JPS6318940B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel sulfonate derivative and a method for producing the same. The sulfonate derivative according to the present invention has the general formula R ₁ SO ₃ CH ₂ CO (CH ₂ ) _n R ₂ () [wherein R ₁ is a phenyl group with or without a substituent (the substituent is a lower alkyl group) , or a lower alkoxy group), R ₂ is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, or a carbobenzoxyamino group, and m is an integer of 3 to 5. R ₁ of the compound represented by the above general formula (),
The lower alkyl group as a substituent for the phenyl group in R ₂ is an alkyl group having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, etc., and the lower alkoxy group as a substituent for R ₁ is, Examples of the alkoxy group having 1 to 5 carbon atoms include methoxy, ethoxy, propoxy, butoxy, and pentoxy, and examples of the halogen atom include fluorine, chlorine, bromine, and iodine. The lower alkoxycarbonyl group in R ₂ has 2 to 6 carbon atoms.
Examples of the acyloxy group include lower acyloxy groups having 2 to 6 carbon atoms, such as acetyloxy, propanoyloxy, butyryloxy, valeryloxy, etc. be able to. The above-mentioned compound of the present invention is a new compound, which has esterase inhibitory activity and chymotrypsin inhibitory activity, and is a compound useful as an antilipidemic agent, an antiinflammatory agent, and an immunomodulator. The compound represented by the general formula () of the present invention can be prepared, for example, by the following method, that is, the compound represented by the general formula N ₂ CHCO (CH ₂ ) _n R ₂ () [wherein m and R ₂ are the same as above] and a sulfonic acid compound represented by the general formula R ₁ SO ₃ H・YH ₂ O () [wherein R ₁ is the same as above and Y represents an integer of 0 to 2], and if desired, an acid catalyst is added. It is produced by hydrolysis in the presence of. The above reaction in the present invention is usually carried out in a solvent, and the solvent is not particularly limited as long as it does not participate in the reaction, and generally ethers such as dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, acetonitrile, chloroform, Aprotic solvents such as dichloromethane, petroleum ether, ligroin, etc. are preferably used.
The ratio of compound () and sulfonic acid compound () to be used can be selected appropriately, but in general, compound ()
It is advantageous to use the sulfonic acid compound (2) in an amount equal to or more than the same molar amount. Also, the reaction temperature is generally about -10
The process advantageously proceeds at a temperature of 60°C to 60°C, preferably about 0°C to room temperature. The compound () used as a raw material is a known compound or a partially new compound, and can be produced from an acid chloride () and diazomethane through the following known reaction. [In the formula, R ₂ and m are the same as above] The reaction between the acid chloride () and diazomethane is usually carried out in a solvent. As the solvent, the above-mentioned solvents that can be used in the reaction of compound () and compound () can be used. Regarding the ratio of the acid chloride (2) to diazomethane, it is generally advantageous to use at least about twice the molar amount of diazomethane to the acid chloride (2). Further, the reaction proceeds advantageously at a temperature of about -10°C to room temperature. The above reaction produces the compound (), which can be used for chromatography,
Although it can be isolated by conventional separation means such as recrystallization, in many cases it can be used in the next reaction without isolation. When R ₂ is an acyloxy group among the sulfonate derivatives produced in this way, a compound in which R ₂ is a hydroxy group can be synthesized by further hydrolysis in the presence of an acid catalyst or the like, if necessary. The above reaction is usually carried out in a solvent, and the solvent is not particularly limited as long as it does not participate in the reaction, but hydrous alcohols such as methanol and ethanol are generally preferably used. The acid used for hydrolysis may be hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, or any acid that serves as a general deacylating agent. The reaction temperature is generally -10 to 50°C, preferably about 0°C to room temperature. The compound of the present invention represented by the general formula () can also be produced by the method shown below. (In the formula, R ₁ , R ₂ , m are the same as above, but R ₂
(excluding hydroxyl groups) The reaction between the keto alcohol () and the sulfonyl chloride () in the above reaction is usually carried out in a solvent using a dehydrochlorination agent. The solvent is not particularly limited as long as it does not participate in the reaction, but chloroform, dichloromethane, dichloroethane, etc. can be used. Examples of dehydrochlorination agents include pyridine, triethylamine, metal alcoholates, DBU [1,8-diazabicyclo(5,4,
0)-7-undecene] and the like can be used. The ratio of keto alcohol () and sulfonyl chloride () to be used is preferably equimolar, and the reaction temperature is -10 to 50°C, preferably about 0°C to
Performed at room temperature. A new compound () is generated by the above method,
It can be isolated by conventional separation means such as column chromatography, recrystallization, vacuum distillation, etc. Next, in order to specifically explain the present invention, Reference Examples and Examples are shown, representative diazomethyl ketones are shown in Table 1, and physical properties of the compounds of the present invention are shown in Table 2. Reference Example 100 ml of a diazomethane ether solution (containing 2.8 g of diazomethane) is prepared from 10 g of N-methyl-N-nitrosourea by a conventional method. below freezing,
1.5 g of γ-chloro-n-butyroyl chloride was added dropwise to the diazomethane ether solution, and after stirring for 30 minutes, excess diazomethane in the reaction solution was removed at room temperature through a nitrogen stream. The ether solution was distilled under reduced pressure to quantitatively obtain pale yellow oily γ-chloro-n-propyl-diazomethylketone (Compound A). MS (M ⁺ ) 146 H-NMR (CDCl ₃ ) δ (ppm) 5.25s (1H), 3.56t (2H), 2.50t (2H), 2.28~
1.95m (2H) Compounds B to F in Table 1 were also synthesized by the same operation. Example 1 1-diazo5-chloro-2-n-pentanone
Dissolve 1.5 g in 50 ml of ether, gradually add 2.1 g of benzenesulfonic acid monohydrate at room temperature, and stir until no nitrogen is generated. After the reaction, the ether layer was washed with water, dried over anhydrous sodium sulfate, and then distilled under reduced pressure. The resulting oil was stirred in ice to crystallize, and the crystals were collected and dissolved in ethanol.
Recrystallized from water, mp: 39-40℃ 2-oxo-
2.3g of 5-chloro-n-pentyl-benzenesulfonate (compound 1) was obtained (yield 81.0%). MS (M ⁺ ) 276 H-NMR (CDCl ₃ ) δ (ppm) 8.00-7.40m (5H), 4.49s (2H), 3.47t (2H),
2.62t (2H), 2.15-1.80m (2H) Elemental analysis (as C ₁₁ H ₁₃ ClSO ₄ ) CN Calculated value (%) 47.74 4.74 Actual value (%) 47.68 5.03 Example 2 Same operation as Example 1 Compounds 2 to 8 were contained. Example 3 1-diazo-5-methoxycarbonyl-2-n
- 1.7 g of pentanone in 50 c.c. of tetrahydrofuran.
2.5 g of p-ethoxybenzenesulfonic acid was gradually added at room temperature, and the obtained oil was recrystallized from ethanol-water in the same manner as in Example 1. 2.2g of -5-methoxycarbonyl-n-pentyl-p-ethoxybenzenesulfonate (Compound 9) was obtained (yield
64.0%). MS (M ⁺ ) 344 H-NMR (CDCl ₃ ) δ (ppm) 7.85d (2H), 7.00d (2H), 4.45s (2H), 4.08q
(2H), 3.64s (3H), 2.55t (2H), 2.30t (2H),
2.05-1.65m (2H), 1.44t (3H) Elemental analysis (as C ₁₅ H ₂₀ SO ₇ ) C H Calculated value (%) 52.33 5.86 Actual value (%) 52.35 5.85 Example 4 Same operation as Example 3 Compounds 10, 11, 13
~15 were synthesized. Example 5 3.4 g of 2-oxo-5-acetoxy-2-n-pentyl-2,4,6-trimethylbenzenesulfonate (compound 15) was dissolved in 20 ml of ethanol, 30 ml of 2N-HCl was added under ice cooling, and the solution was dissolved at room temperature for 3.4 g. Stir for hours. After the reaction, ethanol was distilled off under reduced pressure, the resulting residual liquid was extracted with 50 ml of ether, the ether layer was dried over anhydrous sodium sulfate, and then distilled under reduced pressure, and the resulting oil was subjected to silica gel column chromatography. Separation and purification using E (developing solvent: chloroform) yielded a colorless and transparent oil, 2-oxo-5-
Hydroxy-2-n-pentyl-2,4,6-
Trimethylbenzenesulfonate (compound 12)
0.9g was obtained (yield 30.2%). MS (M ⁺ ) 300 H-NMR (CDCl ₃ ) δ (ppm) 6.98s (2H), 4.05-3.70m (2H), 3.90s (2H),
2.76s (1H), 2.56s (6H), 2.53t (2H), 2.05~
1.70m (2H) MS in Tables 1 and 2 indicates mass spectra,
H-NMR indicates the δ (ppm) value measured in deuterium-substituted chloroform.

【table】

【table】

[Table] Next, the test results of the esterase inhibitory effect, chymotrypsin inhibitory effect, and antihyperlipidemic effect of the compound () 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-HCl buffer (PH8.0), and then add a 50% ethanol solution of the compounds of the present invention shown in Table 2 to this. After that, immediately add purified rat liver microsomal fraction esterase solution (9 μl at 37°C for 1 hour) as an oxygen solution.
(adjusted to hydrolyze mol 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 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 Add 0.1 unit of chymotrypsin as an enzyme solution to a fixed amount of 0.1M Tris-HCl buffer (PH8.0), and add 50% ethanol solution of the present compound shown in Table 2 to a fixed amount of 0.1M Tris-HCl buffer (PH8.0). After adding it to a concentration of ^-4 mol, the reaction was carried out at 37°C 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 (%) = AB/A x 100 A: Amount of ester hydrolysis in reaction system without addition of the compound of the present invention B: Amount of ester hydrolysis in reaction system with addition of the compound of the present invention 3 Antihyperlipidemic effect test 7 weeks Male Wistar rats, aged 200 to 220 g and weighing 200 to 220 g, were used in the test in groups of five. 100 mg of the compound of the present invention was dissolved in 10 ml of olive oil and used in the test. Olive oil containing the compound of the present invention was orally administered to rats at the equivalent of 10 ml/kg using a sonde, and after 2 or 8 hours, 6 ml of whole blood was injected into the descending vena cava under ether anesthesia using a syringe containing heparin. Collect. The obtained blood was heated to 5°C.
Centrifuge at 3000 rpm to obtain plasma. After 2 hours, the triglyceride content of the plasma was measured using a triglyceride measurement kit (Triglyceride-B Test Wako) manufactured by Wako Pure Chemical Industries. Olive oil alone was similarly administered to the control group, and no treatment was administered to the normal group, and the triglyceride content in plasma of both groups was measured in the same manner as the group treated with the compound of the present invention. The hyperlipidemia suppression rate of the compound of the present invention was calculated using the following formula. Inhibition rate (%) = AC/A-B x 100 A: Control group triglyceride content B: Normal group triglyceride content C: Triglyceride content of the compound-treated group of the present invention The above pharmacological test results are shown in Table 3. As is clear from Table 3, the compounds of the present invention have excellent esterase inhibitory effects, chymotrypsin inhibitory effects, and antihyperlipidemic effects, and are useful as antihyperlipidemic agents, anti-inflammatory agents, and immunomodulators.

【table】

Claims (1)

[Claims] 1 General formula R ₁ SO ₃ CH ₂ CO(CH ₂ ) _n R ₂ [In the formula, R ₁ is a phenyl group with or without a substituent (the substituent is a lower alkyl group or a lower alkoxy group), _R2 is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, or a carbobenzoxyamino group, and m is an integer of 3 to 5. 2 General formula N ₂ CHCO (CH ₂ ) _n R ₂ ′ (wherein, R ₂ ′ is a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, or a carbobenzoxyamino group, and m is an integer of 3 to 5. ) and the compound represented by the general formula R ₁ SO ₃ H・YH ₂ O [wherein R ₁ is a phenyl group with or without a substituent (the substituent is a lower alkyl group or a lower alkoxy group) , Y represents an integer from 0 to 2]
If desired, react with a compound represented by
General formula R ₁ SO ₃ CH ₂ CO(CH ₂ ) _n R ₂ [wherein R ₁ and m have the same meanings as above,
_R2 represents a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, or a carbobenzoxyamino group. 3 General formula R ₁ SO ₃ CH ₂ CO(CH ₂ ) _n R ₂ ″ [In the formula, R ₁ is a phenyl group with or without a substituent (as a substituent, a lower alkyl group or a lower alkoxy group), R ₂ ″ is an acyloxy group,
m is an integer of _{3 to 5} ] is hydrolyzed in the _{presence of} an acid catalyst _. m has the same meaning as above]
A method for producing a sulfonate derivative represented by