JP2016155818A - Substituted isoxazole-3-carboxylic acid amide compound or salt thereof, animal external parasite control agent comprising the same, and controlling method - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound highly active against pests, and a pest control agent prepared with the compound.SOLUTION: The present invention provides a substituted isoxazole-3-carboxylic acid amide derivative represented by formula (I) or salt thereof, where Ris H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or the like; Ris H, alkyl, alkylcarbonyl, alkylcarbonylalkyl or the like; Ris a specific substituted phenyl group or substituted benzodioxole group].SELECTED DRAWING: None

Description

  The present invention relates to a novel substituted isoxazole-3-carboxylic acid amide compound or a salt thereof, an animal ectoparasite control agent containing them as an active ingredient, and a method for controlling an animal ectoparasite by applying them. .

Patent Document 1 describes an amide-pyridyl ether compound useful as an animal parasite control agent. This compound has a pyridine ring and is different from the compound of the present invention having an isoxazole ring.
Patent Document 2 describes a wide range of substituted isoxazole-3-carboxylic acid amide derivatives useful as harmful arthropod control agents. This compound is distinguished from the compound of the present invention in that it must include an alkyl substituted with a saturated heterocyclic ring or an unsaturated heterocyclic ring at the R ¹ moiety in the following formula (I).

International Publication No. 2013/003505 International Publication No. 2014/119696

Many pest control agents have been used for many years, but many have various problems such as insufficient efficacy, pests and the like acquiring resistance and limiting their use. Therefore, development of a novel pest control agent with few such drawbacks is desired.
An object of the present invention is to provide a compound that is highly active against ectoparasites of animals that are pests, to provide an animal ectoparasite control agent using the compound, and to animals using the compound It is to provide a method for controlling ectoparasites.

  As a result of studies to solve the above-mentioned problems, the present inventors have found that a novel substituted isoxazole-3-carboxylic acid amide compound represented by the formula (I) or a salt thereof has a low dose and is external to animals. It has been found that it has a very high control effect against parasites, and the present invention has been completed.

  That is, the present invention relates to a substituted isoxazole-3-carboxylic acid amide compound represented by the formula (I) or a salt thereof (hereinafter also referred to as the present compound) and an animal ectoparasite containing the present compound as an active ingredient. Provided is a method for controlling ectoparasites of animals by applying a control agent and an effective amount of the compound of the present invention.

[Wherein, R ¹ represents a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino, mercaptoalkyl, alkylthioalkyl, cyanoalkyl. , Alkylcarbonylalkyl, Y, or alkyl substituted with Y;
Y is a saturated or unsaturated cyclic hydrocarbon group which may be substituted with Z;
Z is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkoxycarbonylamino or nitro;
R ² is a hydrogen atom, alkyl, alkylcarbonyl or alkylcarbonylalkyl;
Alternatively, R ¹ and R ² may be combined with the adjacent nitrogen atom to form a cyclic structure that may be substituted with Z, and the cyclic structure may be further substituted with an alkyl atom, May contain one heteroatom selected from oxygen and sulfur atoms;
R ³ is

Is;
R ⁴ and R ⁷ are each independently halogen, alkyl, haloalkyl, alkenyl, alkynyl optionally substituted with R ⁸ , alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl , alkylsulfonyl, haloalkylsulfonyl, amino, monoalkylamino, dialkylamino, pentafluorosulfanyl, cyano, nitro, optionally substituted with R ⁹ phenoxy, substituted phenyl or R ⁹ may be substituted by R ⁹ A good heterocyclic group;
R ⁵ and R ⁶ are each independently a hydrogen atom, halogen, alkyl or haloalkyl;
R ⁸ is halogen, alkoxy, alkylcarbonyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, trialkylsilyl or a saturated or unsaturated cyclic group which may be substituted with Z, and the cyclic group is substituted with alkyl May contain one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms which may be
R ⁹ is halogen, alkyl, haloalkyl, alkenyl, alkynyl optionally substituted with R ⁸ , alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, Amino, monoalkylamino, dialkylamino, pentafluorosulfanyl, cyano or nitro;
m is an integer from 0 to 5; n is an integer from 0 to 3. ]

  The compound of the present invention has a high control effect against animal ectoparasites. Therefore, according to the present invention, the compound of the present invention is

  In the present specification, unless otherwise specified, the halogen or the halogen as a substituent includes fluorine, chlorine, bromine or iodine. The number of halogens as a substituent may be 1 or 2 or more, and in the case of 2 or more, each halogen may be the same or different. Further, the halogen substitution position may be any position.

In the present specification, unless otherwise specified, the alkyl or alkyl moiety may be either linear or branched. Specific examples thereof include C ₁ such as methyl, ethyl, normal propyl, isopropyl, normal butyl, isobutyl, secondary butyl, tertiary butyl, normal pentyl, neopentyl, 1,2-dimethylpropyl, 2-methylbutyl, and normal hexyl. _-6 , preferably _C1-5 alkyl and the like.

In the present specification, unless otherwise specified, the alkenyl or alkenyl moiety may be either linear or branched. Specific examples thereof include C _2-8 such as vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, isopropenyl, 1-butenyl, 1,3-butadienyl, 1-hexenyl, preferably And C _2-6 alkenyl.

In the present specification, unless otherwise specified, the alkynyl or alkynyl moiety may be linear or branched. Specific examples thereof include C ₂ such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3,3-dimethyl-1-butynyl, 3-methyl-1-butynyl, 1-pentynyl, 1-hexynyl. _-8, and preferably it is an alkynyl of _{C 2-6.}

  In this specification, unless otherwise specified, substituents for substituting alkyl in haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, mercaptoalkyl, alkylthioalkyl, cyanoalkyl and alkylcarbonylalkyl The number of substitutions may be 1 or 2 or more, and in the case of 2 or more, each substituent may be the same or different. In addition, the substitution position of each substituent may be any position of alkyl.

In the present specification, unless otherwise specified, the cyclic group as a substituent may be either saturated or unsaturated. Specific examples thereof include non-aromatic hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl; aromatic hydrocarbon groups such as phenyl, naphthyl and indanyl; Among these cyclic groups, a saturated or unsaturated 3- to 7-membered cyclic group is desirable.
Examples of the heterocyclic moiety in the “heterocyclic group optionally substituted with R ⁹ ” defined by Het include 5-membered monocyclic heterocycle, 6-membered monocyclic heterocycle, polycyclic heterocycle and the like. . The 5-membered monocyclic heterocyclic group includes thienyl such as 2-thienyl and 3-thienyl; furyl such as 2-furyl and 3-furyl; pyrrolyl such as 2-pyrrolyl and 3-pyrrolyl; 2-oxazolyl Oxazolyl such as 4-isozozolyl, 4-isoxazolyl and 5-isoxazolyl; thiazolyl such as 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; 3-isothiazolyl, 4 -Isothiazolyl such as isothiazolyl, 5-isothiazolyl; pyrazolyl such as 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl; imidazolyl such as 2-imidazolyl, 4-imidazolyl, 5-imidazolyl; 2- (1,3, 1,3,4-oxadia, such as 4-oxadiazolyl) Zolyl; 1,2,4-oxadiazolyl such as 3- (1,2,4-oxadiazolyl), 5- (1,2,4-oxadiazolyl); such as 2- (1,3,4-thiadiazolyl) 1,3,4-thiadiazolyl; 1,2,4-thiadiazolyl such as 3- (1,2,4-thiadiazolyl), 5- (1,2,4-thiadiazolyl); 4- (1,2,3 -Thiadiazolyl), 1,2,3-thiadiazolyl such as 5- (1,2,3-thiadiazolyl); 3- (1,2,4-triazolyl), 5- (1,2,4-triazolyl) 1,2,4-triazolyl such as; 1,2,3-triazolyl such as 4- (1,2,3-triazolyl), 5- (1,2,3-triazolyl); 5- (1,2 1,2,3,4-tetrazolyl) and the like; The 6-membered monocyclic heterocyclic group includes pyridyl such as 2-pyridyl, 3-pyridyl and 4-pyridyl; pyrimidyl such as 2-pyrimidyl, 4-pyrimidyl and 5-pyrimidyl; 2-pyrazinyl and 3-pyrazinyl Pyrazinyl such as 3-pyridazinyl, pyridazinyl such as 4-pyridazinyl; 1,3,5-triazinyl such as 2- (1,3,5-triazinyl); 3- (1,2,4-triazinyl) 1,2,4-triazinyl such as 5- (1,2,4-triazinyl), 6- (1,2,4-triazinyl); In addition, as the polycyclic heterocycle, indole; Of these heterocyclic moieties, pyridyl or thienyl is desirable.
As the above-mentioned “cyclic structure formed by combining R ¹ and R ² ”, a saturated monocyclic heterocycle such as aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneimine, piperazine, morpholine, thiomorpholine; Examples thereof include unsaturated monocyclic heterocycles such as pyrrole, pyrazole, and imidazole; polycyclic heterocycles such as indole, and the like.

In the present specification, m represents the number of substitutions of R ⁴ , and n represents the number of substitutions of R ⁷ . When the number of substituents of these substituents is 2 or more, the two or more substituents may be the same or different.

  The salt of the compound of the formula (I) includes any salt that is acceptable in the technical field. For example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; salts with organic carboxylic acids such as tartaric acid, formic acid, acetic acid, citric acid, fumaric acid, maleic acid, trichloroacetic acid, trifluoroacetic acid And salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid.

  The compound of the present invention may have isomers such as geometric isomers, tautomers and optical isomers, and the present invention includes both isomers and isomer mixtures. In this specification, isomers are described as a mixture unless otherwise specified. The present invention also includes various isomers other than those described above within the scope of technical common sense in the technical field.

  Depending on the type of isomer, there may be a chemical structure different from the structural formula described, but those skilled in the art can fully recognize that they are related to isomers, so the scope of the present invention It is clear that it is within.

  Although this invention compound can be manufactured in accordance with the following manufacturing methods and the manufacturing method of a normal salt, it is not limited to these methods.

製法〔１〕中、Ｒ^１、Ｒ^２及びＲ^３の定義は前述の通りである。 Manufacturing method [1]
The compound of the present invention can be produced by the following production method [1].

In the production process [1], the definitions of R ¹ , R ² and R ³ are as described above.

The above production method [1] is a reaction in which a compound of formula (II) and a compound of formula (III) are coupled by Mitsunobu reaction in the presence of an azo reagent and a phosphine reagent to obtain a compound of formula (I). is there.
The compound of formula (II) can be synthesized by the method described below. The compound of formula (III) is commercially available or can be synthesized according to a known method, for example.

  Examples of the azo reagent used include diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), ditertiary butyl azodicarboxylate (DBAD), 1,1 ′-(azodicarbonyl) dipiperidine (ADDP), 1,1′-azobis (N, N-diisopropylformamide) (TIPA), 1,6-dimethyl-1,5,7-hexahydro-1,4,6-tetrazocine-2,5-dione (DHAD) and the like Can be mentioned.

  Examples of the phosphine reagent used include trialkylphosphines such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, triisobutylphosphine, tricyclohexylphosphine; triphenylphosphine, diphenyl (2-pyridyl) And triarylphosphines such as (4-dimethylaminophenyl) diphenylphosphine; and the like.

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds. For example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; hydrocarbons such as normal hexane and normal heptane; acetonitrile, Aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane; diethyl ether, tertiary butyl methyl ether, 1 1, 2-dioxane, tetrahydrofuran (THF), ethers such as 1,2-dimethoxyethane;

  The reaction temperature is generally 0 to 150 ° C., preferably 0 to 40 ° C. The reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.

製法〔２〕中、Ｒ^１、Ｒ^２及びＲ^３の定義は前述の通りである。 Manufacturing method [2]
The compound of the present invention can be produced by the following production method [2].

In the production process [2], the definitions of R ¹ , R ² and R ³ are as described above.

  In the above production method [2], the compound of formula (I) can be synthesized in accordance with a commercially available or known method with a compound of formula (IV) which can be synthesized by the method described below in the presence of a condensing agent and a base. It can be synthesized by reacting the compound of formula (V).

  Examples of the condensing agent used include N, N′-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC-HCl), O- (benzotriazole-1- Yl) -N, N, N ′, N′-tetramethyluronium hexafluoro-phosphate (HBTU), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methyl Examples thereof include morpholinium chloride (DMT-MM).

  The base to be used is not particularly limited as long as the reaction proceeds. For example, tertiary amines such as triethylamine, 4-methylmorpholine, diisopropylethylamine; 1,8-diazabicyclo [5.4.0] -7-undecene (DBU); pyridine; 4- (dimethylamino) pyridine (DMAP) ); One or more of 2,6-lutidine and the like can be appropriately selected and used by mixing.

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, and carbon tetrachloride; hydrocarbons such as normal hexane and normal heptane; esters such as methyl acetate, ethyl acetate, and propyl acetate; acetonitrile, N, Aprotic polar solvents such as N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane; diethyl ether, tertiary butyl methyl ether, 1, 4 1 type or 2 types or more can be suitably selected from ethers, such as dioxane, tetrahydrofuran (THF), 1, 2- dimethoxyethane;

This reaction can be performed in the presence of a catalyst, if necessary. The catalyst can be appropriately selected from 4- (dimethylamino) pyridine and 1-hydroxybenzotriazole.
The reaction temperature is usually 0 to 150 ° C., preferably 0 to 100 ° C. The reaction time is usually 1 to 72 hours, preferably 5 minutes to 24 hours.

  In the production method [2], the compound of formula (IV) is converted into an active derivative such as acid chloride or acid anhydride, and then reacted with the compound of formula (V) in the presence of a base and a solvent. Can also be performed.

  In order to convert the compound of formula (IV) into an acid chloride, thionyl chloride, oxalyl chloride and the like can be used. In order to convert the acid anhydride, acetyl chloride, trifluoroacetyl chloride, or the like can be used. As a reagent to be converted into other active derivatives, ethyl chlorocarbonate, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be used.

The reaction for converting the compound of formula (IV) into an active derivative such as an acid chloride or an acid anhydride can be usually performed in the presence of a solvent. Examples of the solvent include those similar to the production method [1].
The reaction temperature is usually -20 to 80 ° C. The reaction time is usually 1 minute to 48 hours.

  The compound of the formula (I) can be produced by reacting the obtained reaction solution containing the active derivative with the compound of the formula (V) usually in the presence of a base and a solvent.

  The base to be used is not particularly limited as long as the reaction proceeds. For example, tertiary amines such as triethylamine and diisopropylethylamine; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium methoxide and sodium ethoxy Alkali metal alkoxides such as potassium tertiary butoxide; 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, 4- (dimethylamino) pyridine (DMAP), 2,6 -1 type (s) or 2 or more types can be selected from lutidine etc. suitably, and can be used in mixture.

This reaction can usually be performed in the presence of a solvent. Examples of the solvent include those similar to the production method [1].
The reaction temperature is usually -20 to 80 ° C. The reaction time is usually 1 minute to 48 hours.

製法〔３〕中、Ｒ^１、Ｒ^２及びＲ^３の定義は前述の通りであり、Ｒ^ａは−ＣＨ_３又は−ＣＨ_２ＣＨ_３を示す。 Manufacturing method [3]
The compound of the present invention can be produced by the following production method [3].

In the production method [3], the definitions of R ¹ , R ² and R ³ are as described above, and R ^a represents —CH ₃ or —CH ₂ CH ₃ .

  In the above production method [3], the compound of formula (I) comprises a compound of formula (VI) that can be synthesized by the method described below and a compound of formula (V) that is commercially available or that can be synthesized according to a known method. It can be synthesized by reacting.

  This reaction can also be usually performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds. For example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; hydrocarbons such as normal hexane and normal heptane; acetonitrile, Aprotic polar solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane; diethyl ether, tertiary butyl methyl ether, 1 , 4-dioxane, tetrahydrofuran (THF), ethers such as 1,2-dimethoxyethane; alcohols such as methanol, ethanol and isopropyl alcohol; It is possible to use Te.

  The reaction temperature is generally 0 to 150 ° C., preferably 20 to 100 ° C. The reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.

Manufacturing method [4]
The compound of the present invention can be produced by the following production method [4].

In the production method [4], the definitions of R ¹ , R ² , R ⁴ and R ⁹ are as described above, p is an integer of 0 to 4, and q is an integer of 0 to 5. X is a chlorine atom, a bromine atom or an iodine atom, and R ^b represents a hydrogen atom or C _1-6 alkyl which may be the same or different, or two R ^b together represent —CH ₂ CH ₂ —. or _{-C (CH 3) 2 C (} CH 3) 2 - may be formed.

  In the above production method [4], the compound of the formula (I-3) can be synthesized by the method of the production method [1], the production method [2] or the production method [3] in the presence of a metal catalyst and a base (I- It can be synthesized by reacting a compound of 1-X) with a compound of formula (VII) which is commercially available or can be synthesized according to a known method.

  As a metal catalyst to be used, what is generally used in the cross coupling reaction may be used. For example, palladium catalysts such as palladium-carbon, palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium dichloride; metal copper, copper acetate (I), copper acetate (II) Copper catalysts such as copper oxide (I), copper oxide (II), and copper iodide;

  The base to be used is not particularly limited as long as the reaction proceeds. For example, tertiary amines such as triethylamine and diisopropylethylamine; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkaline earth metal carbonates such as calcium carbonate and barium carbonate; lithium hydroxide and sodium hydroxide 1 type, or 2 or more types can be appropriately selected from a mixture of alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; .

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; hydrocarbons such as normal hexane and normal heptane; methanol, Alcohols such as ethanol and isopropyl alcohol; aprotic polar solvents such as acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane 1 type or 2 types or more are appropriately selected from diethyl ether, tertiary butyl methyl ether, ethers such as 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane; water; Combined and can be used.

The reaction temperature is generally 0 to 150 ° C., preferably 20 to 100 ° C. The reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.
This reaction can be performed under an inert gas, if necessary. Examples of the inert gas include argon gas and nitrogen gas.

製法〔５〕中、Ｒ^８aは水素原子、アルキル又はＲ^８であり；Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^８、ｐ及びＸの定義は前述の通りである。 Manufacturing method [5]
The compound of the present invention can be produced by the following production method [5].

In the production process [5], R ^8a is a hydrogen atom, alkyl or R ⁸ ; the definitions of R ¹ , R ² , R ⁴ , R ⁸ , p and X are as described above.

  In the above production method [5], the compound of the formula (I-5) can be synthesized by the production method [1], the production method [2] or the production method [3] in the presence of a palladium catalyst, a copper salt and a base. It can be synthesized by reacting a compound of (I-1-X) with a compound of formula (VIII) which is commercially available or can be synthesized according to a known method.

The palladium catalyst to be used is not particularly limited as long as it is generally used in a cross-coupling reaction, and examples thereof include tetrakis (triphenylphosphine) palladium (0) and bis (triphenylphosphine) palladium dichloride.
Examples of the copper salt to be used include copper (I) iodide.
Examples of the base to be used include those similar to the production method [4].

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, aprotic polar solvents such as acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane; diethyl ether, tertiary butyl 1 type or 2 types or more are appropriately selected from ethers such as methyl ether, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane; tertiary amines such as triethylamine and diisopropylethylamine; Can be used as a mixture.

The reaction temperature is generally 0 to 150 ° C., preferably 20 to 100 ° C. The reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.
This reaction can be performed under an inert gas, if necessary. Examples of the inert gas include argon gas and nitrogen gas.

Intermediate production method [1]
The compound of the formula (II) which is the starting material of the production method [1] can be produced, for example, by the reactions of the following steps (1) to (4).

In the above reaction formula, the definitions of R ¹ , R ² and R ^a are as described above, and L represents a silyl protecting group. Examples of the silyl protecting group include trimethylsilyl, triethylsilyl, tertiary butyldimethylsilyl, dimethyltexylsilyl, triisopropylsilyl, tertiary butyldiphenylsilyl and the like.

Process (1)
In this reaction, the hydroxy group of the compound of formula (IX) is protected to obtain the compound of formula (X). This reaction can be performed in the presence of a protecting reagent and a base.

  Examples of the protecting reagent used include trimethylsilyl chloride (TMSCl), triethylsilyl chloride (TESCl), tertiary butyldimethylsilyl chloride (TBSCl), dimethyl texylsilyl chloride (TDSCl), triisopropylsilyl chloride (TIPSCl), Tertiary butyldiphenylsilyl chloride (TBDPSCl) and the like can be mentioned.

Examples of the base to be used include those similar to the production method [2].
This reaction can usually be performed in the presence of a solvent. Examples of the solvent include those similar to the production method [1].
The reaction temperature is generally 0 to 150 ° C., preferably 0 to 40 ° C. The reaction time is usually 1 minute to 48 hours, preferably 5 minutes to 24 hours.

  The protecting group of hydroxy group and the protecting method can be carried out according to the description in known literature (for example, Protective Groups in Organic Synthesis Forth Edition, John Wiley & Sons, Inc.).

Step (2)
In this reaction, the compound of the formula (X) is hydrolyzed to obtain the compound of the formula (XI). This reaction can be performed according to a known method in general organic synthetic chemistry.

In this reaction, a base and a solvent can be usually used.
The base is not particularly limited as long as the reaction proceeds. For example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metals such as sodium carbonate, potassium carbonate and cesium carbonate One type or two or more types can be appropriately selected from carbonates; alkaline earth metal carbonates such as calcium carbonate and barium carbonate;

  The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, alcohols such as methanol, ethanol, isopropyl alcohol; acetonitrile, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane, etc. Protonic polar solvent; Ether ether such as diethyl ether, tertiary butyl methyl ether, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane; water; Can be mixed and used.

  The reaction temperature is usually 0 to 100 ° C., preferably 0 to 100 ° C. The reaction time is usually 1 minute to 72 hours, preferably 5 minutes to 24 hours.

Process (3)
This is a reaction in which a compound of formula (XI) and a compound of formula (V) are amidated to give a compound of formula (XII). This reaction can be carried out in the same manner as in production method [2].

Process (4)
A reaction in which a compound of formula (XII) is deprotected to give a compound of formula (II). This reaction can be performed in the presence of an acid.
Examples of the acid to be used include inorganic acids such as hydrochloric acid, and organic acids such as acetic acid, formic acid, and trifluoroacetic acid.

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, ethers such as diethyl ether, tertiary butyl methyl ether, 1,4-dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropyl alcohol; water; Or 2 or more types can be selected suitably and can be mixed and used.

  Appropriate deprotection of the protecting group can be carried out according to the description in known literature (for example, Protective Groups in Organic Synthesis Forth Edition, John Wiley & Sons, Inc.).

上記の反応式中、Ｒ^１、Ｒ^２、Ｒ^a及びＬの定義は前述の通りである。 Moreover, the compound of the formula (XII) which is an intermediate of the intermediate production method [1] can also be produced, for example, by the reaction of the next step (5).

In the above reaction formula, the definitions of R ¹ , R ² , ^Ra and L are as described above.

Step (5)
This is a reaction in which a compound of formula (X) and a compound of formula (V) are reacted to amid to obtain a compound of formula (XII). This reaction can be carried out in the same manner as in production method [3].

上記の反応式中、Ｒ^１、Ｒ^２及びＲ^aの定義は前述の通りである。 Moreover, the compound of a formula (II) can also be manufactured by reaction of the following process (6)-(7) or process (8), for example.

In the above reaction formula, the definitions of R ¹ , R ² and R ^a are as described above.

Step (6)
In this reaction, a compound of formula (IX) is hydrolyzed to obtain a compound of formula (XIII). This reaction can be carried out in the same manner as in step (2) of intermediate production method [1].
Step (7)
In this reaction, the compound of the formula (XIII) and the compound of the formula (V) are reacted to amid to obtain a compound of the formula (II). This reaction can be carried out in the same manner as in production method [2] Step (8)
As an alternative method of obtaining the compound of formula (II), the compound of formula (IX) and the compound of formula (V) can be reacted and amidated to obtain the compound of formula (II). This reaction can be carried out in the same manner as in production method [3].

上記の反応式中、Ｒ^３及びＲ^aの定義は前述の通りである。 Intermediate production method [2]
The compound of the formula (IV) which is the starting material for the production method [2] can be produced, for example, by the reactions of the following steps (9) to (10).

In the above reaction formula, the definitions of R ³ and R ^a are as described above.

Step (9)
In this reaction, a compound of formula (VI) is obtained by performing a Mitsunobu reaction using a compound of formula (IX) and a compound of formula (III). This reaction can be carried out in the same manner as in production method [1].

Step (10)
This is a reaction in which a compound of formula (VI) is hydrolyzed to obtain a compound of formula (IV). This reaction can be carried out in the same manner as in step (2) of intermediate production method [1].

上記の反応式中、Ｒ^４、Ｒ^９、Ｒ^ａ、Ｒ^ｂ、ｐ、ｑ及びＸの定義は前述の通りである。 Intermediate production method [3]
Among the compounds of the formula (VI) that are intermediates in the intermediate production method [2], the compound of the formula (VI-3) can be produced, for example, by the reaction of the following step (11).

In the above reaction formula, the definitions of R ⁴ , R ⁹ , R ^a , R ^b , p, q and X are as described above.

Step (11)
In this reaction, a compound of formula (VI-3) is obtained by a coupling reaction between a compound of formula (VI-1-X) and a compound of formula (VII) in the presence of a metal catalyst and a base. This reaction can be carried out in the same manner as in production method [4].

上記の反応式中、Ｒ^４、Ｒ^８、Ｒ^ａ、ｐ、Ｘ及びＲ^８aの定義は前述の通りである。 Intermediate production method [4]
Among the compounds of the formula (VI) that are intermediates in the intermediate production method [2], the compound of the formula (VI-5) can be produced, for example, by the reaction in the following step (12).

In the above reaction formula, the definitions of R ⁴ , R ⁸ , R ^a , p, X and R ^8a are as described above.

Step (12)
In this reaction, a compound of formula (VI-5) is obtained by reacting a compound of formula (VI-1-X) with a compound of formula (VIII) in the presence of a palladium catalyst, a copper salt and a base. This reaction can be carried out in the same manner as in production method [5].

上記の反応式中、Ｒ^cは水素原子又はＲ^３であり；Ｒ^a及びＲ^３の定義は前述の通りである。 Intermediate production method [5]
The compound of the formula (XVI) can be produced, for example, by the reaction in the following step (13).

In the above reaction formula, R ^c is a hydrogen atom or R ³ ; the definitions of R ^a and R ³ are as described above.

Step (13)
In this reaction, a compound of formula (XVI) is reacted with a compound of formula (XV) in the presence of a base to obtain a compound of formula (XVI).

  The base to be used is not particularly limited as long as the reaction proceeds. For example, tertiary amines such as triethylamine and diisopropylethylamine; alkali metal carbonates such as sodium carbonate, potassium carbonate and cesium carbonate; alkali metal hydrides such as sodium hydride and potassium hydride; sodium methoxide and sodium ethoxy Alkali metal alkoxides such as potassium tertiary butoxide; 1,8-diazabicyclo [5.4.0] -7-undecene (DBU), pyridine, 4- (dimethylamino) pyridine (DMAP), 2,6 -1 type, or 2 or more types are suitably selected from lutidine, 1, 4- diazabicyclo [2.2.2] octane (DABCO), etc., and can be mixed and used.

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, and carbon tetrachloride; hydrocarbons such as normal hexane and normal heptane; esters such as methyl acetate, ethyl acetate, and propyl acetate; acetonitrile, N, Aprotic polar solvents such as N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane; diethyl ether, tertiary butyl methyl ether, 1, 4 -One kind or two or more kinds of ethers such as dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane; alcohols such as methanol, ethanol and isopropyl alcohol; Door can be.

The reaction temperature is usually −10 to 150 ° C. The reaction time is usually 1 minute to 72 hours.
This reaction can be performed under an inert gas, if necessary. Examples of the inert gas include argon gas and nitrogen gas.

上記の反応式中、Ｒ^a及びＲ^cの定義は前述の通りである。 Intermediate production method [6]
The compound of the formula (XVI) can also be produced, for example, by the reaction in the following step (14).

In the above reaction formula, R ^a and R ^c are defined as described above.

Step (14)
In this reaction, a compound of formula (XVI) and a compound of formula (XV) are reacted in the presence of a base to obtain a compound of formula (XVI).
Examples of the base to be used include those similar to the intermediate production method [5].

  This reaction can usually be performed in the presence of a solvent. The solvent is not particularly limited as long as the reaction proceeds, and any solvent may be used as long as it is inert to the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, trichloroethane, and carbon tetrachloride; hydrocarbons such as normal hexane and normal heptane; esters such as methyl acetate, ethyl acetate, and propyl acetate; acetonitrile, N, Aprotic polar solvents such as N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), sulfolane; diethyl ether, tertiary butyl methyl ether, 1, 4 -Ether, such as dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane; alcohols such as methanol, ethanol, isopropyl alcohol; water; Rukoto can.

The reaction temperature is usually −10 to 150 ° C. The reaction time is usually 1 minute to 72 hours.
This reaction can be performed under an inert gas, if necessary. Examples of the inert gas include argon gas and nitrogen gas.

  The desirable aspect of the animal ectoparasite control agent containing this invention compound is described below. Examples of animal ectoparasite control agents include harmful ectoparasite control agents that parasitize on the body surface (back, armpit, lower abdomen, inner thigh, etc.) of host animals such as pets, livestock, and poultry. It is done.

  Examples of animal ectoparasites include animal parasitic mites and fleas. There are so many of these types that it is difficult to list them all.

The animal parasitic mites, for example Boophilus microplus (Boophilus microplus), Rhipicephalus sanguineus (Rhipicephalus sanguineus), Haemaphysalis longicornis (Haemaphysalis longicornis), Haemaphysalis flava (Haemaphysalis flava), Adenophora chima tick (Haemaphysalis campanulata), Isukachimadani (Haemaphysalis concinna), Yamatochimadani (Haemaphysalis japonica), H. kitaokai (Haemaphysalis kitaokai), Iyasuchimadani (Haemaphysalis ias), Ixodes ovatus (Ixodes ovatus), I. nipponensis (Ixodes nipponensis), Schulze ticks (Ixodes persulcatus), Takasago testudinarium (Amblyomma testudinarium), Ootogechimadani (Haemaphysalis megaspinosa ), tick such as Dermacentor reticulatus , Dermacentor taiwanesis ; duck ( Dermanyssus gallinae ); Shidani (Ornithonyssus sylviarum), Torisashidani, such as Southern tri sand mite (Ornithonyssus bursa); Nan iodine tsutsugamushi (Eutrombicula wichmanni), red mites (Leptotrombidium akamushi), L. pallidum (Leptotrombidium pallidum), Fuji chiggers (Leptotrombidium fuji), Tosa mites ( Leptotrombidium tosa), Europe Aki mites (Neotrombicula autumnalis), the United States chiggers (Eutrombicula alfreddugesi), chiggers, such as Miyagawa Tama chiggers (Helenicula miyagawai); Inutsumedani (Cheyletiella yasguri), rabbit Tsumedani (Cheyletiella parasitivorax), Nekotsumedani (Cheyletiella blakei) Tsumedani, such as; rabbits 9,000 mite (Psoroptes cuniculi), Ushishokuhidani (Chorioptes bovis), dog ear mites (Otodectes cynotis), mange mites (Sar coptes scabiei ), mite mites such as Notoedres cati ; mite mites such as Demodex canis ; and the like. Among them, the animal ectoparasite control agent containing the compound of the present invention is particularly effective for controlling ticks and the like.

Examples of animal parasitic fleas include ectoparasite worms belonging to the order Flea ( Siphonaptera ), and more specifically fleas belonging to the family Flea family ( Pulicidae ), Nagano family ( Ceratephyllus ), and the like. Examples of fleas belonging to the family flea family include, for example, dog fleas ( Ctenocephalides canis ), cat fleas ( Ctenocephalides felis ), human fleas ( Purex irritans ), elephant fleas ( Echidnophaga gallinacea ), keops mouse fleas ( Xenopsylla cheopis ) Leptopsylla segnis ), European mouse minnow ( Nosopsyllus fasciatus ), and Yamamoto mouse ( Monopsyllus anisus ); Among them, the animal ectoparasite control agent containing the compound of the present invention is effective for controlling fleas belonging to the family Flea, particularly dog fleas, cat fleas and the like.

  Other animal ectoparasites include, for example, lice such as cattle lice, horse lice, sheep lice, cattle white lice, head lice; lice such as cat lice; Can be mentioned.

  Examples of host animals include various pet animals, livestock, poultry and the like. More specifically, dogs, cats, mice, rats, hamsters, guinea pigs, squirrels, rabbits, ferrets, birds (eg, pigeons, parrots, nine-birds, bunting birds, parakeets, juvenile pine, canary etc.), cows, horses, pigs, Sheep, ducks and chickens. Among them, the animal ectoparasite control agent containing the compound of the present invention is effective for controlling pests or ticks that are ectoparasite on companion animals or livestock. Among pet animals or domestic animals, it is particularly effective for dogs, cats, cows or horses.

When the compound of the present invention is used as an animal ectoparasite control agent, it may be used as it is, and together with suitable adjuvants, powders, granules, tablets, powders, capsules, liquid agents, emulsions, aqueous suspensions , Oily suspensions, wettable powders, granules and the like can be formulated and used. In addition to the above-mentioned preparation forms, any preparation forms that are used in the normal field can be used as long as the object of the present invention is met.
Adjuvants used in the formulation include fatty acid salts, benzoates, alkyl sulfosuccinates, dialkyl sulfosuccinates, polycarboxylates, alkyl sulfate esters, alkyl sulfates, alkyl aryl sulfates, alkyl diglycol ether sulfates Salt, alcohol sulfate ester salt, alkyl sulfonate salt, alkyl aryl sulfonate salt, aryl sulfonate salt, lignin sulfonate salt, alkyl diphenyl ether disulfonate salt, polystyrene sulfonate salt, alkyl phosphate ester salt, alkyl aryl phosphate salt , Styryl aryl phosphate, polyoxyethylene alkyl ether sulfate, polyoxyethylene alkyl aryl ether sulfate, polyoxyethylene alkyl aryl ether sulfate, polyoxyethylene Anionic surfactants such as alkyl ether phosphates, polyoxyethylene alkylaryl phosphate salts, naphthalene sulfonate formaldehyde condensates; sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycols Ether, acetylene glycol, acetylene alcohol, oxyalkylene block polymer, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl aryl ether, polyoxyethylene glycol alkyl ether, polyethylene glycol, polyoxyethylene fatty acid ester, poly Oxyethylene sorbitan fatty acid ester, polyoxyethylene glycerin fatty acid ester, Nonionic surfactants such as reoxyethylene hydrogenated castor oil and polyoxypropylene fatty acid esters; cationic surfactants such as cetyltrimethylammonium bromide; water, acetone, acetonitrile, N-methylacetamide, N , N-dimethylacetamide, N, N-dimethylformamide, 2-pyrrolidone, N-methyl-2-pyrrolidone, kerosene, triacetin, methanol, ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, dipropylene glycol, hexylene Glycol, polyethylene glycol, liquid polyoxyethylene glycol, butyl diglycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol Solvents such as monoethyl ether, diethylene glycol normal butyl ether, propylene glycol monomethyl ether, dipropylene glycol monomethyl ether, dipropylene glycol normal butyl ether; butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, Antioxidants such as sodium thiosulfate; film formers such as polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone; olive oil, kapok oil, castor oil, palm oil, coconut oil, coconut oil, sesame oil, corn oil, Rice bran oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil, linseed oil, drill oil, liquid paraffin and other vegetable oils and mineral oils; lactose, sucrose, glucose, starch Flour, corn flour, soybean oil cake, defatted rice bran, calcium carbonate, carriers such as other commercially available feed materials; and the like. Each component of these adjuvants can be used by appropriately selecting one or two or more types without departing from the object of the present invention. In addition to the above-mentioned auxiliary agents, they can be appropriately selected from those known in the art.

  The compounding ratio (weight ratio) of the compound of the present invention and various adjuvants is usually about 0.1: 99.9 to 90:10.

  Administration of the compound of the present invention to the host animal is performed orally or parenterally. Examples of the oral administration method include a method of administering a tablet, liquid agent, capsule, wafer, biscuit, minced meat, other feed, etc. containing the compound of the present invention. As a parenteral administration method, for example, the compound of the present invention is prepared in an appropriate formulation and then taken into the body by intravenous administration, intramuscular administration, intradermal administration, subcutaneous administration, etc .; spot-on ) Treatment, pour-on treatment, spray treatment, chemical bath treatment and the like; and a method of embedding a resin piece containing the compound of the present invention subcutaneously in the host animal.

  The dose of the compound of the present invention to the host animal varies depending on the administration method, administration purpose, disease symptoms, etc., but is usually 0.01 mg to 100 g, preferably 0.1 mg to 10 g, relative to 1 kg body weight of the host animal. Is suitable for administration.

  The present invention also includes a method for controlling animal ectoparasites by the administration method or dosage as described above.

  Further, in the present invention, by controlling harmful animal ectoparasites as described above, various host animal diseases caused by them may be indirectly prevented. Thus, the present invention includes a prophylactic agent for animal diseases caused by ectoparasites containing the compound of the present invention as an active ingredient, and a method for preventing animal diseases caused by ectoparasites.

  When the compound of the present invention is used as an animal ectoparasite control agent, various vitamins, minerals, amino acids, nutrients, enzyme preparations, antipyretics, sedatives, antiphlogistics, bactericides, coloring agents, fragrances as well as adjuvants , And can be used in combination or in combination with preservatives. In addition, if necessary, mixed or used in combination with other various animal drugs and agricultural chemicals such as anthelmintics, anticoccidials, insecticides, acaricides, fleas, nematicides, bactericides, antibacterials, etc. can do. In this case, a more excellent effect may be exhibited. The present invention includes a composition for controlling ectoparasites of animals in which various components as described above are mixed or used together, and also includes a method for controlling ectoparasites of animals using the same.

Next, some preferred embodiments of the substituted isoxazole-3-carboxylic acid amide compound or a salt thereof of the present invention will be exemplified, but these do not limit the present invention.
(1) The substituted isoxazole-3-carboxylic acid amide compound of the above formula (I) or a salt thereof.
(2) The compound or salt thereof according to (1), represented by formula (I-1).

［式中、Ｒ^１、Ｒ^２、Ｒ^４及びｍは、前述の定義の通りである。］

[Wherein R ¹ , R ² , R ⁴ and m are as defined above. ]

(3) R ¹ is a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino, mercaptoalkyl, alkylthioalkyl, cyanoalkyl, Y or alkyl substituted with Y;
Y is a saturated or unsaturated cyclic hydrocarbon group which may be substituted with Z;
Z is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano or nitro;
R ² is a hydrogen atom, alkyl or alkylcarbonyl;
R ⁴ is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, amino, monoalkylamino, dialkylamino, cyano or nitro;
m is an integer of 0-3, The compound or its salt as described in (2).

(4) R ¹ is a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino, mercaptoalkyl, alkylthioalkyl, cyanoalkyl or Alkyl substituted with Y;
The compound according to (2) or a compound thereof, wherein R ⁴ is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cyano or nitro salt.

(5) R ¹ is a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino, mercaptoalkyl, alkylthioalkyl, cyanoalkyl or Alkyl substituted with Y;
Y is a saturated or unsaturated 3-7 membered ring;
R ⁴ is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, cyano or nitro;
The compound or its salt as described in (2) whose m is an integer of 0-2.

(6) R ¹ is a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl, dialkylaminoalkyl, dialkylamino, alkylthioalkyl, cyanoalkyl, alkylcarbonylalkyl, Y, or alkyl substituted with Y. The compound or salt thereof according to (1) or (2).

(7) The compound or salt thereof according to (6), wherein R ¹ is a hydrogen atom, alkyl, Y, or alkyl substituted with Y.

(8) The compound or salt thereof according to (1) or (2), wherein R ² is a hydrogen atom, alkyl or alkylcarbonyl.

(10) R ⁴ and R ⁷ are each independently halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, alkylsulfonyl, amino, dialkylamino, cyano, nitro, R ⁹ The compound or a salt thereof according to (1), which is phenyl which may be substituted with or phenoxy which may be substituted with R ⁹ .

(11) R ⁴ is phenyl optionally substituted by halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, alkylsulfonyl, amino, dialkylamino, cyano, nitro, R ⁹ or substituted with R ⁹ is also good phenoxy, (1), (2), (3), (4) the compound or a salt thereof according to (5) or (6).

(12) The compound or salt thereof according to (11), wherein R ⁴ is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, dialkylamino, cyano, or phenyl optionally substituted with R ⁹ .

(13) The compound or salt thereof according to (11), wherein R ⁴ is halogen, haloalkyl, alkoxy, haloalkoxy, or phenyl optionally substituted with R ⁹ .

(14) The compound or a salt thereof according to (11), wherein R ¹ is alkyl or Y; R ² is a hydrogen atom; R ⁴ is a halogen atom or haloalkoxy; and m is 1 or 2.

［式中、Ｒ^１、Ｒ²、Ｒ⁵、Ｒ⁶、Ｒ^７及びｎは、前述の定義の通りである。］ (15) The compound or salt thereof according to (1), which is represented by formula (I-2).

[Wherein R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and n are as defined above. ]

［式中、Ｒ^１、Ｒ²、Ｒ^４、Ｒ⁹、ｐ及びｑは、前述の定義の通りである。］ (16) The compound or salt thereof according to (2), represented by formula (I-3).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and q are as defined above. ]

［式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ⁹、ｐ及びｑは前述の定義の通りである。］ (17) The compound or salt thereof according to (16) represented by formula (I-3a).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and q are as defined above. ]

［式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^９、ｐ及びｑは前述の定義の通りである。］ (18) The compound or salt thereof according to (16), represented by the formula (I-3b):

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and q are as defined above. ]

［式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^９、ｐ及びｑは前述の定義の通りである。］ (19) The compound or salt thereof according to (16) represented by formula (I-3c).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and q are as defined above. ]

［式中、Ｒ^１、Ｒ²、Ｒ^４、Ｈｅｔ及びｐは、前述の定義の通りである。］ (20) The compound or salt thereof according to (2), represented by formula (I-4).

[Wherein R ¹ , R ² , R ⁴ , Het and p are as defined above. ]

［式中、Ｒ^１、Ｒ²、Ｒ^４、Ｒ⁹及びｐは、前述の定義の通りであり、ｒは０〜４の整数である。］ (21) The compound according to (20) or a salt thereof represented by the formula (I-4a).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ and p are as defined above, and r is an integer of 0 to 4. ]

［式中、Ｒ^１、Ｒ^２、Ｒ⁴、Ｒ^９、ｐ及びｒは前述の定義の通りである。］ (22) The compound according to (21) or a salt thereof represented by the formula (I-4a-1).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and r are as defined above. ]

［式中、Ｒ^１、Ｒ^２、Ｒ⁴、Ｒ^９、ｐ及びｒは前述の定義の通りである。］ (23) The compound according to (21) or a salt thereof represented by the formula (I-4a-2).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and r are as defined above. ]

［式中、Ｒ^１、Ｒ²、Ｒ^４、Ｒ⁹及びｐは、前述の定義の通りであり、ｓは０〜３の整数である。］ (24) The compound or a salt thereof according to (23), wherein R ¹ is alkyl; R ² is a hydrogen atom; R ⁹ is a halogen atom; p is 0 and q is 2.
(25) The compound or salt thereof according to (20), represented by formula (I-4b).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ and p are as defined above, and s is an integer of 0 to 3. ]

［式中、Ｒ^１、Ｒ²、Ｒ⁴、Ｒ⁹、ｐ及びｓは、前述の定義の通りである。］ (26) The compound or salt thereof according to (25), represented by the formula (I-4b-1).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and s are as defined above. ]

［式中、Ｒ^１、Ｒ²、Ｒ^４、Ｒ⁹、ｐ及びｓは、前述の定義の通りである。］ (27) The compound or a salt thereof according to (25) represented by the formula (I-4b-2).

[Wherein R ¹ , R ² , R ⁴ , R ⁹ , p and s are as defined above. ]

(28) The compound or salt thereof according to any one of (21) to (27), wherein R ⁹ is halogen or alkynyl optionally substituted with R ⁸ .

［式中、Ｒ^８aは水素原子、アルキル又はＲ^８であり；Ｒ^１、Ｒ²、Ｒ⁴及びＲ^８は、前述の定義の通りであり、ｐは０〜４の整数である。］ (29) The compound or a salt thereof according to (2), represented by formula (I-5).

[Wherein R ^8a is a hydrogen atom, alkyl or R ⁸ ; R ¹ , R ² , R ⁴ and R ⁸ are as defined above, and p is an integer of 0-4. ]

［式中、Ｒ^８aは水素原子、アルキル又はＲ^８であり；Ｒ^１、Ｒ²、Ｒ⁴及びＲ^８は、前述の定義の通りであり、ｐは０〜４の整数である。］ (30) The compound or salt thereof according to (29), represented by formula (I-5a).

[Wherein R ^8a is a hydrogen atom, alkyl or R ⁸ ; R ¹ , R ² , R ⁴ and R ⁸ are as defined above, and p is an integer of 0-4. ]

［式中、Ｒ^８aは水素原子、アルキル又はＲ^８であり；Ｒ^１、Ｒ²、Ｒ⁴及びＲ^８は前述の定義の通りであり、ｐは０〜４の整数である。］ (31) The compound according to (29) or a salt thereof represented by the formula (I-5b):

[Wherein R ^8a is a hydrogen atom, alkyl or R ⁸ ; R ¹ , R ² , R ⁴ and R ⁸ are as defined above, and p is an integer of 0-4. ]

(32) any one of (29) to (31), wherein R ¹ is alkyl or Y; R ² is a hydrogen atom; R ⁴ is a halogen atom; R ^8a is alkyl; Or a salt thereof.

［式中、Ｒ^８aは水素原子、アルキル又はＲ^８であり；Ｒ^１、Ｒ²、Ｒ⁴及びＲ^８は前述の定義の通りであり、ｐは０〜４の整数である。］ (33) The compound according to (29) or a salt thereof represented by the formula (I-5c).

[Wherein R ^8a is a hydrogen atom, alkyl or R ⁸ ; R ¹ , R ² , R ⁴ and R ⁸ are as defined above, and p is an integer of 0-4. ]

(34) The compound or salt thereof according to (29) to (31) or (33), wherein R ⁸ is alkyl or trialkylsilyl.

  Next, examples of the present invention will be described, but the present invention is not limited thereto.

<Synthesis Example 1>
Synthesis of N-isobutyl-5- (2- (3-bromophenoxy) ethyl) isoxazole-3-carboxamide (Compound No. 1-9)

(1) A solution of 3-bromophenol (0.36 g) and ethyl 5-hydroxyethylisoxazole-3-carboxylate (0.30 g) in toluene (30 mL) was dissolved in triphenylphosphine (0.76 g) at room temperature. ) Was added and stirred for 10 minutes. Thereafter, the mixture was cooled in an ice bath under a nitrogen atmosphere, and 1,1 ′-(azodicarbonyl) dipiperidine (0.74 g) was added. After stirring for 1 hour, the temperature was raised to room temperature, and the mixture was further stirred for 12 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (developing solvent: heptane / ethyl acetate = 98/2 to 95/5, volume ratio, the same shall apply hereinafter), and 5- (2- (3-bromophenoxy). ) Ethyl) ethyl isoxazole-3-carboxylate (0.27 g) was obtained as a yellow oil.
¹ H-NMR (500 MHz, CDCl ₃ , δ ppm): 7.17-7.02 (m, 3H), 6.83-6.81 (m, 1H), 6.58 (s, 1H), 4.44 (q, 2H, J = 7.5 Hz), 4.27 (t, 2H, J = 6.5Hz), 3.30 (t, 2H, J = 6.5Hz), 1.41 (t, 3H, J = 7.5Hz)

(2) To a solution of ethyl 5- (2- (3-bromophenoxy) ethyl) isoxazole-3-carboxylate (0.27 g) obtained in (1) above in ethanol (8 mL), hydroxylated. An aqueous solution in which sodium (0.10 g) was dissolved in water (3 mL) was added, and the mixture was stirred at room temperature for 12 hours. 1M hydrochloric acid was added to acidify the reaction solution to precipitate a solid. The solid was filtered, washed with water and dried to give 5- (2- (3-bromophenoxy) ethyl) isoxazole-3-carboxylic acid (0.14 g) as a white solid.
¹ H-NMR (500 MHz, acetone-d6, δ ppm): 7.24 (t, 1H, J = 8.0 Hz), 7.17-7.11 (m, 2H), 6.98 (dd, 1H, J = 9.0 Hz, 2.0 Hz), 6.83 (t, 1H, J = 6.0Hz), 6.71 (s, 1H), 4.42 (t, 2H, J = 6.0Hz), 3.37 (t, 1H, J = 6.0Hz)

(3) To a solution of 5- (2- (3-bromophenoxy) ethyl) isoxazole-3-carboxylic acid (0.14 g) obtained in (2) above dissolved in DMF (5 mL), isobutylamine ( 0.22 mL), 4-methylmorpholine (0.15 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.17 g), and 1-hydroxybenzotriazole monohydrate (0.14 g) And stirred at room temperature for 12 hours. Thereafter, a saturated aqueous ammonium chloride solution and ethyl acetate were added, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (developing solvent: heptane / ethyl acetate = 80/20 to 70/30) to obtain the desired product (45 mg) as a colorless oil.

<Synthesis Example 2>
Synthesis of N-isobutyl-5- (2- (3- (2,4-difluorophenyl) phenoxy) ethyl) isoxazole-3-carboxamide (Compound No. 3-51)

(1) N-isobutyl-5- (2- (3-bromophenoxy) ethyl) isoxazole-3-carboxamide (Compound No. 1-9) (30 mg) with 1,4-dioxane (2 mL) and To a solution dissolved in water (0.5 mL) under a nitrogen atmosphere, 2,4-difluorophenylboronic acid (20 mg), potassium carbonate (30 mg), and tetrakis (triphenylphosphine) palladium (0) (10 mg) and the mixture was stirred at 90 ° C. for 12 hours. Thereafter, a saturated aqueous ammonium chloride solution was added, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: heptane / ethyl acetate = 80/20 to 70/30) to obtain the desired product (12 mg) as a colorless oil.

<Synthesis Example 3>
Synthesis of N-isobutyl-5- (2- (3- (3,3-dimethyl-1-butynyl) phenoxy) ethyl) isoxazole-3-carboxamide (Compound No. 4-4)

  To a solution of N-isobutyl-5- (2- (3-bromophenoxy) ethyl) isoxazole-3-carboxamide (Compound No. 1-9) (0.12 g) in DMF (3.3 ml), 3 , 3-Dimethyl-1-butyne (0.24ml), Copper (I) iodide (6.22mg), Tetrakis (triphenylphosphine) palladium (0) (40mg) and Triethylamine (0.27ml) in a sealed container The mixture was heated to 100 ° C. and stirred for 3 hours. After allowing to cool to room temperature, water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: heptane / ethyl acetate = 90/10 to 70/30) to obtain the desired product (70 mg) as a white solid.

Next, among the compounds of the present invention represented by the formula (I), representative examples of the compound represented by the formula (I-1) are represented in Table 1 and represented by the formula (I-2). Representative examples of the compound are shown in Table 2, representative examples of the compound represented by the formula (I-4a-2) are shown in Table 3, and typical examples of the compound represented by the formula (I-5b) are shown in Table 3. Each is listed in Table 4.
The compounds described as “Oil” in the column of physical properties in Tables 1 to 4 indicate that they are oily. These compounds can be synthesized based on the above synthesis examples or the above-described production method of the compound of the present invention.
In Tables 1 to 4, Me represents methyl and i-Bu represents isobutyl. The substitution position on the benzene ring of R ³ and R ⁴ depends on the number given to the chemical structural formula in the table. In the columns of R ⁴ , R ⁷ and R ⁹ , the compound represented by “-” represents that it is not substituted with each substituent. In addition, a portion indicated by “● (black circle)” in R ¹ represents bonding to a nitrogen atom at the portion. When R ¹ and R ² together with the adjacent nitrogen atom form a cyclic structure that may be substituted with Z, the portion where the cyclic structure is bonded to the carbonyl group is represented by a wavy line as follows.

For some of the compounds of the present invention, ¹ H-NMR data [measured by ¹ H-nuclear magnetic resonance spectroscopy; δ is a chemical shift value (ppm). Are shown in Tables 5 and 6.

Below, the test example of this invention is described.
Test Example 1 Effect test on wing mite (young ticks) A solution prepared so that the concentration of the compound of the present invention was 100 ppm was coated on a plastic vial. After air drying, 20 juvenile ticks were placed and allowed to stand under constant dark conditions at 25 ° C. and relative humidity of 80-100%. The number of ticks that died 24 hours after drug contact was recorded, and the mortality (%) was determined by the following formula. As a result, the compound no. 1-9, 1-18, 1-26, 1-30, 1-42, 1-65, 1-69, 3-51, 3-61, 4-4, 4-19, 4-20, 4- 22 showed a mortality rate of 85% or more.
Mortality rate (%) = Number of ticks died / Total number of ticks × 100

  Next, formulation examples when the compound of the present invention is used as an animal ectoparasite control agent are described.

Formulation Example 1 Transdermal solvent (1) Compound of the present invention 1 part by weight (2) Propylene glycol 10 parts by weight (3) Isopropanol 89 parts by weight

Formulation Example 2 Transdermal solvent (1) Compound of the present invention 5 parts by weight (2) Hexylene glycol 50 parts by weight (3) Isopropanol 45 parts by weight

Formulation Example 3 Transdermal solvent (1) Compound of the present invention 5 parts by weight (2) Propylene glycol monomethyl ether 50 parts by weight (3) Dipropylene glycol 45 parts by weight

Formulation Example 4 Solvent for transdermal administration (1) Compound of the present invention 10 parts by weight (2) Diethylene glycol monoethyl ether 90 parts by weight

  The compound of the present invention has a high control effect on animal ectoparasites and is useful as an animal ectoparasite control agent.

Claims (14)

A substituted isoxazole-3-carboxylic acid amide compound represented by the formula (I) or a salt thereof.

[Wherein, R ¹ represents a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino, mercaptoalkyl, alkylthioalkyl, cyanoalkyl. , Alkylcarbonylalkyl, Y, or alkyl substituted with Y;
Y is a saturated or unsaturated cyclic group that may be substituted with Z;
Z is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, alkoxycarbonylamino or nitro;
R ² is a hydrogen atom, alkyl, alkylcarbonyl or alkylcarbonylalkyl;
Alternatively, R ¹ and R ² may be combined with the adjacent nitrogen atom to form a cyclic structure that may be substituted with Z, and the cyclic structure may be further substituted with an alkyl atom, May contain one heteroatom selected from oxygen and sulfur atoms;
R ³ is

Is;
R ⁴ and R ⁷ are each independently halogen, alkyl, haloalkyl, alkenyl, alkynyl optionally substituted with R ⁸ , alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl , alkylsulfonyl, haloalkylsulfonyl, amino, monoalkylamino, dialkylamino, pentafluorosulfanyl, cyano, nitro, optionally substituted with R ⁹ phenoxy, substituted phenyl or R ⁹ may be substituted by R ⁹ A good heterocyclic group;
R ⁵ and R ⁶ are each independently a hydrogen atom, halogen, alkyl or haloalkyl;
R ⁸ is halogen, alkoxy, alkylcarbonyl, alkoxycarbonyl, amino, monoalkylamino, dialkylamino, trialkylsilyl, or a saturated or unsaturated cyclic group which may be substituted with Z, and the cyclic group is alkyl 1 or 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom which may be substituted with
R ⁹ is halogen, alkyl, haloalkyl, alkenyl, alkynyl optionally substituted with R ⁸ , alkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, Amino, monoalkylamino, dialkylamino, pentafluorosulfanyl, cyano or nitro;
m is an integer from 0 to 5; n is an integer from 0 to 3. ] The compound or its salt of Claim 1 represented by a formula (I-1).

[Wherein R ¹ , R ² , R ⁴ and m are as defined in claim 1. ] R ¹ is a hydrogen atom, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylamino, dialkylamino, mercaptoalkyl, alkylthioalkyl, cyanoalkyl, Y, or Alkyl substituted with Y;
Y is a saturated or unsaturated cyclic group that may be substituted with Z;
Z is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano or nitro;
R ² is a hydrogen atom, alkyl or alkylcarbonyl;
R ⁴ is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, amino, monoalkylamino, dialkylamino, cyano or nitro;
m is an integer of 0-3, The compound or its salt of Claim 2. The compound or a salt thereof according to claim 2, wherein R ¹ is a hydrogen atom, alkyl, Y, or alkyl substituted with Y. The compound or a salt thereof according to claim 1, wherein R ² is a hydrogen atom, alkyl or alkylcarbonyl. R ⁴ is halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylthio, haloalkylthio, alkylsulfinyl, alkylsulfonyl, amino, dialkylamino, cyano, nitro or phenyl optionally substituted by R ⁹ Item 12. The compound according to Item 1 or a salt thereof. The compound or a salt thereof according to claim 6, wherein R ⁴ is halogen, haloalkyl, alkoxy, haloalkoxy, or phenyl optionally substituted by R ⁹ . The compound or its salt of Claim 1 represented by a formula (I-2).

[Wherein R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ and n are as defined in claim 1. ] The compound or its salt of Claim 2 represented by a formula (I-3).

[Wherein R ¹ , R ² , R ⁴ and R ⁹ are as defined in claim 1, p is an integer of 0 to 4; q is an integer of 0 to 5]. ] The compound or its salt of Claim 2 represented by a formula (I-4).

[Wherein, Het is a heterocyclic group which may be substituted with R ⁹ , R ¹ , R ² , R ⁴ and R ⁹ are as defined in claim 1, and p is 0 to 0] It is an integer of 4. ] The compound or its salt of Claim 2 represented by a formula (I-5).

[Wherein R ^8a is a hydrogen atom, alkyl or R ⁸ ; R ¹ , R ² , R ⁴ and R ⁸ are as defined in claim 1, and p is an integer of 0 to 4] is there. ]   An animal ectoparasite control agent comprising the compound according to claim 1 or a salt thereof as an active ingredient.   A method for controlling ectoparasites of animals by applying an effective amount of the compound or salt thereof according to claim 1.   Use of the compound according to claim 1 or a salt thereof for controlling animal ectoparasites.