JPS5815913A - Cardiac agent - Google Patents

Abstract

PURPOSE:To provide a cardiac agent effective for the remedy of cardiac insufficiency by oral or parenteral administration without causing the side effects such as gastrointestinal disorder, hepatic function disorder, arrhythmia, etc., by using an acylpyridineguanylhydrazone derivative or its salt as an active component. CONSTITUTION:The acylpyridineguanylhydrazone derivative of formula (R<1> and R<2> are H or 1-6 C alkyl) or its salt is used as an active component. Examples of the above compound of formula are, 4-pyridinecarboaldehydogyanylhydrazone, 3-pyridinecarboaldehydoguanylhydrazone, 4-acetylpyridineguanylhydrazone, etc. The compound of formula can be prepared by reacting an acyl pyridine compound with aminoguanidine bicarbonate in a general solvent preferably ethanol, in the presence of a base such as triethylamine, etc. as a catalyst, under heating and refluxing.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a cardiotonic agent, and more particularly to a cardiotonic agent containing an acylpyridineanylhydrazone derivative or a salt thereof.

Cardiac inotropes act on cardiac K111 to strengthen its contractile force, and various drugs have been used to treat heart failure.

However, even if these inotropic agents are administered under strict control, long-term administration may result in side effects such as gastrointestinal disorders, liver dysfunction, and arrhythmia.

We conducted a search for a compound useful as a cardiotonic agent, and as a result, arrived at the present invention. That is, the present invention resides in a cardiotonic agent containing a derivative of general formula (1) or a salt thereof.

The present invention will be explained below.

The acylpyridinanylhydrazone derivative according to the present invention is produced, for example, by the following method.

That is, it is a method of heating and refluxing acylpyridines with aminoguanidi bicarbonate using a general solvent, preferably ethanol, and a base, preferably triethylamine, as a catalyst.

Examples of the acylpyridinanylhydrazone derivatives in the present invention include the following compounds.

Goopyridine carbaldehyde guanyl hydrazone, 3
-Pyridinecarbaldehydeguanylhydrazone, guacetylpyridinanylhydrazone, 3-acetylpyridinanylhydrazone, 3-methyl-μm pyridinecarbaldehydeguanylhydrazone, 3-methyl-guacetylpyridinanylhydrazone, gupropionylpyridinanylhydrazone, −
Mono-pyridine carbaldehyde guanyl hydrazone, co-acetyl pyridine anyl hydrazone.

The obtained acylpyridinanylhydrazone derivative is
Depending on the cost, pharmaceutically acceptable salts such as hydrochloride, lactate, and oxalate can be prepared by conventional methods. can be administered.

Forms in which the medical treatment of the present invention is provided include, for example, powders, granules, tablets, sugar-coated tablets, pills, capsules, liquids, emulsions, ampoules, and injection solutions for oral administration, and of course, forms in which these are combined are also available. Provide vine. For formulation, conventional methods in this field can be used.

The dosage of the cardiotonic drug of the present invention is determined based on age, sex, body weight, sensitivity difference, administration method, administration timing, interval, degree of disease, body-1
It is determined by the physician, including the nature, preparation, type, and type of active ingredient of the pharmaceutical preparation.

For example, in the case of oral administration, body weight tK41i daily allowance, o,
A dosage of about i to 10q/- is selected, but of course it is not limited to this.

Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples.

7-' Reference Example/μm Pyridine carbaldehyde λ, l≠l was dissolved in ethanol 4IO-, and aminoguanidine bicarbonate, 7f, was added while stirring at room temperature. The mixture was heated to reflux for 3 hours.

The solvent was distilled off under reduced pressure, and the resulting solid was crystallized with tetrahydrofuran to obtain a pale orange solid. Dissolve this compound in a small amount of ethanol, add λcohydrogen chloride ethanol solution, collect the precipitated solid, and add salt M*80 2
g (mp cocoa-coa J') was obtained.

(2) Synthesis of q-acetylpyridine-guanylhydrazone Guacetylpyridine 271.211. Aminoguanidine bicarbonate 83611 ethanol λO-, triethylamine λ
- The mixture was heated to reflux for an hour. After cooling, the precipitated solid was separated from each other, and the F solution was concentrated under reduced pressure, and a solid was precipitated. The mixture was washed with ether and dried to obtain a yellow solid of 0211.

