JP2005075781A - (iso-)thiocyanate-based antibacterial and antifungal agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a safe and effective antibacterial and antifungal agent replacing a conventional antibacterial and antifungal agent. <P>SOLUTION: The antibacterial and antifungal agent contains a thiocyanic acid ester of a monoterpene derivative represented by formula R-(CH<SB>2</SB>)<SB>n</SB>-N=SCN (1) and an isothiocyanic acid ester of a monoterpene derivative represented by formula R-(CH<SB>2</SB>)<SB>n</SB>-N=C=S (a) [in formulas, n is an integer of 1-12; and R is any of (2) to (7)]. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to an antibacterial and antifungal agent characterized by containing an (iso) thiocyanate ester of a monoterpene derivative.
Note that the notation of (iso) thiocyanate represents both thiocyanate and isothiocyanate compounds.

In order to prevent various harmful effects caused by the generation, growth and diffusion of harmful bacteria and fungi in industrial products, industrial materials, agricultural and horticultural products, soil, and various sanitary products, antibacterial and antifungal agents are used. In general, it is widely practiced to prevent the generation, growth and spread of mold and various harmful bacteria. As the various antibacterial and antifungal agents used in this case, inorganic metal compounds, quaternary ammonium salt compounds, organic nitrogen compounds, organic nitrogen sulfur compounds, organic halogen compounds, etc. are widely used depending on the purpose. ing.
In addition, natural materials or their components are used as they are, or after being subjected to some processing, and used as antibacterial and antifungal agents. For example, coconut oil and its main component, allyl isothiocyanate, hiba oil, its main component, hinokitiol, chitosan and the like are known. Natural antibacterial and antifungal agents are highly safe and environmentally friendly, but there are few examples that are industrially used. Although natural materials with antibacterial and antifungal properties are known, there are many possible causes that have not been put to practical use, but one of the main causes is that they are effective due to general processing and dilution for normal use. It is conceivable that it is remarkably lowered or even substantially ineffective.
The present inventors have previously found that a monoterpene derivative thiocyanate exhibits an excellent prevention coin against the adhesion of underwater organisms, and filed as Japanese Patent Application No. 2002-47100. In the present invention, the present inventors have further found that the above-mentioned monoterpene derivative thiocyanate and isothiocyanate have an antibacterial and antifungal effect.
Japanese Patent Application No. 2002-47100

  Conventionally, many antibacterial and antifungal agents that have been used are concerned about adverse effects on the human body and the environment, and some are subject to regulation. On the other hand, naturally-occurring antibacterial and antifungal compounds have high safety but are not sufficiently effective. An object of the present invention is to provide a safe and effective antibacterial and antifungal agent that replaces these conventional antibacterial and antifungal agents.

  As a result of intensive research aimed at developing more effective and environmentally friendly compounds as antibacterial and antifungal agents, the present inventors have developed monoterpene derivative (iso) thiocyanate that has been processed from natural material components as an antibacterial agent. The present invention was completed by finding that it is effective against mold resistance.

That is, the present invention relates to formulas (a) and (a);

(Where n is an integer from 1 to 12, R is
And an antibacterial and antifungal agent characterized by containing an (iso) thiocyanate ester of a monoterpene derivative.

  The (iso) thiocyanate ester of the monoterpene derivative represented by the formulas (a) and (a), which is the antibacterial and antifungal agent of the present invention, has high antibacterial and antifungal properties, and generation and growth of harmful bacteria and fungi It is extremely useful for preventing various harmful effects caused by diffusion. Moreover, the antibacterial and antifungal agent of the present invention has a small load on the environment.

  The antibacterial and antifungal agent of the present invention contains a compound represented by the formula (A) and the formula (a) ((iso) thiocyanate ester of a monoterpene derivative) as an active ingredient. The number n of methylene groups of the compounds represented by the formulas (a) and (a) is an integer of 1 to 12, preferably 2 to 10. An (iso) thiocyanate ester having n of 13 or more is difficult to synthesize.

