JPS6330900B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula (): IC≡CCH ₂ X () [wherein, X is a pyrazolyl group, a triazolyl group,
In particular, the present invention relates to iodopropargyl derivatives represented by 1,2,4-triazolyl group or tetrazolyl group, a method for producing the same, and an antifungal agent containing them as active ingredients. The present inventors have already discovered that iodopropargyl compounds having a substituted pyrrole nucleus are useful based on basic research on antifungal substances that began with the antifungal antibiotic pyrrolomycin A (Japanese Patent Application No. 166,926/1982). I discovered something (Japanese Patent Application No. 57-6609). Furthermore, the present inventors synthesized various similar compounds for the purpose of improving these substances, examined their antibacterial activity, and arrived at the present invention. The iodopropargyl compound of the above formula () provided by the present invention is a useful substance exhibiting remarkable bactericidal activity, particularly antifungal activity. The iodopropargyl compound () of the present invention is
to pyrazole, triazole or tetrazole,
In the presence of a base in an inert solvent, an iodopropyne derivative represented by the formula (): IC≡CCH ₂ Y () (wherein Y represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester) is reacted. Manufactured by Among the raw materials used in the production of the present invention, the iodopropyne derivative () is a known compound. , or toluenesulfonyl chloride,
It is obtained as iodopropargyl alcohol sulfonate by reacting it with an esterifying agent such as benzenesulfonyl chloride or methanesulfonic anhydride. Furthermore, pyrazole, which is the other raw material used in the production of the compound of the present invention,
Triazoles and tetrazoles are well-known compounds, already commercially available, and readily available. According to the present invention, the iodopropargyl compound represented by the formula () is prepared by dissolving the pyrazole, triazole or tetrazole in an inert solvent, and adding the iodopropyne derivative represented by the formula () and a base. It is produced by an N-alkylation reaction that introduces an iodopropargyl group onto the ring nitrogen atom.
Examples of inert solvents used in this reaction include benzene, dioxane, dichloromethane, N,N-
Examples include dimethylformamide, especially N,N
-dimethylformamide is preferred. Examples of bases used in the reaction include inorganic bases such as alkali hydroxides and alkali carbonates, as well as organic bases such as triethylamine. When using an alkali hydroxide, the reaction proceeds rapidly at room temperature, but in order to prevent side reactions, it may be carried out under cooling, preferably at 0 to 5°C, or by using an organic base at a temperature of 40 to 60°C. It can also be carried out by heating to ℃.
The target iodopropargyl compound represented by the formula () can be isolated from the reaction mixture by a crystallization method by adding an inert solvent, such as water, or an extraction method using an organic solvent, such as toluene, ethyl acetate, etc. Alternatively, if necessary, well-known purification methods such as chromatography using silica gel or recrystallization using an organic solvent may be used in combination. The actual production of the novel iodopropargyl compound () according to the present invention will be explained below with reference to Examples. Example 1 1-(1'-Iodopropyn-3'-yl)pyrazole [Compound (1)] 136 mg (2 mmol) of pyrazole was dissolved in 5 ml of dimethylformamide, and sodium hydroxide powder was added.
