JPH0873352A - Antihypertensive agent - Google Patents

Abstract

(57) [Summary] [Objective] To develop a hypotensive agent having an action mechanism of renin activation inhibitory action and to provide a more useful hypertensive agent. [Structure] [Chemical 1] An agent for treating hypertension, which comprises an epoxysuccinamic acid derivative represented by or a pharmaceutically acceptable salt thereof.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a therapeutic agent for hypertension, which comprises an epoxysuccinamic acid derivative or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Conventional drug therapy for hypertension includes diuretics such as thiazides, sympathomimetics such as β-blockers, vasodilators such as hydralazine, calcium antagonists such as dihydropyridine derivatives, and angiotensin converting enzyme inhibitors. Antihypertensive agents such as (ACE inhibitors) have been used.
Among them, an angiotensin converting enzyme inhibitor (ACE inhibitor) acts on the renin-angiotensin system which plays an important role in the blood pressure regulation system, and angiotensin I
It is known to inhibit the conversion of angiotensin II to.

In addition to this, as drugs acting on the renin-angiotensin system, studies on renin inhibitors that inhibit renin, which is an enzyme that converts angiotensinogen to angiotensin I, and angiotensin II receptor antagonists have been conducted. Has been done.

On the other hand, it has recently been revealed that the enzyme that converts a renin precursor into active renin is cathepsin B, and that an inhibitor of cathepsin B inhibits renin activation in vitro. (Yasuo Uchiyama et al., Proceedings of the 44th Annual Meeting of the Japanese Society for Cell Biology, page 180, 1991).

However, studies on the renin-activating enzyme have just started, and no renin-activating inhibitor that actually exhibits a hypotensive action at the animal level is known.

[0006]

The cause of hypertension is complicated, and it is desired to develop a therapeutic drug based on a new mechanism of action so that a therapeutic method can be selected according to the patient's condition and complications.

An object of the present invention is to develop an antihypertensive agent having a renin activation inhibitory action as a mechanism of action and to provide a more useful hypertensive agent.

[0008]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the present inventors have disclosed a compound represented by the formula disclosed in JP-A-4-139182 as a specific inhibitor of cathepsin B.

[0009]

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The antihypertensive action of the compound represented by the formula (1) was examined using renin-dependent hypertensive mice (Tsukuba hypertensive mice) obtained by spontaneously mating human renin gene-introduced mice and human angiotensinogen gene-introduced mice. Tsukuba hypertensive mice show a significant increase in blood pressure, and it is known that the blood pressure is lowered to a normal level by a human renin-specific inhibitor (Akiyoshi Fukamizu, Vol. 169 (No. 5), p. 422, 1994).
Year).

As a result of administration of the compound represented by the formula (1) to the present hypertensive mouse and measurement of blood pressure over time, it was found that the compound represented by the formula (1) exhibits a significant blood pressure lowering effect. completed.

That is, the present invention is a therapeutic agent for hypertension which comprises an epoxysuccinamic acid derivative represented by the formula (1) or a pharmaceutically acceptable salt thereof.

In the present invention, the pharmaceutically acceptable salts include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and organic amines such as triethylamine and pyridine. Salt, ammonium salt, lysine, arginine,
Examples thereof include salts with basic amino acids such as ornithine.

The compound represented by the formula (1) is disclosed in Japanese Patent Laid-Open No.
It is a known compound disclosed in JP-A-139182, and can be produced by the method disclosed in this publication.

When the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof is used as a therapeutic agent for hypertension, tablets, pills, capsules, granules, powders, emulsions,
It is orally or parenterally administered in a dosage form such as a suspension, an injection and a suppository. Each of the above-mentioned preparations is produced by a technique which is usually used in the field of preparation, and a usual filler, binder,
Additives such as a disintegrant, a pH adjuster, and a solubilizer can be added.

The dose of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof varies depending on the age, body weight, type of disease and condition of the patient, etc., but usually 10 to 1000 mg per day It can be administered in several divided doses.

[0017]

The compound of the present invention represented by the formula (1) exhibits a strong antihypertensive action and is useful for treating hypertension.

Hereinafter, the effects of the present invention will be specifically shown with reference to test examples.

Test Example 1 Antihypertensive effect in human renin-dependent hypertensive mice 16 renin-dependent hypertensive mice (Tsukuba hypertensive mice) obtained by spontaneously mating human renin-transgenic mice and human angiotensinogen transgenic mice
~ 20-week-old male (body weight 28g) 4 control group,
Compound administration group represented by formula (1) (10 mg / 100
(g body weight) 5 animals were divided into 2 groups. The compound represented by the formula (1) was dissolved in a phosphate buffer and administered intraperitoneally, and only the phosphate buffer was intraperitoneally administered to the control group. Before administration and 30 minutes after administration, the systolic blood pressure was measured by a non-invasive blood pressure recording device PS-200 (manufactured by RIKEN) by the tail cuff method under no anesthesia.

The results are shown in Table 1.

[0021]

[Table 1]

Significant difference from control group *: P =
0.0137 As a result, the compound represented by the formula (1) showed a significant hypotensive action 30 minutes after administration, and it was revealed that the compound is useful as an antihypertensive agent.

[0023]

[Examples] Specific examples of formulation of the drug of the present invention are shown below as Examples. Parts in the examples are by weight unless otherwise specified.

Example 1 Compound of the present invention 10 parts Heavy magnesium oxide 15 parts Lactose 75 parts are uniformly mixed to obtain a powder or granules to prepare a powder. Moreover, this powder was put into a capsule container to prepare a capsule.

Example 2 Compound of the present invention 45 parts Starch 15 parts Lactose 16 parts Crystalline cellulose 21 parts Polyvinyl alcohol 3 parts Water 30 parts After uniformly mixing and mixing, fluidized bed granulation, drying and sieving It was made into granules. Example 3 3 parts of magnesium stearate was added to 97 parts of the granules obtained in Example 2 and compression-molded to give tablets with a diameter of 10 mm.

Example 4 Compound of the present invention 10 parts benzyl alcohol 3 parts physiological saline 87 parts were added and mixed by heating, and then sterilized to obtain an injection.

[0027]

Claims (1)

[Claims] Claims: An agent for treating hypertension, which comprises an epoxysuccinamic acid derivative represented by or a pharmaceutically acceptable salt thereof.