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

• US 7,247,625 B2
• Filed: 09/21/2004
• Issued: 07/24/2007
• Est. Priority Date: 10/09/2003
• Status: Expired due to Fees

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Zhang, Puwen, Kern, Jeffrey
• Primary Examiner(s): Habte; Kahsay
• Application Number:
  US10/946,476
• Publication Number:
  US 20050085470A1
• Time in Patent Office: 1,036 Days
• Field of Search: 544/71, 544/92, 514/230.5
• US Class Current: 514/230.5
• 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 in formula I:

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 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, or tautomer thereof.

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

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 CO₂R_11;

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, or tautomer, thereof.

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

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 the 3 to 6 membered saturated spirocyclic ring;

R₅ is H, OH, halogen, CN, or NO₂;

Q is O or S;

X is O;

or a pharmaceutically acceptable salt, or tautomer thereof.

5. The progesterone receptor modulator according to claim 1 selected from the group consisting of:

6-[(3-chlorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-(4-chlorophenyl)-6-[(3-chlorophenyl)amino]-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3,4-dichlorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3,5-dichlorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4,4-diethyl-6-[(3-fluoro-5-nitrophenyl)amino]-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

3-[(4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)amino]-5-fluorobenzonitrile;

6-[(2,3-dichlorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(2,5-dichlorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3,4-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3,5-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chloro-4-fluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-acetylphenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

5-[(4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)amino]-2-fluorobenzonitrile;

6-[(3-acetyl-4-fluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-[(4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)amino]-2-fluorobenzonitrile;

6-[(2,3-dichlorophenyl)amino]-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(2,3-dichlorophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

1,4,4-trimethyl-6-[(4-nitrophenyl)amino]-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chloro-4-fluorophenyl)amino]-4,4-diethyl-5-fluoro-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chlorophenyl)amino]-4-ethyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chlorophenyl)amino]-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chloro-4-fluorophenyl)amino]-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

5-fluoro-3-[(1-methyl-2-oxo-1,2-dihydrospiro[3,1-benzoxazine-4,1′

-cyclopentan]-6-yl)amino]benzonitrile

6-[(4-bromophenyl)amino]-4-(4-chlorophenyl)-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromophenyl)amino]-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-[(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)amino]benzonitrile;

4-[(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)amino]benzonitrile;

6-[(2,4-dichlorophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

1,4,4-trimethyl-6-(1-naphthylamino)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromophenyl)amino]-1,4-dimethyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3,4-dichlorophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(2-chloro-4-nitrophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(2-methoxyphenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

1,4,4-trimethyl-6-[(2-methylphenyl)amino]-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(2-bromophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-(4-chlorophenyl)-6-[(4-chlorophenyl)amino]-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromo-2-chlorophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-ethoxyphenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromophenyl)amino]-1-ethyl-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(2-ethylphenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

1,4,4-Trimethyl-6-(4-phenoxy-phenylamino)-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(4-Hydroxy-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-[(4-bromophenyl)amino]-4,4-bis(4-chlorophenyl)-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4,4-bis(4-chlorophenyl)-6-[(3-chlorophenyl)amino]-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-benzyl-6-[(4-bromophenyl)amino]-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-benzyl-6-[(2-chlorophenyl)amino]-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-benzyl-6-[(3-chlorophenyl)amino]-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-bromophenyl)amino]-1-isopropyl-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-chlorophenyl)amino]-8-methoxy-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-(4-chlorophenyl)-6-[(3-chlorophenyl)amino]-4-ethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-(4-chlorophenyl)-6-[(3-chlorophenyl)amino]-4-ethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-(4-chlorophenyl)-6-[(3-chlorophenyl)amino]-1,4,8-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chlorophenyl)amino]-4-ethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(3-chlorophenyl)amino]-4-ethyl-1-methyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

4-(4-chlorophenyl)-6-[(3-chlorophenyl)amino]-8-methoxy-1,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-(3-Chloro-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(4-Fluoro-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(4-Methoxy-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

1,4,4-Trimethyl-6-p-tolylamino-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(4-Bromo-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(3,4-Difluoro-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(3,5-Difluoro-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

6-(2-Fluoro-3-methoxy-phenylamino)-1,4,4-trimethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one;

(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate;

(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-2,3-dichlorobenzenesulfonate;

2,3-dichloro-N-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide;

2,3-dichloro-N-(1,4,4-trimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide;

6-{[4-(dimethylamino)phenyl]amino}-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

6-[(4-chlorophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one; and

6-[(2-chlorophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

or a pharmaceutically acceptable salt, or tautomer thereof.

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

6-[(3,4-difluorophenyl)amino]-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione; and

6-[(4-bromophenyl)amino]-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine-2-thione;

or a pharmaceutically acceptable salt, or tautomer thereof.

7. The compound according to claim 1, wherein said compound is selected from the group consisting of 6-(3-chloro-4-fluorophenoxy)-4,4-diethyl-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one and 3-(4,4-diethyl-1-methyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yloxy)-5-fluoro-benzonitrile;

or a pharmaceutically acceptable salt, or tautomer thereof.

8. A pharmaceutical composition comprising a compound according to claim 1 and a physiologically compatible carrier.

11. A method for treating uterine fibroids comprising administering to a patient in need thereof a compound according to claim 1.

12. A method for treating endometriosis comprising administering to a patient in need thereof a compound according to claim 1.

13. A method for treating dysmenorrhea comprising administering to a patient in need thereof a compound according to claim 1.

14. A method for treating breast cancer comprising administering to a patient in need thereof a compound according to claim 1.

15. A method for treating uterine cancer comprising administering to a patient in need thereof a compound according to claim 1.

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

10. The method for contraception according to claim 9, 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.