Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-09-16
2001-04-10
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S183000, C514S184000, C540S473000, C540S474000
Reexamination Certificate
active
06214817
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
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 pentaazacyclopentadecane 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).
2O
2
−
+2H
+
→O
2
+H
2
O
2
(1)
Reactive oxygen metabolites derived from superoxide have been demonstrated to contribute to the tissue pathology in a number of 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 hypertension, 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 of nonhuman derived enzymes, and poor tissue distribution.
In an effort to overcome the problems associated with superoxide dismutase enzymes, several investigations have been made into the design of non-proteinaceous catalysts for the dismutation of superoxide, and their use in various superoxide-related ailments. One group of catalysts which has been shown to be nearly as effective catalysts as the native superoxide dismutase enzymes are the manganese and iron complexes of pentaazacyclopentadecane ligands, described in U.S. Pat. Nos. 5,610,293, 5,637,578, and 5,874,421. These ligands are described as a pentaazacyclopentadecane macrocycle with various substituents on the carbons of the macrocycle, or with cyclic or heterocyclic structures attached to the carbons of the macrocycle. These compounds have been shown to possess catalytic superoxide dismutating activity as well as anti-inflammatory activity and to prevent oxidative damage. In addition, these compounds have been shown to possess analgesic activity in the rat-paw carrageenan hyperalgesia model, U.S. application Ser. No. 09/057,831. Two such described analgesic SOD mimic compounds are Compound A and Compound B:
SUMMARY OF THE INVENTION
Applicants have found that, surprisingly, the addition of substituents to an unsaturated nitrogen-containing heterocyclic moiety on the pentaazacyclopentadecane macrocycle of the above complexes can drastically alter both the superoxide dismutase catalytic activity and increase the efficacy of these complexes as pharmaceutical agents. Applicants have found that compounds of the present invention comprising substituted, unsaturated, nitrogen-containing heterocyclic moieties unexpectedly exhibit a marked increase in potency for the prevention or reversal of opioid tolerance as compared to the previously disclosed complexes with unsubstituted nitrogen-containing heterocyclic moieties. In addition, these substituted, unsaturated, nitrogen-containing heterocyclic compounds are up to ten times more potent as pharmaceutical agents for anti-inflammatory and analgesic compositions and are as good as, or often better than, the parent unsubstituted compounds in applications such as the treatment of endotoxin-induced refractory hypotension. Thus, the compounds of the present invention demonstrate unanticipated improvements in characteristics important for pharmaceuticals over the previously described pentaazacyclopentadecane complexes with unsubstituted nitrogen-containing heterocyclic moieties.
The present invention is directed to low molecular weight catalysts for the dismutation of superoxide radicals (SOD mimics) useful as therapeutic agents for inflammatory disease states and disorders in which superoxide anions are implicated. The SOD mimics of the present invention are manganese or iron complexes of nitrogen-containing fifteen-membered macrocyclic ligands which comprise a substituted, unsaturated, nitrogen-containing heterocyclic moiety, most preferably those with cyclohexyl, hydroxyl alkyl thio, alkyl (2-thioacetic acid) ester, benzyloxy, methoxyarylthio, alkoxycarbonylarylthio, and aryl (2-thioacetic acid) ester substituents. Preferably, the nitrogen-containing heterocyclic moiety is aromatic, more preferably a pyridino moiety.
The present invention is also directed to the pentaazacyclopentadecane macrocycles which comprise a substituted, unsaturated, nitrogen-containing heterocyclic moiety which are precursor ligands of these complexes.
The present invention is also directed to methods of making the above SOD mimics, specifically, novel methods of modifying the substituents on the heterocyclic moiety after chelation with the transition metal ion.
The present invention is also directed towards pharmaceutical compositions comprising the SOD mimics of the present invention in amounts sufficient for the treatment or prevention of disease states or disorders.
In addition, the present invention is directed to methods of using these catalysts to treat various disease states and disorders in which superoxide anions are implicated.
Other objects and features will be in part apparent and in part pointed out hereinafter.
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Aston Karl W.
Fobian Yvette M.
Grapperhaus Margaret Lanahan
Henke Susan L.
Kusturin Carrie L.
Monsanto Company
Raymond Richard L.
Senniger Powers Leavitt & Roedel
Sripada Pavanaram K
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