JPS5940149B2 - Oxindole derivative - Google Patents

Description

[Detailed description of the invention] The present invention relates to novel oxindole derivatives.

The compound of the present invention is a new compound that has not been described in any literature, and has the general formula [wherein R_1 is a hydrogen atom or a lower alkyl group, R_2
represents a hydrogen atom, lower alkyl group or phenyl group, R_3
represents a morpholino group, a 2-pyridyl group, or a 1-piperazinyl group having a lower alkyl group, a lower alkoxy-substituted phenyl group, or a phenyl group as a substituent.

] and its acid addition salts. In the above general formula [I], R_1 and R_2
Lower alkyl group represented by and 1- represented by R_3
Examples of the lower alkyl group substituted with the piperazinyl group include linear or branched alkyl groups having 1 to 3 carbon atoms, and specific examples include methyl, ethyl, propyl, and isopropyl groups.

Examples of the lower alkoxy group in the lower alkoxy-substituted phenyl group substituted with the 1-piperazinyl group represented by R_3 include methoxy, ethoxy, propoxy, and isopropoxy groups. The lower alkoxy group in the lower alkoxy-substituted phenyl group substituted with the 1-piperazinyl group represented by R_3 includes methoxy, ethoxy,
Examples include propoxy and isopropoxy groups. Representative compounds of the present invention are listed below.

03-Methyl-3-morpholinooxindole〇1,3-dimethyl-3-morpholinooxindole 0
1,3-dimethyl-3-[1-(4-0-methoxyphenylpiperazinyl)]oxindole 03-methyl-
3-[1-(4-phenylpiperazinyl)]oxindole 01,3-dimethyl-3-[1-(4-phenylpiperazinyl)]oxindole 03-methyl-3-
[1-(4-methylpiperazinyl)]oxindole 01.3-dimethyl-3-[1-(4-methylpiperazinyl)]oxindole 01-methyl-3-(2-pyridyl)oxindole 03 -Methyl-3-(2-pyridyl)oxindole 01,3-dimethyl-3-
(2-pyridyl)oxindole 01.3-diethyl-3-(2-pyridyl)oxindole 01.3-dipropyl-3-(2-pyridyl)oxindole 01
-Methyl-3-ethyl-3-morpholinooxindole 01-ethyl-3-morpholinooxindole 01
-Methyl-3-phenyl-3-morpholinooxindole 03-phenyl-3-[1-(4-methylpiperazinyl)]oxindole 01-Methyl-3-phenyl-3-(2-pyridyl)oxindole 03 -[1-
(4-(3,4-dimethoxyphenyl)piperazinyl)
] Oxindole The compound of the present invention can be produced by various methods, but a preferred example is a method in which a compound of the general formula [] and a compound of the general formula [] are separated from each other as shown in the following reaction scheme-1. The compound of the present invention is produced by reacting in the presence of a hydrogen halide agent.

Reaction Scheme-1 [In the above formula, when X1 represents a hydrogen atom, X2 represents a halogen atom, and when X1 represents a halogen atom, X
2 represents a hydrogen atom.

R1, R2 and R3 are the same as above. ] In the reaction between the compound of general formula [H] and the compound of general formula [], the compound of general formula []
The ratio of the compound of the formula [] to the compound of the general formula [] is not particularly limited and is appropriately selected within a wide range, but usually the latter is used in an equimolar to excess amount, preferably an equimolar to 3 molar amount of the former.
It is better to use twice the molar amount.

The above reaction is usually carried out using a base compound as a dehydrohalogenating agent. A wide range of known basic compounds can be used, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium ethylate, potassium methylate, butyllithium, sodium hydride, potassium hydride, lithium hydride, and sodium amide. , lithium amide, potassium amide, morpholine, piperazine, piperidine, pyridine, triethylamine, and the like. The amount of such a base compound to be used is not particularly limited and is appropriately selected within a wide range, but is usually from equimolar to excess, preferably equimolar to 1.5 times the amount of the compound of general formula [H]. It is best to use molar amounts. The reaction is carried out either in the absence of a solvent or in the presence of a solvent.
Any inert solvent that does not adversely affect the reaction can be used as the solvent, specifically ethers such as diethyl ether, tetrahydrofuran, monoglyme, diglyme, dioxane, dimethoxyethane, and aromatic solvents such as benzene, toluene, and xylene. Hydrocarbons, hydrocarbons such as pentane, hexane, cyclohexane, acetonitrile,
Examples include N-N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, and the like. The reaction normally proceeds suitably at a temperature of about room temperature to about 200°C, and is completed in about 1 to 30 hours. In the above reaction scheme-1, a compound in which X1 is a hydrogen atom (general formula [a)] and a compound in which X2 is a hydrogen atom (general formula [a)]
]) is preferably carried out as follows.

[In the above formula, X represents a halogen atom, and H? large) is R3
H (R3 is the same as above).

R1 and R2 are the same as above. That is, the reaction between the compound of the above general formula [a] and the compound of the above general formula [a] is carried out in the absence of a solvent or in a suitable solvent in the presence of the above-mentioned dehydrohalogenating agent.

The ratio of the compound of general formula [a] and the compound of general formula [a] to be used is usually an equimolar to excess amount, preferably an equimolar to three times the molar amount of the latter relative to the former. The dehydrohalogenating agent is used in an amount of equimolar to 1.5 molar to the compound of general formula [a].
It is better to use twice the molar amount. Solvents used include ethers such as tetrahydrofuran, diethyl ether, dioxane, diglyme, and dimethoxyethane, benzene,
Aromatic hydrocarbons such as toluene and xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide,
Examples include hexaphosphoric acid triamide. The reaction temperature is usually room temperature to 150°C, preferably room temperature to 100°C. Further, the reaction time is generally about 1 to 24 hours. In the above reaction scheme-1, the reaction between the compound in which X1 is a hydrogen atom (general formula [b]) and the compound in which X2 is a halogen atom (general formula [b]) is carried out as follows. preferable. [In the above formula, X-2 means R3X (X is a halogen atom, R3 is the same as above).

