Processes for preparing isoquinolinones and solid forms of isoquinolinones

• US 8,809,349 B2
• Filed: 01/10/2012
• Issued: 08/19/2014
• Est. Priority Date: 01/10/2011
• Status: Expired

• Current Assignee: Infinity Pharmaceuticals, Inc.
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Ren, Pingda, Martin, Michael, Isbester, Paul, Lane, Benjamin S., Kropp, Jason
• Primary Examiner(s): Padmanabhan, Sreeni
• Assistant Examiner(s): Neagu, Irina
• Application Number:
  US13/347,423
• Publication Number:
  US 20120184568A1
• Time in Patent Office: 952 Days
• Field of Search: 514/263.22, 514/263.2, 514/263.4, 514/309, 544/277
• US Class Current: 514/263.22
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine

Abstract

Polymorphs of chemical compounds that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including P13 kinase activity, are described herein. Also provided herein are processes for preparing compounds, polymorphs thereof, and pharmaceutical compositions thereof.

Claims

1. A compound of Formula (I):

41. A pharmaceutical composition comprising a compound according to claim 1, and one or more pharmaceutically acceptable excipients.

46. The pharmaceutical composition of claim 41, further comprising an amorphous form of a compound of Formula (I).

2. A mixture of two or more compounds of Formula (I):

4. A mixture according to claim 2, wherein the mixture is at least 50% by weight polymorph Form C, or a salt, solvate, or hydrate thereof.

56. The mixture of claim 2, wherein the mixture comprises polymorph Form C and an amorphous form of a compound of Formula (I).

57. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 1:

1.

58. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 2:

1.

59. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 3:

1.

60. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 4:

1.

61. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 5:

1.

62. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 6:

1.

63. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 7:

1.

64. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 8:

1.

65. The mixture of claim 56, wherein the ratio of polymorph Form C to the total amount of an amorphous form of a compound of Formula (I) is greater than about 9:

1.

3. A mixture of two or more compounds of Formula (I):

5. Polymorph Form C of a compound of Formula (I):

6. The polymorph according to claim 5, further comprising at least one characteristic XRPD peak selected from 2θ

=6.6°

(±

0.2°

) and 12.5°

(±

0.2°

).

7. The polymorph according to claim 5, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=6.6°

(±

0.2°

), 10.4°

(±

0.2°

), 12.5°

(±

0.2°

), 13.3°

(±

0.2°

), and 24.3°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=8.8°

(±

0.2°

), 9.9°

(±

0.2°

), 13.4°

(±

0.2°

), 15.5°

(±

0.2°

), 16.9°

(±

0.2°

), 19.8°

(±

0.2°

), 21.3°

(±

0.2°

), 23.6°

(±

0.2°

), 25.3°

(±

0.2°

), and 27.9°

(±

0.2°

).

8. The polymorph according to claim 5, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 3.

52. The polymorph of claim 5, wherein Form C has an endothermic peak at about 203°

C.

53. The polymorph of claim 5, wherein Form C has an endothermic peak at about 206°

C. or about 208°

C.

54. The polymorph of claim 5, wherein Form C has an endothermic peak in the range of about 203°

C. to about 208°

C., and at least one peak selected from an exothermic peak in the range of about 251°

C. to about 254°

C., and an endothermic peak in the range of about 281°

C. to about 283°

C.

55. The polymorph of claim 5, wherein Form C has an endothermic peak at about 208°

C., an exothermic peak at about 254°

C., and an endothermic peak at about 283°

C.

9. Polymorph Form B of a compound of Formula (I):

10. The polymorph according to claim 9, further comprising at least one characteristic XRPD peak selected from 2θ

=14.0°

(±

0.2°

) and 15.0°

(±

0.2°

).

11. The polymorph according to claim 9, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=7.9°

(±

0.2°

), 13.4°

(±

0.2°

), 14.0°

(±

0.2°

), 15.0°

(±

0.2°

), and 23.4°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=9.5°

(±

0.2°

), 12.7°

(±

0.2°

), 13.6°

(±

0.2°

), 14.2°

(±

0.2°

), 15.7°

(±

0.2°

), 19.0°

(±

0.2°

), 22.3°

(±

0.2°

), 24.2°

(±

0.2°

), 24.8°

(±

0.2°

), and 26.9°

(±

0.2°

).

12. The polymorph according to claim 9, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 2.

13. Polymorph Form D of a compound of Formula (I):

14. The polymorph according to claim 13, further comprising at least one characteristic XRPD peak selected from 2θ

=9.2°

(±

0.2°

) and 18.3°

(±

0.2°

).

15. The polymorph according to claim 13, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=9.2°

(±

0.2°

), 11.4°

(±

0.2°

), 17.4°

(±

0.2°

), 18.3°

(±

0.2°

), and 22.9°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=9.8°

(±

0.2°

), 12.2°

(±

0.2°

), 15.8°

(±

0.2°

), 16.2°

(±

0.2°

), 16.8°

(±

0.2°

), 18.9°

(±

0.2°

), 19.9°

(±

0.2°

), 20.0°

(±

0.2°

), 24.9°

(±

0.2°

), and 29.3°

(±

0.2°

).

16. The polymorph according to claim 13, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 4.

17. Polymorph Form E of a compound of Formula (I):

18. The polymorph according to claim 17, further comprising at least one characteristic XRPD peak selected from 2θ

=12.7°

(±

0.2°

) and 13.9°

(±

0.2°

).

19. The polymorph according to claim 17, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=6.7°

(±

0.2°

), 9.3°

(±

0.2°

), 12.7°

(±

0.2°

), 13.9°

(±

0.2°

), and 24.4°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=12.4°

(±

0.2°

), 13.3°

(±

0.2°

), 14.3°

(±

0.2°

), 15.5°

(±

0.2°

), 17.4°

(±

0.2°

), 18.5°

(±

0.2°

), 22.0°

(±

0.2°

), 23.9°

(±

0.2°

), 24.1°

(±

0.2°

), and 26.4°

(±

0.2°

).

20. The polymorph according to claim 17, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 5.

21. Polymorph Form F of a compound of Formula (I):

22. The polymorph according to claim 21, further comprising at least one characteristic XRPD peak selected from 2θ

=14.0°

(±

0.2°

) and 19.2°

(±

0.2°

).

23. The polymorph according to claim 21, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=9.6°

(±

0.2°

), 14.0°

(±

0.2°

), 17.3°

(±

0.2°

), 19.2°

(±

0.2°

), and 24.6°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=12.4°

(±

0.2°

), 16.1°

(±

0.2°

), 16.6°

(±

0.2°

), 17.1°

(±

0.2°

), 20.8°

(±

0.2°

), 21.5°

(±

0.2°

), 22.0°

(±

0.2°

), 24.3°

(±

0.2°

), 25.2°

(±

0.2°

), and 25.4°

(±

0.2°

).

24. The polymorph according to claim 21, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 6.

25. Polymorph Form G of a compound of Formula (I):

26. The polymorph according to claim 25, further comprising at least one characteristic XRPD peak selected from 2θ

=10.6°

(±

0.2°

) and 19.6°

(±

0.2°

).

27. The polymorph according to claim 25, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=6.7°

(±

0.2°

), 9.5°

(±

0.2°

), 10.6°

(±

0.2°

), 19.0°

(±

0.2°

), and 19.6°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=13.4°

(±

0.2°

), 15.0°

(±

0.2°

), 15.8°

(±

0.2°

), 17.8°

(±

0.2°

), 20.7°

(±

0.2°

), 21.2°

(±

0.2°

), 22.8°

(±

0.2°

), 23.8°

(±

0.2°

), 24.3°

(±

0.2°

), and 25.6°

(±

0.2°

).

28. The polymorph according to claim 25, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 7.

29. Polymorph Form H of a compound of Formula (I):

30. The polymorph according to claim 29, further comprising at least one characteristic XRPD peak selected from 2θ

=17.3°

(±

0.2°

) and 18.5°

(±

0.2°

).

31. The polymorph according to claim 29, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=8.9°

(±

0.2°

), 9.2°

(±

0.2°

), 14.1°

(±

0.2°

), 17.3°

(±

0.2°

), and 18.5°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=7.1°

(±

0.2°

), 10.6°

(±

0.2°

), 11.3°

(±

0.2°

), 11.6°

(±

0.2°

), 16.2°

(±

0.2°

), 18.3°

(±

0.2°

), 18.8°

(±

0.2°

), 20.3°

(±

0.2°

), 21.7°

(±

0.2°

), and 24.7°

(±

0.2°

).

32. The polymorph according to claim 29, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 8.

33. Polymorph Form I of a compound of Formula (I):

34. The polymorph according to claim 33, further comprising at least one characteristic XRPD peak selected from 2θ

=11.4°

(±

0.2°

) and 14.2°

(±

0.2°

).

35. The polymorph according to claim 33, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=9.7°

(±

0.2°

), 11.4°

(±

0.2°

), 14.2°

(±

0.2°

), 19.3°

(±

0.2°

), and 24.5°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=9.2°

(±

0.2°

), 14.7°

(±

0.2°

), 15.5°

(±

0.2°

), 16.7°

(±

0.2°

), 17.3°

(±

0.2°

), 18.4°

(±

0.2°

), 21.4°

(±

0.2°

), 22.9°

(±

0.2°

), 29.1°

(±

0.2°

), and 34.1°

(±

0.2°

).