  The compound represented by the formula (a) can be prepared by reacting a thiocyanate after forming a methylene side chain on a monoterpene. For example, by reacting a hydroxyl group-containing monoterpene with a strong alkali to ionize the hydroxyl group of the hydroxyl group-containing monoterpene, 1, n-dihalogenoalkane can be reacted and a methylene side chain can be formed. A compound represented by the formula (A) can be produced by reacting a monoterpene derivative in which a methylene side chain is formed by reacting a hydroxyl group-containing monoterpene with 1, n-dihalogenoalkane and a thiocyanate.

  The compound represented by the formula (a) can be prepared by forming a methylene side chain on a monoterpene, then reacting a thiocyanate to synthesize a thiocyanate, and further isomerizing it. For example, a 1, n-dihalogenoalkane can be reacted by forming a strong alkali on a hydroxyl group-containing monoterpene and ionizing the hydroxyl group of the hydroxyl group-containing monoterpene, thereby forming a methylene side chain. A 1, n-dihalogenoalkane is reacted with a hydroxyl group-containing monoterpene, and a thiocyanate is reacted with a monoterpene derivative that forms a methylene side chain to produce a thiocyanate ester of the monoterpene derivative. The compound represented by the formula (a) can be produced by isomerizing the thiocyanate ester by heating at a high temperature.

As the hydroxyl group-containing monoterpene, geraniol, β-citronellol, linalool, menthol, α-terpineol, or borneol is used.
By using geraniol as the hydroxyl group-containing monoterpene, the (iso) thiocyanate represented by the formula (h) and the formula (h) is converted into the formula (ke) and the formula (i) by using β-citronellol. The (iso) thiocyanate ester represented by formula (co) and formula (j) by using linalool, the (iso) thiocyanate ester represented by formula (sa) and formula (k) by using menthol. The (iso) thiocyanate represented by formula (S) and (I) by using α-terpineol, and the (iso) thiocyanate represented by formula (S) by using borneol. ) And (iso) thiocyanate represented by the formula (m) can be produced.

  Examples of 1, n-dihalogenoalkanes include 1,2-dibromoethane, 1,6-dibromohexane, dibromoalkanes such as 1,10-dibromodecane, and dichloroalkanes such as 1,10-dichlorodecane. it can. N of 1, n-dihalogenoalkane is an integer of 1 to 12, and represents the carbon number of the alkylene group. That is, it corresponds to the number n of methylene groups in the (iso) thiocyanate ester of the monoterpene derivative.

Examples of the strong alkali include alkali metals such as sodium and potassium, alkaline earth metals such as calcium, alkali metal hydroxides such as sodium hydroxide, and basic metal oxides such as silver oxide.
Examples of the thiocyanate include alkali metal salts of thiocyanate such as potassium thiocyanate, sodium thiocyanate, and lithium thiocyanate.

  When ionizing a hydroxyl group-containing monoterpene, a reaction solvent may not be used, and a reaction solvent can also be used. As the reaction solvent, ethers such as diethyl ether and tetrahydrofuran can be used. The reaction temperature can be not higher than the boiling point of the solvent, usually 0-100 ° C, more preferably 10-75 ° C. When the temperature is lower than 0 ° C, ionization of the hydroxyl group-containing monoterpene is difficult to occur, and when the temperature exceeds 100 ° C, side reactions are likely to occur.

  Alcohols such as methanol and ethanol can be used as a solvent for the reaction in which 1, n-dihalogenoalkane is allowed to act on ionized hydroxyl group-containing monoterpene to introduce a methylene side chain. The reaction temperature can be not higher than the boiling point of the solvent, usually 0-100 ° C, more preferably 20-80 ° C. This is because the reaction between the ionized hydroxyl-containing monoterpene and the 1, n-dihalogenoalkane is less likely to occur at temperatures below 0 ° C., and side reactions are likely to occur at temperatures above 100 ° C. The boiling point of methanol and ethanol used as the reaction solvent is preferably set as the reaction temperature.

