Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-11-08
2000-12-05
Powers, Fiona T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514469, A61K 31352
Patent
active
061567930
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to prophylactic/therapeutic agents for atherosclerosis or xanthomatosis, more specifically, prophylactic/therapeutic agents for atherosclerosis or xanthomatosis containing a 2,6-di-t-butylphenol derivative as an active ingredient.
PRIOR ART
Oxidative denaturation of low-density lipoprotein (LDL) has been known as one of important causes of the development and progress of atherosclerosis and xanthomatosis (Steinberg, D., Parthasarathy, S., Carew, T. E., Khoo, J. C. & Witztum, J. L. Beyond Cholesterol; Modifications of low-density lipoprotein that increase its atherogenicity. N. Engl. J. Med. 320; 915-924, 1989). However, reports have shown that probucol which is an antioxidant has no therapeutic effect on atherosclerosis in clinical tests (Walldius, G., Erikson, U., Olsson, A., Bergstrand, L., Hadell, K., Johansson, J., Kaijser, L., Lassvik, C., Molgaard, J., Nilsson, S., Elinder, L. S., Stenport, G. & Holme, I. The effect of probucol on femoral atheroscleroses: the Probucol Quantitative Regression Swedish Trial (PQRST). Am. J. Cardiol. 84, 875-883, 1994).
As to therapy of atherosclerosis, HMGCoA reductase inhibitor which is an antihyperlipidemic agent has so far been reported to inhibit the progress of atherosclerosis (Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383-1389, 1994). However, patients to be treated with the antihyperlipidemic agent are limited to hyperlipidemic patients, and the antihyperlipidemic agent is ineffective for atherosclerosis in the patients with familial hyperlipidemia. An antihyperlipidemic agent is considered to reduce the amount of LDL exposed to oxidative modification, thus showing an antiatherosclerotic effect.
On the other hand, antioxidants capable of directly preventing oxidation of LDL are expected as prophylactic/therapeutic agents for atherosclerosis, but any drugs including the above-mentioned probucol have not been found to have a clinically sufficient effect as a prophylactic/therapeutic agent for atheroscloerosis at present.
An object of the present invention is to provide a novel prophylactic/therapeutic agent for atherosclerosis having a clinically sufficient effect.
DISCLOSURE OF THE INVENTION
As a result of extensive research to solve the above problems, we found that compounds of general formula (1): ##STR2## wherein R.sup.1 represents a hydrogen atom, an acyl group or an arylalkoxycarbonyl group, represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group, or dihydrofuran ring, or heterosubstituted cycloalkyl group in which one or more methylene groups of the cycloalkyl group are replaced by oxygen, sulfur or alkyl-substituted nitrogen atoms, provided that R.sub.6 is absent when R.sup.2 and R.sup.4 together with the oxygen atom form a furan ring have a potent inhibitory effect against atherosclerosis in rabbit atherosclerosis models and murine atherosclerosis models as well as a potent inhibitory effect against xanthomas in murine xanthoma models.
Compounds of general formula (1) have been shown in JPA No. 6-206842/94. The publication contains the antioxidative date of the compounds demonstrating that they are useful as therapeutic agents for atherosclerosis, myocardial infarction and other diseases as well as are effective as antioxidants for ischemic organ disorders such as atherosclerosis, myocardial infarction, cerebral apoplexy, etc., but does not contain any test examples in which models are employed.
MOST PREFERRED EMBODIMENTS OF THE INVENTION
For the definition of R.sup.1 in general formula (1), the acyl group preferably contains 1 to 10 carbon atoms, the examples of which include acetyl, formyl, propionyl and benzoyl groups. The arylalkoxycarbonyl group preferably contains 7
REFERENCES:
patent: 5789436 (1998-08-01), Kato et al.
Stephens, Nigel G. et al., "Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)." The Lancet, vol. 347, pp. 781-786 (1996).
Pratico, Domenico et al., "Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice.", Nature Medicine, vol. 4, No. 10, pp. 1189-1192 (1998).
Bird, David A. et al., "Effect of probucol on LDL oxidation and atherosclerosis in LDL receptor-deficient mice.", Journal of Lipid Research, vol. 39, pp. 1079-1090 (1998).
Zhang, Sunny H. et al., "Paradoxical enhancement of atherosclerosis by Probucol Treatment in Apolipoprotein E-deficient mice.", Journal of Clinical Investigation, vol. 99, No. 12, pp. 2858-2866 (1997).
Abstract in English corresponding to document AG, Jul. 1997.
Abstract in English corresponding to document AF, Mar. 1998.
Japanese Abstract for JP-58-131917, Aug. 1993.
Chugai Seiyaku Kabushiki Kaisha
Powers Fiona T.
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