Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-05
2002-09-10
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S316000, C514S423000, C514S424000, C514S212010, C546S188000, C546S216000, C546S219000, C546S242000, C548S537000, C548S542000, C540S604000
Reexamination Certificate
active
06448267
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a 371 of PCT/GB99/00231, filed Jan. 22, 1999, which claims the benefit of United Kingdom 9801398.0, filed Jan. 22, 1998, the disclosures of which are incorporated herein by reference in their entirety.
The present invention relates to compounds capable of acting both as sources of nitric oxide (NO-donors) and as scavengers of superoxide ion (O
2
−
) (superoxide dismutase (SOD)-mimetic).
Many disease states, including diabetes mellitus and various cardiovascular diseases, are associated with oxidative stress and endothelial dysfunction. In particular, endothelial dysfunction is the hallmark of the pathophysiological process (atherosclerosis) leading to a spectrum of clinically related diseases of the cardiovascular system (e.g. from stable angina pectoris to myocardial infarction (MI) and congestive heart failure), as well as being the primary event in pathologies relating to other body systems involving superoxide and/or other reactive oxygen species (ROS).
For over a century, nitroglycerin (GTN) has been the drug of choice for the treatment of various types of myocardial ischemia (angina), including myocardial infarction, and a mainstay in the treatment of other heart diseases with and without ischemic etiology (congestive heart failure, isolated systolic and resistant hypertension). Because of its pathogenic nature (chronicity with acute exacerbation), prophylactic and acute treatments are necessary to prevent complications with potentially fatal outcomes (>25% death for acute MI).
However, the phenomenon of tolerance to the anti-anginal effects of GTN and to all other existing organic nitrates is of a special clinical significance. In particular, early development of tolerance to the drug is by far the most serious drawback of nitrate therapy, especially during acute myocardial infarction.
Evidence has been provided to support an involvement of the superoxide anion in the mechanism/s underlying nitrate tolerance and cross-tolerance (Munzel et al., J. Clin. Invest. 95, 187-194 (1995)). According to this report, increased levels of superoxide anion were found to accompany tolerance development to GTN in vascular tissue after in vivo administration of the drug. Treatment with superoxide dismutase (SOD) significantly enhanced maximal relaxation of control and tolerant vascular tissue to GTN and other exogenous and endogenous vasodilators. This can be explained on the basis of an enhancing effect of superoxide on the induction of tolerance (pseudo-tolerance). It is believed that if the normally tightly controlled balance between nitric oxide (NO) and superoxide (O
2
−
) in the vascular wall is disturbed, elevated levels of superoxide anion prevail, inactivating NO and furthermore generating toxic peroxynitrite. The protective effect of superoxide dismutase against nitrate tolerance has been demonstrated in vitro (Jia et al., J. Pharmacol. Exp. Ther., 267,371-378 (1993) and Kowaluk et al., J. Pharmacol. Exp. Ther., 255, 109-144 (1990)). However, being an enzyme, SOD is practically cell impermeable and cannot therefore be used therapeutically. There remains therefore a need for a nitrate-based therapy which does not suffer from the problem of nitrate tolerance.
According to the present invention there is provided a chemical compound comprising a nitric oxide (NO) donor and a superoxide (O
2
−
) scavenger.
The nitric oxide donor may comprise any group capable of acting as a source of nitric oxide (NO). Preferably, the nitric oxide donor is an —ONO
2
group. The superoxide scavenger may comprise any group capable of acting as a scavenger of superoxide (O
2
−
). Preferably, the superoxide scavenger is a nitroxide free radical (N→O.) group.
The compounds of the present invention may comprise one or more NO donors and one or more superoxide scavengers.
The compounds of the present invention not only provide a source of nitric oxide but in acting as an antioxidant scavenger of superoxide anion give rise to both a direct benefit derived from removal of injurious superoxide anion and a benefit in protecting both ambient and endogenous and liberated exogenous NO from inactivation by superoxide anion.
Without prejudice to the scope of the present invention, it is believed that oxidative damage is mediated by intracellular redox-active metal reactions catalyzed by highly reactive oxygen species (i.e. hydroxyl radicals). The generation of such reactive oxygen products depends on the availability of their common precursor, the superoxide anion. Mitochondria, microsomes and other various enzyme systems are known to produce superoxide anion that reacts with nitric oxide at or near diffusion controlled rates to form the powerful oxidant peroxynitrite. At pH 7.4, peroxynitrite protonates to form peroxynitrous acid (pKa 6.6) which decays homolytically to form hydroxyl and nitrogen dioxide radicals in addition to a host of other ions. The extent to which these later reactive ions and radicals can cause cellular damage and death depends on the rate of formation of their peroxynitrite precursor. Under control (non-diseased) conditions, where the levels of NO are found in equilibrium between rates of NO-synthesis and degradation, the rate of formation of this peroxynitrite precursor is thought to depend solely on the levels of the superoxide anion. This is particularly important in cases involving “below-normal” levels of “biologically active” NO, such as in diseases for which therapeutic intervention with exogenous NO-donors is clinically indicated. Consequently, the extra- and intra-cellular activity of the enzyme SOD must have a cardinal role in maintaining cellular survival, tissue integrity and adequately balanced physiological function.
Since superoxide anion is an available and continuously-formed by-product generated through normal metabolic processes, and since its elimination is mediated either by dismutation by the enzyme SOD or via its reaction with NO to form the potentially hazardous peroxynitrite, it is now believed that the ultimate means by which a modification and/or treatment of ‘pathological processes’ involving imbalanced ratio of NO to superoxide is by an intervention with therapeutic agents capable of simultaneously and favourably affecting both components; the NO and O
2
−
.
By virtue of the NO donor and superoxide scavenging activities being physically linked in the same molecule, the compounds of the present invention ensure that an increase in the level of NO is accompanied by reduced levels of superoxide thereby avoiding high levels of peroxynitrite and oxidant metabolites thereof. Preferred compounds according to the present invention are of the formula:
Preferred compounds according to the present invention are of the formula:
wherein
R
1
may be the same or different and are independently selected from hydrogen, alkoyl, alkoxy, carboxy, hydroxy, amino, amido, cyano, nitro, thio, sulphonyl, sulphoxide, alkyl groups and groups comprising an NO-donor, provided that at least one R
1
is a group comprising an NO-donor group;
R
2
may the same or different and are independently selected from alkyl groups;
n is an integer 1, 2 or 3;
or a salt thereof
The groups R
1
may be the same or different and are independently selected from hydrogen, alkoyl, alkoxy, carboxy, hydroxy, amino, amido, cyano, nitro, thio, sulphonyl, sulphoxide, alkyl groups and groups comprising an NO-donor group, provided that at least one R
1
is a group comprising an NO-donor. R
1
groups which do not comprise an NO-donor group are preferably hydrogen or alkyl groups. The or each R
1
group comprising an NO-donor group may comprise one or more NO-donor groups. Preferably, the or each NO-donor group is an —ONO
2
group.
The or each R
1
group comprising an NO-donor group may comprise an NO-donor group alone or may comprise an NO-donor group linked via a C
1
to C
20
alkylene chain optionally comprising one or more heteroatoms. The alkylene chain may be branched or unbranched, cyclic or acyclic, saturated or un
Anggard Erik Emil
Haj-Yehia Abdullah Ibrahim
Huang Evelyn Mei
Morrison & Foerster / LLP
Oxon Medica Inc.
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