  The reaction of a monoterpene derivative in which a 1, n-dihalogenoalkane is allowed to act on a hydroxyl group-containing monoterpene to form a methylene side chain and a thiocyanate can be carried out by using a reaction solvent. As the reaction solvent, ketones such as acetone or amides such as N, N-dimethylformamide can be used. The reaction temperature can be not higher than the boiling point of the solvent, usually -60 to 180 ° C, more preferably 20 to 80 ° C. When the temperature is lower than −60 ° C., the reaction between the monoterpene derivative forming the methylene side chain and the thiocyanate hardly occurs, and when the temperature exceeds 180 ° C., the side reaction easily occurs. When using acetone as a reaction solvent, it is preferable to make the boiling point of acetone into reaction temperature.

  The isomerization of the thiocyanate ester of the monoterpene derivative can be performed by using a reaction solvent. As the reaction solvent, amides such as N, N-dimethylformamide can be used. The reaction temperature is usually preferably 30 to 180 ° C, more preferably 50 to 120 ° C. If it is less than 30 ° C, isomerization is difficult to occur, and if it exceeds 180 ° C, side reactions tend to occur.

  The resulting compounds represented by the formulas (a) and (a) can be purified using column chromatography, thin layer chromatography, or the like.

  In the antibacterial and antifungal agent of the present invention, each of the compounds represented by the formulas (a) and (a) can be contained alone or in combination of two or more. The antibacterial and antifungal agent of the present invention can contain 0.00001 to 100% by weight of the compound represented by the formula (A) and / or the formula (a). As long as an appropriate preparation can be prepared, there is no particular upper limit to the concentration. The compound represented by the formula (A) is preferably contained at 0.0001 to 50% by weight, and more preferably 0.01 to 50% by weight.

  The antibacterial and antifungal agent of the present invention can contain not only the compounds represented by the formulas (a) and (a) but also other components. The antibacterial and antifungal agent of the present invention can contain, as another component, a compound that exhibits antibacterial and antifungal properties, that is, a compound that acts as an active ingredient of the antibacterial and antifungal agent. As compounds that act as active ingredients of antibacterial and antifungal agents other than the compounds represented by the formulas (a) and (a), metals such as silver, copper, and zinc, and compounds thereof, and also activated carbon, apatite, Inorganic antibacterial and antifungal agents such as those supported on zeolite, tetravalent metal phosphate, alcohol compounds such as ethanol and butanol, cresol, 4-chloro-3,5-xylenol, o-phenylphenol, etc. Phenolic compounds, aldehyde compounds such as formalin and glutaraldehyde, carboxylic acids such as sorbic acid, benzoic acid and salicylic acid and their salt compounds, ester systems such as propyl p-oxybenzoate and pentyl p-oxybenzoate Compounds, amide compounds such as salicylanilide, 3,4 ', 5-tribromosalicylanilide, benzalkonium Quaternary ammonium salt compounds such as chloride and cetylpyridinium chloride, nitrogen ring compounds such as pyridium, quinolinol and rivanol, nitrogen sulfur ring compounds such as thiabendazole and benzisothiazolone, thiocyanic acid such as methyl isothiocyanate and methylenebis thiocyanate Naturally-derived antibacterial and antifungal agents such as a compound, coconut oil and allyl isothiocyanate as its main component, hiba oil and its main component hinokitiol and chitosan can be used.

  The antibacterial and antifungal agent of the present invention can be prepared in various forms such as a solid carrier adsorbent, a solution, and an emulsion depending on the application. The antibacterial and antifungal agent of the present invention can contain various other components depending on its form. Preparation of the antibacterial and antifungal agent of each form can be performed by a general prescription usually performed.

  The antibacterial and antifungal agent prepared in the form of the solid carrier adsorbent of the present invention can be obtained, for example, by impregnating and adsorbing a compound represented by the formula (A) and / or the formula (a) on various solid carriers. Examples of the solid carrier include activated carbon, zeolite, silica gel, alumina, kaolin, and cellulose. The antibacterial and antifungal agent prepared in the form of a solid carrier adsorbent has a different upper limit because the amount of adsorption varies depending on the type of the solid carrier, but the compound represented by the formula (A) and / or the formula (a) is changed to 0.00001. It is possible to contain -80weight%. When the amount is small, the antibacterial and antifungal effect tends to be hardly recognized, and when the amount is large, there is a tendency that the antibacterial and antifungal effect cannot be absorbed onto the carrier. The compound represented by the formula (A) and / or the formula (a) is preferably contained at 0.0001 to 50% by weight, and more preferably 0.01 to 40% by weight.

  The antibacterial and antifungal agent prepared in the form of the solution of the present invention can be obtained, for example, by dissolving the compound represented by the formula (A) and / or the formula (a) in various solvents. Examples of the solvent include methanol, acetone, toluene, dimethyl sulfoxide, ethyl acetate, N, N-dimethylformamide and the like. The antibacterial and antifungal agent prepared in the form of a solution can contain 0.00001 to 90% by weight of the compound represented by the formula (A) and / or the formula (a). When the amount is small, the antibacterial and antifungal effect tends to be hardly recognized, and when the amount is large, the effect tends not to increase so much. The compound represented by the formula (a) and / or the formula (a) is preferably contained at 0.0001 to 50% by weight, and more preferably 0.01 to 40% by weight.

  The antibacterial and antifungal agent prepared in the form of the emulsion of the present invention can be obtained, for example, by a conventional method in which the compound represented by the formula (A) and / or the formula (a) is dissolved in various solvents and a surfactant is further added. . As the solvent, methanol, acetone, toluene, dimethyl sulfoxide and the like can be used. As the surfactant, nonionic, anionic, cationic, and amphoteric ones can be used as appropriate. For example, a polymer obtained by polymerizing ethylene oxide and / or propylene oxide with alkylphenol, higher alcohol, alkylnaphthol, higher fatty acid, fatty acid ester, dialkyl phosphate amine, etc .; alkyl sulfate ester salt such as sodium lauryl sulfate; 2-ethylhexene Alkyl sulfonates such as sodium sulfonate; aryl sulfonates such as sodium dodecylbenzene sulfonate and the like can be used. The antibacterial and antifungal agent prepared in the form of an emulsion can contain 0.00001 to 50% by weight of the compound represented by the formula (A) and / or the formula (a). When the amount is small, the antibacterial and antifungal effect tends to be hardly recognized, and when the amount is large, the effect tends not to increase so much. The compound represented by the formula (a) and / or the formula (a) is preferably contained at 0.0001 to 50% by weight, and more preferably 0.01 to 40% by weight.

  In addition to these, various adjuvants such as thickeners such as polyvinyl alcohol, carboxymethylcellulose, gelatin, and sodium alginate, and if necessary, antioxidants such as dibutylhydroxytoluene and ultraviolet absorbers such as benzoresorcinol. An appropriate amount of a stabilizer such as can be blended.

  The antibacterial and antifungal agent represented by the formula (A) and / or the formula (a) of the present invention and the antibacterial and antifungal agent prepared in various forms can be used for various products. For example, interior / exterior materials for residential and medical facilities, building materials and civil engineering materials made from various resin materials such as polyvinyl chloride, polyurethane, polyethylene, polypropylene, acrylic resin, nylon, polyethylene terephthalate, silicon, epoxy resin, etc. Antibacterial and antifungal, such as home appliances, miscellaneous goods and toys; antibacterial and antifungal by spraying or dipping on textiles and textiles, leather; emulsion products such as paints, adhesives and latex; slurry products such as pigments and calcium carbonate, And growth control of bacteria and fungi in joint cements; prevention of growth of bacteria and fungi in paint films such as exterior paints; prevention of growth of bacteria and fungi such as paper coatings; wood for building and civil engineering materials Antiseptic of cutting oil; Antibacterial and antifungal of surfactants; Factory Antibacterial and antifungal of cooling towers in manufacturing equipment and air conditioning of buildings; prevention of slime generation and accumulation in pulp and paper factories and sugar and other food manufacturing and processing factories; hygiene in food factories; deodorization in sewage and human waste treatment plants Antibacterial; Prevention of microbial accumulation in industrial freshwater supply systems, etc .; Prevention of microbial contamination and accumulation in oilfield cutting oil, muddy water and secondary oil recovery processes; Prevention of microbial contamination in pools, etc .; It can be used to prevent microbial contamination of medical devices, cosmetics, toiletries, etc .;

  Hereinafter, the present invention will be described with reference to examples and comparative examples, but the scope of the present invention is not limited thereto.

Example 1
<Production of monoterpene derivative thiocyanate>
A three-necked flask equipped with a condenser, a thermometer and a stirrer was charged with 88 ml of geraniol and 50 ml of diethyl ether, and 10 g of finely cut sodium was added thereto. After adding 2 g of potassium iodide, 100 ml of 1,10-dibromodecane was added dropwise over about 1 hour, and then 300 ml of ethanol was added dropwise over about 3 hours and allowed to react for 10 hours under reflux conditions. It was. The reaction product was extracted with ether and then purified by column chromatography to obtain 60 g of an intermediate (monoterpene derivative) (1).
In a similar apparatus, 50 g of intermediate (1), 15 g of potassium thiocyanate and 200 ml of N, N-dimethylformamide were charged and reacted at 80 ° C. for 25 hours. The reaction product was extracted with ether and then purified by column chromatography to obtain 39 g of a thiocyanate ester (1) of a monoterpene derivative.

<Production of isothiocyanate by isomerization of thiocyanate>
In the same apparatus as that used for the production of the monoterpene derivative thiocyanate, 39 g of the monoterpene derivative thiocyanate (1) and 200 ml of N, N-dimethylformamide were charged and isomerized at 100 ° C. for 25 hours. I let you. The reaction product was extracted with ether and then purified by column chromatography to obtain 26 g of a monoterpene derivative isothiocyanate (1).
Subsequently, using the obtained thiocyanate ester (1) or isothiocyanate ester (1), an emulsion of the present invention was prepared at a blending ratio shown in Table 2.

<Evaluation of antibacterial and antifungal performance>
Bacteria: After culturing the test cells on a broth agar medium at 30 ° C. for 24 hours, a bacterial solution for inoculation was prepared using physiological saline to a bacterial count of about 10 ⁶ cfu / ml. Prepare a broth agar plate inoculated with the above bacterial solution, place a paper disk (diameter 10 mm, thickness 1.1 mm) in the center, and obtain 80 μl of the resulting thiocyanate (1) (or isothiocyanate) emulsion. Was soaked in a paper disc to obtain a test medium. After culturing the test medium at 30 ° C. for 24 hours, the growth of the cells on the medium was investigated.

Mold: The test cells were cultured on a malt extract agar medium at 28 ° C. for 5 days, and then the mold spores were suspended in physiological saline supplemented with 1% glycerin to prepare a suspension for inoculation. Prepare a malt extract agar plate inoculated with the above suspension, place a paper disk (diameter 10 mm, thickness 1.1 mm) in the center, and put 80 μl of the resulting thiocyanate (1) emulsion on a paper disk. The test medium was impregnated. After culturing the test medium at 28 ° C. for 1 week, the growth of mold on the medium was investigated. The results of the test are shown in Table 3. As a control, the results in the case of an emulsion not containing an antibacterial and antifungal agent are shown.

  In the antibacterial and antifungal performance evaluation, the presence or absence of colonies around the paper disk, that is, the formation of a blocking circle was visually evaluated. The antibacterial and antifungal performance is evaluated in five stages according to the diameter of the inhibition circle. “5” is an inhibition circle diameter of 40 mm or more, “4” is 30 to 39 mm, “3” is 20 to 29 mm, “2” "10-19 mm," 1 "indicates that no blocking circle was formed.

Examples 2-10
The same apparatus as in Example 1 was charged with a predetermined amount of each monoterpene (A) shown in Table 1 and 50 ml of diethyl ether, and 10 g of finely cut sodium was added thereto. After adding 2 g of potassium iodide, a predetermined amount of each dibromoalkane (B) shown in Table 1 was added dropwise over about 1 hour, and then 300 ml of ethanol was added dropwise over about 3 hours under reflux conditions. For 10 hours. The reaction product was extracted with ether and then purified by column chromatography to obtain intermediates (monoterpene derivatives) (2) to (10). The yield of the obtained intermediate is shown in Table 1.

   A similar apparatus was charged with 50 g of intermediates (2) to (10), potassium thiocyanate (C) in an amount shown in Table 1 and 200 ml of N, N-dimethylformamide, and reacted at 80 ° C. for 25 hours. The reaction product was extracted with ether and then purified by column chromatography to obtain monoterpene derivative thiocyanate esters (2) to (10). The yields of the obtained monoterpene derivative thiocyanate esters (2) to (10) are shown in Table 1.

  In the same apparatus as in Example 1, the yields shown in Table 1 of monoterpene derivatives thiocyanate esters (2) to (10) and 200 ml of N, N-dimethylformamide were charged and reacted at 100 ° C. for 25 hours. . The reaction product was extracted with ether and then purified by column chromatography to obtain isothiocyanate esters (2) to (10) of monoterpene derivatives. Table 1 shows the yield of the obtained monoterpene derivative isothiocyanate esters (2) to (10).

  Next, using the obtained thiocyanate esters (2) to (10) and isothiocyanate esters (2) to (10), an emulsion of the present invention was prepared at the blending ratio shown in Table 2, and the thiocyanate ester (3 ), (5), (7), (9) and the emulsion prepared from the isothiocyanate esters (2), (4), (6), (8), (10) The mold performance was evaluated. The results are shown in Table 3.

<Comparative Example 1>
In place of the monoterpene derivative thiocyanate ester in Example 1, 2-pyridinethiol-1-oxide zinc, which is a commercially available antibacterial agent, was used to prepare an emulsion with the blending ratio shown in Table 2, and the same as in Example 1 The antibacterial and antifungal performance was evaluated.
The results are shown in Table 3.

<Comparative example 2>
In place of the thiocyanate ester of the monoterpene derivative in Example 1, an emulsion was prepared at a blending ratio shown in Table 2 using thiabendazole, which is a commercially available antifungal agent. Evaluation was performed.
The results are shown in Table 3.

  As is clear from the results shown in Table 3, (1), (3), (5), (7), (9) and thiocyanate ester are blended (2). ), (4), (6), (8), all specimens (Examples 1 to 10) of the emulsion prepared from (10), antibacterial and antifungal equivalent to or higher than Comparative Examples 1 and 2 It was confirmed to show sex.

* Tween 80 (polyoxyethylene sorbitan monooleate)

Claims (14)

Formula (A);


(Where n is an integer from 1 to 12, R is
An antibacterial and antifungal agent characterized by containing a thiocyanate ester of a monoterpene derivative. Formula (a);

(Wherein n represents an integer of 1 to 12, and R represents any one of “Chemical Formula 2”), an isothiocyanate ester of a monoterpene derivative. The thiocyanate is represented by the formula (h);
The antibacterial and antifungal agent according to claim 1, which is represented by: The isothiocyanate ester is of the formula (h);
The antibacterial and antifungal agent according to claim 2, which is represented by The thiocyanate ester is of the formula (ke);
The antibacterial and antifungal agent according to claim 1, which is represented by: The isothiocyanate ester is of the formula (i);
The antibacterial and antifungal agent according to claim 2, which is represented by The thiocyanate ester is of the formula (co);
The antibacterial and antifungal agent according to claim 1, which is represented by: The isothiocyanate is represented by formula (j);
The antibacterial and antifungal agent according to claim 2, which is represented by The thiocyanate ester is of the formula (sa);
The antibacterial and antifungal agent according to claim 1, which is represented by: The isothiocyanate ester is of the formula (k);
The antibacterial and antifungal agent according to claim 2, which is represented by The thiocyanate is represented by the formula (b);
The antibacterial and antifungal agent according to claim 1, which is represented by: The isothiocyanate ester is of the formula (l);
The antibacterial and antifungal agent according to claim 2, which is represented by The thiocyanate is represented by the formula (S);
The antibacterial and antifungal agent according to claim 1, which is represented by: The isothiocyanate ester is of the formula (m);
The antibacterial and antifungal agent according to claim 2, which is represented by