JPH09227371A - Atherosclerosis inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine useful for preventing and treating atherosclerosis and diseases caused by the atherosclerosis. SOLUTION: This atherosclerosis inhibitor contains 2-(3,4-dimethoxycinnamoyl) aminobenzoic acid of the formula or its salt as an active ingredient. The compound of the formula (general name: tranilast) has an inhibiting effect against the generation of atherosclerosis, can effectively prevent and treat the atherosclerosis having relied only on dietary therapy, can inhibit the generation of atheroma without changing the level of serum lipids and blood pressure, and thereby is a new atherosclerosis inhibitor quite different from conventional atherosclerosis inhibitors. The inhibitor is useful for preventing and treating diseases caused by the atherosclerosis, such as encephalomalacia, angina, cardiac infarction, renal insufficiency, hypertension, lower extremity arteritis obliterans, extremity gangrene, etc. The compound of the formula or its salt is orally administered at a daily dose of 100-1000mg, preferably 300-600mg, for an adult.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to atherosclerosis (Atherosclerosis, Atherosclerosis).
s) and atherosclerosis (Atherosclerosis, At), which is useful as a preventive and therapeutic drug for diseases caused thereby.
The present invention relates to a suppressive agent.

More specifically, the present invention provides

[0003]

Embedded image

2- (3,4-dimethoxycinnamoyl) aminobenzoic acid (general name: tranilast, hereinafter referred to as tranilast) represented by or a pharmacologically acceptable salt thereof is contained as an active ingredient. The present invention relates to an agent for suppressing atherosclerosis.

[0005] Atherosclerosis is a systemic arterial disease accompanied by atherosclerotic fat deposition under the blood vessels (atheroma, hereinafter referred to as atheroma) and diffuse hardening of the blood vessel wall. Atherosclerosis is an arteriosclerosis (Arteriosclerosis), which is an organized lesion of blood vessels that causes hardening of the wall due to destruction of vascular smooth muscle fibers and rupture of elastic fibers.
It is clearly distinguished from s) as another disease having different onset causes and pathological conditions.

[0006]

BACKGROUND OF THE INVENTION Atherosclerosis is often found especially in arteries such as cardiovascular (coronary blood vessels), aorta, lower extremity blood vessels, kidney and brain, and atherosclerosis of coronary arteries, aorta, etc.
It causes arterial occlusion of the lower limbs, and eventually causes serious diseases such as encephalomalacia, angina, myocardial infarction, renal failure, hypertension, occlusive arterial disease of the lower limbs, and gangrene of the limbs.

No direct preventive and therapeutic drug for such atherosclerosis has been found so far, and since atheroma is composed mainly of cells having lipids and cholesterol crystals, Cholesterol-lowering agents for lowering cholesterol or lipids, antihyperlipidemic agents, etc. are only used. However, these drugs do not directly suppress the development of atheroma, and the drug therapy with such drugs has only a limited therapeutic effect, and therefore, the prevention and treatment of atherosclerosis is difficult. The most common method was diet.

[0008]

As described above, no direct and effective preventive and therapeutic drug for atherosclerosis has been found so far, and a method for preventing and treating atherosclerosis. As I have no choice but to rely on diet,
In this field, development of a drug capable of directly and effectively preventing and treating atherosclerosis has been desired.

[0009]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted diligent research to find a compound showing a direct and effective preventive and therapeutic effect on atherosclerosis, and as a result, tranilast represented by the formula (I) However, surprisingly, the inventors have found that it has an effect of significantly reducing the generation of atheroma and suppressing atherosclerosis, and thus completed the present invention.

[0010] That is, the present inventors have added 6 tranilast to WHHL rabbits, which is an animal model of familial hyperlipidemia.
After continuous administration for a month, it was surprisingly confirmed that the area of atheroma in the thoracic aorta of the tranilast-administered group was significantly lower than that of the control group administered with placebo, and tranilast was associated with atherosclerosis. On the other hand, it was found that it has a remarkable suppressing effect.

[0011] It has already been confirmed that tranilast and its pharmacologically acceptable salt have an action of suppressing the release of chemical mediators in an allergic reaction, an action of suppressing hyperproliferation of collagen, etc., and allergic bronchi flame,
It is already widely used as a therapeutic agent for allergic diseases such as asthma, atopic dermatitis and allergic conjunctivitis, or a therapeutic agent for keloids, hypertrophic scars and the like.

However, it has never been known that tranilast has an inhibitory effect on the generation of atheroma. Moreover, no substance having a direct inhibitory effect on atherosclerosis has been reported so far, and there has been no report suggesting that tranilast has an inhibitory effect on the development of atherosclerosis. Absent.

