JPS6346749B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to sulfonate derivatives. The sulfonate derivative of the present invention is represented by the following general formula []. R ₁ SO ₃ CH ₂ COR ₂ … [] [In the formula, R ₁ represents a pyridyl group or a quinolyl group with or without a lower alkyl group as a substituent, and R ₂ represents a lower alkyl group, a cyclohexyl group, or a cyclohexyl alkyl group. ] The pyridyl group defined for R ₁ above is 2-, 3-
The quinolyl group may be either 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolyl. Each of these groups may also have one or more lower alkyl groups such as methyl, ethyl, and propyl groups as substituents at any position on the ring. In addition, the lower alkyl group defined for _R2 is a straight or branched alkyl group having 1 to 5 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl group, etc., and the cyclohexyl alkyl group is cyclohexyl group. Examples of linear or branched alkyl groups having 1 to 5 carbon atoms having a substituent group include 2-cyclohexylethyl, 1-ethyl-2-cyclohexylethyl, and the like. The present invention also provides a pharmacologically acceptable acid addition salt of the sulfonate derivative represented by the above general formula []. As the acid used to form the acid addition salt, those capable of forming a salt with the pyridyl group or quinolyl group of the above derivatives can be used, and specific examples thereof include inorganic acids such as hydrochloric acid and sulfuric acid, methanesulfonic acid, Examples include organic acids such as toluenesulfonic acid. The sulfonate derivatives represented by the general formula [] and acid addition salts thereof of the present invention have esterase inhibitory activity and chymotrypsin inhibitory activity, and are useful as antilipidemic agents, antiinflammatory agents, and immunomodulators. The method for producing the derivative of the present invention will be described in detail below. The derivative of the present invention is, for example, a sulfonyl chloride represented by the general formula R ₁ SO ₂ Cl ... [] [In the formula, R ₁ is the same as above] and a general formula R ₂ COCH ₂ OH ... [] [In the formula, R ₂ is the same as above] It is obtained by reacting with an α-hydroxyketone represented by the same formula. The above reaction is usually carried out in a solvent in the presence of a base as a dehydrochlorination agent. The solvent is not particularly limited as long as it does not participate in the reaction, and various common solvents can be used. For example, specifically, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform are suitable. Further, the base used as the dehydrochlorination agent may be any of the usual bases, such as pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo(5,4,0)-7-undecene (DBU), etc. used for. The ratio of the sulfonyl chloride represented by the general formula [] and the α-hydroxyketone represented by the general formula [] can be determined as appropriate and is not particularly limited, but it is usually appropriate to use equimolar amounts of both. be. The reaction normally proceeds well at a temperature in the range of about -10 to 50°C, preferably about -5 to 5°C. After completion of the reaction, the derivative of the present invention obtained as described above can be isolated and purified by conventional separation means such as column chromatography and recrystallization. Further, the acid addition salt of the derivative of the present invention obtained as described above can be obtained by dissolving the derivative in a suitable solvent such as ethers such as diethyl ether, dioxane, and tetrahydrofuran, and adding an acid to give the desired salt. It is easily manufactured by Isolation and purification of the salt can also be carried out in the same manner as described above. In order to explain the present invention in more detail, production examples of the derivatives of the present invention will be given below as examples. Example 1 (A) Production of 2,6-lutidine-3-sulfonyl chloride (compound of general formula []) Sodium 2,6-lutidine-3-sulfone
5.0 g of the suspension was suspended in 50 ml of dry benzene, 2.5 g of oxalyl chloride was added dropwise at room temperature, and then 0.5 ml of pyridine was added and the mixture was heated under reflux for 12 hours. Thereafter, the solvent is distilled off under reduced pressure, and the residue is extracted with dichloromethane. The solvent was distilled off from the extract under reduced pressure,
The obtained oil was purified by silica gel column chromatography (developing solvent: chloroform),
2.5 g of 2,6-lutidine-3-sulfonyl chloride was obtained as a pale yellow oil. The result of mass spectrometry (MS) is M ⁺ =205, and it is identified as the target substance. (B) Production of 1-(2,6-lutidine-3-sulfonyloxy)-4-cyclohexyl-2-butanone (compound of general formula []) 2,6-lutidine-3- obtained in (A) above 0.7 g of sulfonyl chloride and 0.6 g of 1-hydroxy-4-cyclohexyl-2-butanone are dissolved in 20 ml of dry dichloroethane, and 0.5 ml of triethylamine is added dropwise under ice cooling. During this time, the temperature of the reaction solution was 5℃.
Be careful not to exceed. After the dropwise addition was completed, stirring was continued for 1 hour at the same temperature, and then the organic layer was washed with diluted hydrochloric acid and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography (developing solvent:
1 with a melting point of 68-69℃
-(2,6-lutidine-3-sulfonyloxy)
-0.6 g of 4-cyclohexyl-2-butanone is obtained. Yield 52.0%. This product was designated as derivative No. 5, and its elemental analysis value, MS analysis result, and deuterium chloroform (CDCl ₃ )
Nuclear magnetic resonance spectroscopy (H-
NMR) results are shown in Table 1. Table 1 also shows the results of measuring the derivatives of the present invention obtained using appropriate starting materials and their physical properties in the same manner as above. In addition, the derivatives of the present invention in Table 1 represent R ₁ in the general formula [].
It is indicated by the type of R ₁ and R ₂ , and the numerical value in parentheses in the elemental analysis value indicates the theoretical value.

[Table] Next, the test results of the esterase inhibitory effect and the chymotrybusin inhibitory effect of the derivative of the present invention () will be explained. 1 Esterase inhibitory effect Add 10 μmol of 50% ethanol solution of methylbutyrate as a substrate to a fixed amount of 0.1M Tris salt buffer (PH8.0), and add to this a 50% ethanol solution of the derivatives of the present invention listed in Table 2. Immediately after adding purified rat liver microsomal fraction esterase solution (at 37℃ for 1 hour) as an enzyme solution,
(adjusted to hydrolyze 9 μmol of methyl butyrate) was added, and the reaction was carried out at 37°C for 60 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 points or more) of the derivative 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 Add 0.1 unit of chymotrypsin as an enzyme solution to a fixed amount of 0.1 mol Tris salt buffer (PH8.0),
Further, a 50% ethanol solution of the derivative of the present invention shown in Table 2 was added in an amount such that the concentration of the derivative of the present invention was 1 x 10 ^-4 mol, and a reaction was carried out at 37°C for 20 minutes. Immediately after the reaction is completed, N-acetyl-L is used 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. Chymotrybusin inhibition rate (%) was calculated by the following formula. Inhibition rate (%) = A ₁ - B / A × 100 A: Amount of ester hydrolyzed in the reaction system without the addition of the derivative of the present invention B: Amount of ester hydrolyzed in the reaction system with the addition of the derivative of the present invention The % inhibitory concentration (IC ₅₀ ) and chymotrypsin inhibition rate (%) are shown in Table 2.

[Table] From Table 2 above, it can be seen that the derivatives of the present invention have esterase inhibitory activity and chymotrybuscin inhibitory activity.

Claims (1)

[Claims] 1 General formula R ₁ SO ₃ CH ₂ COR ₂ [In the formula, R ₁ is a pyridyl group or a quinolyl group with or without a lower alkyl group as a substituent, and R ₂ is a lower alkyl group or a cyclohexyl group. or a cyclohexyl alkyl group] A sulfonate derivative represented by: