JPH0324448B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (); [However, in the formula, R is a hydrogen atom; an alkyl group having 1 to 8 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms; a methylene group; a lower alkenyl group; substituted with a halogen atom, a lower alkoxy group, or a lower alkylthio group. lower alkyl group;

[Formula] (R ₁ represents a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkoxy group, a haloalkoxy group, or a methylenedioxy group,
m is an integer of 1 to 3); benzyl group; methylenedioxybenzyl group; phenoxyalkyl group; phenoxyalkyl group substituted with a halogen atom; naphthyl group or substituted Indicates a pyridyl group which may be ] It relates to an antifungal agent characterized by containing the compound represented by these as an active ingredient. As a result of intensive studies on ketene S,S-acetal, the present inventors discovered that the compound represented by the above general formula () is useful as an antifungal agent, and completed the present invention. . The compound represented by the general formula () can be produced by the method shown below. (However, in the formula, R is the same as above, and X represents a halogen atom, mesyloxy group, or tosyloxy group.) That is, 1-cyanomethylimidazole represented by the structural formula () and carbon disulfide are combined in the presence of a base and a solvent. A compound represented by the general formula () can be obtained by reacting to produce an intermediate represented by the structural formula (), and then reacting this intermediate with an alkyl dihalide represented by the general formula () without isolation. can be obtained. The solvent that can be used in the present invention may be any solvent as long as it does not inhibit the progress of the reaction, and includes, for example, alcohols such as methanol, ethanol, and isopropanol; dimethyl sulfoxide, dimethyl formamide, hexamethylene phosphoramide, and water. can. These solvents can be used alone or in combination. Examples of the base that can be used in the present invention include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc., and these can be used as solids or It can also be used by dissolving it in a solution. The reaction temperature may be selected from the range of 0 to 100°C, but it is particularly preferable to carry out the reaction near room temperature. The reaction time may be appropriately selected from the range of 0.5 to 24 hours. The amount of base used is 1 expressed by the structural formula ()
-The amount may be selected from the range of 2 to 4 times the mole of cyanomethylimidazole. After completion of the reaction, the reaction solution may be treated in a conventional manner, for example, extracted and separated with a suitable solvent, and further purified by recrystallization or column chromatography. The compound represented by the general formula () is often obtained as a mixture of two types of geometric isomers shown below.

【formula】

[Formula] In many cases, the above-mentioned mixture of Z-form and E-form can be isolated into each isomer by appropriate separation means such as recrystallization method, chromatography method, etc. The present invention includes all geometric isomers, ie, E-form and Z-form, as well as mixtures thereof in arbitrary proportions. Representative examples of the compounds represented by the general formula () of the present invention are shown in Table 1.

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【table】

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[Table] The compounds of the present invention are antifungal agents of use in combating fungal infections in humans and animals. For example, they can be used to treat localized, mucosal, and systemic fungal infections caused by Trichophyton, Candida, and other fungi. The compound of the present invention can be mixed with a conventional chemotherapeutically acceptable diluent or carrier and, if desired, other excipients, and can be used in dosage forms such as solutions, creams, ointments, suppositories, and tablets. I can do it. When the compound of the present invention is used as an antifungal agent in the form of a topical application, it can be used in the form of a cream, ointment, liquid, or the like. Practical concentration when used as a coating agent
Probably more than 0.1%. Test example 1 Antibacterial activity test against Trichophyton mentagrophytes 10g of peptone and 40g of glucose were dissolved in 1 part of water.
After adjusting to PH6.0, active ingredient 50ppb (1% DMSO
Solution) containing Sabouraud medium
3ml was poured into a 3.5φcm shear dish to prepare an agar plate medium. Plant 0.1ml of the pre-cultured bacteria in a shear plate,
Culture was carried out at 28°C for 4 to 6 days. The test compounds were tested in duplicate, and judgments were made visually according to the evaluation criteria below. Note) DMSO: Dimethyl sulfoxide evaluation criteria ±: Completely suppresses bacterial growth +: Suppresses bacterial growth: Forms white colonies: The diameter of white colonies increases The results are shown in Table 2.

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[Table] Test Example 2 Treatment test for ringworm disease using guinea pigs A Hartley white male guinea pig (400-600g) was used as the test animal.The hair was shaved in three places on the back of the guinea pig, and the hair was shaved about 3 cm with hair removal cream. After hair was removed in a circular shape, the skin in the area where the hair was removed was lightly rubbed with sandpaper. Trichophyton trichophyton cultured on Sabouraud glucose agar
mentagrophytes) IFO-5466 strain 0.1ml (10 ⁶
The spores/spots were applied to the abraded skin. Three days after the bacterial inoculation, a test drug based on polyethylene glycol 300 was applied once a day at 0.2 ml per bacterial inoculation site for 11 days. Evaluation was performed by visual judgment and reverse culture test. a. Visual judgment: On the day after inoculation, the local symptoms were observed for 15 days. Evaluation Criteria 0: No symptoms observed 1: A few small erythema spots observed 2: Erythema scattered or fused into islands, with redness around the area 3: Scales observed, followed by a thick layer Condition 4 in which crust formation is observed: A condition in which the lesion has reached its peak stage and is accompanied by bleeding. The results are shown in Table 3.

[Table] b Reverse culture test method Fifteen days after inoculation with the bacteria, the guinea pigs were killed by buffeting, and the skin over the entire area where the bacteria had been inoculated was cut and shredded. This skin piece 10
Cells (approximately 5 mm on each side) were placed on Sabouraud glucose agar containing 20 i.u./ml of penicillin G and 40 μg/ml of streptomycin, cultured at 27° C. for 2 weeks, and the presence or absence of bacterial colonies was determined. The results are shown in Table 4.

[Table] Prescription examples are shown below. In addition, parts indicate parts by weight. Formulation Example 1 Mix and dissolve 1 part of compound 35 and 99 parts of polyethylene glycol 300 to prepare a coating solution. Formulation Example 2 2 parts of Compound 53, 40 parts of polyethylene glycol, and 58 parts of polyethylene glycol 1500 are mixed and dissolved under heating, and then cooled to form an ointment. Formulation Example 3 Compound 38 2 parts 1,2-propanediol 5 parts glycerol stearate 5 parts spermaceti 5 parts isopropyl myristate 10 parts polysorbate A mixture of 4 parts was warmed, cooled, and then 69 parts water was added with stirring. Add cream. In addition to the above, pharmaceutical injections, suppositories, and the like can also be prescribed. The acute oral toxicity value (LD ₅₀ ) of the compound of the present invention when administered orally is 1000 mg/Kg for compound No. 35.
Compound No. 53 has a content of 300 mg/Kg or more. Synthesis example Synthesis of 2-(1-imidazolyl)-2-(4-isobutyl-1,3-dithiolane-1,3-dithiolane-2-ylidene)acetonitrile (compounds No. 8 and 9) 1-cyanomethylimidazole 0.55 g (0.005
0.8 g (0.014 mol) of potassium hydroxide powder was added to a mixed solution of 0.4 g (0.005 mol) of carbon disulfide, 0.4 g (0.005 mol) of carbon disulfide, and 10 ml of dimethyl sulfoxide with stirring, and the reaction was carried out at room temperature for 1 hour. Thereafter, 1.5 g (0.006 mol) of 1,2-dibromo-4-methylpentane was added dropwise with stirring, and the reaction was carried out for 2 hours. After the reaction is complete, add 20ml of water to the reaction solution and extract with ethyl acetate.
The organic layer was washed with water and dried. The solvent was distilled off, the residue was purified by silica gel chromatography, and the Z-form was obtained.
0.45 g and 0.3 g of E form were obtained as colorless crystals. Z-form (Compound No. 8) Melting point: 73.3℃ Yield 34% E-form (Compound No. 9) Melting point: 118.1℃ Yield 23%

Claims (1)

[Claims] 1 General formula () [However, in the formula, R is a hydrogen atom; an alkyl group having 1 to 8 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms; a methylene group; a lower alkenyl group; a halogen atom, a lower alkoxy group, or a lower alkylthio group. Substituted lower alkyl group; [Formula] (R ₁ represents a hydrogen atom, a halogen atom, a linear or branched lower alkyl group, a lower alkoxy group, a haloalkoxy group, or a methylenedioxy group, and m is 1 or an integer of 3); benzyl group; methylenedioxybenzyl group; phenoxyalkyl group; phenoxyalkyl group substituted by a halogen atom; naphthyl group or even if substituted Shows good pyridyl group. ) An antifungal agent characterized by containing a compound represented by the following as an active ingredient.