Bicyclic androgen and progesterone receptor modulator compounds and methods

• US 7,696,246 B2
• Filed: 06/23/2005
• Issued: 04/13/2010
• Est. Priority Date: 08/27/1999
• Status: Active Grant

• Current Assignee: Ligand Pharmaceuticals, Inc.
• Original Assignee: Ligand Pharmaceuticals, Inc.
• Inventors: Martinborough, Esther, Zhi, Lin, Van Oeveren, Cornelis Arjan
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US11/165,769
• Publication Number:
  US 20050288350A1
• Time in Patent Office: 1,755 Days
• Field of Search: 549/288, 549/53, 546/197, 514/320, 514/432, 514/457
• US Class Current: 514/457
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/04 for inducing labour or abortion; Uterotonics
• 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 15/10 for impotence
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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: A61P 5/26 Androgens
• CPC Class Codes: A61P 5/28 Antiandrogens
• CPC Class Codes: A61P 5/34 Gestagens
• CPC Class Codes: A61P 5/36 Antigestagens
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: C07D 209/34 in position 2
• CPC Class Codes: C07D 209/96 Spiro-condensed ring systems
• CPC Class Codes: C07D 215/227 : only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 215/36 : Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 215/38 : Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 239/80 : Oxygen atoms
• CPC Class Codes: C07D 265/18 : with hetero atoms directly attached in position 2
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 277/68 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 311/14 : substituted in position 6 and unsubstituted in position 7
• CPC Class Codes: C07D 311/20 : hydrogenated in the hetero ring
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The present invention is directed to compounds, pharmaceutical compositions, and methods for modulating processes mediated by AR and PR. More particularly, the invention relates to nonsteroidal compounds and compositions that are high affinity, high specificity agonists, partial agonists (i.e., partial activators and/or tissue-specific activators) and antagonists for AR and PR. Also provided are methods of making such compounds and pharmaceutical compositions, as well as critical intermediates used in their synthesis.

Claims

1. A compound of the formula:

2. A compound of claim 1, wherein:

R³ and R⁴ each independently is hydrogen or optionally substituted C₁-C₆ alkyl;

R^3A is optionally substituted aryl or heteroaryl;

R⁵ is selected from among hydrogen, halogen and optionally substituted C₁-C₆ alkyl;

R⁷ and R⁸ each independently is hydrogen or halogen; and

R⁹ is hydrogen or halogen.

3. A compound of claim 2, wherein:

R²⁵ through R³⁰ each independently is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionally substituted; and

Y is selected from among O, S, and NOR³.

4. A compound of claim 1, wherein:

R¹ and R² each independently is selected from among COR³, CSR³, SO₂R³, NO, NR³R⁴, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₈ haloalkyl, C₂-C₈ haloalkenyl, C₂-C₈ haloalkynyl, C₁-C₈ heteroalkyl, C₂-C₈ heteroalkenyl, C₂-C₈ heteroalkynyl, (CH₂)_nR^3A, aryl, and heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, and heteroaryl are optionally substituted with F, Cl, Br, I, OR³, NR³R⁴, CN, NO₂, SR³, SOR³, SO₂R³, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R³ and R⁴ each independently is hydrogen or optionally substituted C₁-C₆ alkyl;

R^3A is optionally substituted aryl or heteroaryl;

R⁵ is selected from among hydrogen, halogen and optionally substituted C₁-C₆ alkyl;

R⁷ and R⁸ each independently is hydrogen or halogen;

R⁹ is hydrogen or halogen;

R²⁵ through R³⁰ each independently is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionally substituted; and

Y is selected from among O, S, and NOR³.

