Pest repellent containing monoterpene ketol compound as active ingredient

Abstract

To provide a compound that exhibits excellent repellent effects against blood-sucking pests such as mosquitoes, black flies, stable flies, sandflies, biting midges as well as hygiene pests like houseflies.SOLUTION: The present invention provides a pest repellent containing a monoterpene ketol compound as active ingredient, represented by the general formula 1 [where R1, R2 and R3 each have the following meanings. (1) R1 represents a hydrogen atom, and R2 and R3 represent a carbon-carbon single bond. (2) R2 represents a hydrogen atom, and R1 and R3 represents a carbon-carbon single bond].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an insect repellent containing a monoterpene ketol compound as an active ingredient. [Background technology]

[0002] Conventionally, N,N-diethyl-m-toluamide (hereinafter referred to as Deet) and sec-butyl-2-piperidine-1-carboxylate (hereinafter referred to as Icaridin) have been used in the form of sprays, lotions, creams, etc. as repellents against blood-sucking pests such as mosquitoes including Culex mosquitoes, Aedes mosquitoes, and Anopheles mosquitoes, black flies, and stable flies. Summary of the Invention [Problem to be solved by the invention]

[0003] Deet, which is used as a repellent for blood-sucking pests, has the disadvantages of being limited to a certain number of pest species, being less effective against malaria-carrying mosquitoes such as Anopheles, having an unpleasant odor, being resin-soluble, etc. Icaridin also has the disadvantages of being limited to a certain number of pest species, and having high manufacturing costs. [Means for solving the problem]

[0004] In view of the above circumstances, the present inventors have made extensive research to develop a compound that exhibits pest repellent activity while overcoming the shortcomings of Deet and Icaridin, and have discovered a compound represented by the general formula 1: (chemical 1) TIFF2025009155000001.tif3026 (wherein R1, R2 and R3 have the following meanings. (1) R1 represents a hydrogen atom, and R2 and R3 together represent a carbon-carbon single bond. (2) R2 represents a hydrogen atom, and R1 and R3 together represent a carbon-carbon single bond. The present invention has been accomplished by finding that monoterpene ketol compounds represented by the following formula (I) exhibit extremely high pest repellent activity. Effect of the Invention

[0005] The compound exhibits excellent repellent effect against blood-sucking pests such as mosquitoes, black flies, stable flies, sand flies, and biting midges, as well as sanitary pests such as house flies. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] This compound is a known compound described in the literature, and the details are as follows: (1) The synthesis method of calanketol, in which R1=H, R2 and R3 represent a carbon-carbon single bond, is described in Synthetic Communications, Vol. 17, (2) The synthesis method of pinanketol in which R2=H and R1 and R3 together represent a carbon-carbon single bond is described in Tetrahedron Letters, Vol. 57, P. 420-422 (2016), etc. The above calanketol and pinanketol have stereoisomers, and the present compound includes all of these isomers and mixtures thereof.

[0007] Among the present compounds, preferred examples include 1S,3S,6R-caran-4-on-3-ol and 1S,2S,5S-pinan-3-on-2-ol.

[0008] Specific examples of the present compound are shown below.

[0009] compound 1 1S,3S,6R-Callan-4-on-3-ol TIFF2025009155000002.tif3028

[0010] compound 2 1S,3R,6R-Callan-4-on-3-ol TIFF2025009155000003.tif3027

[0011] compound 3 1S,2S,5S-Pinane-3-one-2-ol TIFF2025009155000004.tif2529

[0012] compound 4 1R,2R,5R-Pinan-3-one-2-ol TIFF2025009155000005.tif2428

[0013] Examples of pests against which the present compound is effective include Anopheles mosquitoes such as A-nopheles albimanus, a malaria-carrying mosquito in tropical regions; A-edes mosquitoes such as Aedes aegypti and Aedes albopictus; Culex pipiens quinquefasciatus and Culex tritaeniorhynchus; blood-sucking pests such as black flies, stable flies, sand flies and midges; and sanitary pests such as house flies.

[0014] When the present compound is used as a pest repellent, depending on the compound, the original substance itself can be used, but it is usually used as a composition formulated with a suitable carrier (hereinafter referred to as the present composition), and is used after being adjusted into the form of, for example, a liquid such as a lotion or aerosol, or a cream.

