Novobiocin Analogues as Anticancer Agents

• US 20100048882A1
• Filed: 10/01/2009
• Published: 02/25/2010
• Est. Priority Date: 11/03/2004
• Status: Active Grant

• Current Assignee: Secretary of The Department of Health and Human Services, University of Kansas
• Original Assignee: University of Kansas
• Inventors: Blagg, Brian S., Neckers, Len, Yu, Xiao Ming
• Granted Patent: US 7,811,998 B2
• Time in Patent Office: Days
• US Class Current: 536/13
• 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. A compound according to Formula I

wherein R¹ is hydrogen, alkyl, aryl or amido;

wherein R² is hydrogen;

hydroxy or —

R⁸—

OR⁹, wherein R⁸ is a covalent bond or alkyl, and R⁹ is C-amido or acyl;

or R² together with R³ 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 R³ is hydrogen;

hydroxy or —

R¹⁰—

OR¹¹, wherein R¹⁰ is a covalent bond or alkyl, and R¹¹ is C-amido or acyl;

or R³ together with R² 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 R⁴ is hydrogen or methyl;

wherein R⁵ is hydrogen or alkyl;

wherein R⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, aryloxy, or aralkoxy;

wherein X₁ is —

O—

, —

CO—

, or —

N—

;

wherein X₂ is —

O—

, —

N—

, —

NR¹⁸—

, —

CR¹⁹—

, or —

CO—

;

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

wherein X₄ is —

CR²⁰—

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

wherein X₅ is —

CR²¹—

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

wherein X₆ is —

CR²²—

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

wherein X₈ is —

CR²³—

or —

N—

, wherein R²³ is hydrogen, alkyl, alkenyl, or alkynyl;

wherein X₉ is ether;

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

CR—

;

wherein n is 1; and

wherein R² and R³ are not simultaneously hydroxy.

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

O— and

X₂ is —

CO—

.

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

CO— and

X₂ is —

O—

.

4. The compound of claim 2 wherein R⁴ and R⁵ are both methyl.

5. The compound of claim 2 wherein X₄ is —

CR²⁰— and

R²⁰ is hydrogen, and wherein X₈ is —

CR²³— and

R²³ is hydrogen or alkyl.

6. The compound of claim 5 wherein R¹ is amido.

7. The compound of claim 6 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); and

4-deshydroxy-8-desmethylnovobiocin.

8. The compound of claim 5 wherein R¹ is hydrogen.

9. The compound of claim 8 selected from the group consisting of:

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3 aH-[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).

10. The compound of claim 2 wherein X₄, is —

CR²⁰— and

R²⁰ is alkyl and wherein R¹ is aryl.

11. The compound of claim 10 selected from the group consisting of:

7-((3aR,4R,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3 aH-[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); and

(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).

12. The compound of claim 2 wherein X₄ is —

CR²⁰— and

R²⁰ is hydrogen, and wherein X₈ is —

CR²³— and

R²³ is alkyl.

13. The compound of claim 12 wherein R¹ is amido.

14. The compound of claim 13 selected from the group consisting of:

4-deshydroxynovobiocin (DHN1); and

(3R,4S,5R,6R)-6-(3-acetamido-2-oxo-2H-chromen-7-yloxy)-8-methyl-5-hydroxy-3-methoxy-2,2-dimethyltetrahydro-2H-pyran-4-yl carbamate (8-methyl A3).

15. A compound according to Formula II:

wherein R² is hydrogen;

hydroxy or —

R⁸—

OR⁹, wherein R⁸ is a covalent bond or alkyl, and R⁹ is C-amido or acyl;

or R² together with R³ 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; and

wherein R³ is hydrogen;

hydroxyl or —

R¹⁰—

OR¹¹, wherein R¹⁰ is a covalent bond or alkyl, and R¹¹ is C-amido or acyl;

or R³ together with R² 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.

16. The compound of claim 15 selected from the group consisting of:

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); and

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

17. A compound according to Formula III:

wherein R² is hydrogen;

hydroxy or —

R⁸—

OR⁹, wherein R⁸ is a covalent bond or alkyl, and R⁹ is C-amido or acyl;

or R² together with R³ 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; and

wherein R³ is hydrogen;

hydroxyl or —

R¹⁰—

OR¹¹, wherein R¹⁰ is a covalent bond or alkyl, and R¹¹ is C-amido or acyl;

or R³ together with R² 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.

18. The compound of claim 17 selected from the group consisting of:

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).