JPH0336831B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel α-ketosulfonic acid ester derivatives. The α-ketosulfonic acid ester 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 (): Het-SO ₃ CH ₂ COR ₁ () [where Het represents a thienyl group or a phenyl group]. It represents a pyrazolyl group with or without a lower alkyl group, a furanyl group with or without a lower alkyl group, or a thiazolyl group with or without a lower alkyl group. R ₁ is a general formula

[Formula] or

[Formula] (wherein R ₂ represents a hydrogen atom or a linear or branched lower alkyl group, and A represents a linear or branched lower alkylene chain). ] In the above general formula (), in the definition of the substituent represented by Het, the lower alkyl group has 1 to 6 carbon atoms.
an alkyl group such as methyl, ethyl, propyl, butyl, pentyl, hexyl, etc.
In addition, the straight chain or branched lower alkyl group represented by _R2 includes a straight chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n- or
iso-propyl, n-, sec-, iso- or tert-butyl, n-pentyl, n-hexyl groups, etc. are used as linear or branched alkylene chains having 1 to 4 carbon atoms. such as methylene, ethylene, trimethylene, tetramethylene, 1-methyl-trimethylene, 1,1-dimethyl-ethylene,
Examples include 1-ethylene-ethylene and the like. As is clear from the structural formula represented by the above general formula (), the compound of the present invention also includes geometric isomers based on a cyclohexane ring. The compound represented by the above general formula () of the present invention can be produced, for example, by the following <Method A> and <Method B>. <Method A> A compound represented by the general formula R ₁ COCHN ₂ () (in which R ₁ has the same meaning as above) and a compound represented by the general formula Het-SO ₃ H () [in the formula, Het is the same as above. Indicates the meaning of ) are reacted. The reaction in Method A above is usually carried out in a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, but generally dimethyl ether, diethyl ether, tetrahydrofuran,
Ethers such as dioxane, aprotic solvents such as acetonitrile, chloroform, dichloromethane, petroleum ether, ligroin, etc. are preferably used. Although the ratio of compound () to compound () to be used may be selected as appropriate, it is generally advantageous to use equimolar or more of compound () to compound (). The reaction generally proceeds advantageously at about -10 to 60°C, preferably about 0°C to room temperature. <Method B> A compound represented by the general formula R ₁ COCH ₂ OH () (in the formula, R ₁ has the same meaning as above) and the general formula Het-SO ₂ Cl () (in the formula, Het has the same meaning as above) ) is reacted with the sulfonyl chloride represented by The reaction in Method B above is carried out in a suitable solvent in the presence of a base as a dehydrochlorination agent. As the solvent, those that do not participate in the reaction, such as halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform, can be suitably used. In addition, the bases used as dehydrochlorination agents include common ones such as pyridine, triethylamine, N,
N-diisopropylethylamine, 1,8-diazabicyclo(5.4.0)-7-undecene (DBU)
etc. may be used advantageously. The ratio of the compound () and the sulfonyl chloride () to be used can be determined as appropriate and is not particularly limited, but it is usually preferable to use them in an equimolar ratio. The reaction is usually about -
It proceeds well at temperatures in the range of 10 to 50°C, preferably about -5 to 5°C. Compounds of the present invention obtained by each of the above methods ()
can be isolated by conventional separation means such as column chromatography, recrystallization, etc. The compound of the present invention () has esterase inhibitory activity and antilipidemic activity, and is useful as an immunomodulator, antilipidemic agent, and anti-inflammatory agent. Next, Table 1 shows representative examples of the compounds represented by the general formula () of the present invention. In the table, MS indicates mass spectrum analysis results (M ⁺ ), and H-NMR indicates
The results of nuclear magnetic resonance spectrum analysis (δ, ppm) measured in CDCl ₃ are shown.