[0015] Carriers used in preparing liquid preparations include, for example, water, alcohols such as methanol, ethanol, cetyl alcohol, glycerin, and polyethylene glycol, ethers such as tetrahydrofuran and dioxane, aliphatic hydrocarbons such as hexane, kerosene, paraffin, and petroleum benzine, and esters such as ethyl acetate.

[0016] The liquid preparation may further contain conventional formulation auxiliary agents such as emulsifiers or dispersants, spreading / wetting agents, suspending agents, preservatives, propellants, etc., and may also contain conventional coating film-forming agents.

[0017] Specific examples of such emulsifiers include soaps, polyoxyethylene fatty acid alcohol ethers such as polyoxyethylene oleyl ether, polyoxyethylene alkylaryl ethers such as polyoxyethylene nonylphenyl ether, polyoxyethylene fatty acid esters, fatty acid glycerides, sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate, sulfates of higher alcohols, and alkylarylsulfonates such as sodium dodecylbenzenesulfonate.

[0018] Examples of such agents include spreading / wetting agents such as glycerin and polyethylene glycol; suspending agents such as casein, gelatin, alginic acid, carboxymethyl cellulose, gum arabic, hydroxypropyl cellulose, and bentonite; preservatives such as salicylic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate; propellants such as dimethyl ether, chlorofluorocarbons, and carbon dioxide gas; cellulose derivatives such as nitrocellulose, acetyl cellulose, acetyl butyryl cellulose, and methyl cellulose; vinyl resins such as vinyl acetate resin; and various film-forming agents such as polyvinyl alcohol.

[0019] Carriers used in preparing creams include, for example, hydrocarbons such as liquid paraffin, petrolatum, paraffin, etc.; silicones such as dimethylsiloxane, colloidal silica, bentonite, etc.; alcohols such as ethanol, stearyl alcohol, lauryl alcohol, etc.; polyhydric alcohols such as polyethylene glycol, ethylene glycol, glycerin, etc.; carboxylic acids such as lauric acid, stearic acid, etc.; esters such as beeswax, lanolin, etc.

[0020] Furthermore, the same pharmaceutical auxiliary as in the liquid preparation can be added. Furthermore, the composition can be prepared in a microencapsulated form and used as a lotion, aerosol, or the like.

[0021] The composition may also contain other pest repellents, antioxidants, other additives, etc. Examples of other pest repellents that may be added include Deet, icaridin, dimethyl phthalate, 2-ethyl-1,3-hexanediol, N-octyl bicycloheptane dicarboximide, p-menthane-3,8-diol, 2,3,4,5-bis(Δ2-butylene)tetrahydrofurfural, di-n-propyl isocinchomeronate, di-n-butyl succinate, 2-hydroxyethyl octyl sulfide, and empenthrin {1-ethynyl-2-methyl-2-pentenyl d-cis, trans-chrysanthemate (cis:trans ratio=2:8)}, and examples of antioxidants include butyl hydroxyanisole, dibutyl hydroxytoluene, tocopherol, and γ-oryzanol.

[0022] The present composition or compound prepared as described above can be applied directly to the skin, etc., or it can be used by coating, impregnating, kneading, dropping, etc., a suitable substrate such as a sheet, film, mesh, or strip, and then covering exposed parts of the skin or clothing with the substrate.

[0023] Examples of the material of the substrate include synthetic fibers and resins such as polyethylene, polypropylene, polyvinylidene chloride, polyester, vinylon, nylon, etc., animal and vegetable fibers such as silk, cotton, wool, etc., inorganic fibers such as aluminum, etc., and mixtures thereof. When using a mesh-like substrate, the finer the mesh, the more preferable, but generally a mesh of about 16 mesh or less is sufficiently effective.

[0024] The amount of the present compound as an active ingredient in the present composition varies depending on the dosage form and application method, but when used in the form of a liquid preparation such as a lotion or aerosol, or a cream, or when contained in a base, it is 0.1 to 70% by weight, preferably 1 to 40% by weight.

