Benzimidazole compound or its salts, canine filariasis control agent containing the compound, and method for using the same

Abstract

The present invention addresses the problem of providing a canine filariasis control agent for animals that exerts excellent efficacy when administered to a target animal, and a method of the use of a canine filariasis control agent in a target animal with the use of aforesaid agent.　The present invention provides a benzimidazole compound represented by general formula (1) [wherein: R represents a hydrogen atom, an alkyl group, etc.; Y1, Y2, Y3, Z1 and Z4 represent a hydrogen atom, etc.; Z2 and Z3 represent a hydrogen atom, a halogen atom, etc.; R1 represents a haloalkyl group, etc.; and X represents an oxygen atom, etc.] or a salt thereof, a canine filariasis control agent for animals comprising the same as an active ingredient, a method of the use thereof, etc.

Description

Technical Field

[0001] The present invention relates to a benzimidazole compound or a salt thereof, a canine filariasis control agent for animals containing the compound as an active ingredient, and a method for using the same.

Background Art

[0002] Canine filariasis infection is caused by canine filaria transmitted by mosquitoes and occurs in many animal species and pets. The mechanism is that when mosquitoes ingest microfilariae (newly hatched larval stage), they repeatedly molt in the body and grow into infective larvae (L3). When the infective larvae reach the host skin when the mosquito feeds on the animal, the larvae invade and start growing in the animal body. The infective larvae molt within 3 to 12 days and enter the fourth stage (L4). After staying in the subcutaneous tissue, abdomen and chest for about 2 months, the L4 larvae undergo the final molt to become young adults and reach the host's heart and pulmonary artery about 70 to 120 days after the initial infection.

[0003] On the other hand, it has been reported that a benzimidazole compound having a pyridyl group at the 2-position and a sulfonyl group at the 2-position is effective in controlling external or internal parasites in animals (see, for example, Patent Document 1). However, in such documents, there is no disclosure at all regarding a benzimidazole compound having a pyridyl group at the 2-position and a substituent such as an alkyl group at the 1-position and the insecticidal effect of the compound against canine filaria.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Conventionally, melarsomine dihydrochloride has been known as a canine filariasis control agent, and it is effective against mature (adult) and immature canine filaria. In addition, canine filaria infection can be prevented by macrolide prophylactic agents, and year-round prevention is recommended regardless of the animal's breeding conditions. Due to such long-term use in animals, there is concern about the development of resistance to existing drugs, and there is a demand for the provision of a new drug that has activity against canine filaria and can be used to treat infections caused by it.

Means for Solving the Problems

[0006] As a result of intensive studies to solve the above problems, the inventors of the present application have found that a benzimidazole compound represented by the general formula (1) having a pyridyl group bonded to the 2-position and a substituent such as an alkyl group at the 1-position, or a salt thereof, not only has an excellent canine filariasis control effect but also can solve the above problems, leading to the present invention. That is, the present invention is [1] General formula (1)

Chemical formula

Effect of the Invention

[0007] The benzimidazole compound or a salt thereof which may have an N-alkyl group or the like to which a pyridyl group is bonded at the 2-position of the present invention has excellent effects as a canine strongyloidiasis control agent.

Mode for Carrying Out the Invention

[0008] In the definition of the general formula (1) of the benzimidazole compound or a salt thereof which may have an N-alkyl group or the like to which a pyridyl group is bonded at the 2-position of the present invention, "halo" means "halogen atom", and represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0009] The "(C1-C6) alkyl group" refers to a linear or branched alkyl group having 1 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, a 3,3-dimethylbutyl group, etc. The "(C2-C6) alkenyl group" refers to a linear or branched alkenyl group having 2 to 8 carbon atoms, such as a vinyl group, an allyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group, a 2-methyl-2-propenyl group, a 1-methyl-2-propenyl group, a 2-methyl-1-propenyl group, a pentenyl group, a 1-hexenyl group, a 3,3-dimethyl-1-butenyl group, etc. The "(C2-C6) alkynyl group" refers to a linear or branched alkynyl group having 2 to 8 carbon atoms, such as an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group, a 3-methyl-1-propynyl group, a 2-methyl-3-propynyl group, a pentynyl group, a 1-hexynyl group, a 3-methyl-1-butynyl group, a 3,3-dimethyl-1-butynyl group, etc.

[0010] The "(C3-C6) cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc. The "(C1-C6) alkoxy group" refers to a linear or branched alkoxy group having 1 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, a 1,1,2-trimethylpropyloxy group, etc.

[0011] Examples of the “(C1-C6) alkylthio group” include linear or branched alkylthio groups having 1 to 6 carbon atoms such as methylthio group, ethylthio group, normal propylthio group, isopropylthio group, normal butylthio group, secondary butylthio group, tertiary butylthio group, normal pentylthio group, isopentylthio group, tertiary pentylthio group, neopentylthio group, 2,3-dimethylpropylthio group, 1-ethylpropylthio group, 1-methylbutylthio group, normal hexylthio group, isohexylthio group, 1,1,2-trimethylpropylthio group, etc. Examples of the “(C1-C6) alkylsulfinyl group” include linear or branched alkylsulfinyl groups having 1 to 6 carbon atoms such as methylsulfinyl group, ethylsulfinyl group, normal propylsulfinyl group, isopropylsulfinyl group, normal butylsulfinyl group, secondary butylsulfinyl group, tertiary butylsulfinyl group, normal pentylsulfinyl group, isopentylsulfinyl group, tertiary pentylsulfinyl group, neopentylsulfinyl group, 2,3-dimethylpropylsulfinyl group, 1-ethylpropylsulfinyl group, 1-methylbutylsulfinyl group, normal hexylsulfinyl group, isohexylsulfinyl group, 1,1,2-trimethylpropylsulfinyl group, etc. Examples of the “(C1-C6) alkylsulfonyl group” include linear or branched alkylsulfonyl groups having 1 to 6 carbon atoms such as methylsulfonyl group, ethylsulfonyl group, normal propylsulfonyl group, isopropylsulfonyl group, normal butylsulfonyl group, secondary butylsulfonyl group, tertiary butylsulfonyl group, normal pentylsulfonyl group, isopentylsulfonyl group, tertiary pentylsulfonyl group, neopentylsulfonyl group, 2,3-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group, 1-methylbutylsulfonyl group, normal hexylsulfonyl group, isohexylsulfonyl group, 1,1,2-trimethylpropylsulfonyl group, etc.