36. The polymorph according to claim 33, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 9.

37. Polymorph Form J of a compound of Formula (I):

38. The polymorph according to claim 37, further comprising at least one characteristic XRPD peak selected from 2θ

=16.4°

(±

0.2°

) and 17.9°

(±

0.2°

).

39. The polymorph according to claim 37, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=9.1°

(±

0.2°

), 16.4°

(±

0.2°

), 17.3°

(+0.2°

), 17.9°

(±

0.2°

), and 18.3°

(±

0.2°

), in combination with at least one XRPD peak selected from 2θ

=9.4°

(±

0.2°

), 10.1°

(±

10.2°

), 10.7°

(±

0.2°

), 14.0°

(±

0.2°

), 14.3°

(±

0.2°

), 15.5°

(±

0.2°

), 16.9°

(±

0.2°

), 19.9°

(±

0.2°

), 24.0°

(±

0.2°

), and 24.7°

(10.2°

).

40. The polymorph according to claim 37, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 10.

42. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I):

43. The pharmaceutical composition according to claim 42, wherein the pharmaceutical composition further comprises at least one non-Form C polymorph selected from Form A, Form B, Form D, Form E, Form F, Form G, Form H, Form I, Form J, or an amorphous form of a compound of Formula (I), or a salt, solvate, or hydrate thereof, wherein

polymorph Form A has the following characteristic X-ray Powder Diffraction (XRPD) peaks:

2θ

=9.6°

(±

0.2°

), 12.2°

(±

0.2°

), and 18.3°

(±

0.21;

polymorph Form B has the following characteristic XRPD peaks;

2θ

=7.9°

(±

0.2°

), 13.4°

(±

0.2°

), and 23.4°

(±

0.2°

);

polymorph Form D has the following characteristic XRPD peaks;

2θ

=11.4°

(±

0.2°

), 17.4°

(±

0.2°

), and 22.9°

(±

0.2°

);

polymorph Form E has the following characteristic XRPD peaks;

2θ

=6.7°

(±

0.2°

), 9.3°

(±

0.2°

), and 24.4°

(±

0.2°

);

polymorph Form F has the following characteristic XRPD peaks;

2θ

=9.6°

(±

0.2°

), 17.3°

(±

0.2°

), and 24.6°

(±

0.2°

);

polymorph Form G has the following characteristic XRPD peaks;

2θ

=6.7°

(±

0.2°

), 9.5°

(±

0.2°

), and 19.0°

(±

0.2°

);

polymorph Form H has the following characteristic XRPD peaks;

2θ

=8.9°

(±

0.2°

), 9.2°

(±

0.2°

), and 14.1°

(±

0.2°

);

polymorph Form I has the following characteristic XRPD peaks;

2θ

=9.7°

(±

0.2°

), 19.3°

(±

0.2°

), and 24.5°

(±

0.2°

); and

polymorph Form J has the following characteristic XRPD peaks;

2θ

=9.1°

(±

0.2°

), 17.3°

(±

0.2°

), and 18.3°

(±

0.2°

).

44. The pharmaceutical composition according to claim 43, wherein the pharmaceutical composition comprises polymorph Form C and polymorph Form A in a ratio of greater than about 9:

1 Form C;

Form A.

45. The pharmaceutical composition according to claim 42, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients selected from silicified microcrystalline cellulose, lactose, mannitol, starch, sorbitol, sucrose, dicalcium phosphate, microcrystalline cellulose, crospovidone, croscarmellose sodium, and sodium starch glycolate, silicon dioxide, silicon dioxide, magnesium silicate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, sodium lauryl sulphate, sodium dodecyl sulphate, Tween®

80, and Lutrol®

.

47. Polymorph Form A of a compound of Formula (I):

48. The polymorph according to claim 47, further comprising at least one characteristic XRPD peak selected from 2θ

=15.6°

(±

0.2°

) and 19.2°

(±

0.2°

).

49. The polymorph according to claim 47, wherein the polymorph has the following characteristic XRPD peaks:

2θ

=9.6°

(±

0.2°

), 12.2°

(±

0.2°

), 15.6°

(±

0.2°

), 18.3°

(±

0.2°

), and 19.2°

(±

0.2°

in combination with at least one XRPD peak selected from 2θ

=9.1°

(±

0.2°

), 9.4°

(±

0.2°

), 12.4°

(±

0.2°

), (14.8°

(±

0.2°

), 16.3°

(±

0.2°

), 17.7°

(±

0.2°

), 21.1°

(±

0.2°

), 21.9°

(±

0.2°

), 24.0°

(±

0.2°

), and 26.9°

(±

0.2°

).

50. The polymorph according to claim 47, wherein the polymorph has substantially all peaks in its XRPD pattern as shown in FIG. 1.

51. The polymorph of claim 47, wherein Form A has an endothermic peak at about 238°

C. or about 239°

C.