Benzoxazine compound or salt thereof, insect growth inhibitor containing said compound, and selective lepidopteran pest control agent containing said compound as active ingredient

Abstract

Disclosed is a benzoxazine compound represented by general formula (1) or a salt thereof, the compound or salt thereof being useful for pest control.

Description

Benzoxazine compound or its salt, insect growth inhibitor containing said compound, and selective lepidopteran pest control agent containing said compound as an active ingredient

[0001] The present invention relates to a benzoxazine compound or a salt thereof, an insect growth inhibitor containing said compound, and a selective lepidopteran pest control agent containing said compound as an active ingredient.

[0002] Juvenile hormone (JH) is a sesquiterpenoid hormone unique to arthropods, including insects. It is a multifunctional hormone involved in a variety of physiological phenomena at all stages from egg to adult, including embryonic development, molting, metamorphosis, sexual maturation, and diapause. For example, during the larval stage, JH is known to regulate molting and metamorphosis by working cooperatively with ecdysteroids (Non-Patent Document 1). It has been revealed that molting from larva to larva occurs when ecdysteroids are secreted in the presence of JH in the body fluids, whereas metamorphosis from larva to pupa or adult occurs when ecdysteroids are secreted in the absence of JH. Furthermore, during the adult stage, JH often acts independently to promote gonadal maturation, such as the synthesis and secretion of vitellogenic proteins in the fat body. JH is also known to play a crucial role in various stages of insect development, including diapause and caste differentiation in social insects. In recent years, methoprene tolerant (hereinafter sometimes referred to as "Met") has been identified as a JH receptor, and has attracted attention as a new target molecule for growth regulators of arthropods, including insects. Therefore, if the activity of Met could be artificially controlled, it would not only disrupt the physiological functions of arthropods, but would also be highly selective for arthropods, making it possible to obtain an ideal pest control agent that would have no or very little effect on humans and mammals and be highly safe. Therefore, research has been conducted on JH and JH analogs (JH-like compounds) that mimic the molecular structure of this JH.

[0003] To date, various JH analogs, such as methoprene and pyriproxyfen, have been developed that exhibit biological activity similar to JH, such as metamorphosis inhibitory activity (e.g., Patent Document 1). However, these JH analogs have the effect of extending the larval stage, and may actually increase damage to insects, such as lepidopteran insects, whose larval stage is the pest stage. Therefore, there is a need for the development of JH antagonists that suppress the action of JH, unlike JH analogs. As a natural JH antagonist, LE3B, a component contained in the fruit of the Japanese quince and whose chemical structure is shown below, has been reported to not only exhibit JH antagonist activity in a reporter gene assay using the JH receptor of Aedes aegypti mosquito, but also to suppress ovarian maturation of Aedes aegypti mosquito (Non-Patent Document 2). On the other hand, synthetic JH antagonists such as ethyl 4-[2-(tert-butylcarbonyloxy)butoxy]benzoate (ETB), ethyl 4-[(6-substituted 2,2-dimethyl-2H-chromen-7-yl)methoxy]benzoate (KF38), and ethyl 4-[(7-substituted 1,4-benzodioxan-6-yl)methyl]benzoate (NY03) have been reported to exhibit precocious metamorphosis-inducing activity in the larvae of the silkworm, Bombyx mori, and the tobacco hornworm (Non-Patent Documents 3 to 6). However, these JH antagonists all have low physiological activity and have not yet been put to practical use. The present inventors have discovered ethyl 3-(4-{[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yl]methyl}phenyl)-2-propenoate (hereinafter referred to as "EMBP"), which exhibits high precocious metamorphosis-inducing activity in silkworm larvae, and have demonstrated that EMBP suppresses the expression of JH early response genes in the silkworm epidermis (Patent Document 2). Furthermore, they have reported that EMBP inhibits the action of JH in a reporter assay using cultured silkworm cells, indicating that EMBP acts as a JH antagonist (Non-Patent Document 7).

[0004] Japanese Patent Publication No. 05-064140 Japanese Patent Application Laid-Open No. 2020-11914

[0005] Insect Biochemistry and Molecular Biology, 2000, Vol.30, p.617-644.Proc. Natl. Acad. Sci., 2015, Vol.112, p.1733-1738.Ent. Exp. Appl., 1982, Vol.31, p.15-23.Annu. Rev. Entomol., 1975, 20, p.417-460.Journal of Pesticide Science, 2010, Vol.35, No.4, p.405-411.Journal of Pesticide Science, 2016, Vol.41, No.2, p.38-43.Pest Management Science, 2023, Vol.79, p. 5341-5348.

[0006] It is believed that compounds with JH agonistic activity can suppress the population density of the next generation by inhibiting pupation and adulthood, but treating herbivorous pests with long life cycles with these compounds with JH agonistic activity may extend the larval period, thereby increasing herbivorous damage, which is problematic. In contrast, compounds with JH antagonistic activity can suppress molting to the pre-final and final-final larval stages, which are the most susceptible to herbivorous damage. This can minimize herbivorous damage by inducing precocious metamorphosis or stunted development, and also suppress the population density of pest insects in the next generation. An objective of the present invention is to provide a new pest control agent that can be put into practical use.

[0007] The present inventors have continued to study the mechanism of action of EMBP at the molecular level, and have conducted exploratory research into new compounds with the aim of creating novel compounds with JH antagonist activity. As a result, they have discovered a new group of compounds that exhibit growth inhibitory activity against insects different from that of EMBP, thereby solving the above-mentioned problems.

[0008] The present invention may include the following disclosures: 1. A benzoxazine compound represented by general formula (1) or a salt thereof: (In the formula, R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, or an alkoxycarbonylethenyl group having 1 to 6 carbon atoms.) 2. The benzoxazine compound or salt thereof according to 1., wherein R1 is an alkyl group having 1 to 6 carbon atoms, R2 is an alkoxycarbonyl group having 1 to 6 carbon atoms, and R3 is a hydrogen atom. 3. Ethyl (E)-3-{4-[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenoate 4. An insect growth inhibitor comprising the benzoxazine compound or salt thereof according to any one of 1. to 3. 10. A selective lepidopteran pest control agent comprising the benzoxazine compound or salt thereof according to any one of claims 1 to 9 as an active ingredient.

[0009] The benzoxazine compound represented by the general formula (1) of the present invention or its salt, unlike EMBP, does not exhibit any precocious metamorphosis-inducing activity in silkworm larvae, while it exhibits growth inhibitory activity against the beet armyworm, an agricultural pest, and has selective biological activity against pests, making it highly likely to be used as a selective pest control agent. Compounds with such pest selectivity have not yet been reported, and they are extremely useful in finding new directions for pest control in the agricultural field in the future.

[0010] 1 is a graph showing the relative fluorescence intensity (%) at each concentration of the compound of the present invention (compound 8b: indicated as EMBOP in FIG. 1 ) and the compound described in Patent Document 2 (EMBP) in the test for confirming JH antagonist activity by reporter assay using cultured silkworm cells in "Test Example 3" of the Examples.

[0011] The present invention will be described in detail below. (Benzoxazine Compound of the Present Invention or a Salt thereof) The compound of the present invention is a benzoxazine compound represented by general formula (1) or a salt thereof. (In the formula, R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, or an alkoxycarbonylethenyl group having 1 to 6 carbon atoms.)

[0012] In the definition of general formula (1) of the present invention, the "alkyl group having 1 to 6 carbon atoms" means a linear alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms, such as a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, a secondary butyl group, a tertiary butyl group, a normal pentyl group, an isopentyl group, a tertiary pentyl group, a neopentyl group, a 2,3-dimethylpropyl group, a 1-ethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl group, a normal hexyl group, an isohexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 1,1,2-trimethylpropyl group, or a 3,3-dimethylbutyl group. The term "alkoxy group having 1 to 6 carbon atoms" refers to a linear alkoxy group having 1 to 6 carbon atoms or a branched alkoxy group having 3 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a normal propoxy group, an isopropoxy group, a normal butoxy group, a secondary butoxy group, a tertiary butoxy group, a normal pentyloxy group, an isopentyloxy group, a tertiary pentyloxy group, a neopentyloxy group, a 2,3-dimethylpropyloxy group, a 1-ethylpropyloxy group, a 1-methylbutyloxy group, a normal hexyloxy group, an isohexyloxy group, or a 1,1,2-trimethylpropyloxy group. The term "halogenated alkyl group having 1 to 6 carbon atoms" refers to a group in which a linear alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms is substituted with a chlorine atom, bromine atom, iodine atom, or fluorine atom, such as a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, perfluoropropyl group, perfluorobutyl group, perfluoropentyl group, perfluorohexyl group, perfluoroisopropyl group, perfluoroisobutyl group, chloromethyl group, chloroethyl group, chloropropyl group, bromomethyl group, bromoethyl group, bromopropyl group, methyl iodide group, ethyl iodide group, or propyl iodide group.The term "alkoxycarbonyl group having 1 to 6 carbon atoms" refers to a group in which an alkoxy having 1 to 6 carbon atoms is bonded to a carbonyl group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, or hexyloxycarbonyl. The term "alkoxycarbonylethenyl group having 1 to 6 carbon atoms" refers to a group in which an alkoxy having 1 to 6 carbon atoms is bonded to a carbonyl group, such as methoxycarbonylethenyl, ethoxycarbonylethenyl, propoxycarbonylethenyl, butoxycarbonylethenyl, tert-butoxycarbonylethenyl, pentyloxycarbonylethenyl, or hexyloxycarbonylethenyl. The term "halogen atom" refers to a chlorine atom, bromine atom, iodine atom, or fluorine atom.

[0013] Examples of salts of the benzoxazine compound represented by general formula (1) of the present invention include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, and hydroiodide; organic acid salts such as acetate, fumarate, maleate, oxalate, methanesulfonate, benzenesulfonate, and paratoluenesulfonate; and salts with inorganic or organic bases such as sodium ion, potassium ion, calcium ion, and trimethylammonium.

[0014] The benzoxazine compound represented by general formula (1) of the present invention or a salt thereof may have one or more asymmetric centers in its structural formula, and may exist as two or more optical isomers and diastereomers, but the present invention encompasses all of the individual optical isomers and mixtures containing them in any ratio. Furthermore, the benzoxazine compound represented by general formula (1) of the present invention or a salt thereof may have two geometric isomers derived from a carbon-carbon double bond in its structural formula, but the present invention encompasses all of the individual geometric isomers and mixtures containing them in any ratio.

[0015] R1 in the general formula (1) of the present invention is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 6 carbon atoms, and more preferably an alkyl group having 1 to 3 carbon atoms. In the general formula (1) of the present invention, R2 and R3 each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, or an alkoxycarbonylethenyl group having 1 to 6 carbon atoms. Among these, it is preferred that R2 represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, or an alkoxycarbonylethenyl group having 1 to 6 carbon atoms, and R3 represents a hydrogen atom. It is further preferred that R2 represents an alkyl group having 1 to 6 carbon atoms or an alkoxycarbonyl group having 1 to 6 carbon atoms, and R3 represents a hydrogen atom. It is particularly preferred that R2 represents an alkoxycarbonyl group having 1 to 6 carbon atoms, and R3 represents a hydrogen atom. Furthermore, when R2 is a substituent other than a hydrogen atom, it is preferably at the 4-position on the benzene ring, and further, when R3 is also a substituent other than a hydrogen atom, it is preferably at the 2- or 3-position on the benzene ring. As the benzoxazine compound represented by general formula (1) of the present invention or a salt thereof, a compound or a salt thereof in which R1 is an alkyl group having 1 to 6 carbon atoms, R2 is an alkoxycarbonyl group having 1 to 6 carbon atoms, and R3 is a hydrogen atom is preferred, and among these, ethyl (E)-3-{4-[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenoate (a compound in which R1 is an ethyl group, R2 is a 4-methoxycarbonyl group, and R3 is a hydrogen atom) is more preferred. As the benzoxazine compound represented by general formula (1) of the present invention or a salt thereof, 1~3 Alkyl, —C 1~4 Alkyl, halogen atom, —C 1~4 Haloalkyl, -NO2, -CH=CHCOOC 1~4Also preferred are compounds or salts thereof selected from the group consisting of alkyl, and hydrogen atoms. The benzoxazine compound or salt thereof represented by general formula (1) of the present invention is a compound or salt thereof in which R2 is selected from the group consisting of -COOMe, -CH=CHCOOMe, -tert-Bu, -Cl, -CHF3, -NO2, and a hydrogen atom (wherein Me represents a methyl group and Bu represents a butyl group). Also preferred are compounds or salts thereof in which R2 is -COOMe (wherein Me represents a methyl group). Also preferred are benzoxazine compounds or salts thereof represented by general formula (1) of the present invention are compounds or salts thereof in which R1 represents an ethyl group or a methyl group. Also preferred are compounds or salts thereof in which R1 represents an ethyl group. Also preferred are benzoxazine compounds or salts thereof represented by general formula (1) of the present invention are compounds or salts thereof in which R2 is -COO-C 1~3 Alkyl, —C 1~4 Alkyl, halogen atom, —C 1~4 Haloalkyl, -NO2, -CH=CHCOOC 1~4 Also preferred are compounds or salts thereof in which R1 is selected from the group consisting of alkyl and hydrogen atoms, and R2 is an ethyl group or a methyl group, and more preferred are compounds or salts thereof in which R1 is an ethyl group. The benzoxazine compound or salt thereof represented by general formula (1) of the present invention is a compound or salt thereof in which R2 is selected from the group consisting of -COOMe, -CH=CHCOOMe, -tert-Bu, -Cl, -CHF3, -NO2, and a hydrogen atom (wherein Me represents a methyl group and Bu represents a butyl group), and R1 is an ethyl group or a methyl group, and more preferred are compounds or salts thereof in which R1 is an ethyl group. The benzoxazine compound or salt thereof represented by general formula (1) of the present invention is a compound or salt thereof in which R2 is -COOMe (wherein Me represents a methyl group) and R1 is an ethyl group or a methyl group, and more preferred are compounds or salts thereof. The benzoxazine compound or salt thereof represented by general formula (1) of the present invention is a compound or salt thereof in which R2 is -COOMe (wherein Me represents a methyl group) and R1 is an ethyl group. The benzoxazine compound or salt thereof represented by general formula (1) of the present invention is a compound or salt thereof in which R2 is -COOMe (wherein Me represents a methyl group) and R1 is an ethyl group. Furthermore, R2 is preferably bonded to the 4-position of the benzene ring to which R2 is bonded. R3 preferably represents a hydrogen atom.

[0016] The benzoxazine compound or a salt thereof of the present invention can be produced, for example, by the production method shown below, but the production method of the benzoxazine compound or a salt thereof of the present invention is not limited to these examples.

[0017] Starting from 6-hydroxybenzodioxane, 7-hydroxybenzodioxane-6-carbaldehyde (1) was synthesized using ethyl magnesium chloride and paraformaldehyde, and the hydroxyl group was protected with chloromethyl methyl ether (2). Further, Baeyer-Villiger oxidation with m-chloroperbenzoic acid was performed, followed by hydrolysis under basic conditions to synthesize 6-methoxymethoxy-7-hydroxy-1,4-benzodioxane (3). This was reacted with 4-fluorobenzonitrile (4) and then reduced to the aldehyde (5) with diisobutylaluminum hydride. Subsequently, a Wittig-Horner reaction was performed to obtain the α,β-unsaturated ester (6). The methoxymethyl group was then deprotected under acidic conditions (7), and the compound (8) was obtained by reaction with benzyl halides bearing various substituents on the benzene ring.

[0018] In producing the benzoxazine compound or a salt thereof of the present invention, after the reaction of each step is completed, post-treatment may be carried out as necessary by a conventional method, and the product may be isolated. That is, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration may be carried out individually or in combination of two or more operations, and the product may be isolated by concentration, crystallization, reprecipitation, column chromatography, etc. Furthermore, the isolated product may be further purified as necessary by carrying out one or more operations such as crystallization, reprecipitation, column chromatography, extraction, stirring and washing of the crystals with a solvent, either individually or in combination of two or more operations. The chemical structure of the product of each step may be confirmed by known techniques, such as nuclear magnetic resonance (NMR), infrared spectroscopy (IR), and mass spectrometry (MS).

[0019] (Insect Growth Inhibitor of the Present Invention) As will be described in detail in the Examples below, the benzoxazine compound or salt thereof of the present invention, unlike EMBP, does not exhibit precocious metamorphosis-inducing activity in silkworms. Furthermore, its activity in reporter assays was approximately 1 / 40 that of EMBP, confirming that it does not have JH antagonist activity in silkworms. On the other hand, it was confirmed that the benzoxazine compound or salt thereof of the present invention exhibits lethal activity by inducing metamorphosis failure in final-instar larvae of the beet armyworm (Spodoptera exigua). Furthermore, it was also confirmed that EMBP induced excessive molting and molting failure in final-instar larvae of the beet armyworm (Spodoptera exigua) at high doses, but did not induce metamorphosis failure. Thus, despite having a similar basic chemical structure to conventional compounds with JH antagonist activity, such as EMBP, the benzoxazine compound or salt thereof of the present invention exhibits biological activity against silkworms and beet armyworms that is significantly different from that of the beet armyworm (Spodoptera exigua). It exhibits a completely unpredictable growth inhibitory activity that induces metamorphosis failure. The insect growth inhibitor of the present invention may contain other components. Examples of such other components include those described in the section on lepidopteran pest control agents below. The insect growth inhibitor may be an insect growth inhibitor consisting of a benzoxazine compound or a salt thereof. The insect growth inhibitor may also be an insect growth inhibitor containing a benzoxazine compound or a salt thereof. The benzoxazine compound or a salt thereof of the present invention can inhibit insect growth by inducing metamorphosis failure. The insect is preferably at least one species selected from the lepidopteran pests described below. The benzoxazine compound or a salt thereof of the present invention can be used in a method for inhibiting insect growth. The method for inhibiting insect growth of the present invention includes a step of contacting the benzoxazine compound or a salt thereof with the insect. Examples of contact methods include spraying, applying, or dropping the compound or a salt thereof, or a composition containing the compound or a salt thereof, onto the insect. The method for inhibiting insect growth of the present invention may further include a step of mixing the benzoxazine compound or a salt thereof with other components. This allows for the production of a composition containing the benzoxazine compound or a salt thereof and other components.Other components include those described below in relation to the lepidopteran pest control agent. In the method for inhibiting insect growth of the present invention, the benzoxazine compound or a salt thereof is used so that it comes into contact with the pest in an amount of preferably 0.001 to 10 μg per pest, more preferably 0.005 to 5 μg, even more preferably 0.01 to 5 μg, even more preferably 0.05 to 5 μg, even more preferably 0.1 to 5 μg, even more preferably 0.2 to 4 μg, even more preferably 0.3 to 3 μg, and even more preferably 0.5 to 2 μg.

[0020] ((Selective) Lepidopteran Pest Control Agent of the Present Invention) The lepidopteran pest control agent containing the benzoxazine compound or a salt thereof of the present invention as an active ingredient functions as a metamorphosis failure inducer against lepidopteran pests, and is effective in controlling lepidopteran pests that are agricultural pests. Furthermore, as described above, the benzoxazine compound or a salt thereof of the present invention does not exhibit any biological activity against silkworms, but induces metamorphosis failure and exhibits growth inhibitory activity against final-stage larvae of the beet armyworm. This characteristic biological activity exhibits a selective control effect against agricultural pests. The selective lepidopteran pest control agent containing the benzoxazine compound or a salt thereof of the present invention as an active ingredient functions as a selective metamorphosis failure inducer against lepidopteran pests, and is effective in selectively controlling agricultural pests. For example, when raising mulberries, which are necessary for raising silkworms, a selective lepidopteran pest control agent containing the benzoxazine compound of the present invention or a salt thereof as an active ingredient can be used to control pests on mulberry, thereby making it possible to exterminate pests that damage mulberry. This makes it possible to feed mulberry plants to which the selective lepidopteran pest control agent has been attached without harming the silkworms, which is useful in agricultural applications.

[0021] The (selective) lepidopteran pest control agent of the present invention is used by mixing with an inert carrier such as a solid carrier or a liquid carrier and formulating it, similar to conventional agricultural chemicals. The selective lepidopteran pest control agent of the present invention can be formulated into a wettable powder, a water-soluble powder, a flowable powder, a microcapsule preparation, an emulsion, a dust, a granule, or the like. The content of the active ingredient consisting of the benzoxazine compound of the present invention or a salt thereof in the (selective) lepidopteran pest control agent of the present invention is usually in the range of 0.1 to 100% by weight, preferably 0.2 to 90% by weight, and more preferably 0.5 to 80% by weight.

[0022] Examples of solid carriers used in formulations include fine powders and granules of clays (kaolin clay, diatomaceous earth, bentonite, Fubasami clay, acid clay, etc.), synthetic hydrous silicon oxide, talc, ceramics, other inorganic minerals (sericite, quartz, sulfur, activated carbon, calcium carbonate, hydrated silica, etc.), chemical fertilizers (ammonium sulfate, ammonium phosphate, ammonium nitrate, urea, ammonium chloride, etc.), and synthetic resins (polyester resins such as polypropylene, polyacrylonitrile, polymethyl methacrylate, polyethylene terephthalate, nylon resins such as nylon-6, nylon-11, nylon-66, polyamide resins, polyvinyl chloride, polyvinylidene chloride, vinyl chloride-propylene copolymers, etc.). Examples of liquid carriers include water, alcohols (methanol, ethanol, isopropyl alcohol, butanol, hexanol, benzyl alcohol, ethylene glycol, propylene glycol, phenoxyethanol, etc.), ketones (acetone, methyl ethyl ketone, cyclohexanone, etc.), aromatic hydrocarbons (toluene, xylene, ethylbenzene, dodecylbenzene, phenylxylylethane, methylnaphthalene, etc.), aliphatic hydrocarbons (hexane, cyclohexane, kerosene, diesel, etc.), esters (ethyl acetate, butyl acetate, isopropyl myristate, ethyl oleate, diisopropyl adipate, diisobutyl adipate, propylene glycol monomethyl ester), and the like. ether acetate, etc.), nitriles (acetonitrile, isobutyronitrile, etc.), ethers (diisopropyl ether, 1,4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol monomethyl ether, propylene glycol monomethyl ether, dipropylene glycol monomethyl ether, 3-methoxy-3-methyl-1-butanol, etc.), amides (N,N-dimethylformamide (hereinafter referred to as "DMF"), N,N-dimethylacetamide, etc.), sulfoxides (dimethyl sulfoxide (hereinafter referred to as "DMSO"), etc.), propylene carbonate, and vegetable oils (soybean oil, cottonseed oil, etc.).

[0023] When formulating the (selective) lepidopteran pest control agent of the present invention, surfactants and other formulation adjuvants can be added as needed. Examples of surfactants include nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, and polyethylene glycol fatty acid esters, and anionic surfactants such as alkyl sulfonates, alkylbenzene sulfonates, and alkyl sulfates. Other formulation adjuvants include adhesives, dispersants, colorants, and stabilizers, specifically, casein, gelatin, sugars (starch, gum arabic, cellulose derivatives, alginic acid, etc.), lignin derivatives, bentonite, synthetic water-soluble polymers (polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acids, etc.), PAP (isopropyl acid phosphate), BHT (2,6-di-tert-butyl-4-methylphenol), and BHA (a mixture of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol).

[0024] When the (selective) lepidopteran pest control agent of the present invention is formulated as a wettable powder, water-soluble powder, flowable powder, microcapsule preparation, or emulsion, it is usually applied after diluting with water so that the concentration of the active ingredient consisting of the benzoxazine compound of the present invention or a salt thereof is 0.1 to 10,000 ppm, and when formulated as a dust or granule, it is applied as is. The (selective) lepidopteran pest control agent of the present invention is preferably used so that the benzoxazine compound or a salt thereof comes into contact with pests in an amount of 0.001 to 10 μg per pest, more preferably 0.005 to 5 μg, even more preferably 0.01 to 5 μg, even more preferably 0.05 to 5 μg, even more preferably 0.1 to 5 μg, even more preferably 0.2 to 4 μg, even more preferably 0.3 to 3 μg, even more preferably 0.5 to 2 μg.

[0025] Examples of lepidopteran pests against which the (selective) lepidopteran pest control agent of the present invention is effective include the following. Lepidoptera pests: moths such as the rice suppressor moth (Chilo suppressalis), rice leafroller (Cnaphalocrocis medinalis), European corn borer (Ostrinia nubilalis), Hellulla undalis, grass moth (Parapediasia teterrella), cotton moth (Notarcha derogata), and Indian meal moth (Plodia interpunctella); common cutworm (Spodoptera litura), armyworm (Pseudaletia separata), armyworm moth (Mamestra brassicae), cutworm moth (Agrotis ipsilon), noctuid moths such as the genera Trichoplusia, Heliotis, and Helicoverpa; white butterflies such as the cabbage white butterfly (Pieris rapae); species of the genus Adoxophyes, pear fruit moth (Grapholita molesta), and codling moth (Cydia Examples of pests that can be effectively controlled include tortrix moths such as Pectinophora pomonella, fruit moths such as Carposina niponensis, leafminers such as Lionetia, tussock moths such as Lymantria and Euploctys, diamondback moths such as Plutella xylostella, tooth moths such as Pectinophora gossypiella, tiger moths such as Hyphantria cunea, and burrowing moths such as Tinea translucens and Tineola bisselliella. The (selective) lepidopteran pest control agent of the present invention is preferably effective against lepidopteran pests (insects) other than those belonging to the family Bombycidae of the order Lepidoptera. Among these, the (selective) lepidopteran pest control agent of the present invention is preferably effective against pests (insects) of the noctuid moths (Lepidoptera: Noctuidae), more preferably effective against pests (insects) belonging to the subfamily Amplexicaule of the family Noctuidae of Lepidoptera, and is particularly preferably effective against the beet armyworm.The (selective) lepidopteran pest control agent of the present invention is preferably used on lepidopteran pests (insects) before pupation, i.e., larvae. The (selective) lepidopteran pest control agent of the present invention is preferably used on final-stage larvae.

[0026] When the selective lepidopteran pest control agent of the present invention is used for controlling animal ectoparasites, application can be by spot-on application, pour-on application, or other methods. Spot-on application typically involves dripping or applying a liquid formulation to the skin of a host animal, such as the back of the scapulae, while pour-on application typically involves pouring a liquid formulation along the dorsal line of the host animal. The amount of treatment to an animal may vary depending on the type of target animal or ectoparasite to be controlled, but is typically 0.05 to 1000 mg / kg, preferably 0.1 to 200 mg / kg, of the active ingredient having JH antagonist activity per kg live weight of the target animal.

[0027] Ectoparasites that can be controlled by the selective lepidopteran pest control agent of the present invention include various harmful arthropods that are known as ectoparasites of host animals, and specific examples thereof include Diptera pests such as the house fly (Musca domestica), the wild house fly (Musca hervei), the black house fly (Musca bezzii), the horn fly (Haematobia irritans), the black spotted black fly (Simulium iwatens), the cow midge (Culicoides oxystoma), the red horse fly (Tabanus chrysurus), the mosquito (Culex pipiens), and the Asian tiger mosquito (Aedes albopictus); Phthiraptera pests such as the cat lice (Haematopinus eurysternus) and the sheep lice (Damalinia ovis); and the cat flea (Ctenocephalides felis) and the dog flea (Ctenocephalides canis), Xenopsylla cheopis, and other flea pests of the order Siphonaptera.

[0028] The benzoxazine compound or its salt of the present invention can be used in a method for controlling lepidopteran pests. The method for controlling lepidopteran pests of the present invention includes a step of contacting the benzoxazine compound or its salt with lepidopteran pests. Examples of contact methods include spraying, applying, or dropping the compound or its salt, or a composition containing the compound or its salt, onto insects. The benzoxazine compound or its salt of the present invention can be used in a method for selectively controlling lepidopteran pests. The method for selectively controlling lepidopteran pests of the present invention includes a step of contacting the benzoxazine compound or its salt with lepidopteran pests. Examples of contact methods include spraying, applying, or dropping the compound or its salt, or a composition containing the compound or its salt, onto lepidopteran pests. The method for controlling lepidopteran pests or the method for selectively controlling lepidopteran pests of the present invention may further include a step of mixing the benzoxazine compound or its salt with other components. This allows for the production of a composition containing the benzoxazine compound or its salt and other components. Examples of other components include those described above in connection with the lepidopteran pest control agent. In the method for controlling lepidopteran pests or the method for selectively controlling lepidopteran pests of the present invention, the benzoxazine compound or its salt is preferably used so that it comes into contact with the pests in an amount of 0.001 to 10 μg per pest, more preferably 0.005 to 5 μg, even more preferably 0.01 to 5 μg, even more preferably 0.05 to 5 μg, even more preferably 0.1 to 5 μg, even more preferably 0.2 to 4 μg, even more preferably 0.3 to 3 μg, and even more preferably 0.5 to 2 μg. Furthermore, in the contacting step, the benzoxazine compound or its salt is preferably brought into contact with the lepidopteran pest (insect), i.e., the larvae, before pupation. In addition, the contacting step preferably involves contacting the benzoxazine compound or a salt thereof with final-instar larvae.

[0029] The benzoxazine compound or its salt of the present invention can be used as a metamorphosis failure inducer for lepidopteran pests. The metamorphosis failure inducer for lepidopteran pests of the present invention comprises the benzoxazine compound or its salt of the present invention. The metamorphosis failure inducer for lepidopteran pests of the present invention may contain other components. Examples of such other components include those described above in relation to the lepidopteran pest control agent. The metamorphosis failure inducer for lepidopteran pests of the present invention is preferably used so that the benzoxazine compound or its salt comes into contact with the pests in an amount of 0.001 to 10 μg per lepidopteran pest, more preferably 0.005 to 5 μg, even more preferably 0.01 to 5 μg, even more preferably 0.05 to 5 μg, even more preferably 0.1 to 5 μg, even more preferably 0.2 to 4 μg, even more preferably 0.3 to 3 μg, and even more preferably 0.5 to 2 μg. The metamorphosis failure inducer for lepidopteran pests of the present invention is preferably used on lepidopteran pests (insects) before pupation, i.e., larvae, and the (selective) lepidopteran pest control agent of the present invention is preferably used on final-stage larvae.

[0030] The benzoxazine compound or its salt of the present invention can be used in a method for inducing metamorphosis failure in lepidopteran pests. The method for inducing metamorphosis failure in lepidopteran pests of the present invention includes a step of contacting the benzoxazine compound or its salt with the lepidopteran pest. Examples of contact methods include spraying, applying, or dropping the compound or its salt, or a composition containing the compound or its salt, onto the lepidopteran pest. The method for inducing metamorphosis failure in lepidopteran pests of the present invention may further include a step of mixing the benzoxazine compound or its salt with other components. This allows for the production of a composition containing the benzoxazine compound or its salt and other components. Examples of other components include those described above in relation to lepidopteran pest control agents. In the method of inducing defective metamorphosis in lepidopteran pests of the present invention, the benzoxazine compound or its salt is preferably used so that it comes into contact with the pest in an amount of 0.001 to 10 μg per pest, more preferably 0.005 to 5 μg, even more preferably 0.01 to 5 μg, even more preferably 0.05 to 5 μg, even more preferably 0.1 to 5 μg, even more preferably 0.2 to 4 μg, even more preferably 0.3 to 3 μg, and even more preferably 0.5 to 2 μg. Furthermore, in the contacting step, the benzoxazine compound or its salt is preferably brought into contact with the lepidopteran pest (insect), i.e., the larvae, before pupation. Furthermore, in the contacting step, the benzoxazine compound or its salt is preferably brought into contact with the final-stage larvae.

[0031] The disclosure of the present invention may also include the following: 1. A benzoxazine compound represented by general formula (1) or a salt thereof. (wherein R1 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R2 and R3 are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, or an alkoxycarbonylethenyl group having 1 to 6 carbon atoms.) 2. A benzoxazine compound or a salt thereof according to 1., wherein R1 is an alkyl group having 1 to 6 carbon atoms, R2 is an alkoxycarbonyl group having 1 to 6 carbon atoms, and R3 is a hydrogen atom. 3. A compound or a salt thereof according to 1. or 2., wherein R2 is bonded to the 4-position of the benzene ring to which R2 is bonded, and R3 is a hydrogen atom. 4. R2 is -COOMe, -CH=CHCOOMe, -tert-Bu, -Cl, -CF 3、 4. The compound according to any one of items 1. to 3., or a salt thereof, wherein R is selected from the group consisting of -NO2, and a hydrogen atom (wherein Me represents a methyl group and Bu represents a butyl group). 5. The compound according to any one of items 1. to 4., or a salt thereof, wherein R is -COOMe (wherein Me represents a methyl group). 6. The compound according to any one of items 1. to 5., or a salt thereof, wherein R represents an ethyl group or a methyl group. 7. The compound according to any one of items 1. to 6., or a salt thereof, wherein R represents an ethyl group. 8. Ethyl (E)-3-{4-[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenoate 9. An insect growth inhibitor comprising the benzoxazine compound according to any one of items 1. to 8., or a salt thereof. 10. An insect growth inhibitor comprising the benzoxazine compound according to any one of items 1. to 8., or a salt thereof. 10. An insect growth inhibitor comprising the benzoxazine compound or a salt thereof according to any one of claims 1 to 9.

[0032] 11. The insect growth inhibitor according to 9. or 10., wherein the insect is at least one species selected from Lepidoptera insects. 12. The insect growth inhibitor according to any one of 9. to 11., wherein the insect is at least one species selected from Lepidoptera insects other than insects belonging to the Bombycidae family of the Lepidoptera order. 13. The insect growth inhibitor according to any one of 9. to 12., wherein the insect is at least one species selected from noctuid moths (Lepidoptera, Noctuidae family). 14. The insect growth inhibitor according to any one of 9. to 13., wherein the insect is at least one species selected from insects belonging to the Noctuidae family of the Lepidoptera order, the subfamily Mamestinae. 15. The insect growth inhibitor according to any one of 9. to 14., wherein the insect is the beet armyworm. 16. The insect growth inhibitor according to 9. to 15., which is used on the insect in its larval stage. 17. The insect growth inhibitor according to any one of items 9. to 16., wherein the benzoxazine compound or its salt is used so as to come into contact with pests in an amount of 0.05 to 5 μg per pest. 18. A method for inhibiting insect growth, comprising a step of applying to an insect the benzoxazine compound or its salt according to any one of items 1. to 8. 19. The method according to item 18., wherein the insect is at least one species selected from Lepidoptera insects. 20. The method according to item 18 or 19., wherein the insect is at least one species selected from Lepidoptera insects other than insects belonging to the Bombycidae family of the Lepidoptera order.

[0033] 21. The method according to any one of 18. to 20., wherein the insect is at least one species selected from insects of the noctuid moths (Lepidoptera, Noctuidae). 22. The method according to any one of 18. to 21., wherein the insect is at least one species selected from insects belonging to the family Noctuidae, subfamily Capillarinae, order Lepidoptera. 23. The method according to any one of 18. to 22., wherein the insect is the beet armyworm. 24. The method according to any one of 18. to 23., wherein, in the contacting step, the benzoxazine compound or its salt is brought into contact with the insect in a larval stage. 25. The method according to any one of 18. to 24., wherein, in the contacting step, the benzoxazine compound or its salt is brought into contact with the pest in an amount of 0.05 to 5 μg per pest. 26.1 to 8. 27. A lepidopteran pest control agent containing, as an active ingredient, the benzoxazine compound or a salt thereof according to any one of 26. 27. The lepidopteran pest control agent according to 26., wherein the lepidopteran pest is at least one species selected from lepidopteran insects other than insects belonging to the family Bombycidae of the order Lepidoptera. 28. The lepidopteran pest control agent according to 26. or 27., wherein the lepidopteran pest is at least one species selected from insects of the class Noctuidae (Lepidoptera, Noctuidae). 29. The lepidopteran pest control agent according to any one of 26. to 28., wherein the lepidopteran pest is at least one species selected from insects belonging to the family Noctuidae of the order Lepidoptera, subfamily Mamestinae. 30. The lepidopteran pest control agent according to 26. to 29., wherein the lepidopteran pest is the beet armyworm. 10. The lepidopteran pest control agent according to any one of claims 1 to 9.

[0034] 31. The lepidopteran pest control agent according to any one of items 26. to 30., which is used against the lepidopteran pest in the larval stage. 32. The lepidopteran pest control agent according to any one of items 26. to 31., wherein the benzoxazine compound or its salt is used so that it comes into contact with the pest in an amount of 0.05 to 5 μg per pest. 33. A selective lepidopteran pest control agent containing, as an active ingredient, the benzoxazine compound or its salt according to any one of items 1. to 8.. 34. The selective lepidopteran pest control agent according to item 33., wherein the lepidopteran pest is at least one species selected from lepidopteran insects other than insects belonging to the family Bombycidae of the order Lepidoptera. 35. 33. or 34., wherein the lepidopteran pest is at least one species selected from insects of the class Noctuidae (Lepidoptera: Noctuidae). 36. The selective lepidopteran pest control agent according to any one of 33. to 35., wherein the lepidopteran pest is at least one species selected from insects belonging to the family Noctuidae, subfamily Mamestinae, order Lepidoptera. 37. The selective lepidopteran pest control agent according to any one of 33. to 36., wherein the lepidopteran pest is the beet armyworm. 38. The selective lepidopteran pest control agent according to any one of 33. to 37., which is used against the lepidopteran pest in the larval stage. 39. The lepidopteran pest control agent according to any one of 33. to 38., wherein the benzoxazine compound or a salt thereof is used so as to come into contact with the pest in an amount of 0.05 to 5 μg per pest. 40.1 to 8. 10. A method for controlling lepidopteran pests, comprising the step of applying the benzoxazine compound or a salt thereof according to any one of the preceding items to lepidopteran pests.

[0035] 41. The method according to 40., wherein the lepidopteran pest is at least one species selected from lepidopteran insects other than insects belonging to the family Bombycidae of the order Lepidoptera. 42. The method according to 40. or 41., wherein the lepidopteran pest is at least one species selected from insects of the class Noctuidae (Lepidoptera: Noctuidae). 43. The method according to any one of 40. to 42., wherein the lepidopteran pest is at least one species selected from insects belonging to the family Noctuidae of the order Lepidoptera, subfamily Mamestinae. 44. The method according to any one of 40. to 43., wherein the lepidopteran pest is the beet armyworm. 45. The method according to any one of 40. to 44., wherein the benzoxazine compound or a salt thereof is brought into contact with the lepidopteran pest in a larval stage in the contacting step. 46. The method according to any one of 40. to 45., wherein in the contacting step, the benzoxazine compound or its salt is brought into contact with the pest in an amount of 0.05 to 5 μg per pest. 47. A method for selectively controlling lepidopteran pests, comprising a step of applying the benzoxazine compound or its salt according to any one of 1. to 8. to the lepidopteran pest. 48. The method according to 47., wherein the lepidopteran pest is at least one species selected from lepidopteran insects other than insects belonging to the family Bombycidae of the order Lepidoptera. 49. The method according to 47. or 48., wherein the lepidopteran pest is at least one species selected from insects of the noctuid moths (Lepidoptera: Noctuidae). 50. The method according to any one of 47. to 49., wherein the lepidopteran pest is at least one species selected from insects belonging to the family Noctuidae of the order Lepidoptera, subfamily Mamestinae.

[0036] 51. The method according to any one of 47. to 50., wherein the lepidopteran pest is the beet armyworm. 52. The method according to any one of 47. to 51., wherein the benzoxazine compound or its salt is brought into contact with the lepidopteran pest in a larval stage in the contacting step. 53. The method according to any one of 47. to 52., wherein the benzoxazine compound or its salt is brought into contact with the pest in an amount of 0.05 to 5 μg per pest in the contacting step. 54. An agent for inducing metamorphosis failure in lepidopteran pests, comprising as an active ingredient the benzoxazine compound or its salt according to any one of 1. to 8.. 55. The agent for inducing metamorphosis failure according to 54., wherein the lepidopteran pest is at least one species of lepidopteran insect other than insects belonging to the family Bombycidae in the order Lepidoptera. 56. The metamorphosis failure inducer according to 54. or 55., wherein the lepidopteran pest is at least one species selected from insects of the noctuid moths (Lepidoptera: Noctuidae). 57. The metamorphosis failure inducer according to any one of 54. to 56., wherein the lepidopteran pest is at least one species selected from insects belonging to the family Noctuidae, subfamily Mamestinae, order Lepidoptera. 58. The metamorphosis failure inducer according to any one of 54. to 57., wherein the lepidopteran pest is the beet armyworm. 59. The metamorphosis failure inducer according to any one of 54. to 58., which is used on the lepidopteran pest in the larval stage. 60. The lepidopteran pest control agent according to any one of 54. to 59., wherein the benzoxazine compound or a salt thereof is used so as to come into contact with the pest in an amount of 0.05 to 5 μg per pest.

[0037] 61. A method for inducing defective metamorphosis in a lepidopteran pest, comprising the step of applying the benzoxazine compound or salt thereof according to any one of 1. to 8. to the lepidopteran pest. 62. The method according to 61., wherein the lepidopteran pest is at least one species selected from lepidopteran insects other than insects belonging to the family Bombycidae of the order Lepidoptera. 63. The method according to 61. or 62., wherein the lepidopteran pest is at least one species selected from insects of the class Noctuidae (Lepidoptera: Noctuidae). 64. The method according to any one of 61. to 63., wherein the lepidopteran pest is at least one species selected from insects belonging to the family Noctuidae of the order Lepidoptera, subfamily Mamestinae. 65. The method according to any one of 61. to 64., wherein the lepidopteran pest is the beet armyworm. 66. 67. The method according to any one of 61 to 66, wherein in the contacting step, the benzoxazine compound or its salt is contacted with the lepidopteran pest in a larval stage. 68. The method according to any one of 61 to 66, wherein in the contacting step, the benzoxazine compound or its salt is contacted with the pest in an amount of 0.05 to 5 μg per pest.

