JPH0114917B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel oxathiolane compounds. The oxathiolane compound of the present invention is represented by the following general formula (1). (In the formula, A is a phenyl group, a phenyl group having a halogen atom, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, a lower acyloxy group, or a formyl group as a substituent, a furyl group, or a 3-
methyl-5-isoxazolyl group, R means a hydrogen atom, a lower alkyl group, or a phenyl group) In the above general formula (1), the halogen atom that is a substituent of the phenyl group is a chloro atom, a bromine atom, or a fluorine atom. Atom, iodine atom, etc. Examples of lower alkyl groups as other substituents include methyl group, ethyl group, propyl group, isopropyl group, and butyl group. Examples of the lower alkoxy group include methoxy group, ethoxy group, propoxy group, isopropoxy group, and butoxy group. Examples of the lower acyloxy group include an acetoxy group, a propionyloxy group, an isopropionyloxy group, a butyryloxy group, and the like. Further, examples of the lower alkyl group defined by R include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and the like. Further, the oxathiolane compound of the present invention includes stereoisomers based on double bonds, as shown in the above general formula (1), and the present invention naturally includes these stereoisomers. The oxathiolane compound of the present invention represented by the above general formula (1) is a new compound that has not been described in any literature, and has a chymotrypsin inhibitory effect, and is used as an anti-inflammatory agent, a combination drug with a peptide physiologically active substance such as insulin,
It is useful as a preservative for fresh foods and as a cancer prevention agent. The oxathiolane compound represented by the general formula (1) of the present invention is produced by the method exemplified below. [Method A] This is a method of reacting β-substituted-α-mercaptopropenoic acid represented by general formula (2) with an acid anhydride represented by general formula (3), and is represented by the following reaction formula. (In the formula, A and R are the same as defined above.) The reaction between the β-substituted α-mercaptopropenoic acid (2) and the acid anhydride (3) is carried out without a solvent or in a solvent. The solvent is not particularly limited as long as it is inert to the reaction, but examples include benzene, toluene,
Examples include aromatic hydrocarbons such as xylene, ethers such as tetrahydrofuran and dioxane, and aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide. The ratio of β-substituted α-mercaptopropenoic acid (2) and acid anhydride (3) to be used may be selected as appropriate; however, in general, the ratio of acid anhydride ( It is advantageous to use an excess of 3), preferably about 2 to 20 times the molar amount. Although the reaction temperature may be selected appropriately, it is generally advantageous to carry out the reaction at about 50 to 200°C. [Method B] This is a method in which a base is allowed to act on the compound represented by general formula (4), and is represented by the following reaction formula. (In the formula, A and R are the same as above, and X means a halogen atom) The reaction between compound (4) and a base is generally carried out in a solvent. The solvent is not particularly limited as long as it is inert to the reaction, but examples include halogenated hydrocarbons such as chloroform, methylene chloride, and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, and xylene, ether, and tetrahydrofuran. and ethers such as dioxane. Various bases can be used, and typical examples include triethylamine, pyridine, picoline, and N-methylpiperidine. The amount of the base to be used can be selected as appropriate, but it is generally advantageous to use the base in an amount of about 1 to 2 times the amount of compound (4). Although the reaction temperature can be appropriately selected, it is generally advantageous to carry out the reaction at room temperature to about 150°C. Compound (4) used as a starting material in this reaction is a new compound that has not been described in any literature, and is produced, for example, from β-substituted-α-mercaptopropenoic acid (2) by the steps shown below. (wherein, A, R and
When reacted, S-acyl compound (6) is generated,
Compound (4) is then obtained by reacting this with a halogen compound such as thionyl chloride or phosphorus pentachloride. Isolation and purification of the compound (1) of the present invention obtained by the above methods A and B are carried out by conventional operations such as extraction, recrystallization, and column chromatography. Hereinafter, the oxathiolane compound of the present invention will be further explained with reference to synthesis examples and tests of chymotrypsin inhibitory effect. Synthesis examples of the oxathiolane compound represented by the general formula (1) are as follows, and the physical properties of the compounds obtained by these synthesis examples are as shown in Table 1. Synthesis Example by Method A Example 1 α-Mercapto-β-phenylpropenoic acid 1.8
g, add 1.8 ml of acetic anhydride to 20 ml of toluene, and add 6
After stirring and refluxing for an hour, the solvent is distilled off. When the residue is separated using a silica gel column, the melting point is 57-59℃.
4-Benzylidene-2-methylene-1,3--
0.86 g of oxathiolan-5-one (compound 1) is obtained (yield 42%). Example 2 3 g of β-(p-chlorophenyl)-α-mercaptopropenoic acid was added to 25 ml of propionic anhydride,
After heating and stirring at 150°C for 3 hours, concentrate. Add ether-petroleum ether to the residue, collect the precipitated crystals, and recrystallize from ethanol to obtain a melting point of 116.
2.2 g of 4-p-chlorobenzylidene-2-ethylidene-1,3-oxathiolan-5-one (compound 5) at -119°C is obtained (yield 62%). Synthesis Example by Method B Example 3 α-Mercapto-β-phenylpropenoic acid 3.6
g of sodium bicarbonate aqueous solution (NaHCO ₃ 3.53
g, 40 ml of water), 3.1 g of phenylacetyl chloride was added dropwise thereto, and the mixture was stirred at room temperature for 1 hour. Next, dilute hydrochloric acid is added to make the mixture acidic, and then extracted with chloroform. After drying over anhydrous sodium sulfate, chloroform is distilled off and the residue is recrystallized from ethanol-water to obtain 3.5 g of β-phenyl-α-(phenylacetylthio)-propenoic acid (yield 59%). β-phenyl-α-(phenylacetylthio)
Add 3.5 g of propenoic acid and 2.37 g of triethylamine to 90 ml of toluene, and add thionyl chloride while stirring on ice.
After adding 1.39 g, stir at room temperature for 1 hour. After refluxing for 7 hours, the solvent was distilled off and the residue was separated using a silica gel column to give 2,4-dibenzylidene-1,3-oxathiolan-5-one (compound 3) with a melting point of 138-140°C. g (yield 39%). Example 4 α-mercapto-β-phenylpropenoic acid 1.8
g is dissolved in a 10% aqueous potassium hydroxide solution, 1.4 g of acetic anhydride is added dropwise with stirring under ice cooling, and the mixture is stirred at room temperature for 30 minutes. Next, dilute hydrochloric acid is added to make the mixture acidic, and the precipitate is collected and recrystallized from ethanol-water to obtain 1.8 g of α-acetylthio-β-phenylpropenoic acid having a melting point of 140-143°C (yield: 81%). Then, the melting point was 57-59℃ by the same operation as in Example 3.
4-benzylidene-2-methylene-1,3-oxathiolan-5-one (compound 1) is obtained (yield 44%). Table 1 below shows the physical properties of the compound of the present invention obtained in the same manner as above.

