Crystalline forms of a phosphoinositide 3-kinase (PI3K) inhibitor
The present invention relates to salts and crystalline forms of 2-(3-(8-Amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, crystalline forms of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-methyl-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, and crystalline forms of 8-amino-N-(2-hydroxy-2-methylpropyl)-3-(2-(methyl-d 3 )-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)imidazo[1,2-a]pyrazine-6-carboxamide, which are PI3K inhibitors useful in the treatment of cancer and other diseases.
1. A crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide, wherein the crystalline form is selected from:
Form IA having an X-ray powder diffraction pattern comprising 4 or more of the following peaks, in terms of 2θ: 8.6°±0.2°; 9.5°±0.2°; 10.3°±0.2°; 13.0°±0.2°; 13.6°±0.2°; 14.2°±0.2°; 14.9°±0.2°; 17.3°±0.2°; 19.2°±0.2°; 20.6°±0.2°; 24.0°±0.2°; and 28.7°±0.2°;
Form IIA having an X-ray powder diffraction pattern comprising 4 or more of the following peaks, in terms of 2θ: 9.1°±0.2°; 11.1°±0.2°; 12.6°±0.2°; 13.5°±0.2°; 18.0°±0.2°; 19.0°±0.2°; 20.5°±0.2°; and 21.9°±0.2°; and
Form IIIA having an X-ray powder diffraction pattern comprising 4 or more of the following peaks, in terms of 2θ: 8.1°±0.2°; 10.6°±0.2°; 13.5°±0.2°; 14.2°±0.2°; 16.4°±0.2°; 17.1°±0.2°; 17.9°±0.2°; 20.3°±0.2°; and 24.1°±0.2°.
2. The crystalline form of claim 1 that is Form IA, having an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
3. The crystalline form of claim 1 that is Form IA, having a DSC thermogram comprising an endothermic peak having a maximum at about 193° C.
4. The crystalline form of claim 1 that is Form IA, having a differential scanning calorimetry thermogram (DSC) substantially as shown in FIG. 2 .
5. The crystalline form of claim 1 that is Form IA, having a thermogravimetric analysis (TGA) substantially as shown in FIG. 3 .
6. The crystalline form of claim 1 that is Form IIA, having an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
7. The crystalline form of claim 1 that is Form I IA, having a DSC thermogram comprising an endothermic peak having a maximum at about 180° C.
8. The crystalline form of claim 1 that is Form IIA, having a differential scanning calorimetry thermogram (DSC) substantially as shown in FIG. 5 .
9. The crystalline form of claim 1 that is Form IIA, having a thermogravimetric analysis (TGA) substantially as shown in FIG. 6 .
10. The crystalline form of claim 1 that is Form IIIA, having an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
11. The crystalline form of claim 1 that is Form IIIA, having a DSC thermogram comprising an endothermic peak having a maximum at about 143° C.
12. The crystalline form of claim 1 that is Form IIIA, having a differential scanning calorimetry thermogram (DSC) substantially as shown in FIG. 8 .
13. The crystalline form of claim 1 that is Form IIIA, having a thermogravimetric analysis (TGA) substantially as shown in FIG. 9 .
14. The crystalline form of claim 1 , which is substantially isolated.
15. A composition comprising the crystalline form of claim 1 .
16. The composition of claim 15 , wherein said composition further comprises at least one pharmaceutically acceptable carrier.
17. A method of inhibiting an activity of PI3Ky kinase, comprising contacting the kinase with a crystalline form of claim 1 .
18. The method of claim 17 , wherein said crystalline form is a selective inhibitor for PI3Kγ over one or more of PI3Kα, PI3Kβ, and PI3Kδ.
19. A method of treating a disease or disorder in a patient, wherein said disease or disorder is associated with abnormal expression or activity of PI3Ky kinase, comprising administering to said patient a therapeutically effective amount of a crystalline form of claim 1 .
20. The method of claim 19 , wherein the disease or disorder is an autoimmune disease or disorder, cancer, cardiovascular disease, or neurodegenerative disease.
21. A process of preparing a crystalline form of the compound 2-(3-(8-amino-6-(trifluoromethyl)imidazo[1,2-a]pyrazin-3-yl)-4-methylphenyl)-3,3,3-trifluoro-2-hydroxypropanamide of claim 1 , comprising dissolving the compound in a solvent to form a mixture and crystallizing the compound from the mixture.
22. The process of claim 21 , wherein the solvent comprises isopropyl acetate.
23. The process of claim 22 , wherein the solvent further comprises heptane.
24. The process of claim 21 , wherein the process further comprises heating the mixture to a temperature of from about 70° C. to about 90° C.
25. The process of claim 24 , wherein the process further comprises cooling the mixture to room temperature.
26. The process of claim 21 , wherein the solvent comprises methanol.
27. The process of claim 21 , wherein the process further comprises heating the mixture to a temperature of from about 50° C. to about 70° C.
28. The process of claim 27 , wherein the process further comprises cooling the mixture to room temperature.
29. The crystalline form of claim 1 , which is Form IA.
30. The crystalline form of claim 1 , which is Form IIA.
31. The crystalline form of claim 1 , which is Form IIIA.