Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-09
2000-03-21
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514369, A61K 31425
Patent
active
060403225
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of thiazolidine derivatives for ameliorating endothelial cell activation.
European patent no. 0139421 describes thiazolidine derivatives of formula (I): ##STR1## in which: R.sup.1 and R.sup.2 are the same or different and each represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl group; group, a (C.sub.5 -C.sub.7 cycloalkane) carbonyl group, an aromatic acyl group which is a benzoyl or naphthoyl group optionally with one or more nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy substituents, a heterocyclic acyl group having one or more oxygen, sulphur or nitrogen hetero atoms and with 4 to 7 ring atoms, an optionally halo-substituted phenylacetyl or phenylpropionyl group, a cinnamoyl group, a (C.sub.1 -C.sub.6 alkoxy) carbonyl group or a benzoyloxycarbonyl group; hydrogen atom, a C.sub.1 -C.sub.5 alkyl group or a C.sub.1 -C.sub.5 alkoxy group, or R.sup.4 and R.sup.5 together represent a C.sub.1 -C.sub.4 alkylenedioxy group; represents any one of the atoms or groups defined for R.sup.3 and may be the same as or different from R.sup.3); and imino (.dbd.NH) group;
The compounds are said to show blood lipid metabolism ameliorating activity and to have the ability to decrease the levels of blood lipid peroxides, blood triglycerides and blood cholesterol.
International patent application publication no. WO94/19347 describes the ability of compounds of formula (I) to inhibit the oxidation and/or peroxidation of low density lipoprotein (LDL)and suggest that the compounds may therefore have utility in the treatment of arteriosclerosis.
We have now surprisingly found that compounds of formula (I) reduce the activation of endothelial cells and are therefore useful in the treatment of disorders associated with endothelial cell activation.
The vascular endothelium maintains a non-thrombogenic surface on the inside of blood vessels, regulates the growth and differentiation of underlying tissues and plays a pivotal role in controlling trafficking of leukocytes in inflammatory conditions. Perturbations in endothelial functioning are implicated in many diseases, including atherosclerotic and inflammatory diseases.
Activation of the endothelial cell in post-capillary venules leads to increased expression of adhesion molecules and consequent recruitment of blood leukocytes into adventitial tissue. Whilst this is a necessary step in the physiological defence mechanisms to foreign bodies, inappropriate endothelial cell activation is implicated in pathological inflammatory states.
The activation state of endothelial cells is at least in part determined by the effect of so-called inflammatory mediators, such as TNF.alpha., interieukin-1. These agents are secreted by inflammatory cells, and cause activation of endothelial cells. A typical response of endothelial cells to such activation is to increase expression of adhesion molecules on the cell surface which allows recruitment of blood leukocytes to sites of inflammation. Therefore the level of adhesion molecules on the surface of endothelial cells can be taken as a measure of activation of the cells under inflammatory stimulus.
Such endothelial cell activation is also thought to be the initiating event for atherosclerotic cardiovascular disease. These arterial plaques contain macrophages and lymphocytes recruited from plasma by adhesion molecules on the endothelial cell surface. The macrophages in particular have been implicated in the acute symptoms (such as angina pectoris, myocardial infarction) associated with atherosclerotic plaques.
In a first aspect, the present invention provides the use of a compound of formula (I): ##STR2## in which: R.sup.1 and R.sup.2 are the same or different and each represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl group; group, a (C.sub.5 -C.sub.7 cycloalkane) carbonyl group, an aromatic acyl group which is a benzoyl or naphthoyl group optionally with one or more nitro, amino, alkylamino, dialkylamino, alkoxy, halo, alkyl or hydroxy substituents, a heterocydic acyl group having
REFERENCES:
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Law: "Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia", J. Clin. Invest., vol. 98, No. 8, Oct. 15, 1996, pp. 1897-1905.
Pober: "Cytokine-mediated activation of vascular endothelium", Am. J. Pathol., vol. 133, No. 8, 1988, pp. 426-433.
Brink Robert H.
Glaxo Wellcome Inc.
Henley III Raymond
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