Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-08-21
1998-11-03
Dentz, Bernard
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142262, 5142305, 544 35, 544 37, 544 38, 544102, 546133, 546137, A16K 31435, C07D40112, C07D41312, C07D41712
Patent
active
058309020
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP96/00491 filed Mar. 1, 1996.
TECHNICAL FIELD
This invention relates to a novel quinuclidine derivative having a tricyclic hetero condensed ring, a salt thereof, a hydrate thereof or a solvate thereof, which has a squalene synthase inhibiting action, and to a squalene synthase inhibitor which contains the compound as the active ingredient.
BACKGROUND ART
It is known that arteriosclerosis induces various diseases. For example, ischemic heart diseases induced by coronary arteriosclerosis have the highest mortality rate next to cancer in Japan, and it is known that cerebral infarction induced by cerebral arteriosclerosis is accompanied by serious secondary diseases such as difficulty of moving, dementia and the like. In addition, since these various diseases induced by arteriosclerosis have been increasing with the increase in aged population and the changes in the dietary life into European and American styles, great concern has been directed toward the development of on effective therapeutic agent.
Increase in the blood cholesterol level is considered important as a main causal factor of arteriosclerosis which is a degenerative disease of the artery. Increase in the blood cholesterol firstly causes increase in blood lipid level and deposition of lipid on the inner membrane of large blood vessel, and the range and degree of these phenomena increase with the advance in years, finally causing ischemic heart diseases such as myocardial infarction, angina pectoris and the like, cerebral arteriosclerotic diseases such as cerebral infarction and the like and clinical symptoms such as aneurysm and the like. In consequence, it is considered that inhibition of the increase in blood cholesterol and its reduction to normal level are markedly effective for the treatment or prevention of the aforementioned various diseases caused by arteriosclerosis.
From the above point of view, attempts have been made to develop various hyperlipemia-treating agents. Cholesterol in the living body is provided as a portion absorbed from food and another portion synthesized in the living body and excreted mainly as bile acid. In the case of humans, 50% or more of the total cholesterol is originated from de novo synthesis in the living body. In consequence, inhibition of an enzyme which is concerned in the biosynthesis of cholesterol seems to be effective in treating hyperlipemia, and lovastatin, simvastatin and pravastatin are now al., Proc. Natl. Acad. Sci., vol. 77, p. 3957 (1980); Tsujita et al., Biochim. Biophs. Acta, vol. 877, p. 50 (1986); and Koga et al., Biochim. Biophs. Acta, vol. 1045, p. 115 (1990)!.
However; the aforementioned known inhibitors aim at 3-hydroxymethylglutaryl coenzyme A reductase (hereinafter, to be referred to as HMG-CoA reductase) as the target enzyme, and this enzyme is located at a relatively early stage of the cholesterol biosynthesis system. Accordingly, it is possible that inhibition of the enzyme by the administration of the aforementioned agents may also induce inhibition of the synthesis of other important metabolic products such as dolichol, ubiquinone, isopentenyl tRNA, p21Ras, low molecular weight G protein and the like which are concerned in intracellular information transfer and cell growth (cf. Trends Biochem. Soc., vol. 4, p. 230 (1993), Cell, vol. 65, p. 1 (1991)).
In fact, it is known that growth of cells does not occur due to interruption of the cell cycle when an HMG-CoA reductase inhibitor is added to the cultured cells (Sakakibara et al., Protein, Nucleic Acid and Enzyme, vol. 39, p. 1508 (1994)), and side effects such as hepatic cytotoxicity and myopathy have also been observed.
In addition, it has been reported that triparanol known as the inhibitor of an enzyme located at a downstream stage of the cholesterol biosynthesis system accumulates desmosterol which causes the cataracts.
In consequence, an inhibitor which targets squalene synthase, an enzyme positioned at a stage after branching into physiologically important metabolic products and before
REFERENCES:
patent: 5654315 (1997-08-01), Brown et al.
Isaka Masahiko
Ishihara Tsukasa
Kakuta Hirotoshi
Matsuda Koyo
Moritani Hiroshi
Dentz Bernard
Yamanouchi Pharmaceutical Co. Ltd.
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