Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs

• US 6,352,996 B1
• Filed: 02/08/2000
• Issued: 03/05/2002
• Est. Priority Date: 08/03/1999
• Status: Expired due to Term

• Current Assignee: Cao Pharmaceuticals Inc.
• Original Assignee: The Stehlin Foundation For Cancer Research
• Inventors: Cao, Zhisong, Giovanella, Beppino C.
• Primary Examiner(s): Lambkin, Deborah C.
• Application Number:
  US09/499,684
• Time in Patent Office: 756 Days
• Field of Search: 514/283, 546/48
• US Class Current: 514/283
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Derivatives of camptothecin as represented by the general formula:

are described, wherein when R₁ is H, R. is a C₂-C₄ alkyl group, a C₆-C₁₅ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₁₅ alkenyl group or a C₂-C₁₅ epoxy group; and when R₂ is a nitro group or an amino group, R₁ is a C₁-C₁₅ alkyl group, a C₁-C₁₅ alkenyl group, a C₃-C₈ cycloalkyl group, or an epoxy group. Liposomal prodrugs including these specific derivatives of camptothecin restrained by a liposomal delivery system are also described. Processes for making these prodrugs and for using them in cancer treatment are also disclosed.

Claims

1. A liposomal prodrug comprising an active component and a liposomal delivery system for delivering said active component, said delivery system comprising a liposome, a micelle and/or a lipid membrane receptacle, which restrains said active component, said active component comprising a compound of the formula:

wherein R₁ is a C₂-C₄ alkyl group, a C₆-C₁₅ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₁₅ alkenyl group or a C₂-C₁₅ epoxy group when R₂ is H; and

R₁ is a C₁-C₁₅ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₁₅ alkenyl group or a C₂-C₁₅ epoxy group when R₂ is NH₂ or NO₂.

2. The liposomal prodrug of claim 1, wherein R₁ is a linear C₂-C₄ alkyl group or C₆-C₁₅ alkyl group when R₂ is H and R₁ is a linear C₁-C₁₅ alkyl group when R₂ is NH₂ or NO₂.

3. The liposomal prodrug of claim 1, wherein R₁ is a linear C₂-C₁₅ alkenyl group or a C₂-C₁₅ epoxy group.

4. The liposomal prodrug of claim 2, wherein R₂ is NH₂.

5. The liposomal prodrug of claim 1, wherein R₂ is NH₂.

6. The liposomal prodrug of claim 3, wherein R₂ is NH₂.

7. The liposomal prodrug of claim 2, wherein R₁ is a linear methyl, ethyl or propyl group and R₂ is NH₂.

8. The liposomal prodrug of claim 1, wherein R₁ is a C₃-C₈ cycloalkyl group and R₂ is NH₂.

9. The liposomal prodrug of claim 1, wherein R₂ is NH₂, and R₁ is CH₃;

CH₂CH₃;

or CH₂CH₂CH₃;

CH═

CH₃;

CH═

CHCH₃(trans) or

10. The liposomal prodrug of claim 1, wherein said delivery system comprises at least one of cholesterol and phospolipids.

11. The liposomal prodrug of claim 1, wherein said delivery system comprises at least one unilamellar liposome.

12. The liposomal prodrug of claim 1, wherein said delivery system comprises at least one micelle and said micelle comprises a surfactant.

13. A method for treating cancer in a patient comprising administering a composition comprising an effective amount of the liposomal prodrug of claim 1, wherein said cancer is responsive to said composition.

14. The method of claim 13, wherein R₁ is a linear C₂-C₄ alkyl group or a C₆-C₁₅ alkyl group where R₂ is H and R₁ is a linear C₁-C₁₅ alkyl group when R₂ is NH, or NO₂.

15. The method of claim 13, wherein R₁ is a linear C₂-C₁₅ alkenyl group or a C₂-C₁₅ epoxy group.

16. The method of claim 14, wherein R₂ is NH₂.

17. The method of claim 15, wherein R₂ is NH₂.

18. The method of claim 14, wherein R₁ is a linear methyl, ethyl or propyl group and R₂ is NH₂.

19. The method of claim 13, wherein R₁ is a C₃-C₈ cycloalkyl group and R₂ is NH₂.

20. The method of claim 13, wherein R₂ is NH₂, and R₁ is CH₃;

CH₂CH₃;

or CH₂CH₂H₃;

CH═

CH₃;

CH═

CHCH₃(trans) or

21. The method of claim 13, wherein said delivery system comprises at least one of cholesterol and phospolipids.

22. The method of claim 13, wherein said delivery system comprises at least one unilamellar liposome.

23. The method of claim 13, wherein said delivery system comprises at least one micelle and said micelle comprises a surfactant.

24. A compound of formula (I):

wherein R₁ is a C₁-C₁₅ alkyl group, a C₃-C₈ cycloalkyl group, a C₂-C₁₅ alkenyl group, or C₂-C₁₅ epoxy group and R₂ is NH₂.

25. The compound of claim 24, wherein R₁ is a linear C₁-C₁₅ alkyl group.

26. The compound of claim 24, wherein R₁ is a linear C₂-C₁₅ alkenyl group.

27. The compound of claim 24, wherein R₁ is C₂-C₁₅ epoxy group.

28. The compound of claim 24, wherein R₁ is a C₃-C₈ cycloalkyl group.

29. The compound of claim 24, wherein R₁ is a linear methyl, ethyl, propyl, butyl, hexyl or octyl group.

30. The compound of claim 24, wherein R₁ is ethyl.

31. A method for treating cancer in a patient comprising administering a composition comprising an effective amount of the compound of claim 24.

32. The method of claim 31, wherein R₁ is a linear C₁-C₁₅ alkyl group.

33. The method of claim 31, wherein R₁ is a linear C₂-C₁₅ alkenyl group.

34. The method of claim 31, wherein R₁ is C₂-C₁₅ epoxy group.

35. The method of claim 31, wherein R₁ is a linear ethyl, propyl, butyl, hexyl, or octyl group.

36. The method of claim 31, wherein R₁ is ethyl.

37. The method of claim 31, wherein R₁ is a linear methyl group.

38. The method of claim 31, wherein R₁ is a C₃-C₈ cycloalkyl group.