OXA-STEROIDS DERIVATIVES AS SELECTIVE PROGESTERONE RECEPTOR MODULATORS

Abstract

The present invention is directed to novel 7-oxa-estra-4,9-diene-3,17-dione derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by at least one 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 C1-6alkyl, C2-4alkenyl, C2-4alkynyl, aryl and heteroaryl; wherein the aryl is optionally substituted with one or more substituents independently selected from halogen, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, nitro, amino, (C1-4alkylamino) and di(C1-4alkyl)amino;R2 is selected from the group consisting of ORA, SRA and —SO2—RA; wherein RA is selected from the group consisting of hydrogen and C1-4alkyl;R3 is selected from the group consisting of C1-6alkyl, C2-4alkenyl, C2-4alkynyl, phenyl, 5- to 6-membered heteroaryl and —CC—R4;R4 is selected from the group consisting of C1-6alkyl, C1-4alkyl-OH, C1-4alkyl-NRCRD, fluorinated C1-4alkyl, C1-4alkyl-O—C1-4alkyl, C3-8cycloalkyl, aryl and heteroaryl; wherein the aryl is optionally substituted with one to three substituents independently selected from halogen, C1-4alkyl, fluorinated C1-4alkyl, C1-4alkoxy, fluorinated C1-4alkoxy, cyano, nitro, amino, (C1-4alkylamino) and di(C1-4alkyl)amino; and wherein RC and RD are each independently selected from the group consisting of hydrogen and C1-4alkyl;or a pharmaceutically acceptable salt, ester or pro-drug thereof.

3. A compound as in claim 2, wherein R1 is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl; wherein the phenyl is optionally substituted with a substituent selected from the group consisting of C1-3alkoxy, amino, (C1-4alkylamino) and di(C1-4alkyl)amino;R2 is —OH;R3 is selected from the group consisting of C1-4alkyl, C2-4alkenyl, C2-4alkynyl and —CC—R4;R4 is selected from the group consisting of C1-4alkyl, —C1-4alkyl-OH, fluorinated C1-3alkyl, —C1-3alkyl-O—C1-3alkyl, —C1-4alkyl-NRCRD, C3-8cycloalkyl, phenyl and 5- to 6-membered heteroaryl; wherein the phenyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, C1-4alkyl, C1-2alkyl, fluorinated C1-2alkyl and cyano; andwherein RC and RD are each independently selected from hydrogen or C1-2alkyl;or a pharmaceutically acceptable salt, ester or pro-drug thereof.

4. A compound as in claim 3, wherein R1 is selected from the group consisting of 4-dimethylamino-phenyl and 4-methoxy-phenyl;R2 is —OH;R3 is selected from the group consisting of —CH2—CH2-CH3, —CH2═CH2, —CH2—CH2═CH2, —CCH, —CC—CH3 and —CC—R4;R4 is selected from the group consisting of t-butyl, —C(CH3)2—OH, trifluoromethyl, methoxy-methyl-, dimethylamino-methyl-, cyclopropyl, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-t-butylphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 4-bromophenyl, 4-cyanophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and 3-thienyl;or a pharmaceutically acceptable salt, ester or pro-drug thereof.

5. A compound as in claim 4, wherein R1 is 4-dimethylamino-phenyl;R2 is (S)—OH;R3 is —CC—R4;R4 is selected from the group consisting of phenyl, 3-methylphenyl, 4-methylphenyl, 4-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-fuorophenyl, 2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-cyanophenyl and 3-thineyl;or a pharmaceutically acceptable salt, ester or pro-drug thereof.

6. A compound as in claim 4, wherein R1 is 4-dimethylamino-phenyl;R2 is (S)—OH;R3 is —CC—R4;R4 is selected from the group consisting of trifluoromethyl, cyclopropyl, 3-methylphenyl, 4-methylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-cyanophenyl and 3-thienyl;or a pharmaceutically acceptable salt, ester or pro-drug 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.