Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof

• US 20080114050A1
• Filed: 11/16/2007
• Published: 05/15/2008
• Est. Priority Date: 08/09/2004
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Grubb, Gary, Wrobel, Jay, Marella, Michael, Fensome, Andrew, McComas, Casey, Melenski, Edward
• Application Number:
  US11/985,606
• Publication Number:
  US 20080114050A1
• Time in Patent Office: Days
• US Class Current: 514/414
• CPC Class Codes: A61P 13/08 of the prostate
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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, and methods for preparing the same, are provided. Pharmaceutical compositions containing these derivatives are described, as is the use thereof in contraception and hormone-related conditions.

Claims

1. A method of inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

2. The method 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 method according to claim 1, wherein R₂ and R₃ are alkyl.

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

5. The method according to claim 1, wherein:

R₁ is hydrogen;

R₂ and R₃ are alkyl;

or

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

CH₂—

(CH₂)_n—

CH₂—

;

n is 0 to 2;

R₄ is hydrogen;

R₆ is fluorine;

R₇ is hydrogen; and

R₉ is alkyl.

6. The method according to claim 3, wherein R₉ is methyl or COOR^A and R^A is tert-butyl.

7. The method according to claim 1, wherein said compound is selected from the group consisting of 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(7′

-fluoro-2′

-oxo-1′

,2′

-dihydrospiro[cyclopropane-1,3′

-indol]-5′

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

5-(7-fluoro-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

tert-butyl 2-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate;

tert-butyl 2-cyano-5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-1-carboxylate;

5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrole-2-carbonitrile;

Methyl-[5-(5-cyano-1-methyl-1H-pyrrol-2-yl)-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate;

5-(1-ethyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(7-fluoro-3,3-dimethyl-2-oxo-1-prop-2-yn-1-yl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-[7-fluoro-3,3-dimethyl-2-oxo-1-(2-phenylethyl)-2,3-dihydro-1H-indol-5-yl]-1-methyl-1H-pyrrole-2-carbonitrile;

5-(1-benzyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(7-fluoro-3,3-dimethyl-2-oxo-1-propyl-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(7-fluoro-1-isobutyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(7-fluoro-1-isopropyl-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(1-allyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(1-cyclohexyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile;

5-(1-cyclopentyl-7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.

8. A method for hormone replacement therapy, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

9. A method of treating hormone-dependent neoplastic disease in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

10. The method according to claim 9, wherein the hormone-dependent neoplastic disease is selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy;

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

11. A method of synchronizing estrus in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

12. A method of treating dysmenorrhea in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

13. 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 compound of the formula:

14. A method of inducing amenorrhea in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

15. A method of treating symptoms of premenstrual syndrome and premenstrual dysphoric disorder, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the formula:

16. 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;

(b) a second phase of from 1 to 11 daily dosage units, at a daily dosage of from about 2 to 50 mg, of a compound of the formula;

wherein;

R₁ is hydrogen, alkyl, substituted alkyl, cycloalkyl, C₃ to C₆ alkenyl, or C₃ to C₆ alkynyl;

R₂ and R₃ are each independently selected from the group consisting of hydrogen, alkyl, and substituted alkyl;

or

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

CH₂—

(CH₂)_n—

CH₂—

;

n is 0, 1, 2, or 3;

R₅ is hydrogen;

R₇ is hydrogen, alkyl, or halogen;

R₈ is hydrogen;

R₉ is hydrogen, alkyl, substituted alkyl, or COOR^A;

R^A is alkyl or substituted alkyl; and

(i) R₄ is halogen and R₆ is hydrogen or halogen;

or

(ii) R₄ is hydrogen and halogen and R₆ is halogen;

or a pharmaceutically acceptable salt thereof; and

(c) optionally, 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;

wherein the total daily dosage units of the first, second and third phases equals 28.

17. The method according to claim 16, wherein the progestational agent is tanaproget.

18. The method according to claim 16, wherein the first phase further comprises co-administering an estrogen at a daily dose of 10 to 35 μ

g.

19. The method according to claim 18, wherein the estrogen is ethinyl estradiol.

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

21. The method according to claim 20, wherein the first phase comprises 21 days.

22. The method according to claim 18, wherein the second phase comprises 3 days.

23. The method according to claim 19, wherein the third phase comprises 4 days.

24. A method of inducing contraception, hormone replacement therapy, treating hormone-dependent neoplastic disease, synchronizing estrus, treating dysmenorrheal, treating dysfunctional uterine bleeding, inducing amenorrhea, and treating 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 compound of the formula: