Peroxynitrite decomposition catalysts and methods of use thereof

• US 20030055032A1
• Filed: 07/29/2002
• Published: 03/20/2003
• Est. Priority Date: 06/03/1999
• Status: Active Grant

• Current Assignee: John T. Groves, Suzanne M. Moeller
• Original Assignee: John T. Groves, Suzanne M. Moeller
• Inventors: Groves, John T., Moeller, Suzanne M.
• Granted Patent: US 6,969,707 B2
• Time in Patent Office: Days
• US Class Current: 514/185
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• 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: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: C07F 13/005 Compounds without a metal-carbon linkage
• CPC Class Codes: C07F 15/025 without a metal-carbon linkage
• CPC Class Codes: C07F 15/045 without a metal-carbon linkage
• CPC Class Codes: C07F 9/005 Compounds of elements of Group 5 of the Periodic Table without metal-carbon linkages

Abstract

This invention provides a novel class of substituted macrocyclic metallic complexes. The complexes are useful as peroxynitrite decomposition catalysts. Pharmaceutical compositions, and methods of making and using the compounds, or a pharmaceutically acceptable salt, hydrate, prodrug, or mixture thereof are also described.

Claims

1. A metallic complex having the Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, or Formula VII:

2. The complex of claim 1, wherein at least two of R₁, R₂, R₃, or R₄, A, B, C, or D include said moiety.

3. The complex of claim 1, wherein at least three of R₁, R₂, R₃, or R₄ A, B, C, or D include said moiety.

4. The complex of claim 1, wherein four of R₁, R₂, R₃, or R₄ A, B, C, or D include said moiety.

5. The complex of claim 4, wherein the at least four moieties are identical.

6. The complex of claim 1, wherein said moiety is selected from the group consisting of CH₂CH═

CH₂, CH₂CONH₂, CH₂CO₂ CH₂CH₃, and CH₂CH₂OCH₂CH₂OCH₂CH₂OCH₃.

7. The complex of claim 1, wherein said Formula is Formula I.

8. The complex of claim 7, wherein said moiety is CH₂CH═

CH₂.

9. The complex of claim 7, wherein R₁, R₂, R₃, and R₄ are CH₂CH═

CH₂.

10. The complex of claim 7, wherein said moiety is (CH₂)_nCONH₂, wherein n is an integer from 1 to 6.

11. The complex of claim 7, wherein said moiety is CH₂CONH₂.

12. The complex of claim 7, wherein R₁, R₂, R₃, and R₄ are CH₂CONH₂.

13. The complex of claim 7, wherein said moiety is (CH₂)_mCO₂ CH₂CH₃, m=1 to 100.

14. The complex of claim 7, wherein said moiety is CH₂CO₂ CH₂CH₃.

15. The complex of claim 7, wherein R₁, R₂, R₃, and R₄ are CH₂CO₂ CH₂CH₃

16. The complex of claim 7, wherein said moiety is CH₂CH₂OCH₂CH₂OCH₂CH₂OCH₃.

17. The complex of claim 7, wherein R₁, R₂, R₃, and R₄ are CH₂CH₂OCH₂CH₂OCH₂CH₂OCH₃.

18. The complex of claim 1, wherein said complex is capable of decomposing peroxynitrite.

19. A pharmaceutical composition comprising the complex of claim 1 and a pharmaceutically acceptable carrier.

22. A method of lowering peroxynitrite levels in a cell or tissue, the method comprising contacting said cell or tissue with a complex of claim 1 in an amount sufficient to lower peroxynitrite levels in said cell or tissue.

23. A method of treating or inhibiting the development of a pathology associated with peroxynitrite damage in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the complex of claim 1.

24. The method of claim 22, wherein said pathology is selected from the group consisting of Alzheimer'"'"'s disease, amyotrophic lateral sclerosis, stroke, AIDS dementia, Huntington'"'"'s disease, atherosclerosis;

chronic inflammation;

autoimmune diseases, cancer, ischemia-reperfusion injury;

septic shock, and chronic graft rejection.

25. The method of claim 23, wherein said subject is a human.

20. A complex of formula I:

21. A pharmaceutical composition comprising the complex of claim 20 and a pharmaceutically acceptable carrier.