12, 13-cyclopropane epothilone derivatives

• US 6,380,395 B1
• Filed: 03/29/1999
• Issued: 04/30/2002
• Est. Priority Date: 04/21/1998
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Vite, Gregory D., Höfle, Gerhard, Kim, Soong-Hoon
• Primary Examiner(s): Wilson, James O.
• Assistant Examiner(s): White, Everett
• Application Number:
  US09/280,192
• Time in Patent Office: 1,128 Days
• Field of Search: 536/7.1, 548/146
• US Class Current: 548/146
• 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 491/04 Ortho-condensed systems

Abstract

The present invention relates to 12,13-position modified epothilone derivatives, methods of preparation of the derivatives and intermediates therefor.

Claims

1. A compound of the formula

wherein:

B₁ and B₂ are selected from the group consisting of H, or OR₆;

R₁, R₂, R₃, and R4, are selected from H, lower alkyl;

R₅ is selected from the group consisting of H, alkyl, substituted alkyl;

R₈ is heterocyclo;

R₉ is hydrogen or lower alkyl;

R₆ is hydrogen or alkyl;

M is CR₁₀R₁₁;

R₁₀ and R₁₁ are selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R₁₂C═

O, R₁₃OC═

O, R₁₄NHC═

O, hydroxy, O-alkyl or O-substituted alkyl, NR₁₅R₁₆;

R₁₂, R₁₃, R₁₄, R₁₅, R₁₇, R₁₈ and R₁₉ are selected from the group consisting of H, alkyl, substituted alkyl, aryl, acyl or substituted aryl;

R₁₆ is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo, R₁₇C═

O, R₁₈OC═

O, R₁₉SO₂, hydroxy, O-alkyl, or O-substituted alkyl;

and any salts, solvates or hydrates thereof.

2. The compound of claim 1 wherein R₈ is a 2-methyl-4-thiazolyl.

3. The compound of claim 2 wherein R₁₀ and R₁₁ are halogen.

4. The compound of claim 3 wherein R₁₀ and R₁₁are chlorine or bromine.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable vehicle or diluent.

13. A pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable vehicle or diluent.

14. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable vehicle or diluent.

15. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable vehicle or diluent.

5. A compound of the formulas

wherein:

B₁ and B₂ are selected from the group consisting of H, or OR₆;

R₁, R₂, R₃, and R₄ are selected from H, lower alkyl;

R₅ is selected from the group consisting of H, alkyl, substituted alkyl;

R₈ is heterocyclo;

R₉ is hydrogen or lower alkyl;

R₆ is hydrogen or alkyl;

M is CH₂;

and any salts, solvates or hydrates thereof.

16. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable vehicle or diluent.

6. The compound of the formula:

17. A pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable vehicle or diluent.

7. The compound of the formula:

18. A pharmaceutical composition comprising the compound of claim 7 and a pharmaceutically acceptable vehicle or diluent.

8. The compound of the formula:

19. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable vehicle or diluent.

9. The compound of the formula:

20. A pharmaceutical composition comprising the compound of claim 9 and a pharmaceutically acceptable vehicle or diluent.

10. The compound of the formula:

21. A pharmaceutical composition comprising the compound of claim 10 and a pharmaceutically acceptable vehicle or diluent.

11. The compound of the formula:

22. A pharmaceutical composition comprising the compound of claim 11 and a pharmaceutically acceptable vehicle or diluent.