JPH04368375A - Isoxazole derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new compound useful as anti-inflammatory, antirheumatic, antimicrobial, antiviral agents, etc. CONSTITUTION:A compound expressed by formula I [R<1> is (halogen-substituted) phenyl or (substitute) thiazolyl; R<2> is lower alkyl; R<3> is amino or lower alkylamino; (n) is 0 or 1], e.g. 5-methylamino-3-[1-(4-chlorophenyl) ethyl]isoxazole. The compound expressed by formula I is obtained by reacting a compound expressed by formula II (R<4> is lower alkyl) with acetonitrile in the presence of a base such as sodium hydride in an inert solvent such as THF, providing a compound expressed by formula III, then subjecting the resultant compound to cyclizing reaction with a hydroxylamine in the presence of a deacidifying agent (e.g. pyridine) in an inert solvent.

Description

[Detailed description of the invention]

0001

FIELD OF THE INVENTION This invention relates to novel isoxazole derivatives.

0002

BACKGROUND OF THE INVENTION The isoxazole derivative of the present invention is a novel compound that has not been described in any literature.

0003

OBJECTS OF THE INVENTION As described below, the present invention aims to provide compounds useful as pharmaceuticals.

0004

According to the present invention, an isoxazole derivative represented by the following general formula (1) is provided.

[0005]

[Chemical 2]

[In the formula, R1 is a phenyl group that may be substituted with a halogen atom or a thiazolyl group that may have one or two substituents selected from lower alkyl groups and phenyl groups, and R2 is a lower an alkyl group, R
3 represents an amino group or a lower alkylamino group, and n is 0 or 1. ] Specific examples of each group in the above general formula (1) include the following groups.

That is, examples of lower alkyl groups include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and hexyl groups.

In addition to the phenyl group, examples of the phenyl group that may be substituted with a halogen atom include 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-chlorophenyl, and 3-chlorophenyl.
, 4-dichlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-iodophenyl and the like.

Examples of the thiazolyl group which may have one or two substituents selected from lower alkyl groups and phenyl groups include 5-thiazolyl, 4-thiazolyl, 2-thiazolyl, 5-(2,4 -dimethyl)thiazolyl, 5-(2,4-diphenyl)thiazolyl, 5-(
Examples include 2-phenyl-4-methyl)thiazolyl group.

Examples of lower alkylamino groups include methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino groups.

The isoxazole derivative of the present invention represented by the above general formula (1) has excellent anti-inflammatory, anti-rheumatic,
It has various pharmacological effects such as antibacterial and antiviral properties, and is useful as a pharmaceutical agent such as an anti-inflammatory agent, anti-rheumatic agent, antibacterial agent, and anti-viral agent.

The isoxazole derivative of the present invention can be produced by various methods. A specific example thereof is shown in the reaction scheme below.

[0013]

[C3]

[In the formula, R1, R2 and n are the same as above. R4 represents a lower alkyl group. ]The above reaction process formula-
In Example 1, the reaction between compound (2) and acetonitrile is carried out in an inert solvent in the presence of a base. Examples of the inert solvent include tetrahydrofuran (THF),
diethyl ether, 1,2-dimethoxyethane, 1,4
-Dioxane etc. can be exemplified. Examples of the base include sodium hydride, sodium amide, potassium hydride,
Examples include sodium methoxide. The amount of acetonitrile used is usually 1.2 to 1.5 with respect to compound (2).
It is preferable to use about twice the molar amount. The reaction may take about 2 to 20 hours at a temperature range from room temperature to the boiling point of the solvent.

[0015] Next, compound (1a) can be obtained by subjecting the obtained compound (3) to a cyclization reaction with hydroxylamine in an inert solvent in the presence of a deoxidizing agent. Here, as the deoxidizing agent, for example, pyridine, triethylamine, 4-dimethylaminopyridine, N,N-dimethylaniline, N-methylmorpholine, etc. can be used. Further, as the inert solvent, for example, ethanol, methanol, etc. can be used. The amount of hydroxylamine used is the compound (3
), and the amount of the deoxidizing agent to be used can be appropriately selected from the range of about 3 to 20 times the molar amount of compound (3). The reaction is completed in about 5 to 24 hours at a temperature range from room temperature to the boiling point of the solvent.

