Manganese or iron complexes of nitrogen-containing...

Details Manganese or iron complexes of nitrogen-containing... Manganese or iron complexes of nitrogen-containing...

1996-03-14

2003-02-25

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S185000, C540S465000

Reexamination Certificate

active

06525041

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compounds effective as catalysts for dismutating superoxide and, more particularly, relates to manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalytically dismutate superoxide.
2. Related Art
The enzyme superoxide dismutase catalyzes the conversion of superoxide into oxygen and hydrogen peroxide according to equation (1) (hereinafter referred to as dismutation). Reactive oxygen metabolites derived from superoxide are postulated to contribute to the tissue pathology in a number of
O
2
−+O
2
−+2H+→O
2
+H
2
O
2
  (1)
inflammatory diseases and disorders, such as reperfusion injury to the ischemic myocardium, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, atherosclerosis, hypertension, metastasis, psoriasis, organ transplant rejections, radiation-induced injury, asthma, influenza, stroke, burns and trauma. See, for example, Bulkley, G. B., Reactive oxygen metabolites and reperfusion injury: aberrant triggering of reticuloendothelial function,
The Lancet
, Vol. 344, pp. 934-36, Oct. 1, 1994; Grisham, M. B., Oxidants and free radicals in inflammatory bowel disease,
The Lancet
, Vol. 344, pp. 859-861, Sep. 24, 1994; Cross, C. E. et al., Reactive oxygen species and the lung,
The Lancet
, Vol. 344, pp. 930-33, Oct. 1, 1994; Jenner, P., Oxidative damage in neurodegenerative disease,
The Lancet
, Vol. 344, pp. 796-798, Sep. 17, 1994; Cerutti, P. A., Oxy-radicals and cancer,
The Lancet
, Vol. 344, pp. 862-863, Sep. 24, 1994 Simic, M. G., et al, Oxygen Radicals in Biology and Medicine, Basic Life Sciences, Vol. 49, Plenum Press, New York and London, 1988; Weiss J. Cell. Biochem., 1991 Suppl. 15C, 216 Abstract C110 (1991); Petkau, A., Cancer Treat. Rev. 13, 17 (1986); McCord, J. Free Radicals Biol. Med., 2, 307 (1986); and Bannister, J. V. et al, Crit. Rev. Biochem., 22, 111 (1987). The above-identified references from
The Lancet
teach the nexus between free radicals derived from superoxide and a variety of diseases. In particular, the Bulkley and Grisham references specifically teach that there is a nexus between the dismutation of superoxide and the final disease treatment.
It is also known that superoxide is involved in the breakdown of endothelium-derived vascular relaxing factor (EDRF), which has been identified as nitric oxide (NO), and that EDRF is protected from breakdown by superoxide dismutase. This suggests a central role for activated oxygen species derived from superoxide in the pathogenesis of vasospasm, thrombosis and atherosclerosis. See, for example, Gryglewski, R. J. et al., “Superoxide Anion is Involved in the Breakdown of Endothelium-derived Vascular Relaxing Factor”,
Nature
, Vol. 320, pp. 454-56 (1986) and Palmer, R. M. J. et al., “Nitric Oxide Release Accounts for the Biological Activity of Endothelium Derived Relaxing Factor”,
Nature
, Vol. 327, pp. 523-26 (1987).
Clinical trials and animal studies with natural, recombinant and modified superoxide dismutase enzymes have been completed or are ongoing to demonstrate the therapeutic efficacy of reducing superoxide levels in the disease states noted above. However, numerous problems have arisen with the use of the enzymes as potential therapeutic agents, including lack of oral activity, short half-lives in vivo, immunogenicity with nonhuman derived enzymes, and poor tissue distribution.
SUMMARY OF THE INVENTION
