Peroxynitrite decomposition catalysts and methods of use thereof
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.
1. A metallic complex having the Formula XII:
or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof, wherein:
at least one of R 1 , R 2 , R 3 , or R 4 , is, independently, a moiety selected from the group consisting of:
—(CH 2 ) n —X;
—(CH 2 ) n —Y;
—CH 2 CH=CH 2 ;
CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 ;
CH 2 CO 2 CH 2 CH 3 ;
(OCH 2 CH 2 ) m —X;
—Y 2 C(Z 1 ) 3 ,
wherein: Z 1 is CH 2 OCH 2 (CH 2 ) n X or CH 2 OCH 2 (CH 2 ) n Y;
—(CH 2 ) n C(O)Y 2 C(Z 2 ) 3 ,
wherein: Z 2 is CH 2 OCH 2 CH 2 C(O)Y 2 C(Z 4 ) 3 , Z 4 is CH 2 OCH 2 CH 2 Z 5 , and Z 5 is CO 2 (CH 2 CH 2 O)m, —COOH; —CONR 2 ; —CONR′ 2 ; —OPO 3 H 2 ; —PO 3 H 2 ; —SO 3 H; —NH 2 ; NR′ 2 ; or —NR′ 3 + ;
—(CH 2 ) n OCH 2 C(CH 2 OH) 3 ;
—(CH 2 ) n OCH 2 CH(CH 2 OH) 2 ;
—(CH 2 ) n OCH 2 C(CH 2 OH) 2 (CH 3 );
—(CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 OH) 3 ] 3 ; and
—CH 2 ) n OCH 2 C[CH 2 OCH 2 C(CH 2 O[CH 2 CH 2 O] m CH 2 CH 2 OX) 3 ] 3 ,
wherein n is an integer from 1 to 10; m is an integer from 1 to 200;
X is —COOH; —CONH 2 ; —CONR′ 2 ; —OPO 3 H 2 ; —PO 3 H 2 ; —SO 3 H; —NH 2 ; —NR′ 2 ; or —NR′ 3 + , further wherein R′ is an alkyl group;
Y is —OH or —(O—CH 2 CH 2 ) m —W; where W is —OH, or —(O—(CH 2 CH 2 ) m ;
Y 2 is selected from the group consisting of—(CH 2 ) n O—, —(CH 2 ) n NH—, and (CH 2 ) n S; and
wherein the remaining R 1 , R 2 , R 3 , and R 4 are hydrogen;
M is selected from the group consisting of Mn, Fe, Ni and V, and
Ligand 1 and Ligand 2 are, independently, absent or selected from the group consisting of halide, oxo, aquo, hydroxo, and alcohol.
2. The complex of claim 1 , wherein at least two of R 1 , R 2 , R 3 , or R 4 include said moiety.
3. The complex of claim 1 , wherein at least three of R 1 , R 2 , R 3 , or R 4 include said moiety.
4. The complex of claim 1 , wherein four of R 1 , R 2 , R 3 , or R 4 include said moiety.
5. The complex of claim 4 , wherein the four moieties are identical.
6. The complex of claim 1 , wherein at least one of Ligand 1 and Ligand 2 is halide, and the remaining Ligand 1 or Ligand 2 is absent or aquo.
7. The complex of claim 1 , wherein at least one of Ligand 1 and Ligand 2 is chloride, and the remaining Ligand 1 or Ligand 2 is absent or aquo.
8. The complex of claim 1 , wherein said moiety is selected from the group consisting of CH 2 CHCH 2 , CH 2 CONH 2 , CH 2 CO 2 CH 2 CH 3 , and CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .
9. The complex of claim 1 , wherein said moiety is CH 2 CH=CH 2 .
10. The complex of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 is CH 2 CH=CH 2 .
11. The complex of claim 1 , wherein said moiety is (CH 2 ) n CONH 2 , wherein n is an integer from 1 to 6.
12. The complex of claim 1 , wherein said moiety is CH 2 CONH 2 .
13. The complex of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 is CH 2 CONH 2 .
14. The complex of claim 1 , wherein said moiety is (CH 2 ) m CO 2 CH 2 CH 3 , m =1 to 100.
15. The complex of claim 1 , wherein said moiety is CH 2 CO 2 CH 2 CH 3 .
16. The complex of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 is CH 2 CO 2 CH 2 CH 3 .
17. The complex of claim 1 , wherein said moiety is CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .
18. The complex of claim 1 , wherein each of R 1 , R 2 , R 3 , and R 4 is CH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .
19. A pharmaceutical composition comprising the complex of claim 1 and a pharmaceutically acceptable carrier.
20. A complex having the formula:
or a pharmaceutically acceptable base or acid addition salt, hydrate, ester, solvate, prodrug, metabolite, stereoisomer, or mixtures thereof.
21. A pharmaceutical composition comprising the complex of claim 20 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 20 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 20 .
24. The method of claim 23 , 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.