[0016]

[C4]

[In the formula, R1, R2 and n are the same as above. ] In the methylation reaction of compound (1a) in the above reaction scheme-2, compound (1a) is first reacted with methyl orthoformate,
50℃~ in orthoformic acid ester such as ethyl orthoformate
This is carried out by heating the reflux temperature condition for 2 to 10 hours and then concentrating the resulting residue, which is then treated with a reducing agent in an inert solvent. Examples of the inert solvent include alcohols such as methanol and ethanol, and ethers such as diethyl ether and THF. Examples of the reducing agent include sodium borohydride and lithium aluminum hydride. The amount of the reducing agent to be used is preferably at least 1.2 times the molar amount of compound (1a) as a hydride. The reaction is carried out at a temperature of 0 to 50°C for 1 to 3 hours.

The target compounds in each step shown in the above reaction schemes can be easily isolated and purified by conventional separation means. Examples of such means include adsorption chromatography,
Examples include preparative thin layer chromatography, recrystallization, and solvent extraction.

Furthermore, the compound of the present invention can be easily converted into a pharmaceutically acceptable acid addition salt by subjecting it to an addition reaction with a suitable acidic compound according to a conventional method, and the acid addition salt can be converted into a pharmaceutically acceptable acid addition salt in the free form. It has the same pharmacological activity as the compound of the present invention, and the present invention also includes such acid addition salts. Examples of acidic compounds that can form the above acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, and benzenesulfonic acid. For example, organic acids such as

Furthermore, the compound of the present invention represented by the general formula (1) naturally includes optical isomers. These isomers can be separated by a conventional resolution method, such as a method using an optical resolving agent.

[0021]

EXAMPLES In order to explain the present invention in more detail, examples of the production of the compounds of the present invention will be given below as examples.

[0022]

[Example 1] 5-amino-3-(1-phenylethyl)
Production of isoxazole 1.75 g of 60% sodium hydride was suspended in 30 ml of THF, and 2.1 g of acetonitrile and 6.0 g of ethyl 2-phenylpropionate were mixed in THF (20 ml) under ice cooling.
) solution was added and refluxed for 5 hours. After the reaction was completed, THF was distilled off under reduced pressure, and the residue was made acidic by adding 1N hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane = 1:4) to obtain 3-oxo-4
-4.2 g of phenylpentanenitrile was obtained.

1.0 g of the compound obtained above was dissolved in 20 ml of ethanol, and 6 hydroxylamine hydrochloride was added under ice cooling.
05 mg, then 5.5 ml of pyridine was added, and the mixture was heated at room temperature for 20 min.
Stir for hours. The reaction mixture was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane = 1:4),
870 mg of the target compound was obtained.

The structure and physical properties (melting point and 1 H-NMR) of the obtained compound are shown in Table 1.

[0025]

Examples 2 to 4 In the same manner as in Example 1, the compounds shown in Table 1 were produced. The structure and physical properties of the obtained compound are also listed in Table 1.

[0026]

[Example 5] Production of 5-methylamino-3-[1-(4-chlorophenyl)ethyl]isoxazole Example 2
1.0 g of the compound obtained in 13.3 ethyl orthoformate
g and heated under reflux for 5 hours. After distilling off ethyl orthoformate under reduced pressure, the residue was dissolved in 20 ml of ethanol, and 204 mg of sodium borohydride was added under ice cooling.
Stirred at room temperature for 1.5 hours. After the reaction was completed, it was concentrated under reduced pressure, ice water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate: n-hexane =
1:3) to obtain 570 mg of the target compound.
The structure and physical properties of the obtained compound are shown in Table 1.

[0027]

[Table 1]

Claims (1)

[Claims] Claim 1: General formula [Formula 1] [wherein R1 is a phenyl group which may be substituted with a halogen atom or has 1 to 2 groups selected from a lower alkyl group and a phenyl group as a substituent] In a certain thiazolyl group, R2 represents a lower alkyl group, R3 represents an amino group or a lower alkylamino group, and n is 0 or 1. ] An isoxazole derivative represented by: