Synthesis of epothilones, intermediates thereto and analogues thereof

• US 20040053910A1
• Filed: 05/09/2003
• Published: 03/18/2004
• Est. Priority Date: 08/23/2002
• Status: Active Grant

• Current Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Original Assignee: Sloan-Kettering Institute For Cancer Research (Memorial Sloan-Kettering Cancer Center)
• Inventors: Danishefsky, Samuel J., Chou, Ting-Chao, Gabarda, Ana E., Dong, Huajin, Rivkin, Alexey, Fumikiko, Yoshimura
• Granted Patent: US 7,649,006 B2
• Time in Patent Office: Days
• US Class Current: 514/183
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 313/00 Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/02 containing two hetero rings
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 493/04 Ortho-condensed systems

Abstract

The present invention provides compounds of formula (I):

as described generally and in classes and subclasses herein. The present invention additionally provides pharmaceutical compositions comprising compounds of formula (I) and provides methods of treating cancer comprising administering a compound of formula (I).

Claims

1. A compound of the formula:

45. A pharmaceutical composition for the treatment of cancer comprising a compound of any one of claims 1-32 and a pharmaceutically acceptable excipient.

50. A pharmaceutical composition for the treatment of cancer comprising:

a therapeutically effective amount of a compound of any one of claims 1-43, or pharmaceutically acceptable salts thereof; and

a pharmaceutically acceptable carrier or diluent,

wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.001 to about 40 mg compound per kg body weight of a subject.

51. A method of treating cancer comprising:

administering a therapeutically effective amount of a compound of any one of claims 1-32 to a subject in need thereof.

52. The method of claim 51, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.001 mg to about 40 mg compound per kg body weight.

53. The method of claim 51, wherein the therapeutically effective amount of the compound is an amount sufficient to deliver about 0.1 mg to about 25 mg compound per kg body weight.

2. A compound of the formula:

3. The compound of claim 2 wherein R_B is methyl.

4. The compound of claim 2 wherein R_B is —

CF₃.

5. The compound of claim 2, 3, or 4, wherein R₈ is methyl.

8. The compound of claim 2, 3, or 4, wherein R₈ is —

CH₂OH.

9. The compound of claim 2, 3, or 4, wherein R₈ is —

CH₂NH₂.

10. A compound of the formula:

11. The compound of claim 10, wherein R_B is methyl.

12. The compound of claim 10, wherein R_B is —

CF₃.

13. The compound of claim 10, 11, or 12, wherein R₈ is methyl.

14. The compound of claim 10, 11, or 12, wherein R₈ is —

CH₂OH.

15. The compound of claim 10, 11, or 12, wherein R₈ is —

CH₂NH₂.

16. A compound of the formula:

17. The compound of claim 16, wherein R_B is methyl.

18. The compound of claim 16, wherein R_B is —

CF₃.

19. The compound of claim 16, 17, or 18, wherein R₈ is methyl.

20. The compound of claim 16, 17, or 18, wherein R₈ is —

CH₂OH.

21. The compound of claim 16, 17, or 18, wherein R₈ is —

CH₂NH₂.

22. A compound of the formula:

23. A compound of the formula:

24. The compound of claim 23 wherein R_B is methyl.

25. The compound of claim 23 wherein R_B is —

CF₃.

26. The compound of claim 23, 24, or 25, wherein R₈ is methyl.

27. The compound of claim 23, 24, or 25, wherein R₈ is —

CH₂OH.

28. The compound of claim 23, 24, or 25, wherein R₈ is —

CH₂NH₂.

29. A compound of the formula:

30. The compound of claim 29 wherein R_B is methyl.

31. The compound of claim 29 wherein R_B is —

CF₃.

32. The compound of claim 29, 30, or 31, wherein R₈ is methyl.

33. The compound of claim 29, 30, or 31, wherein R₈ is —

CH₂OH.

34. The compound of claim 29, 30, or 31, wherein R₉ is —

CH₂NH₂.

35. A compound of the formula:

36. A compound of the formula:

37. A compound of the formula:

38. A compound of the formula:

39. A trans-9,10-dehydro-cis-12,13-dehydroepothilone analog.

40. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an IC₅₀ of less than 0.01 in a CCRF-CEM cell line.

41. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an IC₅₀ of less than 0.05 in a CCRF-CEM cell line.

42. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an IC₅₀ of less than 0.01 in a CCRF-CEM cell line resistant to Taxol.

43. The trans-9,10-dehydro-cis-12,13-dehydroepothilone analog, wherein the analog is characterized by an IC₅₀ of less than 0.05 in a CCRF-CEM cell line resistant to Taxol.

44. A pharmaceutical composition comprising a trans-9,10-dehydro-cis-12,13-dehydroepothilone analog and a pharmaceutically acceptable excipient.

46. The pharmaceutical composition of claim 44 or 45 further comprising Cremophor.

47. The pharmaceutical composition of claim 44 or 45 further comprising Cremophor and ethanol.

48. The pharmaceutical composition of claim 44 or 45, wherein the compound is suspended in 1:

1 Cremophor/EtOH.

49. The pharmaceutical composition of claim 44 or 45 further comprising an additional cytotoxic agent.

54. A method for making an epothilone or an epothilone analog, comprising:

providing a compound having Formula 1

55. The method according to claim 54 where the compound has Formula 2

56. The method according to claim 54 where C₁₀ and C₉ are bonded together by a triple bond.

57. The method according to claim 55 further comprising converting at least one double bond of the compound to an epoxide.