[0012] One or more halogen atoms may be substituted at the position where the above-mentioned “(C1-C6) alkyl group”, “(C2-C6) alkenyl group”, “(C2-C6) alkynyl group”, “(C3-C6) cycloalkyl group”, “(C1-C6) alkoxy group”, “(C1-C6) alkylthio group”, “(C1-C6) alkylsulfinyl group”, or “(C1-C6) alkylsulfonyl group” can be substituted. When there are two or more halogen atoms to be substituted, the halogen atoms may be the same or different. They are respectively denoted as “halo (C1-C6) alkyl group”, “halo (C2-C6) alkenyl group”, “halo (C2-C6) alkynyl group”, “halo (C3-C6) cycloalkyl group”, “halo (C1-C6) alkoxy group”, “halo (C1-C6) alkylthio group”, “halo (C1-C6) alkylsulfinyl group”, or “halo (C1-C6) alkylsulfonyl group”.

[0013] Expressions such as “(C1-C6)”, “(C2-C6)”, and “(C3-C6)” indicate the range of the number of carbon atoms of various substituents. Furthermore, the above definition can also be shown for the group to which the above substituent is linked. For example, in the case of “(C1-C6) alkoxy (C1-C6) alkyl group”, it indicates that a linear or branched alkoxy group with 1 to 6 carbon atoms is bonded to a linear or branched alkyl group with 1 to 6 carbon atoms.

[0014] Examples of the “(C1-C6) alkoxycarbonyl group” include linear or branched alkoxycarbonyl groups composed of an alkoxy group having 1 to 6 carbon atoms and a carbonyl group, such as methoxycarbonyl group, ethoxycarbonyl group, normal propoxycarbonyl group, isopropoxycarbonyl group, normal butoxycarbonyl group, secondary butoxycarbonyl group, tertiary butoxycarbonyl group, normal pentyloxycarbonyl group, isopentyloxycarbonyl group, tertiary pentyloxycarbonyl group, neopentyloxycarbonyl group, 2,3-dimethylpropyloxycarbonyl group, 1-ethylpropyloxycarbonyl group, 1-methylbutyloxycarbonyl group, normal hexyloxycarbonyl group, isohexyloxycarbonyl group, 1,1,2-trimethylpropyloxycarbonyl group, etc.

[0015] The “aryl group” refers to an aromatic hydrocarbon group having 6 to 10 carbon atoms, such as phenyl group, 1-naphthyl group, 2-naphthyl group, etc.

[0016] Examples of the salts of the benzimidazole compound represented by the general formula (1) of the present invention include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, etc., organic acid salts such as acetate, fumarate, maleate, oxalate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc., and salts with inorganic or organic bases such as sodium ion, potassium ion, calcium ion, trimethylammonium, etc.

[0017] The benzimidazole compound represented by the general formula (1) of the present invention or its salts may have one asymmetric center in its structural formula, and the present invention includes all of the respective optical isomers and mixtures containing them in any ratio. Further, the benzimidazole compound represented by the general formula (1) of the present invention or its salts may have two geometric isomers derived from a carbon-carbon double bond in its structural formula, and the present invention includes all of the respective geometric isomers and mixtures containing them in any ratio. Furthermore, the benzimidazole compound represented by the general formula (1) of the present invention or its salts may have tautomers in its structural formula, and the present invention includes all of the respective tautomers and mixtures containing them in any ratio.

[0018] In the benzimidazole compound represented by the general formula (1) or its salts, which is the active ingredient of the canine filariasis control agent of the present invention, R is preferably (a1) a hydrogen atom; (a2) a (C1-C6) alkyl group; (a3) a halo(C1-C6)alkyl group; (a4) a (C2-C6) alkenyl group; (a5) a (C2-C6) alkynyl group; (a6) a (C1-C6) alkoxy(C1-C6)alkyl group; (a7) a (C1-C6) alkylthio(C1-C6)alkyl group; (a8) a (C1-C6) alkoxycarbonyl(C1-C6)alkyl group; (a9) a (C1-C6) alkoxycarbonyl group; (a11) an aryl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a12) an aryl(C1-C6)alkyl group; (a13) an aryl(C1-C6)alkyl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a14) an aryl(C2-C6)alkenyl group; (a16) an aryl(C1-C6)alkoxy(C1-C6)alkyl group; (a20) R 3 R 4 an N-thiocarbonyl group (where R 3 and R 4 are the same as above); or (a21) R 3 R 4 an N-sulfonyl group (where R 3and R 4 is the same as above); and R 1 is preferably, (b1) a (C1-C6) alkyl group; (b2) a halo(C1-C6)alkyl group; (b3) a (C3-C6) cycloalkyl group; (b5) an aryl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; or (b9) an aryl(C1-C6)alkyl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, ((l) a nitro group, and (m) a trimethylsilyl group; and Y 1 Y 2 and Y 3 are preferably both (c1) a hydrogen atom; and Z 1 and Z 4 are preferably the same or different and are (d1) a hydrogen atom; (d2) a halogen atom; or (d3) a (C1-C6) alkyl group; and Z 2 and Z 3Preferably, they may be the same or different, and include (e1) a hydrogen atom; (e2) a halogen atom; (e3) a (C1-C6) alkyl group; (e4) a (C1-C6) alkoxy group; (e5) a halo (C1-C6) alkyl group; (e6) a halo (C1-C6) alkoxy group; (e7) an aryloxy group; or (e9) an arylcarbonyl group. Preferably, X is an oxygen atom.

[0019] The benzimidazole compounds represented by general formulas (1) and (1-1) or salts thereof, which are the active ingredients of the canine strongyloidiasis control agent of the present invention, can be produced, for example, by the following production methods, but the present invention is not limited thereto.

[0020] Production Method 1

Chemical Formula

[0021] Production Method of Step [A] The nitrile compound represented by general formula (2-2) can be produced by reacting the compound represented by general formula (2-3) with the compound represented by general formula (4) in the presence of a base and an inert solvent.

[0022] Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; acetate salts such as sodium acetate and potassium acetate; alkali metal alkoxides such as potassium t-butoxide, sodium methoxide, and sodium ethoxide; tertiary amines such as triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undec-7-ene; and nitrogen-containing aromatic compounds such as pyridine and dimethylaminopyridine. The amount used is usually in the range of 1 to 10 times the molar amount of the compound represented by general formula (4).

[0023] The inert solvent used in this reaction may be any that does not significantly inhibit the progress of this reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, etc., chain or cyclic ethers such as diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, etc., esters such as ethyl acetate, etc., amides such as dimethylformamide, dimethylacetamide, etc., ketones such as acetone, methyl ethyl ketone, etc., polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc. can be exemplified as inert solvents, and these inert solvents can be used alone or in admixture of two or more.

[0024] Since this reaction is an equimolar reaction, each reactant may be used in an equimolar amount, but any of the reactants may also be used in excess. The reaction temperature can be carried out from room temperature to the boiling point range of the inert solvent used, and the reaction time is not constant depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.

[0025] After completion of the reaction, the target product can be isolated from the reaction system containing the target product by a conventional method, and if necessary, the target product can be produced by purification with recrystallization, column chromatography, etc. Also, the next step may be carried out without isolating the intermediate from the reaction system.

[0026] Production method of step [B] The carboxylic acid compound represented by the general formula (2-1) can be produced by reacting the nitrile compound represented by the general formula (2-2) in the presence of a base and an inert solvent.

[0027] Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc., and acetate salts such as sodium acetate, potassium acetate, etc., and the amount used is usually in the range of 1 to 10 times the molar amount of the compound represented by the general formula (2-2).

[0028] As the inert solvent used in this reaction, any solvent that does not significantly inhibit the progress of this reaction may be used. For example, alcohols such as methanol, ethanol, propanol, and isopropanol; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; chain or cyclic ethers such as diethyl ether, methyl tert-butyl ether, dioxane, and tetrahydrofuran; amides such as dimethylformamide and dimethylacetamide; ketones such as acetone and methyl ethyl ketone; polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone; and water can be exemplified. These inert solvents can be used alone or in a mixture of two or more.

[0029] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by a conventional method, and if necessary, the target product can be produced by purification using recrystallization, column chromatography, etc.

[0030] Production method of step [C] The amide compound represented by the general formula (2) can be produced by reacting the carboxylic acid compound represented by the general formula (2-1) with the diamino compound represented by the general formula (3) in the presence of a condensing agent, a base, and an inert solvent.

[0031] Examples of the condensing agent used in this reaction include diethyl cyanophosphate (DEPC), carbonyldiimidazole (CDI), 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), chloro carbonates, 2-chloro-1-methylpyridinium iodide, etc. The amount used can be appropriately selected from the range of 1 to 1.5 times the molar amount of the compound represented by the general formula (2-1).

[0032] Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.; acetate salts such as sodium acetate, potassium acetate, etc.; alkali metal alkoxides such as potassium t-butoxide, sodium methoxide, sodium ethoxide, etc.; tertiary amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, etc.; nitrogen-containing aromatic compounds such as pyridine, dimethylaminopyridine, etc. The amount used is usually in the range of 1 to 10 times the molar amount of the compound represented by the general formula (2-1).

[0033] The inert solvent used in this reaction may be any that does not significantly inhibit the progress of this reaction. Examples include aromatic hydrocarbons such as benzene, toluene, xylene, etc.; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc.; halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, etc.; chain or cyclic ethers such as diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, etc.; esters such as ethyl acetate, etc.; amides such as dimethylformamide, dimethylacetamide, etc.; ketones such as acetone, methyl ethyl ketone, etc.; polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, etc., and inert solvents such as nitrogen-containing aromatic compounds such as pyridine. These inert solvents can be used alone or in combination of two or more.

[0034] Since this reaction is an equimolar reaction, each reactant can be used in an equimolar amount, but any reactant can also be used in excess. The reaction temperature can be carried out from room temperature to the boiling point range of the inert solvent used, and the reaction time is not fixed depending on the reaction scale and reaction temperature, but can be in the range of several minutes to 48 hours.

[0035] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by a conventional method, and if necessary, the target product can be produced by purification using recrystallization, column chromatography, etc. Also, the next step may be carried out without isolating the intermediate from the reaction system.

[0036] Production method of step [D] The benzimidazole compound represented by the general formula (1-1) can be produced by reacting the amide compound represented by the general formula (2) in the presence or absence of an acid and an inert solvent.

[0037] Examples of the acid used in this reaction include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, and benzoic acid; sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid; and phosphoric acid. The amount used can be appropriately selected from the range of 0.01 to 50 times the molar amount of the amide compound represented by the general formula (2).

[0038] The inert solvent used in this reaction may be any solvent that does not significantly inhibit the progress of the reaction. Examples include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; chain or cyclic ethers such as diethyl ether, methyl tert-butyl ether, dioxane, and tetrahydrofuran; esters such as ethyl acetate; amides such as dimethylformamide and dimethylacetamide; ketones such as acetone and methyl ethyl ketone; and polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone. These inert solvents can be used alone or in a mixture of two or more.

[0039] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by a conventional method, and if necessary, the target product can be produced by purification using recrystallization, column chromatography, etc.

[0040] Manufacturing method of engineering [E] The benzimidazole compound represented by the general formula (1) can be produced by reacting the benzimidazole compound represented by the general formula (1-1) with a compound represented by RL (where L represents a leaving group such as a halogen atom) in the presence of an inert solvent and a base.

[0041] Examples of the base used in this reaction include inorganic bases such as sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc., and acetate salts such as sodium acetate, potassium acetate, etc. The amount used is usually in the range of 1 to 10 moles per mole of the compound represented by the general formula (1-1).

[0042] The amount of the compound represented by RL used is usually in the range of 1 to 10 moles per mole of the compound represented by the general formula (1-1).

[0043] The inert solvent that can be used in this reaction may be any that does not significantly inhibit this reaction. Examples include aromatic hydrocarbons such as benzene, toluene, xylene, etc., halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, etc., halogenated aromatic hydrocarbons such as chlorobenzene, dichlorobenzene, etc., and chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF), dioxane, etc. These inert solvents can be used alone or in a mixture of two or more.

[0044] The reaction temperature in this reaction may usually be in the range from about 0 °C to the boiling point of the solvent used. The reaction time varies depending on the reaction scale, reaction temperature, etc., and is not constant, but can be appropriately selected in the range of several minutes to 48 hours.

[0045] After the reaction is completed, the target product can be isolated by a conventional method, and if necessary, the target product can be produced by purification by recrystallization, distillation, etc.

[0046] Next, specific examples of the compounds of the present invention and their intermediates are shown below. In the following table, Me represents a methyl group, Et represents an ethyl group, n-Pro represents a normal propyl group, n-Bu represents a normal butyl group, n-Hex represents a normal hexyl group, c-Pen represents a cyclopentyl group, Ph represents a phenyl group, Bn represents a benzyl group, and TMS represents a trimethylsilyl group.

[0047] Physical properties are melting point (°C) or H 1 -NMR. H 1 -NMR data are shown in Tables 4 and 5.

