Estrieno[3,2-b]/[3,4-c]pyrrole derivatives useful as modulators of the estrogen receptors

• US 7,074,779 B2
• Filed: 07/02/2003
• Issued: 07/11/2006
• Est. Priority Date: 07/02/2003
• Status: Expired due to Fees

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Inventors: Sui, Zhihua, Zhang, Xuqing
• Primary Examiner(s): Badio, Barbara P.
• Application Number:
  US10/612,138
• Publication Number:
  US 20050004090A1
• Time in Patent Office: 1,105 Days
• Field of Search: 540/49, 514/176
• US Class Current: 514/176
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07J 71/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring spiro-condensed heterocyclic rings C07J21/00, C07J33/00, C07J43/00

Abstract

The present invention is directed to novel estrieno[3,2-b]/[3,4-c]pyrrole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and diseases mediated by an estrogen receptor.

Claims

1. A compound of formula (I)

2. A compound as in claim 1 wherein

R¹ is selected from the group consisting of hydrogen, hydroxy, A, —

O-A, C(O)-A and —

SO₂-A;

n is an integer from 0 to 1;

each R² is independently selected from the group consisting of carboxy, halogen, -A, —

C(O)-A, —

C(O)O-A, cyano, —

S-A, —

SO-A, —

SO₂-A, —

SO₂—

NH₂, —

SO₂—

NH(alkyl) and —

SO₂—

N(alkyl)₂;

m is an integer from 0 to 1;

each R³ independently selected from the group consisting of -A, —

O-A, —

S-A, —

NH-A and —

C(O)-A;

p is an integer from 1 to 2;

R⁴ is selected from the group consisting of hydroxy, —

NH₂, —

NH(A), —

N(A)₂, —

C(O)NH₂, —

C(O)—

NH(A), —

SO₂—

NH₂, —

SO₂—

NH(A) and —

OC(O)-A, when the R⁴ is in a β

-orientation;

R⁴ is selected from the group consisting of hydroxy, carboxy, cyano, -A, alkenyl, -alkenyl-A, alkynyl, -alkynyl-A, —

O-A, —

NH₂, —

NH(A), —

N(A)₂, —

N(A)-C(O)-A, —

NH—

C(O)-A, —

C(O)—

N(A)₂, —

C(O)—

NH₂, —

C(O)—

NH-A, —

SO₂—

N(A)₂, —

SO₂—

NH(A), —

SO₂—

NH₂, —

N(A)-SO₂-A, —

NH—

SO₂-A, —

C(O)O-A, —

OC(O)H and —

OC(O)-A, when the R⁴ in an α

-orientation;

alternatively, when p is 2, two R⁴ groups may be taken together as oxo or ═

N(OH);

q is an integer from 0 to 1;

R⁵ is selected from the group consisting of carboxy, halogen, lower alkyl, and —

C(O)-A;

wherein the alkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy or alkoxy;

wherein each A is independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, heteroaryl and heterocycloalkyl;

wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy, lower alkyl, lower alkoxy, nitro, cyano, amino, lower alkylamino or di(lower alkyl)amino;

or a pharmaceutically acceptable salt thereof.

3. A compound as in claim 2 wherein

R¹ is selected from the group consisting of hydrogen and —

SO₂-alkyl;

n is 0;

m is 0;

p is an integer from 1 to 2;

R⁴ is selected from the group consisting of hydroxy and —

O—

C(O)-alkyl;

wherein the alkyl portion of the —

O—

C(O)-alkyl group is optionally substituted with a carboxy group;

alternatively when p is 2, two R⁴ groups are taken together as oxo;

q is 0;

or a pharmaceutically acceptable salt thereof.

4. A compound as in claim 3 wherein

R¹ is selected from the group consisting of hydrogen and —

SO₂—

CH₃;

n is 0;

m is 0;

p is an integer from 1 to 2;

R⁴ is selected from the group consisting of hydroxy and —

O—

C(O)-n-butyl and —

O—

C(O)—

CH₂CH₂CH₂CH₂—

CO₂H;

alternatively when p is 2, two R⁴ groups are taken together as oxo;

q is 0;

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1.

10. A process for making a pharmaceutical composition comprising mixing a compound of claim 1 and a pharmaceutically acceptable carrier.