R1 and R2 are the same as above. ] In other words, the reaction between the compound of the above general formula [b] and the compound of the above general formula [b] produces sodium ethylate, sodium methylate, butyl lithium, sodium hydride, potassium hydride, lithium hydride, sodium amide, lithium. The reaction is carried out in the presence of a dehydrohalogenating agent such as amide or potassium amide, without a solvent, or in a suitable solvent.

The ratio of the compound of general formula [b] and the compound of general formula [b] to be used is usually an equimolar to excess molar amount, preferably an equimolar to twice molar amount of the latter relative to the former. The dehydrohalogenation agent is equimolar to 1.5 molar to the compound of general formula [b].
It is better to use twice the molar amount. A wide range of inert solvents can be used that do not adversely affect the reaction, including diethyl ether, tetrahydrofuran, monoglyme, diglyme, ethers such as dioxane and dimethoxyethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. hydrocarbons such as pentane, hexane, cyclohexane, acetonitrile, N-N-dimethylformamide,
Examples include dimethyl sulfoxide and hexamethyl phosphoric triamide. The reaction temperature is usually room temperature to 200°C, preferably about 50 to 150°C. Further, the reaction time is generally about 1 to 30 hours. The compound of the present invention can also be produced by the method shown in Reaction Scheme-2 below.

Reaction Scheme-2 [In the above formula, R4 represents a lower alkyl group, and X3 and X4 represent a halogen atom.

(Bashuichi means R3. R1 and R2 are the same as above.) The compound of general formula [1] obtained by the above method can be easily converted into an acid addition salt.

As the acid used to form such acid addition salts, any of various pharmacologically acceptable acids can be used, including hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Examples include inorganic acids such as acetic acid, lactic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, p-tosylic acid, and benzoic acid. *} The general formula obtained in this way [
After the completion of the above reaction, the compound 1] and its acid addition salt can be easily obtained by conventional separation methods such as solvent extraction, dilution, precipitation, recrystallization, column chromatography, preparative thin layer chromatography, etc. Isolated and purified. The compound of general formula [1] and its acid addition salt of the present invention are used to synthesize indrichone derivatives represented by general formula [] useful as anti-ulcer agents and antihypertensive agents as shown in the following reaction scheme-3. It is useful as an intermediate for oxidation, and also has gastric acid secretion suppressing and hypotensive effects, and is an anti-ulcer agent.
Useful as an antihypertensive agent. Reaction Scheme-3 The present invention will be further clarified with the following production examples.

Production Example 1 2.27 ml of 3-methyl-3-bromooxindole was suspended in 30 ml of anhydrous ether, and a solution of 1.97 morpholine dissolved in 5 ml of ether was added dropwise with stirring at room temperature.4.
Stir for 5 hours.

Ether is distilled off, water and methylene chloride are added to the residue, and the methylene chloride solution is separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue is recrystallized from emeno-ether to give colorless prismatic crystals of 3-methyl-3-morpholinooxindole 2.17. Melting point 178-1800C*
? NMRδDMSO: 1.37ppm (3H, .s13th CH3) 2.40
〜2・70ppm (4H,.m1 morpholino group 2・6
hydrogen at position) 3.30 to 3.60 ppm (4H,.m1 hydrogen at position 3 and 5 of morpholino group) 6.60 to 7.20 ppm
m (4H.m, hydrogen at positions 4, 5, 6, and 7 of oxindole) 10.13 ppm (1H,.br.s, hydrogen at position 1 of oxindole) Production examples 2 to 6 Using appropriate starting materials (・Similar to Production Example 1, the following 1st
The compounds shown in the table are obtained.

Preparation Example 7 0.57 ml of 50% oily sodium hydride is suspended in dry dimethoxyethane 5a.

Add 1.67 ml of 1,3-dimethyloxindole to this suspension in 5 ml of dry dimethoxyethane while stirring at room temperature.
Add the solution dropwise and stir for 1 hour. A solution of 3.2 y of 2-bromopyridine in 5 ml of dry dimethoxyethane is added dropwise to the solution while stirring at room temperature. Stir at room temperature for 5 hours and further under reflux for 8 hours. Pour the reaction solution into ice water and extract with ether. The ether solution is washed with water and saturated saline, and then dried over potassium carbonate. After distilling off the solvent, the residue was subjected to alumina column chromatography (talc basic alumina 50).
t activity grade). Elution with benzene gives 1.57 g of 1,3-dimethyl-3-(2-pyridyl)oxindole as a colorless oil. NMRδCD
Cl3: 1.73ppm (3H, CH3 at .s13 position)
3.23ppm (CH3 at position 11 of 3H1s) 6.60~
7.60ppm (3H,.m1 3, 4, 5 of pyridyl group
Hydrogen at position 8.30 to 8.50 ppm (hydrogen at position 6 of 1H1ml pyridyl group) Production Example 8 3-(2-
pyridyl)oxindole is obtained.

Yellow-brown powdery crystals, melting point 223.5-226°C Production Example 9
0.5y of 50% oily sodium hydride is suspended in 15ml of diphenyl ether.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a hydrogen atom or a lower alkyl group, R_2
represents a hydrogen atom, lower alkyl group or phenyl group, R_3
represents a morpholino group, a 2-pyridyl group, or a 1-piperazinyl group having a lower alkyl group, a lower alkoxy-substituted phenyl group, or a phenyl group as a substituent. ] Oxindole derivatives and acid addition salts thereof.