METHODS FOR TREATING INFLAMMATORY DISEASES AND PHARMACEUTICAL COMBINATIONS USEFUL THEREFOR

• US 20140243273A1
• Filed: 05/07/2014
• Published: 08/28/2014
• Est. Priority Date: 11/07/2011
• Status: Abandoned Application

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Kadiyala, Irina Nikolaevna, Jamzad, Shahla, Sewell, Kathryn Lea, Hoock, Thomas Carl, Taylor, Lori Kell
• Application Number:
  US14/271,589
• Publication Number:
  US 20140243273A1
• Time in Patent Office: Days
• US Class Current: 514/16.6
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/52 Purines, e.g. adenine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/02 Immunomodulators
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides method of treating or lessening the severity of a disease selected from spondyloarthropathy, systemic lupus erythematosus, rheumatoid arthritis, or any combination thereof comprising the administration of a compound of Formula I and an optional co-therapy (e.g., chemotherapy agent, DMARD, or any combination thereof). The present invention also provides a pharmaceutical composition comprising a compound of Formula I, a method of manufacturing a pharmaceutical composition comprising a compound of Formula I, and a method of administering a pharmaceutical composition comprising a solid form of a compound of Formula I.

Claims

1. A method for treating or lessening the severity of a disease selected from spondyloarthropathy, systemic lupus erythematosus, rheumatoid arthritis, or any combination thereof comprising administering to a patient in need thereof a chemotherapy agent and a compound of Formula I

2. The method of claim 1, wherein the chemotherapy agent comprises methotrexate, azathioprine, cyclosporine, cyclophosphamide, 6-mercaptopurine, or any combination thereof.

3. The method of either of claim 1 or 2, wherein the chemotherapy agent comprises an injectable formulation or an oral formulation.

4. The method of any one of claims 1-3, wherein the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

5. The method of any one of claims 1-4, wherein R² is H or F.

6. The method of any one of claims 1-5, wherein R³ is H or Cl.

7. The method of any one of claims 1-6, wherein each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

8. The method of any one of claims 1-7, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

9. The method of any one of claims 1-8, wherein R¹⁴ is H or methyl.

10. The method of any one of claims 1-9, wherein R⁷ is an unsubstituted C_1-3 aliphatic.

11. The method of any one of claims 1-9, wherein R⁷ is a C_1-3 aliphatic substituted with 1-3 occurrences of F.

12. The method of any one of claims 1-9, wherein R⁷ is a group selected from —

CH₂CH₃, —

CH₂CF₃, —

CH₂CH₂CH₃, or —

CHCH₃CH₃.

13. The method of claim 1, wherein the compound of Formula I is selected from:

14. The method of any one of claims 1-13, wherein the compound of Formula I is administered at least once per day.

15. The method of any one of claims 1-14, wherein the compound of Formula I is administered at least twice per day.

16. The method of any one of claims 1-15, wherein the compound of Formula I is orally administered to the patient in need thereof.

17. The method of any one of claims 1-14, wherein at least about 100 mg of the compound of Formula I is administered to the patient once per day.

18. The method of any one of claims 1-14, wherein at least about 150 mg of the compound of Formula I is administered to the patient once per day.

19. The method of any one of claims 1-14, wherein at least about 200 mg of the compound of Formula I is administered to the patient once per day.

20. The method of any one of claims 1-16, wherein at least about 100 mg of the compound of Formula I is administered to the patient twice per day.

21. The method of any one of claims 1-20, wherein the spondyloarthropathy is a condition selected from peripheral spondyloarthropathy, axial spondyloarthropathy, reactive arthritis, Reiter'"'"'s syndrome, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, Crohn'"'"'s disease, or any combination thereof.

22. A method for treating or lessening the severity of a disease selected from systemic lupus erythematosus, ulcerative colitis, Crohn'"'"'s disease, ankylosing spondylitis, reactive arthritis, Reiter'"'"'s syndrome, psoriatic arthritis, peripheral spondyloarthropathy, axial spondyloarthropathy, or any combination thereof comprising administering to a patient in need thereof a compound of Formula I

23. The method of claim 22, further comprising administering a chemotherapy agent to the patient.

24. The method of claim 22, wherein the chemotherapy agent comprises methotrexate, azathioprine, cyclosporine, cyclophosphamide, 6-mercaptopurine, or any combination thereof.

25. The method of either of claim 23 or 24, wherein the chemotherapy agent comprises an injectable formulation or an oral formulation.

26. The method of any one of claims 23-25, wherein the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

27. The method of any one of claims 22-26, wherein R² is H or F.

28. The method of any one of claims 22-27, wherein R³ is H or Cl.

29. The method of any one of claims 22-28, wherein each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

30. The method of any one of claims 22-29, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

31. The method of any one of claims 22-30, wherein R¹⁴ is H or methyl.

32. The method of any one of claims 22-31, wherein R⁷ is an unsubstituted C_1-3 aliphatic.

33. The method of any one of claims 22-31, wherein R⁷ is a C_1-3 aliphatic substituted with 1-3 occurrences of F.

34. The method of any one of claims 22-31, wherein R⁷ is a group selected from —

CH₂CH₃, —

CH₂CF₃, —

CH₂CH₂CH₃, or —

CHCH₃CH₃.

35. The method of claim 22, wherein the compound of Formula I is selected from:

36. The method of any one of claims 22-35, wherein the compound of Formula I is administered at least once per day.

37. The method of any one of claims 22-36, wherein the compound of Formula I is administered at least twice per day.

38. The method of any one of claims 22-37, wherein the compound of Formula I is orally administered to the patient in need thereof.

39. The method of any one of claims 22-38, wherein at least about 100 mg of the compound of Formula I is administered to the patient once per day.

40. The method of any one of claims 22-39, wherein at least about 150 mg of the compound of Formula I is administered to the patient once per day.

41. The method of any one of claims 22-40, wherein at least about 200 mg of the compound of Formula I is administered to the patient once per day.

42. The method of any one of claims 22-38, wherein at least about 100 mg of the compound of Formula I is administered to the patient twice per day.

43. A method for treating or lessening the severity of a disease selected from rheumatoid arthritis, systemic lupus erythematosus, peripheral spondyloarthropathy, axial spondyloarthropathy, ulcerative colitis, Crohn'"'"'s disease, ankylosing spondylitis, reactive arthritis, Reiter'"'"'s syndrome, psoriatic arthritis, or any combination thereof comprising administering to a patient in need thereof a chemotherapy agent and a pharmaceutical composition comprising a compound of Formula I

44. The method of claim 43, wherein the chemotherapy agent comprises methotrexate, azathioprine, cyclosporine, cyclophosphamide, 6-mercaptopurine, or any combination thereof.

45. The method of either of claim 43 or 44, wherein the chemotherapy agent comprises an injectable formulation or an oral formulation.

46. The method of any one of claims 43-45, wherein the patient is administered from about 5 mg to about 100 mg of the chemotherapy agent per month.

47. The method of any one of claims 43-46, wherein R² is H or F.

48. The method of any one of claims 43-47, wherein R³ is H or Cl.

49. The method of any one of claims 43-48, wherein each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

50. The method of any one of claims 43-49, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

51. The method of any one of claims 43-50, wherein R¹⁴ is H or methyl.

52. The method of any one of claims 43-51, wherein R⁷ is an unsubstituted C_1-3 aliphatic.

53. The method of any one of claims 43-51, wherein R⁷ is a C_1-3 aliphatic substituted with 1-3 occurrences of F.

54. The method of any one of claims 43-51, wherein R⁷ is a group selected from —

CH₂CH₃, —

CH₂CF₃, —

CH₂CH₂CH₃, or —

CHCH₃CH₃.

55. The method of claim 43, wherein the compound of Formula I is selected from:

56. The method of any one of claims 43-55, wherein the pharmaceutical composition further comprises a tablet.

57. The method of claim 56, wherein the tablet further comprises a diluent, a binder, a glidant, a disintegrant, a surfactant, a lubricant, or any combination thereof.

58. The method of either of claim 56 or 57, wherein the tablet is administered at least once per day.

59. The method of claim 58, wherein the tablet comprises at least about 10 mg of the compound of Formula I.

60. The method of claim 59, wherein the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.

61. The method of either of claim 56 or 57, wherein the tablet is administered at least twice per day.

62. The method of claim 61, wherein the tablet comprises at least about 10 mg of the compound of Formula I.

63. The method of claim 62, wherein the tablet comprises from about 15 mg to about 100 mg of the compound of Formula I.

64. The method of either of claim 56 or 57, further comprising administering once per day at least one tablet comprising the pharmaceutical composition.

65. The method of either of claim 56 or 57, further comprising administering twice per day at least one tablet comprising the pharmaceutical composition.

66. The method of either of claim 64 or 65, wherein each tablet further comprises from about 5 mg to about 100 mg of the compound of Formula I.

67. A method for treating or lessening the severity of a disease selected from rheumatoid arthritis, systemic lupus erythematosus, peripheral spondyloarthropathy, axial spondyloarthropathy, ulcerative colitis, Crohn'"'"'s disease, ankylosing spondylitis, reactive arthritis, Reiter'"'"'s syndrome, psoriatic arthritis, or any combination thereof comprising administering to a patient in need thereof a compound of Formula I

68. The method of claim 67, wherein about 100 mg of the compound of formula I is administered to the patient once per day.

69. The method of claim 67, wherein about 150 mg of the compound of formula I is administered to the patient once per day.

70. The method of claim 67, wherein about 200 mg of the compound of formula I is administered to the patient once per day.