[0048]

Chemical formula

[0049]

Table 1

[0050]

Chemical formula

[0051]

Table 2

[0052]

Table 3

[0053]

Table 4

[0054]

Table 5

[0055] The canine filariasis control agent of the present invention contains a benzimidazole compound represented by the general formula (1) or a salt thereof as an active ingredient. The animals targeted by the canine filariasis control agent of the present invention are livestock such as cattle, pigs, rabbits, and birds, or pets such as dogs, rabbits, or cats (hereinafter referred to as target animals, excluding humans), preferably dogs, but not limited thereto. In the present invention, control includes prevention and treatment.

[0056] Canine filariasis is caused by nematodes of the order Spirurida, specifically, (a) nematodes of the family Onchocercidae, such as Brugia spp. of the genus Brugia, including Brugia malayi, Brugia pahangi, Brugia patei; Dipetalonema spp. of the genus Dipetalonema, including Dipetalonema reconditum; Dirofilaria spp. of the genus Dirofilaria, including Dirofilaria immitis; Filaria spp. of the genus Filaria, including Filaria oculi; Onchocerca spp. of the genus Onchocerca, including Onchocerca cervicalis, Onchocerca gibsoni, Onchocerca gutturosa; (b) nematodes of the family Setariidae, such as Setaria spp. of the genus Setaria, including Setaria digitata, Setaria equina, Setaria labiatopapillosa, Setaria marshalli; Wuchereria spp. of the genus Wuchereria, including Wuchereria bancrofti; (c) nematodes of the family Filariidae, such as Parafilaria spp. of the genus Parafilaria, including Parafilaria multipapillosa; Stephanofilaria spp. of the genus Stephanofilaria) is known to be caused by, but not limited to, Stephanofilaria assamensis, Stephanofilaria dedoesi, Stephanofilaria kaeli, Stephanofilaria okinawaensis, Stephanofilaria stilesi, etc.

[0057] When using the control agent of the present invention, other components may not be added, and the benzimidazole compound may be used as it is. Usually, however, an excipient such as a solid carrier or a liquid carrier is added to the benzimidazole compound or its salts, and tablets, powders, granules, capsules, water-soluble agents, liquids, wettable powders, and suspensions are formulated according to a normal method (for example, the method described in "Pharmaceutics" edited by Akio Otsuka et al., 1995, Nankodo). It is preferably used after being formulated. Examples of excipients that are solid carriers include lactose, sucrose, glucose, corn starch, gelatin, casein, starch, gum arabic, cellulose derivatives, alginic acid, and the like. Examples of excipients that are liquid carriers include water, glycerin, vegetable oils, fatty acids, fatty acid esters, sorbitol, and the like.

[0058] The control agent of the present invention may further contain, for example, organic minerals such as peptide zinc and peptide iron, inorganic minerals such as zinc carbonate, manganese carbonate, iron sulfate, and magnesium carbonate, vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, pantothenic acid, and nicotinic acid, alfalfa meal, and pressed sorghum. In addition, in order to enhance palatability, flavors and the like may be administered simultaneously. If necessary, ordinary additives such as antibacterial agents, antifungal agents, insecticides, antioxidants, pigments, flavoring agents, flavor enhancers, and enzymes may be mixed, and it is preferably formulated into forms such as powders, granules, liquids, tablets, etc. by ordinary methods. These formulations may usually contain a benzimidazole compound or a salt thereof as an active ingredient in a weight ratio of about 0.01 to 95% by weight.

[0059] The control agent of the present invention formulated in this way can be used as it is or diluted with water or the like. Further, other ordinary additives such as antibacterial agents, antifungal agents, insecticides, antioxidants, pigments, flavoring agents, flavor enhancers, and enzymes may be mixed or used in combination simultaneously or non-simultaneously.

[0060] There are no special restrictions on the administration of the control agent of the present invention to the target animals, and it can be carried out by conventionally known methods such as spraying and mixing in the feed as described below. The dosage is an amount effective for the control effect of canine filariasis in the target animals, that is, when other conditions are equal, the amount by which the control effect of canine filariasis in the target animals is enhanced when the control agent of the present invention is administered compared to when it is not administered.

[0061] The method of mixing, gelling, and allowing free intake of the active ingredient of the control agent of the present invention to be administered to the target animals can be carried out either in the hatchery or on the farm. It can also be carried out during the transportation of the target animals from the hatchery to the farm.

[0062] In addition, a gelling preparation in which a powder of a predetermined amount of water-soluble polysaccharide is blended with the active ingredient of the control agent of the present invention is prepared, diluted with water when used in hatcheries and farms to form a gel-like solid, and administered to the target animals (i.e., free intake, direct administration into the crop) can also be carried out.

[0063] The formulated control agent is usually used alone, but can be diluted with water and used as a formulated dilution solution (i.e., drinking water dilution administration). The concentration of the active ingredient in the formulated dilution solution is usually preferably in the range of about 10 to 10,000 ppm, more preferably in the range of about 35 to 5,000 ppm. Examples of the method of administering the formulated dilution solution include a method of dissolving about 0.01 to 500 g of the control agent in 1 L of water and treating it according to the administration volume. Preferably, a method of dissolving about 0.035 to 350 g in 1 L of water and administering it is mentioned.

[0064] To administer the formulated dilution solution thus prepared to the target animals, the formulated dilution solution may be administered using a drinking water addition device or the like. The administration volume of the formulated dilution solution may be appropriately determined according to the size, growth status, breeding density, and administration method of the target animals, etc., but is usually preferably about 300 to 2,000 liters per 10,000 birds.

[0065] The timing and period of administration of the control agent of the present invention are, in the case of egg-laying breeds and meat breeds, preferably administered continuously throughout the entire period of the target animals, preferably during the chick stage (chickens at 0 to 5 weeks old after hatching) or at 0 to 5 weeks after birth.

[0066] The dosage of the control agent may be appropriately determined according to the type and size of the target animals, etc., but generally the total dosage is preferably in the range of 0.005 to 2 g. More preferably, it is in the range of 0.005 to 1 g.

[0067] The control agent composition of the present invention is obtained by adding the above control agent to animal feed, drinking water, physiological electrolyte solution, etc. to form a control agent composition. The addition amount of the control agent is preferably in the range of about 0.005 to 10.0% by weight based on the total amount of the control agent composition.

[0068] The feed, drinking water, or physiological electrolyte solution for target animals used in the control agent composition of the present invention may be any commonly used ones and is not particularly limited. Examples of these include corn, rice, wheat, sorghum, soybean meal, bran, defatted rice bran, fish meal, skim milk powder, dried whey, fats and oils, alfalfa meal, northern ocean meal, soybean oil, powdered refined beef tallow, wheat flour, rapeseed oil, meat and bone meal (feather meal), animal fats and oils, calcium phosphate, corn gluten meal, molasses, corn germ meal, calcium carbonate, tricalcium phosphate, sodium chloride, choline chloride, vitamins (vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin D, vitamin E, calcium pantothenate, nicotinamide, folic acid, etc.), amino acids (lysine, methionine, etc.), trace inorganic salts (magnesium sulfate, iron sulfate, copper sulfate, zinc sulfate, potassium iodide, cobalt sulfate, etc.), probiotics, etc., and feeds prepared by appropriately mixing them.

[0069] In addition, the control agent composition of the present invention may further contain, for example, organic minerals such as zinc peptide and iron peptide, inorganic minerals such as zinc carbonate, manganese carbonate, iron sulfate, and magnesium carbonate, vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, pantothenic acid, and nicotinic acid, alfalfa meal, waxy corn, etc. Also, in order to enhance palatability, flavors and the like may be administered simultaneously.

[0070] There is no particular limitation on the method of administering the control agent composition of the present invention to target animals, and it can be administered by a feeding method using appropriate methods such as spraying and mixing in the feed as described below. The dosage of the control agent composition is, in short, an amount effective for the control effect of canine filariasis in target animals, that is, when other conditions are equal, the amount that enhances the control effect of canine filariasis in target animals when the control agent composition of the present invention is administered compared to when it is not administered.

[0071] The timing and duration of administration of the control agent composition of the present invention are preferably administered continuously throughout the entire period of the target animal in the case of egg-laying breeds and meat breeds, preferably during the chick stage (chickens at 0 to 5 weeks old after hatching) or from birth to 5 weeks old. More preferably, it is administered continuously for 0 to 21 days after hatching or from birth to 21 days old.

[0072] When the control agent composition of the present invention is used by being formulated in feed for target animals, the benzimidazole compound or its salts can be used in a proportion of about 0.0005 to 5% by weight, preferably about 0.05 to 2% by weight. When it is used by being added to drinking water or a physiological electrolyte solution, the benzimidazole compound or its salts can be used in a proportion of about 0.035 to 3.5% by weight, preferably about 0.035 to 1.4% by weight.

[0073] The control method of the present invention includes the step of administering an effective amount of the control agent or the control agent composition of the present invention to the target animal. In this method, the control agent composition can be given to the animal by a usual method. The above-mentioned effective amount varies depending on circumstances such as the type of the preparation, the target animal, and the period of ingestion, and can be appropriately selected by increasing or decreasing without being related to the above range.

[0074] Specifically, for example, it is diluted with water to a concentration suitable for administering the control agent of the present invention to the target animal, and the resulting diluted solution is administered to the target animal. The dilution ratio may be applied according to the conventional drinking water dilution administration method. For example, a diluted solution of about 5 to 10 times is preferably used. Further, the control agent of the present invention is diluted with water to a predetermined concentration, and a water-soluble polysaccharide is added and mixed therewith under stirring to form a uniform solution, which is left at room temperature or stored in a cold place (for example, a refrigerator, etc.) to obtain a gel-like solid. Alternatively, when using a gelling agent (for example, agar, gelatin, etc.) that dissolves at high temperature and solidifies at low temperature, the gelling agent is added in advance to the medium for preparing the control agent of the present invention, the medium is sterilized by high-pressure steam and then cooled, and this is left at room temperature or stored in a cold place (for example, a refrigerator, etc.) to obtain a gel-like solid. The gel-like solid thus obtained may be administered to the target animal. The gel strength in the case of gelation is generally 200 to 2000 g / cm 2 is appropriate. When using agar, it varies depending on the type of agar, but generally corresponds to a concentration of 0.5 to 3.0%.

[0075] Examples of the polysaccharide used for gelling the control agent of the present invention in an aqueous medium include agar, carrageenan, carboxymethyl cellulose, starch, mannan, gelatin, sodium alginate, gum arabic, locust bean gum, xanthan gum, chitosan, guar gum, pectin, propyl glycol alginate, arabinogalactan, ghatti gum, tamarind seed gum, pullulan, morpholine fatty acid salt, curdlan, tragacanth gum, etc. Among these polysaccharides, it is particularly preferable to use agar, starch, mannan, and gelatin from the viewpoints of low cost and easy availability.

[0076] For example, when the gel-like solid is administered to poultry, if it is administered to poultry at approximately 0 to 7 days old with low drinking water volume and feed intake, the genetic program (habit) of the poultry that tries to ingest the solids on the floor with its beak can efficiently ingest the required amount of the control agent of the present invention in a short time. At this time, if probiotics, vaccines, drugs, nutrients, etc. that were difficult to administer to young poultry as described above are mixed with the control agent of the present invention as needed and gelled with a water-soluble polysaccharide, they can also be efficiently administered to poultry simultaneously with the control agent of the present invention. In addition, the supply of water and nutrients during the chick stage is extremely important for subsequent productivity. When administering nutrients, carbohydrates such as monosaccharides such as glucose, mannose, fructose and their oligosaccharides, disaccharides such as sucrose, proteins such as skim milk, lipids, and in addition, vitamins, minerals, etc. can be mentioned.

[0077] In addition, existing canine filariasis control agents can also be used in combination for the purpose of reinforcing or complementing the effects of the canine filariasis control agent of the present invention. In the case of combined use, a preparation in which two or more active ingredients are mixed before administration may be used, or two or more different preparations may be administered separately.

Examples

[0078] Hereinafter, the present invention will be described in more detail with reference to production examples, formulation examples and test examples of the present invention, but the present invention is not limited to these examples in any way.

[0079] Reference Example 1. Method for producing 5-cyano-2-(2,2,3,3,3-pentafluoropropyloxy)pyridine

Chemical formula

[0080] Reference Example 2. Method for producing 6-(2,2,3,3,3-pentafluoropropyloxy)nicotinic acid

Chemical formula

[0081] Production Example 1. Method for producing 5,6-dibromo-2-(6-(2,2,3,3,3-pentafluoropropyloxy)pyridin-3-yl)benzimidazole (Compound No. 1-5)

Chemical formula

[0082] Production Example 2. Method for producing 5,6-dibromo-2-(6-(2,2,3,3,3-pentafluoropropyloxy)pyridin-3-yl)-1-methylbenzimidazole (Compound No. 2-58)

Chemical formula

[0083] Formulation Example 1. Powder 25 parts of the benzimidazole compound and 25 parts of lactose were well mixed in a mortar, and then the mixture was thoroughly stirred and mixed to obtain a powder.

[0084] Formulation Example 2. Granules Add 25 parts of the benzimidazole compound and 25 parts of lactose, and stir and mix well. Next, add an appropriate amount of water to these mixtures, stir further, then granulate this with a granulator and dry by ventilation to obtain granules.

[0085] Formulation Example 3. Wettable powder Mix 25 parts of the benzimidazole compound, 65 parts of diatomaceous earth, 5 parts of a higher alcohol sulfate ester, and 5% of an alkylnaphthalene sulfonate uniformly and pulverize finely to obtain a wettable powder.

[0086] Test Example 1. Evaluation test on the effect on the larval movement of Dirofilaria immitis Inoculate 500 L-1 stage larvae of Dirofilaria immitis diluted in a predetermined preparation solution into each well of a 96-well plate, and add a DMSO dilution solution of the benzimidazole compound represented by the general formula (1) of the present invention or its salts to make the final concentration 50 ppm. Then, leave it standing for 3 days and investigate its motility. Based on the inhibitory power of the DMSO solution alone, the motility inhibition rate of each treatment group was corrected and calculated, and the determination was made according to the following criteria.

[0087] Determination criteria A... Corrected motility inhibition rate 100% B... Corrected motility inhibition rate 99% - 90% C... Corrected motility inhibition rate 89% - 80% D... Corrected motility inhibition rate 79% - 50%

[0088] As a result, 1-1, 1-3, 1-4, 1-5, and 2-58 of the compounds of the present invention showed activity of A.

[0089] Test Example 2. Evaluation test on the effect on the development of Dirofilaria immitis For each hole of the 24-hole plate, a predetermined preparation solution, 8 to 20 L-3 stage larvae of canine filarial worms, and a DMSO dilution solution of the benzimidazole compound of the present invention were added to make the final concentration 50 ppm. Seven days later, the larvae that had developed into the L-4 stage were counted, and the growth inhibition rate from L3 stage larvae to L4-stage larvae was calculated.

[0090] As a result, among the compounds represented by the general formula (1) of the present invention, the compounds of compound numbers 1-5, 2-5, 2-7, 2-18, 2-20, 2-22 and 2-25 showed a growth inhibition rate of 50% or more.

Industrial Applicability

[0091] According to the present invention, it is possible to provide a canine filarial worm control agent for target animals that exhibits excellent effects when administered to target animals, and a method for using the canine filarial worm control agent for target animals using the same.

Claims

1. General formula (1) 【Chemical 1】 {In the formula,[[]] R is,[[]] (a1) a hydrogen atom; (a2) (C １ -C ６ ) alkyl group; (a3) Halo (C １ -C ６ ) alkyl group; (a4) (C ２ -C ６ ) alkenyl group; (a5) (C ２ -C ６ ) alkynyl group; (a6) (C １ -C ６ ) alkoxy (C １ -C ６ ) alkyl group; (a7) (C １ -C ６ ) alkylthio (C １ -C ６ ) alkyl group; (a8) (C １ -C ６ ) alkoxycarbonyl (C １ -C ６ ) alkyl group; (a9) (C １ -C ６ ) alkoxycarbonyl group; (a10) an aryl group; (a11) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )alkyl group, (c) a halo(C １ -C ６ )alkyl group, (d) a (C １ -C ６ )alkoxy group, (e) a halo(C １ -C ６ )alkoxy group, (f) a (C １ -C ６ )alkylthio group, (g) a halo(C １ -C ６ )alkylthio group, (h) a (C １ -C ６ )alkylsulfinyl group, (i) a halo(C １ -C ６ )alkylsulfinyl group, (j) a (C １ -C ６ )alkylsulfonyl group, (k) a halo(C １ -C ６ )alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; an aryl group having 1 to 5 substituents selected therefrom. (a12) aryl (C １ -C ６ ) alkyl group; (a13) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and is an aryl(C １ -C ６ )-alkyl group having 1 to 5 substituents selected therefrom; (a14) aryl (C ２ -C ６ ) alkenyl group; (a15) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and has 1 to 5 substituents selected therefrom, and an aryl(C ２ -C ６ )-alkenyl group; (a16) aryl (C １ -C ６ ) alkoxy (C １ -C ６ ) alkyl group; (a17) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and has 1 to 5 substituents selected from aryl(C １ -C ６ )-alkoxy(C １ -C ６ )-alkyl group; (a18) R ３ R ４ N group (where R ３ and R ４ may be the same or different, (aa) a hydrogen atom, (ab) a (C １ -C ６ alkyl group, (ac) a (C １ -C ６ alkoxy group, (ad) a (C １ -C ６ alkoxycarbonyl group, (ae) a (C １ -C ６ alkylsulfonyl group, (af) halo(C １ -C ６ alkylsulfonyl group, or (ag) a phenyl group.)); (a19) R ３ R ４ N-carbonyl group (where R ３ and R ４ are the same as above); (a20) R ３ R ４ N-thiocarbonyl group (where R ３ and R ４ are the same as above); or (a21) R ３ R ４ N-sulfonyl group (where R ３ and R ４ are the same as above); is shown. R １ is (b1) (C １ -C ６ ) alkyl group; (b2) Halo (C １ -C ６ ) alkyl group; (b3) (C ３ -C ６ ) cycloalkyl group; (b4) an aryl group; (b5) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; an aryl group having 1 to 5 substituents selected therefrom. (b6) (C ２ -C ６ ) alkenyl group; (b7) (C ２ -C ６ ) alkynyl group; (b8) aryl (C １ -C ６ ) alkyl group; or (b9) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )alkyl group, (c) a halo(C １ -C ６ )alkyl group, (d) a (C １ -C ６ )alkoxy group, (e) a halo(C １ -C ６ )alkoxy group, (f) a (C １ -C ６ )alkylthio group, (g) a halo(C １ -C ６ )alkylthio group, (h) a (C １ -C ６ )alkylsulfinyl group, (i) a halo(C １ -C ６ )alkylsulfinyl group, (j) a (C １ -C ６ )alkylsulfonyl group, (k) a halo(C １ -C ６ )alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and is an aryl(C １ -C ６ )alkyl group having 1 to 5 substituents selected therefrom; is shown. Y １ , Y ２ , and Y ３ may be the same or different, (c1) a hydrogen atom; (c2) (C １ -C ６ ) alkyl group; or (c3) Halo (C １ -C ６ ) alkyl group; is shown. Z １ and Z ４ may be the same or different, (d1) a hydrogen atom; (d2) a halogen atom; or (d3) (C １ -C ６ ) alkyl group; is shown. Z ２ and Z ３ may be the same or different, (e1) a hydrogen atom; (e2) a halogen atom; (e3) (C １ -C ６ ) alkyl group; (e4) (C １ -C ６ ) alkoxy group; (e5) Halo (C １ -C ６ ) alkyl group; (e6) Halo (C １ -C ６ ) alkoxy group; (e7) an aryloxy group; (e8) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ ) alkyl group, (c) a halo(C １ -C ６ ) alkyl group, (d) a (C １ -C ６ ) alkoxy group, (e) a halo(C １ -C ６ ) alkoxy group, (f) a (C １ -C ６ ) alkylthio group, (g) a halo(C １ -C ６ ) alkylthio group, (h) a (C １ -C ６ ) alkylsulfinyl group, (i) a halo(C １ -C ６ ) alkylsulfinyl group, (j) a (C １ -C ６ ) alkylsulfonyl group, (k) a halo(C １ -C ６ ) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; an aryloxy group having 1 to 5 substituents selected therefrom (e9) an arylcarbonyl group; or (e10) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ ) alkyl group, (c) a halo(C １ -C ６ ) alkyl group, (d) a (C １ -C ６ ) alkoxy group, (e) a halo(C １ -C ６ ) alkoxy group, (f) a (C １ -C ６ ) alkylthio group, (g) a halo(C １ -C ６ ) alkylthio group, (h) a (C １ -C ６ ) alkylsulfinyl group, (i) a halo(C １ -C ６ ) alkylsulfinyl group, (j) a (C １ -C ６ ) alkylsulfonyl group, (k) a halo(C １ -C ６ ) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and represents an arylcarbonyl group having 1 to 5 substituents selected therefrom. X is an oxygen atom, a sulfur atom, or R ３ N (where R ３ is the same as above); is shown. However, R １ is a 2,2,3,3,3-pentafluoropropyl group, and compounds in which R, Y １ , Y ２ , Y ３ , Z １ , Z ２ , Z ３ , and Z ４ are hydrogen atoms and X is an oxygen atom are excluded.} A canine filarial worm disease control agent for animals, characterized by containing a benzimidazole compound represented by the formula or a salt thereof as an active ingredient.

2. R is,[[]] (a1) a hydrogen atom; (a2) (C １ -C ６ ) alkyl group; (a3) Halo (C １ -C ６ ) alkyl group; (a4) (C ２ -C ６ ) alkenyl group; (a5) (C ２ -C ６ ) alkynyl group; (a6) (C １ -C ６ ) alkoxy (C １ -C ６ ) alkyl group; (a7) (C １ -C ６ ) alkylthio(C １ -C ６ ) alkyl group; (a8) (C １ -C ６ ) alkoxycarbonyl (C １ -C ６ ) alkyl group; (a9) (C １ -C ６ ) alkoxycarbonyl group; (a11) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; an aryl group having 1 to 5 substituents selected therefrom. (a12) aryl (C １ -C ６ ) alkyl group; (a13) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and has 1 to 5 substituents selected therefrom, and is an aryl(C １ -C ６ )-alkyl group; (a14) aryl (C ２ -C ６ ) alkenyl group; (a16) aryl (C １ -C ６ ) alkoxy (C １ -C ６ ) alkyl group; (a20) R ３ R ４ N-thiocarbonyl group (where R ３ and R ４ are the same as above); or (a21) R ３ R ４ N-sulfonyl group (where R ３ and R ４ are the same as above); is shown, R １ is (b1) (C １ -C ６ ) alkyl group; (b2) Halo (C １ -C ６ ) alkyl group; (b3) (C ３ -C ６ ) cycloalkyl group; (b5) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and has 1 to 5 substituents; or (b9) may be the same or different, and is selected from (a) a halogen atom, (b) a (C １ -C ６ )-alkyl group, (c) a halo(C １ -C ６ )-alkyl group, (d) a (C １ -C ６ )-alkoxy group, (e) a halo(C １ -C ６ )-alkoxy group, (f) a (C １ -C ６ )-alkylthio group, (g) a halo(C １ -C ６ )-alkylthio group, (h) a (C １ -C ６ )-alkylsulfinyl group, (i) a halo(C １ -C ６ )-alkylsulfinyl group, (j) a (C １ -C ６ )-alkylsulfonyl group, (k) a halo(C １ -C ６ )-alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, and represents an aryl(C １ -C ６ )-alkyl group having 1 to 5 substituents selected therefrom; Y １ , Y ２ , and Y ３ both represent (c1) a hydrogen atom; Z １ and Z ４ may be the same or different, (d1) a hydrogen atom; (d2) a halogen atom; or (d3) (C １ -C ６ ) alkyl group; is shown as Z ２ and Z ３ may be the same or different, (e1) a hydrogen atom; (e2) a halogen atom; (e3) (C １ -C ６ ) alkyl group; (e4) (C １ -C ６ ) alkoxy group; (e5) Halo (C １ -C ６ ) alkyl group; (e6) Halo (C １ -C ６ ) alkoxy group; (e7) an aryloxy group; or (e9) an arylcarbonyl group; is shown, X is, an oxygen atom; is shown, The canine filarial worm disease control agent for animals according to Claim 1.

3. For the production of a canine filarial worm disease control agent for animals, general formula (1) [Chemical Formula 2] {In the formula,[[]] R is,[[]] (a1) a hydrogen atom; (a2) a (C1-C6) alkyl group; (a3) a halo(C1-C6) alkyl group; (a4) a (C2-C6) alkenyl group; (a5) a (C2-C6) alkynyl group; (a6) a (C1-C6) alkoxy(C1-C6) alkyl group; (a7) a (C1-C6) alkylthio(C1-C6) alkyl group; (a8) a (C1-C6) alkoxycarbonyl(C1-C6) alkyl group; (a9) a (C1-C6) alkoxycarbonyl group; (a10) an aryl group; (a11) may be the same or different, (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6) alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6) alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6) alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6) alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group, an aryl group having 1 to 5 substituents selected therefrom; (a12) an aryl(C1-C6) alkyl group; (a13) An aryl(C1-C6)alkyl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6)alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6)alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6)alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6)alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6)alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a14) An aryl(C2-C6)alkenyl group; (a15) An aryl(C2-C6)alkenyl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6)alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6)alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6)alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6)alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6)alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a16) An aryl(C1-C6)alkoxy(C1-C6)alkyl group; (a17) May be the same or different, and is an aryl (C1-C6) alkoxy (C1-C6) alkyl group having 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo (C1-C6) alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo (C1-C6) alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo (C1-C6) alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo (C1-C6) alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo (C1-C6) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a18) An R3R4N group (wherein R3 and R4 may be the same or different and represent (aa) a hydrogen atom, (ab) a (C1-C6) alkyl group, (ac) a (C1-C6) alkoxy group, (ad) a (C1-C6) alkoxycarbonyl group, (ae) a (C1-C6) alkylsulfonyl group, (af) a halo (C1-C6) alkylsulfonyl group, or (ag) a phenyl group.); (a19) An R3R4N carbonyl group (wherein R3 and R4 are the same as above); (a20) An R3R4N thiocarbonyl group (wherein R3 and R4 are the same as above); or (a21) An R3R4N sulfonyl group (wherein R3 and R4 are the same as above); R1 is (b1) A (C1-C6) alkyl group; (b2) A halo (C1-C6) alkyl group; (b3) A (C3-C6) cycloalkyl group; (b4) An aryl group; (b5) An aryl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (b6) A (C2-C6) alkenyl group; (b7) A (C2-C6) alkynyl group; (b8) An aryl(C1-C6)alkyl group; or (b9) An aryl(C1-C6)alkyl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6)alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6)alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6)alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6)alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6)alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; Y1, Y2, and Y3 may be the same or different, (c1) A hydrogen atom; (c2) A (C1-C6) alkyl group; or (c3) A halo(C1-C6)alkyl group; Z1 and Z4 may be the same or different, (d1) A hydrogen atom; (d2) A halogen atom; or (d3) A (C1-C6) alkyl group; Z2 and Z3 may be the same or different, (e1) A hydrogen atom; (e2) A halogen atom; (e3) A (C1-C6) alkyl group; (e4) A (C1-C6) alkoxy group; (e5) A halo(C1-C6)alkyl group; (e6) Halo (C1-C6) alkoxy group; (e7) Aryloxy group; (e8) May be the same or different, and is an aryloxy group having 1 to 5 substituents selected from (a) halogen atom, (b) (C1-C6) alkyl group, (c) halo (C1-C6) alkyl group, (d) (C1-C6) alkoxy group, (e) halo (C1-C6) alkoxy group, (f) (C1-C6) alkylthio group, (g) halo (C1-C6) alkylthio group, (h) (C1-C6) alkylsulfinyl group, (i) halo (C1-C6) alkylsulfinyl group, (j) (C1-C6) alkylsulfonyl group, (k) halo (C1-C6) alkylsulfonyl group, (l) nitro group, and (m) trimethylsilyl group; (e9) Arylcarbonyl group; or (e10) May be the same or different, and is an arylcarbonyl group having 1 to 5 substituents selected from (a) halogen atom, (b) (C1-C6) alkyl group, (c) halo (C1-C6) alkyl group, (d) (C1-C6) alkoxy group, (e) halo (C1-C6) alkoxy group, (f) (C1-C6) alkylthio group, (g) halo (C1-C6) alkylthio group, (h) (C1-C6) alkylsulfinyl group, (i) halo (C1-C6) alkylsulfinyl group, (j) (C1-C6) alkylsulfonyl group, (k) halo (C1-C6) alkylsulfonyl group, (l) nitro group, and (m) trimethylsilyl group; X represents an oxygen atom, a sulfur atom, or R3N (where R3 is the same as above); However, it excludes the compound in which R1 is a 2,2,3,3,3-pentafluoropropyl group, R, Y1, Y2, Y3, Z1, Z2, Z3, and Z4 are hydrogen atoms, and X is an oxygen atom.} Use of the benzimidazole compound represented by the formula or a salt thereof.

4. R is (a1) Hydrogen atom; (a2) (C1-C6) alkyl group; (a3) Halo (C1-C6) alkyl group; (a4) (C2-C6) alkenyl group; (a5) (C2-C6) alkynyl group; (a6) a (C1-C6) alkoxy(C1-C6) alkyl group; (a7) a (C1-C6) alkylthio(C1-C6) alkyl group; (a8) a (C1-C6) alkoxycarbonyl(C1-C6) alkyl group; (a9) a (C1-C6) alkoxycarbonyl group; (a11) an aryl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6) alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6) alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6) alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6) alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a12) an aryl(C1-C6) alkyl group; (a13) an aryl(C1-C6) alkyl group which may be the same or different and has 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo(C1-C6) alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo(C1-C6) alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo(C1-C6) alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo(C1-C6) alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo(C1-C6) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; (a14) an aryl(C2-C6) alkenyl group; (a16) an aryl(C1-C6) alkoxy(C1-C6) alkyl group; (a20) an R3R4N thiocarbonyl group (wherein R3 and R4 are the same as defined above); or (a21) an R3R4N sulfonyl group (wherein R3 and R4 are the same as defined above); provided that R1 is (b1) (C1-C6) alkyl group; (b2) halo (C1-C6) alkyl group; (b3) (C3-C6) cycloalkyl group; (b5) may be the same or different, an aryl group having 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo (C1-C6) alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo (C1-C6) alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo (C1-C6) alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo (C1-C6) alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo (C1-C6) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; or (b9) may be the same or different, an aryl (C1-C6) alkyl group having 1 to 5 substituents selected from (a) a halogen atom, (b) a (C1-C6) alkyl group, (c) a halo (C1-C6) alkyl group, (d) a (C1-C6) alkoxy group, (e) a halo (C1-C6) alkoxy group, (f) a (C1-C6) alkylthio group, (g) a halo (C1-C6) alkylthio group, (h) a (C1-C6) alkylsulfinyl group, (i) a halo (C1-C6) alkylsulfinyl group, (j) a (C1-C6) alkylsulfonyl group, (k) a halo (C1-C6) alkylsulfonyl group, (l) a nitro group, and (m) a trimethylsilyl group; and Y1, Y2, and Y3 all represent (c1) a hydrogen atom; Z1 and Z4 may be the same or different. (d1) A hydrogen atom; (d2) A halogen atom; or (d3) A (C1-C6) alkyl group; and Z2 and Z3 may be the same or different. (e1) A hydrogen atom; (e2) A halogen atom; (e3) A (C1-C6) alkyl group; (e4) A (C1-C6) alkoxy group; (e5) A halo (C1-C6) alkyl group; (e6) A halo (C1-C6) alkoxy group; (e7) An aryloxy group; or (e9) An arylcarbonyl group; X represents an oxygen atom; The use according to claim 3.

Images