Stereochemical Wortmannin derivatives

• US 5,480,906 A
• Filed: 07/01/1994
• Issued: 01/02/1996
• Est. Priority Date: 07/01/1994
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Creemer, Lawrence C., Kirst, Herbert A.
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): Trinh, Ba K.
• Application Number:
  US08/269,716
• Time in Patent Office: 550 Days
• Field of Search: 549/275, 514/453
• US Class Current: 514/453
• 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
• CPC Class Codes: C07D 493/06 Peri-condensed systems

Abstract

This invention relates to derivatives of Wortmannin and particularly to 11,17 substituted derivatives of Wortmannin. The invention also relates to a method of using these compounds as PI-3-kinase inhibitors and as anti-tumor agents.

Claims

1. A compound of the formula:

##STR19## wherein;

R₁ is ##STR20## or OR₃ ;

R₂ is ##STR21## or OR₃ ;

each R₃ individually is hydrogen, arylacyl, C₃ -C₈ acyl or substituted acyl; and

when R₁ is ##STR22## or OH, R₂ is not ##STR23##

2. The compound of claim 1 wherein:

R₁ is O-acyl and

R₂ is ##STR24##

3. The compound of claim 1 wherein R₁ is OR₃.

4. The compound of claim 3 wherein R₃ is C₃ -C₈ acyl or substituted acyl.

5. A compound of claim 1 having the general formula:

##STR25## wherein R₁ is O-C₃ -C₈ acyl, or a substituted derivative thereof; and

R₂ is ##STR26##

6. The compound of claim 5 wherein R₁ is O-C₃ -C₈ acyl.

7. A compound of claim 1 having the formula:

##STR27##

8. A compound of claim 1 having the formula:

##STR28##

9. A compound of claim 1 having the formula:

##STR29##

10. A compound of claim 1 having the formula:

##STR30##

11. A compound of claim 1 having the formula:

##STR31##

12. A compound of claim 1 having the formula:

##STR32##

13. A compound of claim 1 having the formula:

##STR33##

14. A compound of claim 1 having the formula:

##STR34##

15. A compound of claim 1 having the formula:

##STR35##

16. A compound of claim 1 having the formula:

##STR36##

17. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 1.

18. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 5.

19. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 7.

20. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 8.

21. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 9.

22. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 10.

23. A method of inhibiting PI-3-kinase activity mammals comprising administering to a mammal an effective amount of the compound of claim 11.

24. A method of inhibiting PI-3-kinase activity mammals comprising administering to a mammal an effective amount of the compound of claim 12.

25. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 13.

26. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 14.

27. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 15.

28. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 16.

29. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 5, and wherein R₁ is --OH.

30. A method of inhibiting PI-3-kinase activity in mammals comprising administering to a mammal an effective amount of the compound of claim 5 and wherein R₁ is ##STR37##

31. A pharmaceutical formulation comprising an effective amount of the compound of claim 1, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.

32. A pharmaceutical formulation comprising an effective amount of the compound of claim 5, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.

33. A pharmaceutical formulation comprising an effective amount of the compound of claim 6, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.

34. A pharmaceutical formulation comprising an effective amount of the compound of claim 7, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.

35. A pharmaceutical formulation comprising an effective amount of the compound of claim 8, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.