Salts and crystalline forms of a PD-1/PD-L1 inhibitor

Patent metadata

Field	Value
Publication number	US-11866451-B2
Application number	US-202017094396-A
Country	US
Kind code	B2
Filing date	Nov 10, 2020
Priority date	Nov 11, 2019
Publication date	Jan 9, 2024
Grant date	Jan 9, 2024

Abstract

This application relates to solid forms and salt forms of the PD-1/PD-L1 inhibitor 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid), including processes of preparation thereof, where the solid forms and salt forms are useful in the treatment of various diseases including infectious diseases and cancer.

First claim

What is claimed is:

1. A salt, which is 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

2. The salt of claim 1 , wherein the salt is Form I of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

3. The salt of claim 2 , characterized by having an X-ray powder diffraction pattern as substantially shown in FIG. 7 .

4. The salt of claim 2 , characterized by having a DSC thermogram substantially as depicted in FIG. 8 .

5. The salt of claim 2 , characterized by having a thermogravimetric analysis (TGA) thermogram substantially as depicted in FIG. 9 .

6. The salt of claim 2 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 5.7, 8.5, 9.6, 9.9, 11.8, 12.3, 13.1, 13.4, 13.8, 14.2, 14.5, 15.4, 15.8, 16.8, 17.3 and 17.6 degrees.

7. The salt of claim 2 , characterized by having characteristic X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), at 5.7, 8.5, 9.6, 9.9, 11.8, 12.3, 13.1, 13.4, 13.8, 14.2, 14.5, 15.4, 15.8, 16.8, 17.3 and 17.6 degrees.

8. The salt of claim 2 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having a first endothermic peak with an onset temperature at 31.1° C.±3° C. and a maximum at 91.4° C.±3° C., and a second endothermic peak with an onset temperature at 231.0° C.±3° C. and a maximum at 236.4° C.±3° C.

9. The salt of claim 1 , wherein the salt is Form II of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

10. The salt of claim 9 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 4.6, 6.9, 8.9, 11.2, 11.7, 13.2, 13.9, 14.3, 14.8, 16.0, 16.7, 17.2, 17.9, 25.3 and 25.6 degrees.

11. The salt of claim 9 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having a first endothermic peak with an onset temperature at 22.2° C.±3° C. and a maximum at 89.7° C.±3° C., and a second endothermic peak with an onset temperature at 251.7° C.±3° C. and a maximum at 258.3° C.±3° C.

12. The salt of claim 1 , wherein the salt is Form III of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

13. The salt of claim 12 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 9.2, 11.2, 14.9, 17.0, 17.8, 19.7, 24.4 and 25.9 degrees.

14. The salt of claim 12 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having an endothermic peak with an onset temperature of 247±3° C. and a maximum at 258±3° C. in a differential scanning calorimetry (DSC) thermogram.

15. The salt of claim 1 , wherein the salt is Form IV of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

16. The salt of claim 15 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 5.4, 8.8, 10.9, 13.0, 15.1, 16.2, 17.5, 21.9 and 26.3 degrees.

17. The salt of claim 15 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having an endothermic peak with an onset temperature of 268±3° C. and a maximum at 273±3° C.

18. The salt of claim 1 , wherein the salt is Form V of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

19. The salt of claim 18 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 5.8, 9.1, 13.4, 14.8, 16.6, 17.1, 18.1 and 19.3 degrees.

20. The salt of claim 18 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having an endothermic peak with an onset temperature of 241±3° C. and a maximum at 249±3° C.

21. The salt of claim 1 , wherein the salt is Form VII of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

22. The salt of claim 21 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 5.7, 9.9, 11.5, 14.1, 14.9, 17.0 and 24.4 degrees.

23. The salt of claim 21 , wherein the differential scanning calorimetry (DSC) thermogram characterized by having a first endothermic peak with an onset temperature at 44±3° C. and a maximum at 85±3° C., and a second endothermic peak with an onset temperature at 260±3° C. and a maximum at 274±3° C. in a differential scanning calorimetry (DSC) thermogram.

24. The salt of claim 1 , wherein the salt is Form VIII of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

25. The salt of claim 24 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 6.6, 11.2, 13.1, 14.7, 16.7, 19.0 and 24.1 degrees.

26. The salt of claim 24 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having a first endothermic peak with an onset temperature at 44±3° C. and a maximum at 78±3° C., and a second endothermic peak with an onset temperature at 246±3° C. and a maximum at 253±3° C.

27. The salt of claim 1 , wherein the salt is Form IX of 4,4′-(((((2,2′-dichloro-[1,1′-biphenyl]-3,3′-diyl)bis(azanediyl))bis(carbonyl))bis(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-2,5-diyl))bis(ethane-2,1-diyl))bis(bicyclo[2.2.1]heptane-1-carboxylic acid) di-hydrochloric acid salt.

28. The salt of claim 27 , characterized by having at least four X-ray powder diffraction (XRPD) peaks, in terms of 2-theta (±0.2 degrees), selected from 3.8, 6.6, 10.7, 13.1, 15.3, 16.3, 17.5 and 19.1 degrees.

29. The salt of claim 27 , wherein the differential scanning calorimetry (DSC) thermogram is characterized by having a first endothermic peak with an onset temperature at 43±3° C. and a maximum at 64±3° C., and a second endothermic peak at 116±3° C. and a maximum at 132±3° C., and a third endothermic peak at 266±3° C. and a maximum at 276±3° C.

30. A pharmaceut

Assignees

• Incyte Corp

Inventors

• Jia Zhongjiang
• Chen Shili
• Li Yi
• Martin Timothy
• Shen Bo
• Su Naijing
• Zhou Jiacheng
• Li Qun

Classifications

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• C07C61/135

  having three rings · CPC title

• C07C211/56

  the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title