Processing

Please wait...

Settings

Settings

Goto Application

1. WO2020117988 - CDK9 INHIBITORS AND POLYMORPHS THEREOF FOR USE AS AGENTS FOR TREATMENT OF CANCER

Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

[ EN ]

CLAIMS

1. A crystalline form of a compound having the following structure (I):


or a tautomer or zwitterionic form thereof.

2. The crystalline form of claim 1, comprising Form B.

3. The crystalline form of claim 1, consisting essentially of Form B.

4. The crystalline form of claim 1, 2 or 3, wherein the crystalline form is

substantially pure.

5. The crystalline form of any one of claims 1-4, characterized by an x-ray powder diffraction pattern comprising at least three peaks at 2-theta angles selected from the group consisting of 4.8 ± 0.2°, 10.8 ± 0.2°, 13.7 ± 0.2°, 14.9 ± 0.2°, 20.0 ± 0.2° and 24.6 ± 0.2°.

6. The crystalline form of claim 5, characterized by an x-ray powder diffraction pattern comprising at least four peaks at 2-theta angles selected from the group consisting of 4.8 ± 0.2°, 10.8 ± 0.2°, 13.7 ± 0.2°, 14.9 ± 0.2°, 20.0 ± 0.2° and 24.6 ± 0.2°.

7. The crystalline form of claim 6, characterized by an x-ray powder diffraction pattern comprising at least five peaks at 2-theta angles selected from the group consisting of 4.8 ± 0.2°, 10.8 ± 0.2°, 13.7 ± 0.2°, 14.9 ± 0.2°, 20.0 ± 0.2° and 24.6 ± 0.2°.

8. The crystalline form of any one of claims 1-4, characterized by an x-ray powder diffraction pattern comprising peaks at the following 2-theta angles: 10.8 ± 0.2°, 14.9 ± 0.2° and 20.0 ± 0.2°.

9. The crystalline form of claim 8, characterized by an x-ray powder diffraction pattern comprising peaks at the following 2-theta angles: 4.8 ± 0.2°, 10.8 ± 0.2°, 14.9 ± 0.2° and 20.0 ± 0.2°.

10. The crystalline form of claim 9, characterized by an x-ray powder diffraction pattern comprising peaks at the following 2-theta angles: 4.8 ± 0.2°, 10.8 ± 0.2°, 13.7 ± 0.2°, 14.9 ± 0.2° and 20.0 ± 0.2°.

11. A crystalline form of a compound having the following structure (I):


or a tautomer or zwitterionic form thereof, having an x-ray powder diffraction pattern substantially in accordance with that depicted in FIG.1.

12. The crystalline form of any one of claims 1-11, characterized by a differential scanning calorimetry thermogram comprising an endothermic peak at about 264 °C.

13. The crystalline form of any one of claims 1-12, characterized by a differential scanning calorimetry thermogram substantially in accordance with that depicted in FIG.8.

14. The crystalline form of any one of claims 1-13, wherein the crystalline form is of a compound having structure (II):


15. A pharmaceutical composition comprising a crystalline form of any one of claims 1-14 and a pharmaceutically acceptable carrier or excipient.

16. The pharmaceutical composition of claim 15, formulated for oral administration. 17. The pharmaceutical composition of claim 15 or 16, in the form of a capsule. 18. The pharmaceutical composition of claim 15 or 16, in the form of a tablet.

19. The pharmaceutical composition of any one of claims 15-18, further comprising one or more additional therapeutic agents.

20. The pharmaceutical composition of any one of claims 15-19, provided in the form of a rapid release formulation.

21. The pharmaceutical composition of any one of claims 15-20, wherein the

pharmaceutically acceptable carrier or excipient is anhydrous lactose or cornstarch.

22. The pharmaceutical composition of any one of claims 15-21, further comprising a glidant.

23. The pharmaceutical composition of claim 22, wherein the glidant is colloidal silicon dioxide.

24. The pharmaceutical composition of any one of claims 15-23, further comprising a lubricant.

25. The pharmaceutical composition of claim 24, wherein the lubricant is

magnesium stearate.

26. The pharmaceutical composition of any one of claims 15-25, further comprising a disintegrant.

27. The pharmaceutical composition of claim 26, wherein the disintegrant is partly pregelatinized starch, low-substituted hydroxyl propyl cellulose or carmellose calcium.

28. A pharmaceutical composition comprising:

from about 0.5 weight percent to about 11.25 weight percent of a compound having the following structure (I):


or a tautomer, pharmaceutically acceptable salt or zwitterionic form thereof; and from about 85 weight percent to about 99.5 weight percent of a

pharmaceutically acceptable carrier or excipient.

29. The pharmaceutical composition of claim 28, comprising from about 0.5 weight percent to about 1 weight percent of a compound having structure (I), or a tautomer or zwitterionic form thereof.

30. The pharmaceutical composition of claim 29, comprising about 1 mg of a

compound having structure (I), or a tautomer or zwitterionic form thereof. 31. The pharmaceutical composition of claim 28, comprising from about 10.5

weight percent to about 11.25 weight percent of a compound having structure (I), or a tautomer or zwitterionic form thereof.

32. The pharmaceutical composition of claim 31, comprising about 16 mg of a compound having structure (I), or a tautomer or zwitterionic form thereof. 33. The pharmaceutical composition of any one of claims 28-30, comprising from about 95 weight percent to about 99.5 weight percent of a pharmaceutically acceptable carrier or excipient.

34. The pharmaceutical composition of any one of claims 28-32, comprising from about 85 weight percent to about 90 weight percent of a pharmaceutically acceptable carrier or excipient.

35. The pharmaceutical composition of any one of claims 28-34, wherein the pharmaceutically acceptable carrier or excipient is anhydrous lactose or cornstarch.

36. The pharmaceutical composition of any one of claims 28-35, further comprising a glidant.

37. The pharmaceutical composition of claim 36, comprising about 1 weight percent of the glidant.

38. The pharmaceutical composition of claim 36 or 37, wherein the glidant is

colloidal silicon dioxide.

39. The pharmaceutical composition of any one of claims 28-38, further comprising a lubricant.

40. The pharmaceutical composition of claim 39, comprising about 1% of the

lubricant.

41. The pharmaceutical composition of claim 40, wherein the lubricant is

magnesium stearate.

42. The pharmaceutical composition of any one of claims 28-41, further comprising a disintegrant.

43. The pharmaceutical composition of claim 42, wherein the disintegrant is partly pregelatinized starch, low-substituted hydroxyl propyl cellulose or carmellose calcium.

44. A pharmaceutical composition comprising:

about 0.6 weight percent of a compound having the following structure (I):

,


or a tautomer, pharmaceutically acceptable salt or zwitterionic form thereof; about 97.4 weight percent of anhydrous lactose;

about 1 weight percent colloidal silicon dioxide; and

about 1 weight percent magnesium stearate.

45. A pharmaceutical composition comprising:

about 11 weight percent of a compound having the following structure (I):


or a tautomer, pharmaceutically acceptable salt or zwitterionic form thereof; about 87 weight percent of anhydrous lactose;

about 1 weight percent colloidal silicon dioxide; and

about 1 weight percent magnesium stearate.

46. A pharmaceutical composition comprising:

about 0.6 weight percent of a compound having the following structure (I):


or a tautomer, pharmaceutically acceptable salt or zwitterionic form thereof; and from about 98 weight percent to about 99.5 weight percent of cornstarch.

47. A pharmaceutical composition comprising:

about 11 weight percent of a compound having the following structure (I):


or a tautomer, pharmaceutically acceptable salt or zwitterionic form thereof; and about 88 weight percent of cornstarch.

