Coccidiosis control agent and method of using the coccidiosis control agent

Abstract

The technical problem of the present invention is to develop and provide a coccidiosis control agent having excellent anti-coccidiosis activity and capable of preventing the collective outbreak of coccidiosis and a method of using the same. The present invention provides a coccidiosis control agent and a method of using the same, wherein the coccidiosis control agent comprises a benzimidazole compound or a salt thereof represented by the general formula (1) as an active ingredient, wherein the general formula (1) {wherein, R 1 represents a halogenated alkyl group, X represents an oxygen atom, R represents an alkyl group, Y represents a halogen atom, m represents 0 or 1, Z represents an alkyl group or a halogen atom, and n represents 0, 1 or 2.

Description

Technical Field

[0001] The present invention relates to a coccidiosis control agent containing a benzimidazole compound or a salt thereof as an active ingredient and a method for using the coccidiosis control agent. Background Art

[0002] Coccidiosis, known as one of the protozoan parasitic diseases, is an infectious disease caused by protozoa of the genus Coccidia, which infects poultry such as chickens, turkeys, domestic ducks, quails, ducks, etc., and shows various symptoms such as gastrointestinal bleeding, growth inhibition, and death. In recent years, poultry has been raised in a concentrated and large-scale manner, and the spread of coccidiosis infection has brought huge economic losses to breeders. Therefore, as coccidiosis prevention and control agents, sulfonamides, nitrofurans, quinolines, anti-thiamine agents, benzamides, naphthoquinone derivatives (such as Patent Document 1), polyether antibiotics, etc. have been developed and used, but due to the narrow safety range, when the meat and eggs of animals administered with these agents are eaten by humans, there is a problem of the transfer of the agents remaining in the animal to the human body, which limits its usage and administration period. In addition, due to the long-term use of agents, the problem of the emergence of drug-resistant strains and reduced efficacy has also been generated.

[0003] On the other hand, it is known that certain benzimidazole compounds or salts thereof can be used as insecticides and acaricides, external parasiticides or internal parasiticides for agricultural and horticultural purposes (for example, Patent Document 2), but there is no description of the control effect on coccidiosis.

[0004] Prior art literature

[0005] Patent Literature

[0006] Patent Document 1: Japanese Patent Application Publication No. 2004-51510

[0007] Patent Document 2: International Publication No. 2019 / 225663 Pamphlet Summary of the invention

[0008] Technical problem solved by the invention

[0009] It is desirable to overcome the disadvantages of the prior art and develop a coccidiosis control agent having excellent anticoccidial activity and capable of preventing a collective outbreak of coccidiosis and a method of using the same.

[0010] Technical means of solving problems

[0011] As a result of intensive studies to solve the above problems, the inventors of the present application have found that a benzimidazole compound having an N-alkylsulfonyl group bonded to the 2-position and represented by the general formula (1) or a salt thereof not only has an excellent coccidiosis control effect but also can solve the above problems, thereby completing the present invention.

[0012] That is, the invention of this application is as follows.

[0013] [1] A benzimidazole compound represented by the following general formula (1) or a salt thereof as an active ingredient,

[0014] General formula (1)

[0015] [Chemical formula 1]

[0016]

[0017] {where,

[0018] R represents (a1) (C1-C8) alkyl; (a2) (C3-C8) cycloalkyl; or (a3) ​​halogenated (C1-C8) alkyl,

[0019] R 1 represents (b1) (C1-C8) alkyl; (b2) halo (C1-C8) alkyl; (b3) (C3-C8) cycloalkyl; (b4) (C1-C8) alkoxy (C1-C8) alkyl; (b5) aryl; or (b6) having the same or different radicals selected from (a) halogen atoms, (b) (C1-C6) alkyl, (c) halo (C1-C6) alkyl, (d) (C1-C6) alkoxy (C1-C6)alkylsulfonyl, (e) halogenated (C1-C6)alkoxy, (f) (C1-C6)alkylthio, (g) halogenated (C1-C6)alkylthio, (h) (C1-C6)alkylsulfinyl, (i) halogenated (C1-C6)alkylsulfinyl, (j) (C1-C6)alkylsulfonyl, (k) halogenated (C1-C6)alkylsulfonyl and (l) trimethylsilyl,

[0020] X represents O, S, SO, SO2 or NR 2 (Here R 2 represents a hydrogen atom, a (C1-C6)alkyl group, a (C1-C6)alkylcarbonyl group, a (C1-C6)alkoxycarbonyl group, a (C1-C6)alkylsulfonyl group; or a halogenated (C1-C6)alkylsulfonyl group).

[0021] or, NR 2 R 2 Can be used with R 1 Bonding, with bonding R 2 The nitrogen atom of the alkylene group forms an unsubstituted or monosubstituted 5- to 8-membered saturated nitrogen-containing aliphatic heterocycle, wherein the substituent is ethoxycarbonyl or (C5-C8)alkylenedioxy, wherein the alkylenedioxy is bonded to the same carbon atom.

[0022] Y represents a (c1) halogen atom,

[0023] m represents 0 or 1.

[0024] Z represents the same or different (d1) halogen atoms; or (d2) (C1-C8) alkyl groups,

[0025] n represents 0, 1, or 2.

[0026] Among them, there is no (C1-C8)alkylsulfonyl group, (C1-C8)alkoxy (C1-C8)alkylsulfonyl group, (C3-C8)cycloalkylsulfonyl group, or halogenated (C1-C8)alkylsulfonyl group at the 2-position and 4-position of the pyridine ring.

[0027] [2] The coccidiosis control agent according to [1], comprising a benzimidazole compound or a salt thereof as an active ingredient, wherein

[0028] R represents (a1) (C1-C8) alkyl,

[0029] R 1 represents (b1) a (C1-C8) alkyl group; (b2) a halo (C1-C8) alkyl group; (b3) a (C3-C8) cycloalkyl group; or (b6) an aryl group having 1 to 5 substituents which are the same or different and are selected from the group consisting of (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 and (l) a trimethylsilyl group,

[0030] X represents O, S or NR 2 (R 2 Same as above),

[0031] Y represents a (c1) halogen atom,

[0032] m represents 0 or 1,

[0033] Z is the same or different and represents (d1) a halogen atom; or (d2) a (C1-C8) alkyl group,

[0034] n represents 0, 1, or 2.

[0035] [3] The coccidiosis control agent according to [1], comprising a benzimidazole compound or a salt thereof as an active ingredient, wherein

[0036] R represents (a1) (C1-C8) alkyl,

[0037] R 1 represents (b1) a halogenated (C1-C8) alkyl group,

[0038] m means 0.

[0039] [4] The coccidiosis control agent according to [1], comprising a benzimidazole compound or a salt thereof as an active ingredient, wherein

[0040] R represents (a1) (C1-C8) alkyl,

[0041] R 1 represents (b1) a halogenated (C1-C8) alkyl group,

[0042] m represents 0,

[0043] Z is the same or different and represents (d1) a halogen atom; or (d2) a (C1-C8) alkyl group,

[0044] n represents 2.

[0045] [5] A method for using a coccidiosis control agent, wherein:

[0046] An effective amount of the coccidiosis control agent described in any one of [1] to [4] is administered to a target animal (excluding humans).

[0047] [6] The method for using the coccidiosis control agent according to [5], wherein:

[0048] The target animals are birds.

[0049] [7] The method for using the coccidiosis control agent according to [5], wherein:

[0050] The target animals are chickens.

[0051] [8] A method for preventing and treating coccidiosis, wherein:

[0052] The coccidiosis control agent described in any one of [1] to [4] is administered to a target animal (excluding humans).

[0053] [9] The method for preventing and treating coccidiosis according to [8], wherein:

[0054] The target animals are birds.

[0055]

[10] The method for preventing and treating coccidiosis according to [8], wherein:

[0056] The target animals are chickens.

[0057]

[11] A benzimidazole compound represented by the following general formula (1-1) or a salt thereof,

[0058] General formula (1-1)

[0059] [Chemical formula 2]

[0060]

[0061] {In the formula, R 1 represents (b1) (C1-C8) alkyl; (b2) halo (C1-C8) alkyl; (b3) (C3-C8) cycloalkyl; (b4) (C1-C8) alkoxy (C1-C8) alkyl; (b5) aryl; or (b6) having the same or different radicals selected from (a) halogen atoms, (b) (C1-C6) alkyl, (c) halo (C1-C6) alkyl, (d) (C1-C6) alkoxy (C1-C6)alkylsulfonyl, (e) halogenated (C1-C6)alkoxy, (f) (C1-C6)alkylthio, (g) halogenated (C1-C6)alkylthio, (h) (C1-C6)alkylsulfinyl, (i) halogenated (C1-C6)alkylsulfinyl, (j) (C1-C6)alkylsulfonyl, (k) halogenated (C1-C6)alkylsulfonyl and (l) trimethylsilyl,

[0062] X represents O, S, SO, SO2 or NR 2 (Here R 2 represents a hydrogen atom, a (C1-C6)alkyl group, a (C1-C6)alkylcarbonyl group, a (C1-C6)alkoxycarbonyl group, a (C1-C6)alkylsulfonyl group; or a halogenated (C1-C6)alkylsulfonyl group).

[0063] or, NR 2 R 2 Can be used with R 1 Bonding, with bonding R 2 The nitrogen atom of the alkylene group forms an unsubstituted or monosubstituted 5- to 8-membered saturated nitrogen-containing aliphatic heterocycle, wherein the substituent is ethoxycarbonyl or (C5-C8)alkylenedioxy, wherein the alkylenedioxy is bonded to the same carbon atom.

[0064] Y represents a (c1) halogen atom,

[0065] m represents 0 or 1.

[0066] Z represents the same or different (d1) halogen atoms; or (d2) (C1-C8) alkyl groups,

[0067] n represents 0, 1, or 2.

[0068] Among them, there is no (C1-C8)alkylsulfonyl group, (C1-C8)alkoxy (C1-C8)alkylsulfonyl group, (C3-C8)cycloalkylsulfonyl group, or halogenated (C1-C8)alkylsulfonyl group at the 2-position and 4-position of the pyridine ring.

[0069]

[12] The benzimidazole compound or its salt according to

[11] , wherein

[0070] R 1 represents (b1) a (C1-C8) alkyl group; (b2) a halo (C1-C8) alkyl group; (b3) a (C3-C8) cycloalkyl group; or (b6) an aryl group having 1 to 5 substituents which are the same or different and are selected from the group consisting of (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 and (l) a trimethylsilyl group,

[0071] X represents O, S or NR 2 (R 2 Same as above),

[0072] Y represents a (c1) halogen atom,

[0073] m represents 0 or 1,

[0074] Z is the same or different and represents (d1) a halogen atom; or (d2) a (C1-C8) alkyl group,

[0075] n represents 0, 1, or 2.

[0076]

[13] The benzimidazole compound or its salt according to

[11] , wherein

[0077] R 1 represents (b1) a halogenated (C1-C8) alkyl group,

[0078] m means 0.

[0079]

[14] The benzimidazole compound or its salt according to

[11] , wherein

[0080] R 1 represents (b1) a halogenated (C1-C8) alkyl group,

[0081] m represents 0,

[0082] Z is the same or different and represents (d1) a halogen atom; or (d2) a (C1-C8) alkyl group,

[0083] n represents 2.

[0084]

[15] A coccidiosis control agent comprising the benzimidazole compound or a salt thereof according to any one of

[11] to

[14] as an active ingredient.

[0085]

[16] A method for using a coccidiosis control agent, wherein:

[0086] An effective amount of the coccidiosis control agent described in

[15] is administered to a target animal (excluding humans).

[0087]

[17] The method for using the coccidiosis control agent according to

[16] , wherein:

[0088] The target animals are birds.

[0089]

[18] The method for using the coccidiosis control agent according to

[16] , wherein:

[0090] The target animals are chickens.

[0091]

[19] A method for preventing and treating coccidiosis, wherein:

[0092] The benzimidazole compound or a salt thereof according to any one of

[11] to

[14] is administered to a target animal (excluding humans).

[0093]

[20] The method for preventing and treating coccidiosis according to

[19] , wherein:

[0094] The target animals are birds.

[0095]

[21] The method for preventing and treating coccidiosis according to

[19] , wherein:

[0096] The target animals are chickens.

[0097] Effects of the Invention

[0098] The benzimidazole compound having an N-alkylsulfonyl group and a pyridyl group bonded to the 2-position or its salts of the present invention has excellent effects as a coccidiosis control agent. In addition, the present invention also provides a coccidiosis control agent composition for livestock containing the control agent. DETAILED DESCRIPTION

[0099] In the definitions of the general formulas (1) and (1-1) of the benzimidazole compounds (having an N-alkylsulfonyl group) having a pyridyl group bonded to the 2-position or their salts of the present invention, "halogen" means a "halogen atom", which means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

[0100] The “(C1-C8)alkyl” refers to a linear or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, 2,3-dimethylpropyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 1,1,2-trimethylpropyl, 3,3-dimethylbutyl, n-heptyl, 2-heptyl, 3-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, isoheptyl, and n-octyl. The “(C2-C8)alkenyl” refers to, for example, vinyl, allyl, isoheptyl, and n-octyl. The term "(C2-C8)alkynyl" refers to a linear or branched alkenyl group having 2 to 8 carbon atoms, such as propenyl, 1-butenyl, 2-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-methyl-1-propenyl, pentenyl, 1-hexenyl, 3,3-dimethyl-1-butenyl, heptenyl and octenyl. The term "(C2-C8)alkynyl" refers to a linear or branched alkenyl group having 2 to 8 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl, 2-methyl-3-propynyl, pentynyl, 1-hexynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, heptynyl and octynyl.

[0101] “(C1-C6)alkyl” refers to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, 2,3-dimethylpropyl, 1-ethylpropyl, 1-methylbutyl, 2-methylbutyl, n-hexyl, isohexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 3-methylpentyl, 1,1,2-trimethylpropyl, 3,3-dimethylbutyl and the like, which are linear or branched alkyl groups having 1 to 6 carbon atoms.

[0102] The “(C3-C8) cycloalkyl” represents, for example, a cyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The “(C1-C8) alkoxy” represents, for example, a linear or branched alkoxy group having 1 to 8 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentyl, tert-pentyloxy, neopentyloxy, 2,3-dimethylpropoxy, 1-ethylpropoxy, 1-methylbutoxy, n-hexyloxy, isohexyloxy, 1,1,2-trimethylpropoxy, n-heptyloxy, and n-octyloxy.

[0103] The “(C3-C6) cycloalkyl” represents, for example, a cyclic alkyl group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The “(C1-C6) alkoxy” represents, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, tert-pentoxy, neopentoxy, 2,3-dimethylpropoxy, 1-ethylpropoxy, 1-methylbutoxy, n-hexyloxy, isohexyloxy, and 1,1,2-trimethylpropoxy.

[0104] Examples of the "(C1-C8)alkylthio group" include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, tert-pentylthio, neopentylthio, 2,3-dimethylpropylthio, 1-ethylpropylthio, 1-methylbutylthio, n-hexylthio, isohexylthio, 1,1,2-trimethylpropylthio, n-heptylthio, n-octylthio and the like. The alkylthio group having 1 to 8 atoms, as the “(C1-C8)alkylsulfinyl group”, for example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, tert-pentylsulfinyl, neopentylsulfinyl, 2,3-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, A linear or branched alkylsulfinyl group having 1 to 8 carbon atoms such as sulfinyl, 1-methylbutylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl, 1,1,2-trimethylpropylsulfinyl, n-heptylsulfinyl, and n-octylsulfinyl; as the "(C1-C8)alkylsulfonyl group", for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl The invention also includes a linear or branched alkylsulfonyl group having 1 to 8 carbon atoms, such as a sec-butylsulfonyl group, a tert-butylsulfonyl group, a n-pentylsulfonyl group, an isopentylsulfonyl group, a tert-pentylsulfonyl group, a neopentylsulfonyl group, a 2,3-dimethylpropylsulfonyl group, a 1-ethylpropylsulfonyl group, a 1-methylbutylsulfonyl group, a n-hexylsulfonyl group, an isohexylsulfonyl group, a 1,1,2-trimethylpropylsulfonyl group, a n-heptylsulfonyl group and a n-octylsulfonyl group.

[0105] Examples of the “(C1-C6)alkylthio group” include a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, tert-pentylthio, neopentylthio, 2,3-dimethylpropylthio, 1-ethylpropylthio, 1-methylbutylthio, n-hexylthio, isohexylthio, and 1,1,2-trimethylpropylthio. Examples of the “(C1-C6)alkylsulfinyl group” include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, tert-pentylsulfinyl, neopentylsulfinyl, 2,3-dimethylpropylthio, 1-ethylpropylthio, 1-methylbutylthio, n-hexylthio, isohexylthio, and 1,1,2-trimethylpropylthio. Examples of the “(C1-C6)alkylsulfinyl group” include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, tert-pentylsulfinyl, neopentylsulfinyl, 2,3-dimethylpropylthio The “(C1-C6)alkylsulfonyl group” includes, for example, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, tert-pentylsulfonyl, neopentylsulfonyl, 2,3-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, 1-methylbutylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl and 1,1,2-trimethylpropylsulfonyl. As the “(C1-C6)alkylsulfonyl group”, for example, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms, such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, tert-pentylsulfonyl, neopentylsulfonyl, 2,3-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, 1-methylbutylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl and 1,1,2-trimethylpropylsulfonyl

[0106] The "(C1-C8)alkyl", "(C2-C8)alkenyl", "(C2-C8)alkynyl", "(C3-C8)cycloalkyl", "(C1-C8)alkoxy", "(C1-C8)alkylthio", "(C1-C8)alkylsulfinyl" or "(C1-C8)alkylsulfonyl" may be substituted with one or more halogen atoms at the optionally substituted positions. When the number of substituted halogen atoms is two or more, the halogen atoms may be the same or different. They are respectively represented as "halogenated (C1-C8)alkyl", "halogenated (C2-C8)alkenyl", "halogenated (C2-C8)alkynyl", "halogenated (C3-C8)cycloalkyl", "halogenated (C1-C8)alkoxy", "halogenated (C1-C8)alkylthio", "halogenated (C1-C8)alkylsulfinyl" or "halogenated (C1-C8)alkylsulfonyl".

[0107] The optionally substituted positions of “(C1-C6)alkyl”, “(C2-C6)alkenyl”, “(C2-C6)alkynyl”, “(C3-C6)cycloalkyl”, “(C1-C6)alkoxy”, “(C1-C6)alkylthio”, “(C1-C6)alkylsulfinyl” or “(C1-C6)alkylsulfonyl” may be substituted with one or two or more halogen atoms. When the number of substituted halogen atoms is two or more, the halogen atoms may be the same or different. They are respectively represented as “halogenated (C1-C6)alkyl”, “halogenated (C2-C6)alkenyl”, “halogenated (C2-C6)alkynyl”, “halogenated (C3-C6)cycloalkyl”, “halogenated (C1-C6)alkoxy”, “halogenated (C1-C6)alkylthio”, “halogenated (C1-C6)alkylsulfinyl” or “halogenated (C1-C6)alkylsulfonyl”.

[0108] Expressions such as "(C1-C6)", "(C2-C6)", "(C3-C6)", "(C1-C8)", "(C2-C8)", "(C3-C8)" indicate the range of carbon number of various substituents. Furthermore, the above definition can also be expressed for groups connected to the above substituents. For example, "(C3-C8)cycloalkyl(C1-C8)alkyl" indicates that a cycloalkyl group having 3 to 8 carbon atoms is bonded to a linear or branched alkyl group having 1 to 8 carbon atoms.

[0109] Examples of salts of the benzimidazole compound represented by the general formula (1) or (1-1) of the present invention include inorganic acid salts such as hydrochlorides, sulfates, nitrates, and phosphates; organic acid salts such as acetates, fumarates, maleates, oxalates, methanesulfonates, benzenesulfonates, and p-toluenesulfonates; and salts formed with inorganic or organic bases such as sodium ions, potassium ions, calcium ions, and trimethylammonium.

[0110] The benzimidazole compound or its salt represented by the general formula (1) or (1-1) of the present invention may have one asymmetric center in its structural formula, and the present invention includes all optical isomers and mixtures thereof in any ratio.

[0111] Among the benzimidazole compounds or salts thereof represented by the general formula (1) as the active ingredient of the coccidiosis control agent of the present invention,

[0112] R is preferably (a1) (C1-C8) alkyl.

[0113] R 1Preferred are (b1) (C1-C8) alkyl; (b2) halo (C1-C8) alkyl; (b3) (C3-C8) cycloalkyl; or (b6) an aryl group having 1 to 5 substituents which are the same or different and are selected from (a) a halogen atom, (b) (C1-C6) alkyl, (c) halo (C1-C6) alkyl, (d) (C1-C6) alkoxy, (e) halo (C1-C6) alkoxy, (f) (C1-C6) alkylthio, (g) halo (C1-C6) alkylthio, (h) (C1-C6) alkylsulfinyl, (i) halo (C1-C6) alkylsulfinyl, (j) (C1-C6) alkylsulfonyl, (k) halo (C1-C6) alkylsulfonyl and (l) trimethylsilyl.

[0114] X is preferably O, S or NR 2 (R 2 Same as above).

[0115] Y is preferably a (c1) halogen atom, and m is preferably 0 or 1.

[0116] Z is preferably the same or different and is (d1) a halogen atom; or (d2) a (C1-C8) alkyl group, and n is preferably 0, 1 or 2.

[0117] More preferably, R represents (a1) (C1-C8) alkyl, R 1 represents (b1) a halogenated (C1-C8) alkyl group, wherein m is 0.

[0118] More preferably, R represents (a1) (C1-C8) alkyl, R 1 represents (b1) a halogenated (C1-C8) alkyl group, m is 0, Z is the same or different, represents (d1) a halogen atom; or (d2) a (C1-C8) alkyl group, n is 2.

[0119] The benzimidazole compound represented by the general formula (1-1) or a salt thereof of the present invention is useful as an intermediate for producing the benzimidazole compound represented by the general formula (1) or a salt thereof.

[0120] It should be noted that the inventors of the present application have confirmed that the benzimidazole compound represented by the general formula (1) is rapidly hydrolyzed in the presence of water and converted into the corresponding benzimidazole compound represented by the general formula (1-1). In addition, it has also been confirmed that when the blood of the target animal after administration of the benzimidazole compound represented by the general formula (1) or its salt is analyzed, the corresponding benzimidazole compound represented by the general formula (1-1) is detected. Therefore, the preventive and therapeutic activity of the benzimidazole compound represented by the general formula (1) or its salt against coccidiosis may depend on the benzimidazole compound represented by the general formula (1-1) or its salt as an intermediate, and the benzimidazole compound represented by the general formula (1) or its salt is more likely to act as a prodrug.

[0121] Furthermore, as shown in the following examples, the benzimidazole compounds represented by the general formula (1-1) or their salts also showed coccidiosis control activity. Therefore, the benzimidazole compounds represented by the general formula (1-1) or their salts themselves are useful as active ingredients of coccidiosis control agents.

[0122] In the benzimidazole compound or its salt represented by the general formula (1-1) of the present invention,

[0123] R 1 Preferred are (b1) (C1-C8) alkyl; (b2) halo (C1-C8) alkyl; (b3) (C3-C8) cycloalkyl; or (b6) an aryl group having 1 to 5 substituents which are the same or different and are selected from (a) a halogen atom, (b) (C1-C6) alkyl, (c) halo (C1-C6) alkyl, (d) (C1-C6) alkoxy, (e) halo (C1-C6) alkoxy, (f) (C1-C6) alkylthio, (g) halo (C1-C6) alkylthio, (h) (C1-C6) alkylsulfinyl, (i) halo (C1-C6) alkylsulfinyl, (j) (C1-C6) alkylsulfonyl, (k) halo (C1-C6) alkylsulfonyl and (l) trimethylsilyl.

[0124] X is preferably O, S or NR 2 (R 2 Same as above).

[0125] Y is preferably a (c1) halogen atom, and m is preferably 0 or 1.

[0126] Z is preferably the same or different (d1) halogen atom; or (d2) (C1-C8) alkyl, and n is preferably 0, 1 or 2.

[0127] More preferably R 1 represents (b1) a halogenated (C1-C8) alkyl group, wherein m is 0.

[0128] Further optimization of R 1 represents (b1) a halogenated (C1-C8) alkyl group, m is 0, Z is the same or different, represents (d1) a halogen atom; or (d2) a (C1-C8) alkyl group, n is 2.

[0129] The benzimidazole compounds represented by the general formula (1) and (1-1) or their salts, which are active ingredients of the coccidiosis control agent of the present invention, can be produced, for example, by the following production method, but the present invention is not limited thereto.

[0130] Manufacturing method 1

[0131] [Chemical formula 3]

[0132]

[0133] Manufacturing method of step [A]

[0134] The nitrile compound represented by the general formula (2-2) can be produced by reacting a compound represented by the general formula (2-3) with a compound represented by the general formula (4) in the presence of a base and an inert solvent.

[0135] Examples of the base used in the reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; acetates such as sodium acetate and potassium acetate; alkali metal alkoxides such as potassium tert-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 and dimethylaminopyridine, etc., and the amount used is usually in the range of 1 to 10 times the mole of the compound represented by the general formula (4).

[0136] The inactive solvent used in the present reaction may be any solvent that does not significantly inhibit the progress of the present reaction. Examples of the inactive solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, 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; polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone, and the like. These inactive solvents may be used alone or in combination of two or more.

[0137] Since the reaction is an equimolar reaction, each reactant can be used in equimolar amounts, or any reactant can be used in excess. The reaction temperature can be carried out in the range of room temperature to the boiling point of the inactive solvent used, and the reaction time depends on the reaction scale and the reaction temperature, but is not constant, and can be carried out in the range of several minutes to 48 hours.

[0138] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by conventional methods, and the target product can be obtained by purification by recrystallization, column chromatography, etc. In addition, the next step can be carried out without isolating the intermediate from the reaction system.

[0139] Manufacturing method of step [B]

[0140] The carboxylic acid compound represented by the general formula (2-1) can be produced by reacting a nitrile compound represented by the general formula (2-2) in the presence of a base and an inert solvent.

[0141] The base used in this reaction includes, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; acetates such as sodium acetate and 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).

[0142] The inactive solvent used in this reaction is any solvent that does not significantly inhibit the progress of the reaction. Examples thereof include water and the following inactive solvents: 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. These inactive solvents can be used alone or in combination of two or more.

[0143] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by conventional methods, and can be purified by recrystallization, column chromatography, etc. as needed to obtain the target product.

[0144] Manufacturing method of step [C]

[0145] The amide compound represented by the general formula (2) can be produced by reacting a carboxylic acid compound represented by the general formula (2-1) and a diamino compound represented by the general formula (3) in the presence of a condensing agent, a base and an inert solvent.

[0146] Examples of the condensing agent used in the present reaction include diethyl cyanophosphate (DEPC), carbonyldiimidazole (CDI), 1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC·HCl), chlorocarbonates, 2-chloro-1-methylpyridinium iodide, and the like. The amount used can be appropriately selected and used in the range of 1 to 1.5 times the molar amount of the compound represented by the general formula (2-1).

[0147] Examples of the base used in the reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.; acetates such as sodium acetate and potassium acetate; alkali metal alkoxides such as potassium tert-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 and dimethylaminopyridine, etc., and the amount used is usually in the range of 0.1 to 10 times the molar amount of the compound represented by the general formula (2-1).

[0148] The inactive solvent used in the present reaction is any solvent that does not significantly inhibit the progress of the present reaction. Examples of the inactive solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, 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; polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone; and nitrogen-containing aromatic compounds such as pyridine. These inactive solvents can be used alone or in combination of two or more.

[0149] Since the reaction is an equimolar reaction, each reactant can be used in equimolar amounts, or any reactant can be used in excess. The reaction temperature can be carried out in the range of room temperature to the boiling point of the inactive solvent used, and the reaction time depends on the reaction scale and the reaction temperature, but is not constant, and can be carried out in the range of several minutes to 48 hours.

[0150] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by conventional methods, and the target product can be obtained by purification by recrystallization, column chromatography, etc. In addition, the next step can be carried out without isolating the intermediate from the reaction system.

[0151] Manufacturing method of step [D]

[0152] The benzimidazole compound represented by the general formula (1-1) can be produced by reacting an amide compound represented by the general formula (2) in the presence of an acid and an inert solvent.

[0153] Examples of the acid used in the 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; phosphoric acid, etc. The amount used can be appropriately selected and used in the range of 0.01 to 10 times the molar amount of the amide compound represented by the general formula (2).

[0154] The inactive solvent used in the present reaction is any solvent that does not significantly inhibit the progress of the present reaction. Examples of the inactive solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, 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; polar solvents such as dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, and N-methylpyrrolidone. These inactive solvents can be used alone or in combination of two or more.

[0155] After the reaction is completed, the target product can be isolated from the reaction system containing the target product by conventional methods, and can be purified by recrystallization, column chromatography, etc. as needed to obtain the target product.

[0156] Manufacturing method of step [E]

[0157] 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 sulfonyl chloride represented by RSO2Cl in the presence of an inert solvent and a base.

[0158] 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, and acetates such as sodium acetate and potassium acetate. The amount used is usually in the range of 1 to 10 times the molar amount of the compound represented by the general formula (1-1).

[0159] The amount of sulfonyl chloride represented by RSO2Cl used is usually within a range of 1-fold to 10-fold mol relative to the compound represented by the general formula (1-1).

[0160] The inactive solvent that can be used in this reaction is any one that does not significantly inhibit the reaction, and examples thereof include: aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene; and chain or cyclic ethers such as diethyl ether, tetrahydrofuran (THF), and dioxane. These inactive solvents can be used alone or in combination of two or more.

[0161] The reaction temperature in the present reaction may usually be within a range of 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 may be appropriately selected within a range of several minutes to 48 hours.

[0162] After the reaction is completed, the target product can be isolated by conventional methods and can be purified by recrystallization, distillation, etc. as needed to produce the target product.

