JPH0645541B2 - Heart failure preventive and therapeutic agents - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel prophylactic / therapeutic agent for heart failure.

[Prior art]

It is known that so-called heart failure, in which the heart is unable to pump a sufficient amount of blood according to the demand for organs of the living body, is often caused by hypertrophy of the heart or myocardium due to excessive burden on the myocardium. Has been. That is, hypertrophy of the heart and myocardium causes changes in myocardial ultrastructure, impaired energy production mechanism related to myocardial contraction, increased myocardial oxygen consumption, etc., which reduces myocardial contractility [Internal Medicine, Volume 2, Pages 66-69, (Published by Nakayama Shoten, February 5, 1982)]. Further, clinically, as the cardiac output decreases due to a decrease in myocardial contractile force, venous congestion occurs due to a ventricular inflow disorder, resulting in systemic dyspnea due to pulmonary congestion.

As a treatment for such heart failure itself, digitalis preparations having a cardiotonic action such as digitoxin and digoxin or xanthine preparations such as caffeine and theophylline have been conventionally used in order to avoid a decrease in myocardial contractile force. However, the digitalis drug works well when there is an absolute decrease in the decrease in cardiac output in response to the physical demand known as low-output cardiac failure, but a decrease in cardiac output called high-output cardiac failure is compared. There is a problem of adaptability that it does not respond well when it is mild. Also, unlike other drugs, there is not much difference between the drug efficacy and the amount of side effects, and digitalis preparations cause so-called digitalis intoxication such as nausea, headache, bradycardia, extrasystole, and angina symptoms when continuously used. There is a problem of doing. Further, xanthine preparations have the advantage of having both cardiotonic action and diuretic action, but there is a problem in that they are both ineffective and not so effective.

[Problems to be solved]

The present invention intends to provide a new type of drug for preventing and treating heart failure based on its action of suppressing and improving hypertrophy of the heart and myocardium, which is completely different from digitalis preparations and xanthine preparations for treating heart failure based on inotropic effect. It is a thing.

[Structure and Effect of Invention]

The present invention has the general formula (However, R ¹ and R ² are lower alkyl groups, R ³ is a phenyl-substituted lower alkyl group, and R ⁴ is a hydrogen atom or a lower alkyl group.) The present invention relates to a prophylactic / therapeutic agent for heart failure containing an acceptable salt as an active ingredient.

Examples of the compound which is the active ingredient of the present invention include compounds represented by the general formula (I)
In the above, for example, R ¹ is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group, and R ² is a methyl group, an ethyl group, n -Propyl group, isopropyl group, n-
A lower alkyl group having 1 to 4 carbon atoms such as a butyl group and an isobutyl group, R ³ is a phenyl-substituted lower alkyl group such as a benzyl group, a phenethyl group, a phenylpropyl group and a phenylbutyl group, and R ⁴ is a hydrogen atom Alternatively, a compound which is a lower alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group and an isobutyl group can be mentioned.

Among these, preferred compounds include compounds of the general formula (I) in which R ¹ is a methyl group, R ² is a methyl group, R ³ is a phenethyl group, and R ⁴ is a hydrogen atom or an ethyl group. Can be mentioned.

Since the compound (I) has 3 asymmetric carbon atoms in the molecule, it exists as 4 types of diastereoisomers or 8 types of optical isomers, and the present invention includes any isomers. To do. However, among these optical isomers, compounds suitable for pharmaceutical use include compounds (I) at the 4-position of the oxoimidazolidine ring and the formula —NH—CH (R ³ ) COOR ⁴
And a compound in which all of the 2-position carbon atoms of the amino acid moieties represented by are S configurations. Examples of the compound suitable for pharmaceutical use include the 4-position of the oxoimidazolidine ring, the 2-position of the alkanoyl moiety represented by the formula —COCH (R ² ) — and the formula —NH—CH (R ³ COOR in the compound (I). Compounds in which all of the 2-position carbon atoms of the amino acid moiety represented by ⁴ are in the S configuration are mentioned.

The 2-oxo-imidazolidine derivative (I) or a pharmacologically acceptable salt thereof has an effect of suppressing and improving hypertrophy of the heart or myocardium, and prevents / improves reduction of myocardial contraction force due to myocardial hypertrophy. Since the drug of the present invention is capable of treating heart failure (eg, congestive heart failure, compensatory heart failure, etc.)
Or congestion of various organs such as lungs and liver due to such heart failure,
It can be used to treat various conditions such as dyspnea, pulmonary edema, systemic edema, peripheral cyanosis, nocturnal paroxysmal dyspnea, and asthma. Also, edema, pulmonary circulatory failure, hypertension,
Since various symptoms such as valvular heart disease easily cause heart failure due to myocardial hypertrophy, it can be used for the prevention of heart failure in patients having such symptoms.

For example, (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1) was added to a spontaneously hypertensive rat (SHR), which is a pathological model animal having hypertension and hypertrophy of the heart. -Ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid 5 mg / kg / day was orally administered for 10 weeks, the heart weight (4S) -1-methyl-3-{(2S) -2- [N-((1S) -1-carboxy-3-phenylpropyl), which can significantly increase, ie, suppress myocardial hypertrophy. Amino] propionyl}
-2-oxo-imidazolidine-4-carboxylic acid 0.5 mg
The same effect can be obtained when / kg / day is intraperitoneally administered for 10 weeks.

Furthermore, the toxicity of the above compound (I) is extremely low, and for example, (4S) -1-methyl-3-{(2S) -2-[-(1
S) -1-Carboxy-3-phenylpropyl) amino] propionyl} -2-oxo-imidazolidine-4
-Carboxylic acid or (4S) -1-methyl-3-{(2
S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2
-Oxo-imidazolidine-4-carboxylic acid was orally administered to a rat at a dose of 5 g / kg, and no rat death was observed even after observing for 5 days after the administration.

The compound (I), which is the active ingredient of the present invention, can be used for medicinal use in any form of a free acid (and / or free base) or a pharmaceutically acceptable salt thereof. Salts can be formed with organic and inorganic bases.

Examples of the pharmaceutically acceptable salt of compound (I) include organic acid addition salts such as succinate, maleate, fumarate and methanesulfonate: hydrochloride, hydrobromide, sulfate , Inorganic acid addition salts such as phosphates; salts with organic bases such as lysine salts and ornithine salts; salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts.

The prophylactic / therapeutic agent of the present invention containing Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient can be administered orally or parenterally, and the degree of disease, the age and weight of the patient And, the dose of compound (I) or a pharmacologically acceptable salt thereof is usually 0.05 to 100 mg / kg, preferably 0.1 to 25 mg per day in the case of oral administration, though it varies depending on the condition.
/ kg, and usually 1 μg / kg2 per day for parenteral administration
It is suitable to administer the dose to be mg / kg, preferably 1 μg / kg to 0.5 mg / kg.

Furthermore, compound (I) or a pharmaceutically acceptable salt thereof can be used as a mixture with an excipient suitable for oral or parenteral administration. As such an excipient, for example, starch, lactose, glucose, potassium phosphate, corn starch, gum arabic, stearic acid and any other commonly used excipient can be used. These pharmaceutical preparations may be tablets, pills, couples, solid preparations such as suppositories, liquid preparations such as solutions, suspensions and emulsions, and these preparations may be sterilized. May contain auxiliary agents such as stabilizers, wetting agents and emulsifiers.

The compound (I) which is the active ingredient of the present invention can be produced by the method described in JP-B-60-58233.

