C7 heterosubstituted acetate taxanes

• US 6,673,833 B2
• Filed: 02/02/2001
• Issued: 01/06/2004
• Est. Priority Date: 02/02/2000
• Status: Expired due to Fees

• Current Assignee: FSU Research Foundation, Inc.
• Original Assignee: FSU Research Foundation, Inc.
• Inventors: Holton, Robert A.
• Primary Examiner(s): Trinh, Ba K.
• Application Number:
  US09/776,393
• Publication Number:
  US 20020065305A1
• Time in Patent Office: 1,068 Days
• Field of Search: 514/471, 514/444, 514/449, 514/337, 549/60, 549/473, 549/510, 549/511
• US Class Current: 514/471
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

Taxanes having a heterosubstituted acetate substituent at C(7), a hydroxy substituent at C(10), and a range of C(2), C(9), C(14), and side chain substituents.

Claims

1. A taxane having the formula:

wherein

R₂ is acyloxy;

R₇ is heterosubstituted acetate;

R₉ is keto, hydroxy, or acyloxy;

R₁₀ is hydroxy;

R₁₄ is hydrido or hydroxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl or heterocyclo;

X₅ is —

COX₁₀, —

COOX₁₀, or —

CONHX₁₀;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and

Ac is acetyl.

2. The taxane of claim 1 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂ -C₈ alkenyl, or C₂-C₈ alkynyl.

3. The taxane of claim 1 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

4. The taxane of claim 1 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

5. The taxane of claim 1 wherein R₁₄ is hydrido.

6. The taxane of claim 5 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

7. The taxane of claim 5 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

8. The taxane of claim 5 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

9. The taxane of claim 1 wherein R₂ is benzoyloxy.

10. The taxane of claim 9 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

11. The taxane of claim 9 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

12. The taxane of claim 9 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

13. The taxane of claim 1 wherein R₁₄ is hydrido and R₉ is keto.

14. The taxane of claim 13 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C8 alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

15. The taxane of claim 13 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

16. The taxane of claim 13 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

17. The taxane of claim 1 wherein R₂ is benzoyloxy and R₉ is keto.

18. The taxane of claim 17 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C8 alkenyl, or C₂-C₈ alkynyl.

19. The taxane of claim 17 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

20. The taxane of claim 17 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

21. The taxane of claim 1 wherein R₁₄ is hydrido and R₂ is benzoyloxy.

22. The taxane of claim 21 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

23. The taxane of claim 21 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

24. The taxane of claim 21 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

25. The taxane of claim 1 wherein R,₄ is hydrido, R₉ is keto, and R₂ is benzoyloxy.

26. The taxane of claim 25 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

27. The taxane of claim 25 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —

COOX₁₀ and X₁₀ substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

28. The taxane of claim 25 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

29. The taxane of claim 25 wherein X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

30. The taxane of claim 29 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, cycloalkyl or alkenyl.

31. The taxane of claim 29 wherein X₃ is furyl or thienyl.

32. The taxane of claim 29 wherein X₃ is cycloalkyl.

33. The taxane of claim 1 wherein R₇ is R_7aCOO—

and R_7a is a heterosubstituted methyl group wherein the heteroatom may be substituted to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester or ether.

34. The taxane of claim 33 wherein R_7a is a heterosubstituted methyl group wherein the heteroatom may be substituted to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, or acyloxy.

35. The taxane of claim 33 wherein R_7a is a heterosubstituted methyl group wherein the heteroatom may be substituted to form an alkoxy, alkenoxy, aryloxy, hydroxy, or acyloxy.

66. A composition for oral administration comprising the taxane of claim 1 and at least one pharmaceutically acceptable carrier.

67. The composition of claim 66 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

68. The composition of claim 67 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

69. The composition of claim 67 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

70. The composition of claim 67 wherein X₃ is substituted or unsubstituted furyl or thienyl, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

73. A method for inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 1 and at least one pharmaceutically acceptable carrier.

74. The method of claim 73 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

75. The method of claim 74 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

76. The method of claim 74 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

77. The method of claim 74 wherein X₃ is substituted or unsubstituted furyl or thienyl, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

36. A taxane having the formula

R₇ is R_7aCOO—

;

R₁₀ is hydroxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl or heterocyclo;

X₅ is —

COX₁₀, —

COOX₁₀, or —

CONHX₁₀;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and

R_7a is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon of which R_7a is a substituent.

37. The taxane of claim 36 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

38. The taxane of claim 37 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

39. The taxane of claim 37 wherein R₇ is R_7aCOO—

and R_7a is a heterosubstituted methyl group wherein the heteroatom may be substituted to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester or ether, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ wherein X₁₀ is t-butyl.

40. The taxane of claim 37 wherein R₇ is R_7aCOO—

and R_7a is a heterosubstituted methyl group wherein the heteroatom may be substituted to form an alkoxy, alkenoxy, aryloxy, hydroxy, acyloxy, ester or ether, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ wherein X₁₀ is t-butyl.

41. The taxane of claim 37 wherein R₇ is R_7aCOO—

and R_7a is a heterosubstituted methyl group wherein the heteroatom may be substituted to form an alkoxy, aryloxy, or acyloxy, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ wherein X₁₀ is t-butyl.

42. The taxane of claim 37 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

43. The taxane of claim 36 wherein X₃ is furyl or thienyl.

44. The taxane of claim 43 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

45. The taxane of claim 43 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

46. The taxane of claim 37 wherein X₃ is cycloalkyl.

47. The taxane of claim 46 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

48. The taxane of claim 46 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

49. The taxane of claim 37 wherein X₃ is isobutenyl.

50. The taxane of claim 49 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

51. The taxane of claim 49 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

52. The taxane of claim 36 wherein R₇ is alkoxyacetyloxy or acyloxyacetyloxy.

53. The taxane of claim 52 wherein X₃ is furyl, thienyl, pyridyl, alkyl or alkenyl.

54. The taxane of claim 53 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

55. The taxane of claim 53 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

56. The taxane of claim 52 wherein X₃ is cycloalkyl.

57. The taxane of claim 56 wherein X₅ is —

COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —

COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.

58. The taxane of claim 56 wherein X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

59. The taxane of claim 36 wherein X₃ is furyl or thienyl, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ wherein X₁₀ is t-butyl.

60. The taxane of claim 36 wherein X₃ is substituted or unsubstituted furyl, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ wherein X₁₀ is t-butyl.

61. The taxane of claim 36 wherein X₃ is substituted or unsubstituted thienyl, and X₅ is —

COX₁₀ wherein X₁₀ is phenyl, or X₅ is —

COOX₁₀ wherein X₁₀ is t-butyl.

62. The taxane of claim 36 wherein X₃ is isobutenyl, and X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

63. The taxane of claim 36 wherein X₃ is alkyl, and X₅ is —

COX₁₀ and X₁₀ is phenyl, or X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

64. The taxane of claim 36 wherein X₃ is furyl or thienyl, X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

65. The taxane of claim 36 wherein X₃ is isobutenyl or cycloalkyl, X₅ is —

COOX₁₀ and X₁₀ is t-butyl.

71. A composition for oral administration comprising the taxane of claim 36 and at least one pharmaceutically acceptable carrier.

72. A composition for oral administration comprising the taxane of claim 43 and at least one pharmaceutically acceptable carrier.

78. A method of inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 36 and at least one pharmaceutically acceptable carrier.

79. A method of inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of claim 43 and at least one pharmaceutically acceptable carrier.