[0038] The present invention will be explained below by way of examples, including synthesis examples of compounds, physical property data, and test examples, but the technical scope of the present invention is not limited to these examples. 1 H-NMR (Bruker Biospin AV400M, 400 MHz, internal standard: TMS) data was used.

[0039] <Synthesis Example and Physical Properties Data> 7-Hydroxy-1,4-benzodioxane-6-carbaldehyde (1) 6-Hydroxy-1,4-benzodioxane (5.0 g, 32.8 mmol) was dissolved in 30 mL of THF and cooled with ice water. 3 M ethylmagnesium bromide THF solution (65.7 mL, 131 mmol) was added dropwise to this solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 30 mL of benzene. To this solution, hexamethylphosphoric triamide (14.7 g, 82.1 mmol) and 7.0 g of paraformaldehyde were added, and the mixture was heated at 80°C overnight. The reaction mixture was acidified with 1 M hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dehydrated over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1) to obtain compound (1) (4.50 g, 76%). 1 H-NMR (CDCl3) δ: 4.30 (4H, m, OCH2CH2O), 6.45 (1H, s, phenyl), 7.01 (1H, s, phenyl), 9.66 (1H, s, OH), 10.92 (1H, s, CHO).

[0040] 7-Methoxymethoxy-1,4-benzodioxane-6-carbaldehyde (2) Compound (1) (4.50 g, 24.9 mmol) was dissolved in 100 mL of dichloromethane and cooled with ice water. Diisopropylethylamine (4.84 g, 37.4 mmol) and chloromethyl methyl ether (3.02 g, 37.4 mmol) were added to this solution, and the mixture was stirred under ice cooling for 7 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with 1 M aqueous sodium hydroxide solution, water, and saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was then added to the residue, and the mixture was recrystallized to obtain compound (2) (4.30 g, 77%). 1 H-NMR (CDCl3) δ: 3.51 (3H, s, OCH3), 4.27 (4H, m, OCH2CH2O), 5.20 (2H, s, OCH2O), 6.72 (1H, s, phenyl), 7.36 (1H, s, phenyl), 10.30 (1H, s, CHO).

[0041] 7-Methoxymethoxy-6-hydroxy-1,4-benzodioxane (3) Compound (2) (4.30 g, 19.2 mmol) was dissolved in 100 mL of dichloromethane and cooled with ice water. m-Chloroperbenzoic acid (containing water) (5.67 g, 23.0 mmol) was added to this solution and stirred at 50°C overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in 50 mL of ethanol, and 10 mL of 1 M aqueous sodium hydroxide was added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then 50 mL of saturated aqueous ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1) to obtain compound (3) (3.63 g, 89%). 1 H-NMR (CDCl3) δ: 3.51 (3H, s, OCH3), 4.19 (4H, m, OCH2CH2O), 5.09 (2H, s, OCH2O), 5.68 (1H, s, OH), 6.49 (1H, s, phenyl), 6.66 (1H, s, phenyl).

[0042] 4-(7-Methoxymethoxy-1,4-benzodioxan-6-yloxy)benzonitrile (4) Compound (3) (2.0 g, 9.4 mmol) was dissolved in 20 mL of dimethyl sulfoxide, and then anhydrous sodium carbonate (1.95 g, 14.1 mmol) and 4-fluorobenzonitrile (1.71 g, 14.1 mmol) were added, followed by stirring at 80°C overnight. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with 1 M aqueous sodium hydroxide solution, water, and saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 2:1) to give compound (4) (1.67 g, 57%). 1H-NMR (CDCl3) δ: 3.34 (3H, s, OCH3), 4.25 (4H, m, OCH2CH2O), 4.99 (2H, s, OCH2O), 6.64 (1H, s, phenyl), 6.80 (1H, s, phenyl), 6.94 (2H, d, J=8.9 Hz, phenyl), 7.56 (1H, d, J=8.9 Hz, phenyl).

[0043] 4-(7-Methoxymethoxy-1,4-benzodioxan-6-yloxy)benzaldehyde (5) Compound (4) (1.0 g, 3.2 mmol) was dissolved in 20 mL of dichloromethane and then cooled to ice temperature. A 1 M diisobutylaluminum hydride hexane solution (4.79 mL, 4.8 mmol) was added to this solution and stirred under ice cooling for 7 hours. After adding 30 mL of saturated aqueous ammonium chloride, the reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and dehydrated over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain compound (5) (0.96 g, 95%). 1 H-NMR (CDCl3) δ: 3.34 (3H, s, OCH3), 4.25 (4H, m, OCH2CH2O), 4.99 (2H, s, OCH2O), 6.66 (1H, s, phenyl), 6.81 (1H, s, phenyl), 6.99 (2H, d, J=8.8 Hz, phenyl), 7.81 (2H, d, J=8.8 Hz, phenyl), 9.90 (1H, s, CHO).

[0044] Ethyl (E)-3-[4-(7-methoxymethoxy-1,4-benzodioxan-6-yloxy)phenyl]-2-propenate (6a) Compound (5) (0.90 g, 2.8 mmol) was dissolved in 20 mL of ethanol, and then triethyl phosphonoacetate (0.77 g, 3.4 mmol) and sodium ethoxide (0.23 g, 3.4 mmol) were added and the mixture was stirred at 50°C overnight. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 3:1) to obtain compound (6a) (1.00 g, 91%). 1 H-NMR (CDCl3) δ : 1.33 (3H, t, J=7.1 Hz, CH3), 3.37 (3H, s, OCH3), 4.25 (6H, m, OCH2CH2O, OCH2), 5.01 (2H, s, OCH2O), 6.31 (1H, d, J=16.0 Hz, CH), 6.62 (1H, s, phenyl), 6.79 (1H, s, phenyl), 6.90 (2H, d, J=8.8 Hz, phenyl), 7.44 (2H, t, J=8.8 Hz, phenyl), 7.63 (1H, d, J=16.0 Hz, CH).

[0045] Compound (6b) was synthesized using trimethyl phosphonoacetate and sodium methoxide in the same manner as compound (6a). Only the yield and NMR data are shown below. Methyl (E)-3-[4-(7-methoxymethoxy-1,4-benzodioxan-6-yloxy)phenyl]-2-propenate (6b) Yield: 100% 1H-NMR (CDCl3) δ : 3.37 (3H, s, OCH3), 3.79 (3H, s, OCH3), 4.24 (4H, m, OCH2CH2O), 5.01 (2H, s, OCH2O), 6.31 (1H, d, J=16.0 Hz, CH), 6.62 (1H, s, phenyl), 6.79 (1H, s, phenyl), 6.90 (1H, d, J=8.7 Hz, phenyl), 7.44 (1H, d, J=8.7 Hz, phenyl), 7.64 (1H, d, J=16.0 Hz, CH).

[0046] Ethyl (E)-3-[4-(7-hydroxy-1,4-benzodioxan-6-yloxy)phenyl]-2-propenate (7a) Compound (6a) (1.00 g, 2.6 mmol) was dissolved in 20 mL of ethanol, and then 2 mL of concentrated hydrochloric acid was added and stirred at room temperature overnight. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. Diethyl ether was added to the resulting residue and recrystallized to obtain compound (7a) (0.76 g, 89%). 1 H-NMR (CDCl3) δ: 1.33 (3H, t, J=7.1 Hz, CH3), 4.24 (6H, m, OCH2CH2O, OCH2), 5.04 (1H, s, OH), 6.33 (1H, d, J=16.0 Hz, CH), 6.53 (1H, s, phenyl), 6.60 (1H, s, phenyl), 6.98 (2H, d, J=8.7 Hz, phenyl), 7.48 (3H, d, J=8.7 Hz, phenyl), 7.63 (1H, d, J=16.0 Hz, CH).

[0047] Compound (7b) was synthesized in the same manner as compound (7a). Only the yield and NMR data are shown below. Methyl (E)-3-[4-(7-hydroxy-1,4-benzodioxan-6-yloxy)phenyl]-2-propenate (7b) Yield: 85% 1H-NMR (CDCl3) δ: 3.80 (3H, s, OCH3), 4.22 (6H, m,OCH2CH2O), 5.03 (1H, br, OH), 6.34 (1H, d, J=16.0 Hz, CH), 6.53 (1H, s, phenyl), 6.60 (1H, s, phenyl), 6.98 (2H, d, J=8.7 Hz, phenyl), 7.48 (2H, d, J=8.7 H, phenyl z), 7.65 (1H, d, J=16.0 Hz, CH).

[0048] Ethyl (E)-3-[4-(7-benzyloxy-1,4-benzodioxan-6-yloxy)phenyl]-2-propenate (8a): Compound 8a. Compound (7a) (0.060 g, 0.18 mmol) was dissolved in 5 mL of N,N-dimethylformamide, and benzyl bromide (0.036 g, 0.21 mmol) and anhydrous potassium carbonate (0.029 g, 0.21 mmol) were added, followed by stirring overnight at 50° C. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with 1 M aqueous sodium hydroxide solution, water, and saturated brine, dehydrated over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give compound (8a) (0.073 g, 96%). 1 H-NMR (CDCl3) δ:1.33 (3H, t, J=7.1 Hz, CH3), 4.25 (7H, m, OCH2CH2O, OCH2), 4.94 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.59 (1H, s, phenyl), 6.67 (1H, s, phenyl), 6.90 (2H, d, J=8.7 Hz, phenyl), 7.10 (2H, m, phenyl), 7.23 (2H, m, phenyl), 7.37 (1H, m, phenyl), 7.44 (2H, t, J=8.7 Hz, phenyl), 7.65 (1H, d, J=16.0 Hz, CH).

[0049] Compounds 8b to 8i were synthesized in the same manner as compound 8a above, using the corresponding benzyl halides. Compound 8j was synthesized in the same manner as compound 8a above, except that compound (7b) was used instead of compound (7a) and the corresponding benzyl halides were used. Only the yield and NMR data are shown below. Ethyl (E)-3-{4-[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8b): Compound 8b Yield 76% 1 H-NMR (CDCl3) δ:1.34 (3H, t, J=7.1 Hz, CH3), 3.90 (3H, s, OCH3), 4.26 (6H, m, OCH2CH2O, OCH2), 4.99 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.56 (1H, s, phenyl), 6.68 (1H, s, phenyl), 6.90 (2H, d, J=8.6 Hz, phenyl), 7.18 (2H, t, J=8.6 Hz, phenyl), 7.45 (2H, d, J=8.6 Hz, phenyl), 7.65 (1H, d, J=16.0 Hz, CH), 7.91 (2H, d, J = 8.6 Hz, phenyl).

[0050] Ethyl (E)-3-{4-[7-(3-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8c): Compound 8c, 100% yield 1H-NMR (CDCl3) δ : 1.33 (3H, t, J=7.1 Hz, CH3), 3.89 (3H, s, OCH3), 4.25 (6H, m, OCH2CH2O, OCH2), 4.98 (2H, s, OCH2), 6.31 (1H, d, J=16.0 Hz, CH), 6.58 (1H, s, phenyl), 6.68 (1H, s, phenyl), 6.90 (2H, d, J=8.6 Hz, phenyl), 7.29 (2H, m, phenyl), 7.44 (2H, d, J=8.6 Hz), 7.64 (1H, d, J=16.0 Hz), 7.90 (2H, m, phenyl).

[0051] Ethyl (E)-3-(4-{7-[4-(2-methoxycarbonyl)ethenylbenzyloxy]-1,4-benzodioxan-6-yloxy}phenyl)-2-propenate (8d): Compound 8d, yield 85% 1 H-NMR (CDCl3) δ:1.34 (3H, t, J=7.1 Hz, CH3), 3.80 (3H, s, OCH3), 4.26 (6H, m, OCH2CH2O, OCH2), 4.95 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.39 (1H, d, J=16.0 Hz, CH), 6.57 (1H, s, phenyl), 6.68 (1H, s, phenyl), 6.90 (2H, d, J=8.7 Hz, phenyl), 7.13 (2H, d, J=8.1 Hz, phenyl), 7.39 (2H, d, J=8.1 Hz, phenyl), 7.45 (2H, d, J=8.7 Hz, phenyl), 7.63 (1H, d, J=16.0 Hz, CH), 7.65 (1H, d, J=16.0 Hz, CH).

[0052] Ethyl (E)-3-{4-[7-(4-t-butylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8e): Compound 8e, yield 74% 1H-NMR (CDCl3)δ:1.28 (9H, s, CH3), 1.33 (3H, t, J=7.1 Hz, CH3), 4.25 (6H, m, OCH2CH2O, OCH2), 4.91 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.61 (1H, s, phenyl), 6.66 (1H, s, phenyl), 6.90 (2H, d, J=8.7 Hz, phenyl), 7.05 (2H, d, J=8.6 Hz, phenyl), 7.26 (2H, d, J=8.6 Hz, phenyl), 7.44 (2H, d, J=8.7 Hz), 7.65 (1H, d, J=16.0 Hz, CH).

[0053] Ethyl (E)-3-{4-[7-(4-methoxybenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8f): Compound 8f, 100% yield 1 H-NMR (CDCl3) δ:1.33 (3H, t, J=7.1 Hz, CH3), 3.76 (3H, s, OCH3), 4.25 (6H, m, OCH2CH2O, OCH2), 4.87 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.59 (1H, s, phenyl), 6.66 (1H, s, phenyl), 6.76 (2H, d, J=8.8 Hz, phenyl), 6.88 (2H, d, J=8.8 Hz, phenyl), 7.02 (2H, d, J=8.8 Hz, phenyl), 7.44 (2H, d, J=8.8 Hz, phenyl), 7.65 (1H, d, J = 16.0 Hz, CH).

[0054] Ethyl (E)-3-{4-[7-(4-chlorobenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8 g): Compound 8 g, yield 78% 1H-NMR (CDCl3) δ : 1.34 (3H, t, J=7.1 Hz, CH3), 4.25 (6H, m, OCH2CH2O, OCH2), 4.90 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.56 (1H, s, phenyl), 6.67 (1H, s, phenyl), 6.88 (2H, d, J=8.6 Hz, phenyl), 7.03 (2H, d, J=8.6 Hz, phenyl), 7.20 (2H, d, J=8.6 Hz, phenyl), 7.44 (2H, t, J=8.6 Hz, phenyl), 7.65 (1H, d, J=16.0 Hz, CH).

[0055] Ethyl (E)-3-{4-[7-(4-trifluoromethylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8h): Compound 8h, yield 96% 1 H-NMR (CDCl3) δ : 1.33 (3H, t, J=7.1 Hz, CH3), 4.26 (6H, m, OCH2CH2O, OCH2), 4.99 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.57 (1H, s, phenyl), 6.69 (1H, s, phenyl), 6.90 (2H, d, J=8.7 Hz, phenyl), 7.23 (2H, d, J=8.1 Hz, phenyl), 7.45 (2H, d, J=8.7 Hz, phenyl), 7.49 (2H, d, J=8.1 Hz, phenyl), 7.64 (1H, d, J=16.0 Hz, CH).

[0056] Ethyl (E)-3-{4-[7-(4-nitrobenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8i): Compound 8i, yield 97% 1H-NMR (CDCl3) δ : 1.34 (3H, t, J=7.1 Hz, CH3), 4.25 (6H, m, OCH2CH2O, OCH2), 5.03 (2H, s, OCH2), 6.33 (1H, d, J=16.0 Hz, CH), 6.56 (1H, s, phenyl), 6.70 (1H, s, phenyl), 6.91 (2H, d, J=8.7 Hz, phenyl), 7.28 (2H, t, J=8.7 Hz, phenyl), 7.46 (2H, d, J=8.7 Hz, phenyl), 7.64 (1H, d, J=16.0 Hz, CH), 8.10 (2H, d, J=8.7 Hz, phenyl).

[0057] Methyl (E)-3-{4-[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenate (8j): Compound 8j, yield 92% 1 H-NMR (CDCl3) δ : 3.80 (3H, s, OCH3), 3.89 (3H, s, OCH3), 4.24 (4H, m, OCH2CH2O), 4.99 (2H, s, OCH2), 6.32 (1H, d, J=16.0 Hz, CH), 6.56 (1H, s, phenyl), 6.68 (1H, s, phenyl), 6.90 (2H, d, J=8.6 Hz, phenyl), 7.18 (2H, d, J=8.6 H, phenyl z), 7.45 (2H, d, J=8.6 Hz, phenyl), 7.66 (1H, d, J=16.0 Hz, CH), 7.90 (2H, d, J=8.6 Hz, phenyl).

[0058] Test Example 1: Confirmation test of growth inhibitory activity using final-instar larvae of the beet armyworm. The beet armyworm larvae were reared in an incubator with a 16-hour light period and an 8-hour dark period at 25±2°C, and fed with Insector LFS (manufactured by Nippon Nosan Kogyo Co., Ltd.). The beet armyworm larvae were used within 24 hours of molting. The test compounds used were compounds 8a to 8j, which are specific examples of the compounds of the present invention, and EMBP obtained by the production method described in Patent Document 2. The test compounds were diluted with acetone to concentrations of 0.5 μg / μL, 0.05 μg / μL, 0.005 μg / μL, and 0.0005 μg / μL. 2 μL of each acetone solution was applied to the dorsal thorax of the test insects, ten of whom were treated with each test compound. As a control, test insects were treated with acetone only. After treatment, they were reared under normal conditions, and the number of individuals that underwent excessive molting, abnormal molting, or abnormal metamorphosis, as well as the number of individuals that metamorphosed into normal pupae, were counted. The results are shown in Table 1. In Table 1, compound 8b is listed alongside "EMBOP."

[0059]

[0060] The results in Table 1 demonstrate that the benzoxazine compounds of the present invention represented by general formula (1) are a group of compounds that exhibit metamorphosis inhibitory activity against Spodoptera exigua. Among all the test compounds, compound 8b (EMBOP) in particular exhibited strong metamorphosis inhibition against Spodoptera exigua when treated at 1 μg per test insect. Meanwhile, EMBP, which has been reported in Patent Document 2 to exhibit JH antagonist activity against silkworm larvae, exhibited excessive molting and molting inhibitory activity at high doses, demonstrating biological activity different from that of the compounds of the present invention, such as compound 8b.

[0061] Test Example 2: Confirmation test of precocious metamorphosis-inducing activity (anti-JH activity) using third-instar silkworm larvae. Silkworm larvae (Shunrei x Shogetsu) were fed Silkmate 2S (manufactured by Nippon Nosan Kogyo Co., Ltd.) in an incubator with a 12-hour light / dark cycle at 25±2°C. The silkworm larvae were used 24 hours after third-instar molting. The test compounds used were compounds 8a-8j, which are specific examples of the compounds of the present invention, and EMBP, prepared by the method described in Patent Document 2. The test compounds were diluted with acetone to concentrations of 0.5 μg / μL, 0.05 μg / μL, and 0.005 μg / μL. 2 μL of acetone solution was then applied to the dorsal thorax of 20 test larvae per test compound. Control larvae were treated with acetone only and then reared under normal conditions. Each test was performed twice. The anti-JH activity of the test compounds was evaluated as the average percentage obtained by dividing the number of test insects that underwent precocious metamorphosis by the number of test insects used in the test (20). The test compounds and their anti-JH activity are shown in Table 2. In Table 2, compound 8b is listed as "EMBOP."

[0062]

[0063] The results in Table 2 show that EMBP, which has been reported to exhibit JH antagonist activity in silkworms, exhibited high activity in inducing precocious metamorphosis. On the other hand, it was revealed that the benzoxazine compound of the present invention represented by general formula (1), which induces metamorphosis failure in beet armyworms, does not exhibit any JH antagonist activity in silkworms.

[0064] Test Example 3: Confirmation of JH Antagonist Activity by Reporter Assay Using Cultured Silkworm Cells Compound 8b (EMBOP), a specific example of a compound of the present invention, and EMBP obtained by the production method described in Patent Document 2 were used as test compounds. BmN_JF&AR cells, cultured silkworm cells genetically modified to express firefly luciferase protein in response to JH, were used. When these cells were simultaneously treated with JH and a JH antagonist, the expression of firefly luciferase, which is normally induced by JH, was inhibited by the JH antagonist, resulting in a decrease in luciferase activity (Fluc). This phenomenon was utilized to confirm the JH antagonist activity of the test compound. JH1, the major JH in silkworms, was used in each of the following experimental groups, and the following experimental groups and controls were prepared using a 96-well plate. Experimental group: 100 μL of medium containing JH1 (final concentration 1 nM) + 1 μL of DMSO solution in which each test compound was dissolved Control: 100 μL of medium not containing JH1 + 1 μL of DMSO In the experimental group and the control group described above, BmN_JF&AR cells (5 × 10 5 100 μL of medium containing 100 μL of ... (Calculation formula) Normalized response (%) = {(mean Fluc value at test concentration - Mean n ) ÷ (Mean Fluc at 0.1 nM n )}×100 Mean n: Mean Fluc value of the control. A graph obtained by performing nonlinear regression using GraphPad Prism (ver. 9) from the normalized response (%) at each test concentration is shown in Figure 1. In Figure 1, compound 8b is represented as "EMBOP."

[0065] The JH antagonist activity of each test compound was calculated from Figure 1 using GraphPad Prism (ver. 9) as the 50% inhibitory concentration (IC) of EMBP and EMBOP. 50 The IC of EMBP was calculated and evaluated. 50 is 4.5 nM, and the IC of compound 8b 50 was calculated to be 176 nM. From the above, it was revealed that EMBP, which exhibits high precocious metamorphosis-inducing activity in silkworm larvae, also exhibits high JH antagonist activity in vitro. On the other hand, it was revealed that compound 8b, a specific example of the compound of the present invention, which exhibits growth inhibitory activity against beet armyworm but does not exhibit precocious metamorphosis-inducing activity in silkworms, has JH antagonist activity that is approximately 1 / 40 of that of EMBP.

[0066] The results of the above "Test Examples 1" to "Test Examples 3" revealed that compound 8b, a specific example of the compound of the present invention, exhibits metamorphosis inhibitory activity against beet armyworm, but does not act as a JH antagonist against silkworm both in vivo and in vitro.

[0067] Unlike EMBP described in Patent Document 2, the benzoxazine compound represented by general formula (1) of the present invention or its salt does not exhibit any precocious metamorphosis-inducing activity in silkworm larvae, while exhibiting growth inhibitory activity against the agricultural pest beet armyworm, demonstrating selective biological activity against pests. It has been revealed that this compound has high potential as a selective pest control agent. Compounds with such pest selectivity have not yet been reported, and they will be extremely useful in identifying new directions for pest control in the agricultural field. This application claims priority based on Patent Application No. 2024-103654 filed in Japan on June 27, 2024, the entire contents of which are incorporated herein by reference.

Claims

1. A benzoxazine compound represented by general formula (1) or a salt thereof: (In the formula, R1 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; R2 and R3 each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogenated alkyl group having 1 to 6 carbon atoms, or an alkoxycarbonyl group having 1 to 6 carbon atoms; and A represents -CR4=CR5-, -CHR4-CHR5-, -CH2-, or -NR6 (R4 to R6 each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms).) 2. The benzoxazine compound or salt thereof according to claim 1, wherein R1 is an alkyl group having 1 to 6 carbon atoms, R2 is an alkoxycarbonyl group having 1 to 6 carbon atoms, R3 is a hydrogen atom, and A is -CH=CH-.

3. Ethyl (E)-3-{4-[7-(4-methoxycarbonylbenzyloxy)-1,4-benzodioxan-6-yloxy]phenyl}-2-propenoate.

4. An insect growth inhibitor comprising the benzoxazine compound or salt thereof according to any one of claims 1 to 3.

5. A selective lepidopteran insect pest control agent containing the benzoxazine compound or its salt according to any one of claims 1 to 3 as an active ingredient.

6. An insect growth inhibitor comprising the benzoxazine compound or salt thereof according to any one of claims 1 to 3.

7. A lepidopteran pest control agent containing the benzoxazine compound or its salt according to any one of claims 1 to 3 as an active ingredient.

8. An agent for inducing metamorphosis failure in lepidopteran pests, comprising the benzoxazine compound or its salt according to any one of claims 1 to 3 as an active ingredient.

9. A method for inhibiting the growth of insects, comprising the step of contacting the insects with the benzoxazine compound or salt thereof according to any one of claims 1 to 3.

10. A method for controlling lepidopteran pests, comprising the step of contacting the benzoxazine compound or salt thereof according to any one of claims 1 to 3 with the lepidopteran pests.

11. A method for inducing metamorphosis failure in a lepidopteran pest, comprising the step of contacting the benzoxazine compound or salt thereof according to any one of claims 1 to 3 with the lepidopteran pest.

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