JPH0434548B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a novel triiodoallyltetrazole, a method for producing the compound, and an antibacterial and antifungal agent containing the compound as an active ingredient. [Prior art] Conventionally, 2,3,3-triiodoallyl alcohol (Japanese Patent Publication No. 53-20484), its alkyl ethers (Japanese Patent Publication No. 53-20006), and aralkyl ethers (Japanese Patent Publication No. 47-39099) have been used for antibacterial, It is known to exhibit antifungal effects. Many of these compounds do not necessarily have sufficient antibacterial or antifungal activity, and have drawbacks such as poor cure rates in vitro, e.g., in animal experiments for diseases caused by bacteria or fungi. Ta. Excellent antibacterial and antifungal agents not only have high activity in vitro, but also have the ability to inhibit the growth of a wide range of bacteria and fungi. Therefore, it is necessary to have excellent permeability and retention in the skin tissue, and it is also extremely important that side effects such as irritation to the skin and local areas are small. However, there are very few drugs that meet these requirements. [Object of the invention] The novel triiodoallyl of the present invention has the effect of inhibiting the growth of a wide range of bacteria and fungi, has excellent permeability and retention in skin tissue, and has little irritation to the skin, local areas, etc. The object of the present invention is to provide a tetrazole, a method for producing the same, and an antibacterial and antifungal agent containing the compound. [Structure of the invention] The present invention is based on the general formula A novel triiodoallyltetrazole represented by R represents an alkyl group or a benzyl group having 2 or more carbon atoms. In addition, this compound can be expressed by the general formula R′-SO ₂ O-CH ₂ CI=CI ₂ (2) where R′ represents an alkyl group or a phenyl group with or without a substituent. In the formula, R has the same meaning as above, by reacting a compound represented by the general formula A method for obtaining a novel triiodoallyltetrazole represented by the formula in which R has the same meaning as above. and general formula In the formula, R represents the same meaning as above, and is an antibacterial and antifungal agent containing a novel triiodoallyltetrazole as an active ingredient. General formula of the present invention In the formula, R is an alkyl group having 2 or more carbon atoms, preferably a straight or branched alkyl group having 2 to 15 carbon atoms, or a benzyl group. These compounds are all novel compounds that have not been described in any literature. The representative compounds are as follows. Compound (1) 2-(2',3',3'-triiodoallyl)
-5-n-heptyltetrazole compound (2) 1-(2',3',3'-triiodoallyl)
-5-n-heptyltetrazole compound (3) 2-(2',3',3'-triiodoallyl)
-5-n-pentyltetrazole compound (4) 1-(2',3',3'-triiodoallyl)
-5-n-pentyltetrazole compound (5) 2-(2',3',3'-triiodoallyl)
-5-t-butyltetrazole compound (6) 1-(2',3',3'-triiodoallyl)
-5-t-butyltetrazole compound (7) 2-(2',3',3'-triiodoallyl)
-5-t-propyltetrazole compound (8) 1-(2',3',3'-triiodoallyl)
-5-n-propyltetrazole compound (9) 2-(2',3',3'-triiodoallyl)
-5-isopropyltetrazole compound (10) 1-(2',3',3'-triiodoallyl)
-5-isopropyltetrazole compound (11) 2-(2',3',3'-triiodoallyl)-5-ethyltetrazole compound (12) 1-(2',3',3'-triiodoallyl) -5-Ethyltetrazole compound (13) 2-(2',3',3'-triiodoallyl)-5-n-butyltetrazole compound (14) 1-(2',3',3'-triiodo Allyl)-5-n-butyltetrazole compound (15) 2-(2',3',3'-triiodoallyl)-5-isobutyltetrazole compound (16) 1-(2',3',3'- Triiodoallyl)-5-isobutyltetrazole compound (17) 2-(2′,3′,3′-triiodoallyl)-5-decyltetrazole compound (18) 1-(2′,3′,3′- Triiodoallyl)-5-decyltetrazole compound (19) 2-(2′,3′,3′-triiodoallyl)-5-benzyltetrazole compound (20) 1-(2′,3′,3′- triiodoallyl)
−
5-Benzyltetrazole The compound of the present invention can be obtained by reacting a 5-carbon alkyl or benzyl-substituted tetrazole with a reactive derivative of triiodoallylic alcohol. The reaction formula is shown below. In the formula, X is a halogen atom or a hydroxyl group activated as a sulfonic acid ester, and R has the same meaning as above. This reaction consists of 2,3,3-triiodoallyl halide or 2,3,3-triiodoallylsulfonate (4) shown by formula (4), 35-substituted tetrazole (3), and a basic reagent. For example, if the reaction is carried out in the presence of an alkali hydroxide, a tertiary amine, an alkali carbonate, an alkali bicarbonate, etc., in a solution of an inert solvent such as N,N dimethylformamide, dioxane, tetrahydrofuran, etc., the desired product can be reacted. Iodoallyltetrazole (1) can be produced in good yield. The 2,3,3-triiodoallyl halide used in this reaction includes 2,3,3-triiodoallyl chloride, 2,3,3-triiodoallyl bromide, etc. As the alkyl or phenyl sulfonic acid ester of allyl alcohol (compound represented by formula (2)), 2,3,3-triiodoallyl methanesulfonate, 2,3,3-triiodoallyl n-butanesulfonate , 2,3,3-triiodoallyl n-octanesulfonate, 2,3,3-triiodoallylbenzenesulfonate, 2,3,3-
Triiodoallyl 4-methoxybenzenesulfonate, 2,3,3-triiodoallyltrimethylbenzenesulfonate, 2,3,3-triiodoallyl 2-cyanobenzenesulfonate, 2,
In addition to 3,3-triiodoallyl triisopropylbenzenesulfonate, 2,3,3-triiodoallyl 5-ethoxybenzenesulfonate,
Substituted phenylsulfonic acid esters in which the benzene ring is substituted with one or more electron-withdrawing substitutions, such as halogen atoms, nitro groups, carbamoyl groups, alkoxycarbamoyl groups, etc. For example, 2,3,3-
Triiodoallyl 4-chlorobenzenesulfonate, 2,3,3-triiodoallyl 4-nitrobenzenesulfonate, 2,3,3-triiodoallyl 4-carbamoylbenzenesulfonate,
2,3,3-triiodoallyl 2,4,5-trichlorobenzenesulfonate, 2,3,3-triiodoallyl 4-chloro-3-nitrobenzenesulfonate, 2,3,3-triiodoallyl 3,
4-dichlorobenzenesulfonate, 2,3,3
-Triiodoallyl 2,4-dinitrobenzenesulfonate and the like can be used. When phenyl sulfonic acid ester of 2,3,3-triiodoallylic alcohol (formula (2)) having an electron-withdrawing substituent on the benzene ring is used, the reaction proceeds rapidly, making it difficult to synthesize using conventional methods. It easily reacts with low-reactivity tetrazoles, which were difficult to produce by the method, and produces various useful 2,3,3-
Triiodoallytetrazole compounds can be produced. Next, the uses of the compounds of the present invention will be described. The compounds of the present invention are useful as antibacterial and antifungal agents,
In particular, it has a strong growth-inhibiting effect on a wide range of bacteria and fungi, so it is used in the medical field, animal and other livestock medicine, agriculture, and industrial fields to prevent undesirable effects caused by the growth of bacteria and fungi. It is useful for improving various symptoms and conditions. In other words, for medical purposes, for example, Candida genus,
As a therapeutic agent for external diseases caused by molds such as Aspergillus, Trichophyton, and Cryptococcus, the active ingredient in liquid preparations and ointments is formulated in the range of 0.1 to 5%, preferably 0.5 to 2%, and applied to the affected area. It can be applied to achieve the therapeutic purpose. In addition, other medical or pet animals,
It can be used as a sterilizer or disinfectant for animals such as livestock to prevent the growth of pathogenic bacteria and fungi, or to treat external diseases caused by these growths. Furthermore, the compounds of the present invention also show utility in agricultural and industrial fields. In particular, these fields include agricultural and industrial products and manufacturing, such as seeds, seedlings, wood, agricultural and horticultural crops, woodwork, pure crafts, leather, fibers, adhesives, paints, pulp, circulating water for cooling, and synthetic resins. The occurrence of putrefactive bacteria and mold in the environment causes a serious loss in the value of products. Since the compound of the present invention exhibits a growth inhibiting effect on harmful bacteria and fungi in these 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 compound of the present invention can be used in formulations supported on commonly used carriers, such as oil solvents, emulsions, pastes, powders,
Examples include hydrating powders, aerosols, antifungal paints, and adhesives. Examples of carriers used include inorganic solid carriers such as clay, talc, bentonite, kaolin, silicic anhydride, and calcium carbonate, organic solvent carriers such as kerosene, ligroin, xylene, dimethylformamide, and dimethyl sulfoxide, dimethyl ether, and fluorocarbon gas. Examples include ionic and nonionic surfactants, and auxiliary agents to further enhance the formulation effect.
There are also polymeric compounds such as vinyl acetate and methylcellulose, which can also be used in combination with other antiseptic and antifungal agents such as thiabendazole, and organophosphorus insecticides and fungicides. The content of the compound of the invention in the formulation may vary widely depending on the formulation, but generally from 0.01 to 95% by weight, preferably from 0.2 to 10% by weight.
A range of weight percent is suitable. [Effects of the Invention] Table 1 below shows the antibacterial activity of the compounds of the present invention, and Tables 2 and 3 show the antifungal activities of the compounds of the present invention.

【table】

【table】

〔Example〕

Example 1 2-(2',2',3'-triiodoallyl)-5-n
-heptyltetrazole [compound (1)] and 1-
((2′,2′,3′-triiodoallyl)-5-n-heptyltetrazole [Compound (2)] Dissolve 6.83 g of 5-n-heptyltetrazole in 100 ml of dry benzene and prepare 2,3,3- Triiodoallyl-p-nitrobenzenesulfonate 23.8g
and 4 g of triethylamine were added and reacted for 1.5 hours. The reaction solution was washed with an aqueous sodium bicarbonate solution and further dried over anhydrous magnesium sulfate. The benzene solution was concentrated under reduced pressure to obtain compound (1) and compound (2) as a mixture. Gross yield 22.4g (98
%) of the crude mixture was separated by column chromatography using 40 g of silica gel (solvent system: toluene-ethyl acetate, 10:1 to 4:1), and each compound was obtained as a pure substance. Compound (2)
0.68g brown solid, elemental analysis C, 23.10%; H,
2.81%; N _, 9.44%; I, _{63.16%: Calculated as C11H17N4I3 , C22.55} %; H, 2.92%; N, 9.56
%; I, 64.97%. Yield of compound (1): 1.19 g, colorless crystals, mp 69.8-70.2°C (recrystallized from water-methanol), elemental analysis C, 22.46%; H, 2.85%; N,
9.32%; calculated value C as C ₁₁ H ₁₇ N ₄ I ₃ , 22.55
%; H, 2.92%; N, 9.56%: I, 64.97%. Example 2 2-(2',3',3'-triiodoallyl)-5-n
-pentyltetrazole [compound (3)] and 1-
(2',3',3'-triiodoallyl)-5-n-pentyltetrazole [Compound (4)] Dissolve 0.70 g of 5-n-pentyltetrazole in 10 ml of anhydrous dimethylformamide and powder sodium hydroxide. Add 0.20g and stir well to make a homogeneous solution. 2,3,3-triiodoallyl-
2.94 g of p-toluenesulfonate was added to this solution under ice cooling, and the reaction was continued under cooling for 1 hour and then overnight at room temperature. Add the reaction solution to 100ml of ethyl acetate and 50ml of water.
ml, and the ethyl acetate layer is washed with saturated brine and dried. When the ethyl acetate extract was concentrated, a pale red solid remained. Yield: 2.63 g (95%) The crude product was subjected to silica gel chromatography (solvent system: benzene-
Purify the compound with ethyl acetate = 10:1 to 4:1)
(3) and (4) were separated. Yield of compound (3): 0.83g (29
%) Pale red oil, elemental analysis value C, 19.00%; H,
2.27%; N, 9.95%: _Calcd for _C9H13N4I3 C, 19.37%; _H , 2.35%; _N , 10.04%. Compound
Yield of (4): 1.45 g (52%), mp 105.4-107.3°C, elemental analysis C, 19.50%; H, 2.32%; N, 9.82%.
Calculated as C ₉ H ₁₃ N ₄ I ₃ C, 19.37%; H, 2.35
%; N, 10.04%. Example 3 2-(2',3',3'-triiodoallyl)-5-t
-butyltetrazole [compound (5)] and 1-
(2',3',3'-triiodoallyl)-5-t-butyltetrazole [Compound (6)] 252 mg of 5-t-butyltetrazole, 0.28 ml of triethylamine and 2,3,3-triiodoallyl-P - 1.40 g of nitrobenzene sulfonate was mixed in 15 ml of benzene, and the mixture was further heated under reflux for 30 minutes over an aqueous solution. After cooling the reaction solution, it was washed twice with water and then dried over anhydrous sodium sulfate. A solid (compound (5)) and a mixture of compound (6) obtained by concentrating the benzene solution were recrystallized from 2 ml of methanol to obtain compound (5) as colorless crystals. Yield 568 mg (52
%) mp108-110℃, elemental analysis value C, 17.70%;
H, 1.89%; _N , 9.61%: Calcd for _C8H11N4I3 C, 17.67%; _H , 2.04%; _N , 10.38%. The methanol mother liquor was concentrated, and the residue was purified by silica gel chromatography to obtain an additional 0.41 g of compound (5).
and 0.20 g of compound (6) were obtained. Example 4 2-(2',3',3'-triiodoallyl)-5-n
-Propyltetrazole [Compound (7)] and 1-
(2',3',3'-triiodoallyl)-5-n-propyltetrazole [Compound (8)] Using 426 mg (3.8 mmol) of 5-n-propyltetrazole and an equivalent amount of the reaction reagent, in benzene,
2.03 g (99%) of a mixture of compounds (7) and (8) was obtained in the same manner as in Example 3, except that the reaction was carried out at 60° C. for 30 minutes. The mixture was purified by silica gel chromatography (solvent system: toluene-ethyl acetate = 10:1 to 4:1) to separate the mixture. Yield of compound (7): 609 mg (30
%) mp85.3~87.2℃, elemental analysis value C, 15.91%;
H, 1.64%; N, 10.30%. _{Calcd for C7H9H4N4I3} C, 15.78%; _H , 1.71%; _N , 10.57%.
Yield of compound (8) 1.27g (63%) mp130.1-132.5
°C, elemental analysis value C, 15.84%; H, 1.61%; N,
10.38%; I, 71.65%. Calculated value as C ₇ H ₉ N ₄ I ₃ C, 15.87%; H, 1.77%; N, 10.57%; I,
71.85%. Example 5 2-(2′,3′,3′-triiodoallyl)-5-isopropyltetrazole [compound (9)] and 1-
(2',3',3'-triiodoallyl)-5-isopropyltetrazole [Compound (10)] Using 560 mg (5 mmol) of 5-isopropyltetrazole and an equivalent amount of reaction reagent, 60
2.62 g of a mixture of compounds (9) and (10) was obtained in the same manner as in Example 3, except that the reaction was carried out at ℃ for 35 minutes (crude yield: 98%).
The mixture was purified by column chromatography using 100 g of silica gel (solvent system: toluene-ethyl acetate = 10:1) to separate each compound. Yield of compound (9) 1.00g (36%), mp113.0~
114.7℃, elemental analysis value C, 15.64%; H, 1.60%;
N, 10.41%. Calculated value C as C ₇ H ₉ N ₄ I ₃ , 15.87
%; H, 1.71%, N, 10.57%. Yield of compound (10)
1.33% (50%), mp173.0-176.5°C, elemental analysis value C, 15.65%; H, 1.62%; N, 10.40%.
Calculated value as C ₇ H ₉ N ₄ I ₃ C, 15.87%; H, 1.71
%; N, 10.57%. Example 6 2-(2′,3′,3′-triiodoallyl)-5-benzyltetrazole [compound (19)] and 1-
(2',3',3'-triiodoallyl)-5-benzyltetrazole [Compound (20)] 5-benzyltetrazole 320 mg (2 mmol)
and equal amounts of reaction reagents at 60°C in benzene.
The same operation as in Example 3 was carried out, except that the reaction was carried out for a certain period of time, to obtain 1.23 g (97%) of a mixture of compounds (19) and (20). The mixture was purified by silica gel chromatography and separated. Yield of compound (19) 405mg (35%), mp141.7~
146.9℃ Elemental analysis value C, 23.37%; H, 1.54%; N,
9.79%. Calculated value C as C ₁₁ H ₉ N ₄ I ₃ , 22.86%;
H, 1.57%; N, 9.70%. Yield of compound (20) 601mg (52%), mp142.0 ~
143.2℃ Elemental analysis value C, 22.98%, H; 1.50%,
N; 9.50%, calculated value C as C ₁₁ H ₉ H ₉ N ₄ I ₃ ,
22.86%; H, 1.57%; N, 9.70%. Example 7 2-(2′,3′,3′-triiodoallyl)-5-ethyltetrazole [compound (11)] and 1-
(2',3',3'-triiodoallyl)-5-ethyltetrazole [Compound (12)] 5-ethyltetrazole 485 mg (5 mmol)
and equivalent amounts of reaction reagents at 60°C in 30 ml of benzene.
A mixture of compounds (11) and (12) was obtained in the same manner as in Example 3, except that the reaction was carried out for 1 hour, and further subjected to silica gel chromatography (solvent system benzene-ethyl acetate 10:1 to 4:1). Each was separated. Yield of compound (11): 0.72 g (28%), elemental analysis C, 14.22%; H, 1.41%; N, 10.55%.
Calculated value as C ₆ H ₇ N ₄ I ₃ C, 13.97%; H, 1.37
%; N, 10.86%. Yield of compound (12): 1.63g
(62%), elemental analysis value C, 13.99%; H, 1.47%;
N, 9.99%. Calculated value C as C ₆ H ₇ N ₄ I ₃ , 13.17
%; H, 1.37%; N, 10.86%.

Claims (1)

[Claims] 1. General formula A triiodoallyltetrazole represented by the formula in which R represents an alkyl group or a benzyl group having 2 or more carbon atoms. 2 General formula: R′-SO ₂ O-CH ₂ CI=CI ₂ In the formula, R′ represents an alkyl group or a phenyl group with or without a substituent. A general formula characterized by reacting a compound represented by the formula in which R represents an alkyl group or a benzyl group having 2 or more carbon atoms. A method for producing triiodoallyltetrazole, where R has the same meaning as in the previous term. 3 General formula An antibacterial and antifungal agent characterized by containing as an active ingredient a triiodoallyltetrazole represented by the following formula, in which R represents an alkyl group or a benzyl group having 2 or more carbon atoms.