【table】

【table】

[Table] The elemental analysis results regarding nitrogen (N) of Compounds 21 and 22 were as follows. N Compound 21 Compound 22 Calculated value (%) 6.70 6.27 Actual value (%) 6.58 6.14 The chymotrypsin inhibitory effect test conducted on the compound of the present invention and the comparative drug TPCK (tosylphenylalanine chlormethyl ketone) was as follows. Table 2 shows the results for representative compounds. Chymotrypsin inhibition test Test compound dimethyl sulfoxide solution 0.05
ml, chymotrypsin 2μg/ml buffer solution (0.4M
Tris-HCl buffer; PH8.0) 0.9ml, acetyl-
0.05 ml of a 100 mM dimethyl sulfoxide solution of L-tyrosine ethyl ester is mixed and reacted at 37°C for 30 minutes. After the reaction is complete, add 1 ml of hydroxylamine solution (equal amounts of 3.5N caustic soda and 2M hydroxylamine hydrochloride) and add 37
After incubation at ℃ for 30 minutes, 0.5 ml of a 4N hydrochloric acid solution containing 6% trichloroacetic acid and 2 ml of a 0.04N hydrochloric acid solution containing 0.11M ferric chloride were added to develop the remaining substrate, and the absorbance at 500 nm was measured. The inhibitory effect on chymotrypsin was determined.

【table】

Claims (1)

[Claims] 1. General formula (In the formula, A is a phenyl group, a phenyl group having a halogen atom, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, a lower acyloxy group, or a formyl group as a substituent, a furyl group, or a 3-
methyl-5-isoxazolyl group, R means a hydrogen atom, lower alkyl group or phenyl group)
An oxathiolane compound represented by