JPS649290B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a cardiotonic agent, and more particularly to a cardiotonic agent containing a pyridinone derivative or a salt thereof. Cardiotropes have the effect of directly acting on the heart to strengthen its contractile force, and various drugs have been used to treat heart failure. However, even if these cardiotonic agents are administered under strict control, when administered for a long period of time, side effects such as gastrointestinal disorders, liver dysfunction, and arrhythmia may occur. The present inventors have searched for a compound that is highly active as a cardiotonic agent and can therefore exert a cardiotonic effect with a small dose, and have arrived at the present invention. That is, the present invention is based on the general formula () or (')

【formula】

[Formula] (wherein, X represents a hydrogen atom, a cyano group, or an amino group, and Y represents a hydrogen atom, a halogen atom, or a nitro group, provided that when X is a hydrogen atom,
Y is not a hydrogen atom, and R is a lower alkyl group having 1 to 6 carbon atoms). The present invention will be explained in detail below. The pyridinone derivative in the present invention is produced, for example, by the following route. For example,

[Formula] is also above

It is used as a condensation raw material in place of [Formula]. Examples of pyridinone derivatives in the present invention include the following compounds. 3-amino-5-nitro-6-methyl-2
(1H)-pyridinone, 3-amino-5-nitro-6-ethyl-2
(1H)-pyridinone, 3-amino-5-nitro-6-isopropyl-
2(1H)-pyridinone, 3-amino-5-bromo-6-methyl-2
(1H)-pyridinone, 3-amino-5-chloro-6-ethyl-2
(1H)-pyridinone, 3-amino-5-fluoro-6-methyl-2
(1H)-pyridinone, 3-amino-5-bromo-6-ethyl-2
(1H)-pyridinone, 3-cyano-5-nitro-6-ethyl-2
(1H)-pyridinone, 3-cyano-5-nitro-6-isopropyl-
2(1H)-pyridinone, 3-cyano-5-bromo-6-ethyl-2
(1H)-pyridinone, 1,2-dihydro-2-oxo-6-ethyl-
Nicotinonitrile, 1,2-dihydro-2-oxo-5-nitro-
6-Methyl-nicotinamide, 5-nitro-6-methyl-2(1H)-pyridinone, and the resulting pyridinone derivatives can be treated with pharmaceutically acceptable salts, such as hydrochloride, lactate, and sulfur, by conventional methods, if necessary. It can be an acid salt. The cardiotonic agent according to the present invention can be administered by an appropriate oral or parenteral administration method. The pharmaceutical composition of the present invention may be provided in a form for oral administration, such as powders, granules, tablets, sugar-coated tablets, pills, capsules, and liquid preparations, and for parenteral administration, such as suppositories, suspensions, solutions, emulsions, etc. Examples include ampoules and injection solutions. Of course, a combination of these can also be provided. 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 medical condition, physical condition, nature/preparation/type of pharmaceutical preparation, etc.
It is determined by a doctor, taking into consideration the type of active ingredient, etc. For example, in the case of oral administration, 1 kg body weight per day
A dosage of about 0.1 to 10 mg/Kg is selected, but of course it is not limited to this. Hereinafter, the present invention will be explained in more detail with reference to Examples. Reference Example 1 Synthesis of 3-amino-5-nitro-6-methyl-2(1H)-pyridinone (Compound 1) 39.6 g of acetaldehyde dimethyl acetal,
32.6 g of cyanoacetamide was added to 450 ml of water, and then 15 ml of acetic acid was added, followed by neutralization with piperidine.
The reactor is heated and kept at reflux for 15 hours. Thereafter, it was cooled, and the crystals were collected and dried. 32.5 g of crude 1,2-dihydro-2-oxo-6-methyl-nicotinonitrile was obtained. The above product is then nitrated. 30.4 g of the above 1,2-dihydro-2-oxo-6-methyl-nicotinonitrile was added to 300 ml of concentrated sulfuric acid, and while stirring, 34.7 g of potassium nitrate was slowly added at below 35° C. over 1 hour. then 35℃
Continue stirring for another 3 hours, then raise the temperature to 40℃.
Stirred for 1.5 hours. The contents were poured into ice water 1 and the precipitated crystals were collected and dried to obtain 42.78 g of 1,2-dihydro-2-oxo-5-nitro-6-methyl-nicotinoamide. (Compound 4) Next, an amination reaction is performed. For the amination reaction, ordinary Hofmann decomposition was used. 70 g of caustic soda was dissolved in 800 ml of water, 11 ml of bromine was added under ice cooling, and the mixture was stirred for 15 minutes. Furthermore, the above 1,2-dihydro-2-oxo-5-nitro-
Added 32.8 g of 6-methyl-nicotinamide.
Stirred for 1.5 hours. The mixture was then heated to 70°C, cooled after 3 hours, and neutralized to pH 7 with concentrated hydrochloric acid. . The crystals were dried to obtain 17.0 g of 3-amino-5-nitro-6-methyl-2(1H)-pyridinone. Reference Example 2 Synthesis of 3-amino-5-bromo-6-methyl-2(1H)-pyridinone (Compound 2) 1,2-dihydro-2-oxo-6-methyl-nicotinonitrile obtained in Reference Example 1 5.1g of acetic acid 120
ml and heated to 120°C to dissolve, and 2.5 ml of bromine was added. After keeping it at 120°C for 20 minutes, it was cooled, and the contents were poured into 200ml of ice water to collect crystals and dry them. 1,2-dihydro-2-oxo-5-bromo-
6.7 g of 6-methylnicotinonitrile was obtained. 1.5 g of this product was dissolved in 8 ml of 90% sulfuric acid and a hydrolysis reaction was carried out at 75°C for 2 hours. After cooling, it was poured into 40 ml of ice water and the precipitated crystals were dried. As a result, 1.4 g of 1,2-dihydro-2-oxo-5-bromo-6
-Methyl-nicotinamide was obtained. Next, we perform Hoffman decomposition. 18.7 g of caustic soda was dissolved in 30 ml of water, 0.31 ml of bromine was added under ice cooling, and the mixture was stirred for 15 minutes. In addition, 1,2-dihydro-2-oxo-5-bromo-6
-Methyl-nicotinamide 1.0g was added, stirred for 1.5 hours, heated and reacted at 70°C for 3.5 hours. After cooling, it was neutralized to pH 7-8 with 12N hydrochloric acid. Dry the crystals and obtain 0.759 g of 3-amino-5-bromo-6.
-Methyl-2(1H)-pyridinone was obtained. Reference example 3 5-nitro-6-methyl-2(1H)-
Synthesis of pyridinone (compound 3) Add 20 g of 6-methyl-2(1H)-pyridinone to about 60 ml of concentrated sulfuric acid, add 10 ml of fuming nitric acid, and hold at 30°C.
The reaction is allowed to proceed for the next 2 hours. The reaction solution was poured into 600 ml of cold water, and the precipitated crystals were collected and dried to obtain 3.84 g of crude crystals. 250 ml of methanol was added to 3.84 g of this crystal, refluxed, cooled, the precipitated crystals were taken and dried, and 2.66 g of 5-nitro-6-methyl-2 (1H) was obtained.
- Obtained pyridinone. Reference example 4 1,2-dihydro-2-oxo-6-
Synthesis of ethyl-nicotinonitrile (compound 5) 18.6 g of sodium methoxide in 350 ml of ether
was added, and while stirring, a mixed solution of 23.5 g of methyl ethyl ketone and 24.1 g of ethyl formate was added dropwise over 20 minutes. After being left at room temperature for 2 days, the solvent was evaporated to dryness. So 27.0g of cyanoacetamide and 160ml of water
After adding 3.2 ml of acetic acid, the mixture was neutralized with piperidine. After heating under reflux for 2 hours, cool and PH with acetic acid.
Acidified to 5-6. The precipitated crystals were collected and dried to obtain 4.63 g of 1,2-dihydro-2-oxo-6-ethyl-nicotinonitrile. The usefulness of these compounds as cardiotonic agents has been demonstrated using standard pharmacological test methods, such as significant increases in the contractile force of isolated papillary muscle in dogs and isolated left atrial muscle in guinea pigs, and cardiac contractility in anesthetized dogs. demonstrated by its effectiveness in causing a significant increase in The pharmacological and toxicity test methods are described below. 1. Method using canine isolated papillary muscle cross-reflux specimens Canine isolated papillary muscle cross-reflux specimens are prepared using the method of Endo and Hashimoto [American Journal of Physiology (American J. Physiol.) Vol. 218, 1459].
1463, 1970, USA Reference]. A compound dissolved in a solvent is injected proximally into the specimen,
The effect on papillary muscle contraction was recorded. 2. Method using isolated left atrium of guinea pig A male guinea pig weighing 200 to 300 g was hit on the back of the head, and the left atrium was immediately removed. The left atrium was kept warm at 35°C with Krebs-Hensreit solution.
It was fixed at the bottom of a 30 ml organ bath. The Krebs-Hensreit solution in the organ bath contains 95% _O2 and 5
A gas mixture consisting of % _CO2 was bubbled through. A string was attached to the atrial appendage of the left atrium, the other end of the string was connected to a transducer, and the isometric tension was measured. A resting tension of 0.5 g was applied to the specimen. The specimen was electrically driven via two platinum electrodes with a square wave of 1 millisecond duration and a voltage of 1.5 times the threshold twice per second. After preparation and stabilization for 30 minutes, the compound dissolved in solvent was added to the organ bath and the reaction was recorded. 3 Method using anesthetized dogs Male and female mixed dogs weighing 8 to 15 kg were used. Dogs: 30mg/
The patient was anesthetized with Kg (intravenous injection) of pentobarbital sodium and artificial respiration was performed. A thoracotomy was made between the fourth and fifth left ribs, and the fifth rib was removed. The heart sac was incised and the heart exposed. An electromagnetic flowmeter probe was attached to the ascending aorta to measure aortic blood flow, which was used as an approximate index of cardiac output (CO).
A polyethylene cannula was inserted into the left ventricle, the left ventricular pressure was measured, and the rate of change in left ventricular pressure (dp/dt) was determined electrically. A strain measurement gauge is attached to the left ventricular wall, and the contractile force (Cont) of the right ventricular muscle is measured.
was measured. Systemic blood pressure was measured from the left femoral artery. Heart rate was measured by electrocardiogram (lead 1).
The compound dissolved in the solvent was administered intravenously through the left femoral vein. 4 Acute toxicity Acute toxicity (LD ₅₀ value) when administered intravenously to male mice was determined by the method of Richfield and Wilcoxon [J. Phormacol. Exp. Ther. Volume 96, pages 99-113,
1949, United States Reference]. When the above-mentioned pharmacological tests were conducted, all of the cardiotonic agents of the present invention increased the contractile force of the papillary muscle of dogs and the left atrial muscle of Guinea pigs, and the maximum rate of change in left ventricular pressure (dp/dtmax) of anesthetized dogs Cont , increase in CO,
ie caused an increase in cardiac contractility. The rate of increase in papillary muscle contractility in dogs when 100 and 300 μg of these compounds were administered, the rate of increase in left atrial contractility in guinea pigs when 10 ^-5 and 3 × 10 ^-5 g/ml were administered, and 1.3 mg/mL of these compounds. dp/dt of anesthetized dog when administering Kg
The increase rate of max Cont CO is shown in Table 1. Table 2 also shows the acute toxicity ( _LD50 value) when these compounds were administered intravenously to male mice.

【table】

【table】

Claims (1)

[Claims] 1 General formula () or (') [Formula] [Formula] (wherein, X represents a hydrogen atom, a cyano group, or an amino group, and Y represents a hydrogen atom, a halogen atom, or a nitro group) Expression, however, when X is a hydrogen atom,
A cardiotonic agent containing a pyridinone derivative or a salt thereof, wherein Y is not a hydrogen atom and R represents a lower alkyl group having 1 to 6 carbon atoms.