Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-12
2000-08-29
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540490, A61K 31553, A61P 910, C07D26714, C07D41306, C07D41314
Patent
active
061109096
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to a benzoxazepine compound having an activity of lowering cholesterol-level and an activity of lowering triglyceride-level and useful for prophylaxis and therapy of hyperlipemia.
BACKGROUND ART
Abnormal increase of concentrations of lipids in plasma is called "hyperlipidemia" or "hyperlipemia". Serum lipids include cholesterol (cholesterol ester, free cholesterol), phospholipid (lecithin, sphingomyelin, etc.), triglyceride (neutral fat), free fatty acid and other sterols. Increase of cholesterol and triglyceride is especially taken up as a problem from the clinical viewpoint [cf. Common Disease Series No.19 Koshikessho (hyperlipemia) compiled by Haruo Nakamura, published by Nankodo].
Therefore, adequate control of lipid concentration in blood is remarkably important for the prophylaxis or therapy of various diseases related to arteriosclerosis typically exemplified by ischemic heart disease and cerebral infarction. And, hypertriglyceridemia is considered to accompany pancreatic disorders.
As pharmaceutical compositions for lowering cholesterol in blood, attention has been drawn to those for controlling the biosynthesis of cholesterol, besides those of inhibiting its absorption by binding bile acid including, among others, cholestyramine, colestipol (for example, U.S. Pat. No. 4,027,009), and those of suppressing the intestinal absorption of cholesterol by inhibiting acyl coenzyme A cholesterol acyl transferase (ACAT) including melinamide (French Patent No.1476569). As pharmaceutical preparations for controlling the biosynthesis of cholesterol, lovastatin (U.S. Pat. No. 4,231,938), simvastatin (U.S. Pat. No. 4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which are capable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase, are provided for medicinal use. However, when HMG-CoA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis of some other components such as ubiquinone, dolichol and heme A, which are necessary for the living body, is also inhibited, so that occurrences of undesirable side effects to be caused thereby are feared.
While, as agents of lowering triglyceride, fibrinoic acid type compounds, for example, clofibrate (UK Patent 860303) and fenofibrate (German Patent 2250327), are provided for medicines, they are prohibited to use together with statin type compounds for the fear of causing liver-toxicity.
Squalene synthetase is an enzyme taking part in the essential stage of the cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene.
On the other hand, the compounds expected as inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase are disclosed in Journal of Medicinal Chemistry, Vol.51, No.10, pp.1869-1871, 1988, JPA H1(1989)-213288, JPA H2(1990)-101088, JPA H2(1990)-235820, JPA H2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)-68591, JPA H3(1991)-148288, and U.S. Pat. Nos. 5,019,390, 5,135,935, WO9215579 and WO9309115.
Incidentally, hyperlipemia is also called "hyperlipoproteinemia" and is classified into the following six types (WHO classification) taking lipoproteins into consideration. low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), very-low-density lipoprotein (.beta. VLDL),
DISCLOSURE OF INVENTION
Through intensive investigations from the above viewpoints, the present inventors synthesized, for the first time, a 4,1-benzoxazepine compound with the characteristic feature having specific substituents at 1-, 3-, 5- and 7-positions, and found that this compound has unexpectedly excellent lipid-level lowering activity based on the specific chemical structure, thus accomplishing the present invention.
More specifically, the present invention relates to: ##STR2## wherein R stands for a lower alkyl group optionally substituted by hydroxyl group which may be substituted, X stands for an optionally substituted carbamoyl group or an optionally substituted hete
REFERENCES:
patent: 5885979 (1999-03-01), Yukimasa et al.
Sugiyama Yasuo
Tozawa Ryuichi
Yukimasa Hidefumi
Coleman Brenda
Conlin David G.
Holmes Jennifer K.
Shah Mukund J.
Takeda Chemical Industries Ltd.
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