Tricycloundecane compounds useful as modulators of nuclear hormone receptor function

• US 20070088029A1
• Filed: 10/17/2006
• Published: 04/19/2007
• Est. Priority Date: 10/18/2005
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Xiao, Hai-Yun, Balog, James, Fairfax, David, Martin, Gregory, Salvati, Mark
• Granted Patent: US 7,550,458 B2
• Time in Patent Office: Days
• US Class Current: 514/229.800
• CPC Class Codes: C07D 471/18 Bridged systems
• CPC Class Codes: C07D 498/18 Bridged systems

Abstract

Tricycloundecanes compounds, methods of using such compounds in the treatment of nuclear hormone receptor-associated conditions such as cancer and immune disorders, and pharmaceutical compositions containing such compounds are disclosed.

Claims

1. A compound of the following formula I:

2. The compound of claim 1, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

in which Y is O or CR¹R².

3. The compound of claim 2, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

in which Z¹ and Z² are each independently H, alkyl, and/or substituted alkyl.

4. The compound of claim 3, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

in which Q¹, Q², Q³, and Q⁴ are each independently H, alkyl, and/or substituted alkyl;

or Q¹ and Q² together form ═

O;

or Q³ and Q⁴ together form ═

O.

5. The compound of claim 4, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

in which G is substituted aryl.

6. The compound of claim 5, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

in which X¹ and X² are each CH.

7. The compound of claim 4, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

in which one of X¹ and X² is CR¹, and the other of X¹ and X² is N.

8. A pharmaceutical composition comprising:

a) at least one compound according to claim 1 or a pharmaceutically-acceptable salt, solvate, or prodrug thereof; and

b) a pharmaceutically acceptable carrier or diluent.

9. The pharmaceutical composition of claim 8, in which Y is O or CR¹R².

10. The pharmaceutical composition of claim 9, in which Z¹ and Z² are each independently H, alkyl, and/or substituted alkyl.

11. The pharmaceutical composition of claim 10, in which Q¹, Q², Q³, and Q⁴ are each independently H, alkyl, or substituted alkyl;

or Q¹ and Q² together form ═

O;

or Q³ and Q⁴ together form ═

O.

12. The pharmaceutical composition of claim 11, in which G is substituted aryl.

13. The pharmaceutical composition of claim 12, in which X¹ and X² are each CH.

14. The pharmaceutical composition of claim 12, in which one of X¹ and X² is CR¹, and the other of X¹ and X² is N.

15. A method of modulating the function of a nuclear hormone receptor which comprises administering to a mammalian species in need thereof an effective nuclear hormone receptor modulating amount of at least one compound according to claim 1, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof.

16. The method of claim 15, in which Y is O or CR¹R².

17. The method of claim 16, in which Z¹ and Z² are each independently H, alkyl, and/or substituted alkyl.

18. The method of claim 15 wherein the nuclear hormone receptor is selected from estrogen receptor, androgen receptor, progesterone receptor, glucocorticoid receptor, mineralocorticoid receptor, aldosterone receptor, and steroid and xenobiotic receptor.

19. The method of claim 15 wherein said nuclear hormone receptor is androgen receptor or mutated androgen receptor.

20. A method for treating a condition or disorder comprising administering to a mammalian species in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically-acceptable salt, solvate, or prodrug thereof;

wherein said condition or disorder is selected from the group consisting of;

proliferate diseases, cancers, benign prostate hypertrophia, adenomas and neoplasies of the prostate, benign or malignant tumor cells containing an androgen receptor, heart disease, angiogenic conditions or disorders, hirsutism, acne, hyperpilosity, inflammation, immune modulation, seborrhea, endometriosis, polycystic ovary syndrome, androgenic alopecia, hypogonadism, osteoporosis, suppressing spermatogenisis, libido, cachexia, anorexia, inhibition of muscular atrophy in ambulatory patients, androgen supplementation for age related decreased testosterone levels in men, cancers expressing an estrogen receptor, prostate cancer, breast cancer, endometrial cancer, hot flushes, vaginal dryness, menopause, amennoreahea, dysmennoreahea, contraception, pregnancy termination, cancers containing a progesterone receptor, menopause, cyclesynchrony, meniginoma, fibroids, labor induction, autoimmune disease, Alzheimer'"'"'s disease, psychotic disorders, drug dependence, non-insulin dependent Diabetes Mellitus, dopamine receptor mediated disorders, congestive heart failure, disregulation of cholesterol homeostasis, and attenuation of metabolism of a pharmaceutical agent.