Imidazoline derivatives, preparation methods thereof, and their applications in medicine

Patent metadata

Field	Value
Publication number	US-9586947-B2
Application number	US-201314425207-A
Country	US
Kind code	B2
Filing date	Aug 26, 2013
Priority date	Sep 4, 2012
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

New imidazoline derivatives represented by formula (I):

preparation methods thereof, pharmaceutical compositions comprising such derivatives, and applications of such derivatives in preparing androgen receptor antagonists and medicaments for treating diseases such as prostate cancer are described.

First claim

We claim:

1. 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
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; and
the heterocyclyl is a 3 to 6-membered ring having 1 to 2 oxygen atoms; and
m is 0, 1, or 2.

2. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , being a compound of formula (II) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein R′ is hydrogen or halogen.

3. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein Z 1 and Z 2 are each methyl.

4. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is cyano and R 5 is haloalkyl.

5. The compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 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 , 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 compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof 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 compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is alkyl substituted with one or more hydroxy groups.

8. A compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

9. A process of preparing the compound of formula (I) according to claim 1 , or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a step of

reacting a compound of formula (I-A) with a compound of formula (I-B) under an alkaline condition to obtain a compound of formula (I);
wherein LG is a leaving group.

10. A process of preparing the compound of formula (I) according to claim 1 , or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising a step of:

condensing a compound of formula (I-A) with a compound of formula (I-C) in the presence of triphenylphosphine or tri-n-butylphosphine, and azodicarboxylate to obtain a compound of formula (I).

11. A pharmaceutical composition comprising a therapeutically effective amount of the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable carrier, diluent, or excipient.

12. The process according to claim 9 , wherein the leaving group (LG) is halogen or p-toluenesulfonyloxy.

13. The process according to claim 10 , wherein the azodicarboxylate is 1,1′-(azodicarbonyl)dipiperidine or diisopropyl azodicarboxylate.

14. A method for treating an androgen receptor-mediated disorder or disease, the method comprising a step of administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 11 , wherein the androgen receptor-mediated disorder or disease is prostate cancer or prostatic hyperplasia.

15. The method according to claim 14 , wherein the prostate cancer is hormone sensitive prostate cancer or hormone refractory prostate cancer.

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound, or a

Assignees

• Shanghai hengrui pharmaceutical co ltd
• Jiangsu Hengrui Medicine Co

Inventors

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

Classifications

• A61P43/00

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

• A61P5/28

  Antiandrogens · CPC title

• A61P33/08

  for Pneumocystis carinii · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P1/14

  Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents · CPC title