Novobiocin Analogues Having Modified Sugar Moieties

• US 20090163709A1
• Filed: 02/20/2009
• Published: 06/25/2009
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: University of Kansas
• Original Assignee: University of Kansas
• Inventors: Blagg, Brian
• Granted Patent: US 8,212,012 B2
• Time in Patent Office: Days
• US Class Current: 544/65
• 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:

wherein R¹ is hydrogen, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, aralkyl, carboxyl, amido, amino, sulfanyl, sulfenyl, sulfonyl, or ether;

or R¹ together with X² and the atom to which R¹ is attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

or R¹ together with X⁴ and the atom to which R¹ is attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X₁ is —

O—

, —

CO—

, or —

N—

;

wherein X₂ is —

O—

, —

N—

, —

NR¹⁸—

, —

CR¹⁹—

, or —

CO—

; and

wherein R¹⁸ and R¹⁹ are hydrogen, alkyl, alkenyl, or alkynyl;

or X₂ together with R¹ and the atom to which R¹ is attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X₄ is —

O—

, —

CR²⁰—

, CO—

, or —

N—

, wherein R²⁰ is hydrogen, alkyl, alkenyl, alkynyl, or hydroxy;

or wherein X₄ together with R¹ and the atoms to which they are attached form a heterocyclic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X₅, is —

CR²¹—

or —

N—

, wherein R²¹ is hydrogen, alkyl, alkenyl, alkynyl, or alkoxy;

wherein X₆, is —

CR²²—

or —

N—

, wherein R²² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

or X₆ together with X₉ and the carbon at position 7 form a heterocylic ring having 4 to 8 ring members with at least one heteroatom selected from oxygen or nitrogen;

wherein X₈, is —

CR²³—

or —

N—

, wherein R²³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy or halogen;

wherein X₉ is hydroxyl, —

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

OAc, —

O-sugar, or —

O-azasugar, —

O-pyridine, —

O-pyrrolino, —

O-alcohol, alcohol, ester, amino, amido, carbamate, phosphate ester, or mesylate; and

wherein at least one of X₁, X₂, X₄, X₅, X₆, X₈ is not —

CR—

.

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 method 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-sugar which is a mono-hydroxylated or poly-hydroxylated furanose, pyranose, or oxepanose sugar.

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

O-sugar selected from the group consisting of

6. The compounds of claim 5 wherein R¹ is an amido which is —

NHCOCH₃.

7. The compounds of claim 1 wherein X₉ is a —

O-sugar wherein said sugar is a 6-membered sugar ring having a 3′

-hydroxy.

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

O-azasugar.

9. The compounds of claim 8 wherein said azasugar is 1,3-azasugar or 1,4-azasugar.

10. The compounds of claim 2 wherein X₉ is —

OAc.

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

12. The compounds of claim 1 wherein X₉ is —

O-cyclohexyl substituted with at least one hydroxyl.

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

COR″

, and R¹ is hydrogen or alkyl and R″

is aryl according to;

wherein R²⁴ and R²⁵ are independently hydrogen, alkyl, amino, halo, hydroxy, or alkoxy.

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

COR″

, and wherein R¹ is hydrogen and R″

is aryl according to;

wherein X is ether or amino;

wherein R²⁴ is alkoxy;

wherein R²⁵ is hydrogen, hydroxy, alkoxy, or aryloxy; and

wherein R²⁶ is hydrogen, alkoxy, aryloxy, or amino.

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

COR″

, and wherein R¹ is hydrogen and R″

is a an indole according to;

or a R″

is a pendant aryl according to;

16. The compounds of claim 1 wherein X₄ is —

CH—

, X₅ is —

CR²¹—

, X₆ is —

CR²²—

, X₈, is —

CR²³—

according to;

wherein R¹ is an amido which is NR′

COR″

, and R¹ is hydrogen and R″

is alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocylic, aryl, or aralkyl;

wherein X₁ is O—

, —

CO—

, or —

N—

;

wherein X₂ is —

O—

, —

N—

, —

CR¹⁹—

or —

CO—

, wherein R¹⁹ is hydrogen, alkyl, alkenyl, alkynyl;

wherein R²¹ is hydrogen, alkyl, alkenyl, alkynyl, or alkoxy;

wherein R²² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein R²³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy, or halogen;

wherein X₉ is hydroxyl, —

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

OAc, —

O-sugar, or —

O-azasugar, —

O-pyridine, —

O-pyrrolino, —

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

17. The method of claim 16 wherein the compounds are coumarin compounds wherein X₁ is —

O— and

X₂ is —

CO—

.

18. The compounds of claim 16 wherein X₉ is an —

O-sugar which is a mono-hydroxylated or poly-hydroxylated furanose, pyranose, or oxepanose sugar.

19. The compounds of claim 16 wherein X₉ is an —

O-sugar selected from the group consisting of

20. The compounds of claim 16 wherein X₉ is a —

O-sugar wherein said sugar is a 6-membered sugar ring having a 3′

-hydroxy.

21. The compounds of claim 16 wherein X₉ is an —

O-azasugar.

22. The compounds of claim 21 wherein said azasugar is 1,3-azasugar or 1,4-azasugar.

23. The compounds of claim 16 wherein X₉ is —

OAc.

24. The compounds of claim 16 wherein X₉ is —

O-cyclohexyl substituted with at least one hydroxyl.

25. The compounds of claim 16 wherein R¹ is an amido which is NR′

COR″

, and R¹ is hydrogen or alkyl and R″

is aryl according to;

wherein R²⁴ and R²⁵ are independently hydrogen, alkyl, amino, halo, hydroxy, or alkoxy.

26. The compounds according to claim 16 wherein R¹ is an amido which —

NHCOCH₃ or is —

NR′

COR″

, and R¹ is hydrogen and R″

is aryl according to;

wherein R²⁴ and R²⁵ are alkoxy.

27. The compounds according to claim 16 wherein R¹ is an amido which is NR′

COR″

, and wherein R¹ is hydrogen and R″

is aryl according to;

wherein R²⁴ and R²⁵ are independently hydrogen, alkyl, or alkoxy.

28. The compounds according to claim 16 wherein R¹ is an amido which is NR′

COR″

, and wherein R¹ is hydrogen and R″

is aryl according to;

wherein X is ether or amino;

wherein R²⁴ is alkoxy;

wherein R²⁵ is hydrogen, hydroxy, alkoxy, or aryloxy; and

wherein R²⁶ is hydrogen, alkoxy, aryloxy, or amino.

29. The compounds according to claim 16 wherein R¹ is an amido which is NR′

COR″

, and wherein R¹ is hydrogen and R″

is a an indole according to;

or a R″

is a pendant aryl according to;

30. The compounds of claim 16 wherein R²² and R²³ are independently alkyl or alkoxy, and R²¹ is hydrogen.

34. The compounds of claim 18 where wherein R¹ is an amido which is —

NHCOCH₃.

31. Compounds according to:

wherein R¹ is an amido which is NR′

COR″

, and R¹ is hydrogen and R″

is alkyl, alkenyl, alkynyl, alkoxy, carbocyclic, heterocylic, aryl, or aralkyl;

wherein X₁ is —

O—

, —

CO—

, or —

N—

;

wherein X₂ is —

O—

, —

N—

, —

CR¹⁹—

or —

CO—

, wherein R¹⁹ is hydrogen, alkyl, alkenyl, alkynyl;

wherein R²¹ is hydrogen, alkyl, alkenyl, alkynyl, or alkoxy;

wherein R²² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, halogen, or nitro;

wherein R²³ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkoxy or halogen;

wherein X₉ is

wherein X and Y are independently carbon, nitrogen, or oxygen,

wherein R^a, R^b, R^c, and R^d are independently hydrogen, alkyl, or acyl; and

wherein one or both of R^a and R^b is omitted if X is nitrogen or oxygen, respectively; and

wherein one or both of R^c and R^d is omitted if Y is nitrogen or oxygen, respectively.

wherein R^e and R^f are independently hydrogen or hydroxy; and

wherein the dashed line represents an optional double bond.

32. The compounds according to claim 31 wherein R¹ is an amido which is NR′

COR″

, and R′

is hydrogen and R″

is aryl according to;

wherein R²⁴ and R²⁵ are alkoxy.

33. The compounds according to claim 31 wherein X₉ is selected from the group consisting of:

wherein R^a, R^b, R^c, and R^d are independently hydrogen, alkyl, or acyl; and

wherein R^e and R^f are independently hydrogen or hydroxy.