Crystalline form of androgen receptor inhibitor and preparation method thereof

Patent metadata

Field	Value
Publication number	US-10150739-B2
Application number	US-201615757652-A
Country	US
Kind code	B2
Filing date	Aug 23, 2016
Priority date	Sep 10, 2015
Publication date	Dec 11, 2018
Grant date	Dec 11, 2018

Abstract

A crystalline form of an androgen receptor inhibitor and its preparation method are provided. In particular, provided are crystal form I of (S)-4-(3-(4-(2,3-dihydroxypropoxy)phenyl)-4,4-dimethyl-5-carbonyl-2-thioimidazolin-2-yl)-2-(trifluoromethyl)benzonitrile (a compound of formula (I)) and its preparation method. The method includes (a) adding any crystal form or amorphous form of the compound of formula (I) to an organic solvent to obtain a solution and heating the solution until it is clear, followed by cooling the solution to precipitate a crystal; and (b) filtering, washing, and drying the crystal. The obtained crystal form I of the compound of formula (I) has good chemical stability and crystal form stability, and the crystallization solvent used has low toxicity and residue, and is thus better for use in clinical treatment.

First claim

What is claimed is:

1. A crystal form I of a compound of formula (I):

wherein the crystal form I has a characteristic X-ray powder diffraction spectrum comprising peaks at diffraction angles (2θ) of about 9.97, 15.17, 16.77, 19.91, and 24.06.

2. A crystal form I of a compound of formula (I):

wherein the crystal form I has a characteristic X-ray powder diffraction spectrum as shown in FIG. 1 .

3. The crystal form I of the compound of formula (I) according to claim 1 , further comprising peaks at diffraction angles (2θ) of about 9.97, 15.17, 16.77, 19.91, and 24.06.

4. A pharmaceutical composition, comprising the crystal form I of the compound of formula (I) according to claim 1 , and a pharmaceutically acceptable carrier.

5. A pharmaceutical composition, comprising the crystal form I of the compound of formula (I) according to claim 2 , and a pharmaceutically acceptable carrier.

6. A method of preparing the crystal form I of the compound of formula (I) according to claim 1 , comprising:
(a) adding any crystal form or amorphous form of the compound of formula (I) into an organic solvent to obtain a solution, heating the solution until it is clear, and then cooling the solution to precipitate a crystal, wherein the organic solvent is selected from the group consisting of esters, ketones, nitriles, and ethers, each of which having 5 or less carbon atoms, or a mixture thereof; and
(b) filtering the crystal, then washing and drying the filtered crystal form I.

7. The method according to claim 6 , wherein the solvent in (a) is a single solvent selected from the group consisting of ethyl acetate, acetone, isopropyl acetate, tetrahydrofuran, and acetonitrile, or the solvent is a mixed solvent comprising a mixture of acetone and isopropyl ether; a mixture of ethyl acetate and n-hexane; a mixture of ethyl acetate and isopropyl ether; or a mixture of ethyl acetate and methyl tert-butyl ether.

8. The method according to claim 7 , wherein a volume ratio of the two solvents in the mixed solvent is 1:10 to 10:1.

9. The method according to claim 7 , wherein the solvent is a mixed solvent comprising a mixture of ethyl acetate and isopropyl ether.

10. A method of treating an androgen receptor-related disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 4 .

11. The method according to claim 10 , wherein the androgen receptor-related disease is prostate cancer.

12. A method of treating an androgen receptor-related disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 5 .

13. The method according to claim 12 , wherein the androgen receptor-related disease is prostate cancer.

14. A method of inhibiting androgen receptor in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 4 .

15. A method of inhibiting androgen receptor in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 5 .

16. The method according to claim 7 , wherein a volume ratio of the two solvents in the mixed solvent is 1:1.

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Wu Guaili
• Guo Changshan
• Zhong Liang
• Lu Yun

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D233/86 Primary

  Oxygen and sulfur atoms, e.g. thiohydantoin · CPC title

• A61K31/4166

  having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title