90 mg was added, stirred well at 20-25°C, and then cooled on ice. After adding 0.67 g (2 mmol) of iodopropargyl alcohol/p-toluenesulfonic acid ester and stirring for 2 hours, the mixture was left at 20 to 25°C overnight. Ethyl acetate and water were added to extract the reaction solution, and the ethyl acetate layer was washed with water, dried, and concentrated under reduced pressure, leaving a crystalline substance. This was subjected to silica gel chromatography (solvent system benzene/ethyl acetate =
10/1) and purified with 1-(1'-iodopropyne-
330 mg of 3'-yl)pyrazole crystals were obtained. mp.94～
95℃. Elemental analysis values: C31.73%, H2.20%, N12.61
%; Calculated value as C ₆ H ₅ N ₂ I: C31.03%, H2.16
%, N12.60%. Example 2 1-(1'-iodopropyn-3'-yl)-1,
2,4-Triazole [Compound (2)] 160 mg (2.3 mmol) of 1,2,4-triazole was added with 3 ml of dimethylformamide and 90 mg of sodium hydroxide powder, stirred at 20-25°C for 1 hour, and then cooled on ice. . Iodopropargyl alcohol/p-toluenesulfonic acid ester in the reaction solution
0.67 g (2 mmol) was added and stirred for 4 hours while the temperature of the solution was gradually raised to room temperature. Add 20 ml of water to the reaction solution, extract twice with 20 ml of ethyl acetate,
The combined ethyl acetate solutions were washed three times with saturated brine and dried. The ethyl acetate solution was concentrated under reduced pressure, and the remaining crystalline material was washed with a small amount of water-methanol mixture to obtain 1-(1'-iodopropyn-3'-yl)-1,2,4-triazole crystals. . Yield 263mg (56%); mp・126-128℃; Elemental analysis values: C25.87%, H1.73%, _N18.33 %; Calculated value _{as C5H4N3I} : C25.77%, H1.73%, N18.03%. Example 3 1-(1'-iodopropyn-3'-yl)tetrazole [compound (3)] and 2-(1'-iodopropyn-3'-yl)tetrazole [compound (4)] Tetrazole 160 mg (2 mmol) was dissolved in 5 ml of dimethylformamide, 90 mg of sodium hydroxide powder was added, stirred, and cooled on ice. 0.67 g (2 mmol) of iodopropargyl alcohol/p-toluenesulfonic acid ester was added, and the mixture was allowed to react for 4 hours under ice-cooling, and then left overnight at 20 to 25°C. Add 20 ml of water to the reaction solution and dilute with 20 ml of ethyl acetate.
Extracted twice. The ethyl acetate layers were combined, washed with water, dried, and concentrated under reduced pressure to leave a colorless crude product.
The Rf value of the crude product was determined by silica gel thin layer chromatography (solvent system: benzene-ethyl acetate 4:1 ratio).
It was shown to be a mixture of two substances showing values of 0.74 and 0.34. The mixture was separated and purified by column chromatography using 50 g of silica gel (solvent system: benzene-ethyl acetate 5:1 ratio), and 2-(1'-iodopropyn-3'-yl) was extracted from the fraction showing an Rf value of 0.74.
183 mg of tetrazole crystals were obtained (yield 39%).
mp.92~95℃; Elemental analysis value: C20.27%, H1.30%,
N23.88%; Calculated value as C ₄ H ₃ N ₄ I: C20.53%,
H1.29%, N23.94%; PMR spectrum (δ,
_CDCl3 ) 5.50ppm ( _-CH2- ), 8.45ppm (tetrazole CH). From the fraction with an Rf value of 0.34, 258 mg of 1-(1'-iodopropyn-3'-yl)tetrazole crystals were obtained (yield 55%). mp.92~95℃; Elemental analysis value:
C20.62%, H1.26%, N23.96%; Calculated values as C ₄ H ₃ N ₄ I: C20.53%, H1.29%, N23.94%;
PMR spectrum (δ, CDCl ₃ ) 5.30ppm (CH ₂
-), 8.66ppm (tetrazole CH). Tables 1 and 2 show the antifungal activities of compounds (1) to (4) represented by formulas () produced in Examples 1 to 3.
Shown below.

【table】

【table】

[Table] The novel iodopropargyl compound of the present invention represented by the above formula () is useful as an antifungal agent. In particular, the compound of the present invention exhibits a growth-inhibiting effect on a wide range of fungi, so it can be used in various fields of medicine, agriculture, and industry to improve unfavorable conditions caused by the growth of bacteria and fungi. It's useful. That is, for medical use, for example, as a therapeutic agent for external diseases caused by fungi such as Candida, Aspergillus, Trichophyton, and Cryptococcus, it is preferably 0.1 to 5% as an active ingredient in liquid preparations and ointments.
It can be mixed in a range of 0.5 to 2% and applied to the affected area to achieve the therapeutic goal. Furthermore, for medical purposes, it can be included as a disinfectant for machinery and equipment and other active ingredients for the purpose of preventing the growth of pathogenic bacteria and molds and maintaining a sterile environment. Furthermore, the iodopropargyl compound represented by formula () of the present invention also shows usefulness in the agricultural and industrial fields. In particular, in these fields, agricultural and industrial products such as seeds, seedlings, wood, agricultural and horticultural crops, woodwork products, paper crafts, leather, fibers, adhesives, paints, and synthetic resins, as well as their manufacturing environments, such as spoilage in irrigation water, are particularly important. The growth of bacteria and mold causes a serious loss in the value of products. Since the iodopropargyl compound of the present invention exhibits a growth inhibiting effect on harmful bacteria and fungi in the agricultural and industrial fields, it can be used for the purpose of maintaining the quality of products in these fields and preserving the environment. In the agricultural and industrial fields, the iodopropargyl compound of the present invention can be used in formulations supported on commonly used carriers, such as oil solvents, emulsions, pastes, powders, wettable powders, aerosols, and antifungal paints. can give. The carrier used is
For example, inorganic solid carriers such as clay, talc, bentonite, kaolin, silicic anhydride, calcium carbonate, tyrosine, ligroin, xylene, DMF,
Organic solvent carriers such as DMSO, dimethyl ether,
Examples include gas carriers such as chlorofluorocarbon gas, and auxiliary agents to further enhance formulation effects include ionic and nonionic surfactants, and polymeric compounds such as vinyl acetate and methyl cellulose. It is also possible to use it in combination with other preservatives and fungicides, and insecticides such as chlordane. The content of the iodopropargyl compound of the present invention in actual use may vary widely depending on the formulation, but is generally in the range of 0.01 to 95% by weight, preferably 0.2 to 10% by weight. Examples of formulations as agricultural and industrial antifungal agents are listed below. Formulation Example 1 Wettable powder 40 parts by weight of 1-(1'-iodopropyn-3'-yl)pyrazole, 5 parts by weight of polyoxyethylene alkylaryl ether, 3 parts by weight of lignin sulfonic acid, and 52 parts by weight of diatomaceous earth are uniformly ground and mixed. Then you will get a hydrating powder containing 40% of the active ingredient. Formulation Example 2 Granules 1-(1'-iodopropyn-3'-yl)-1,
12 parts by weight of 2,4-triazole, 1 part by weight of calcium lignosulfonate, 30 parts by weight of bentonite and 57 parts by weight of clay are uniformly ground and mixed, then an appropriate amount of water is added and kneaded, followed by granulation. When dried, granules containing 12% of the active ingredient are obtained. Formulation Example 3 Emulsion 20 parts by weight of 1-(1'-iodopropyn-3'-yl)tetrazole, 30 parts by weight of dimethylformamide, 35 parts by weight of xylene, and 15 parts by weight of polyoxyethylene alkylaryl ether are uniformly mixed to form the active ingredient. An emulsion containing 20% is obtained. Formulation Example 4 Powder 3 parts by weight of 2-(1'-iodopropyn-3'-yl)tetrazole, 0.5 parts by weight of silicic anhydride fine powder, 0.5 parts by weight of calcium stearate, 50 parts by weight of clay and 46 parts by weight of talc were uniformly ground; When mixed, a powder containing 3% of the active ingredient is obtained.

Claims (1)

[Claims] 1. An iodopropargyl compound represented by the formula (): IC≡CCH ₂ X () [wherein X represents a pyrazolyl group, a triazolyl group, or a tetrazolyl group]. 2. Reacting pyrazole, triazole or tetrazole with an iodopropyne derivative represented by the formula (): IC≡CCH ₂ Y () (wherein Y represents a halogen atom or a hydroxyl group activated as a sulfonic acid ester). A method for producing an iodopropargyl compound represented by the characteristic formula (): IC≡CCH ₂ X () (wherein X represents a pyrazolyl group, a triazolyl group, or a tetrazolyl group). 3. An antifungal agent containing as an active ingredient an iodopropargyl compound represented by the formula (): IC≡CCH ₂