JPS6147833B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel substituted thiobiuret compounds. The substituted thiobiuret compounds according to the present invention have the general formula (In the formula, R ₁ , R ₂ and R ₃ are lower alkyl groups, R ₄ is a phenyl group, and a phenyl group or aralkyl group having a halogen atom, lower alkyl group, lower alkoxy group or trifluoromethyl group as a substituent. and X and Y each independently represent an oxygen atom or a sulfur atom. The lower alkyl group represented by R ₁ , R ₂ , and R ₃ of the substituted thiobiuret compound represented by the above general formula (1) and the lower alkyl group represented as a substituent of the phenyl group of R ₄ have 1 to 6 carbon atoms. A chain or branched alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl group, etc., and a lower alkoxy group as a substituent of the phenyl group in R ₄ is an alkoxy group having 1 to 5 carbon atoms. For example, methoxy, ethoxy, propoxy,
Examples of the halogen atom include fluorine, chlorine, bromine, and iodine, and examples of the aralkyl group include benzyl and phenethyl groups. The substituted thiobiuret compound of the present invention is a novel compound that has anti-inflammatory, analgesic, anti-allergic, diuretic, anti-bacterial and anti-spasmodic effects, and is a compound useful as an anti-inflammatory agent or analgesic. . The substituted thiobiuret compound according to the present invention can be obtained by, for example, reacting urea or thiourea represented by general formula (2) with isocyanate or isothiocyanate represented by general formula (3) as shown in the reaction formula below. is synthesized by (In the formula, R ₁ , R ₂ , R ₃ , R ₄ , X and Y are the same as above.) In this reaction, urea or thiourea represented by general formula (2) and The isocyanate or isothiocyanate used is a known compound, and the reaction is usually carried out in a solvent or without a solvent. The solvent is not particularly limited as long as it does not participate in the reaction, and generally includes ether,
Ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenoalkanes such as chloroform, dichloromethane and dichloroethane are used. Although this reaction proceeds satisfactorily even in the absence of a catalyst, an acidic catalyst or a basic catalyst can also be used as the catalyst. As acidic catalysts, for example, Lewis acids such as stannic chloride, titanium tetrachloride, aluminum chloride, etc. are used, and as basic catalysts, for example, sodium hydride, sodium amide, etc. are used. The ratio of the urea or thiourea represented by the general formula (2), the isocyanate or isothiocyanate represented by the general formula (3), and the catalyst may be selected as appropriate, but it is generally advantageous to use equimolar amounts. It is. Although the reaction temperature may be selected as appropriate, it generally proceeds advantageously when carried out at a temperature of -20°C to about reflux of the solvent. In a reaction using an acidic catalyst, a complex of thiobiuret and metal precipitates from the reaction solution after the reaction is completed. Thiobiuret is easily released from the metal complex by mixing it with a water-immiscible solvent in a mixture of water or an acidic aqueous solution. These can be isolated by conventional separation means such as recrystallization, column chromatography, etc. Examples of substituted thiobiuret derivatives represented by general formula (1) are as follows, and the compounds obtained by these examples are shown in Table 1. Example 1 5-(3-trifluoromethylphenyl)-
Synthesis of 1,1,3-trimethyl-4-thiobiuret (Compound No. 20) 1.44 g (0.03 mol) of sodium hydride (50% oily) was suspended in 80 ml of anhydrous tetrahydrofuran with stirring.
1,1,3-trimethylurea 3g below 10℃
(0.03 mol) was added and stirred at room temperature overnight. The reaction solution was cooled to below 0°C, and a solution of 6.0 g (0.03 mol) of 3-trifluoromethylphenyl isothiocyanate in 10 ml of anhydrous tetrahydrofuran was added dropwise, followed by stirring at below 0°C for 4 hours. After completion of the reaction, the mixture was acidified with acetic acid, water was added, the solvent was distilled off under reduced pressure, and the mixture was extracted with ether and dried over sodium sulfate. After distilling off the ether and isolating the residue using silica gel column chromatography (solvent system: benzene:acetone=5:1),
Recrystallized from ether to give 5-(3-trifluoromethylphenyl)-1,1,3-trimethyl-
6.8 g of 4-thiobiuret was obtained. (Yield 75%) Examples 2 to 6 Synthesis of compounds No. 12, 14, 16, 18, and 22 As 1,1,3-trimethylurea and isothiocyanate, phenylisothiocyanate and 4- Chlorphenyl isothiocyanate, 4
Synthesis was performed in the same manner as in Example 1 using -methylphenylisothiocyanate, 4-methoxyphenylisothiocyanate, and benzylisothiocyanate. Example 7, 8 Synthesis of compounds Nos. 23 and 24 Using 1-ethyl-1,3-dimethylurea and phenylisothiocyanate and benzylisothiocyanate, respectively, in the same manner as in Example 1. Synthesized. Example 9 5-(4-chlorophenyl)-1,1,3-trimethyl-2-thiobiuret (Compound No. 15)
Synthesis of 1,1,3-trimethylthiourea 5.9g (0.05
mol) in 50 ml of dry dichloroethane, 4-
Add 7.6 g (0.05 mol) of chlorphenyl isocyanate, cool to below 0°C, and add 13 g (0.05 mol) of anhydrous stannic chloride to 10 ml of dry dichloroethane.
After the solution was added dropwise, the mixture was stirred at room temperature overnight. Collect the precipitate from the reaction mixture, wash it with dichloroethane, then add 50 ml of chloroform and 10% aqueous hydrochloric acid solution.
40 ml and stirred. The organic layer was separated, washed with water, and dried with sodium sulfate. Chloroform was distilled off, and the residue was subjected to silica gel column chromatography (solvent system;
After isolation with chloroform:ethanol=10:1), recrystallization from ether gave 11.2 g of 5-(4-chlorophenyl)-1,1,3-trimethyl-2-thiobiuret. (Yield 83%) Examples 10 to 13 Synthesis of compounds No. 13, 17, 19, and 21 1,1,3-trimethylthiourea and isocyanates such as phenyl isocyanate and 4-methyl fluoride, respectively. Synthesis was performed in the same manner as in Example 9 using enyl isocyanate, 4-methoxyphenyl isocyanate, and 3-trifluoromethyl phenyl isocyanate. Next, the anti-edema effect, analgesic effect, and acute toxicity of the compound of the present invention were measured by the following test methods, and the results are shown in Table 2. Anti-edema effect Acute carrageenan edema test method [Memoto Pharmacology Journal,
56 , 575 (1960)], 100 mg/Kg or 200 mg/Kg of the drug was orally administered to 6 to 8 male Wistar rats (body weight 150 to 180 g) in each group after an overnight fast, and the drug was administered orally for 1 hour. Afterwards, a inflammatory substance (1% carrageenan solution, 0.1 ml/rat) was subcutaneously injected into the footpad, and the foot volume was measured over time. The anti-edema effect was expressed as the edema suppression rate (%) 3 hours after injection of the inflammatory substance. Analgesic effect 1 Acetic acid stretching method Koster et al.'s method [Federation Proceedings
18 , 412 (1959)], 6 to 8 male DDY mice (body weight 20 to 25 g) were used in each group, and after an overnight fast, 50 mg/Kg, 100 mg/Kg, or 20 mg/Kg of the drug was orally administered. One hour later, 0.2 ml of 0.7% acetic acid was intraperitoneally administered to each animal, and the stretching symptoms were observed to determine the inhibition rate (%). 2 Modified Hafner method Modified method of Fujimura et al. [Kyoto University Chemical Research Institute Report No. 25]
36 (1951)], using 6 to 8 male DDY mice (body weight 20 to 25 g) in each group, after an overnight fast, 45 minutes after oral administration of 100 mg/Kg or 200 mg/Kg of the drug. Threshold dose of morphine hydrochloride (1.5-2.5
mg/Kg) was injected subcutaneously, and the pain response due to the cream was observed for 1 hour thereafter to determine the suppression rate (%). Acute Toxicity Test The drug was orally administered to male DDY mice (body weight 20-25 g) after an overnight fast. General symptoms after administration were observed for 7 days and expressed as the number of deaths/number of animals per group relative to the dose (mg/Kg). In the above tests, all drugs were suspended in 0.25% carboxymethyl cellulose solution.

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Claims (1)

[Claims] 1. General formula (In the formula, R ₁ , R ₂ and R ₃ are lower alkyl groups, R ₄ is a phenyl group, and a phenyl group or aralkyl group having a halogen atom, lower alkyl group, lower alkoxy group or trifluoromethyl group as a substituent. and X and Y each independently represent an oxygen atom or a sulfur atom).