Pharmaceutically active compounds and methods of use thereof

• US 20040242614A1
• Filed: 05/17/2004
• Published: 12/02/2004
• Est. Priority Date: 11/20/2001
• Status: Active Grant

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Rosowsky, Andre, Forsch, Ronald A.
• Granted Patent: US 7,119,095 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/08 for leprosy
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 33/08 for Pneumocystis carinii
• CPC Class Codes: C07D 239/49 with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
• CPC Class Codes: C07D 239/95 with hetero atoms directly attached in positions 2 and 4
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention relates to dihydrofolate reductase inhibitors having an aromatic group and a heteroaromatic group linked by a methylene group; and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such dihydrofolate reductase inhibitors.

Claims

1. A compound according to Formula I:

2. A compound according to claim 1 wherein R_A is hydrogen at each occurrence of R_A in Formula I.

3. A compound according to claim 1 of the Formula II:

4. A compound of any one of claims 1 through 3 where W is carboxylate.

5. A compound of any one of claims 1 through 3 where W is hydrogen.

12. A compound of claim 1 or claim 6, wherein the compound has an IC₅₀ of 50 μ

M or less against a DHFR enzyme.

13. A compound of claim 1 or claim 6, wherein the compound has an IC₅₀ of 25 μ

M or less against a DHFR enzyme.

14. A compound of claim 1 or claim 6, wherein the compound has an IC₅₀ of 10 μ

M or less against a DHFR enzyme.

15. A compound of claim 1 or claim 6, wherein the compound has an IC₅₀ of 5 μ

M or less against a DHFR enzyme.

16. A compound of claim 1 or claim 6, wherein the compound has an IC₅₀ of 1 μ

M or less against a DHFR enzyme.

17. A compound of claim 1 or claim 6, wherein the compound has an IC₅₀ of 0.5 μ

M or less against a DHFR enzyme.

18. A compound of claim 12, wherein the DHFR enzyme is a DHFR enzyme of a parasite.

19. A compound of claim 18, wherein the parasite is capable of causing a disease or infection in a mammal.

20. A compound of claim 19, where the disease or infection caused by the parasite is selected from the group consisting of malaria, trypanosomiasis, leprosy, toxoplasmosis, and pneumocystis carinii pneumonia.

21. A compound of claim 18, wherein the parasite is selected from the group consisting of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium.

22. A compound according to claim 1 or claim 6, wherein a binding selectivity of the compound is about 1, wherein the binding selectivity is a ratio of the compound'"'"'s IC₅₀ for binding mammalian DHFR enzymes to the compound'"'"'s IC₅₀ for binding IC₅₀ for binding parasitic DHFR enzymes.

23. A compound according to claim 24, where the binding selectivity of the compound is about 2.

24. A compound according to claim 22, where the binding selectivity of the compound is about 4.

25. A compound according to claim 22, where the binding selectivity of the compound is about 8.

26. A compound according to claim 22, where the binding selectivity of the compound is about 16.

27. A compound according to claim 22, where the binding selectivity of the compound is about 20.

28. A compound according to claim 22, where the binding selectivity of the compound is about 50.

29. A pharmaceutical composition comprising a compound of claim 1 or claim 6, and a pharmaceutically acceptable carrier.

30. A method for treating a mammal suffering or susceptible to a parasitic infection or disorder, comprising administering to the mammal an effective amount of a compound or composition of claim 1 or claim 6.

31. A method of claim 30 wherein the mammal is immuno-compromised.

32. The method of claim 30, wherein the mammal is HIV-positive.

33. The method of claim 30, wherein the mammal is suffering from an acquired immune deficiency disorder.

34. The method of claim 30, wherein the mammal is suffering from an autoimmune disorder or disease.

35. The method of claim 30, wherein the mammal has a parasitic infection.

36. The method of claim 30, wherein the parasitic infection causes a disease or illness is selected from the group consisting of malaria, trypanosomiasis, leprosy, toxoplasmosis, and pneumocystis carinii pneumonia.

37. The method of claim 36, wherein the parasitic infection is a Pneumocystis carinii (Pc), Toxoplasma gondii or Mycobacterium avium infection.

38. A method for treating an immuno-comprised mammal comprising administering to the mammal an effective amount of a compound or composition of claim 1 or claim 6.

39. The method of claim 38, wherein the mammal is HIV-positive.

40. The method of claim 38, wherein the mammal has AIDS.

41. The method of claim 38, wherein the mammal has an autoimmune disorder.

42. The method of claim 30 wherein the mammal is a human.

43. The method of claim 38 wherein the mammal is a human.

6. A compound according to Formula III:

7. A compound according to claim 6, wherein R_A is hydrogen at each occurrence of R_A in Formula II.

8. A compound according to claim 6, of the Formula IV

9. A compound according to claim 6, of the Formula V

10. A compound of any one of claims 6 through 9 where W is carboxylate.

11. A compound of any one of claims 6 through 9 where W is hydrogen.