Use of cysteine derivatives for the preparation of a medicament intended to treat pathologies which result from the formation of the heterotrimeric G protein

Abstract

The invention relates to the use of cysteine derivatives for preparing a medicament intended to treat diseases which result from the formation of the heterotrimeric G protein. These diseases include in particular diseases linked to the following biological functions or disorders: smell, taste, perception of the light, neurotransmission, neurodegeneration, endocrine and exocrine gland functions, autocrine and paracrine regulation, arterial tension, embryogenesis, benign cell proliferation, oncogenesis, viral infection, immunological functions, diabetes, obesity, and benign :and malign proliferative diseases. Said cysteine derivatives include in particular: bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide (I), and bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphtyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl) disulphide (II).

1 - 12 . (canceled)  
     
     
         13 . A method of treating a disorder selected from oncogenesis, begnin and malign proliferative diseases in a patient comprising administering to said patient an amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of hydrogen, lower alkyl and lower alkylthio, R 2  and R 3  are individually hydrogen or lower alkyl, R 4  is  
       
         
           
           
               
               
           
         
       
       or ═O, R 5  is selected from the group consisting of a)hydrogen and b) lower alkyl, lower alkenyl, lower alkynyl, aryl, aryl lower alkyl, heterocycle and heterocycle lower alkyl, all unsubstituted or substituted with a member selected from the group consisting of lower alkyl, —O—R 10 , —S(O) m —R 10 ,  
       
         
           
           
               
               
           
         
       
       —NH—(SO 2 )—R 11 —COOR 12   
       
         
           
           
               
               
           
         
       
       m is an integer from 0 to 2, R 6  and R 7  are individually selected from the group consisting of a) hydrogen, b) unsubstituted  
       
         
           
           
               
               
           
         
       
       and c) lower alkyl, aryl, aryl lower alkyl, heterocycle and heterocycle lower alkyl, unsubstituted or substituted with a member of the group consisting of —OH, halogen, lower alkyl, lower alkoxy,  
       
         
           
           
               
               
           
         
       
       —COOH and  
       
         
           
           
               
               
           
         
       
       or taken together with the carbon atom to which they are attached form aryl or heterocycle, R 8  and R 9  are individually selected from the group consisting of a) hydrogen and b) lower alkyl, aryl lower alkyl, heterocycle and heterocycle lower alkyl, all unsubstituted or substituted with a member of the group consisting of —OH, halogen, lower alkyl, lower alkoxy,  
       
         
           
           
               
               
           
         
       
       taken together with the carbon atoms to which they are attached form aryl or heterocycle, R 10  and R 1  are individually selected from the group consisting of hydrogen, lower alkyl, aryl, aryl lower alkyl, heterocycle and heterocycle lower alkyl, R 13  is unsubstituted lower alkyl or lower alkyl substituted with a member selected from the group consisting of aryl, aryl lower alkyl, heterocycle and heterocycle lower alkyl, R 13  is unsubstituted lower alkyl or lower alkyl substituted with a member selected from the group consisting of lower alkyl, —O—R 10 , —S(O) m —R 10  and  
       
         
           
           
               
               
           
         
       
       R 14  is hydrogen or lower alkyl, it being understood that Al can also be a dimmer when two R 1  are hydrogen, and its non-toxic, pharmaceutically acceptable salts, sufficient to treat said disorder.  
     
     
         14 . The method of  claim 13  wherein the disorder is a begnin proliferative disease.  
     
     
         15 . The method of  claim 13  wherein the disorder is a malign proliferative disease.  
     
     
         16 . The method of  claim 13  wherein the compound used is selected from the group consisting of 
 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methylphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;    7-(2-amino-1-oxo-3-thiopropyl)-8-butyl-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2]pyrazine;    7-(2-amino-1-oxo-3-thiopropyl)-8-(1-methylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;    bis-1,1′-[7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine disulphide;    bis-1,1′-7-(2-amino-1-oxo-3-thiopropyl-(2-(1-naphthyl)-8-(2-methylpropyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazin-7-yl) disulphide;    7-(2-amino-1-oxo-3-thioprpyl)-8-(cyclohexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;    7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylmethoxy)methyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;    7-(2-amino-2-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(1-phenylmethoxy)-ethyl-5,6,7,8-tetrahydroimidazo[1.2a-pyrazine;    7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine;    7-(2-amino-1-oxo-3-thioproyl)-2-(2-methoxyphenyl)-8-(phenoxyethyl)-5,6,7,8-tetrahydro-imidazo[1.2a]pyrazine, or its dimeric form;    7-(2-amino-1-oxo-3-thiopropyl)-2-(2-methoxyphenyl)-8-(phenylsulphonylethyl)-5,6,7,8-tetrahydro-imidazo[1.2a]pyrazine;    and the non-toxic, pharmaceutically acceptable salts of the latter.    
     
     
         17 . The method of  claim 13  wherein the compound used is 7-(2-amino-1-oxo-3-thiopropyl)-8-(cyclhexylmethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1.2a]pyrazine or a non-toxic, pharmaceutically acceptable salt of the latter.