[0025] The amount of the composition to be used is usually 1 cm2 of skin. 2The amount of the present compound is 0.01 to 2 mg, preferably 0.05 to 1 mg, per unit, and these amounts are also used when the present compound is used alone for treatment. The above-mentioned treatment amount varies depending on the type of formulation, the target pest species, its density, time of use, weather conditions, age of the user, etc., and can be increased or decreased without being limited to the above range. EXAMPLES

[0026] The present invention will be explained in more detail below with reference to Reference Examples, Formulation Examples and Test Examples, but the present invention is not limited to these examples.

[0027] First, the preparation examples of the compounds of the present invention are shown. The starting compounds 1S,3S,4S,6R-caran-3,4-diol and 1S,3R,4R,6R-caran-3,4-diol used in the preparation examples were both synthesized by the method described in JP-A-5-4901 (1993). In addition, 1S,2S,5S-pinan-3-on-2-ol and 1R,2R,5R-pinan-3-on-2-ol were both commercially available as reagents and were purchased from Tokyo Kasei.

[0028] First, a reference example will be given. [Reference example 1] 1S,3S,6R-Callan-4-on-3-ol Method for producing (compound (1)) 2.00g (11.8×10-3 mol) of 1S,3S,4S,6R-caran-3,4-diol and 30ml of dichloromethane were placed in a 50ml eggplant flask and cooled to 0°C while stirring. 3.00g (13.9×10-3 mol) of pyridinium chlorochromate was added to the mixture over 5-10 minutes, and the mixture was stirred at 0°C for 5 hours. 30ml of diethyl ether was added, and the mixture was filtered through Florisil and concentrated to obtain 1.80g of crude compound. The mixture was subjected to silica gel column chromatography to obtain 1.10g of colorless oily compound (2).

[0029] [Reference example 2] 1S,3R,6R-Callan-4-on-3-ol Method for producing (compound (2)) In a 50-mL recovery flask, 1.00 g (5.88 × 10-3 mol) of 1S,3R,4R,6R-caran-3,4-diol and 20 mL of dichloromethane were placed and cooled to 0°C while stirring. 1.52 g (7.05 × 10 -3 mol) was added over 5 to 10 minutes, and the mixture was stirred for 5 hours at 0° C. 20 ml of diethyl ether was added, and the mixture was filtered through Florisil, and then the solvent was concentrated to obtain 0.95 g of a crude compound. The mixture was subjected to silica gel column chromatography to obtain 0.56 g of compound (2) as a colorless oil.

[0030] Formulation examples are shown below. Note that parts are by weight, and the compounds are represented by the compound numbers described in paragraphs 0009 to 0012.

[0031] [Formulation Example 1] 10 parts of compounds (1) to (4) are dissolved in ethanol to make a total of 35 parts, and the solution is filled into an aerosol container. After attaching a valve, 65 parts of a 1:1 mixture (propellant) of freon 11 and freon 12 are pressurized and filled through the valve to obtain an aerosol.

[0032] [Formulation Example 2] 5 parts of compound (1) and 5 parts of compound (2) are dissolved in ethanol to make a total of 35 parts, and the solution is filled into an aerosol container. Then, the same treatment as in Preparation Example 1 is carried out to obtain an aerosol.

[0033] [Formulation Example 3] To 10 parts of compound (3), 10 parts of stearic acid, 2 parts of cetyl alcohol, 1 part of lanolin, 2 parts of liquid paraffin, and 62 parts of water are added, and the mixture is heated to dissolve and mix. 13 parts of heated glycerin is then added and thoroughly stirred to obtain a cream.

[0034] [Formulation Example 4] A mixture of 6 parts of stearic acid, 0.5 parts of lanolin, and 6 parts of Tween 60 (trade name: polyoxyethylene sorbitan monostere) is heated to 80°C, and this is added to a mixture (60°C) of 75 parts of water and 2.5 parts of salicylic acid, and 10 parts of compound (1) are added with rapid stirring to obtain a lotion.

[0035] Next, the usefulness of this compound as an active ingredient of a pest repellent will be demonstrated by test examples.

[0036] [Test Example 1] Compounds 1 and 2 were diluted to a given concentration with ethanol (Fujifilm Wako Pure Chemical special grade reagent). One hundred Aedes aegypti mosquitoes were released into a nylon gossamer cage (30 cm x 30 cm x 30 cm) and 3% sugar water was provided as bait. The back of the left hand (surface area approx. 0.016 m) wearing a disposable glove 2 0.2 ml of ethanol (Blank) or ethanol solution of each compound was dropped onto the back of the hand and spread over the entire back of the hand. 2 or 2.0 g AI / m 2 The gloves were treated with the compound. The wrist and hands were placed in a cage containing mosquitoes, and the palm was pressed against the side of the cage to prevent the mosquitoes from settling, at which point the test began (Figure 1). The number of test insects (attracted insects) that remained motionless on the entire glove on the back of the hand was counted at one-minute intervals for five minutes after the start of the test. Seven cages were prepared, and the test was conducted in rotation. Each treatment was repeated three times, and the repellency rate against Aedes aegypti was calculated using the following formula: Repellency rate (%) = (1 - average number of insects attracted to the treated area / average number of insects attracted to the blank area) x 100

[0037] TIFF2025009155000006.tif8384

[0038] [Test Example 2] Each compound was diluted to a given concentration with acetone (Fujifilm Wako Pure Chemical special grade reagent). 1.5 mL of acetone (blank) or acetone solution of each compound was dropped onto a qualitative filter paper (ADVANTEC No. 2, diameter 90 mm), and the mixture was air-dried for approximately 5 minutes in a fume hood. 2 Compound-treated filter paper was prepared. A nylon gossamer cage (30 cm x 30 cm x 30 cm) was fitted with blank filter paper and 2.0 g AI / m 2 The test was started by hanging one of the compound-treated filter papers and releasing 300 test insects (Fig. 1, Fig. 2). From the start of the test until 6 hours later, the number of test insects that had settled on each filter paper (number of settled insects) was counted every hour. 2 Three replicates were performed for each. The average number of settled insects was calculated based on the number of settled insects from 0 hours (initial period) to 6 hours, and the repellency rate of each compound was calculated from the average number of settled insects using the following formula. Average number of settled insects = Average number of settled insects from 0 hours to 6 hours after three repetitions Repellency rate (%) = (1 - average number of fixed and undead insects for each compound / average number of fixed insects in the blank) x 100

[0039] TIFF2025009155000007.tif3184 Test method: Hanging filter paper method Test insects: Culex pipiens adult females, 300 per cage Filter paper type: ADVANTEC No. 2 qualitative filter paper, diameter 90 mm *1 Average number of settled insects = Average number of settled insects from 0 hours to 6 hours after three repetitions *2 Repellency rate (%) = (1 - average number of settled insects in the treatment area / average number of settled insects in the blank area) x 100

Claims

1. General formula Chemical formula 1 【Chemistry 1】 [In the formula, R 1 , R 2 and R 3 represents the following meaning. (1) R 1 represents a hydrogen atom, R 2 and R 3 and represent a carbon-carbon single bond. (2) R 2 represents a hydrogen atom, R 1 and R 3 and represent a carbon-carbon single bond.

1. A pest repellent comprising, as an active ingredient, a monoterpene ketol compound represented by the formula:

2. The monoterpene ketol compound is 1 represents a hydrogen atom; R 2 and R 3 2. The insect repellent according to claim 1, which is a monoterpene ketol compound in which:

3. 3. The insect repellent according to claim 2, wherein the monoterpene ketol compound is 1S,3S,6R-caran-4-on-3-ol.

4. 3. The insect repellent according to claim 2, wherein the monoterpene ketol compound is 1S,3R,6R-caran-4-on-3-ol.

5. The monoterpene ketol compound is ２ represents a hydrogen atom; R １ and R ３ 2. The insect repellent according to claim 1, which is a monoterpene ketol compound in which:

6. 3. The insect repellent according to claim 2, wherein the monoterpene ketol compound is 1S,2S,5S-pinan-3-on-2-ol.

7. 3. The insect repellent according to claim 2, wherein the monoterpene ketol compound is 1R,2R,5R-pinan-3-on-2-ol.

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