Super-oxide dismutase mimetics

摘要

The present invention relates to compounds which are effective as catalysts for dismutating superoxide and, more particularly, the manganese or iron complexes of substituted, unsaturated heterocyclic 16-membered macrocyclic complexes that catalytically dismutate superoxide. It also relates to methods of using these complexes to reduce the concentration or the effects of superoxide, pharmaceutical compositions comprising these compounds or their metal complexes, and methods of treating conditions associated with excessive superoxide activity.

主权项

1. A method to treat a condition associated with excessive superoxide activity wherein the condition is selected from the group consisting of edema, vascular relaxation, osteoarthritis, rheumatoid arthritis, atherosclerosis, and inflammatory bowel disease, the method comprising administering to a patient in need of such treatment the compound of formula (1):wherein:
each R1 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, ═O, OR, S(O)tR, NR2, COOR, CONR2, wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group; each R2 is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one or more groups selected from halo, OR, S(O)tR, NR2, COOR, CONR2, wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl, and wherein two R groups on one N can cyclize to form a saturated azacyclic group; each R3 is H or a protecting group; wherein any two R1 on a single carbon can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted, and which can contain a heteroatom selected from N, O and S as a ring member; and any two R1 on adjacent carbon atoms, and any two R2 groups on adjacent carbon atoms, can cyclize to form a ring having 3-8 ring atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain a heteroatom selected from N, O and S as a ring member; and any two of R1 and R2 on carbon atoms separated by a single Nitrogen atom can cyclize to form a ring having 3-8 atoms, which ring can be substituted and can be aromatic or non-aromatic, and can contain, in addition to the N between the carbon atoms to which linked groups are attached, an additional heteroatom selected from N, O and S as a ring member; each m is independently 0 or 1; each n and p is independently 0-2; L represents a three-atom linker corresponding to —C(R1)p—NR3—C(R1)p— or an optionally substituted pyridine-2,6-diyl group; and M represents H or a metal cation; or a pharmaceutically acceptable salt thereof.