5-Aryl-indan-1-one and analogs useful as progesterone receptor modulators

• US 20070066675A1
• Filed: 09/18/2006
• Published: 03/22/2007
• Est. Priority Date: 09/19/2005
• Status: Active Grant

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Zhang, Puwen, Trybulski, Eugene, Terefenko, Eugene, Kern, Jeffrey
• Granted Patent: US 7,319,152 B2
• Time in Patent Office: Days
• US Class Current: 514/408
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: C07D 207/34 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 to ring carbon atoms
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 333/22 Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
• CPC Class Codes: C07D 333/28 Halogen atoms

Abstract

Compounds of formula I or II are provided, wherein R₁—R₈ are defined herein, and pharmaceutical compositions and kits containing these compounds.

Also provides are methods of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease using the compounds of formula I, formula II, or formula III, wherein R₂—R₄ and R₉ are defined herein.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein:

R₁ and R₂ are, independently, H or C₁ to C₆ alkyl;

R₃ is a 5 membered heteroaryl ring containing in its backbone 1 NR^C heteroatom and substituted with 0 to 3 substituents selected from the group consisting of H, CN, and C₁ to C₃ alkyl;

R₄, R₅, R₆, R₇, and R₈ are H.

3. The compound according to claim 1, wherein R₃ is 1-methyl-2-cyanopyrrole, 1-methyl-2-cyano-4-acetylpyrrole or 2-chlorothiophene.

4. The compound according to claim 1, wherein R₁ is heteroaryl or aryl.

5. The compound according to claim 1, wherein R₃ is of the structure:

6. The compound according to claim 1, wherein R₃ is of the structure:

7. The compound according to claim 1 which is 1-methyl-5-(5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrrole-2-carbonitrile.

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

12. A method of inducing contraception, providing hormone replacement therapy, or treating cycle-related symptoms, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to claim 1.

13. A method of treating or preventing benign or malignant neoplastic disease, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to claim 1.

9. A compound of formula II:

10. The compound according to claim 9, wherein:

R₁ and R₂ are fused to form (a), (b), or (c).

11. A pharmaceutical composition comprising a compound of claim 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

14. A method of inducing contraception, providing hormone replacement therapy, treating cycle-related symptoms, or treating or preventing benign or malignant neoplastic disease, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound according to claim 9.

15. A method of providing hormone replacement therapy or treating cycle-related symptoms, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula III:

16. A method of inducing contraception or treating or preventing benign or malignant neoplastic disease, comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of formula III:

17. 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 structure;

wherein;

R₂ is selected from the group consisting of H, halogen, C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R₃ is heteroaryl or substituted heteroaryl;

R₄ is H, halogen, CN, OH, NO₂, alkoxy, or lower alkyl;

R₉ is H, F, or C₁ to C₃ alkyl;

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.

18. 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 compound of the structure;

wherein;

R₂ is selected from the group consisting of H, halogen, C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R₃ is heteroaryl or substituted heteroaryl;

R₄ is H, halogen, CN, OH, NO₂, alkoxy, or lower alkyl;

R₉ is H, F, or C₁ to C₃ alkyl;

or a pharmaceutically acceptable salt thereof;

(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 progestational agent equal in progestational activity to about 35 to about 100 μ

g levonorgestrel; 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.

19. 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 the structure;

wherein;

R₂ is selected from the group consisting of H, halogen, C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R₃ is heteroaryl or substituted heteroaryl;

R₄ is H, halogen, CN, OH, NO₂, alkoxy, or lower alkyl;

R₉ is H, F, or C₁ to C₃ alkyl;

or a pharmaceutically acceptable salt thereof; and

wherein, each daily dosage unit contains 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.

20. 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 compound of a compound of the structure;

wherein;

R₂ is selected from the group consisting of H, halogen, C₁ to C₆ alkyl, CF₃, CF₂CF₃, C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, C₃ to C₈ cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;

R₃ is heteroaryl or substituted heteroaryl;

R₄ is H, halogen, CN, OH, NO₂, alkoxy, or lower alkyl;

R₉ is H, F, or C₁ to C₃ alkyl;

or a pharmaceutically acceptable salt thereof;

(b) a second phase of from 1 to 11 daily dosage units of a progestational agent equal in progestational activity to about 35 to about 150 μ

g levonorgestrel, each daily dosage unit containing said progestational agent 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.