CRYSTALLINE FORMS OF AP26113, AND PREPARATION METHOD THEREOF

• US 20190322646A1
• Filed: 10/25/2017
• Published: 10/24/2019
• Est. Priority Date: 10/25/2016
• Status: Active Grant

• Current Assignee: Crystal Pharmatech Co. Ltd.
• Original Assignee: Crystal Pharmatech Co. Ltd.
• Inventors: Chen, Minhua, Zhang, Yanfeng, Wang, Jinqiu, Liu, Kai, Zhang, Xiaoyu
• Granted Patent: US 10,544,129 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The present disclosure relates to two novel crystalline forms of AP26113 and processes for preparation thereof. The crystalline form CS1 and crystalline form CS2 of the present disclosure have advantages in solubility and stability, are suitable for development, and provide a better choice for preparation of pharmaceutical compositions containing AP26113, which is of great significance for drug development.

Claims

1. A crystalline form CS2 of AP26113, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 17.1°

±

0.2°

, 22.9°

±

0.2° and

28.7°

±

0.2°

using CuKα

radiation.

2. The crystalline form CS2 according to claim 1, wherein the X-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 27.3°

±

0.2°

, 21.4°

±

0.2° and

5.7°

±

0.2°

using CuKα

radiation.

3. The crystalline form CS2 according to claim 1, wherein the X-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 11.4°

±

0.2°

, 8.7°

±

0.2° and

16.0°

±

0.2°

using CuKα

radiation.

4. A process for preparing crystalline form CS2 according to claim 1, wherein the process comprises:

1) keeping the solid of crystalline form CS1 under 30% RH-80% RH at room temperature for 1-30 days to get Form CS2;

or

2) dissolving AP26113 free base in a solvent mixture of alcohols and water, filtering and then stirring the filtrate at a temperature between −

20°

C.-0°

C. until solid precipitates, keeping the obtained wet cake under 30% RH-75% RH at 25°

C.-40°

C. to get crystalline form CS2.

5. The process for preparing crystalline form CS2 according to claim 4, wherein, in method 1):

said humidity is 50% RH-80% RH;

said keeping time is 5-16 days;

in method

     2);

said alcohol is methanol;

said volume ratio of alcohol and water is 93;

7-98;

2;

said keeping temperature is 35°

C., said keeping humidity is 40% RH.

11. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS2 according to claim 1, and pharmaceutically acceptable carriers, diluents or excipients.

12. Crystalline form CS2 according to claim 1 for use in preparing drugs of small molecule tyrosine kinase inhibitors.

13. A method of treating ALK positive non-small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of CS2 according to claim 1.

6. A crystalline form CS1 of AP26113, wherein the X-ray powder diffraction pattern shows characteristic peaks at 2theta values of 5.5°

±

0.2°

, 21.6°

±

0.2° and

10.8°

±

0.2°

using CuKα

radiation.

7. The crystalline form CS1 according to claim 6, wherein the X-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 16.2°

±

0.2°

, 21.0°

±

0.2° and

27.1°

±

0.2°

using CuKα

radiation.

8. The crystalline form CS1 according to claim 6, wherein the X-ray powder diffraction pattern shows 1 or 2 or 3 characteristic peaks at 2theta values of 8.5°

±

0.2°

, 11.8°

±

0.2° and

18.6°

±

0.2°

using CuKα

radiation.

9. A process for preparing crystalline form CS1 according to claim 6, wherein the process comprises:

1) dissolving AP26113 free base in a solvent mixture of alcohols and aromatic hydrocarbons, and then evaporating the solution at 30°

C.-60°

C. for 1-10 days to obtain crystalline form CS1;

or

2) dissolving AP26113 free base in a solvent mixture of ethanol and aromatic hydrocarbons or a single solvent selected from aromatic hydrocarbons saturated with water, filtering and then stirring the filtrate at −

20°

C.-0°

C. until solid precipitates, the obtained solid is crystalline form CS1;

or

3) dissolving AP26113 free base in a solvent mixture of methanol and aromatic hydrocarbons, filtering and then stirring the filtrate at −

20°

C.-0°

C. until solid precipitates, drying the obtained wet cake to get Form CS1.

10. The process for preparing crystalline form CS1 according to claim 9, wherein, in method 1):

said alcohol is isopropanol, said aromatic hydrocarbon is toluene, said volume ratio of alcohol and aromatic hydrocarbon is 1;

4-1;

2, said evaporation temperature is 35°

C.-50°

C.;

in method

     2);

said aromatic hydrocarbon is toluene;

said volume ratio of ethanol and aromatic hydrocarbon is 1;

4, said water-saturated aromatic hydrocarbon is water-saturated toluene;

in method

     3);

said aromatic hydrocarbon is toluene, said volume ratio of methanol and aromatic hydrocarbon is 1;

9.

14. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of crystalline form CS1 according to claim 6, and pharmaceutically acceptable carriers, diluents or excipients.

15. Crystalline form CS1 according to claim 6 for use in preparing drugs of small molecule tyrosine kinase inhibitors.

16. A method of treating ALK positive non-small cell lung cancer, comprising administering to a patient in need thereof a therapeutically effective amount of CS1 according to claim 6.