6-Amino-1,4-dihydro-benzo[d][1,3]oxazin-2-ones and analogs useful as progesterone receptor modulators

• US 20070225281A1
• Filed: 05/21/2007
• Published: 09/27/2007
• Est. Priority Date: 10/09/2003
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Zhang, Puwen, Kern, Jeffrey
• Granted Patent: US 7,354,915 B2
• Time in Patent Office: Days
• US Class Current: 514/230.500
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: C07D 265/18 with hetero atoms directly attached in position 2

Abstract

Compounds having the structure of formula I are provided. In formula I, R₁ is H, OH, substituted or unsubstituted C₁ to C₃ alkyl, C₁ to C₃ perfluoroalkyl, or COR₆; R₆ is H, substituted or unsubstituted C₁ to C₄ alkyl, aryl, substituted or unsubstituted C₁ to C₄ alkoxy, substituted or unsubstituted C₁ to C₃ aminoalkyl; R₂ and R₃ are H, substituted or unsubstituted C₁ to C₆ alkyl, C₁ to C₆ perfluoroalkyl, substituted or unsubstituted C₂ to C₆ alkenyl, substituted or unsubstituted C₂ to C₆ alkynyl, substituted or unsubstituted C₃ to C₆ cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclic; or R₂ and R₃ are fused to form spirocyclic rings; R₄ is NHR₇, OR₇, NHSO₂R₇, or OSO₂R₇; Q is O, S, NR₈, or CR₉R₁₀; or a pharmaceutically acceptable salt, ester, or prodrug thereof. Such compounds are useful as progesterone receptor modulators and for treating progesterone receptor related conditions.

Claims

1. A progesterone receptor modulator having the formula:

2. The progesterone receptor modulator according to claim 1, wherein:

R₁ is selected from the group consisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, and C₁ to C₃ perfluoroalkyl;

R₂ and R₃ are independently selected from the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ perfluoroalkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₆ cycloalkyl, substituted C₃ to C₆ cycloalkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;

or R₂ and R₃ are fused to form the optionally substituted 3 to 8 membered saturated spirocyclic ring;

R₄ is selected from the group consisting of NHR₇, OR₇, NHSO₂R₇, and SO₂R₇;

R₇ is selected from the group consisting of (a) and (b);

(a) said aryl ring which is optionally substituted with one to three substituents independently selected from the group consisting of H, halogen, OH, CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, COR_B, CR_B═

NOR_C, OCOR_B, and NR_CCOR_B; and

(b) said 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂ and N, wherein said heterocyclic ring is optionally substituted with one or more substituents independently selected from the group consisting of H, halogen, OH, CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, COR_B, CR_B═

NOR_C, OCOR_B, and NR_CCOR_B;

R_B is selected from the group consisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl;

R_C is selected from the group consisting of H, C₁ to C₃ alkyl, and substituted C₁ to C₃ alkyl;

R₅ is H, OH, halogen, CN, or NO₂;

or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

3. The progesterone receptor modulator according to claim 1, wherein:

R₄ is NHR₇;

R₈ is selected from the group consisting of CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, SO₂CF₃, and OR₁₁;

R₉ and R₁₀ are independently selected from the group consisting of C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, NO₂, CN, and CO₂R₁₁;

R₁₁ and R₁₂ are independently selected from the group consisting of H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, acyl and sulfonyl;

or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

4. The progesterone receptor modulator according to claim 1, wherein:

R₁ is Me or CF₃

R₂ and R₃ are independently selected from the group consisting of C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, C₂ to C₄ alkenyl, substituted C₂ to C₄ alkenyl, C₂ to C₄ alkynyl, substituted C₂ to C₄ alkynyl, C₃ to C₅ cycloalkyl, substituted C₃ to C₅ cycloalkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;

or R₂ and R₃ are fused to form an optionally substituted 3 to 6 membered saturated spirocyclic ring;

R₅ is H, OH, halogen, CN, or NO₂;

Q is O or S;

or a pharmaceutically acceptable salt, tautomer, or prodrug thereof.

5. A pharmaceutical composition comprising a progesterone receptor modulator according to claim 1 and a physiologically compatible carrier.

