JPH03251540A - Vasodilator - Google Patents

Abstract

PURPOSE:To provide a vasodilator not causing adverse actions such as excessive vasodepressor, readily employed and useful for the treatment of cardiac failure, acute cardiac infraction, etc., by compounding a specific tripeptide or a salt thereof as an active ingredient. CONSTITUTION:A vasodilator contains a tripeptide of the formula (Asp is L- aspartic acid residue; Gly is glycine residue; Lys is L-lysine residue) or a salt thereof as an active ingredient. The salt of the tripeptide includes inorganic salts such as hydrochloride, sulfate and phosphate, acetate and citrate. The tripeptide is administered in a dose of 0.01-10mg/kg a day in a case of oral administration and in a dose of 10-1000mug/kg a day in a case of parenteral administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a vasodilator useful for treating diseases such as heart failure, acute myocardial infarction, and hypertension.

[Prior Art] It is well known that therapy using vasodilators is useful for cardiovascular diseases such as heart failure, acute myocardial infarction, and hypertension.

These vasodilators are classified into three main groups based on the vascular system they act on:
It can be divided into

(1) Drugs that primarily dilate the arterial system. For example, hydralazine, phentolamine, calcium channel blockers, fedipine, verapamil, etc.).

(2) Drugs that primarily dilate the venous system. For example, nitro compounds or nitrites such as nitroglycerin or isosorbide nitrate.

(3) Drugs that dilate both arteries and veins almost equally.

For example, nitroprusside, α1 blockers (such as prazosin), angiotensin converting enzyme inhibitors.

The mechanisms of action of these drugs include direct action on peripheral vascular smooth muscle (hydralazine, nitro compounds, nitroprusside), inhibition of vasoconstriction via the sympathetic nervous system (α1 blocker), and inhibition of vascular smooth muscle cells. It is also known to inhibit the influx of calcium ions (calcium antagonist).

The above drugs are used depending on symptoms and changes in hemodynamics, and each has high clinical value.

[Problem to be solved by the invention]

Among the above-mentioned vasodilators, nitroprusside has a strong vasodilatory effect and has the advantage of being quick-acting, but has the inconvenience of having to be carefully administered intravenously using a metered-dose infusion device due to its short half-life. In addition, there is also the problem that sometimes the blood pressure decreases excessively.

The present invention provides a vasodilator that has a vasodilatory effect similar to that of nitroprusside, but is free from side effects such as causing an excessive drop in blood pressure and is easy to use.

[Means to solve the problem]

The present inventors have synthesized various peptides derived from the Fc region of IgE or peptides similar thereto, and have been intensively investigating their various pharmacological activities including antiallergic activity. The present invention was completed based on the unexpected discovery that some substances exhibit vasodilatory effects similar to those of nitroprusside.

That is, the present invention provides the following formula [I] H-Asp-Gly-Lys-OH (I) (however,
Regarding a vasodilator containing as an active ingredient a tripeptide represented by (Asp is an L-aspartic acid residue, Gly is a glycine residue, and LyS is an L-lysine residue) or a pharmaceutically acceptable salt thereof. It is something.

The above H-Asp-Gly-Lys-OH is a novel peptide discovered by the present inventors and has usefulness as an anti-allergic agent (Japanese Patent Application No. 1-256871
issue).

The above tripeptide is BoC-Gly-OH (however, B
oc represents a t-butyloxycarbonyl group) and a monolysine derivative represented by H-Lys(Z)-0Bzl (where Z is a benzyloxycarbonyl group and Bzl represents a benzyl group). The derivative was subjected to dehydration condensation to give Boc-Gly-Lys(Z)-0Bzl, then the BoC group was removed with acid, and this was added to Z-Asp(OB
It is obtained by adding a monoaspartic acid derivative represented by zl)-0H, dehydration condensation, and then catalytic reduction.

However, the manufacturing method described here is just an example, and it is obvious that other manufacturing methods can also be used.

Pharmaceutically acceptable salts of the tripeptide represented by H-Asp-Gly-Lys-OH include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, citrate, and fumaric acid. Salts, organic acid salts such as tartrates and lactates, alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts.

The above pharmaceutically acceptable salts can be prepared by removing the protecting group in the final step of synthesis and then adding an acid such as hydrochloric acid or acetic acid, or adding a base such as sodium hydroxide or potassium hydroxide to form the corresponding salt. Alternatively, after the tripeptide represented by formula [I] is isolated, an acid or a base can be added in the same manner as above to form a salt.

The vasodilator of the present invention may take any appropriate form for oral or parenteral administration. Typical methods of administration include oral, rectal, percutaneous, subcutaneous, intravenous, intramuscular, inhalation, or intranasal routes.

In these administration methods, the vasodilators of the invention can be administered in the form of various pharmaceutical formulations. The forms of these pharmaceutical preparations include tablets, hard capsules, soft capsules, granules, powders, lozenges, half-open tablets, syrups, creams, ointments, lozenges, injections, suspensions, and inhalers. agents, aerosol agents, etc. It can also be made into double-layer tablets, multi-layer tablets, etc. together with other vasodilators and other medicines.

