DI-ESTER PRODRUGS OF CAMPTOTHECIN, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTICAL APPLICATIONS

• US 20100305148A1
• Filed: 04/13/2010
• Published: 12/02/2010
• Est. Priority Date: 12/23/2003
• Status: Abandoned Application

• Current Assignee: Abraxis Bioscience LLC (Bristol-Myers Squibb Company)
• Original Assignee: Abraxis Bioscience LLC (Bristol-Myers Squibb Company)
• Inventors: Soon-Shiong, Patrick, Desai, Neil P., Tao, Chunlin, Yu, Cheng Zhi
• Application Number:
  US12/759,144
• Publication Number:
  US 20100305148A1
• Time in Patent Office: Days
• US Class Current: 514/283
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: C07D 491/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07D 498/14 Ortho-condensed systems

Abstract

The present invention is related to 10,20-di-O ester derivatives of camptothecin and pharmaceutical formulations thereof. The compounds and pharmaceutical formulations of the present invention possess increased biological life span and bioavailability and reduced toxicity, while maintaining anti-cancer activity.

Claims

1-54. -54. (canceled)

55. A di-ester compound having the following structure:

56. The di-ester compound of claim 55, wherein each of R₁, R₂, R₃ and R₄ is H, and R is (CH₂)_nSR₅, R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₄-C₁₀ aryl, and n is 1 or 2.

57. The di-ester compound of claim 55, wherein each of R₁, R₂ and R₃ is H, R₄ is CH₂CH₃, and R is (CH₂)_nSR₅, R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl, or C₄-C₁₀ aryl, and n is 1 or 2.

58. The di-ester compound of claim 55, wherein each of R₁, R₂ and R₃ is H, R₄ is Si(CH₃)₂C(CH₃)₃, and R is (CH₂)_nSR₅, R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₄-C₁₀ aryl, and n is 1 or 2.

59. The di-ester compound of claim 55, wherein R₁ is CH₂N(CH₃)₂, each of R₂, R₃ and R₄ is H, and R is (CH₂)_nSR₅, R₅ is C₁-C₆ alkyl, C₂-C₆ alkenyl or C₄-C₁₀ aryl, and n is 1 or 2.

60. A method to inhibit the enzyme topoisomerase I in an animal in need thereof comprising administering to the animal an effective amount of a composition comprising at least one di-ester compound of claim 55.

61. A method to treat cancer in a patient comprising administering a composition comprising at least one di-ester compound of claim 55 to said patient in an amount effective to treat said cancer.

62. The method of claim 61, wherein said cancer is lung, breast, colon, prostate, melanoma, pancreas, stomach, liver, brain, kidney, uterus, cervix, ovaries, urinary tract, gastrointestinal, or leukemia.

63. The method of claim 61, wherein said cancer is solid tumor or blood borne tumor.

64. The method of claim 61, wherein said composition is administered orally, parenterally, intramuscularly, transdermally or by an airborne delivery system.

65. The method of claim 61, wherein said composition is a nanoparticle containing said at least one di-ester compound.

66. A method to treat breast cancer in a patient comprising administering a composition comprising at least one di-ester compound of claim 55 to said patient in an amount effective to treat said cancer.