【table】

[Table] Next, examples of the present invention will be shown and explained in detail. Example 1 Thiophene-2-sulfonyl chloride 1.8g
and 1.8 g of 1-hydroxy-2-(4-isopropylcyclohexyl)-2-ethanone were dissolved in 3 ml of dichloromethane, and 1.7 ml of triethylamine was added dropwise while cooling to below 5°C. After dropping, stir at 10°C or lower for 1 hour. After the reaction is completed, the mixture is poured into ice-hydrochloric acid and extracted with 20 ml of chloroform. The chloroform layer is washed with water and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 1-
(2-thiophenesulfonyloxy)-2-(4-
1.8 g of isopropyl-cyclohexyl)-2-ethanone (compound 1) is obtained. (Yield 55.3%) Example 2 Compounds 2 to 5 listed in Table 1 above were synthesized by performing the same operation as in Example 1. Example 3 1.8 g of 1-diazo-3-(4-methyl-cyclohexyl)-2-propanone was dissolved in 50 ml of ether, and 3 g of 2-methyl-furan-5-sulfonic acid was added at room temperature to stop the generation of nitrogen. Stir until it's gone. After the reaction, wash with water and dry with anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the resulting oil was separated and purified using silica gel column chromatography (the developing solvent was chloroform) to obtain 1-(2-methyl-furan-5- 1.8 g of sulfonyloxy)-3-(4-methyl-cyclohexyl)-3-propanone (compound 6) are obtained. (Yield 57.3%) Example 4 Compound 7 listed in Table 1 above was synthesized by performing the same operation as in Example 3. Next, the test results of the esterase inhibitory effect and the chymotrypsin inhibitory effect of the compound () of the present invention will be explained. 1 Esterase inhibitory effect A 50% ethanol solution of 10 μmol of methylbutyrate as a substrate was added to a fixed amount of 0.1M Tris-HCl buffer (PH8.0), and then a 50% ethanol solution of the compounds of the present invention shown in Table 2 was added to this. Immediately after adding purified rat liver microsome fraction esterase solution (adjusted to hydrolyze 9 μmol of methylbutyrate in 1 hour at 37°C) as an enzyme solution, incubate at 37°C for 60 hours. The reaction was carried out for minutes. After the reaction is complete, ferric salt is added to the hydroxamic acid derivative of methylbutyrate using alkaline hydroxylamine, and the resulting red color is measured by colorimetry (wavelength
540 nm) and the remaining methylbutyrate content was quantified. The esterase inhibition rate at various concentrations (3 or more points) of the compound of the present invention is plotted on the vertical axis,
The 50% inhibitory concentration (IC ₅₀ ) was determined from a straight line obtained by plotting the logarithm of the concentration on the horizontal axis. 2 Chymotrypsin inhibitory effect 0.1 unit of chymotrypsin was added as an enzyme solution to a fixed amount of 0.1M Tris-HCl buffer (PH8.0), and then a 50% ethanol solution of the compound of the present invention shown in Table 2 was added, and the mixture was heated to 37°C. The reaction was carried out for 20 minutes. Immediately after the reaction, N-acetyl-L was added as a substrate.
-10 μmol of tyrosine ethyl ester (ATEE) was added, and the reaction was carried out at 37° C. for 30 minutes. After the reaction was completed, the amount of ATEE remaining was determined by the hydroxamic acid method, which is the same method used to measure esterase inhibitory activity. Chymotrypsin inhibition rate (%) was calculated using the following formula. Inhibition rate (%) = A - B / A × 100 A: Amount of ester hydrolysis in the reaction system without the addition of the compound of the present invention B: Amount of ester hydrolysis in the reaction system with the addition of the compound of the present invention The 50% inhibitory concentration (IC ₅₀ ) and percentage inhibition of chymotrypsin (in 1×10 ⁻⁴ mol) are shown in Table 2. As is clear from Table 2, the compounds of the present invention have esterase inhibitory activity and chymotrypsin inhibitory activity, and are useful as antihyperlipidemic agents, antiinflammatory agents, and immunomodulators.

【table】

Claims (1)

[Claims] 1 General formula Het-SO ₃ CH ₂ COR ₁ [In the formula, Het is a thienyl group, a pyrazolyl group with or without a phenyl group, a furanyl group with or without a lower alkyl group, or a lower alkyl group. Indicates a thiazolyl group with or without a group. R ₁ is the general formula [Formula] or [Formula] (wherein R ₂ is a hydrogen atom or a linear or branched lower alkyl group, and A is a linear or branched lower alkylene chain. ) represents a group. ] An α-ketosulfonic acid ester derivative represented by the following.