48. The pharmaceutical composition of claim 46 or 47, further comprising about 1 weight percent magnesium stearate.

49. The pharmaceutical composition of any one of claims 28-48, comprising the zwitterionic form of the compound having structure (I), the zwitterionic form having the following structure


50. The pharmaceutical composition of claim 49, comprising Form B.

51. A unit dose form comprising a pharmaceutical composition of any one of claims 15-50.

52. A method for treating a disease associated with overexpression of a cyclin- dependent kinase (CDK) in a mammal in need thereof, comprising

administering to the mammal a therapeutically effective amount of a crystalline form of any one of claims 1-14, or a pharmaceutical composition of any one of claims 15-50 or a unit dose form of claim 51.

53. The method of claim 52, wherein the disease is cancer.

54. The method of claim 53, wherein the cancer is a hematologic cancer.

55. The method of claim 54, wherein the hematologic cancer is selected from acute myelogenous leukemia (AML), follicular lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma (MM), and non-Hodgkin’s lymphoma.

56. The method of claim 54, wherein the hematologic cancer is myelodysplasic syndrome (MDS).

57. The method of claim 53, wherein the cancer comprises a solid tumor.

58. The method of claim 53 or 57, wherein the cancer is bladder cancer.

59. The method of claim 53 or 57, wherein the cancer is lung cancer.

60. The method of claim 53 or 57, wherein the cancer is liver cancer.

61. The method of claim 53 or 57, wherein the cancer is prostate cancer.

62. The method of claim 53 or 57, wherein the cancer is a sarcoma.

63. The method of claim 53 or 57, wherein the cancer is renal cell carcinoma.

64. The method of any one of claims 53-63, wherein the cancer is c-Myc-altered. 65. The method of claim 64, wherein the cancer is lymphoma.

66. The method of claim 65, wherein the lymphoma is Burkitt lymphoma.

67. The method of claim 65, wherein the lymphoma is B-cell lymphoma or T-cell lymphoma.

68. The method of claim 64, wherein the cancer is cervical cancer, colon cancer, ovarian cancer, breast cancer, lung cancer, prostate cancer, colorectal cancer, pancreatic cancer, gastric cancer or uterine cancer.

69. The method of any one of claims 53-68, wherein the cancer is a primary cancer. 70. The method of any one of claims 53-69, wherein the cancer is a metastatic

cancer.

71. The method of any one of claims 52-70, wherein the crystalline form, the pharmaceutical composition or the unit dose form is administered orally.

72. A method for preparing crystalline Form B of a compound having the following structure (II):


the method comprising:

contacting amorphous compound having the following structure (I):


or a tautomer or zwitterionic form thereof, with an acid in a solvent, thereby preparing the crystalline Form B of the compound having structure (II).

73. The method of claim 72, wherein the acid has at least one pKa value that is less than about 5.

74. The method of claim 72 or 73, wherein the acid has a pKa value of greater than about 1.

75. The method of claim 72, 73 or 74, wherein the acid is an organic acid.

76. The method of claim 75, wherein the acid is selected from maleic acid, acetic acid, citric acid or propionic acid.

77. The method of claim 76, wherein the acid is maleic acid.

78. The method of claim any one of claims 72-77, wherein the solvent is tetrahydrofuran, methanol, ethanol, butanol, methyl ethyl ketone, acetone, diisopropylether, ethyl acetate or water, or a combination of any of the foregoing.

79. The method of any one of claims 72-78, wherein the solvent is an organic

solvent.

80. The method of any one of claims 72-79, wherein the solvent comprises

tetrahydrofuran.

81. A method for preparing crystalline Form B of a compound having the following structure (II):


the method comprising:

contacting a compound having the following structure (V):


or a tautomer, salt or zwitterionic form thereof, with an acid in a solvent, thereby preparing the crystalline Form B of the compound having structure (II). 82. The method of claim 81, wherein the acid has at least one pKa value that is less than about 5.

83. The method of claim 81 or 82, wherein the acid has a pKa value of greater than about 1.

84. The method of claim 81, 82 or 83, wherein the acid is an organic acid.

85. The method of claim 84, wherein the acid is maleic acid.

86. The method of claim any one of claims 81-85, wherein the solvent is

tetrahydrofuran, methanol, ethanol, butanol, methyl ethyl ketone, acetone, diisopropylether, ethyl acetate or water, or a combination of any of the foregoing.

87. The method of any one of claims 81-85, wherein the solvent is an organic solvent.

88. The method of any one of claims 81-87, wherein the solvent is a mixture of methanol and acetone.

89. The method of any one of claims 81-88, wherein the molar ratio of acid to compound having structure (V), or a tautomer or zwitterionic form thereof, is from about 0.4:1 to about 1.1:1.

90. The method of claim 89, wherein the molar ratio of acid to compound having structure (V), or a tautomer or zwitterionic form thereof, is about 0.5:1.

91. A method for preparing a compound having the following structure (I):


or a salt, tautomer or zwitterionic form thereof, the method comprising:

(a) contacting a compound having the following structure (IV):

or a tautomer or salt thereof, with di-tert-butylhalophosphonate in the presence of an amine base, thereby forming a compound having the following structure (V):


or a tautomer or salt thereof; and

(b) contacting the compound having structure (V), or a tautomer or salt thereof, with an acid,

thereby preparing a compound having structure (I), or a salt, tautomer or zwitterionic form thereof.

92. The method of claim 91, wherein the amine base is an organic amine base. 93. The method of claim 92, wherein the organic amine base is

diisopropylethylamine.

94. The method of claim 91, 92 or 93, further comprising contacting di-tert- butylphosphonate with carbon tetrahalide to prepare the di-tert- butylhalophosphonate.

95. The method of claim 94, wherein the di-tert-butylhalophosphonate is prepared in situ with the compound having structure (IV) by contacting di-tert- butylphosphonate with carbon tetrahalide.

96. The method of any one of claims 91-95, wherein the acid is hydrochloric acid or acetic acid, or a combination thereof.

97. The method of any one of claims 91-96, wherein the compound formed in step (b) is a salt of a compound having structure (I).

98. The method of claim 97, further comprising contacting the salt of a compound having structure (I) formed in step (b) with a base, thereby forming the compound having structure (I), or a tautomer or zwitterionic form thereof.

99. The method of claim 98, wherein the base is ammonium bicarbonate.

100. The method of any one of claims 91-95, wherein the acid is maleic acid.

101. The method of any one of claims 91-100, wherein the compound formed in step (b) is a compound having structure (II):

.


102. A method for preparing crystalline Form B of a compound having the following structure (II):


the method comprising:

(a) contacting a compound having the following structure (IV):

or a tautomer or salt thereof, with di-tert-butylhalophosphonate in the presence of an amine base, thereby forming a compound having the following structure (V):


or a tautomer or salt thereof; and

(b) contacting the compound having structure (V), or a tautomer or salt thereof, in an organic solvent, with an acid having at least one pKa value that is less than about 5 and a pKa value of greater than about 1 in an organic solvent, thereby preparing crystalline Form B of a compound having structure (II).

103. A method for preparing crystalline Form B of a compound having the following structure (II):


the method comprising:

(a) contacting a compound having the following structure (IV):


or a tautomer or salt thereof, with di-tert-butylhalophosphonate in the presence of an amine base, thereby forming a compound having the following structure (V):


or a tautomer or salt thereof;

(b) contacting the compound having structure (V), or a tautomer or salt thereof, with an acid having a pKa value of less than about 1, thereby forming a salt of a compound having the following structure (I):


(c) contacting the salt of a compound having structure (I) with a base, thereby forming amorphous compound having structure (I); and

(d) contacting the amorphous compound having structure (I), in an organic solvent, with an acid having at least one pKa value that is less than about 5 and a pKa value of greater than about 1,

thereby preparing crystalline Form B of the compound having structure (II).

104. A combination comprising a crystalline form of any one of claims 1-14, and an additional therapeutic agent.

105. The combination of claim 104, further comprising a pharmaceutically

acceptable carrier or excipient.

106. The method of any one of claims 52-71, further comprising administering to the mammal an additional therapeutic agent.