58. The method according to claim 57 where the compound has formula where R is H or a protecting group and R₁ s an aryl group

59. The method according to claim 57 where the compound has a formula

60. The method according to claim 59 where R₁ has Formula 3

61. The method according to claim 60 where X and Y independently are selected from the group consisting of O, N and S.

62. The method according to claim 60 where R₁ is an imidazole, a thiazole or an oxazole.

63. The method according to claim 60 where R₁ is

64. The method according to claim 55 where the compound has the formula

65. The method according to claim 55 and further comprising converting double bonds of the compound to epoxides and/or aziridines.

66. The method according to claim 65 where the compound has formula

67. The method according to claim 66 where R₁ is

68. The method according to claim 54 where R is H, and converting the compound involves forming an epoxide at C-12, C-13.

69. The method according to claim 54 where R substituents are protecting groups, and converting the compound involves:

removing the protecting groups; and

forming an epoxide at C-12, C-13.

70. The method according to claim 54 where providing the compound comprises:

making a precursor compound by coupling a first compound having Formula 4

71. The method according to claim 70 where X of Formula 4 is PPh₃⁺.

72. The method according to claim 70 where X of Formula 4 is a sulfone.

73. The method according to claim 70 where Y of Formula 5 is CHO.

74. The method according to claim 54 where the epothilone is selected from the group consisting of epothilone A, epothilone B, epothilone C, epothilone D, epothilone E and epothilone F.

75. The method according to claim 55 where R₂—

R₅ independently are H or methyl.

76. The method according to claim 55 where all R₆ substituents are methyl.

77. A compound having according to the formula

78. The compound according to claim 77 where R₁ is

79. The compound according to claim 78 where X and Y independently are selected from the group consisting of O, N and S.

80. The compound according to claim 79 where R₁ is an imidazole, a thiazole or an oxazole.

81. The compound according to claim 77 where R₁ is

82. The compound according to claim 77 where the compound is

83. The compound according to claim 77 where the compound has the formula

84. The compound according to claim 82 where C₁₃ and C₁₂ are carbons in a double bond, R₃ is H and R₄ is lower alkyl.

85. The compound according to claim 82 where at least one of R₅ and R₆ are H.

86. The compound according to claim 82 where R₅ and R₆ are H.

87. The compound according to claim 82 where R₇ is lower alkyl.

88. The compound according to claim 87 where R₇ is methyl.

90. The compound according to claim 82 where C₁₀ and C₉ are bonded together by a double bond.

91. The compound according to claim 82 where C₁₀ and C₉ are bonded together by a triple bond.

89. The compound according to 82 where C₃ and C₁₂ are bonded together by a single bond, and R₃ and R₄ are bonded to 0 in an epoxide.

92. A method for making an epothilone or an epothilone analog by converting a starting compound into the epothilone or epothilone analog, the method comprising:

93. The method according to claim 92 where reducing the starting compound yields a compound having a formula

94. The method according to claim 93 further comprising converting the C₁₂—

C₁₃ double bond to an epoxide.

95. The method according to claim 92 where reducing the starting compound yields a compound having the formula

96. The method according to claim 95 and further comprising oxidizing at C₉-C₁₀ to yield a compound having the formula

97. The method according to claim 92 where the reducing the starting compound yields a product selected from the group consisting of epothilone C and epothilone D.

98. A method for making an epothilone or an epothilone analog by converting a starting compound into the epothilone or epothilone analog, the method comprising:

providing a starting compound having a formula

where R is H or a protecting group, R₁ is an aryl group, R₂—

R₅ substituents independently are selected from the group consisting of H and lower alkyl groups, and R₆ substituents independently are selected from the group consisting of lower alkyl groups; and

oxidizing the starting compound at C₉-C₁₀, C₁₂—

C₁₃, or both.

99. The method according to claim 98 where R₂-R₅ independently are H or methyl.

100. The method according to claim 98 where all R₆ substituents are methyl.

101. The method according to claim 98 where the starting compound is oxidized at C₉-C₁₀, and further comprising reducing the double bond at C₁₂-C₁₃.

102. The method according to claim 101 where the epothilone product is selected from the group consisting of epothilone A, epothilone B, epothilone E and epothilone F.

103. The method according to claim 98 where oxidizing the starting compound at C₉-C₁₀ yields an epoxide having a formula

104. The method according to claim 98 where oxidizing the starting compound yields an aziridine-containing compound.

105. The method according to claim 98 where oxidizing yields a compound having a formula where R is H or a protecting group and R₁ is an aryl group.

106. The method according to claim 105 where R₁ is

107. The method according to claim 101 where R₁ has a formula

108. The method according to claim 107 where X and Y independently are selected from the group consisting of O, N and S.

109. The method according to claim 107 where R₁ is an imidazole, a thiazole or an oxazole.

110. The method according to claim 107 where R₁ is

111. The method according to claim 98 where oxidizing the starting compound yields an aziridine at C₉-C₁₀, C₁₂-C₁₃, or both.

112. The method according to claim 98 where R is H, and oxidizing the starting compound involves forming an epoxide at C₁₂-C₁₃ of the starting compound.

113. The method according to claim 112 where the epoxide has the formula

114. The method according to claim 112 where the epoxide has a formula

115. The method according to claim 112 where R substituents are protecting groups, and oxidizing the starting compound involves:

removing the protecting groups; and

forming an epoxide at C₁₂-C₁₃ of the starting compound.

116. A method for making an epothilone or an epothilone analog by converting a starting compound into the epothilone or epothilone analog, the method comprising:

providing a starting compound having a formula

117. A method for making an epothilone or an epothilone analog by converting a starting compound into the epothilone or epothilone analog, the method comprising:

providing a starting compound having a formula