JPS6122017A - Antiarteriosclerotic agent - Google Patents

Abstract

PURPOSE:An arteriosclerotic agent, containing a specific compound well known as a hypotensive agent and vasodilator or a salt thereof as an active constituent, and having powerful blood plasma cholesterol reducing action and remarkably improved arteriosclerotic index. CONSTITUTION:An arteriosclerotic agnt containing 2-(4-diphenylmethyl-1-piperazinyl )ethylmethyl 2,6-dimethyl-4-( 3-nitrophenyl )-1,4-dihydropyridine-3,5-dicarboxylate expressed by the formula or a salt thereof (described in Kokai No. 58- 201765) as an active constituent. The compound expressed by the formula has more powerful blood plasma cholesterol reducing action than clofibrate, and is capable of remarkably improving the arteriosclerotic index. The low toxicity thereof renders the compound useful as a remedy for hyperlipemia, arteriosclerosis, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 2,6-dimethytv-4-(3-nitropheny/v)-1,4-dihydropyridine-3,5-cica μbonic acid 2-(4 -Jihueniμmechi/v-1-Bipezini/
The present invention relates to an agent for arteriosclerosis containing L/)ethylmethy/L/ (hereinafter abbreviated as compound) or a physiologically acceptable salt thereof as an active ingredient.

The chemical structural formula of conventional technology compound engineering is represented by the following formula, and is disclosed in JP-A-58-
Publication No. 201765 describes the chemical compound, its physiologically acceptable salt production method, its physical and chemical properties, and its effects such as blood pressure lowering, peripheral vasodilation, coronary artery dilation, and cerebral vasodilation. effects and renal vasodilatory effects have been described5.

(I) Problem to be solved by the invention According to mortality statistics in developed countries, cardiovascular disease, which is diagnosed as a cause of more than 5096 deaths, is caused by sclerotic changes such as atherosclerosis in the arterial portion of the vascular system. Very often the cause is.

This type of atherosclerotic change, which can result in partial or complete occlusion of the vascular lumen, causes tissue damage and can induce local tissue necrosis, such as fatal infarctions in the heart and brain.

The present invention provides significant plasma total cholesterol reduction! It is an object of the present invention to provide a drug that exhibits a lowering effect and can significantly improve the arteriosclerotic index.

As a result of repeated research on chemical compounds, the present inventors have found that chemical compounds have a strong effect of lowering plasma cholesterol-μ and have an effect on arteriosclerotic index (low-density lipoprotein cholesterol-μ) ((L
It was discovered that DL44 LDL)-Ch))/high-density riboprotein cholesterol A/(HDL-Ch)) was significantly improved, and based on this knowledge, the present invention was completed.

That is, the present invention is an agent for arteriosclerosis containing a chemical compound or a physiologically acceptable salt thereof as an active ingredient.

As physiologically acceptable salts, non-toxic salts are preferred, such as salts with inorganic acids (hydrochlorides).

hydrobromide, phosphate, sulfate, etc.), salts with organic acids (acetate, succinate, maleate, fumarate,
malate, tartrate, methanesium phonate, etc.).

Among the above compounds or their physiologically acceptable salts, the acute toxicity test results for ζ dihydrochloride in rats are as follows.

(Note) Values within 0 indicate the 95th confidence limit.

When the present compound It or its compound is used as an agent for arteriosclerosis, the daily dose for adults is 5.
~aooq, preferably 10-150 Da.

When administering this compound to humans, the method of administration may be either oral or parenteral.

Compositions for oral administration include solid or liquid drug layers, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, and Kabu 7μ tablets (including soft capsules). , white, powder, emulsion, 1% clouding agent, etc. Such compositions are produced by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Examples include skewers, and injections include subcutaneous injections, subcutaneous injections, and intramuscular injections. Such injections are prepared by a method known per se, that is, by suspending or emulsifying the compound in a sterile aqueous or oily liquid commonly used for injections. Physiological saline is an aqueous solution for injection.

Examples include isotonic suspension, and if necessary, a suitable suspending agent such as sodium chloride, nonionic surfactant, etc., may be used in combination. Examples of the oily liquid include sesame oil and soybean oil, and benzyl benzoate, benzyl alcohol, etc. may be used in combination as a solubilizing agent. The prepared injection solution is usually filled into suitable ampoules.

"Effects of the Invention" The drug of the present invention has a powerful plasma cholesterol effect! It has the effect of lowering the arteriosclerosis index (low-density riboprotein: I vy
, Tea-*((LDL+vLDL)-ch))/high-density riboprotein cholesterol A/(HDI,-Ch))
can be significantly improved.

Also, because the compound and its salts have low toxicity, they cause hyperlipidemia,
It is extremely useful as a therapeutic agent for arteriosclerosis and various diseases caused by it.

Using the compound dihydrochloride (Compound I, 2HC1), we compared its lipid-lowering effect and improvement of the vascular stiffness index with clofibrate, a commercially available agent for arteriosclerosis, and the results are as follows. It is.

(Margins below) As is clear from the table above, the compound treated with 2HC1 showed a remarkable effect of lowering plasma total cholesteria μ and significantly improved the arteriosclerosis index in hypercholesterolemic rats. These effects are more obvious than clofibrate.
It is excellent.

Next, a method for testing the lipid-lowering effect of this drug is shown.

Test method Six-week-old male ExTiC tuts (Atheroacler
osi@vol. 28, p. 453, year 191T] (7 for each group)
ljl in CE-2 feed (Nihon Talea Co., Ltd.)
A high Ch diet supplemented with Threstero-A/(Ch), 0.2% sodium cholate, and olive oil at 5 was fed. Each rat had free access to soybean and water. Throughout the experimental period,
The control group received gum arabic solution, and the sample group received compound l.2.
A gum arabic suspension of HC1 was given once a day during sunset.

After 4 and 8 days, blood was collected from the tail vein under anesthesia, centrifuged, and fractionated.
-Ch) was measured by an enzymatic method. After 8 days, lipoproteins were separated from the plasma by ultracentrifugation using Airfup;e (Peckman), and HDL-Ch(A) was measured by an enzymatic method. HDL-Ch from plasma T-Ch value
The value after subtracting il t-(LDL+VLDL) -ah
(B) and the arteriosclerotic index (atherogen
ic 1nciex sB/A) was calculated. Comparison of each value between the sample group and the control group was carried out using the 7-test.

Claims (1)

[Claims] 2,6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid 2-(4
-Diphenylmethyl-1-piperazinyl)ethylmethyl or a physiologically acceptable salt thereof as an active ingredient.