9. A method for treating uterine fibroids comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

10. A method for treating endometriosis comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

11. A method for treating dysmenorrhea comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

12. A method for treating breast cancer comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

13. A method for treating uterine cancer comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

14. A method for treating ovarian cancer comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

15. A method for treating prostate cancer comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

16. A method for treating meningioma comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

17. A method for treating acne comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

18. A method for treating hirsutism comprising administering to a patient in need thereof a progesterone receptor modulator according to claim 1.

6. A method for contraception comprising administering to a female of child-bearing age a progesterone receptor modulator having the formula:

7. The method for contraception according to claim 6, 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 an antiprogestin compound of formula I; 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.

8. A method for hormone replacement therapy comprising administering to a patient in need thereof a progesterone receptor modulator having the formula:

19. A kit comprising:

(i) a dosage form of a progesterone receptor modulator having formula I;

wherein;

R₁ is H, OH, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ perfluoroalkyl, or COR₆;

R₆ is H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, aryl, substituted aryl, C₁ to C₄ alkoxy, substituted C₁ to C₄ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R₂ and R₃ are independently selected from the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ perfluoroalkyl, C₂ to C₆ alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₆ cycloalkyl, substituted C₃ to C₆ cycloalkyl, aryl, substituted aryl, heterocyclic, and substituted heterocyclic;

or R₂ and R₃ are fused to form;

(i) an optionally substituted 3 to 8 membered saturated spirocyclic ring;

(ii) an optionally substituted 3 to 8 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds;

or

(iii) an optionally substituted 3 to 8 membered saturated spirocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S, and N;

R₄ is NHR₇, OR₇, NHSO₂R₇, OSO₂R₇, NCH₃R₇ or NCH₃SO₂R₇;

R₇ is selected from the group consisting of (a) and (b);

(a) an aryl ring which is optionally substituted with one to three independent substituents selected from the group consisting of H, halogen, OH, CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₂ to C₃ alkenyl, substituted C₂ to C₃ alkenyl, C₂ to C₃ alkynyl, substituted C₂ to C₃ alkynyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₅ to C₈ aryloxy, substituted C₅ to C₈ aryloxy, C₁ to C₃ thioalkoxy, substituted C₁ to C₃ thioalkoxy, amino, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, COR_B, CR_B═

NOR_C, OCOR_B, NR_CCOR_B, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of N, O, and S; and

(b) a 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂ and N and optionally substituted with one to three independent substituents selected from the group consisting of H, halogen, OH, CN, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, C₂ to C₃ alkenyl, substituted C₂ to C₃ alkenyl, C₂ to C₃ alkynyl, substituted C₂ to C₃ alkynyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C to C₃ thioalkoxy, substituted C to C₃ thioalkoxy, amino, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, COR_B, CR_B═

NOR_C, OCOR_B, NR_CCOR_B, and 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of N, O, and S;

R_B is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

R_C is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

R₅ is H, OH, halogen, CN, NO₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₁ to C₆ alkoxy, substituted C₁ to C₆ alkoxy, amino, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

Q is O, S, NR₈, or CR₉R₁₀;

R₈ is selected from the group consisting of CN, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, SO₂CF₃, OR₁, and NR₁₁R₁₂;

R₉ and R₁₀ are independent substituents selected from the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO₂, CN, and CO₂R₁₁;

or CR₉R₁₀ comprise a six membered ring as shown by the structure below;

R₁₁ and R₁₂ are independently selected from the group consisting of H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, acyl, and sulfonyl;

X is O, S, NR^E, or CR^ER^F

R^E and R^F are independently H, C₁ to C₄ lower alkyl, or C₁ to C₄ perfluoroalkyl;

or a pharmaceutically acceptable salt, tautomer, or prodrug thereof; and

(ii) a physiologically compatible carrier.

20. The kit according to claim 19, wherein said kit further comprises at least one additional active component selected from the group consisting of an estrogen and a selective estrogen receptor modulator.

21. The kit according to claim 19, wherein said kit 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 progesterone receptor modulator of formula I at a daily dosage of from about 2 to 50 mg; and

c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.

22. The kit according to claim 19, wherein said kit 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 100 μ

g levonorgestrel;

b) a second phase of from 1 to 11 daily dosage units of a progesterone receptor modulator of formula I at a daily dosage of from about 2 to 50 mg; and

c) optionally, a third phase of an orally and pharmaceutically acceptable placebo for the remaining days of the cycle in which no antiprogestin, progestin or estrogen is administered.

23. A prodrug of a progesterone receptor modulator having the formula: