Crystalline form I of tyrosine kinase inhibitor dimaleate and preparation methods thereof

Patent metadata

Field	Value
Publication number	US-9309226-B2
Application number	US-201314412762-A
Country	US
Kind code	B2
Filing date	Jun 4, 2013
Priority date	Jul 12, 2012
Publication date	Apr 12, 2016
Grant date	Apr 12, 2016

Abstract

Provided are crystalline Form I of (R,E)-N-(4-(3-chloro-4-(pyridin-2-yl-methoxy)-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl)-3-(1-methylpyrrolidin-2-yl) propenamide dimaleate (called SHR1258 dimaleate for short), preparation methods thereof, and pharmaceutical compositions containing the same. The crystalline Form I of SHR1258 dimaleate has good crystal stability and chemical stability, and can be used in the preparation of medicaments for treating diseases related to EGFR receptor tyrosine kinase or HER-2 receptor tyrosine kinase.

First claim

What is claimed is:

1. A form I crystal of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl) acrylamide dimaleate, wherein using Cu—Kα radiation to obtain an X-ray diffraction pattern represented by 2θ angle (interplanar crystal spacing), the form I crystal has the X-ray diffraction pattern comprising characteristic peaks at 6.28 (14.06), 6.74 (13.10), 10.60 (8.34), 11.58 (7.64), 13.50 (6.55), 14.90 (5.94), 15.80 (5.60), 18.26 (4.85), 20.66 (4.30), 21.14 (4.20), 22.96 (3.87), 24.34 (3.65), 25.54 (3.49), and 26.12 (3.41).

2. A method for preparing the form I crystal of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate according to claim 1 , the method comprising the following steps:
1) heating a mixture of any crystal form or amorphous form of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide and maleic acid, or a solid of any crystal form or amorphous form of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate, in a sufficient quantity of organic solvent to dissolve the crystal form or amorphous form or the solid of any crystal form or amorphous form to obtain a solution, then cooling the solution to cause crystallization; said organic solvent is one or more of a solvent selected from the group consisting of alcohols with no more than three carbons, acetone, ethyl acetate, and tetrahydrofuran; and
2) filtering, washing, and drying the crystals obtained in step (1).

3. The method according to claim 2 , wherein the organic solvent in step (1) is isopropyl alcohol.

4. The method according to claim 2 , wherein the organic solvent in step (1) is a mixture of solvents of ethanol and tetrahydrofuran.

5. A pharmaceutical composition comprising the form I crystal of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate according to claim 1 and a pharmaceutically acceptable carrier.

6. The method according to claim 2 , wherein the organic solvent is selected from the group consisting of ethanol, isopropyl alcohol, tetrahydrofuran, and mixtures thereof.

7. A method of treating cancer, the method comprising administering the pharmaceutical composition according to claim 5 to a subject in need of treatment thereof, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, epidermal squamous carcinoma and gastric cancer.

8. The form I crystal of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl) acrylamide dimaleate according to claim 1 , having the X-ray diffraction pattern of FIG. 1 .

9. A method for preparing the form I crystal of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate according to claim 8 , the method comprising:
1) heating a mixture of any crystal form or amorphous form of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide and maleic acid, or a solid of any crystal form or amorphous form of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate, in a sufficient quantity of organic solvent to dissolve the crystal form or amorphous form or the solid of any crystal form or amorphous form to obtain a solution, then cooling the solution to cause crystallization; said organic solvent is one or more of a solvent selected from the group consisting of alcohols with no more than three carbons, acetone, ethyl acetate, and tetrahydrofuran; and
2) filtering, washing, and drying the crystals obtained in step (1).

10. The method according to claim 9 , wherein the organic solvent in step (1) is isopropyl alcohol.

11. The method according to claim 9 , wherein the organic solvent in step (1) is a mixture of solvents of ethanol and tetrahydrofuran.

12. The method according to claim 9 , wherein the organic solvent is selected from the group consisting of ethanol, isopropyl alcohol, tetrahydrofuran, and mixtures thereof.

13. A pharmaceutical composition comprising the form I crystal of (R,E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)-phenylamino)-3-cyano-7-ethoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide dimaleate according to claim 8 and a pharmaceutically acceptable carrier.

14. A method of treating cancer, the method comprising administering the pharmaceutical composition according to claim 13 to a subject in need of treatment thereof, wherein the cancer is selected from the group consisting of lung cancer, breast cancer, epidermal squamous carcinoma and gastric cancer.

Assignees

• Jiangsu Hengrui Medicine Co

Inventors

• Sun Piaoyang
• Wu Guaili
• Yuan Bo
• Chen Yongjiang

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

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

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title