Farnesyl derivatives and pharmaceutical compositions containing them
View Patent ↗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.