4,6 Di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene

Details 4,6 Di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene 4,6 Di-t-butyl-5-hydroxy-2,3-dihydrobenzothiophene

1996-10-09

1998-08-04

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549 51, 549 52, 549 53, 549 54, 549 59, 549 60, 564162, A61K 3138, C07D33352, C07D33364, C07C32100

Patent

active

057894361

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP95/00706 filed Apr. 11, 1995.
1. Technical Field
This invention relates to compounds which prevent the oxidative modification of LDL, more particularly, to compounds useful as therapeutics of arteriosclerosis, myocardial infarction, etc.
2. Background Art
Atherosclerosis is one of the principal causes of ischemic diseases such as angina pectoris, myocardial infarction and cerebral apoplexy. The mechanism of initiation and progression of atherosclerosis is closely related to the oxidative modification of LDL. The modified LDLs are not recognized by the LDL receptor but by the scavenger receptor, to induce the foam cell formation which is characterized by cholesterol accumulation.
The modification of LDL is caused by endothelial cells, smooth muscle cells, macrophages, etc. and the modified LDLs are eventually taken by macrophages via the scavenger or other pathways. It is additionally known that the modification of LDL by these cells is similar to the oxidative modification of LDL by Cu.sup.2+.
LDL is chiefly composed of cholesterol esters, phospholipids and apo-B-100. The oxidative modification of LDL is shown from various aspects, for example fragmentation of apo-B-100 by the generated radicals, the reaction between the lipid peroxidation products and the free amino groups in apo-B-100 lysine residues, and the transformation of phosphatidyl choline to a lyso-form. One of the most established phenomena in LDL oxidation is an increase of thiobarbituric acid reactive substances (TBARS) as a result of the lipid peroxidation. Oxidized LDL, or LDL that has undergone such oxidative modification, causes the foam cell formation and the cholesterol accumulation by the scavenger and other pathways.
Under these circumstances, it is expected that compounds having the inhibitory action on lipid peroxidation can inhibit the initiation and progression of atherogenic lesions by preventing the oxidative modification of LDL and, hence, have the potential to work as therapeutics of arteriosclerosis.
In ischemic diseases such as cerebral apoplexy and myocardial infarction, various active oxygen species are generated during blood reperfusion at ischemic sites and tissue disorders can be exacerbated by the disruption of cell membranes and other effects caused by the lipid peroxidation. It is expected that compounds having the anti-oxidative activity can prevent the tissue disorders in ischemic lesions by removing the various active oxygen species and lipid peroxidation and, hence, have the potential to work as therapeutics of ischemic diseases.
Vitamin E is known as a natural antioxidant and studies have been made to develop synthetic antioxidants using vitamin E as the basic skeleton but no completely satisfactory products have yet been synthesized.
Some of the compounds of the present invention which are represented by formula (I) shown below are described, by their generic concept, in British Patent Publication GB 2224028, but the publication has no mention of antioxidant activity and applicability as therapeutics of arteriosclerosis.


DISCLOSURE OF THE INVENTION

An object of the present invention is to provide antioxidants useful for the treatment of arteriosclerosis and other ischemic diseases such as myocardial infarction and cerebral apoplexy, as well as intermediates useful for preparing said compounds.
The inventors of the present invention thought that the reason for the insufficient efficacy of conventional antioxidants, such as the compounds disclosed in Japanese Patent Publication Laid-Open No. 121975/90, is that their activity is lost before they reach the target site. Because they easily react with various free radical species besides lipid peroxidation related radicals. Based on this assumption, the inventors have conducted extensive investigations for the purpose of developing efficient antioxidants having higher reaction specificity. It has been found as a result that the above object is accomplished by the compounds represented by formula (I): ##STR2## wherein R.sub.1 repr

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