Griseofulvin derivatives

Abstract

The present invention relates to compounds of the following general formula (I), or to a pharmaceutically acceptable salt thereof, as well as to the uses thereof as a drug, in particular for treating cancerous or precancerous hyperproliferative conditions, and to the pharmaceutical compositions containing same.

1 . A compound of following formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       where:
    represents a single or double bond; 
 Y is C═O, C═S, CH 2 , CH—OR 1 , CHN 3 , CHNR 2 R 3 , C═N—OR 4 , C═N—NR 5 R 6 , 
 Z is a hydrogen atom or a R 9  group, and 
 X is a CH—R 10  group when   represents a single bond or a C—R 10  group when   represents a double bond, 
 
       with:
 R 1  to R 5  each independently representing a hydrogen atom or a (C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkyl-aryl, aryl-(C 1 -C 6 )alkyl or 5- or 6-membered heterocycle group; 
 R 6  representing a hydrogen atom or a (C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkyl-aryl, aryl-(C 1 -C 6 )alkyl, C(O)NH 2 , C(S)NH 2  or 5- or 6-membered heterocycle group; 
 R 9  representing —R 14 , —NHR 14 , —CH 2 —NHR 14 , —CH 2 —NH—C(O)—R 14 , —NH—CH 2 —R 14 , —NH—NH—R 14 , —NH—C(O)—R 14 , —NH—C(O)—CH 2 —R 14 , —NH—CH 2 —C(O)—R 14 , —NH—CH 2 —C(O)—O—R 14 , —NH—CH 2 —C(O)—NH—R 14 , —NH—SO 2 —R 14 , —S(O)—R 14 , —SO 2 —R 14 , —S(O)—CH 2 —R 14 , —SO 2 —CH 2 —R 14  or —NR 16 R 17 ; 
 R 10  representing a —S(O)R 15  or —S(O) 2 R 15  group; 
 R 14  representing a (C 1 -C 6 )alkyl, carbocycle, heterocycle, biaryl, carbocycle-(C 1 -C 6 )alkyl or heterocycle-(C 1 -C 6 )alkyl group, optionally substituted; 
 R 15  representing optionally substituted (C 1 -C 6 )alkyl, optionally substituted aryl, (C 1 -C 6 )alkyl-aryl, aryl-(C 1 -C 6 )alkyl, carbocycle, optionally substituted heterocycle, biaryl, carbocycle-(C 1 -C 6 )alkyl or heterocycle-(C 1 -C 6 )alkyl, and 
 R 16  and R 17  together forming, with their carrier nitrogen atom, a heterocycle optionally substituted with —R 14 , —OR 14  or —NHR 14 . 
 
     
     
         2 . The compound according to  claim 1 , wherein:
 R 1  to R 5  are each independently a hydrogen atom or a (C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkyl-aryl or aryl-(C 1 -C 6 )alkyl group; and   R 6  is a hydrogen atom or a (C 1 -C 6 )alkyl, aryl, (C 1 -C 6 )alkyl-aryl, aryl-(C 1 -C 6 )alkyl, C(O)NH 2  or C(S)NH 2  group.   
     
     
         3 . The compound according to  claim 1 , wherein Y is C═O, C═S, CH—OR 1 , CHN 3 , CHNR 2 R 3 , C═N—OR 4  or C═N—NR 5 R 6 . 
     
     
         4 . The compound according to  claim 1 , wherein Y is C═O, CH—OR 1 , CHN 3 , CHNR 2 R 3 , C═N—OR 4  or C═N—NR 5 R 6 . 
     
     
         5 . The compound according to  claim 1 , wherein Y is C═O, CH—OR 1 , C═N—OR 4  or C═N—NR 5 R 6 . 
     
     
         6 . The compound according to  claim 1 , wherein Y is a C═O or CH—OR 1  group. 
     
     
         7 . The compound according to  claim 1 , wherein Y is C═O. 
     
     
         8 . The compound according to  claim 1 , wherein Z is a hydrogen atom. 
     
     
         9 . The compound according to  claim 1 , wherein R 10  preferably represents a —S(O) 2 R 15  group. 
     
     
         10 . The compound according to  claim 1 , wherein R 15  is a (C 1 -C 6 )alkyl group optionally substituted with one or more groups selected from among CO 2 R 26 , OR 27  and NR 28 R 29 ; an aryl group; a (C 1 -C 6 )alkyl-aryl group; or an aryl-(C 1 -C 6 )alkyl group. 
     
     
         11 . The compound according to  claim 1 , selected from among: 
       
         
           
                 
                 
               
                     
                 
                   Compound 
                     
                 
                   N° 
                   Structures 
                 
                     
                 
                   145 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   146 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   147 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   148 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . A pharmaceutical composition comprising at least one compound according to  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         13 . A method for treating cancerous and pre-cancerous hyperproliferative pathologies comprising the administration of an efficient dose of a compound according to  claim 1  to a person in need thereof. 
     
     
         14 . The method according to  claim 13 , wherein the cancerous or pre-cancerous hyperproliferative pathology is selected from among lung cancer, breast cancer, brain cancer and skin cancers. 
     
     
         15 . The method according to  claim 14 , wherein the skin cancer is selected from among actinic keratosis, solar keratosis, keratinocyte intraepithelial neoplasia, cutaneous papilloma, in situ squamous cell carcinoma, squamous cell carcinoma, pre-cancerous skin lesions, basal cell carcinoma, Bowen's disease, Dubreuilh's melanoma, condylomas, Merkel's cell tumour, Paget's disease, and cutaneous-mucosal lesions caused by human papilloma virus. 
     
     
         16 . The method according to  claim 15 , wherein the basal cell carcinoma is in surface and nodular forms.