Tetrahydro-1H-pyrido[3,4-b]indole anti-estrogenic drugs
The present disclosure provides tetrahydro-1H-pyrido[3,4-b]indole compounds or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer, N-oxide and/or substituted derivative or, optionally in a pharmaceutical composition, for the modulation of disorders mediated by estrogen, or other disorders as more fully described herein.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X is CH 2 — or —O—;
Y is
R 1 and R 2 are each hydrogen;
R 3 and R 4 are each independently selected from hydrogen and halo, and when one of R 3 or R 4 is halo, the other of R 3 or R 4 is hydrogen;
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 0 -C 4 (C 3 -C 6 cycloalkyl), or C 1 -C 6 heteroalkyl;
R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 0 -C 4 (C 3 -C 6 cycloalkyl); and
R 7 and R 8 are each independently selected from hydrogen and C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein X is —O—.
3. The compound of claim 1 , wherein Y is
4. The compound of claim 1 , wherein Y is
5. The compound of claim 3 , wherein R 5 is C 1 -C 6 alkyl.
6. The compound of claim 4 , wherein R 5 is C 1 -C 6 haloalkyl.
7. The compound of claim 1 , wherein R 6 is C 1 -C 6 haloalkyl.
8. The compound of claim 1 , wherein R 7 is C 1 -C 6 alkyl and R 8 is hydrogen.
9. The compound of claim 1 , wherein the compound is of Formula I(a):
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , wherein R 5 is C 1 -C 6 alkyl.
11. The compound of claim 10 , wherein R 6 is C 1 -C 6 haloalkyl.
12. The compound of claim 11 , wherein R 6 is —CH 2 CF(CH 3 ) 2 .
13. The compound of claim 9 , wherein R 7 is C 1 -C 6 alkyl and R 8 is hydrogen.
14. The compound of claim 1 , wherein the compound is of Formula I(c):
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein R 5 is C 1 -C 6 haloalkyl.
16. The compound of claim 15 , wherein R 5 is —CH 2 F.
17. The compound of claim 16 , wherein R 6 is C 1 -C 6 haloalkyl.
18. The compound of claim 17 , wherein R 6 is —CH 2 CF(CH 3 ) 2 .
19. The compound of claim 18 , wherein R 7 is C 1 -C 6 alkyl and R 8 is hydrogen.
20. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22. The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
24. A method for treating a disorder mediated by the estrogen receptor in a patient, which comprises administering to the patient a therapeutically effective amount of the compound of claim 1 , optionally in a pharmaceutically acceptable carrier.
25. The method of claim 24 , wherein the disorder is selected from the group consisting of breast cancer, ovarian cancer, endometrial cancer, vaginal cancer, lung cancer, bone cancer, uterine cancer and endometriosis.
26. The method of claim 24 , further comprising administering the compound in combination or alternation with another anti-cancer agent for the treatment of cancer.
27. The method of claim 24 , further comprising administering the compound in combination or alternation with an estrogen or a partial estrogen receptor antagonist for the treatment of a postmenopausal disorder.
28. The compound of claim 20 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
29. The method of claim 25 , wherein the cancer is breast cancer.