Chemical synthesis of a highly potent epothilone
A highly active synthetic epothilone compound whose activity exceeds that of either epothilone EpoA or EpoB when assayed as a cytotoxic agent against a cancer cell line is disclosed as is a pharmaceutical composition containing the synthetic epothilone.
1. A compound that corresponds in structure to Formula A-1, A-2, A-3 or A-4
wherein R A is an aromatic ring having the structure
wherein the depicted five-membered ring is aromatic and contains at least two ring atoms that are other than carbon,
each of X 1 , X 2 and X 3 is independently S, NR 1 , N, CH, or CR 2 ,
R 1 is C 1 -C 8 -hydrocarbyl or methylene-C 1 -C 8 -hydrocarbylether, and
R 2 is selected from the group consisting of C 1 -C 8 -hydrocarbyl, O—C 1 -C 8 -hydrocarbyl, halo, S—C 1 -C 8 -hydrocarbyl, methylenethio-C 1 -C 8 -hydrocarbyl and methylenethio-C 1 -C 8 -acyl, with the proviso that when X 2 is S and X 3 is CR 2 , R 2 is other than C 1 -C 8 -hydrocarbyl, O—C 1 -C 8 -hydrocarbyl or S—C 1 -C 8 -hydrocarbyl; when X 1 is CH and X 2 is NR 1 , X 3 is other than CH or CR 2 ; when X 1 is NR 1 and X 2 is CH, X 3 is other than CR 2 ; when X 1 is CH and X 2 is N, X 3 is other than CH or CR 2 wherein R 2 is CH 3 .
2. The compound according to claim 1 wherein X 1 is CH.
3. The compound according to claim 1 wherein X 1 is N.
4. The compound according to claim 1 wherein X 1 is NR 1 .
5. The compound according to claim 1 wherein X 1 is CR 2 .
6. The compound according to claim 1 wherein X 1 is S.
7. The compound according to claim 1 wherein X 2 is S.
8. The compound according to claim 1 wherein X 2 is NR 1 .
9. The compound according to claim 1 wherein X 2 is N.
10. The compound according to claim 1 wherein X 2 is CR 2 .
11. The compound according to claim 1 wherein X 3 is CR 2 .
12. The compound according to claim 1 wherein X 3 is CH.
13. The compound according to claim 1 wherein X 3 is NR 1 .
14. The compound according to claim 1 wherein R 1 is C 1 -C 8 -hydrocarbyl.
15. The compound according to claim 1 wherein R 2 is C 1 -C 8 -hydrocarbyl.
16. The compound according to claim 1 wherein R 2 is halo.
17. The compound according to claim 1 wherein R A is
18. The compound according to claim 1 that corresponds in structure to Formula A-1.
19. A compound that corresponds in structure to Formula C-1, C-2, C-3 or C-4
wherein R C is an aromatic ring having a structure selected from the group consisting of
20. A compound that corresponds in structure to the formula
21. A compound that corresponds in structure to the formula
22. A composition containing a pharmaceutically effective amount of a compound of claim 1 dissolved or dispersed in a pharmaceutically acceptable diluent.
23. The composition according to claim 22 wherein R A is
24. A pharmaceutical composition comprising a compound according to claim 18 present in an effective amount dissolved or dispersed in a pharmaceutically acceptable diluent.