Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-05-19
1995-10-31
Haley, Jacqueline
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514535, 514568, 5483425, 560 34, 562439, A61K 31415, A61K 31195, C07C27534, C07D23360
Patent
active
054629586
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage Application of PCT/JP93/00961,filed Jul. 12, 1993 and published on Feb. 3, 1994 as WO/94/02452.
FIELD OF THE INVENTION
The present invention relates to a benzene derivative or a pharmacologically acceptable salt thereof which is useful as a medicine.
DESCRIPTION OF THE RELATED PRIOR ART
Cerebrovascular diseases such as cerebral apoplexy and myocardial infarction which rank high in the list of death causes in Japan are mostly caused by arteriosclerosis as its terminal symptoms. The number of patients with arteriosclerosis has steadily increased with the westernization of eating habits and the increase in the aged population and accordingly the number of patients with cerebral apoplexy and myocardial infarction also keeps on increasing.
As is well known, the lethality of patients with cerebral apoplexy and myocardial infarction is extremely high and even if these patients avoid death, many of them suffer from serious sequelae.
Accordingly, it is extremely important to prevent or medically treat arteriosclerosis before these serious diseases are caused.
Although antihypolipidemic medicines which are effective in lowering the content of lipid, particularly cholesterol in the blood have hitherto been mainly used for the prevention and medical treatment of arteriosclerosis, no decisively effective medicine has been found as of yet, so that various studies are now in progress on arteriosclerosis and preventive and medically treating medicines therefor.
Recently, it has been found that cholesterol O-acyl transferase (or acyl-CoA: cholesterol O-acyl transferase) (hereinafter abbreviated to "ACAT") present in the arterial wall participates in the formation of fat striae which are observed in arteriosclerosis (atherosclerosis).
More precisely, it has been clarified that the excess accumulation of cholesterol ester on the arterial wall is causative of atheromatous lesion and the formation of cholesterol ester is catalyzed by the ACAT.
Accordingly, it is expectable that the inhibition of the ACAT may control the excess accumulation of cholesterol ester on arterial wall to thereby depress the formation and evolution of artheromatous lesion.
Meanwhile, the ACAT is also known to participate in the intestinal absorption of cholesterol. Specifically, dietary cholesterol and cholesterol released into the intestines by the adaptation of a living body itself in a state mixed with bile are absorbed as free cholesterol from the intestines, esterified by the action of ACAT, packed into chylomicrons and released into the blood.
Accordingly, since the free cholesterol absorbed from the intestines is saturated by the inhibition of the ACAT in intestines, it is expectable that the intestinal absorption of cholesterol may be controlled.
Although compounds exhibiting an inhibitory activity against ACAT have been proposed in, for example, U.S. Pat. Nos. 4,628,662, 4,489,094, 4,489,090, 4,824,848 and 4,285,951 and Japanese Patent Publication-A Nos. 184070/1988, 281058/1984, 41655/1985, 277851/1987, 258866/1987, 28848/1988, 258060/1988, 19016/1989, 93569/1989, 208860/1989, 6455/1990, 6457/1990 and 6456/1990, these compounds are different from compounds of the present invention in the chemical structures.
DISCLOSURE OF THE INVENTION
The present inventors have extensively studied for many years on a compound which exhibits an inhibitory activity against ACAT of the arterial wall and the intestines to thereby hinder the excess accumulation of cholesterol ester on the arterial wall and the intestinal absorption of cholesterol with their attentions being paid to ACAT. As a result, they have found that a specific benzene derivative or a pharmacologically acceptable salt thereof can attain the object as will be described below. The present invention has been accomplished on the basis of this finding.
The compound of the present invention is a benzene derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof: ##STR3## [wherein R.sup.1 represents a carbo
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T. Kimura et al., Journal of Medicinal Chemistry, May, 1993, vol. 36, 1641-1653.
Cross et al., J. Med. Chem., vol. 28, pp. 1427-1432, 1985.
Chemical Abstracts, No. 117176d, vol. 119, No. 11, Sep. 13, 1993, p. 924.
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Hayashi Kenji
Hiyoshi Hironobu
Horie Toru
Kobayashi Hiroko
Kokushi Motoji
Eisai Co. Ltd.
Haley Jacqueline
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