Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1993-01-14
2001-03-20
Moezie, Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S185000, C514S186000
Reexamination Certificate
active
06204259
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(II) or manganese(III) complexes of nitrogen-containing sixteen-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
{dot over (−)}+O
2
{dot over (−)}+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, 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).
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
The present invention is directed to low molecular weight mimics of superoxide dismutase (SOD) useful as therapeutic agents for inflammatory disease states and disorders which are mediated, at least in part, by superoxide. The SOD mimics of the present invention are manganese(II) or manganese(III) complexes of nitrogen-containing sixteen-membered macrocyclic ligands.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to manganese(II) or manganese(III) complexes of nitrogen-containing sixteen-membered macrocyclic ligands which catalyze the conversion of superoxide into oxygen and hydrogen peroxide. These complexes can be represented by the formula:
wherein R, R′, R
1
, R′
1
, R
2
, R′
2
, R
3
, R′
3
, R
4
, R′
4
, R
5
, R′
5
, R
6
, R′
6
, R
7
, R′
7
, R
8
, R′
8
, R
9
, R′
10
, R
10
and R′
10
independently represents hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, alkylcycloalkyl, alkylcycloalkenyl, alkenylcycloalkyl, alkenylcycloalkenyl, heterocyclic, aryl and aralkyl radicals; R
1
or R′
1
and R
2
or R′
2
, R
3
or R′
3
and R
4
or R′
4
, R
3
or R′
3
and R
5
or R′
5
, R
4
or R′
4
and R or R′
5
, R
6
or R′
6
and R
7
or R′
7
, R
8
or R′
8
and R
9
or R′
9
, and R
10
or R′
10
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; R or R′ and R
1
or R′
1
, R
2
or R′
2
and R
3
or R′
3
or R
4
or R′
4
, R
4
or R′
4
or R 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
10
or R′
10
together with the carbon atoms to which they are attached independently form a nitrogen containing heterocycle having 2 to 20 carbon atoms provided that when the nitrogen containing heterocycle is an aromatic heterocycle which does not contain a hydrogen attached to the nitrogen, the hydrogen attached to the nitrogen as shown in the above formula, which nitrogen is also in the macrocyclic ligand or complex, and the R groups attached to the same carbon atoms of the macrocycle are absent; R and R′, R
1
and R′
1
, R
2
and R′
2
, R
3
and R′
3
, R
4
and R′
4
, R and R′
5
, R
6
and R′
6
, R
7
and R′
7
, R
8
and R′
8
, R
9
and R′
9
, and R
10
and R′
10
together with the carbon atom to which they are attached independently form a saturated, partially saturated, or unsaturated ring structure having 3 to 20 carbon atoms; and one of R, R′, R
1
, R′
1
, R
2
, R′
2
, R
3
, R′
3
, R
4
, R′
4
, R
5
, R′
5
, R
6
, R′
6
, R
7
, R′
7
, R
8
, R′
8
, R
9
, R′
9
, R
10
and R′
10
together with a different one of R, R′, R
1
, R′
1
, R
2
, R′
2
, R
3
, R′
3
, R
4
, R′
4
, R
5
, R′
5
, R
6
, R′
6
, R
7
, R′
7
, R
8
, R′
8
, R
9
, R′
9
, R
10
and R′
10
which is attached to a different carbon atom in the macrocyclic ligand may be bound to form a strap represented by the formula
&Parenopenst;CH
2
&Parenclosest;
x
M&Parenopenst;CH
2
&Parenclosest;
w
L&Parenopenst;CH
2
&Parenclosest;J&Parenclosest;CH
2
&Parenclosest;
y
wherein w, x, y and z independently are integers from 0 to 10 and M, L and J are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, alkaryl, alkheteroaryl, aza, amide, ammonium, oxa, thia, sulfonyl, sulfinyl, sulfonamide, phosphoryl, phosphinyl, phosphino, phosphonium, keto, ester, carbamate, urea, thiocarbonyl, borates, boranes, boraza, silyl, siloxy, silaza and combinations thereof; and combinations thereof. Thus, the complexes of the present invention can have any combinations of R groups, saturated, partially saturated or unsaturated cyclics, nitrogen containing heterocycles, saturated, partially saturated or unsaturated ring structures and straps as defined above.
The “R” groups attached to the carbon atoms of the macrocycle can be in the axial or equatorial position relative to the macrocycle. When the “R” group is other than hydrogen or when two adjacent “R” groups, i.e., on adjacent carbon atoms, together with the carbon atoms to which they are attached form a saturated, partially saturated or unsaturated cyclic or a nitrogen containing heterocycle, or when two R groups on the same carbon atom together with the carbon atom to which they are attached form a saturated, partially saturated or unsaturated ring structure, it is preferred that at least some of the “R” groups are in the equatorial position for reasons of improved activity and stability. This is particularly true when the complex contains more than one “R” group which is not hydrogen.
X, Y and Z represent suitable ligands or charge-neutralizing anions which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). X, Y and Z are independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxyge
Aston Karl W.
Lennon Patrick J.
Modak Anil S.
Neumann William L.
Riley Dennis P.
Moezie Minna
Monsanto Company
Senniger Powers Leavitt & Roedel
Wang S.
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