Substituted 4-phthalimidocarboxanilides as inhibitors of purine salvage phosphoribosyltransferases

• US 6,221,877 B1
• Filed: 04/12/2000
• Issued: 04/24/2001
• Est. Priority Date: 04/12/2000
• 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: Kuntz, Irwin D., Munagala, Narsimha R., Wang, Ching C., Ortiz de Montellano, Paul R., Aronov, Alex M.
• Primary Examiner(s): Higel, Floyd D.
• Assistant Examiner(s): Wright, Sonya N.
• Application Number:
  US09/547,531
• Time in Patent Office: 377 Days
• Field of Search: 514/417, 514/297, 514/414, 546/105, 548/480, 548/462, 548/463, 548/474, 548/479
• US Class Current: 514/297
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: C07B 2200/11 Compounds covalently bound to a solid support
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide

Abstract

The use of certain heterocyclic derivatives for treating parasitic protozoa infections in mammals, in particular bovine trichomoniasis and giardiasis, is disclosed.

Claims

1. A compound of the formula:

wherein;

R¹ is selected from the group consisting of;

 

and a fused three-membered aryl or heteroaryl group;

R², R³ and R⁴ are independently selected from the group consisting of H, lower alkyl and halo;

X is selected from the group consisting of —

CH₂—

O— and

—

O—

CH₂—

;

R⁵ is aryl;

R⁶, R⁷ and R⁸ are independently selected from the group consisting of H and lower alkyl;

R⁹ is lower alkyl and R¹⁰ is a cyclic aliphatic ring, or R⁹ and R¹⁰ can be taken together to form a cyclic aliphatic ring; and

Y is selected from the group consisting of NH and O;

or the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 where R¹ is:

3. The compound of claim 2 where R² is selected from the group consisting of H and halo.

4. The compound of claim 2 where R³ is selected from the group consisting of H and lower alkyl.

5. The compound of claim 2 where R⁴ is selected from the group consisting of H, lower alkyl and halo.

6. The compound of claim 2 where R⁵ is selected from the group consisting of phenyl, substituted phenyl and naphthyl.

7. The compound of claim 1 where R¹ is:

8. The compound of claim 7 where R⁶ is lower alkyl.

9. The compound of claim 7 where R⁷ is lower alkyl.

10. The compound of claim 7 where R⁸ is lower alkyl.

11. The compound of claim 1 where R¹ is:

12. The compound of claim 11 where R⁹ is lower alkyl and R¹⁰ is a cyclic aliphatic ring.

13. The compound of claim 1 where R¹ is:

14. The compound of claim 13 where Y is NH.

15. The compound of claim 13 where Y is O.

16. The compound of claim 1 where R¹ is a fused three-membered aryl or heteroaryl group.

17. The compound of claim 16 where R¹ is anthryl or acridinyl.

18. A pharmaceutical composition for the treatment of parasitic protozoa infections in mammals by inhibiting hypoxanthine-guanine-xanthine phosphoribosyltransferase or guanine phosphoribosyltransferase in the purine salvage pathways of said parasitic protozoa, which composition comprises the compound of claim 1 in a pharmaceutically acceptable carrier.

19. A method of treating in mammals a parasitic protozoa infection that is alleviated by treatment with an inhibitor of hypoxanthine-guanine-xanthine phosphoribosyltransferase or guanine phosphoribosyltransferase in the purine salvage pathways of parasitic protozoa, which method comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of claim 1.

20. The method of claim 19 wherein the disease state is bovine trichomomasis.

21. The method of claim 19 wherein the disease state is giardiasis.

22. The method of claim 19 wherein said compound is in a pharmaceutical composition which contains a pharmaceutically acceptable carrier.