Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1993-05-17
1996-04-09
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
A61K 3119
Patent
active
055062660
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the control of free radical induced damage which arises from reperfusion injury to tissues and in particular to the control of heart damage.
BACKGROUND OF THE INVENTION
Damage to the fabric of the heart is one of the commonest causes of human morbidity and mortality. The most usual mode of treatment for patients who have suffered a myocardial infarction is simply the administration of thrombolytic agents. However, in reperfusion injury, although the tissue damage is dependent on the duration of anoxia, the damage is believed to be exacerbated by the sudden perfusion of oxygen leading to the generation of various free radical species. Although many studies have implicated the involvement of free radical species in the cellular damage observed in myocardial reperfusion injury as well as reperfusion injury to other tissues, their nature, source and location nevertheless remain controversial.
Investigations on isolated heart preparations with coronary artery ligation have shown that the incorporation of hydroxyl radical scavengers and desferrioxamine prior to reperfusion decreases the incidence of heart arrhythmias and other markers of radical-mediated damage on reperfusion, such work being discussed by Rice-Evans et al, Free Rad. Res. Comm., 1989, 7, 49. The role of desferrioxamine in limiting myocardial ischaemic/reperfusion injury has also been confirmed by Reddy et al, Free Rad. Biol. Med., 1989, 7, 45, using experiments in dogs.
DESCRIPTION OF THE INVENTION
We have now found, however, that certain other hydroxamate compounds exhibit a much superior effect to desferrioxamine in the control of heart damage resulting from free radical induced damage arising from reperfusion injury.
Accordingly the present invention comprises the use of a compound of formula (I) ##STR2## in which R and R' are each separately selected from aliphatic hydrocarbon groups, aryl groups and aliphatic hydrocarbon groups substituted by an aryl group, in the manufacture of a medicament, for the control of free radical induced damage arising from reperfusion injury in tissue.
Certain compounds of formula (I) are described for use as intermediates for the preparation of herbicidal compounds as described in U.S. Pat. No. 4,507,148. U.S. Pat. No. 4,604,407 discloses novel hydroxamate compounds, including compounds of formula (I), which inhibit the enzyme lipoxygenase and as such are useful as anti-allergy agents. European Patent Application 0 365 210 discloses hydroxamic acid derivatives, including in particular compounds of formula (I) in which R is methyl, n-propyl or phenyl and R' is undecyl, which are also lipoxygenase inhibitors and indicated to be useful in the treatment of bronchial asthma, allergies, inflammatory diseases and ischaemic heart disorders. European Patent Application 0 273 451 discloses hydroxamate compounds, including compounds of formula (I), which are also lipoxygenase inhibitors, and are indicated to prevent the formation of certain mediators which are implicated in certain inflammatory and allergic disease states. Inhibition of lipoxygenase and prevention of the formation of such mediators as a result alleviates the inflammatory and allergic conditions resulting therefrom.
However, we are not aware of any previous indication in the literature of the compounds of formula (I) being used in the treatment and prevention of reperfusion injury.
As indicated, the compounds (I) contain groups R and R' which are separately selected from aliphatic hydrocarbon groups, aryl groups and aliphatic hydrocarbon groups substituted by an aryl group. The term aliphatic hydrocarbon group is used herein in relation to both the unsubstituted and the substituted groups to include both acyclic and cyclic groups which may be unsaturated or saturated, the acyclic groups having a branched chain or especially a straight chain. Preferred unsubstituted groups are those of up to 8, 10 or 12 carbon atoms, particularly of 1 to 6 carbon atoms for the acyclic groups and 3 to 6 carbon atoms for the cyclic groups, for e
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patent: 5187192 (1993-02-01), Brooks et al.
C. Rice-Evans et al "The Suppression of Iron Release . . . " Free Radical Res. Commun. vol. 7 No. 1, 1989 Harwood-Acad. Pub. (GB), pp. 45-54.
B. Ramesh Reddy et al "Early Treatment with Deferoxamine . . . " Free Radical Biol. & Medicine vol. 7 No. 1, 1989, Pergamon Press (US), pp. 45-52.
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Davies Michael J.
Rice-Evans Catherine A.
British Technology Group Limited
Henley III Raymond
Weddington Kevin E.
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