JP4338022B2 - (Iso) thiocyanate antibacterial and antifungal agent - Google Patents

Description

The present invention relates to an antibacterial and antifungal agent comprising an isothiocyanate 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, and chitosan 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 previously found that a monoterpene derivative thiocyanate exhibits an excellent preventive effect 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 isothiocyanate has 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 to develop a more effective and environmentally friendly compound as an antibacterial and antifungal agent, the present inventors have obtained a monoterpene derivative isothiocyanate processed from a natural material component as an antibacterial and antifungal property. The present invention has been completed.

That is, the present invention provides the formula (a);
(A)

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

  The isothiocyanate ester of the monoterpene derivative represented by the formula (a), which is an antibacterial and antifungal agent of the present invention, has high antibacterial and antifungal properties and prevents various harmful effects caused by the generation, growth and diffusion of harmful bacteria and fungi. It is extremely useful to do. 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) (an isothiocyanate 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. It is difficult to synthesize (iso) thiocyanate having n of 13 or more.

(A)
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. By reacting a hydroxyl group-containing monoterpene with 1, n-dihalogenoalkane and reacting a monoterpene derivative with a methylene side chain with a thiocyanate, a thiocyanate ester of the monoterpene derivative was prepared. 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 (l) by using borneol. ) And (iso) thiocyanate represented by the formula (m) can be produced.

(Ku)
(Ke)
(Co)
(Sa)
(Shi)
(Su)

(H)
(I)
(J)
(K)
(L)
(M)

  Examples of 1, n-dihalogenoalkanes include 1,2-dibromoethane, 1,6-dibromohexane, dibromoalkanes such as 1,10-dibromodecane, dichloroalkanes such as 1,10-dichlorodecane, and the like. it can. N of 1, n-dihalogenoalkane is an integer of 1 to 12, and represents the number of carbon atoms 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.

  For reactions in which 1, n-dihalogenoalkane is allowed to act on ionized hydroxyl group-containing monoterpene to introduce methylene side chains, alcohols such as methanol and ethanol can be used as a solvent. The reaction temperature can be not higher than the boiling point of the solvent, usually 0-100 ° C, more preferably 20-80 ° C. When the temperature is lower than 0 ° C., the reaction between the ionized hydroxyl group-containing monoterpene and the 1, n-dihalogenoalkane is difficult to occur, and when the temperature exceeds 100 ° C., the side reaction is likely to occur. 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 hardly occurs, 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.

  The antibacterial and antifungal agent of the present invention can contain one or more compounds represented by the formula (a). 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). 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 compound represented by the formula (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 compound represented by formula (a), metals such as silver, copper, and zinc, and compounds thereof, as well as activated carbon, apatite, zeolite, and tetravalent metal Inorganic antibacterial and antifungal agents such as those supported on phosphate, alcohol compounds such as ethanol and butanol, phenol compounds such as cresol, 4-chloro-3,5-xylenol, o-phenylphenol, Aldehyde compounds such as formalin and glutaraldehyde, carboxylic acids such as sorbic acid, benzoic acid and salicylic acid and their salt compounds, ester compounds such as propyl p-oxybenzoate and pentyl p-oxybenzoate, salicylanilide, Amide compounds such as 3,4 ′, 5-tribromosalicylanilide, Quaternary ammonium salt compounds such as luconium chloride and cetylpyridinium chloride, nitrogen ring compounds such as pyridium, quinolinol, and rivanol, nitrogen sulfur ring compounds such as thiabendazole and benzisothiazolone, methyl isothiocyanate, methylene bis thiocyanate, etc. Naturally-derived antibacterial and antifungal agents such as thiocyanic acid compounds, coconut oil and allyl isothiocyanate as a main component thereof, hiba oil and hinokitiol and chitosan as its main component 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 the compound represented by 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 solid carrier, but contains 0.00001 to 80% by weight of the compound represented by the formula (a) Is possible. 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) 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) 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). 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) 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) 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). 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) 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) 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, Inhibition of growth 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 construction materials 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 sedimentation in oilfield cutting oil, mud 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.

Reference 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 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. It was. The reaction product was extracted with ether and purified by column chromatography to obtain 26 g of isothiocyanate ester (1) of a monoterpene derivative.
Subsequently, using the obtained thiocyanate ester (1) or isothiocyanate ester (1), an emulsion 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 the 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. Table 3 shows the test results. 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” "" Indicates 10 to 19 mm, and "1" indicates that no blocking circle was formed.

Reference Examples 7 and 9 and Examples 2 to 6, 8, and 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.

  In a similar apparatus, 50 g of intermediates (2) to (10), potassium thiocyanate (C) in an amount shown in Table 1 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 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 Reference Example 1, the amount of the monoterpene derivative thiocyanate esters (2) to (10) shown in Table 1 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 yields of the obtained isothiocyanate esters (2) to (10) of the monoterpene derivative.

  Next, using the obtained thiocyanate esters (2) to (10) and isothiocyanate esters (2) to (10), emulsions were prepared at the blending ratios shown in Table 2, and thiocyanate esters (3), ( 5), (7), (9) and the emulsion prepared from the isothiocyanate esters (2), (4), (6), (8), (10) have antibacterial and antifungal properties in the same manner as in Reference Example 1. Evaluation was performed. The results are shown in Table 3.

<Comparative Example 1>
Instead of the thiocyanate ester of the monoterpene derivative in Reference Example 1, an emulsion was prepared using 2-pyridinethiol-1-oxide zinc, which is a commercially available antibacterial agent, at the blending ratio shown in Table 2, and the same as in Reference 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 Reference Example 1, an emulsion was prepared using thiabendazole, which is a commercially available antifungal agent, with the blending ratio shown in Table 2. 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 samples of the emulsions prepared from (10) (Reference Examples 1, 7, 9, Examples 2 to 6, 8, 10), Comparative Example 1 and It was confirmed that the antibacterial and antifungal properties were equal to or higher than 2.

Claims (1)

Formula (a);
(A)
(Wherein n represents an integer of 1 to 12, and R represents any one of the following [Chemical Formula 2] ), containing an isothiocyanate ester of a monoterpene derivative, .