Experimental Example 1 Inhibitory action on myocardial hypertrophy <Experimental method> (4S) -1-methyl-3-{(2
S) -2- [N-((1S) -1-ethoxycarbonyl-3-phenylpropyl) amino] propionyl} -2
-Oxo-imidazolidine-4-carboxylic acid / hydrochloride was dissolved in distilled water to prepare 4-week-old spontaneously hypertensive rats (SH
R, 6 animals per group) was forcibly orally administered (dosage: 5 mg / kg / day) once daily for 10 weeks using a gastric sonde.

Then, under ether anesthesia, the lower axilla of the SHR was cut to cause exsanguination, the heart weight was measured, and the weight per 100 g of body weight (relative heart weight) was calculated. The heart cross-sectional area was determined by the following method.

Measurement method of heart cross-sectional area After measuring the weight of the excised heart, it is immersed and fixed in 10% neutral buffered formalin solution for about 1 week, cut at a constant cleavage plane that crosses the left and right ventricles, and a specimen with a thickness of about 2 mm. And Then, this sample was embedded in paraffin according to a conventional method (Note 1) only for refixation overnight, and a hematoxylin-eosin (HE) stained sample was prepared.

An optical microscope image of the HE-stained sample obtained above was used to determine the ratio of the myocardial portion stained with eosin and the gap between the myocardium (the gap accompanying the preparation of the sample) using an image analyzer (Note 2).

Then, the real area was obtained from the stereomicroscopic image of the HE-stained sample by using an image analyzer, and the value obtained by multiplying the obtained real area by the ratio of the myocardial portion obtained was obtained as the cross-sectional area of the heart.

(Note 1): [Pathology Technical Manual 3, Pathology Specimen Creation Technology, edited by the Japanese Society of Pathology (March 30, 1981, Ito Dental Agent Publishing)
(Published by KK)] (Note 2): (Nikon 3-tube TV camera and Nikon Luzex II, manufactured by Nihon Kogaku) <Effects> The results are shown in Table 1 below.

From the above results, it is clear that the compound as the active ingredient of the present invention suppressed relative heart weight and cardiac cross-sectional area by 13% and suppressed myocardial hypertrophy as compared with the drug-non-administered group.

Experimental Example 2 Myocardial hypertrophy suppressing effect <Experimental method> (4S) -1-methyl-3-{(2
S) -2- [N-((1S) -1-carboxy-3-phenylpropyl) amino] propionyl} -2-oxo-imidazolidine-4-carboxylic acid hydrochloride is administered intraperitoneally (dosage: 0.5 mg / kg / day), and the relative heart weight was calculated in the same manner as in Experimental Example 1 to confirm the myocardial hypertrophy suppressing effect of the above-mentioned sample compounds.

<Results> The results are as shown in Table 2 below.

From the above results, it is clear that the compound which is the active ingredient of the present invention suppressed relative heart weight by 8% and suppressed myocardial hypertrophy as compared with the drug-non-administered group.

Example 1 <Manufacturing Method> Lactose and corn starch are added to the main ingredient and mixed well, and then a solution of polyvinylpyrrolidone dissolved in purified water is added and kneaded to granulate. After drying the obtained granules, magnesium stearate is added and compressed to give tablets.

Example 2 <Manufacturing Method> A tablet is obtained by treating the above formulation in the same manner as in Example 1.

Example 3 <Manufacturing Method> The main drug and sodium chloride are dissolved in distilled water for injection, filtered through a filter having a pore size of 0.22 μm, filled in an ampoule and sterilized to obtain an injection.

Example 4 <Manufacturing Method> Sodium chloride is dissolved in distilled water for injection, the main drug is added, and the mixture is dissolved with a sodium hydrogen carbonate solution. Then pore size 0.
An injection is obtained by filtering with a 22 μm filter, filling an ampoule, and sterilizing.

Claims (1)

[Claims] 1. A general formula (However, R ¹ and R ² are lower alkyl groups, R ³ is a phenyl-substituted lower alkyl group, and R ⁴ is a hydrogen atom or a lower alkyl group.) A prophylactic / therapeutic agent for heart failure containing an acceptable salt as an active ingredient.