Furthermore, in the case of tablets, a regular coating is applied as necessary.
For example, sugar-coated tablets or enteric-coated tablets can be used.

When preparing solid preparations such as tablets, granules, and powders, known additives such as lactose, sucrose, glucose, crystalline cellulose, cornstarch, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, and hydroxypropyl cellulose are used in the preparation. , gum arabic,
Polyvinylpyrrolidone, polyethylene glycol, magnesium stearate, talc, etc. can be added.

For semi-solid formulations, materials such as vegetable waxes, microcrystalline waxes, fats such as tarolanoline can be added.

When preparing a liquid formulation, additives such as sodium chloride, sorbitol, glycerin, olive oil, almond oil, propylene glycol, ethylene glycol, and ethyl alcohol can be added.

The dosage of the peptide represented by formula [I] depends on the patient's age,
The dosage can be adjusted as appropriate depending on body weight, symptoms, etc., but the dosage for oral administration is 001 to 10 mg/day.
kg, the amount for parenteral administration is 10-1.0 kg per day
00μg/kg.

[Examples] In the following examples, we will show the vasodilatory effect of the peptide represented by the formula [■] and its effects on the circulatory system, such as blood pressure and heart rate. Explain that it is used as a medicine.

(Example 1) Peptide represented by formula (I) (H-Asp-Gly-L
The thoracic aorta of a male rabbit weighing 2.5 to 3 kg was removed.
An aortic spiral strip specimen with a width of 4 mm and a length of 25 to 30 mm was prepared. In 10 ml of Tyrode's solution, the aortic spiral specimen was suspended under a load of 2 g at 37±1° C. while a gas mixture of 95 g wt % oxygen and 5 g wt % carbon dioxide was aerated, and maintained for 1 h to stabilize. Next, potassium chloride was added to a final concentration of 104 mM or norepinephrine was added to a final concentration of 10-'M to induce vasoconstriction.
Gly-Lys-OH was administered cumulatively and the vascular relaxation response was observed. The comparative drug is nitroprusside (
sodium salt) and verapamil were used.

Tables 1 and 2 show the results of the vasodilatory effects of the peptide of formula [I] and the comparative drug expressed in terms of relaxation rate using blood vessels constricted with potassium chloride and norepinephrine, respectively. It is.

Table 1 Formula for potassium-induced vasoconstriction [1]
Table 2 Effects of the peptide of formula [I] and comparative drugs on norepinephrine-induced vasoconstriction Verapamil 7.1 6B, 3 97.1 100 00 Margin below Verapamil 0 4.6 20,6 47.1 6
8.6 From the results in Tables 1 and 2, the peptide of formula (1) shows almost no relaxing effect on vasoconstriction induced by potassium, but has a dose-dependent effect on vasoconstriction induced by norepinephrine. The effect was found to be more similar to that of nitroprusside than that of verapamil.

(Example 2) Peptide represented by formula [I] (H-Asp-Gly-L
Effect of ys-OH) on the circulatory system In order to investigate the effect of the peptide represented by formula [I] on the circulatory system, this peptide was intravenously administered to rats and blood pressure, heart rate, and electrocardiogram were observed. did.

After anesthetizing Wista male rats weighing 300-350 g with urethane (1.5 g/Kg intravenously), arterial pressure was measured via a transducer from a cannula inserted into the left femoral artery, and heart rate was measured using an electrocardiogram (electrocardiogram). (2) The heart rate was measured using a heart rate needle using the R wave of lead) as a trigger.

The peptide was dissolved in physiological saline at a dose of 30 mg per kg of rat body weight and administered through the femoral vein. FIG. 1 is a graph showing the blood pressure (average blood pressure) and heart rate of rats after administration of the present peptide.

Blood pressure decreased immediately after administration, and 1 minute later, blood pressure reached its minimum value (9% decrease compared to the average blood pressure before administration). However, 3 minutes after administration, the blood pressure returned to the pre-administration level. On the other hand,
Heart rate decreased by 7% immediately after administration, and the decrease lasted for 60 minutes. Furthermore, in the electrocardiogram, slight prolongation of the QT interval was observed immediately after administration, but there was no change in the QRS width.

[Effects of the Invention] The peptide represented by formula [I] exhibits a vasodilatory effect similar to that of nitroprusside. According to the present invention, it was possible to provide a drug that does not cause side effects such as an excessive drop in blood pressure and is easy to use as a vasodilator.

[Brief explanation of drawings]

Claims (1)

[Claims] 1. The following formula [I] H-Asp-Gly-Lys-OH [I] (where Asp is an L-aspartic acid residue, Gly is a glycine residue, and Lys is an L-lysine residue) A vasodilator containing, as an active ingredient, a tripeptide represented by (indicating a group) or a pharmaceutically acceptable salt thereof.