[0163] Next, specific examples of the compounds of the present invention and their intermediates are shown below. In the following table, Me represents methyl, Et represents ethyl, n-Pro represents n-propyl, n-Bu represents n-butyl, n-Pen represents n-pentyl, n-Hex represents n-hexyl, c-Pro represents cyclopropyl, c-Pen represents cyclopentyl, c-Hep represents cycloheptyl, Ph represents phenyl, and TMS represents trimethylsilyl. Physical properties are represented by melting point (°C) or H 1 -NMR. H 1 -NMR data are shown in Tables 5 and 9.

[0164] [Chemical formula 4]

[0165]

[0166] [Table 1]

[0167] Table 1

[0168] Compound No. <![CDATA[R 1 ]]> X <![CDATA[Y 1 ]]> <![CDATA[Y 2 ]]> <![CDATA[Y 3 ]]> <![CDATA[Z 1 ]]> <![CDATA[Z 2 ]]> <![CDATA[Z 3 ]]> <![CDATA[Z 4 ]]> R physical properties 1-1 <![CDATA[CF3CF2CH2]]> O H H H H Br H H E 130-131 1-2 <![CDATA[CF3CF2CH2]]> O H H H H H Br H E 154-159 1-3 <![CDATA[CF3CF2CH2]]> O H H H H Me Me H E 148-149 1-4 <![CDATA[CF3CF2CH2]]> O H H H H Cl Cl H E 177-178 1-5 <![CDATA[CF3CF2CH2]]> O H H H H Br Br H E 184-186 1-6 <![CDATA[CF3CF2CH2]]> O H H H H H H H Me 170-172 1-7 <![CDATA[CF3CF2CH2]]> O H H H H H H H E 105-106 1-8 <![CDATA[CF3CF2CH2]]> O H H H H H H H c-Pro 97-98 1-9 <![CDATA[CF3CF2CH2]]> O H H H H H H H n-Bu 86-87 1-10 <![CDATA[CF3CF2CH2]]> O H H H H H H H <![CDATA[CF3]]> 104-106 1-11 <![CDATA[CF3CH2]]> O H H H H H H H E 99-101 1-12 <![CDATA[CHF2CF2CH2]]> O H H H H H H H E 77-78 1-13 <![CDATA[CF3CF2CF2CH2]]> O H H H H H H H E 99-101 1-14 <![CDATA[4-CF3SO2Ph]]> O H H H H H H H E 122-123 1-15 <![CDATA[4-CF3SOPh]]> O H H H H H H H E 120-121 1-16 <![CDATA[4-CF3SPh]]> O H H H H H H H E 135-136 1-17 <![CDATA[4-CF3OPh]]> O H H H H H H H E 137-138 1-18 4-TMSPh O H H H H H H H E 147-149 1-19 n-Hex O H H H H H H H E 67-68 1-20 n-Pro O H H H H H H H E 90-91 1-21 <![CDATA[CH3OCH2CH2]]> O H H H H H H H E 111-112 1-22 c-Pen O H H H H H H H E 81-82 1-23 <![CDATA[CF3CH2]]> O Cl H H H H H H E 102-105 1-24 <![CDATA[CHF2CF2CH2]]> O Cl H H H H H H E 98-99 1-25 <![CDATA[CF3CF2CH2]]> O Cl H H H H H H E 88-90 1-26 n-Pro <![CDATA[SO2]]> H H H H H H H E 134-135 1-27 n-Pro SO H H H H H H H E 118-119 1-28 n-Pro S H H H H H H H E 110-111 1-29 n-Pro N(n-Pro) H H H H H H H E 102-103

[0169] [Chemical formula 5]

[0170]

[0171] [Table 2]

[0172] Table 2

[0173] Compound No. <![CDATA[R 1 ]]> X <![CDATA[Y 1 ]]> <![CDATA[Y 2 ]]> <![CDATA[Y 4 ]]> <![CDATA[Z 1 ]]> <![CDATA[Z 2 ]]> <![CDATA[Z 3 ]]> <![CDATA[Z 4 ]]> R physical properties 2-1 <![CDATA[CF3CF2CH2]]> O H H H H H H H E NMR

[0174] [Chemical formula 6]

[0175]

[0176] [Table 3]

[0177] Table 3

[0178] Compound No. <![CDATA[R 1 ]]> × <![CDATA[Y 2 ]]> <![CDATA[Y 3 ]]> <![CDATA[Y 4 ]]> <![CDATA[Z 1 ]]> <![CDATA[Z 2 ]]> <![CDATA[Z 3 ]]> <![CDATA[Z 4 ]]> R physical properties 3-1 <![CDATA[CF3CF2CH2]]> O H H H H H H H E 93-94

[0179] [Chemical formula 7]

[0180]

[0181] [Table 4]

[0182] Table 4

[0183]

[0184] [Table 5]

[0185] Table 5

[0186]

[0187] [Chemical formula 8]

[0188]

[0189] [Table 6]

[0190] Table 6

[0191] Intermediate No. <![CDATA[R 1 ]]> X <![CDATA[Y 1 ]]> <![CDATA[Y 2 ]]> <![CDATA[Y 3 ]]> <![CDATA[Z 1 ]]> <![CDATA[Z 2 ]]> <![CDATA[Z 3 ]]> <![CDATA[Z 4 ]]> physical properties 11-1 <![CDATA[CF3CF2CH2]]> O H H H H Br H H 192-193 11-3 <![CDATA[CF3CF2CH2]]> O H H H H Me Me H 163-165 11-4 <![CDATA[CF3CF2CH2]]> O H H H H Cl Cl H 198-201 11-5 <![CDATA[CF3CF2CH2]]> O H H H H Br Br H 218-220 11-6 <![CDATA[CF3CF2CH2]]> O H H H H H H H 234-239 11-11 <![CDATA[CF3CH2]]> O H H H H H H H 247-248 11-12 <![CDATA[CHF2CF2CH2]]> O H H H H H H H 186-203 11-17 <![CDATA[4-CF3OPh]]> O H H H H H H H 214-215 11-18 4-TMSPh O H H H H H H H NMR 11-19 n-Hex O H H H H H H H 170-171 11-20 n-Pro O H H H H H H H NMR 11-21 <![CDATA[CH3OCH2CH2]]> O H H H H H H H NMR 11-22 c-Pen O H H H H H H H 237-238 11-23 <![CDATA[CF3CH2]]> O Cl H H H H H H 182-184 11-24 <![CDATA[CHF2CF2CH2]]> O Cl H H H H H H 98-99 11-26 n-Pro <![CDATA[SO2]]> H H H H H H H NMR 11-27 n-Pro SO H H H H H H H NMR 11-28 n-Pro S H H H H H H H 194-195 11-29 n-Pro N(n-Pro) H H H H H H H 187-188

[0192] [Chemical formula 9]

[0193]

[0194] [Table 7]

[0195] Table 7

[0196] Intermediate No. <![CDATA[R 1 ]]> X <![CDATA[Y 1 ]]> <![CDATA[Y 2 ]]> <![CDATA[Y 4 ]]> <![CDATA[Z 1 ]]> <![CDATA[Z 2 ]]> <![CDATA[Z 3 ]]> <![CDATA[Z 4 ]]> physical properties 12-1 <![CDATA[CF3CF2CH2]]> O H H H H H H H 106-107

[0197] [Chemical formula 10]

[0198]

[0199] [Table 8]

[0200] Table 8

[0201]

[0202] [Table 9]

[0203] Table 9

[0204]

[0205] The target animals of the coccidiosis control agent of the present invention are livestock such as cattle, pigs, rabbits, birds, or pets such as dogs, rabbits or cats (hereinafter referred to as target animals, but excluding humans), preferably birds (poultry), more preferably chickens, but not limited thereto. In addition, in the present invention, control includes prevention and treatment.

[0206] Coccidiosis is an infectious disease mainly caused by protozoa belonging to the genus Eimeria or Isospora (for example, described in Revised Veterinary Parasitology and Parasitology (1) General Theory / Protozoa, published on November 20, 2007, Kodansha Scientific).

[0207] As coccidiosis caused by the genus Eimeria, it is known that coccidiosis in chickens is caused by Eimeria tenella, Eimeria acervulina, Eimeria necatrix, Eimeria brunetti, Eimeria maxima, Eimeria mivati, Eimeria mitis, Eimeria precox, Eimeria hagani, etc., and in the case of turkeys, it is known that coccidiosis is caused by Eimeria meleagrimitis, Eimeria adenoides, Eimeria gallopovonis, etc. On the other hand, coccidiosis of ruminants such as cattle and sheep is known to be caused by Eimeria bovis, Eimeria zuernii, Eimeria auburnensis, Eimeria ellipsoidalis, Eimeria arloingi, Eimeria ovina, Eimeria parva, etc. Coccidiosis of pigs is known to be caused by Eimeria debliecki, Eimeria scabra, etc. It is known that coccidiosis in rabbits is caused by Eimeria stiedai, Eimeria perforans, Eimeria magna, Eimeria media, Eimeria irresidua, Eimeria piriformis, Eimeria neoleporis, Eimeria intenstinalis, Eimeria matsubayashii, etc., but is not limited thereto.

[0208] In addition, as coccidiosis caused by the genus Isospora (also called the genus Cystoisospora), Isospora alamataensis, Isospora anseris, Isospora bigemina, Isosporabronchocelae, Isospora heydorni, Isospora mandari, Isospora mejiro, Isosporaperomysci, Isospora rara, Isospora thibetana, Isospora canis, Isospora ohioensis, Isospora felis, Isospora rivolta, Isospora suis, etc. are known, but are not limited to these.

[0209] When using the control agent of the present invention, it is also possible to use the benzimidazole compound or its salt directly without adding any other ingredients, but usually a solid carrier, a liquid carrier and other excipients are further added to the benzimidazole compound or its salt, preferably according to the usual method (such as "Pharmaceuticals" compiled by Akihiro Otsuka et al., recorded in Nanjiangtang in 1995, etc.) It is formulated into tablets, powders, granules, capsules, aqueous solvents, liquids, wettable powders and suspensions, etc. and then used. As the excipient of the solid carrier, for example, lactose, sucrose, glucose, corn starch, gelatin, casein, starch, gum arabic, cellulose derivatives, alginic acid, etc. can be cited. In addition, as the excipient of the liquid carrier, for example, water, glycerol, vegetable oil, fatty acid, fatty acid ester, sorbitol, etc. can be cited.

[0210] 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, magnesium carbonate, vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, pantothenic acid, niacin, alfalfa powder, corn flakes, etc. In addition, in order to improve the taste, flavors may be given at the same time. As needed, common additives such as antibacterial agents, antifungal agents, insect repellents, antioxidants, pigments, flavoring agents, flavoring agents, and enzymes may be mixed, and preferably, the preparations are used in the form of powders, granules, liquids, tablets, etc. by common methods. These preparations may generally contain about 0.01 to 95% by weight of a benzimidazole compound or its salt as an active ingredient by weight.

[0211] The control agent of the present invention thus formulated can be used directly or after dilution with water, etc. In addition, other common additives such as antibacterial agents, antifungal agents, insect repellents, antioxidants, pigments, flavoring agents, flavoring agents, enzymes, etc. can also be mixed or used in combination simultaneously or non-simultaneously.

[0212] There is no particular limitation on the administration of the control agent of the present invention to the target animal, and the method known in the art such as spreading or mixing in feed described later can be adopted. The dosage is an amount effective for the control of coccidiosis in the target animal, that is, when the control agent of the present invention is administered, the control effect of coccidiosis in the target animal is enhanced compared with the case where no administration is performed, under the same other conditions.

[0213] The method of mixing the active ingredients of the control agent of the present invention to be administered to the target animal, gelling it and allowing it to be freely ingested can be implemented in either a hatchery or a brooding farm. In addition, it can also be implemented during the transportation of poultry from a hatchery to a brooding farm.

[0214] In addition, a method can be implemented in which a powdered preparation for gelation is prepared by mixing a given amount of water-soluble polysaccharides with the active ingredient of the control agent of the present invention, and when used in hatcheries and farms, the preparation is diluted with water to form a gel-like solid, and then administered to the target animal (i.e., free ingestion, direct intracapsular administration).

