Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-20
2001-07-03
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S282000, C546S048000, C546S071000
Reexamination Certificate
active
06255317
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a cholesterol biosynthesis inhibitor. More specifically, the present invention relates to a new class of inhibitor which specifically inhibits the sterol 14-reductase which is involved in the distal pathway of cholesterol biosynthesis. The inhibitor comprises an extract obtained by extracting
Corydalis Turtschaninowii Besser
with a solvent, or an organic layer obtained by partitioning an extract from
Corydalis Turtschaninowii Besser
with an organic solvent. The extract contains 7,8,13,13&agr;-tetrahydrocoridaline or its derivatives, as a main igredient. The present invention also relates to a novel compound of formula (1) as set forth below and to the use of the extract or the compound of formula (1) for treating hypercholesterolemia or hyperlipidaemia.
BACKGROUND ART
Cholesterol is an important vital constituent of cell membrane in mammal and is involved in cell division, growth, development and control of differentiation, and also is a precursor of various essential metabolites (for example, steroid hormones, bile acids). However, it may cause hyperlipidaemia which leads to atherosclerosis if its intake or production within the body is excess. Hyperlipidaemia leads to cardiovascular disease which is a leading cause of death in humans. It is usually caused when cholesterol or triglyceride has exceeded a proper level (i.e., total cholesterol level for adults at the age of between 30 and 40 is about 200 mg/dl), and then, deposited to the inner wall of an artery to form atheroma plaques, thereby blood flow being inhibited which causes cardiac failure or cerebral stroke. Cholesterol is synthesized mainly in the liver in mammals and the synthetic pathway thereof is started from acetyl-CoA and is completed after at least 32 steps of enzyme reactions.
Cholesterol biosynthesis which occurs in mammal can be summarized according to the enzyme reaction patterns in which each intermediate is formed as in the following reaction scheme 1.
In the above reaction scheme, steps I and II undergo polymerization, and steps II and III undergo cyclization. In step IV, transformation, demethylation, isomerization or reduction of steroid ring is proceeded. Cholesterol biosynthesis is carefully controlled by the multi-step regulation, i.e., the so-called multivalent coordinate regulation. For example, 3-&bgr;-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) is the main rate-limiting enzyme in the cholesterol biosynthesis. It reduces HMG-CoA synthesized from acetyl-CoA during the early stage of the biosynthetic pathway starting from acetate (C2) to mevalonate (C6) and is inhibited in vivo by the fimal product, cholesterol. More specifically, the activity of this enzyme is controlled by dietary cholesterol, oxysteroids and mevalonate derivatives in a feed-back inhibition manner. For the past decade, the lipid-lowering agents have been developed based on their inhibiting activities against this enzyme. Most of currently marketed therapeutic agents for hyperlipidaemia which have been developed based on such mechanism include, for example, statins including lovastatin, pravastatin, simvastatin, atorvastatin, and cerivastatin. However, if cholesterol biosynthesis is suppressed by inhibiting the activity of HMG-CoA reductase which is the rate liniting enzyme at the early stage of cholesterol biosynthesis, there may be many side effects that the synthesis of many important biomolecules such as dolicol, isopentenyl pyrophosphate, haem A, and ubiquinone which are also derived from mevalonate are suppressed together.
Therefore, it may be advantageous to block cholesterol biosynthesis at a step distal to HMG CoA reductase in order to prevent depletion of such essential intermediates.
Accordingly, recent researches have been focused on the development of new type of therapeutic agents for hyperlipidaemia which can effectively block only the post-squalene steps without interfering HMG-CoA reductase activity. For example, the activation mechanisms of the distal enzymes responsible for the postsqualene pathway in the cholesterol biosynthesis which comprises the sequence of ‘squalene→lanosterol→zymosterol→desmosterol→cholesterol’ have been studied and attempts to screen and develop a drug which can specifically inhibit the activity of the target enzyme responsible for the distal pathway of cholesterol biosynthesis based have been made. Especially, based on the inhibitory activity of squalene epoxidase responsible for the pathway of ‘squalene→lanosterol’, a benzylamine series compound, NB598 has been developed by Banyu Pharmaceutical Co. of Japan; Squalenestatin I has been developed by the researchers of Glaxo Wellcome Limited, a British company on the basis of its inhibition of squalene synthase which is responsible for the synthesis of squalene from farnesyl pyrophosphate.
RPR107393 has been developed as a potent squalene synthase inhibitor by researchers at Rhone-Poulenc, France. Further, Taton et al. have reported MDL 28,815 having 8-azadecaline ring based on the inhibition of 2,3-oxidosqualene cyclase responsible for the cyclization reaction in which squalene epoxide is converted into methylsterol (See, Biochem. Biophys. Res. Commun. 1986, 138, 764-70). These NB598, Squalenestatin I, RPR107393 and MDL 28,815 which inhibit the activities of enzymes responsible for the post-mevalonate pathway in the cholesterol biosynthetic pathway have a merit that they can selectively inhibit the cholesterol biosynthesis without effecting on the production of other important intermediates which are derived from mevalonate, differently from drugs that have a target on HMG-CoA reductase responsible for the early stage of cholesterol biosynthesis.
However, these agents are not yet currently marketed as therapeutic agents for hyperlipidaemia.
DISCLOSURE OF THE INVENTION
The present inventors have conducted an extensive research for many years in order to develop a novel class of cholesterol biosynthetic inhibitor which specifically inhibits the enzyme involved in the steps of ‘lanosterol→cholesterol’. As a result, the inventors have surprisingly discovered that an extract obtained from
Corydalis Turtschaninowii Besser
which has been used in the prescription of sedative agent or hemostatic agent in the oriental medicine for thousand years strongly inhibits the activity of sterol 14-reductase which catalyzes the reduction of 4,4-dimethyl-8,14-dien-3&bgr;-ol and thus have completed the present invention.
Based on these findings, it is possible to provide a cholesterol biosynthesis inhibitor which comprises an extract obtained from
Corydalis Turtschaninowii Besser
containing 7,8,13,13&agr;-tetrahydrocoridaline as the main component which specifically inhibits the sterol 14-reductase in the distal pathway of the cholesterol biosynthesis.
It is therefore an object of the present invention to provide a cholesterol biosynthesis inhibitor which comprises an extract obtained by extracting
Corydalis Turtschaninowii Besser
with one or more solvent selected from the group consisting of water, alcohols, such as methanol, ethanol, and dichloromethane and/or an organic fraction obtained by partitioning an extract from
Corydalis Turtschaninowii Besser
with an organic solvent such as dichloromethane.
Another object of the present invention is to provide a cholesterol biosynthesis inhibitor which comprises the components isolated from the organic fraction of the above
Corydalis Turtschaninowii Besser
extract or synthetic derivatives of the components.
A further object of the present invention is to provide protoberberine(5,6-dihydrodibenzo-[a,g]quinolizinium) derivatives or 13,13&agr;-didehydroberbine derivatives or the salts thereof which can be represented by formula (1) as set forth below.
Still another object of the present invention is to provide a composition for inhibiting cholesterol biosynthesis, especially inhibiting sterol 14-reductase, which comprises 7,8,13,13&agr;-tetrahydrocoridaline, or protoberberine (5,6-dihydrodibenzo-[
Jhong Tae Neung
Kim Eui Deok
Kim Jung Ho
Kim Seung Un
Lee You Suk
HANWHA Chemical Corporation
Hunton & Williams
Rotman Alan L.
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