JPS61215391A - Imidazo(1,5-a)pyridin-3-one derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I or formula II (R1 is alkyl, pyridyl, thienyl, lower alkoxy, or phenyl which is monosubstituted or disubstituted with lower alkylthio; R2 is H or alkyl; with the proviso that R1 and R2 are not lower alkyl simultaneously). EXAMPLE:A compound shown by the formula III. USE:A cardiac, antiasthmatic agent, or preventive against arteriosclerosis having improved positive inotropic action on the heart, increasing action on coronary blood stream volume, increasing action on heart rate, low toxicity, bronchodilatory action and inhibitory action on blood platelet aggregation. PREPARATION:A compound shown by the formula IV is reacted with a compound (e.g., compound shown by the formula V, etc.) shown by the formula R1COCl usually in an organic solvent such as benzene, etc. in the presence of an acid binder (e.g., dimethylaniline, et.) and a catalyst [e.g., 4-(N,N-dimethyl) aminopyridine, etc.] at room temperature - the boiling point of the solvent for 1-10hr. Then, if necessary, the prepared compound shown by the formula I is reduced to give a compound shown by the formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION (Field of Industrial Application) The present invention relates to a novel compound that has excellent cardiotonic action and is useful as a cardiotonic drug, and a method for producing the same.

(Prior art) As an imidazopyridine derivative similar to the compound of the present invention,
The general formula (
II) It has been described that the substance has diuretic and antihypertensive effects. Also, Pharmaco Edizione Centifica (F
irmaco, Ed, Sci, ) 197530 (
3) 197-207 (Chem, Ab, 82-156
177S) has the general formula (Iv) (wherein rl is OH
, chlorine, methyl, methoxy, ethoxy, benzyl, amine, and r2 represents hydrogen or phenyl. ) has been reported.

The compound represented by the general formula (III) is different from the compound of the present invention, and has extremely weak cardiotonic and coronary vasodilatory effects.
It cannot be used as a medicine.

(Problems to be Solved by the Invention) The purpose of the present invention is to discover a new compound having an excellent cardiotonic effect and to provide an industrially advantageous production method thereof.

(Means for Solving the Problems) The present inventors have solved the problem by formula (1) or (II) (wherein R1 is an alkyl group, a pyridyl group, a chenyl group, a lower alkoxy group, or a lower alkylthio group). (R2 represents a hydrogen atom or an alkyl group, except when R1 and R2 are both lower alkyl groups.) and its pharmaceutically acceptable phenyl group. The salt has an excellent positive inotropic effect on the heart and an effect on increasing coronary flow, and has a weak effect on increasing heart rate and low toxicity, making it suitable as a cardiotonic agent for the treatment of heart diseases such as congestive heart failure. It was discovered that this compound is a useful compound. The compounds of the present invention also have bronchodilatory effects and platelet aggregation inhibitory effects, and are useful as anti-asthma drugs and arteriosclerosis preventive drugs.

In producing the compound of the present invention, a compound represented by the general formula (V) (wherein R2 has the same meaning as above) and a compound represented by the general formula R1COCl (M) (wherein R1 has the same meaning as above) are used. ) in the presence of an acid binder in an organic solvent. As the organic solvent, general inert solvents such as benzene, toluene, acetone, ethyl acetate, chloroform, and methylene chloride can be used, and as the acid binder, dimethylaniline,
Organic and inorganic bases such as trimethylamine, sodium carbonate, and sodium hydroxide can be used. The reaction is carried out at room temperature to the boiling point of the solvent for 1 to 10 hours.

The compound of the present invention represented by the general formula (II) is produced by reducing the compound represented by the general formula (1) obtained as described above using a reducing agent.

The reduction is preferably carried out by catalytic reduction with hydrogen over radium-carbon at room temperature and normal pressure.

(Example) Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Chemical product 1 Imidazo(1,5-a)pyridin-3-one 26f 1
00TI31 suspended in benzene, N,N-dimethylaniline 4,81 and a catalytic amount of 4-(N,N-dimethyl)
Added aminopyridine.

This suspension was cooled, and 3.52 g of innicotinic acid chloride hydrochloride was added thereto while stirring while maintaining the internal temperature at 5 to 10°C. After stirring at room temperature overnight, the reaction solution was concentrated and the residue was dissolved in 100Tn1 of water. The mixture was neutralized with a 1M aqueous sodium carbonate solution and concentrated under reduced pressure again.

20ml of methanol was added to the residue, insoluble matter was removed by filtration, and the solvent was distilled off. Silica gel column chromatography (developing solvent, chloroform/methanol = 4)
The target compound was isolated and purified by recrystallization from ethyl acetate to obtain the target compound 2.2f. Yield: 474 cm Melting point: 214-215°C Example 2 Compound 10 2-inpropylimidazo(1,5-a)pyridine-3
2.81 of -one was dissolved in 20- of pyridine. While cooling and stirring to maintain the internal temperature at 0 to 5°C, 3.71 g of 4-methylthiobenzoyl chloride was added, and finally a catalytic amount of 4-(N,N-dimethyl)aminopyridine was added. After stirring at room temperature overnight, the solvent was distilled off under reduced pressure, 200 rnl of ethyl acetate was added to the residue, and the insoluble matter was filtered. From the mixture obtained by concentrating the mother liquor, the target compound was isolated using silica gel column chromatography, and purified by recrystallization from benzene-n-hexane to obtain the target compound 2.
-isopropyl-1-(4'-methylthio)benzoylimidazo C1=5-a) pyridin-3-one3. CM'
t- got it. Yield: 579°C Melting point: 134-135°C Example 3 Compound 5 1-yne nicotinoyl imidazo (1
t5-a) Dissolve pyridine-3-oy6001MI in 30-methanol and dissolve
was added and reduced using an atmospheric pressure catalytic reduction apparatus. The reaction was stopped when the theoretical amount of hydrogen was absorbed, the catalyst was filtered off, and the mother liquor was concentrated under reduced pressure. Use silica gel column chromatography to remove the residue! The target product 450H9 was obtained using W. Yield: 73.8°C Melting point: 184.5-186°C Table 1 shows representative examples of the compounds of the present invention and their physical constants.

(Effects of the Invention: Pharmacological Effects) Next, representative examples of the pharmacological activities of the compounds obtained by the present invention will be described.

1. Cardiotropic Arch, Int.

Pharmacodyn, ) Volume 155, Page 251, 196
Erjavek, F., Adamic, S.
, etc., with some modifications. That is, the guinea pig was killed, the occipital artery was cut, the occipital artery was cut, the heart was exsanguinated, the heart was removed, a gas mixture (95% oxygen, 5% carbon dioxide) was aerated, the blood was washed out in 7-cellite solution, the left atrium was cut into Krebs, and the animal was kept at 30°C. Adipose tissue attached to the left atrium was removed and a specimen was prepared. One end of the prepared specimen was fixed with a thread to the Kreps-Henserite solution reaction tank, and the other end was connected with a thread to a Zhang Quadran juicer to record the contraction. In addition, an electrical stimulation device and a stain pole were set on the specimen, and electrical stimulation was applied to the specimen so that the contraction tension remained constant. The test compound was dissolved and diluted in dimethyl sulfoxide or acetone in advance to prepare a constant concentration, and a constant amount was added to the Krebs-Henseleit liquid reaction tank to measure changes in contractile force. The results are shown in Table 2.

8g2 Table 2 Coronary blood flow dilation effect Measured using guinea pig hearts using the Langendoff method. Medical Research Series (Med-
icml Research 5eries) A 3
187 pages (1968).

The results are shown in Table 3.

Table 3: Bronchodilator effect, anti-pharmacodynamics and therapy (Arch, Int.

Pharmacodyn,) Volume 111, 392-400
It was performed according to the method of F. P. Luduena et al., p. 1957.

That is, after killing Mormono+1, the lungs are removed together with the trachea, a cannula is inserted into the trachea, and the cannula is perfused with Cytairode's solution. Methacholine (methac)
oline) 0.05 r After the trachea was perfused with 7 ml of Tyrode's solution, Tyrode's solution containing a constant concentration of the test compound was perfused, and the increase/decrease in the amount of perfusion was measured. The results are shown in Table 4.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is an alkyl group, a pyridyl group, a thienyl group, or a lower alkoxy group or a phenyl group mono- or di-substituted with a lower alkylthio group, R_2 represents a hydrogen atom or an alkyl group (except when R_1 and R_2 are both lower alkyl groups) and their pharmaceuticals acceptable salt. 2. Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 and R_2 have the same meanings as above, except when R_1 and R_2 are lower alkyl groups at the same time.) 3. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is an alkyl group, a pyridyl group, a thienyl group, or a phenyl group mono- or di-substituted with a lower alkoxy group or a lower alkylthio group, and R_2 is hydrogen. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ ( In the formula, R_1 and R_2 have the same meanings as above.)
A method for producing a compound represented by