It is an object of the invention to provide manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands that are low molecular weight mimics of superoxide dismutase (SOD) which are useful as therapeutic agents for inflammatory disease states or disorders which are mediated, at least in part, by superoxide. It is a further object of the invention to provide manganese (II) or iron (III) complexes of nitrogen-containing fifteen-membered macrocyclic ligands which are useful as magnetic resonance imaging (MRI) contrast agents having improved kinetic stability, improved oxidative stability and improved hydrogen bonding. It is yet a further object of the invention to provide MRI contrast agents in which the biodistribution of the contrast agents can be controlled.
According to the invention, manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands are provided in which at least one adjacent pair of carbon atoms in the macrocyclic ligand are substituted with alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radicals wherein at least one of the substituents on the adjacent carbons is substituted with —OR
10
, —NR
10
R
11
, —COR
10
, —CO
2
R
10
, —CONR
10
R
11
, —O—(—(CH
2
)
a
—O)
b
—R
10
, —SR
10
, —SOR
10
, —SO
2
R
10
, —SO
2
NR
10
R
11
, —N(OR
10
)(R
11
), —P(O)(OR
10
)(OR
11
), —P(O)(OR
10
)(R
11
) and —OP(O)(OR
10
)(OR
11
) wherein R
10
and R
11
are independently selected from hydrogen or alkyl groups, and a and b are integers independently selected from 1 to 6.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which catalyze the conversion of superoxide into oxygen and hydrogen peroxide. These complexes can be represented by the formula:
wherein at least one pair of “R” groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R
9
or R′
9
and R or R′, R
1
or R′
1
and R
2
or R′
2
, R
3
or R′
3
and R
4
or R′
4
, R
5
or R′
5
and R
6
or R′
6
, and R
7
or R′
7
and R
8
or R′
8
are substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radicals wherein the substituents are independently selected from the group consisting of —OR
10
, —NR
10
R
11
, —COR
10
, —CO
2
R
10
, —CONR
10
R
11
, —O—(—(CH
2
)
a
—O)
b
—R
10
, —SR
10
, —SOR
10
, —SO
2
R
10
, —SO
2
NR
10
R
11
, —N(OR
10
)(R
11
), —P(O)(OR
10
)(OR
11
), —P(O)(OR
10
)(R
11
) and —OP(O)(OR
10
)(OR
11
); or at least one pair of “R” groups on adjacent carbon atoms of the macrocycle selected from the group consisting of R
9
or R′
9
and R or R′, R
1
or R′
1
and R
2
or R′
2
, R
3
or R′
3
and R
4
or R′
4
, R
5
or R′
5
and R
6
or R′
6
, and R
7
or R′
7
and R
8
or R′
8
are independently selected wherein one “R” group of the pair is an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl radical and the other “R” group on the adjacent carbon atom of the macrocycle is a substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cycloalkyl or substituted cycloalkenyl radical wherein the substituents are independently selected from the group consisting of —OR
10
, —NR
10
R
11
, —COR
10
, —CO
2
R
10
, —CONR
10
R
11
, —O—(—(CH
2
)
a
—O)
b
—R
10
, —SR
10
, —SOR
10
, —SO
2
R
10
, —SO
2
NR
10
R
11
, —N(OR
10
)(R
11
), —P(O)(OR
10
)(OR
11
), —P(O)(OR
10
)(R
11
) and —OP(O)(OR
10
)(OR
11
); or combinations thereof; wherein R
10
and R
11
are independently selected from the group consisting of hydrogen and alkyl groups, and a and b are integers independently selected from 1 to 6; and the remaining “R” groups are hydrogen or, optionally, are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkenylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals and radicals attached to the &agr;-carbon of &agr;-amino acids; or R
1
or R′
1
and R
2
or R′
2
, R
3
or R′
3
and R
4
or R′
4
, R
5
or R′
5
and R
6
or R′
6
, R
7
or R′
7
and R
8
or R′
8
, and R
9
or R′
9
and R or R′ together with the carbon atoms to which they are attached independently form a saturated, partially saturated or unsaturated cyclic having 3 to 20 carbon atoms; or R or R′

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