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

• US 20080119537A1
• Filed: 11/16/2007
• Published: 05/22/2008
• Est. Priority Date: 09/19/2005
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Trybulski, Eugene, Terefenko, Eugene, Zhang, Puwen, Kern, Jeffrey
• Application Number:
  US11/985,808
• Publication Number:
  US 20080119537A1
• Time in Patent Office: Days
• US Class Current: 514/427
• 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 and pharmaceutical compositions and kits containing these compounds are provided. Also provided 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.

Claims

1. A compound of formula (I) or (II):

(I) a compound of formula (I);

wherein;

R₁ and R₂ are, independently, 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;

provided that both R₁ and R₂ are not H;

or

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

(a) a carbon-based 3 to 6 membered saturated spirocyclic ring;

(b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds;

or

(c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂, and NR^C;

wherein rings (a)-(c) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C₁ to C₃ alkyl;

R₃ is (i) or (ii);

(i) a 5 or 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, and SO₂ and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO₂, OH, amino, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ alkylamino, C═

NOR^C, COR^D, and NR^CCOR^D;

or

(ii) a 5 or 6 membered heteroaryl ring containing in its backbone 1 or 3 NR^C heteroatoms and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO₂, OH, amino, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ alkylamino, C═

NOR^C, COR^D, and NR^CCOR^D;

R^C is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, CN, or COR^D;

R^D is H, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, or C₁ to C₄ alkylamino;

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

R₅, R₆, R₇, and R₈ are, independently, H, F, or C₁ to C₃ alkyl;

or a pharmaceutically acceptable salt thereof;

or

(II) a compound of formula (II);

wherein;

(i) R₁ and R₂ are, independently, heteroaryl or substituted heteroaryl;

or

R₁ and R₂ are fused to form a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂, and NR^C, wherein the carbon-based ring is optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C₁ to C₃ alkyl;

R₃ is a saturated 5 or 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂, and NR^C and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO₂, OH, amino, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ alkylamino, C═

NOR^C, COR^D, and NR^CCOR^D;

or

R^C is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, CN, or COR^D;

R^D is H, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, or C₁ to C₄ alkylamino;

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

R₅ and R₆, are, independently, H, F, or C₁ to C₃ alkyl;

or a pharmaceutically acceptable salt thereof;

or

(ii) R₁ and R₂ are, independently, 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;

provided that both R₁ and R₂ are not H;

or

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

(a) a carbon-based 3 to 6 membered saturated spirocyclic ring;

(b) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone one or more carbon-carbon double bonds;

or

(c) a carbon-based 3 to 6 membered spirocyclic ring having in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂, and NR^C;

wherein rings (a)-(c) are optionally substituted by 1 to 3 substituents selected from the group consisting of F, Cl, and C₁ to C₃ alkyl;

R₃ is a saturated 6 membered heteroaryl ring containing in its backbone 1 to 3 heteroatoms selected from the group consisting of O, S, SO, SO₂, and NR^C and substituted with 0 to 3 substituents selected from the group consisting of H, halogen, CN, NO₂, OH, amino, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, C₁ to C₄ alkylamino, C═

NOR^C, COR^D, and NR^CCOR^D;

or

R^C is absent, H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, CN, or COR^D;

R^D is H, C₁ to C₄ alkyl, C₁ to C₄ alkoxy, or C₁ to C₄ alkylamino;

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

R₅ and R₆ are, independently, H, F, or C₁ to C₃ alkyl;

or a pharmaceutically acceptable salt thereof.

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

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

4. A method of inducing contraception, providing hormone replacement therapy, or 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 of claim 1.

5. 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:

6. 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:

7. 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;

(I) 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;

or

(II) 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.

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 the structure;

wherein;

(I) 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 C₃alkyl;

or a pharmaceutically acceptable salt thereof;

or

(II) 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.

9. A pharmaceutical composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, wherein said compound of formula II is:

10. 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 of formula II: