JPH0113467B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel sulfonate derivatives and salts thereof. The sulfonate 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 is a hydrogen atom or a phenyl group, R ₂ is a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and R ₃ is an alkyl group, a cyclohexyl alkyl group that may have a lower alkyl group as a substituent, or Indicates a cyclohexyl group that may have a lower alkyl group as a substituent.) The terms lower alkyl group, lower alkoxy group, and alkyl group used in the definition of R ₂ and R ₃ in the above general formula () are as follows. shows. Lower alkyl group: A linear or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl group, etc. Lower alkoxy group: a linear or branched alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy groups, etc. Alkyl group: a linear or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, pentyl, hexyl, octyl, isopropyl, isobutyl, tert-butyl, 1-ethylpentyl group, etc. The present invention also includes a pharmacologically acceptable acid addition salt of the sulfonate derivative represented by the above general formula (), ie, a salt of the amino group of the derivative and an acid. Examples of the acid used to form the salt include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid and toluenesulfonic acid. The salt-forming reaction with these acids can be easily carried out according to conventional methods. The sulfonate derivatives represented by the general formula () and salts thereof of the present invention have esterase inhibitory effects and chymotrypsin inhibitory effects, and are useful as pharmaceuticals such as antilipidemic agents, anti-inflammatory agents, and immunomodulators. The compound of the present invention and its salt can be produced, for example, by the following <Method A> and <Method B>. <Method A> α-haloketone represented by the general formula XCH ₂ COR ₃ () (in the formula, X is a halogen atom, and R ₃ has the same meaning as above) and the general formula (In the formula, R ₂ has the same meaning as above) By reacting with silver sulfonate represented by the general formula (In the formula, R ₂ and R ₃ have the same meanings as above.) The compound (I-a) of the present invention is obtained. This 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 lower alcohols such as methanol and ethanol, polar solvents such as acetone, acetonitrile, and dimethylformamide, and ethers such as tetrahydrofuran and dioxane are particularly preferably used. . Although the ratio of compound () and compound () to be used may be selected as appropriate, it is generally advantageous to use equimolar amounts. Further, the reaction temperature is generally from room temperature to about the boiling point temperature of the solvent, and the reaction proceeds advantageously within this range. <Method B> (In the formula, R ₂ and R ₃ have the same meanings as above.) By reducing the compound represented by the general formula (In the formula, R ₂ and R ₃ have the same meanings as above.) The compound (I-b) of the present invention is obtained. The reduction reaction of the compound () in the above can usually be carried out according to a conventional method using a known reducing agent. Various reducing agents that can selectively reduce nitro groups can be used. Among these, activated iron produced by reacting iron powder with hydrochloric acid shows particularly good results. Any solvent may be used as long as it does not participate in the reaction, and benzene, toluene, etc. are generally preferably used. Further, the reaction temperature is preferably set near the boiling point temperature of the solvent, and the reaction advantageously proceeds at this temperature. The compounds of the present invention obtained by the above <Method A> and <Method B> can be isolated and purified by conventional separation means such as column chromatography, recrystallization, etc. The salt of the sulfonate derivative thus obtained can be easily produced, for example, by dissolving the derivative in an ether solvent such as diethyl ether, dioxane, or tetrahydrofuran, and reacting the solution with an appropriate acid. Examples will be given below to further explain the present invention. Table 1 below shows representative examples of raw material compounds (compounds of general formula ()) used for producing the compounds of the present invention and their physical properties. Further, Table 2 shows the compounds of the present invention obtained in each example and their physical properties. In each table, H-NMR indicates the nuclear magnetic resonance spectrum analysis result (δ, ppm) measured in deuterated chloroform, and C (%) in the elemental analysis value is:
F (%) indicates the calculated value, and F (%) indicates the actual measured value.

【table】

【table】

【table】

【table】

[Table] Example 1 1-(4-nitrobenzenesulfonyloxy)-
4.0 g of 2-pentanone (compound A) was added to 300 g of benzene.
ml, added 40 g of activated iron, and heated and stirred for 5 hours (0.5 cc of water was added several times during heating and stirring). After the reaction, insoluble materials were separated, the liquid was concentrated under reduced pressure, and the resulting oil was separated and purified using silica gel column chromatography (the developing solvent was chloroform).
m.p 2.6 g of 1-(4-aminobenzenesulfonyloxy)-2-pentanone (compound 1) at 67-68°C
(yield 68.5%) Example 2 Compounds 5, 7, 9 were obtained by the same operation as in Example 1.
~13 were synthesized. Example 3 1-(4-aminobenzenesulfonyloxy)-
2.0 g of 2-pentanone (compound 1) was dissolved in 50 ml of anhydrous ether, and dry hydrogen chloride was introduced under ice cooling. After the reaction, the precipitate was collected, washed with ether, and dried. Thus, 1-(4-aminobenzenesulfonyloxy)-2-pentanone with a m.p of 300°C or higher
2.1 g of hydrochloride (compound 2) was obtained (yield 91.9%). Example 4 Compounds 3, 4, and
6 and 8 were synthesized. Example 5 3.0 g of 1-iodo-2-heptanone and 4-(N-
6.5 g of silver phenylamino)benzenesulfonate were added to 50 ml of acetonitrile. The mixture was stirred at room temperature for 24 hours. After the reaction, insoluble matter was separated and the liquid was concentrated under reduced pressure. The obtained oil was separated and purified by silica gel column chromatography (the developing solvent was chloroform) to obtain crude crystals, which were recrystallized from ethanol to give 1-[4-( 2 g of N-phenylamino)-benzenesulfonyloxy]-2-heptanone (compound 14) was obtained (yield 44.4%). 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: Add 10μmol 50% 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 compounds of the present invention shown in Table 2, the purified rat liver microsome fraction esterase solution (37
(adjusted to hydrolyze 9 μmol of methylbutyrate in 1 hour at 37°C) and 60°C at 37°C.
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 points or more) of the compound of the present invention was plotted on the vertical axis, and the logarithm of the concentration was plotted on the horizontal axis, and the 50% inhibitory concentration (IC ₅₀ ) was determined from the straight line obtained. 2 Chymotrypsin inhibitory effect 0.1 unit of chymotrypsin was added as an enzyme solution to a fixed amount of 0.1 molar Tris-HCl buffer (PH8.0), and then 50 units of chymotrypsin as shown in Table 2 was added.
After adding the % ethanol solution, the reaction was carried out at 37°C for 20 minutes. Immediately after the reaction, N-acetyl-
10μ of L-tyrosine ethyl ester (ATEE)
mol 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 (%) = AB/A x 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 3. As is clear from Table 3, 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 (In the formula, R ₁ is a hydrogen atom or a phenyl group, R ₂ is a hydrogen atom, a lower alkyl group, or a lower alkoxy group, and R ₃ is an alkyl group, a cyclohexyl alkyl group that may have a lower alkyl group as a substituent, or cyclohexyl group which may have a lower alkyl group as a substituent) and salts thereof.