TETRACYCLIC STEROID DERIVATIVES USEFUL AS PROGESTERONE RECEPTOR MODULATORS

Abstract

The present invention is directed to tetracyclic steroid derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by a progesterone or glucocorticoid receptor.

Description

Claims

1. A compound of formula (I)

2. A compound as in claim 1, wherein R1 is selected from the group consisting of NRARB, —ORA, —SRA and —SO2—RA; wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-2alkyl;R2 is selected from the group consisting of C1-4alkyl, fluorinated C1-4alkyl, —C1-4alkyl-OH, C2-4alkenyl, —C2-4alkenyl-OH, —C2-4alkenyl-CF3, C2-4alkynyl, —C2-4alkynyl-CF3, —C2-4alkynyl-phenyl, —C(O)—C2-4alkyl, and —C(O)—C2-4alkenyl; wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy and fluorinated C1-4alkoxy;R3 is —OH;alternatively, R2 and R3 are taken together with the carbon atom to which they are bound to form C(O) or 2-(3-methylene-tetrahydro-furanyl);or a pharmaceutically acceptable salt, ester or prodrug thereof.

3. A compound as in claim 2, wherein R1 is selected from the group consisting of NRARB, —ORA, —SRA and —SO2—RA; wherein RA and RB are each independently selected from C1-2alkyl;R2 is selected from the group consisting of fluorinated C1-3alkyl, C2-4alkenyl, —C2-4alkenyl-OH, C2-4alkynyl; —C2-4alkynyl-CF3, —C2-4alkynyl-phenyl, and —C(O)—C2-4alkenyl; wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl and fluorinated C1-3alkyl;R3 is —OH;alternatively, R2 and R3 are taken together with the carbon atom to which they are bound to form C(O) or 2-(3-methylene-tetrahydro-furanyl);or a pharmaceutically acceptable salt, ester or prodrug thereof.

4. A compound as in claim 3, wherein R1 is selected from the group consisting of dimethylamino, methoxy, methylthio and methylsulfonyl;R2 is selected from the group consisting of —CF2—CF3, —CH(═CH2)—CH3, —CH2—CH═CH2, —CCH, —CC—CH3, —CC—CF3, —CC-phenyl, —CC-(4-trifluoromethyl-phenyl), —CC-(4-t-butyl-phenyl), —CC-(2-fluor-phenyl), —CC-(3-fluoro-phenyl), —CC-(4-fluoro-phenyl), —CC-(3,5-difluoro-phenyl), —CH(═CH2)—CH2—CH2—OH and —C(O)—CH═CH2;R3 is —OH;alternatively, R2 and R3 are taken together with the carbon atom to which they are bound to form C(O) or 2-(3-methylene-tetrahydro-furanyl);or a pharmaceutically acceptable salt, ester or prodrug thereof.

5. A compound as in claim 4, wherein R1 is selected from the group consisting of dimethylamino, methoxy and methylthio;R2 is selected from the group consisting of —CF2—CF3, —CH(═CH2)—CH3, —CCH and —CC—CH3;R3 is —OH;or a pharmaceutically acceptable salt thereof.

6. A compound as in claim 4, wherein R1 is selected from the group consisting of dimethylamino, methoxy and methylthio;R2 is selected from the group consisting of —CF2—CF3, —CH(═CH2)—CH3, —CCH, —CC-phenyl, —CC-(2-fluoro-phenyl), —CC-(4-fluoro-phenyl) and —CC-(4-trifluoromethyl-phenyl);R3is —OH;alternatively, R2 and R3 are taken together with the carbon atom to which they are bound to form 2-(3-methylene-tetrahydro-furanyl);or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.

8. A pharmaceutical composition made by mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

10. A method of treating a disorder mediated by a progesterone or glucocorticoid receptor, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

11. A method of contraception comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

12. The method of claim 10, wherein the disorder mediated by the progesterone receptor is selected from the group consisting of secondary amenorrhea; dysfunctional bleeding; uterine leiomyomata; endometriosis; polycystic ovary syndrome; carcinoma of the endometrium, carcinoma of the ovary, carcinoma of the breast, carcinoma of the colon, carcinoma of the prostate, adenocarcinomas of the ovary, adenocarcinomas of the breast, adenocarcinomas of the colon, adenocarcinomas of the prostate and side effects of cyclic menstrual bleeding.

13. The method of claim 10, wherein the disorder mediated by the glucocorticoid receptor is selected from the group consisting of Type II diabetes mellitus, impaired oral glucose tolerance, elevated blood glucose levels and Syndrome X.

14. A method of treating a disorder mediated by a progesterone or glucocorticoid receptor comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 7.

15. The use of a compound as in claim 1 for the preparation of a medicament for treating: (a) secondary amenorrhea; (b) dysfunctional bleeding; (c) uterine leiomyomata; (d) endometriosis; (e) polycystic ovary syndrome; (f) carcinoma of the endometrium, (g) carcinoma of the ovary, (h) carcinoma of the breast, (i) carcinoma of the colon, (j) carcinoma of the prostate, (k) adenocarcinomas of the ovary, (l) adenocarcinomas of the breast, (m) adenocarcinomas of the colon, (n) adenocarcinomas of the prostate, (o) side effects of cyclic menstrual bleeding, (p) Type II diabetes mellitus, (q) impaired oral glucose tolerance, (r) elevated blood glucose levels, (s) Syndrome X or (t) for contraception, in a subject in need thereof.

16. A compound of formula (II)

17. A compound as in claim 16, wherein R1 is selected from the group consisting of —SRA and —SO2—RA; wherein RA and RB are each independently selected from the group consisting of hydrogen and C1-2alkyl;R2 is selected from the group consisting of C1-4alkyl, fluorinated C1-4alkyl, —C1-4alkyl-OH, C2-4alkenyl, —C2-4alkenyl-OH, —C2-4alkenyl-CF3, C2-4alkynyl, —C2-4alkynyl-CF3, —C2-4alkynyl-phenyl, —C(O)—C2-4alkyl, and —C(O)—C2-4alkenyl; wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy and fluorinated C1-4alkoxy;or a pharmaceutically acceptable salt, ester or prodrug thereof.

18. A compound as in claim 17, wherein R1 is selected from the group consisting of —SRA; wherein RA is selected from C1-3alkyl;R2 is selected from the group consisting of —CC-phenyl; wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl and fluorinated C1-3alkyl;or a pharmaceutically acceptable salt, ester or prodrug thereof.

19. A compound as in claim 18, selected from the group consisting of the compound of formula (IIa)