Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-04-17
1996-11-12
Dentz, Bernard
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
549336, 568650, C07D30779
Patent
active
055741789
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP93/01489 filed Oct. 18, 1993 and published as WO94/08930 Apr. 28, 1994.
TECHNICAL FIELD
This invention relates to compounds for preventing the oxidative modification of LDL, particularly, to compounds useful as therapeutics of arteriosclerosis, myocardial infarction and other ischemic diseases. More specifically, the invention relates to compounds represented by the following general formula (I), as well as compounds represented by the general formula (II) which are useful intermediates for the synthesis of compounds (I): ##STR2## (where R.sup.1 is a hydrogen atom or an acyl group; R.sup.2 is a lower alkyl group; R.sup.3 is a hydrogen atom or a lower alkyl group; R.sup.4, R.sup.5 and R.sup.6, which may be the same or different, are a hydrogen atom or an optionally substituted alkyl, alkenyl, alkynyl or aryl group; R.sup.2 and R.sup.4, when taken together, may form a 5-membered ring; R.sup.5 and R.sup.6, when taken together, may form a cycloalkyl group or a heterocyclic group in which at least one methylene on the ring of a cycloalkyl group is substituted by an oxygen atom, a sulfur atom or an alkyl-substituted nitrogen atom, provided that R.sup.6 is not present if the ring formed by R.sup.2 and R.sup.4 taken together is a benzofuran ring); ##STR3## (where R.sup.3 has the same meaning as defined above; A is a protective group; R.sup.a is a hydrogen atom or a lower alkyl group; and m is an integer of 0 or 1).
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
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Cynshi Osamu
Kato Yoshiaki
Ohba Yasuhiro
Tamura Kunio
Yoshida Mitsutaka
Chugai Seiyaku Kabushiki Kaisha
Dentz Bernard
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