Synthesis of epothilones, intermediates thereto, analogues and uses thereof

• US 20050033059A1
• Filed: 12/04/2001
• Published: 02/10/2005
• Est. Priority Date: 12/03/1996
• Status: Active Grant

• Current Assignee: Aaron Balog, Dai-Shi Su, Dang Fang Meng, Erik J. Sorensen, Kenneth A. Savin, Peter Bertinato, Samuel J. Danishefsky, Ted Kamenecka, Ting-Chao Chou
• Original Assignee: Aaron Balog, Dai-Shi Su, Dang Fang Meng, Erik J. Sorensen, Kenneth A. Savin, Peter Bertinato, Samuel J. Danishefsky, Ted Kamenecka, Ting-Chao Chou
• Inventors: Sorensen, Erik J., Danishefsky, Samuel J., Chou, Ting-Chao, Meng, Dang Fang, Kamenecka, Ted, Bertinato, Peter, Savin, Kenneth A., Su, Dai-Shi, Balog, Aaron
• Granted Patent: US 6,972,335 B2
• Time in Patent Office: Days
• US Class Current: 548/204
• 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 31/335 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: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• 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 compound having the structure:

2. The compound of claim 1 having the structure:

30. A pharmaceutical composition for treating cancer comprising a compound of claim 1, 3, 5, 7, or 8 and a pharmaceutically suitable carrier.

31. A method of treating cancer in a subject suffering therefrom comprising administering to the subject a therapeutically effective amount of a compound of claim 1, 3, 5, 7 or and a pharmaceutically suitable carrier.

32. The method of claim 31 wherein the cancer is a solid tumor.

33. The method of claim 31 wherein the cancer is breast cancer.

45. A composition comprising an amount of the compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 43 or 44 effective to inhibit the growth of multidrug resistant cells and a pharmaceutically acceptable carrier.

46. The composition of claim 45, further comprising an amount of a cytotoxic agent.

47. The composition of claim 46, wherein the cytotoxic agent is an anticancer agent.

48. The composition of claim 47, wherein the anticancer agent is adriamycin.

49. The composition of claim 47, wherein the anticancer agent is vinblastin.

50. The composition of claim 47, wherein the anticancer agent is paclitaxel.

51. The composition of claim 45, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

52. A method of inhibiting the growth of multidrug resistant cells comprising contacting the multidrug resistant cells with an amount of the compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 43 or 44 effective to inhibit the growth of multidrug resistant cells in combination with a pharmaceutically acceptable carrier.

53. The method of claim 52, further comprising administering an amount of a cytotoxic agent.

54. The method of claim 53, wherein the cytotoxic agent is an anticancer agent.

55. The method of claim 54, wherein the anticancer agent is adriamycin.

56. The method of claim 55, wherein the anticancer agent is vinblastin.

57. The method of claim 55, wherein the anticancer agent is paclitaxel.

58. The method of claim 55, wherein the effective amount of the compound is between about 0.01 mg/kg to about 25 mg/kg of body weight.

3. A compound having the structure:

4. The compound of claim 3 having the structure:

5. A compound having the structure:

6. The compound of claim 5 having the structure:

7. A compound having the structure:

8. A compound having the structure:

9. A compound having the structure:

10. A compound having the structure:

11. A compound having the structure:

12. The compound of claim 11 wherein R′

is TBS, R″

is TPS and X is (OMe)₂.

13. A compound having the structure:

14. The compound of claim 13 wherein R is acetyl and X is iodo.

15. A compound having the structure:

16. A compound having the structure:

17. A compound having the structure:

18. A method of preparing a Z-haloalkene ester having the structure:

19. The method of claim 18 wherein X is iodine.

20. The method of claim 18 wherein the halomethylene transfer agent is Ph₃P═

CR′

I or (Ph₃P⁺CHR′

I)I^˜

21. A method of preparing an optically pure compound having the structure:

22. The method of claim 21 wherein the allylic organometallic reagent is an allyl(trialkyl)stannane.

23. The method of claim 21 wherein the condensing step is effected using a reagent comprising a titanium tetraalkoxide and an optically active catalyst.

24. The method of claim 23 wherein the optically active catalyst is S(−

)BINOL.

25. A method of preparing an open-chain aldehyde having the structure:

26. A method of preparing an epothilone having the structure.

27. A method of preparing an epothilone precursor having the structure:

28. The method of claim 27 wherein the conditions leading to intramolecular olefin metathesis require the presence of an organometallic catalyst.

29. The method of claim 27 wherein the catalyst is a Ru or Mo complex.

34. A method of preparing a Z-iodoalkene ester having the structure:

35. A method of preparing an open-chain aldehyde having the structure:

36. The method of claim 35 wherein R is acetyl;

R′

is TBS;

R″

is TPS;

R*₂B is derived from 9-BBN; and

Y is (OMe)₂.

37. A method of preparing a protected epothilone having the structure:

38. The method of claim 37 wherein R′

and R″

are TBS.

39. A method of preparing an epothilone having the structure:

40. The method of claim 39 wherein R′

and R″

are TBS.

41. A method of preparing a cyclic diol having the structure:

42. The method of claim 41 wherein R′

is TBS and R″

is TPS.

43. A purified compound having the structure:

44. A purified compound having the structure: