Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US RE41,990 E1
• Filed: 01/04/2007
• Issued: 12/07/2010
• Est. Priority Date: 12/03/1996
• Status: Expired due to Term

• 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: Su, Dai-Shi, Danishefsky, Samuel J., Meng, Dongfang, Chou, Ting-Chao, Kamenecka, Ted, Bertinato, Peter, Savin, Kenneth A., Sorensen, Erik J., Balog, Aaron
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US11/649,750
• Time in Patent Office: 1,433 Days
• Field of Search: 514/365, 548/204, 548/510, 549/271
• US Class Current: 514/365
• CPC Class Codes: A61K 31/335 having oxygen as the only ring hetero atom, e.g. fungichromin
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/425 Thiazoles
• CPC Class Codes: A61K 31/475 having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine vincamine A61K31/4375
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07C 69/007 Esters of unsaturated alcohols having the esterified hydroxy group bound to an acyclic carbon atom
• CPC Class Codes: C07D 277/24 Radicals substituted by oxygen atoms
• 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 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 493/04 Ortho-condensed systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof. Also provided are analogues related to epothilone A and B and intermediates useful for preparing same. The present invention further provides novel compositions based on analogues of the epothilones and methods for the treatment of cancer and cancer which has developed a multidrug-resistant phenotype.

Claims

1. A purified compound having the a structure:

or a compound having the structure;

wherein R₁, R₂, and R₃ are each independently H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR₄R₅, N-hydroximino, or N-alkoxyimino, wherein R₄ and R₅ are independendy H, phenyl, benzyl, linear or branched chain alkyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, wherein X is H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, and Y is H or linear or branched chain alkyl;

Z is O, N(OR₆) or N—

NR₇R₈, wherein R₆, R₇ and R₈ are independently H or a linear or branched chain alkyl or alkoxy;

and

n is 0, 1, 2, or 3;

wherein when the compound is of the formula;

R₁ is other than H, methyl, ethyl, n-propyl, n-hexyl, CH₂OH, (CH₂)₃OH, or

2. The compound of claim 1, wherein R₁=hydrogen, methyl, ethyl, propyl, hexyl, 2-(1,3-dioxolanyl)methyl, hydroxymethyl or hydroxypropyl.

3. The compound of claim 1, wherein Z═

O.

4. The compound of claim 1, wherein R₂ is hydrogen, and R₃ is methyl.

5. The compound of claim 1, wherein n=3.

6. The compound of claim 1, wherein R″

is —

CY═

CHX, and X is 2-methyl-1,3-thiazol-4-yl, and Y is H.

7. A purified compound having the structure:

wherein R₁ is H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR₄R₅, N-hydroximino, or N-alkoxyimino, wherein R₄ and R₅ are independently H, phenyl, benzyl, linear or branched chain alkyl,

wherein R₁ is other than H, methyl, ethyl, n-propyl, n-hexyl, CH₂OH, (CH₂)₃OH, or

8. The compound of claim 7, wherein R₁ is substituted or unsubstituted, linear or branched chain alkyl.

9. The compound of claim 7, wherein R₁ is linear or branched chain alkyl, optionally substituted by hydroxy, fluorine, cyclic acetal, or NR₄R₅, wherein R₄ and R₅ are independently H, phenyl, benzyl, or linear or branched chain alkyl.

10. The compound of claim 7, wherein R₁ is linear or branched chain alkyl substituted by fluorine.

11. The compound of claim 7, wherein R₁ is linear or branched chain alkyl substituted by hydroxy.

12. The compound of claim 7, wherein R₁ is linear or branched chain alkyl substituted by NR₄R₅, wherein R₄ and R₅ are independently H, phenyl, benzyl, or linear or branched chain alkyl.

13. The compound of claim 7, wherein R₁ is linear or branched chain alkyl substituted by cyclic acetal.

14. The compound of claim 7, wherein R₁ is linear or branched chain alkyl substituted by a substituted carboxy group.

15. The compound of claim 7, wherein R₁ is ethyl, and the compound has the structure:

16. The compound of claim 7, wherein R₁ is propyl and the compound has the structure:

17. The compound of claim 7, wherein R₁ is hexyl and the compound has the structure:

18. The compound of claim 7, wherein R₁ is 2-(1,3--dioxolanyl)methyl and the compound has the structure:

19. The compound of claim 7, wherein R₁ is hydroxymethyl and the compound has the structure:

20. The compound of claim 7, wherein R₁ is hydroxypropyl and the compound has the structure:

21. The compound of claim 7, wherein R₁ is a linear or branched chain alkyl substituted by aroyloxy.

22. The compound of claim 7, wherein R₁ is a linear or branched chain alkyl substituted by substituted or unsubstituted benzoyloxy.

23. The compound of claim 7, wherein R₁ is a propyl group substituted by benzoyloxy, and the compound has the structure:

24. A pharmaceutical composition comprising:

a compound having a structure;

or a compound having a structure;

wherein R₁, R₂, and R₃ are each independantly H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR₄R₅, N-hydroximino, or N-alkoxyimino, wherein R₄ and R₅ are independently H, phenyl, benzyl, linear or branched chain alkyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, wherein X is H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, and Y is H or linear or branched chain alkyl;

Z is O, N(OR₆) or N—

NR₇R₈, wherein R₆, R₇ and R₈ are independently H or a linear or branched chain alkyl or alkoxy;

and

n is 0, 1, 2, or 3; and

wherein when the compound is of the formula;

R₁ is other than H, methyl, ethyl, n-propyl, n-hexyl, CH₂OH, (CH₂)₃OH, or

and

a pharmaceutically acceptable carrier,

said composition optionally further comprising a cytotoxic agent.

25. The compound of claim 24, wherein R₁=hydrogen, methyl, ethyl, propyl, hexyl, 2-(1,3-dioxolanyl)methyl, hydroxymethyl or hydroxypropyl.

26. The pharmaceutical composition of claim 24, wherein in the compound Z═

O.

27. The pharmaceutical composition of claim 24, wherein in the compound R₂ is hydrogen, and R₃ is methyl.

28. The pharmaceutical composition of claim 24, wherein in the compound n=3.

29. The pharmaceutical composition of claim 24, wherein in the compound R″

is —

CY═

CHX, and X is 2-methyl-1,3-thiazol-4-yl, and Y is H.

49. The pharmaceutical composition of claim 24 or 30, wherein the cytotoxic agent is an anticancer agent.

50. The pharmaceutical composition of claim 49, wherein the anticancer agent is adnamycin adriamycin.

51. The pharmaceutical composition of claim 49, wherein the anticancer agent is vinblastin.

52. The pharmaceutical composition of claim 49, wherein the anticancer agent is paclitaxel.

30. A pharmaceutical composition comprising:

a compound having the structure;

wherein R₁ is H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR₄R₅, N-hydroximino, or N-alkoxyimino, wherein R₄ and R₅ are independently H, phenyl, benzyl, linear or branched chain alkyl,

wherein R₁ is other than H, methyl, ethyl, n-propyl, n-hexyl, CH₂OH, (CH₂)₃OH, or

 

and

a pharmaceutically acceptable carrier,

said composition optionally further comprising a cytotoxic agent.

31. The pharmaceutical composition of claim 30, wherein in the compound R₁ is substituted or unsubstituted, linear or branched chain alkyl.

32. The pharmaceutical composition of claim 30, wherein in the compound R₁ is linear or branched chain alkyl, optionally substituted by hydroxy, fluorine, cyclic acetal, or NR₄R₅, wherein R₄ and R₅ are independently H, phenyl, benzyl, or linear or branched chain alkyl.

33. The pharmaceutical composition of claim 30, wherein in the compound R₁ is linear or branched chain alkyl substituted by fluorine.

34. The pharmaceutical composition of claim 30, wherein in the compound R₁ is linear or branched chain alkyl substituted by hydroxy.

35. The pharmaceutical composition of claim 30, wherein in the compound R₁ is linear or branched chain alkyl substituted by NR₄R₅, wherein R₄ and R₅ are independently H, phenyl, benzyl, or linear or branched chain alkyl.

36. The pharmaceutical composition of claim 30, wherein in the compound R₁ is linear or branched chain alkyl substituted by cyclic acetal.

37. The pharmaceutical composition of claim 30, wherein in the compound R₁ is linear or branched chain alkyl substituted by a substituted carboxy group.

38. The pharmaceutical composition of claim 30, wherein in the compound R₁ is hydrogen and the compound has the structure:

39. The pharmaceutical composition of claim 30, wherein in the compound R₁ is methyl and the compound has the structure:

40. The pharmaceutical composition of claim 30, wherein in the compound R₁ is ethyl and the compound has the structure:

41. The pharmaceutical composition of claim 30, wherein the compound R₁ is propyl and the compound has the structure:

42. The pharmaceutical composition of claim 30, wherein in the compound R₁ is hexyl and the compound has the structure:

43. The pharmaceutical composition of claim 38, wherein in the compound R₁ is 2-(1,3-dioxolanyl)methyl and the compound has the structure:

44. The pharmaceutical composition of claim 30, wherein in the compound R₁ is hydroxymethyl and the compound has the structure:

45. The pharmaceutical composition of claim 30, wherein in the compound R₁ is hydroxypropyl and the compound has the structure:

46. The pharmaceutical composition of claim 30, wherein in the compound R₁ is a linear or branched chain alkyl substituted by aroyloxy.

47. The pharmaceutical composition of claim 30, wherein in the compound R₁ is a linear or branched chain alkyl substituted by substituted or unsubstituted benzoyloxy.

48. The pharmaceutical composition of claim 30, wherein in the compound R₁ is a propyl group substituted by benzoyloxy, and the compound has the structure:

53. A method of treating cancer in a subject comprising:

administering to the subject a therapeutically effective amount of a compound having the structure;

or a compound having the structure;

wherein R₁, R₂, and R₃ are each independently H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR₄R₅, N-hydroximino, or N-alkoxyimino, wherein R₄ and R₅ are independently H, phenyl, benzyl, linear or branched chain alkyl;

R″

is —

CY═

CHX, or H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, wherein X is H, linear or branched chain alkyl, phenyl, or 2-methyl-1,3-thiazol-4-yl, and Y is H or linear or branched chain alkyl;

Z is O, N(OR₆) or N—

NR₇R₈, wherein R₆, R₇ and R₈ are independently H or a linear or branched chain alkyl or alkoxy; and

n is 0, 1, 2, or 3,

said method optionally further comprising administering a cytotoxic agent.

