Farnesyl derivatives and pharmaceutical compositions containing them

Abstract

Novel farnesyl derivatives which are inhibitors of the prenylated protein methyltransferase enzyme, and useful as anti-cancer drugs, have the following formula: wherein R 1 represents farnesyl, geranyl or geranyl-geranyl; Z represents C—R 6 or N; R 2 represents H, CN, the groups COOR 7 , SO 3 R 7 , CONR 7 R 8 and SO 2 NR 7 R 7 , wherein R 7 and R 8 are each independently hydrogen, alkyl, alkenyl, and the groups COOM and SO 3 M, wherein M is a cation; R 3 , R 4 , R 5 and R 6 are each independently hydrogen, carboxyl, alkyl, alkenyl, aminoalkyl, nitroalkyl, nitro, halo, amino, mono- or di-alkylamino, mercapto, mercaptoalkyl, azido, or thiocyanato; X represents O, S, SO, SO 2 , NH or Se; and the quaternary ammonium salts and N-oxides of the compounds of formula I wherein Z is N.

1. A compound of the formula: 
                 
 
       wherein
 R 1  represents farnesyl, geranyl  or geranyl-geranyl;  
 Z represents C—R 6 ;  
 R 2  represents H, CN, the groups COOR 7 , SO 3 R 7 , CONR 7 R 8 , and SO 2 NR 7 R 8 , wherein R 7  and R 8  are each independently hydrogen, alkyl, alkenyl, and the groups COOM and SO 3 M, wherein M is a cation;  
 R 3 , R 4 , R 5  and R 6  are each independently hydrogen, carboxyl, alkyl, alkenyl, aminoalkyl, nitro, halo, amino, mono- or di-alkylamino  dialkylamino, or mercapto, alkylthio and wherein only one of R 3 , R 4 , R 5  and R 6  are other than hydrogen, alkyl, or halogen;  
 X represents O, S, SO, SO 2 , or NH; and  
 with the proviso that when R 1  is geranyl, X is O, R 2  is H and two of R 3 , R 4  and R 5  are each H, then the third one is not alkyl, alkythio or F;    when R 1  is geranyl, X is SO 2  and R 2  and two of R 3 , R 4  and R 5  are each H then the third is not alkyl; and    (a) when R 1  is farnesyl and either X is O and R 4  is NH or OH or X is S, SO, SO 2 SO 2  or NH and R 4  is OH and at least one of R 2 , R 3  and R 5  is different from hydrogen, alkyl or halogen; and    ( b )  when Z is CH, X is O and R   2   , R   3    and R   5    are hydrogen, then R   4    is not carboxyl.      
 
     
     
       2. A compound according to  claim 1  having the formula: 
                 
 
     
     
       3. A compound according to  claim 1  having the formula: 
                 
 
     
     
       4. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 2  together with a pharmaceutically acceptable carrier. 
     
     
       5. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to  claim 3  together with a pharmaceutically acceptable carrier. 
     
     
       6. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the formula: 
                 
 
       wherein
 R 1  represents farnesyl, geranyl  or geranyl-geranyl;  
 R 2  represents H, CN, CO 2 M and SO 3 M, wherein M is a cation, CO 2 R 7 , SO 3 R 7 , CONR 7 R 8  and SO 2 NR 7 R 8 , wherein R 7  and R 8  are independently hydrogen, alkyl, alkenyl; and  
 R 3 , R 4 , R 5  and R 6  are each independently hydrogen, alkyl, alkenyl, aminoalkyl, nitro, halo, amino, mono- or di-alkylamino  dialkylamino, mercapto, or alkylthio and wherein only one of R 3 , R 4 , R 5  and R 6  are other than hydrogen, alkyl, or halogen;  
 X represents O, S, SO, SO 2 , or NH; and  
 with proviso that 
 when R 1  is farnesyl and either X is O and R 4  is NH 2  or OH or X is S, SO, SO 2  or NH and R 4  is OH and then at least one of R 2 , R 3  and R 5  is different from hydrogen, alkyl or halogen;  
 together with a pharmaceutically acceptable carrier.  
 
     
     
       7. A compound of the formula:
                   
       
         wherein  
           R   1    represents farnesyl or geranyl - geranyl;    
         
           R 
           2  
           represents CN, the groups COOR 
           7 
           , CONR 
           7 
           R 
           8 
           , wherein R 
           7  
           and R 
           8  
           are each independently hydrogen, alkyl or alkenyl, and COOM wherein M is a cation;  
         
           R   3   , R   4   , R   5   , and R   6    are each independently hydrogen, alkyl, alkenyl, aminoalkyl, nitro, halo, amino, mono -  or dialkylamino, mercapto, or alkylthio; and    
         
           X represents S.