3-Pyridinecarbaldehyde2. / IA I was dissolved in 4AOtdK of ethanol, and while stirring at room temperature, 2.7.2F of aminoguanidine bicarbonate was added. Furthermore, 2-triethylamine was added.

The mixture was heated to reflux for S, S hours. A small amount of insoluble matter was separated and the solvent was distilled off under reduced pressure. Ether was added to the residue, and the solid was washed separately with ether. The obtained solid was dried under reduced pressure and crystallized with tetrahydrofuran to obtain a pale yellow solid. Add a 1.2rs structured hydrogen ethanol solution to the ethanol,
The precipitated solids were reconsolidated with ethanol-water to obtain 0.0% hydrochloride. rt, S'(mpJjJ' -260°)
I got it.

The usefulness of the acylpyridinanylhydrazone derivatives of the present invention as cardiotonic agents was demonstrated by the pharmacological test method of Chojun, for example, by causing a significant increase in the contractile force of the isolated papillary muscle of dogs and the Wll left atrial muscle of guinea pigs, and by the use of anesthesia. It is distinguished by its effectiveness in causing a significant increase in cardiac contractility in dogs. The pharmacological and acute toxicity test methods are described below.

/, A method using a cross-flow camphor for canine extraction mammary muscles *g* The book is Endo and Hashimoto's method [American Journal
J, Physiol, Vol. 2/I, p. 63, 7Q, USA]. Method using isolated left atrium of n2 guinea pig Body weight: −00 to 3
A male guinea pig No. 001 was hit on the back of the head and the left atrium was immediately removed.

The left atrioventricular ostium was placed in an organ bath filled with 30 d of Krebs-Henslide solution kept at 31°C. Kreps-Hensleit solution KFi in the organ bath 71 o, and! - Aerate a mixed gas consisting of co, and 9. heart in the left atrium]! A string was attached to the ``9'' and the other end of the string was connected to the transdeacer to measure isometric tension.
A resting tension of y was applied. The specimen was electrically driven via a single platinum electrode with a square wave of duration/millisecond and voltage 3 times the dark value twice every 7 seconds. 11 After stabilizing for 30 minutes after preparation, the compound dissolved in the solvent was added to the organ bath and the reaction was recorded.

3. Method using anesthetized dogs Mongrel dogs of both sexes weighing 1-/j14 were used. The dog is JO*/K
Anesthetize with bentoparbital sodium (intravenous injection),
Artificial respiration was performed. A thoracotomy was made between the fourth and fifth left ribs, and the fifth rib was removed. The cardiac membrane was incised and the heart exposed.

An electromagnetic flowmeter glove was attached to the ascending aorta to measure aortic blood flow, which was used as an approximate index of cardiac output (CO). A bolietele/caniere was inserted into the left ventricle, the left ventricular pressure was determined, and the rate of change in the left ventricular pressure f dp/dt was electrically determined. A strain measurement gauge was placed on the right ventricular wall to measure the contractile force (cont) of the right ventricular muscle. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured using an electrocardiogram (Mflj). The compound dissolved in a solvent was administered intravenously into the left femoral vein.

False acute toxicity Acute toxicity (LD,) when administered intravenously to male mice.

value) is based on the Litchfield and Willkokmen method [Journal of Pharmacology and Experimental Therapeutics (J, Pharmaco.
1, Fixp, Ther., Vol. 6, p. 3, Iyu, USA].

When the above pharmacological test was conducted, the contractile force of dog papillary muscle and guinea pig left atrial muscle was increased, and the maximum rate of change in left ventricular pressure (dp/dtmaz) during anesthesia was increased.
o, causing an increase in cardiac contractility.

The main rule is the rate of increase in dog papillary muscle contractile force when administering 100,300j111, /f''.

J X / (f” Rate of increase in left atrial contraction force of guinea pigs when I/lri was administered, and / , J q/K
Anesthetized dp/dtmax when g is administered, 0
The increase rates of ont and Co are shown in Table/. In addition, acute toxicity (LD,
. Table 2 shows n / / / / 7,・″ / / 7/ //″ /

Claims (1)

[Claims] (1) Acylpyridinanylhydrazone derivatives represented by the general formula (I) (wherein R" and R" represent hydrogen or a lower alkyl group having a carbon number of -4),
or cardiac drugs containing its salts.