JPH0113708B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel sulfonic acid ester derivatives. The sulfonic 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 []. [In the formula, R ₁ represents a lower alkyl group, a lower alkoxy group, or a hydrogen atom, and R ₂ and R ₃ each represent a lower alkyl group, or are bonded to each other and have 4 to 6 carbon atoms together with the carbon atoms to which they are bonded. may form a cycloalkyl group. l represents an integer of 1 to 3. ] In the above general formula (), lower alkyl groups represented by R ₁ , R ₂ and R ₃ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl groups, etc., and lower alkoxy groups represented by R ₁ include Methoxy, ethoxy, propyloxy groups, etc., R ₂
Examples of the cycloalkyl group having 4 to 6 carbon atoms which can be formed by bonding and R ₃ with each other and the bonding carbon atoms include a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, respectively. Further, the compounds of the present invention include compounds having stereoisomers, and the present invention includes all such isomers. The compound represented by the above general formula () of the present invention can be produced, for example, by the following method. general formula [In the formula, R ₂ and R ₃ are the same as above. ] Diazo compound and general formula [In the formula, R ₁ , l and m are the same as above. ] is reacted with the compound represented by The above reaction 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 ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, and dioxane; acetonitrile, chloroform,
Aprotic solvents such as dichloromethane; petroleum ether, ligroin, etc. are preferably used. The ratio of the diazo compound () to the compound () to be used may be selected as appropriate, but it is generally advantageous to use the compound () in an amount of about 1.2 to 2 times the mole of the diazo compound (). Although the reaction temperature is not particularly limited, it is generally about -10 to 60°C, preferably about 0°C to room temperature, and the reaction proceeds advantageously at this temperature. The diazo compound () used as a raw material in the above reaction is usually as shown in the reaction formula below.
It can be obtained by reacting a known carboxylic acid compound () with thionyl chloride (SOCl ₂ ) to obtain the compound ( ), and then reacting this with diazomethane (CH ₂ N ₂ ). The reaction between the carboxylic acid compound () and thionyl chloride and the reaction between the resulting compound () and diazomethane can be carried out according to conventional methods. For example, the reaction between compound () and diazomethane can be carried out in the same solvent as exemplified in the method for producing the compound of the present invention, using diazomethane in an amount of 2 times or more moles relative to compound (), and from about -10°C to room temperature. It is advantageously carried out under moderate temperature conditions. Details of each of the above reactions are as shown in Reference Examples below. Compound of the present invention obtained by the above method ()
can be isolated by conventional separation means such as column chromatography, recrystallization, vacuum distillation, etc. The sulfonic acid ester derivative () of the present invention thus obtained has esterase inhibitory activity, antilipemic activity, etc., and is useful as an immunomodulator, antilipemic agent, etc. Hereinafter, production examples of the compound represented by the general formula () used for producing the present compound () will be listed as reference examples, and then production examples of the present invention compound () will be listed as examples. The compounds obtained in each example and their physical properties are shown in Table 1.
and shown in Table 2. In each table, MS indicates the mass spectrum analysis results (M ⁺ ), and H-NMR indicates the nuclear magnetic resonance spectrum analysis results (δ value, ppm, CDCl ₃
medium). Reference Example 1 Excess thionyl chloride is added to 5 g of 4,4-dimethyl-cyclohexylcarboxylic acid, and the mixture is heated and stirred for 3 hours. After the reaction, excess thionyl chloride is distilled off under reduced pressure, and 10 ml of benzene is added to the residual liquid, which is then distilled under reduced pressure to obtain oily 4,4-dimethyl-cyclohexylcarbonyl chloride. Next, 2.0 g of the 4,4-dimethyl-cyclohexylcarbonyl chloride obtained above was added dropwise at room temperature into 100 ml of a diazomethane ether solution prepared from 10 g of nitrosourea, and the mixture was stirred at room temperature for about 1 hour after the dropwise addition. After the reaction, the solvent was distilled off under reduced pressure,
1-Diazo-2-(4,4-dimethyl-cyclohexyl)-2-ethanone (compound A) is quantitatively obtained as a pale yellow oil. Reference example 2 4-methyl-4-propyl-cyclohexylcarboxylic acid, spiro[4,5]-decane-8 instead of 4,4-dimethyl-cyclohexylcarboxylic acid
-Using each of carboxylic acid and spiro[5,5]-undecane-4-carboxylic acid as raw materials, each compound B to D shown in Table 1 below was prepared in the same manner as in Reference Example 1.
get.

[Table] Example 1 1.8 g of 1-diazo-2-(4,4-dimethyl-cyclohexyl)-2-ethanone (compound A) was dissolved in 50 ml of ether, and 3.5 g of benzenesulfonic acid was added at room temperature and nitrogen was added. Stir until no more occurs. After the reaction is completed, it 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-(benzenesulfonyloxy)-2-(4,4-dimethyl-cyclohexyl)-2 with a melting point of 34.5-35°C. - Obtain 2.5 g of ethanone (compound 1) (yield 80.6%). Example 2 Compounds 2 to 11 shown in Table 2 below were synthesized by carrying out the same operation as in Example 1 using appropriate raw materials.

【table】

[Table] Next, pharmacological tests conducted on the sulfonic acid ester derivatives of the present invention will be explained. 1 Esterase inhibitory effect Add 50% of 10μmol of methylbutyrate as a substrate to a fixed amount of 0.1M Tris-HCl buffer (PH8.0).
After adding an ethanol solution and further adding a 50% ethanol solution of the compound of the present invention, a purified rat liver microsome fraction esterase solution (to hydrolyze 9 μmol of methylbutyrate at 37°C for 1 hour) was added. ) and at 37°C.
Run the reaction for 60 minutes. After the reaction is complete, ferric salt is added to the hydroxamic acid derivative of methylbutyrate with alkaline hydroxylamine, and the resulting red color is measured by colorimetry (wavelength
540 nm) and quantify the remaining methylbutyrate content. 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 ) is determined from the straight line obtained by plotting the logarithm of the concentration on the horizontal axis. 2 Chymotrypsin inhibitory effect Add an enzyme solution (0.1 unit of chymotrypsin) to a fixed amount of 0.1M Tris-HCl buffer (PH8.0), and then add a 50% ethanol solution of the compound of the present invention, and then incubate at 37°C. Run the reaction for 20 minutes. Immediately after the completion of the reaction, N-acetyl-
Add 10 μmol of L-tyrosine ethyl ester (ATEE) and carry out the reaction at 37° C. for 30 minutes. After the reaction is completed, the remaining amount of ATEE is determined by the hydroxamic acid method, which is the same method used to measure esterase inhibitory activity. Chymotrypsin inhibition rate (%) is calculated by the following formula. Inhibition rate (%) = (AB)/A x 100 A: Amount of ester hydrolyzed in the reaction system without addition of the compound of the present invention. B: Amount of ester hydrolysis in the reaction system to which the compound of the present invention was added. Table 3 shows the 50% inhibitory concentration (IC ₅₀ ) of the compounds of the present invention against esterase and the inhibition rate of chymotrypsin (at 1×10 ⁻⁴ mol) obtained by the above method.

[Table] As is clear from Table 3, the compound of the present invention has esterase inhibitory activity and chymotrypsin inhibitory activity, and is useful as an antihyperlipidemic agent, an antiinflammatory agent, and an immunosuppressant.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ represents a lower alkyl group, a lower alkoxy group, or a hydrogen atom, and R ₂ and R ₃ each represent a lower alkyl group, or are bonded to each other and together with the carbon atoms to which they are bonded, have a carbon number of 4 to 6 cycloalkyl group may be formed. l represents an integer of 1 to 3. ] A sulfonic acid ester derivative represented by.