Crystalline forms of GSK1278863, preparation method and pharmaceutical use thereof

Patent metadata

Field	Value
Publication number	US-11117871-B2
Application number	US-202016818368-A
Country	US
Kind code	B2
Filing date	Mar 13, 2020
Priority date	Sep 15, 2017
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

The present disclosure relates to crystalline form CS1 and CS9 of a hypoxia-inducible factor prolyl hydroxylase inhibitor compound (I) GSK1278863, processes for preparation, and uses for preparing drugs treating and/or preventing anemia thereof.

First claim

The invention claimed is:

1. A crystalline form CS1 of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine, wherein the X-ray powder diffraction pattern of said crystalline form shows characteristic peaks at 2theta values of 6.4°±0.2°, 7.5°±0.2°, and 7.9°±0.2° using CuKα radiation.

2. The crystalline form CS1 according to claim 1 , wherein the X-ray powder diffraction pattern shows one or more characteristic peaks at 2theta values of 17.2°±0.2°, 21.0°±0.2°, 24.0°±0.2% and 19.3°±0.2° using CuKα radiation.

3. A process for preparing crystalline form CS1 of N-[( 1 , 3 -dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine, wherein the process comprises:
(1) dissolving N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine into a solvent selected from the group consisting of a cyclic ether and a ketone to obtain a solution, wherein said cyclic ether is tetrahydrofuran; said ketone is acetone, methyl isobutyl ketone, or a mixture thereof, evaporating the obtained solution at 10-50° C. for crystallization to obtain crystalline form CS1; or
(2) dissolving N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine into 1,4-dioxane, adding water for crystallization, separating and drying to obtain crystalline form CS1.

4. The process for preparing crystalline form CS1 according to claim 3 , wherein in method (1), said evaporation temperature is room temperature or 50° C.; in method (2), said crystallization time is 0.5-24 h.

5. The process for preparing crystalline form CS1 according to claim 4 , wherein in method (1), said ketone is acetone or methyl isobutyl ketone; in method (2), said crystallization time is 2 h.

6. A crystalline form CS9 of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine, wherein the X-ray powder diffraction pattern of said crystalline form shows characteristic peaks at 2theta values of 4.6°±0.2°, 6.6°±0.2°, and 21.1°±0.2° using CuKα radiation.

7. The crystalline form CS9 according to claim 6 , wherein the X-ray powder diffraction pattern shows one or more characteristic peaks at 2theta values of 9.4°±0.2°, 20.2°±0.2°, and 24.2°±0.2° using CuKα radiation.

8. A process for preparing crystalline form CS9 of N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine, wherein the process comprises:
(1) dissolving N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine into methyl tert-butyl ether and adding a polymer mixture to obtain a solution, wherein said polymer mixture is composed of polycaprolactone, polyoxyethylene, polymethyl methacrylate, hydroxyethyl cellulose, and sodium alginate of equal mass, evaporating the solution at 10-70° C. for crystallization; or
(2) dissolving N-[(1,3-dicyclohexylhexahydro-2,4,6-trioxo-5-pyrimidinyl)carbonyl]glycine into a solvent mixture of an ester and an alcohol to obtain a solution, wherein said ester is ethyl acetate; said alcohol is ethanol; and volume ratio of said ester and said alcohol is 1:10-10:1, and evaporating the solution at 10-70° C. for crystallization.

9. The process for preparing crystalline form CS9 according to claim 8 , wherein in method (1), said evaporation temperature is 50° C.; in method (2), said evaporating temperature is 50° C.

10. The process for preparing crystalline form CS9 according to claim 9 , wherein in method (2), said volume ratio of said ester and said alcohol is 1:1.

11. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of the crystalline form CS1 according to claim 1 , and pharmaceutically acceptable carriers, diluents or excipients.

12. A method of treating anemia comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form CS1 according to claim 1 .

13. A pharmaceutical composition, wherein said pharmaceutical composition comprises a therapeutically effective amount of the crystalline form CS9 according to claim 6 , and pharmaceutically acceptable carriers, diluents or excipients.

14. A method of treating anemia, comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form CS9 according to claim 6 .

15. The method of treating anemia according to claim 12 , where the subject is a human.

16. The method of treating anemia according to claim 14 , where the subject is a human.

Assignees

• Glaxosmithkline Ip No 2 Ltd

Inventors

• Chen Minhua
• Zhang Yanfeng
• Wang Jinqiu
• Zhang Xiaoyu

Classifications

• C07D239/62 Primary

  Barbituric acids · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/515

  Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital · CPC title

• A61P7/06

  Antianaemics · CPC title