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

• US 5,696,109 A
• Filed: 06/07/1995
• Issued: 12/09/1997
• Est. Priority Date: 12/07/1992
• Status: Expired due to Term

• Current Assignee: Eukarion, Inc.
• Original Assignee: Eukarion, Inc.
• Inventors: Malfroy-Camine, Bernard, Doctrow, Susan Robin
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US08/485,489
• Time in Patent Office: 916 Days
• Field of Search: 514/185, 514/184, 514/492, 514/501, 514/502, 514/505
• US Class Current: 514/185
• CPC Class Codes: A61K 2800/522 Antioxidants; Radical scavengers
• CPC Class Codes: A61K 2800/58 Metal complex; Coordination compounds
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 31/555 containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 8/49 containing heterocyclic compounds
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 39/06 Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: A61Q 19/00 Preparations for care of the skin
• CPC Class Codes: C07C 251/24 having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
• 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 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. A method for arresting or treating a free radical-associated disease state by administering to a patient a therapeutically-effective dose of an antioxidant salen-metal complex pharmaceutical composition comprising an antioxidant salen-metal complex of the formula:

##STR15## wherein M is selected from the group consisting Mn, Co, Fe, V, Cr, and Ni;

A is an anion;

n is either 0, 1, or 2;

X₁, X₂, X₃ and X₄ are independently selected from the group consisting of silyls, aryls, arylalkyls, primary alkyls, secondary alkyls, tertiary alkyls, alkoxys, aryloxys, aminos, quaternary amines, heteroatoms, halides and hydrogen;

Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are independently selected from the group consisting of hydrogen, halides, alkyls, aryls, arylalkyls, alkoxys, silyl groups, aminos and alkyls or aryls bearing heteroatoms, alkoxys, or halides; and

R₁, R₂, R₃ and R₄ are independently selected from the group consisting of hydrogen, aryl, fatty acid esters, substituted alkoxyaryls, heteroatom-bearing aromatic groups, arylalkyls, primary alkyls, secondary alkyls, and tertiary alkyls.

2. The method of claim 1, wherein the antioxidant salen-metal complex is selected from the group consisting of:

##STR16##

3. The method of claim 1, wherein the antioxidant salen-metal complex is selected from the group consisting of:

##STR17##

4. The method of claim 3, wherein the salen-metal complex is ##STR18##

5. The method of claim 1, wherein the antioxidant salen-metal complex is formulated in a pharmaceutically acceptable form with an excipient or carrier.

6. The method of claim 1, wherein the free radical-associated disease state is:

neurological damage from Parkinson'"'"'s disease, Alzheimer'"'"'s disease or transient cerebral anoxia injury, cardiac tissue necrosis resulting from cardiac ischemia, autoimmune neurodegeneration, acute lung injury from sepsis and/or endotoxemia, neuronal damage resulting from anoxia or trauma, or iatrogenic free-radical toxicity.

7. The method of claim 1, wherein the patient is a non-human veterinary animal.

8. The method of claim 6, wherein the salen-metal complex is ##STR19##

9. A method for treating cardiac tissue necrosis resulting from cardiac ischemia or acute lung injury from sepsis or endotoxemia, neuronal damage resulting from anoxia, or iatrogenic free-radical neurotoxicity toxicity resulting from MPTP intoxication, comprising administering to a patient a therapeutically effective dose of an antioxidant salen-metal complex selected from the group consisting of:

##STR20##

10. The method of claim 9, wherein the antioxidant salen-metal complex is ##STR21##

11. A method for treating ischemia or reoxygenation injury, comprising administering to a patient a therapeutically-effective dose of an antioxidant salen-metal complex pharmaceutical composition comprising an antioxidant salen-metal complex of the formula:

##STR22## wherein M is selected from the group consisting of Mn, Co, Fe, V, Cr, and Ni;

A is an anion;

n is either 0, 1, or 2;

X₁, X₂, X₃ and X₄ are independently selected from the group consisting of silyls, aryls, arylalkyls, primary alkyls, secondary alkyls, tertiary alkyls, alkoxys, aryloxys, aminos, quaternary amines, heteroatoms, halides and hydrogen;

Y₁, Y₂, Y₃, Y₄, Y₅, and Y₆ are independently selected from the group consisting of hydrogen, halides, alkyls, aryls, arylalkyls, alkoxys, silyl groups, aminos and alkyls or aryls bearing heteroatoms, alkoxys, or halides; and

R₁, R₂, R₃ and R₄ are independently selected from the group consisting of hydrogen, aryl, fatty acid esters, substituted alkoxyaryls, heteroatom-bearing aromatic groups, arylalkyls, primary alkyls, secondary alkyls, and tertiary alkyls.

12. The method of claim 11, wherein the antioxidant salen-metal complex is selected from the group consisting of:

##STR23##

13. The method of claim 11, wherein the antioxidant salen-metal complex is selected from the group consisting of:

##STR24##

14. The method of claim 13, wherein the salen-metal complex ##STR25##