Crystal of tricyclic compound

Patent metadata

Field	Value
Publication number	US-11236107-B2
Application number	US-201816639395-A
Country	US
Kind code	B2
Filing date	Aug 17, 2018
Priority date	Aug 18, 2017
Publication date	Feb 1, 2022
Grant date	Feb 1, 2022

Abstract

The present application relates to a crystal of a tricyclic compound, in particular to a crystal of (S)-8-(4,4-difluorocyclohexyl)-8H-thieno[3,4]pyrrolo[1,5-a]imidazole, a preparation method therefor, a crystal composition and a pharmaceutical composition thereof and the use thereof. The X-ray powder diffraction spectrum of the crystal of the compound of formula I in the present application, represented by a 2θ value, has a diffraction peak at about 11.49°, 15.05°, 20.14°, 21.53° or 21.79°. The crystal of the compound of formula I in the present application has excellent physical properties, high safety and metabolic stability, and has a good inhibitory effect on IDO and a high medicinal value.

First claim

What is claimed is:

1. A crystal of (S)-8-(4,4-difluorocyclohexyl)-8H-thieno[3,4]pyrrolo[1,5-a]imidazole represented by formula I,

wherein an X-ray powder diffraction spectrum thereof has diffraction peaks expressed by 2θ values at 11.49±0.2°, 11.99±0.2°, 15.05±0.2°, 20.14±0.2°, 21.53±0.2° or 21.79±0.2°.

2. The crystal according to claim 1 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks expressed by 2θ values at 11.49±0.2°, 11.99±0.2°, 15.05±0.2°, 17.99±0.2°, 18.24±0.2°, 19.44±0.2°, 20.14±0.2°, 21.53±0.2°, 21.79±0.2°, 25.09±0.2°, 27.20±0.2° or 28.00±0.2°.

3. The crystal according to claim 2 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks expressed by 2θ values at 11.49±0.2°, 11.99±0.2°, 15.05±0.2°, 17.99±0.2°, 18.24±0.2°, 19.44±0.2°, 20.14±0.2°, 21.53±0.2°, 21.79±0.2°, 23.64±0.2°, 23.98±0.2°, 25.09±0.2°, 27.20±0.2°, 28.00±0.2°, 29.35±0.2°, 31.22±0.2°, 32.01±0.2°, 32.21±0.2°, 36.70±0.2° or 38.87±0.2°.

4. The crystal according to claim 3 , wherein the X-ray powder diffraction spectrum thereof has diffraction peaks expressed by 2θ values at 11.49±0.2°, 11.99±0.2°, 13.89±0.2°, 15.05±0.2°, 17.99±0.2°, 18.24±0.2°, 19.44±0.2°, 20.14±0.2°, 21.02±0.2°, 21.53±0.2°, 21.79±0.2°, 23.64±0.2°, 23.98±0.2°, 25.09±0.2°, 25.64±0.2°, 26.84±0.2°, 27.20±0.2°, 28.00±0.2°, 28.46±0.2°, 29.35±0.2°, 31.22±0.2°, 32.01±0.2°, 32.21±0.2°, 32.89±0.2°, 34.18±0.2°, 35.02±0.2°, 35.81±0.2°, 36.70±0.2° or 38.87±0.2°.

5. The crystal according to claim 1 , wherein the differential scanning calorimetry diagram has an absorption peak at 207±5° C.

6. A crystal composition, wherein the crystal according to claim 1 accounts for 50% or more by weight of the crystal composition.

7. A pharmaceutical composition, comprising the crystal according to claim 1 or the crystal composition according to claim 6 .

8. The crystal composition according to claim 6 , wherein the crystal accounts for 80% or more by weight of the crystal composition.

9. The crystal composition according to claim 8 , wherein the crystal accounts for 90% or more by weight of the crystal composition.

10. The crystal composition according to claim 9 , wherein the crystal accounts for 95% or more by weight of the crystal composition.

11. A method for treating indoleamine 2,3-dioxygenase-mediated immunosuppressive disease in a subject in need thereof comprising administering the crystal according to claim 1 .

12. A method for preparing the crystal according to claim 1 , comprising: (1) dissolving the compound of formula I in an organic solvent until solution being clear, which is filtered to remove insoluble substance; (2) concentrating filtrate obtained in step (1) to a solid-liquid mixed state, producing a solid-liquid mixture which is dissolved by heating, stirred with refluxing for 1 to 2 hours, and cooled for crystallization.

13. The method according to claim 12 , wherein the organic solvent in step (1) is one solvent or a mixed solvent selected from methanol, ethanol, acetonitrile, acetone, butanone, tetrahydrofuran, and 1,4-dioxane.

14. The method according to claim 12 , wherein a molar volume ratio of the compound of formula I to the organic solvent in step (1) is 1 mmol:5-10 mL.

15. The method according to claim 12 , wherein, in step (2), when the filtrate is concentrated to a solid-liquid mixed state, a volume of the organic solvent in the solid-liquid mixture accounts for 15% to 30% of a total volume of the organic solvent in step (1).

16. The method according to claim 12 , wherein a temperature of the refluxing in step (2) is 50° C. to 80° C.

17. The method according to claim 12 , wherein a temperature of cooling for crystallization in step (2) is 20° C. to 30° C.

18. The method according to claim 12 , further comprising: (3) filtering; and (4) drying.

19. The method according to claim 12 , wherein the organic solvent in step (1) is methanol or ethanol.

20. The method according to claim 12 , wherein a molar volume ratio of the compound of formula I to the organic solvent step (1) is 1 mmol:8-10 mL.

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Liu Shilan
• Wang Dahai
• Liang Guibai
• Wang Honglin
• Hu Guoping
• Li Jian
• Chen Shuhui

Classifications

• A61P37/06 Primary

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title