54. The method of claim 53, wherein in the compound R₁=hydrogen, methyl, ethyl, propyl, hexyl, 2-(1,3-dioxolanyl)methyl, hydroxymethyl or hydroxypropyl.

55. The method of claim 53, wherein in the compound Z═

O.

56. The method of claim 53, wherein in the compound R₂ is hydrogen, and R₃ is methyl.

57. The method of claim 53, wherein in the compound n=3.

58. The method of claim 53, wherein in the compound R″

is —

CY═

CHX, and X is 2-methyl-1,3-thiazol-4-yl, and Y is H.

78. The method of claim 53 or 59, wherein the method further comprises administering a cytotoxic agent, wherein said cytotoxic agent is an anticancer agent.

79. The method of claim 78, wherein the anticancer agent administered is adriamycin.

80. The method of claim 78, wherein the anticancer agent administered is vinblastin.

81. The method of claim 78, wherein the anticancer agent administered is paclitaxel.

82. The method of claim 53 or 59, wherein the cancer is a solid tumor.

83. The method of claim 53 or 59, wherein the cancer is breast cancer, melanoma, leukemia or ovarian cancer.

84. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.001 mg/kg to about 40 mg/kg of body weight.

85. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg to about 40 mg/kg of body weight.

86. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.001 mg/kg to about 25 mg/kg of body weight.

87. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

88. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.001 mg/kg to about 10 mg/kg of body weight.

89. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg to about 10 mg/kg of body weight.

90. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.001 mg/kg to about 1.0 mg/kg of body weight.

91. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 0.01 mg/kg to about 1.0 mg/kg of body weight.

92. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is 25 mg/kg or greater of body weight.

93. The method of claim 53 or 59, wherein the therapeutically effective amount of the compound is between about 25 mg/kg to about 40 mg/kg of body weight.

59. A method for treating cancer in a subject comprising:

administering to a subject a therapeutically effective amount of a compound having the structure;

wherein R₁ is H, or linear or branched chain alkyl, which alkyl may be singly or multiply substituted by hydroxy, substituted or unsubstituted alkoxy, substituted or unsubstituted carboxy, carboxaldehyde, substituted or unsubstituted, linear or branched alkyl, substituted or unsubstituted cyclic acetal, fluorine, NR₄R₅, N-hydroximino, or N-alkoxyimino, wherein R₄ and R₅ are independently H, phenyl, benzyl, linear or branched chain alkyl,

said method optionally further comprising administering a cytotoxic agent.

60. The method of claim 59, wherein in the compound R₁ is substituted or unsubstituted, linear or branched chain alkyl.

61. The method of claim 59, wherein in the compound R₁ is linear or branched chain alkyl, optionally substituted by hydroxy, fluorine, cyclic acetal, or NR₄R₅, wherein R₄ and R₅ are independently H, phenyl, benzyl, or linear or branched chain alkyl.

62. The method of claim 59, wherein in the compound R₁ is linear or branched chain alkyl substituted by fluorine.

63. The method of claim 59, wherein in the compound R₁ is linear or branched chain alkyl substituted by hydroxy.

64. The method of claim 59, wherein in the compound R₁ is linear or branched chain alkyl substituted by NR₄R₅, wherein R₄ and R₅ are independently H, phenyl, benzyl, or linear or branched chain alkyl.

65. The method of claim 59, wherein in the compound R₁ is linear or branched chain alkyl substituted by cyclic acetal.

66. The method of claim 59, wherein in the compound R₁ is linear or branched chain alkyl substituted by a substituted carboxy group.

67. The method of claim 59, wherein in the compound R₁ is hydrogen and the compound has the structure:

68. The method of claim 59, wherein in the compound R₁ is methyl and the compound has the structure:

69. The method of claim 59, wherein in the compound R₁ is ethyl and the compound has the structure:

70. The method of claim 59, wherein in the compound R₁ is propyl and the compound has the structure:

71. The method of claim 59, wherein in the compound R₁ is hexyl and the compound has the structure:

72. The method of claim 59, wherein in the compound R₁ is 2-(1,3-dioxolanyl)methyl and the compound has the structure:

73. The method of claim 59, wherein in the compound R₁ is hydroxymethyl and the compound has the structure:

74. The method of claim 59, wherein in the compound R₁ is hydroxypropyl and the compound has the structure:

75. The method of claim 59, wherein in the compound R₁ is a linear or branched chain alkyl substituted by aroyloxy.

76. The method of claim 59, wherein in the compound R₁ is a linear or branched chain alkyl substituted by substituted or unsubstituted benzoyloxy.

77. The method of claim 59, wherein in the compound R₁ is a propyl group substituted by benzoyloxy, and the compound has the structure: