Novobiocin analogues as anticancer agents

• US 20060199776A1
• Filed: 11/03/2005
• Published: 09/07/2006
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: United States Department Of Health And Human Services (Government of the United States of America), University of Kansas
• Original Assignee: United States Department Of Health And Human Services (Government of the United States of America)
• Inventors: Blagg, Brian S., Neckers, Len, Yu, Xiao Ming
• Granted Patent: US 7,608,594 B2
• Time in Patent Office: Days
• US Class Current: 514/43
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 17/075 Benzo[b]pyran-2-ones

Abstract

Novel analogues and derivatives of novobiocin are provided, including compounds having modifications to the amide side chain, coumarin ring, and sugar moieties. The compounds of the present invention are useful as heat shock protein 90 inhibitors, and may be used as anticancer and neuroprotective agents.

Claims

1. The compounds according to Formula I

2. The coumarin compounds of claim 1 wherein X₁ is —

O— and

X₂ is —

CO—

.

3. The isocoumarin compounds of claim 1 wherein X₁ is —

CO— and

X₂ is —

O—

.

4. The compounds of claim 1 wherein R⁴ and R⁵ are both hydrogen.

5. The compounds of claim 1 wherein R⁴ and R⁵ are independently hydrogen or methyl, and R⁶ is hydrogen.

6. The compounds of claim 1 such X₁ is nitrogen, R¹ together with X₂ and the atom to which R¹ is attached form a heterocyclic ring according to the following Formula I(F):

7. The compounds according to claim 6 wherein X₄, X₅, X₆, and X₈ are all —

CH—

, R^b is oxidized to form a carbonyl, and n is 1 according to the Formula I(F)(i);

8. The compounds according to claim 6 wherein X₉ is —

O—

, and R² and R³ are hydroxyl, R⁴ and R⁵ are methyl, R⁶ is methoxy, and n is 1 according to the Formula I(F)(ii);

9. The compounds of claim 1 such that XI is nitrogen, X₂ is —

CO—

, and R¹ together with X₄ and the atom to which R¹ is attached form a heterocyclic ring according to the following Formula I(G);

10. The compounds according to claim 9 wherein X₄, X₅, X₆, X₈ are all —

CH—

, and n is 1 according to the Formula I(G)(i);

11. The compounds according to claim 10, wherein X₉, is —

O— and

R² and R³ are hydroxyl, R⁴ and R⁵ are methyl, R⁶ is methoxy, and n is 1 according to the Formula I(G)(iii);

12. The compounds of claim 1 wherein that X₅ is nitrogen, X₁ is oxygen, and X² is —

CO—

according to the Formula I(H);

13. The compounds according to claim 12 wherein X₄, X₆, X₈ are all —

CH—

, and n is 1 according to the Formula I(H)(i);

14. The compounds according to claim 1 wherein R⁵ is hydrogen, and R² and R³ are independently —

OH, or —

OCONH₂.

15. The compounds according to claim 1 wherein X₆, is —

CR²¹—

, and R²¹ is methoxy, ethoxy, or nitro, and R² and R³ are independently —

OH, or —

OCONH₂.

16. The compounds of claim 1 such that X₆ is carbon and X₉ is nitrogen, and X₆ together with X₉ and the carbon at position 7 form a heterocyclic ring according to the following Formula I(J):

17. The compounds according to claim 16 wherein R^b is oxidized to form a carbonyl according to the Formula I(J)(i):

18. The compounds according to claim 17 wherein X₁ is —

O— and

X₂ is —

CO—

.

19. The compounds of claim 1 wherein X₁ is —

CO— and

X₂ is —

NR¹⁸—

according to the Formula I(K);

20. The compounds according to claim 19 wherein X₄, X₅, X₆, X₈ are all —

CH—

, and n is 1 according to the Formula I(K)(i);

21. The compounds of claim 1 wherein X₄, is —

CR²⁰— and

R²⁰ is hydrogen and wherein X₈ is —

CR²³— and

R²³ is hydrogen.

22. The compounds of claim 1 wherein that X₁ is —

N— and

X₂ is —

CH—

according to the Formula I(L);

23. The compounds according to claim 22 wherein X₄, X₅, X₆, X₈ are all —

CH— and

n is 1 according to the Formula I(L)(i);

24. The compounds of claim 1

wherein X₄, X₅, X₆, X₈ are all —

CH—

,

wherein X₁ is —

O—

.

wherein X₂ is —

CO—

,

wherein X₉ is the ether —

O—

,

and R² and R³ are hydroxyl, according to the formula;

25. Dimers of the compounds of claim 1, which are shown below:

26. Dimers of the compounds of claim 25 wherein R² and R³ are both hydroxyl, and R⁴ and R⁵ are both methyl, and R⁶ is methoxy according to the formula shown below:

27. A dimer of claim 26, which is X comprises a heterocylic pyrole as shown below:

28. A method of inhibiting heat-shock protein 90 activity by administering one of more of the compounds of claim 1 to a cell, and observing a decrease in the expression of a heat-shock protein 90 client protein.

29. The method of claim 28 wherein said client protein comprises Her-2, phospho-AKT, or HIF-1alpha.

30. The compounds selected from the group consisting of:

N-(7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2-oxo-2H-chromen-3-yl)acetamide (A1);

(2R,3R,4R,5R)-2-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-4-hydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-3-yl carbamate (A2);

(3R,4S,5R,6R)-6-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-5-hydroxy-3-methoxy-2,2-dimethyl tetrahydro-2H-pyran-4-yl carbamate (A3);

N-(7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-2-oxo-2H-chromen-3-yl)acetamide (A4);

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-2H-chromen-2-one (B1);

(3R,4S,5R,6R)-5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-4-yl carbamate (B2);

(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-3-yl carbamate (B3);

7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one (B4);

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-4-methyl-3-phenyl-2H-chromen-2-one (C1);

(3R,4S,5R,6R)-5-hydroxy-3-methoxy-2,2-dimethyl-6-(4-methyl-2-oxo-3-phenyl-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-4-yl carbamate (C2);

(2R,3R,4R,5R)-4-hydroxy-5-methoxy-6,6-dimethyl-2-(4-methyl-2-oxo-3-phenyl-2H-chromen-7-yloxy)-tetrahydro-2H-pyran-3-yl carbamate (C3);

7-((2R,3R,4S,5R)-3,4-dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-2H-pyran-2-yloxy)-4-methyl-3-phenyl-2H-chromen-2-one (C4);

.

8-(7-Methoxy-6,6-dimethyl-2-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-chromen-2-one (D1);

Carbamic acid 4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-8-yloxy)-tetrahydro-pyran-3-yl ester (D2);

carbamic acid 5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-8-yloxy)-tetrahydro-pyran-4-yl ester (D3);

8-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-one (D4);

6-(7-Methoxy-6,6-dimethyl-2-oxo-tetrahydro-[1,3]dioxolo[4,5-c]pyran-4-yloxy)-chromen-2-one (E1);

Carbamic acid 5-hydroxy-3-methoxy-2,2-dimethyl-6-(2-oxo-2H-chromen-6-yloxy)-tetrahydro-pyran-4-yl ester (E2);

Carbamic acid 4-hydroxy-5-methoxy-6,6-dimethyl-2-(2-oxo-2H-chromen-6-yloxy)-tetrahydro-pyran-3-yl ester (E3); and

6-(3,4-Dihydroxy-5-methoxy-6,6-dimethyl-tetrahydro-pyran-2-yloxy)-chromen-2-one (E4).