Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof

• US 20060030615A1
• Filed: 07/06/2005
• Published: 02/09/2006
• Est. Priority Date: 08/09/2004
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Wrobel, Jay Edward, Marella, Michael Anthony, Melenski, Edward George, McComas, Casey Cameron, Fensome, Andrew
• Application Number:
  US11/175,457
• Publication Number:
  US 20060030615A1
• Time in Patent Office: Days
• US Class Current: 514/414
• CPC Class Codes: A61K 31/403 condensed with carbocyclic rings, e.g. carbazole
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/24 of the sex hormones
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond

Abstract

Pyrrole-oxindole derivatives useful as progesterone receptor antagonists are provided. Pharmaceutical compositions containing these derivatives are described, as is the use thereof in contraception and hormone-related conditions.

Claims

1. A composition comprising a progesterone receptor antagonist comprising a compound of formula I:

2. The composition according to claim 1, wherein

R₁ is hydrogen or alkyl;

R₂ and R₃ are taken together to form a ring and together contain —

CH₂—

(CH₂)_n—

CH₂—

;

n is 1 or 2.

3. The composition according to claim 1, wherein R₂ and R₃ are each an alkyl.

4. The composition according to claim 3, wherein R₂ or R₃ is ethyl.

5. The composition according to claim 3, wherein R₂ or R₃ is methyl.

6. The composition according to claim 1, wherein R₉ is C₁-C₄ alkyl.

7. The composition according to claim 6, wherein R₉ is methyl.

8. The composition according to claim 1, wherein said compound is selected from the group consisting of:

1-methyl-5-(2′

-oxo-1′

,2′

-dihydrospiro[cyclobutane-1,3′

-indol]-5′

-yl)-1H-pyrrole-2-carbonitrile;

1-methyl-5-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-2-carbonitrile;

5-(3-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

1-methyl-5-(2′

-oxo-1′

,2′

-dihydrospiro[cyclopropane-1,3′

-indol]-5′

-yl)-1H-pyrrole-2-carbonitrile;

1-methyl-5-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-2-carbonitrile

9. The composition according to claim 1, wherein R₉ is COOR^A and R^A is tert-butyl.

10. The composition according to claim 1, wherein the composition comprises a low dose of a compound selected from the group consisting of:

5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-[(3R)-3-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;

5-[(3S)-3-ethyl-2-oxo-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;

5-[(3R)-3-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile; and

5-[(3S)-3-ethyl-3-methyl-2-oxo-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile.

11. The composition according to claim 1 further comprising a pharmaceutically acceptable carrier or excipient.

12. A method for inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

13. A method for hormone replacement therapy in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

14. A method for treating hormone-dependent neoplastic disease in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

15. The method according to claim 13, wherein the hormone-dependent neoplastic disease is selected from the group consisting of:

uterine myometrial fibroids;

endometriosis;

benign prostatic hypertrophy; and

carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary, and meningioma.

16. A method of synchronizing estrus in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

17. A method of treating dysmenorrhea in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

18. A method of treating dysfunctional uterine bleeding in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

19. A method of inducing amenorrhea in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

20. A method of treating to symptoms of premenstrual syndrome and premenstrual dysphoric disorder in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a composition of claim 1.

21. A method of contraception which comprises administering to a female of child bearing age for 28 consecutive days:

a) a first phase of from 14 to 24 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 100 μ

g levonorgestrel; and

b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of an antiprogestin compound according to claim 1.

22. The method according to claim 21, wherein said medicament further comprises a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo for the remaining days of the 28 consecutive days in which no antiprogestin, progestin or estrogen is administered.

23. The method according to claim 21, wherein the progestational agent is tanaproget.

24. The method according to claim 21, wherein the first phase further comprises co-administering an estrogen at a daily dose of 10 to 35 μ

g.

25. The method according to claim 21, wherein the second phase further comprises co-administering an estrogen at a daily dose of 10 to 35 μ

g.

26. The method according to claim 24, wherein the estrogen is ethinyl estradiol.

27. The method according to claim 25, wherein the estrogen is ethinyl estradiol.

28. The method according to claim 21, wherein the first phase comprises 18 to 24 days.

29. The method according to claim 21, wherein the first phase comprises 21 days.

30. The method according to claim 21, wherein the second phase comprises 3 days.

31. The method according to claim 22, wherein the third phase comprises 4 days.

32. A pharmaceutically useful kit adapted for daily oral administration which comprises:

a) 14 to 21 daily dosage units of a progestational agent equal in progestational activity from about 35 to about 150 μ

g levonorgestrel;

b) 1 to 11 daily dosage units of an antiprogestin compound of claim 1, each daily dosage unit containing an antiprogestin compound at a daily dosage of from about 2 to 50 mg; and

c) one or more packages for said daily dosage units.

33. The pharmaceutically useful kit according to claim 32, further comprising daily dosage units of an orally and pharmaceutically acceptable placebo, wherein the total daily dosage units in said kit is 28.