As described above, tranilast has an inhibitory effect on the development of atheroma, and is useful as an effective preventive or therapeutic agent for atherosclerosis and diseases caused by it, which conventionally had to rely on diet therapy. Is. Moreover, it is a very characteristic atherosclerosis inhibitor, which is completely different from conventional antihyperlipidemic agents and the like, which suppresses the generation of atheroma without changing the serum lipid level and blood pressure at all. is there.

[0014] Thus, tranilast has an inhibitory effect on the development of atheroma, and as a prophylactic and therapeutic agent for atherosclerosis, further, diseases caused by atherosclerosis, for example, encephalomalacia, angina pectoris. , Is useful as a preventive and therapeutic agent for myocardial infarction, renal failure, hypertension, occlusive arterial disease of the lower extremities, gangrene of the limbs, and the like. Therefore, by using tranilast or a pharmacologically acceptable salt thereof as an active ingredient, a pharmaceutical composition useful as a prophylactic and therapeutic agent for atherosclerosis and diseases resulting therefrom can be produced.

When such a pharmaceutical composition is used for actual treatment, various dosage forms are used depending on the usage.
Examples of such dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules and other oral administration agents and injections, suppositories, patches and other parenteral administration agents. .

These pharmaceutical compositions are mixed with appropriate excipients such as excipients, disintegrants, binders, lubricants, etc. according to the dosage form by a conventional pharmaceutical method, and the mixture is prepared according to a conventional method. It can be manufactured by dispensing.

For example, the powder is prepared by adding, to the tranilast represented by the formula (I) or a salt thereof, appropriate excipients, lubricants and the like, if necessary, and thoroughly mixing them.

Tablets are prepared by adding an appropriate excipient, disintegrant, binder, lubricant, etc. to tranilast or a salt thereof, if necessary, and compressing according to a conventional method. If necessary, such a tablet may be appropriately coated to give a film-coated tablet, a sugar-coated tablet, an enteric-coated tablet, or the like.

The capsules are prepared by, for example, adding suitable excipients, lubricants, etc., if necessary, and mixing them well, and then filling them into suitable capsules. Further, after granules or fine granules are formed by a conventional method, they may be filled.

When the pharmaceutical composition of the present invention is used for actual treatment, the dose of tranilast or its pharmacologically acceptable salt as the active ingredient is appropriately determined depending on the body weight, age, sex and degree of disease of the patient. In the case of oral administration, which is determined, in the range of 100 mg to 1000 mg per day for an adult,
Preferably, 300 to 600 mg is administered daily.

[0021]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The contents of the present invention will be described in more detail with reference to the following examples.

[0022]

【Example】

Example 1 Effectiveness of tranilast on the development of atheroma WHHL rabbit (2 months old) of familial hyperlipidemia animal model
Twenty-two, 300 per kilogram of body weight every day
tranilast administration group (1 mg)
0 birds, hereinafter referred to as T group) and a placebo-administered control group (12 birds, hereinafter referred to as C group), which were bred for 6 months each, and then blood pressure was measured and blood was collected, and the thoracic aorta was removed, and atheroma was extracted. Plaque (Atheromatus)
Plaque, hereinafter referred to as atheroma plaque) was measured, and the ratio (%) of the atheroma plaque area to the arterial area was compared. In addition, serum total cholesterol, triglyceride, HDL cholesterol and β-VLD
The L value was measured and compared. The results were as follows.

[0023]

Example 2 Formulations Various formulations are produced according to the following formulations. The type and formulation of the dosage form are not limited to those listed as examples of preparation.

(A) Powder (10 times powder) 100 g of tranilast and 900 g of lactose are mixed well,
Powder containing 100 mg of tranilast in 1 g, 100
Make 0 g.

(B) Powder (2 times powder) Mix well with 500 g of tranilast and 500 g of lactose,
Powder containing 500 mg of tranilast in 1 g, 100
Make 0 g.

(C) Tablet 100 g tranilast, 50 g lactose, 6% HPC lactose 4
0 g, potato starch 6 g and talc stearate 4 g are mixed well and tableted.
1. Make 1000 tablets, containing 0 mg.

(D) Capsule 100 g of tranilast, 90 g of lactose, 6 g of potato starch and 4 g of calcium stearate are mixed well, filled into a hard capsule and 1 tranilast in 1 capsule is filled.
Make 1000 capsules containing 00mg capsules.

Claims (1)

[Claims] (1) Formula (1) An atherosclerosis inhibitor, which comprises 2- (3,4-dimethoxycinnamoyl) aminobenzoic acid represented by or a pharmacologically acceptable salt thereof as an active ingredient.