Inhibition of glutathione transferase by haloenol lactones

• US 5,767,147 A
• Filed: 04/21/1995
• Issued: 06/16/1998
• Est. Priority Date: 04/21/1995
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Hammock, Bruce D., Zheng, Jiang, Jones, A. Daniel, Mitchell, Alyson E.
• Primary Examiner(s): OWENS, AMELIA A
• Application Number:
  US08/426,593
• Time in Patent Office: 1,152 Days
• Field of Search: 549/273, 549/294, 549/293, 549/321, 514/460, 514/473, 514/471, 514/459
• US Class Current: 514/459
• CPC Class Codes: C07D 307/58 One oxygen atom, e.g. butenolide
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: Y10S 977/893 Deposition in pores, molding, with subsequent removal of mold
• CPC Class Codes: Y10S 977/896 Chemical synthesis, e.g. chemical bonding or breaking
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition
• CPC Class Codes: Y10T 436/20 Oxygen containing

Abstract

This invention relates to novel haloenol lactone compounds. These compounds have the following general structure: ##STR1## in which Ar is an aryl group and Y is a haloenol lactone moiety. The compounds of the invention are useful for the specific measurement of particular isoenzymes of glutathione S-transferase. Measurement of glutathione S-transferase isoenzymes has importance in diagnostic medicine. The compounds of the invention are also useful for treatment of drug resistance in cancer and for preventing herbicide resistance in plants.

Claims

1. A compound having the formula:

##STR5## in which;

Ar is an aryl group;

R¹ and R² ;

a) together form a double bond between carbon atoms 1 and 2;

b) together form an epoxy group between carbon atoms 1 and 2;

or

c) are the same or different and are independently selected from the group consisting of H, OH, glutathione thioether, glutathione-S-oxide thioether, and glutathione-S,S-dioxide thioether;

R³ is selected from the group consisting of H, OH, glutathione thioether, glutathione-S-oxide thioether, and glutathione-S,S-dioxide thioether; and

Y is a haloenol lactone.

2. The compound of claim 1 wherein Ar is a radical of the formula:

##STR6## in which;

R⁴, R⁵, R⁶, R⁷, and R⁸ are the same or different and are independently selected from the group consisting of H, a C₁ -C₅ alkyl group, a C₁ -C₅ alkoxy group, a halogen, NO₂, and CF₃.

3. The compound of claim 2 wherein Y is a radical of the formula:

##STR7## wherein X is a halogen.

4. The compound of claim 3 wherein R⁴ -R⁸ are H;

R¹ and R² together form a double bond between carbon atoms 1 and 2; and

R³ is H.

5. The compound of claim 3 wherein R⁴ -R⁸ are H;

R¹ and R² together form an epoxy group between carbon atoms 1 and 2; and

R³ is H.

6. The compound of claim 2 wherein Y is selected from the group consisting of:

##STR8## wherein X is a halogen.

7. The compound of claim 1 wherein Ar is a naphthyl group optionally substituted with one or more members selected from the group consisting of H, a C₁ -C₅ alkyl group, a C₁ -C₅ alkoxy group, a halogen, NO₂, and CF₃.

8. The compound of claim 7 wherein Y is a radical selected from the group consisting of:

##STR9## wherein X is a halogen.

9. The compound of claim 1 wherein R² and R³ are H, and R¹ is selected from the group consisting of glutathione thioether, glutathione-S-oxide thioether, and glutathione-S, S-dioxide thioether.

10. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a unit dosage for an animal of a compound having the formula:

##STR10## in which;

Ar is an aryl group;

R¹ and R² ;

a) together form a double bond between carbon atoms 1 and 2;

b) together form an epoxy group between carbon atoms 1 and 2;

or

c) are the same or different and are independently selected from the group consisting of H, OH, glutathione thioether, glutathione-S-oxide thioether, and glutathione-S,S-dioxide thioether;

R³ is selected from the group consisting of H, OH, glutathione thioether, glutathione-S-oxide thioether, and glutathione-S,S-dioxide thioether; and

wherein Y is a haloenol lactone.

11. The composition of claim 10 wherein Ar is a radical of the formula:

##STR11## in which;

R⁴, R⁵, R⁶, R⁷, and R⁸ are the same or different and are independently selected from the group consisting of H, a C₁ -C₅ alkyl group, a C₁ -C₅ alkoxy group, a halogen, NO₂, and CF₃.

12. The composition of claim 11 wherein Y is a radical of the formula:

##STR12## wherein X is a halogen.

13. The composition of claim 12 wherein R⁴ -R⁸ are H;

R¹ and R² together form a double bond between carbon atoms 1 and 2; and

R³ is H.

14. The composition of claim 12 wherein R⁴ -R⁸ are H;

R¹ and R² together form an epoxy group between carbon atoms 1 and 2; and

R³ is H.

15. The composition of claim 10 wherein said animal is a mammal.

16. A method of inhibiting a glutathione S-transferase enzyme in an animal, said method comprising the administration of a pharmaceutically acceptable carrier and an amount of a compound of the formula:

##STR13## in which;

Ar is an aryl group;

R¹ and R² ;

a) together form a double bond between carbon atoms 1 and 2;

b) together form an epoxy group between carbon atoms 1 and 2;

or

c) are the same or different and are independently selected from the group consisting of H, OH, glutathione thioether, glutathione-S-oxide thioether, and glutathione-S,S-dioxide thioether;

R³ is selected from the group consisting of H, OH, glutathione thioether, glutathione-S-oxide thioether, and glutathione-S,S-dioxide thioether; and

Y is a haloenol lactone,

wherein said amount is effective for inhibiting a glutathione S-transferase in said animal.

17. The method of claim 16 wherein Ar is a radical of the formula:

##STR14## in which;

R⁴, R⁵, R⁶, R⁷, and R⁸ are the same or different and are independently selected from the group consisting of H, a C₁ -C₅ alkyl group, a C₁ -C₅ alkoxy group, a halogen, NO₂, and CF₃.

18. The method of claim 17 wherein Y is a radical of the formula:

##STR15## wherein X is a halogen.

19. The method of claim 18 wherein R⁴ -R⁸ are H;

R¹ and R² together form a double bond between carbon atoms 1 and 2; and

R³ is H.

20. The method of claim 18 wherein R⁴ -R⁸ are H;

R¹ and R² together form an epoxy group between carbon atoms 1 and 2; and

R³ is H.

21. The method of claim 16 wherein said animal is a mammal.