Crystalline form of a PD-1/PD-L1 inhibitor

Patent metadata

Field	Value
Publication number	US-11760756-B2
Application number	US-202117520264-A
Country	US
Kind code	B2
Filing date	Nov 5, 2021
Priority date	Nov 6, 2020
Publication date	Sep 19, 2023
Grant date	Sep 19, 2023

Abstract

The present invention relates to crystalline forms of the PD-1/PD-L1 inhibitor (R)-1-((7-cyano-2-(3′-(3-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1,7-naphthyridin-8-ylamino)-2,2′-dimethylbiphenyl-3-yl)benzo[d]oxazol-5-yl)methyl)pyrrolidine-3-carboxylic acid, including methods of preparation thereof, and related synthetic intermediates, where the compound is useful in the treatment of various diseases including infectious diseases and cancer.

First claim

What is claimed is:

1. A crystalline form of Compound 1:

wherein the form is non-solvated, and the form is:
Form I, which has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 4.5, 7.9, 10.8, 13.1, 15.0, 17.3, 18.0, 20.8, 21.7, and 25.3 degrees; or
Form IV, which has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 6.5, 7.4, 12.3, 14.8, 17.4, 18.9, 19.8, and 24.2 degrees.

2. The crystalline form of claim 1 , having Form I, wherein the form has at least four XRPD peaks, in terms of 2-theta (±0.2 degrees), selected from 4.5, 7.9, 10.8, 13.1, 15.0, 17.3, 18.0, 20.8, 21.7, and 25.3 degrees.

3. The crystalline form of claim 1 , having Form I, wherein the form has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 4.5, 7.9, 10.8, 13.1, 15.0, 17.3, and 20.8 degrees.

4. The crystalline form of claim 1 , having Form I, wherein the form has at least four XRPD peaks, in terms of 2-theta (±0.2 degrees), selected from 4.5, 7.9, 10.8, 13.1, 15.0, 17.3, and 20.8 degrees.

5. The crystalline form of claim 1 , having Form I, wherein the form has an XRPD pattern as substantially shown in FIG. 1 .

6. The crystalline form of claim 1 , having Form I, which has a first endothermic peak with an onset temperature (±3° C.) at 23° C. and a maximum at 98° C. and a second endothermic peak with an onset temperature (±3° C.) at 147° C. and a maximum at 159° C. in a DSC thermogram.

7. The crystalline form of claim 1 , having Form I, wherein the form has a DSC thermogram substantially as shown in FIG. 2 .

8. The crystalline form of claim 1 , having Form I, wherein the form has a TGA thermogram substantially as shown in FIG. 3 .

9. The crystalline form of claim 1 , having Form IV, wherein the form has at least four XRPD peaks, in terms of 2-theta (±0.2 degrees), selected from 6.5, 7.4, 12.3, 14.8, 17.4, 18.9, 19.8, and 24.2 degrees.

10. The crystalline form of claim 1 , having Form IV, which has a first endothermic peak with an onset temperature (±3° C.) at 31° C. and a maximum at 62° C. and a second endothermic peak with an onset temperature (±3° C.) at 135° C. and a maximum at 145° C. in a DSC thermogram.

11. A crystalline form of Compound 1:

or a solvate thereof, wherein the form is a tetrahydrofuran solvate, and the form is:
Form II, which has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 7.5, 9.9, 12.8, 13.4, 14.4, 15.0, 17.1, 19.8, and 23.3 degrees;
Form III, which has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 5.9, 8.0, 12.6, 15.1, 17.0, 18.4, and 18.9 degrees; or
Form V, which has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 5.8, 8.0, 12.5, 15.1, 16.3, 17.0, 18.3, 18.9, 20.7, and 21.7 degrees.

12. The crystalline form of claim 11 , having Form II, wherein the form has at least four XRPD peaks, in terms of 2-theta (±0.2 degrees), selected from 7.5, 9.9, 12.8, 13.4, 14.4, 15.0, 17.1, 19.8, and 23.3 degrees.

13. The crystalline form of claim 11 , having Form II, which has a first endothermic peak with an onset temperature (±3° C.) at 68° C. and a maximum at 95° C. and a second endothermic peak with an onset temperature (±3° C.) at 153° C. and a maximum at 165° C. in a DSC thermogram.

14. The crystalline form of claim 11 , having Form III, wherein the form has at least four XRPD peaks, in terms of 2-theta (±0.2 degrees), selected from 5.9, 8.0, 12.6, 15.1, 17.0, 18.4, and 18.9 degrees.

15. The crystalline form of claim 11 , having Form III, which has a first endothermic peak with an onset temperature (±3° C.) at 23° C. and a maximum at 56° C. and a second endothermic peak with an onset temperature (±3° C.) at 106° C. and a maximum at 122° C. in a DSC thermogram.

16. The crystalline form of claim 11 , having Form V, wherein the form has at least four XRPD peaks, in terms of 2-theta (±0.2 degrees), selected from 5.8, 8.0, 12.5, 15.1, 16.3, 17.0, 18.3, 18.9, 20.7, and 21.7 degrees.

17. The crystalline form of claim 11 , having Form V, which has a first endothermic peak with an onset temperature (±3° C.) at 23° C. and a maximum at 48° C. and a second endothermic peak with an onset temperature (±3° C.) at 113° C. and a maximum at 117° C. in a DSC thermogram.

18. A pharmaceutical composition comprising a crystalline form of claim 1 , and a pharmaceutically acceptable carrier or excipient.

19. A solid oral dosage form comprising the pharmaceutical composition of claim 18 .

20. A process of preparing the crystalline form of claim 1 ,

which is Form I, comprising converting a tetrahydrofuran solvate of Compound 1 to said Form I.

21. The process of claim 20 , wherein the tetrahydrofuran solvate is Form II of Compound 1, wherein Form II has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 7.5, 9.9, 12.8, 13.4, 14.4, 15.0, 17.1, 19.8, and 23.3 degrees.

22. The process of claim 20 , wherein the converting comprises slurrying the Form II in a solvent component to form the Form I, wherein Form II has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 7.5, 9.9, 12.8, 13.4, 14.4, 15.0, 17.1, 19.8, and 23.3 degrees.

23. The process of claim 22 , wherein the slurrying comprises preparing a suspension comprising the Form II and a solvent component.

24. The process of claim 22 , wherein the slurrying comprises preparing a suspension comprising the Form II and a solvent component; heating the suspension to a temperature of about 35° C. to about 70° C.; and after said heating, cooling the suspension to a temperature of about 15° C. to about 25° C. to form the Form I as a solid; wherein the solvent component comprises acetone and water.

25. The process of claim 20 , wherein the converting comprises drying the Form II to form the Form I, wherein Form II has at least one XRPD peak, in terms of 2-theta (±0.2 degrees), selected from 7.5, 9.9, 12.8, 13.4, 14.4, 15.0, 17.1, 19.8, and 23.3 degrees.

26. A process of preparing the crystalline, tetrahydrofuran solvate of claim 11 ,

which is Form II,
comprising:
treating a solution comprising tetrahydrofuran and Compound 1 potassium salt:

with a metal scavenger or an ion exchange resin; and
precipitating Form II of Compound 1.

27. The process of claim 26 , wherein the treating comprises treating with the metal scavenger and the ion exchange resin.

28. The process of claim 26 , wherein the solution further comprises a C 1-6 alcohol, and wherein the C 1-6 alcohol comprises methanol.

29. The process of claim 26 about 55° C.; after said cooling, filtering the solution and concentrating filtrate; and after concentrating said filtrate, adding seed crystals of Form I to said concentrated filtrate to provide a suspension.

30. The process of claim

Assignees

• Incyte Corp

Inventors

• Jia Zhongjiang
• Chen Shili
• Li Mei
• Liu Pingli
• Pan Yongchun
• Wu Yongzhong
• Zhou Jiacheng

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title