JPS6146476B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel oxazole derivatives. The oxazole derivative of the present invention is a novel compound that has not been described in any literature, and is represented by the following general formula (1). [In the formula, R is a lower alkyl group, a phenyl group, a naphthyl group, or a group consisting of a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a cyano group, a halogen atom, and a phenyl group as a substituent. Indicates a phenyl group that may have 1 to 3 groups selected from Y represents an oxygen atom or a sulfur atom. n represents 2 or 3. ] The compound represented by the above general formula (1) has a local anesthetic effect and a platelet aggregation inhibiting effect, and is useful as a local anesthetic, a prophylactic or therapeutic agent for thrombosis, and the like. Specifically, each group shown in the above general formula (1) is as follows. Lower alkyl group...methyl, ethyl, propyl,
Isopropyl, butyl, tert-butyl, pentyl, hexyl groups, etc. Naphthyl group...α-naphthyl group, β-naphthyl group, etc. Halogen atoms: fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, etc. Halo lower alkyl group: trifluoromethyl, tribromomethyl, trichloromethyl, triiodomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl group, etc. Lower alkoxy groups: methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy groups, etc. Lower alkylthio groups: methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, pentylthio, hexylthio groups, etc. A phenyl group that may have 1 to 3 groups selected from the group consisting of an alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a cyano group, a halogen atom, and a phenyl group as a substituent... ... phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl, 4-propylphenyl, 4-isopropylphenyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl,
2,3,5-trimethylphenyl, 2,3,6-
Trimethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-
Trifluoromethylphenyl, 3-tribromomethylphenyl, 3-trichloromethyl-phenyl, 3-triiodomethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 4-ethoxy Phenyl, 4-propoxyphenyl, 4-isopropoxyphenyl, 4
-butoxyphenyl, 4-tert-butoxyphenyl, 2-methylthiophenyl, 3-methylthiophenyl, 4-methylthiophenyl, 2-methyl-
4-methylthiophenyl, 3-methyl-4-methylthiophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-chlorophenyl, 3-fluorophenyl, 4-bromphenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, 2,4-dibromophenyl, 2
-Phenylphenyl, 3-Phenylphenyl, 4
-phenyl phenyl group, etc. The compound of the present invention can be manufactured by various methods, and one preferred example thereof is the method shown below. [In the formula, X represents a halogen atom, and R' represents a halogen atom. R and Y are the same as above. ] That is, the compound of the present invention can be obtained by reacting a known halogen compound represented by general formula (2) or a known epoxy compound represented by general formula (3) with a known diamine represented by general formula (4), and then The resulting general formula
Reacting the compound represented by (5) with carbon disulfide,
Furthermore, it is produced by reacting the obtained compound represented by general formula (6) with an alkyl halide represented by general formula (7), and finally reacting the obtained compound represented by general formula (8) with a base. Ru. The reaction between the compound of general formula (2) or (3) and the compound of general formula (4) is usually carried out in a suitable solvent. Various organic solvents can be used as long as they do not adversely affect the reaction, such as lower alcohols such as methanol, ethanol, and isopropanol, ethers such as diethyl ether, terahydrofuran, and dioxane, benzene, and toluene. , aromatic hydrocarbons such as xylene, ethyl acetate, and the like. The ratio of the compound of general formula (2) or (3) and the compound of general formula (4) to be used is not particularly limited and can be appropriately selected within a wide range, but usually at least an equimolar amount of the latter to the former. degree,
It is preferable to use 5 to 7 times the molar amount. The reaction can be carried out either at room temperature or under heating,
The reaction proceeds suitably near the boiling point of the solvent, and is generally completed in about 1 to 10 hours. The reaction between the compound of general formula (5) and carbon disulfide is carried out without a solvent or in a suitable solvent. As the solvent, a wide variety of organic solvents can be used as long as they do not adversely affect the reaction, and specific examples include the lower alcohols, ethers, aromatic hydrocarbons, and the like. Among these solvents, lower alcohols are particularly preferred. The ratio of the compound of general formula (5) and carbon disulfide to be used is not particularly limited and may be appropriately selected within a wide range, but usually the latter is used in at least an equimolar amount, preferably an equimolar amount, relative to the former. It is preferable to use about 2 to 2 times the molar amount.
The reaction temperature is not particularly limited and can be carried out under ice-cooling, at room temperature, or under heating, but usually after reacting at around room temperature for about 1 to 5 hours, the solvent is removed and the residue is heated to 100% It is best to heat it to around 130℃. In this way, a compound of general formula (6) is produced. The reaction between the compound of general formula (6) and the compound of general formula (7) is generally carried out in an organic solvent. As the organic solvent, a wide range of organic solvents can be used that do not adversely affect the reaction, and specific examples include lower alcohols such as methanol and ethanol, halogenated hydrocarbons such as carbon tetrachloride, methylene chloride, and chloroform, acetone, and tetrahydrofuran. I can give an example. general formula
The ratio of the compound of (6) and the compound of general formula (7) is not particularly limited and can be appropriately selected within a wide range, but usually the latter is used in an amount equivalent to 10 times the molar amount of the former. It is preferable to use about 1.5 to 3 times the molar amount. The reaction proceeds either under cooling, at room temperature, or under heating, but is preferably carried out at around room temperature. The reaction time is usually 1
~10 hours. When reacting the compound of general formula (8) with a base, it may be carried out in an organic solvent that does not adversely affect the reaction, such as lower alcohols such as methanol, ethanol, isopropanol, acetone, tetrahydrofuran, etc., or in water. Good. As the base, a wide range of conventionally known bases can be used, such as organic bases such as ammonia and triethylamine;
Mention may be made of inorganic bases such as sodium carbonate, potassium carbonate, sodium bicarbonate and the like. The amount of such a base to be used is not particularly limited, but it is usually used in an equimolar to 50-fold molar amount, preferably an equimolar to 5-fold molar amount, relative to the compound of general formula (8). The reaction can be carried out under cooling, at room temperature, or under heating, but preferably proceeds at room temperature to about 100°C.
Further, the reaction time is usually about 1 to 20 hours. The compound of the present invention is thus produced. The compound of the present invention thus obtained can be easily isolated and purified from the reaction mixture by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. The compounds of the present invention can easily form salts with common pharmaceutically acceptable acids. Examples of such acids include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid, and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, succinic acid, and benzoic acid. Can be mentioned. Next, reference examples and examples will be given to further specifically illustrate the compounds of the present invention, but the compounds of the present invention are not limited thereto. Reference Example 1 84 g of ethylenediamine is added to 300 ml of methanol, and while heating the mixture to 60-70°C, 100 ml of a methanol solution of 30 g of 2,3-epoxypropyl (4-methylphenyl) ether is added dropwise over 1 hour. After the dropwise addition was completed, the mixture was refluxed for 2 hours, and then the solvent and excess ethylenediamine were distilled off under reduced pressure.
1-(2-aminoethylamino)-3- as a residue
(4-methylphenoxy)-2-propanol is obtained. Without isolating the 1-(2-aminoethylamino)-3-(4-methylphenoxy)-2-propanol obtained above, this residue was dissolved in 300 ml of ethanol and 20 ml of carbon disulfide was added to form a precipitate. generate. After leaving it for 1 hour, separate the precipitate by decantation and gradually heat it on an oil bath at 120 °C.
℃ and continue heating at 120℃ for 1 hour. When this reaction product is hot, isopropanol
Add 200ml. The crystals that precipitate after cooling are collected and recrystallized from isopropanol methanol to determine the melting point.
31 g of 1-[2-hydroxy-3-(4-methylphenoxy)propyl]-2-imidazolidinethione at 141-142 DEG C. is obtained. Example 1 2.3.5.6-tetrahydro-2-(4-methylphenoxymethyl)imidazo[2.1-
b] Production of oxazole 5 g of 1-[2-hydroxy-3-(4-methylphenoxy)propyl]-2-imidazolidinethione and 3 ml of methyl iodide are added to 100 ml of acetone and stirred at room temperature for 3 hours. Filter the precipitated crystals and add 200 ml of water containing 5 g of potassium carbonate to the crystals.
and ethyl acetate 200ml and add 10
Stir for a minute. The organic layer is separated, dried (MgSO ₄ ), and concentrated. 200 ml of isopropyl alcohol is added to the resulting oily substance, and the mixture is refluxed for 3 hours. The crystals obtained by concentrating the reaction solution were recrystallized from methyl acetate-isopropyl ether to obtain 2,3,5,6-tetrahydro-2-(4-methylphenoxymethyl)imidazo[2,1]oxazole. obtain. Melting point: 115 DEG -117 DEG C. Compounds of Examples 2 to 8 listed in Table 1 below are obtained in the same manner as in Example 1.

【table】

[Table] Example 9 2,3,6,7-tetrahydro-2-phenylthiomethyl-5H-oxazolo [3,2-a]
Production of pyrimidine/hydriodide 1-(2-hydroxy-3-phenylthiopropyl)perhydropyrimidine-2-thione 3g
and 3 ml of methyl iodide were added to 100 ml of acetone, and the mixture was stirred at room temperature for 3 hours. Take the precipitated crystals and add them to 100ml of ethanol and 28% ammonia water.
Add to 10ml of the mixture and stir for 3 hours. The reaction solution was concentrated and the resulting crystals were recrystallized from ethyl acetate ethanol to give 2,3,6,7-tetrahydro-2-phenylthiomethyl-5-H-oxazolo[3,2-a]pyrimidine. Obtain iodide. Melting point: 157-159°C Compounds of Examples 10-15 listed in Table 2 below are obtained in the same manner as in Example 9.

【table】

Claims (1)

[Claims] 1. General formula [In the formula, R is a lower alkyl group, a phenyl group, a naphthyl group, or a group consisting of a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a cyano group, a halogen atom, and a phenyl group as a substituent. Indicates a phenyl group that may have 1 to 3 groups selected from Y represents an oxygen atom or a sulfur atom. n represents 2 or 3. ] An oxazole derivative represented by these and its salt.