Bivalent inhibitors of IAP proteins and therapeutic methods using the same
Inhibitors of IAP proteins and compositions containing the same are disclosed. Methods of using the IAP protein inhibitors in the treatment of diseases and conditions wherein inhibition of IAP proteins provides a benefit, like cancers, also are disclosed.
1. A compound having a structure
wherein X is selected from the group consisting of
and —SO 2 —;
Y is selected from the group consisting of —NH—, —O—, and —S—, or Y is null when X is —SO 2 —;
R is selected from the group consisting of
wherein ring A is a C 4-8 aliphatic ring
wherein the B ring is phenyl, naphthyl, pyridinyl, pyridazinyl, pyrazinyl, or pyrimidinyl and the B rings are optionally substituted with halo, CF 3 or both; and
R 1 is selected from the group consisting of —(CH 2 ) 4-10 —,
wherein Z is O, S, or NH, and
wherein n is 0, 1, or 2 and the
rings are optionally substituted with C 1-3 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein R is
wherein p is 0 to 4,
wherein q is 0 to 2, or —(CH 2 ) 2-4 —C 6 H 5 .
3. The compound of claim 2 wherein R is
4. The compound of claim 1 wherein R 1 is
wherein n is 0 or 1.
5. The compound of claim 4 wherein R 1 is
6. The compound of claim 1 wherein X is
and Y is —NH—.
7. The compound of claim 1 wherein X is SO 2 and Y is null.
8. The compound of claim 1 wherein X is
and Y is —NH—.
9. The compound of claim 1 wherein X and X′ are
and Y is —O—.
10. A compound selected from the group consisting of
11. A compound selected from the group consisting of
12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.
13. A method of treating a breast cancer or an ovarian cell line cancer comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof.
14. The method of claim 13 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the breast cancer or ovarian cell line cancer.
15. The method of claim 14 wherein the compound of claim 1 and the second therapeutic agent are administered simultaneously.
16. The method of claim 14 wherein the compound of claim 1 and the second therapeutic agent are administered separately.
17. The method of claim 14 wherein the second therapeutic agent is one or more of a chemotherapeutic agent and radiation.
18. The method of claim 14 wherein the compound of claim 1 and the second therapeutic agent are administered from a single composition.
19. The method of claim 14 wherein the compound of claim 1 and the second therapeutic agent are administered from separate compositions.
20. The method of claim 14 wherein the compound of claim 1 is administered prior to the second therapeutic agent.
21. The method of claim 14 wherein the compound of claim 1 is administered after the second therapeutic agent.
22. A compound having a structure