USRE41990EExpiredUtilityPatentIndex 74
Synthesis of epothilones, intermediates thereto, analogues and uses thereof
Est. expiryDec 3, 2016(expired)· nominal 20-yr term from priority
Inventors:DANISHEFSKY SAMUEL JBERTINATO PETERSU DAI-SHIMENG DONGFANGCHOU TING-CHAOKAMENECKA TEDSORENSEN ERIK JBALOG AARONSAVIN KENNETH A
A61P 35/02A61P 35/00A61K 45/06A61K 31/335C07D 417/14C07D 417/06A61K 31/704A61K 31/70C07F 7/1804A61K 31/475C07D 313/00C07C 69/007A61K 31/425A61K 31/337C07D 493/04C07D 277/24
74
PatentIndex Score
2
Cited by
546
References
93
Claims
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
exact text as granted — not AI-modified1. A purified compound having the a structure:
or a compound having the structure:
wherein R 1 , R 2 , and R 3 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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino, wherein R 4 and R 5 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(OR 6 ) or N—NR 7 R 8 , wherein R 6 , R 7 and R 8 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:
R 1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH 2 OH, (CH 2 ) 3 OH, or
2. The compound of claim 1 , wherein R 1 =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 R 2 is hydrogen, and R 3 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 R 1 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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino, wherein R 4 and R 5 are independently H, phenyl, benzyl, linear or branched chain alkyl,
wherein R 1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH 2 OH, (CH 2 ) 3 OH, or
8. The compound of claim 7 , wherein R 1 is substituted or unsubstituted, linear or branched chain alkyl.
9. The compound of claim 7 , wherein R 1 is linear or branched chain alkyl, optionally substituted by hydroxy, fluorine, cyclic acetal, or NR 4 R 5 , wherein R 4 and R 5 are independently H, phenyl, benzyl, or linear or branched chain alkyl.
10. The compound of claim 7 , wherein R 1 is linear or branched chain alkyl substituted by fluorine.
11. The compound of claim 7 , wherein R 1 is linear or branched chain alkyl substituted by hydroxy.
12. The compound of claim 7 , wherein R 1 is linear or branched chain alkyl substituted by NR 4 R 5 , wherein R 4 and R 5 are independently H, phenyl, benzyl, or linear or branched chain alkyl.
13. The compound of claim 7 , wherein R 1 is linear or branched chain alkyl substituted by cyclic acetal.
14. The compound of claim 7 , wherein R 1 is linear or branched chain alkyl substituted by a substituted carboxy group.
15. The compound of claim 7 , wherein R 1 is ethyl, and the compound has the structure:
16. The compound of claim 7 , wherein R 1 is propyl and the compound has the structure:
17. The compound of claim 7 , wherein R 1 is hexyl and the compound has the structure:
18. The compound of claim 7 , wherein R 1 is 2 -( 1 , 3 --dioxolanyl)methyl and the compound has the structure:
19. The compound of claim 7 , wherein R 1 is hydroxymethyl and the compound has the structure:
20. The compound of claim 7 , wherein R 1 is hydroxypropyl and the compound has the structure:
21. The compound of claim 7 , wherein R 1 is a linear or branched chain alkyl substituted by aroyloxy.
22. The compound of claim 7 , wherein R 1 is a linear or branched chain alkyl substituted by substituted or unsubstituted benzoyloxy.
23. The compound of claim 7 , wherein R 1 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 R 1 , R 2 , and R 3 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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino, wherein R 4 and R 5 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(OR 6 ) or N—NR 7 R 8 , wherein R 6 , R 7 and R 8 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:
R 1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH 2 OH, (CH 2 ) 3 OH, or
and
a pharmaceutically acceptable carrier,
said composition optionally further comprising a cytotoxic agent.
25. The compound of claim 24 , wherein R 1 =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 R 2 is hydrogen, and R 3 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.
30. A pharmaceutical composition comprising:
a compound having the structure:
wherein R 1 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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino, wherein R 4 and R 5 are independently H, phenyl, benzyl, linear or branched chain alkyl,
wherein R 1 is other than H, methyl, ethyl, n-propyl, n-hexyl, CH 2 OH, ( CH 2 ) 3 OH, 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 R 1 is substituted or unsubstituted, linear or branched chain alkyl.
32. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is linear or branched chain alkyl, optionally substituted by hydroxy, fluorine, cyclic acetal, or NR 4 R 5 , wherein R 4 and R 5 are independently H, phenyl, benzyl, or linear or branched chain alkyl.
33. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is linear or branched chain alkyl substituted by fluorine.
34. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is linear or branched chain alkyl substituted by hydroxy.
35. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is linear or branched chain alkyl substituted by NR 4 R 5 , wherein R 4 and R 5 are independently H, phenyl, benzyl, or linear or branched chain alkyl.
36. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is linear or branched chain alkyl substituted by cyclic acetal.
37. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is linear or branched chain alkyl substituted by a substituted carboxy group.
38. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is hydrogen and the compound has the structure:
39. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is methyl and the compound has the structure:
40. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is ethyl and the compound has the structure:
41. The pharmaceutical composition of claim 30 , wherein the compound R 1 is propyl and the compound has the structure:
42. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is hexyl and the compound has the structure:
43. The pharmaceutical composition of claim 38 , wherein in the compound R 1 is 2 -( 1 , 3 -dioxolanyl)methyl and the compound has the structure:
44. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is hydroxymethyl and the compound has the structure:
45. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is hydroxypropyl and the compound has the structure:
46. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is a linear or branched chain alkyl substituted by aroyloxy.
47. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is a linear or branched chain alkyl substituted by substituted or unsubstituted benzoyloxy.
48. The pharmaceutical composition of claim 30 , wherein in the compound R 1 is a propyl group substituted by benzoyloxy, and the compound has the structure:
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.
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 R 1 , R 2 , and R 3 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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino, wherein R 4 and R 5 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(OR 6 ) or N—NR 7 R 8 , wherein R 6 , R 7 and R 8 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 R 1 =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 R 2 is hydrogen, and R 3 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.
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 R 1 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, NR 4 R 5 , N-hydroximino, or N-alkoxyimino, wherein R 4 and R 5 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 R 1 is substituted or unsubstituted, linear or branched chain alkyl.
61. The method of claim 59 , wherein in the compound R 1 is linear or branched chain alkyl, optionally substituted by hydroxy, fluorine, cyclic acetal, or NR 4 R 5 , wherein R 4 and R 5 are independently H, phenyl, benzyl, or linear or branched chain alkyl.
62. The method of claim 59 , wherein in the compound R 1 is linear or branched chain alkyl substituted by fluorine.
63. The method of claim 59 , wherein in the compound R 1 is linear or branched chain alkyl substituted by hydroxy.
64. The method of claim 59 , wherein in the compound R 1 is linear or branched chain alkyl substituted by NR 4 R 5 , wherein R 4 and R 5 are independently H, phenyl, benzyl, or linear or branched chain alkyl.
65. The method of claim 59 , wherein in the compound R 1 is linear or branched chain alkyl substituted by cyclic acetal.
66. The method of claim 59 , wherein in the compound R 1 is linear or branched chain alkyl substituted by a substituted carboxy group.
67. The method of claim 59 , wherein in the compound R 1 is hydrogen and the compound has the structure:
68. The method of claim 59 , wherein in the compound R 1 is methyl and the compound has the structure:
69. The method of claim 59 , wherein in the compound R 1 is ethyl and the compound has the structure:
70. The method of claim 59 , wherein in the compound R 1 is propyl and the compound has the structure:
71. The method of claim 59 , wherein in the compound R 1 is hexyl and the compound has the structure:
72. The method of claim 59 , wherein in the compound R 1 is 2-(1,3-dioxolanyl)methyl and the compound has the structure:
73. The method of claim 59 , wherein in the compound R 1 is hydroxymethyl and the compound has the structure:
74. The method of claim 59 , wherein in the compound R 1 is hydroxypropyl and the compound has the structure:
75. The method of claim 59 , wherein in the compound R 1 is a linear or branched chain alkyl substituted by aroyloxy.
76. The method of claim 59 , wherein in the compound R 1 is a linear or branched chain alkyl substituted by substituted or unsubstituted benzoyloxy.
77. The method of claim 59 , wherein in the compound R 1 is a propyl group substituted by benzoyloxy, and the compound has the structure:
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.Cited by (0)
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