Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof

• US 7,317,037 B2
• Filed: 07/06/2005
• Issued: 01/08/2008
• Est. Priority Date: 08/09/2004
• Status: Active Grant

• Current Assignee: Zoetis Services LLC (Zoetis Incorporated)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Grubb, Gary Sondermann, Wrobel, Jay Edward, Marella, Michael Anthony, Melenski, Edward George, McComas, Casey Cameron, Fensome, Andrew
• Primary Examiner(s): Anderson; Rebecca
• Assistant Examiner(s): Barker; Michael P.
• Application Number:
  US11/175,824
• Publication Number:
  US 20060030717A1
• Time in Patent Office: 916 Days
• Field of Search: 548/411, 548/466, 514/414, 206/569, 206/570
• 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 compound of formula I:

2. The compound 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.

3. The compound according to claim 1, wherein R₂ or R₃ is methyl or ethyl.

4. The compound according to claim 1, wherein:

R₁ is hydrogen;

R₂ and R₃ are C₁ to C₂ alkyl;

R₆ is fluorine;

R₇ is hydrogen; and

R₉ is alkyl.

5. The compound according to claim 1, wherein R₉ is methyl or COOR^A and R^A is tert-butyl.

6. The compound according to claim 1, wherein said compound is 5-(4-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile.

7. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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

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

g levonorgestrel;

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

(c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo;

wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28.

9. A method for preparing a compound of claim 1 comprising:

(a) alkylating an optionally substituted oxindole;

(b) brominating the product of step (a); and

(c) coupling the product of step (b) with a 2-cyanopyrrole.

10. The method according to claim 9, wherein said optionally substituted oxindole is of the structure:

11. The method according to claim 9, wherein the product of step (a) is of the structure:

12. The method according to claim 9, wherein the product of step (b) is of the structure:

13. The method according to claim 9, wherein said cyanopyrrole is of the structure:

14. A method for preparing a compound of claim 1 comprising:

(a) coupling a 5-bromo substituted oxindole and a pyrrole boronic acid containing a protecting group;

(b) converting the product of step a) to the nitrile; and

(c) removing said protecting group from the product of step b).

15. The method according to claim 14, wherein said 5-bromo substituted oxindole is of the structure:

16. The method according to claim 14, wherein said pyrrole boronic acid is of the structure:

17. The method according to claim 14, wherein the product of step (b) is of the structure:

18. A method for preparing a compound of claim 1, comprising:

(a) alkylating an optionally substituted oxindole of the structure;

19. The compound according to claim 1 which is 5-(4′

-fluoro-2′

-oxo-1′

,2′

-dihydrospiro[cyclopropane-1,3′

-indol]-5′

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

20. A compound of formula I:

21. The compound according to claim 20, wherein said compound is selected from the group consisting of 5-(7′

-fluoro-2′

-oxo-1′

,2′

-dihydrospiro[cyclobutane-1,3′

-indol]-5′

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

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

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

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

22. The compound according to claim 20, 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.

23. The compound according to claim 20, wherein R₂ or R₃ is methyl or ethyl.

24. The compound according to claim 20, wherein R₉ is methyl or COOR^A and R^A is tert-butyl.

25. The compound according to claim 20, 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-(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-pyrrole-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.

26. A pharmaceutical composition comprising a compound of claim 20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

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

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

g levonorgestrel;

(b) a second phase of from 1 to 11 daily dosage units of a compound of claim 20, each daily dosage unit containing said compound at a daily dosage of from about 2 to 50 mg; and

(c) a third phase of daily dosage units of an orally and pharmaceutically acceptable placebo;

wherein the total number of the daily dosage units in the first phase, second phase and third phase equals 28.

28. A method for preparing a compound of claim 20, comprising:

(a) alkylating an optionally substituted oxindole;

(b) brominating the product of step (a); and

(c) coupling the product of step (b) with a 2-cyanopyrrole.

29. The method according to claim 28, wherein said optionally substituted oxindole is of the structure:

30. The method according to claim 28, wherein the product of step (a) is of the structure:

31. The method according to claim 28, wherein the product of step (b) is of the structure:

32. The method according to claim 28, wherein said cyanopyrrole is of the structure:

33. A method for preparing a compound of claim 20, comprising:

(a) coupling a 5-bromo substituted oxindole and a pyrrole boronic acid containing a protecting group;

(b) converting the product of step a) to the nitrile; and

(c) removing said protecting group from the product of step b).

34. The method according to claim 33, wherein said 5-bromo substituted oxindole is of the structure:

35. The method according to claim 33, wherein said pyrrole boronic acid is of the structure:

36. The method according to claim 33, wherein the product of step (b) is of the structure:

37. A method for preparing a compound of claim 20, comprising:

(a) alkylating an optionally substituted oxindole of the structure;