12. A method of contraception comprising co-therapy with a therapeutically effective amount of a compound as in claim 1 and a progestogen or a progestogen antagonist.

5. A compound of the formula (II)

6. A compound as in claim 5 wherein

R¹ is selected from the group consisting of hydrogen, hydroxy, A, —

O-A, C(O)-A and —

SO₂-A;

n is an integer from 0 to 1;

each R² is independently selected from the group consisting of carboxy, halogen, -A, —

C(O)-A, —

C(O)O-A, cyano, S-A —

SO-A, —

SO₂-A, —

SO₂—

NH₂, —

SO₂—

NH(alkyl) and —

SO₂—

N(alkyl)₂;

m is an integer from 0 to 1;

each R³ independently selected from the group consisting of -A, —

O-A, —

S-A, —

NH-A and —

C(O)-A;

p is an integer from 1 to 2;

R⁴ is selected from the group consisting of hydroxy, —

NH₂, —

NH(A), —

N(A)₂, —

C(O)NH₂, —

C(O)—

NH(A), —

SO₂—

NH₂, —

SO₂—

NH(A) and —

OC(O)-A, when the R⁴ in a β

-orientation;

R⁴ is selected from the group consisting of hydroxy, carboxy, cyano, -A, alkenyl, -alkenyl-A, alkynyl, -alkynyl-A, —

O-A, —

NH₂, —

NH(A), —

N(A)₂, —

N(A)-C(O)-A, —

NH—

C(O)-A, —

C(O)—

N(A)₂, —

C(O)—

NH₂, —

C(O)—

NH-A, —

SO₂—

N(A)₂, —

SO₂—

NH(A), —

SO₂—

NH₂, —

N(A)-SO₂-A, —

NH—

SO₂-A, —

C(O)O-A, —

OC(O)H and —

OC(O)-A, when the R⁴ is in an α

-orientation;

alternatively, when p is 2, two R⁴ groups may be taken together as oxo or ═

N(OH);

q is an integer from 0 to 1;

R⁵ is selected from the group consisting of carboxy, halogen, lower alkyl, and —

C(O)-A;

wherein the alkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy or alkoxy;

wherein each A is independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, heteroaryl and heterocycloalkyl;

wherein the aryl, aralkyl, cycloalkyl, heteroaryl or heterocycloalkyl group is optionally substituted with one to two substituents independently selected from halogen, hydroxy, carboxy, lower alkyl, lower alkoxy, nitro, cyano, amino, lower alkylamino or di(lower alkyl)amino;

or a pharmaceutically acceptable salt thereof.

7. A compound as in claim 6 wherein

R¹ is selected from the group consisting of hydrogen and —

SO₂-alkyl;

n is an integer from 0 to 1;

R² is selected from the group consisting of —

S-(alkyl);

m is 0;

p is an integer from 1 to 2;

R⁴ is selected from the group consisting of hydroxy, alkynyl and —

O—

C(O)-(alkyl);

alternatively, when p is 2, two R⁴ groups are taken together as oxo;

q is 0;

or a pharmaceutically acceptable salt thereof.

8. A compound as in claim 7 wherein

R¹ is selected from the group consisting of hydrogen and —

SO₂—

CH₃;

n is an integer from 0 to 1;

R² is —

S—

CH₃;

m is 0;

p is an integer from 1 to 2;

R⁴ is selected from the group consisting of hydroxy, ethynyl and —

OC(O)-n-butyl;

alternatively, when p is 2, two R⁴ groups are taken together as oxo;

q is 0;

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 5.

14. A process for making a pharmaceutical composition comprising mixing a compound of claim 5 and a pharmaceutically acceptable carrier.

16. A method of contraception comprising co-therapy with a therapeutically effective amount of a compound as in claim 5 and a progestogen or a progestogen antagonist.

11. A method for treating a disorder mediated by an estrogen receptor, wherein the disorder is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.

15. A method for treating a disorder mediated by an estrogen receptor, wherein the disorder is selected from the group consisting of osteoporosis, hot flashes, vaginal dryness, breast cancer and endometriosis.

17. A method of contraception comprising co-therapy with a therapeutically effective amount of a compound of formula (II) and a progestogen or a progestogen antagonist, wherein formula (II) is as follows: