Methods of treating androgen receptor-mediated disorders with imidazoline derivatives

Patent metadata

Field	Value
Publication number	US-9895355-B2
Application number	US-201715411517-A
Country	US
Kind code	B2
Filing date	Jan 20, 2017
Priority date	Sep 4, 2012
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

Methods for treating androgen receptor-mediated diseases, such as breast cancer, with imidazoline derivatives of formula (I) are provided:

First claim

We claim:

1. A method for treating breast cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein:
A is —CR′;
R′ is hydrogen, halogen, or alkyl;
Z 1 and Z 2 are each independently alkyl;
R 1 is S and R 2 is O;
R 3 is alkyl, wherein the alkyl is substituted with one or more groups selected from the group consisting of halogen, cyano, amino, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —C(O)NR 7 R 8 , —S(O) m R 6 , —C(O)R 6 , —OC(O)R 6 , —NR 7 C(O)R 8 , —NR 7 C(O)OR 8 , and —C(O)OR 6 , wherein the C 3-6 cycloalkyl and heterocyclyl are each optionally substituted with one or more groups selected from the group consisting of halogen, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, -OR 6 , —C(O)NR 7 R 8 , —S(O) m R 6 , —C(O)R 6 , —OC(O)R 6 , —NR 7 C(O)R 8 , —NR 7 C(O)OR 8 , and —C(O)OR 6 ;
R 4 and R 5 are each independently selected from the group consisting of cyano, nitro, alkyl, haloalkyl, hydroxy, hydrogen, alkoxy, and haloalkoxy;
R 6 is hydrogen, alkyl, halogen, or alkoxy wherein the alkyl and alkoxy are each optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, and alkoxy;
R 7 and R 8 are each independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, haloalkyl, hydroxyalkyl, and alkoxy;
the heterocyclyl is a 3 to 6 membered ring having 1 to 2 oxygen atoms; and
m is 0, 1, or 2.

2. The method according to claim 1 , wherein R′ is hydrogen or halogen.

3. The method according to claim 1 , wherein Z 1 and Z 2 are each methyl.

4. The method according to claim 1 , wherein R 4 is cyano and R 5 is haloalkyl.

5. The method according to claim 1 , wherein R 3 is alkyl, the alkyl is substituted with one or more groups selected from the group consisting of halogen, cyano, amino, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —C(O)NR 7 R 8 , —S(O) m R 6 , and —C(O)OR 6 , wherein the C 3-6 cycloalkyl and heterocyclyl are each optionally substituted with one or more groups selected from the group consisting of halogen, cyano, amino, alkyl, haloalkyl, hydroxyalkyl, —OR 6 , —C(O)NR 7 R 8 , —S(O) m R 6 , and —C(O)OR 6 ;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen and alkyl, wherein the alkyl is optionally substituted with one or more groups selected from the group consisting of halogen, cyano, hydroxy, amino, oxo, alkyl, and haloalkyl;
the heterocyclyl is a 3 to 6 membered ring having 1 to 2 oxygen atoms; and
m is 2.

6. The method according to claim 1 , wherein R 3 is alkyl substituted with one or more groups selected from the group consisting of halogen, cyano, amino, C 3-6 cycloalkyl, heterocyclyl, —OR 6 , —C(O)NR 7 R 8 , —S(O) m R 6 , and —C(O)OR 6 ;
R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, alkyl, and haloalkyl;
the heterocyclyl is a 3 to 6 membered ring having 1 to 2 oxygen atoms; and
m is 2.

7. The method according to claim 1 , wherein R 3 is alkyl substituted with one or more hydroxy groups.

8. The method according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

9. A method for treating breast cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

Assignees

• Shanghai hengrui pharmaceutical co ltd
• Jiangsu Hengrui Medicine Co
• Shanghai Hengru Pharmaceutical Co Ltd

Inventors

• Lu Hejun
• Sun Piaoyang
• Fei Hongbo
• Jiang Hongjian
• Wang Haowei
• Dong Qing

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P5/28

  Antiandrogens · CPC title

• A61P33/08

  for Pneumocystis carinii · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P15/10

  for impotence · CPC title