5. A compound of claim 1, wherein:

R¹ and R² taken together form a three- to nine-membered heteroalkyl or heteroalkenyl ring, wherein the heteroalkyl or heteroalkenyl ring are optionally substituted with F, Cl, Br, I, OR³, NR³R⁴, C₁-C₄ alkyl, C₁-C₄ haloalkyl or C₁-C₄ heteroalkyl;

R³ and R⁴ each independently is hydrogen or optionally substituted C₁-C₆ alkyl;

R^3A is optionally substituted aryl or heteroaryl;

R⁵ is selected from among hydrogen, halogen and optionally substituted C₁-C₆ alkyl;

R⁷ and R⁸ each independently is hydrogen or halogen;

R⁹ is hydrogen or halogen;

R²⁵ through R³⁰ each independently is hydrogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, wherein the C₁-C₆ alkyl and C₁-C₆ haloalkyl are optionally substituted; and

Y is selected from among O, S, and NOR³.

6. A compound of claim 1, wherein:

R¹ and R² are taken together to form one of;

7. A compound of claim 1, wherein:

R¹⁰ is selected from among;

8. A compound of claim 1, wherein:

R¹⁰ is selected from among;

9. A compound of claim 1, wherein:

R¹⁰ is;

10. A compound of claim 1, wherein R¹⁰ is:

11. A compound of claim 1, wherein R¹⁰ is:

12. A compound of claim 1, wherein R¹⁰ is:

13. A compound according to claim 1, wherein the compound is an androgen receptor modulator.

14. A compound according to claim 13, wherein the compound is an androgen receptor antagonist.

15. A compound according to claim 13, wherein the compound is an androgen receptor agonist.

16. A compound according to claim 13, wherein the compound is an androgen receptor partial agonist.

17. A compound according to claim 1, wherein the compound is a progesterone receptor modulator.

18. A compound according to claim 17, wherein the compound is a progesterone receptor antagonist.

19. A compound according to claim 17, wherein the compound is a progesterone receptor agonist.

20. A compound according to claim 17 wherein the compound is a progesterone receptor partial agonist.

21. A compound according to claim 1, wherein the compound is selected from among:

6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound

     474);

6-N,N-Diethylamino-4-trifluoromethylcoumarin (Compound

     480);

6-N,N-Dipropylamino-4-trifluoromethylcoumarin (Compound

     481);

6-(N-Isobutyl-N-propylamino)-4-trifluoromethyl coumarin (Compound

     483); and

6-(N-2,2,2-Trifluoroethyl-N-propylamino)-4-trifluoromethylcoumarin (Compound

     484).

22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula:

23. A pharmaceutical composition according to claim 22, wherein the compound is an androgen receptor modulator.

24. A pharmaceutical composition according to claim 23, wherein the compound is an androgen receptor antagonist.

25. A pharmaceutical composition according to claim 23, wherein the compound is an androgen receptor agonist.

26. A pharmaceutical composition according to claim 23, wherein the compound is an androgen receptor partial agonist.

27. A pharmaceutical composition according to claim 22, wherein the compound is a progesterone receptor modulator.

28. A pharmaceutical composition according to claim 27, wherein the compound is a progesterone receptor antagonist.

29. A pharmaceutical composition according to claim 27, wherein the compound is a progesterone receptor agonist.

30. A pharmaceutical composition according to claim 27, wherein the compound is a progesterone receptor partial agonist.

31. A pharmaceutical composition according to claim 27, wherein the composition comprises one or more compounds selected from among:

6-(bis-2,2,2-Trifluoroethyl)amino-4-trifluoromethylcoumarin (Compound

     474);

6-N,N-Diethylamino-4-trifluoromethylcoumarin (Compound

     480);

6-N,N-Dipropylamino-4-trifluoromethylcoumarin (Compound

     481);

6-(N-Isobutyl-N-propylamino)-4-trifluoromethylcoumarin (Compound

     483); and

6-(N-2,2,2-Trifluoroethyl-N-propylamino)-4-trifluoromethylcoumarin (Compound

     484).

32. A pharmaceutical composition according to claim 22, wherein the composition is formulated for oral, topical, intravenous, suppository or parenteral administration.