 4-hydroxydiphenylamine; and the compound which inhibits calpains is selected from the group consisting of benzyl (1S)-1-({[(1S)-1 formyl-3-methylbutyl]amino}carbonyl)-3-methylbutylcarbamate, benzyl (1S)-1-{[(1-benzyl-2-oxoethyl)amino]carbonyl}-3-methylbutylcarbamate, benzyl ester of [1-[[1-formylpentyl)amino]carbonyl-3-methylbutyl]carbamic acid (calpeptin) and 3-(4-iodophenyl)-2-mercapto-2-propenoic acid.  
   
   
       21 - 27 . (canceled)  
   
   
       28 . A method of treating a disorder of the central nervous system in a warm-blooded animal comprising administering to warm-blooded animals in need thereof an effective amount of a composition of  claim 13.