71. The method of claim 67, wherein about 100 mg of the compound of formula I is administered to the patient twice per day.

72. The method of any one of claims 67-71, further comprising administering to the patient a chemotherapy agent.

73. The method of any one of claims 67-72, wherein R² is H or F.

74. The method of any one of claims 67-73, wherein R³ is H or Cl.

75. The method of any one of claims 67-74, wherein each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

76. The method of any one of claims 67-75, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

77. The method of any one of claims 67-76, wherein R¹⁴ is H or methyl.

78. The method of any one of claims 67-77, wherein R⁷ is an unsubstituted C_1-3 aliphatic.

79. The method of any one of claims 67-77, wherein R⁷ is a C_1-3 aliphatic substituted with 1-3 occurrences of F.

80. The method of any one of claims 67-77, wherein R⁷ is a group selected from —

CH₂CH₃, —

CH₂CF₃, —

CH₂CH₂CH₃, or —

CHCH₃CH₃.

81. The method of any one of claims 67-80, wherein the compound of Formula I is selected from:

82. A pharmaceutical composition comprising:

a. a compound of Formula I

83. The pharmaceutical composition of claim 82, wherein X¹ is N, CH, or CF.

84. The pharmaceutical composition of either of claim 82 or 83, wherein R″

is H or methyl.

85. The pharmaceutical composition of any one of claims 82-84, wherein R² is H or F.

86. The pharmaceutical composition of any one of claims 82-85, wherein each of R⁸ and R⁹ is independently selected from methyl, ethyl, propyl, iso-propyl, butyl, or tert-butyl.

87. The pharmaceutical composition of any one of claims 82-86, wherein each of R⁸ and R⁹ is independently selected from methyl or ethyl.

88. The pharmaceutical composition of any one of claims 82-87, wherein R¹⁴ is H or methyl.

89. The pharmaceutical composition of any one of claims 82-88, wherein R⁷ is an unsubstituted C_1-3 aliphatic.

90. The pharmaceutical composition of any one of claims 82-88, wherein R⁷ is a C_1-3 aliphatic substituted with 1-3 occurrences of F.

91. The pharmaceutical composition of any one of claims 82-88, wherein R⁷ is a group selected from —

CH₂CH₃, —

CH₂CF₃, —

CH₂CH₂CH₃, or —

CHCH₃CH₃.

92. The pharmaceutical composition of any one of claims 82-91, wherein the compound of Formula I is selected from:

93. The pharmaceutical composition of any one of claims 82-92, further comprising a diluent, and the diluent comprises lactose, sorbitol, cellulose, calcium phosphate, starch, sugar, or any combination thereof.

94. The pharmaceutical composition of claim 93, wherein the diluent comprises lactose and has a concentration of about 10 wt % or greater by weight of the composition.

95. The pharmaceutical composition of any one of claims 82-94, further comprising a disintegrant, and the disintegrant comprises sodium croscarmellose, sodium starch glycolate, or any combination thereof.

96. The pharmaceutical composition of claim 95, wherein the disintegrant comprises sodium croscarmellose and has a concentration of about 10 wt % or less by weight of the composition.

97. The pharmaceutical composition of any one of claims 82-96, further comprising a wetting agent, and the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polyoxyethylene 20 sorbitan mono-oleate, or any combination thereof.

98. The pharmaceutical composition of claim 97, wherein the wetting agent comprises sodium lauryl sulfate and has a concentration of about 10 wt % or less by weight of the composition.

99. The pharmaceutical composition of any one of claims 82-98, further comprising a binder, and the binder comprises microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, modified cellulose, or any combination thereof.

100. The pharmaceutical composition of claim 99, wherein the binder comprises microcrystalline cellulose and has a concentration of at least about 1 wt % by weight of the composition.

101. The pharmaceutical composition of any one of claims 82-100, further comprising a glidant, and the glidant comprises colloidal silicon dioxide, talc, or any combination thereof.

102. The pharmaceutical composition of claim 101, wherein the glidant comprises colloidal silicon dioxide and has a concentration of 2 wt % or less by weight of the composition.

103. The pharmaceutical composition of any one of claims 82-102, further comprising a lubricant, and the lubricant comprises magnesium stearate, stearic acid, hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

104. The pharmaceutical composition of claim 103, wherein the lubricant comprises magnesium stearate and has a concentration of less than about 2 wt % by weight of the composition.

105. The pharmaceutical composition of any one of claims 82-104, further comprising a colorant.

106. The pharmaceutical composition of any one of claims 82-105, wherein the composition comprises about 25 wt % to about 35 wt % of the compound of Formula I by weight of the composition.

107. The pharmaceutical composition of any one of claims 82-106, wherein the composition comprises from about 45 wt % to about 55 wt % of the compound of Formula I by weight of the composition.

108. The pharmaceutical composition of any one of claims 82-107, wherein the composition comprises a tablet.