Novobiocin analogues having modified sugar moieties

• US 8,212,012 B2
• Filed: 02/20/2009
• Issued: 07/03/2012
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: Blagg, Brian S. J.
• Primary Examiner(s): LEWIS, PATRICK T
• Application Number:
  US12/390,175
• Publication Number:
  US 20090163709A1
• Time in Patent Office: 1,229 Days
• Field of Search: None
• US Class Current: 536/13
• CPC Class Codes: C07D 407/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 487/14 Ortho-condensed systems
• CPC Class Codes: C07H 19/00 Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof

Abstract

Novobiocin analogues useful as Hsp90 inhibitors in the treatment of cancer, neuroprotection, and autoimmune disorders.

Claims

1. Compounds according to Formula I:

2. The compounds of claim 1 wherein X₉ is —

O-cycloalkyl substituted with at least one amino, alkyl, halo, or hydroxyl group, —

OAc, —

O-azasugar, —

O-pyridine, —

O-pyrrolino, —

O-alcohol, alcohol, ester, amino, amido, carbamate, or phosphate ester.

3. The compound of claim 1 wherein the compounds are coumarin compounds wherein X₁ is —

O— and

X₂ is —

CO—

.

4. The compounds of claim 1 wherein X₉ is an —

O-azasugar.

5. The compounds of claim 4 wherein said azasugar is 1,3-azasugar or 1,4-azasugar.

6. The compounds of claim 2 wherein X₉ is —

OAc.

7. The compounds of claim 1 which are selected from the group consisting of:

8. The compounds of claim 1 wherein X₉ is —

O-cyclohexyl substituted with at least one hydroxyl.

9. The compounds of claim 1 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen or alkyl and R″

is aryl according to;

10. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is aryl according to;

11. The compounds according to claim 1 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is a an indole according to;

12. The compounds of claim 1 wherein X₄ is —

CH—

, X₅ is —

CR²¹—

, X₆ is —

CR²²—

, X₈, is —

CR²³—

according to;

13. The compound of claim 12 wherein the compounds are coumarin compounds wherein X₁ is —

O— and

X₂ is —

CO—

.

14. The compounds of claim 12 wherein X₉ is an —

O-azasugar.

15. The compounds of claim 14 wherein said azasugar is 1,3-azasugar or 1,4-azasugar.

16. The compounds of claim 12 wherein X₉ is —

OAc.

17. The compounds of claim 12 wherein X₉ is —

O-cyclohexyl substituted with at least one hydroxyl.

18. The compounds of claim 12 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen or alkyl and R″

is aryl according to;

19. The compounds according to claim 12 wherein R¹ is an amido which —

NHCOCH₃ or is —

NR′

COR″

, and R′

is hydrogen and R″

is aryl according to;

20. The compounds according to claim 12 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is aryl according to;

21. The compounds according to claim 12 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is aryl according to;

22. The compounds according to claim 12 wherein R¹ is an amido which is NR′

COR″

, and wherein R′

is hydrogen and R″

is a an indole according to;

23. The compounds of claim 12 wherein R²² and R²³ are independently alkyl or alkoxy, and R²¹ is hydrogen.

27. The compounds of claim 12 where wherein R¹ is an amido which is —

NHCOCH₃.

24. Compounds according to:

25. The compounds according to claim 24 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl according to;

26. The compounds according to claim 24 wherein X₉ is selected from the group consisting of: