Synthetic catalytic free radical scavengers useful as antioxidants for prevention and therapy of disease

• US 20060149089A1
• Filed: 02/23/2006
• Published: 07/06/2006
• Est. Priority Date: 12/07/1992
• Status: Active Grant

• Current Assignee: Eukarion, Inc.
• Original Assignee: Eukarion, Inc.
• Inventors: Malfroy-Camine, Bernard, Doctrow, Susan Robin
• Granted Patent: US 7,582,786 B2
• Time in Patent Office: Days
• US Class Current: 556/32
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage

Abstract

The invention provides antioxidant salen-metal complexes, compositions of such antioxidant salen-metal complexes having superoxide activity, catalase activity, and/or peroxidase activity, compositions of salen-metal complexes in a form suitable for pharmaceutical administration to treat or prevent a disease associated with cell or tissue damage produced by free radicals such as superoxide, and cosmetic and free radical quenching formulations of salen metal compounds.

Claims

1-24. -24. (canceled)

25. A salen-metal compound having antioxidant activity and having a structural formula of Structure XXIII or Structure XXIV as shown in FIG. 26E, wherein:

M is selected from the group consisting of Mn, Co, Cu, Fe, V, Cr and Ni;

A is an axial ligand selected from the group consisting of Cl, F, O, Br and acetyl;

X₂, X₃ and X₄ are independently selected from the group consisting of hydrogen, lower alkoxy, halide and aryloxy;

Y₂, Y₃ and Y₄ are independently selected from the group consisting of hydrogen, lower alkoxy, halide and aryloxy; and

R₁, R₂, R₃ and R₄ are independently selected from the group consisting of hydrogen, aryl, substituted aryl, heteroatom-bearing aromatic, arylalkyl, lower alkoxy and halide and wherein one of R₁ and R₂ is optionally covalently linked to one of R₃ and R₄ thereby forming a cyclic structure.

26. The salen-metal compound of claim 25 having a structural formula of Structure XXIII as shown in FIG. 26E.

27. The salen-metal compound of claim 25 having a structural formula of Structure XXIV as shown in FIG. 26E.

28. The salen-metal compound of claim 25 wherein M is Mn.

29. The salen-metal compound of claim 25 wherein the axial ligand is selected from the group consisting of Cl and acetyl.

30. The salen-metal compound of claim 29 wherein the axial ligand is an acetyl group.

31. The salen-metal compound of claim 29 wherein the axial ligand is chloride.

32. The salen-metal compound of claim 25 wherein X₂, X₃, X₄, Y₂, Y₃ and Y₄ are each hydrogen.

33. The salen-metal compound of claim 25 wherein R₁, R₂, R₃ and R₄ are independently hydrogen.

34. The salen-metal compound of claim 25 wherein one of R₁ and R₂ is covalently linked to one of R₃ and R₄ thereby forming a cyclic structure.

35. The salen-metal compound of claim 34 wherein the cyclic structure is a six-membered ring.

36. The salen-metal compound of claim 35 wherein said compound has the structure of compound C82 shown in FIG. 24G.

37. The salen-metal compound of claim 25 wherein said compound has superoxide dismutase activity.

38. The salen-metal compound of claim 25 wherein said compound has catalase activity.

39. The salen-metal compound of claim 25 wherein said compound has peroxidase activity.

40. The salen-metal compound of claim 25 wherein said compound has superoxide dismutase activity and catalase activity and peroxidase activity.

41. A pharmaceutically acceptable composition comprising a salen-metal compound of claim 25 and an excipient or carrier.

42. The pharmaceutically acceptable composition of claim 41 in the form of a tablet, capsule, ampule, inhalable composition, suppository, or injectable composition.

43. A method of inhibiting damage to cells induced by reactive oxygen species comprising contacting cells having oxidative stress with a salen-metal compound of claim 25 comprising a salen-metal compound of claim 25.

44. A method of preventing, arresting or treating free radical-associated disease comprising administering to a subject a therapeutically-effective dose of the pharmaceutically acceptable composition of claim 41.