[0215] The control agent obtained by formulation is usually used alone, and can be used as a formulation diluent after being diluted with water (i.e., diluted and administered with drinking water). The concentration of the active ingredient in the formulation diluent is usually preferably in the range of about 10 to 10,000 ppm, and more preferably in the range of about 35 to 5,000 ppm. As a method for administering the formulation diluent, generally, there can be mentioned a method in which about 0.01 to 500 g of the control agent is dissolved in 1 L of water and the amount of the solution is prepared for administration. Preferably, there can be mentioned a method in which about 0.035 to 350 g is dissolved in 1 L of water and the dosage is administered.

[0216] In order to administer the thus prepared preparation dilution to the target animal, the preparation dilution can be administered using a drinking water adding device, etc. The dosage of the preparation dilution can be appropriately determined according to the size, growth status, stocking density and administration method of the target poultry, but is usually preferably about 300 to 2000 liters per 10,000 poultry.

[0217] The administration time and implementation period of the control agent of the present invention are continuous throughout the life of the target animals in egg-laying and meat-producing species, preferably during the chick stage (chickens 0 to 5 weeks old after hatching).

[0218] The dosage of the control agent can be appropriately determined according to the type and size of the target animal, and is generally preferably in the range of 0.005 to 2 g, more preferably 0.005 to 1 g, based on the total dosage.

[0219] The control agent composition of the present invention is prepared by adding the control agent to animal feed, drinking water, physiological electrolyte solution, etc. The amount of the control agent added is preferably in the range of about 0.005 to 10.0% by weight relative to the total amount of the control agent composition.

[0220] The object animal feed or drinking water or physiological electrolyte solution used in the control agent composition of the present invention is not particularly limited as long as it is commonly used. As these examples, it is possible to enumerate: feeds prepared by appropriately mixing corn, rice, wheat, sorghum, soybean meal, bran, defatted rice bran, fish meal, skimmed milk powder, dry whey, grease, alfalfa meal, white fish meal, soybean oil, powdered purified tallow, wheat flour, rapeseed oil, meat and bone meal (feather meal), animal fat, 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.

[0221] The control agent composition 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, magnesium carbonate, vitamins such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, pantothenic acid, niacin, alfalfa powder, corn flakes, etc. In addition, flavors may be added at the same time to improve palatability.

[0222] There is no particular limitation on the method of administering the control composition of the present invention to the target animal, and the administration method can be an appropriate method such as spreading or mixing in feed as described later. It should be noted that the dosage of the control composition is, in general, an amount effective for the coccidia control effect on the target animal, that is, when other conditions are the same, the control effect of coccidia on poultry is enhanced when the control composition of the present invention is administered compared to when it is not administered.

[0223] Regarding the administration period and implementation period of the control agent composition of the present invention, in egg-laying species and meat-producing species, it is continued throughout the entire period of the target animal, preferably administered in the chick stage (chickens 0 to 5 weeks old after hatching), and more preferably continuously administered from 0 to 21 days after hatching.

[0224] When the control agent composition of the present invention is used in conjunction with the feed for the target animal, the benzimidazole compound or its salt can be used in a ratio of about 0.0005 to 5% by weight, preferably about 0.05 to 2% by weight. In addition, when added to drinking water or physiological electrolyte solution for use, the benzimidazole compound or its salt can be used in a ratio of about 0.035 to 3.5% by weight, preferably about 0.035 to 1.4% by weight.

[0225] The control method of the present invention has a step of administering an effective amount of the control agent of the present invention or the control agent composition of the present invention to the target animal. In this method, the control agent or the control agent composition can be administered to the animal in a conventional manner. The effective amount varies depending on the type of preparation, the target animal, the period of ingestion, etc., and can be appropriately selected by increasing or decreasing it regardless of the above range.

[0226] Specifically, for example, the control agent of the present invention is diluted with water to a concentration suitable for administration to the target animal, and the obtained dilution is administered to the target animal. In addition, the dilution ratio can be applied according to the conventional drinking water dilution administration method, for example, it is preferred to use a dilution of about 5 to 10 times. In addition, the control agent of the present invention is diluted with water to a given concentration, and the water-soluble polysaccharides are added thereto and mixed under stirring to form a uniform solution, which is placed at room temperature or stored in a cool place (such as a refrigerator, etc.) to obtain a gel-like solid. Alternatively, when using a gelling agent that dissolves at high temperature and solidifies at low temperature (such as agar, gelatin, etc.), a gelling agent is added to the control agent of the present invention in advance, and it is placed at room temperature or stored in a cool place (such as a refrigerator, etc.) to obtain a gel-like solid. The gel-like solid obtained in this way can also be administered to poultry. In addition, the gel strength during gelation is approximately 200 to 2000 g / cm 2 The appropriate concentration is 0.5 to 3.0%, and when agar is used, it varies depending on the type of agar, but is generally equivalent to a concentration of 0.5 to 3.0%.

[0227] As polysaccharides for gelling the control agent of the present invention in an aqueous medium, for example, agar, carrageenan, carboxymethyl cellulose, starch, mannan, gelatin, sodium alginate, gum arabic, locust bean gum, xanthan gum, chitosan, guar gum, pectin, propylene glycol alginate, arabinogalactan, Ghatti gum, tamarind gum, pullulan, morpholine fatty acid salt, curdlan, tragacanth gum, etc. Among these polysaccharides, agar, starch, mannan, and gelatin are particularly preferably used from the viewpoint of being cheap and easily available.

[0228] For example, if the above-mentioned gel-like solid is administered to poultry of about 0 to 7 days old with less drinking water and feed intake, the genetic program (habit) of the poultry to ingest the solid on the floor with its beak can save effort to ingest the necessary amount of the control agent of the present invention in a short time. At this time, if the probiotics, vaccines, drugs, nutrition, etc. that are difficult to administer to poultry in the young poultry stage as described above are also mixed with the control agent of the present invention as needed, and gelled with water-soluble polysaccharides, the control agent of the present invention can also be efficiently administered to poultry at the same time. In addition, the supply of water and nutrition during the chick period is very important for the subsequent productivity. When nutrition is given, in addition to carbohydrates such as monosaccharides such as glucose, mannose, fructose and their oligomers, disaccharides such as sucrose, proteins such as skim milk, and lipids, vitamins, minerals, etc. can also be supplemented.

[0229] In addition, in order to strengthen or supplement the effect of the coccidiosis control agent of the present invention, existing coccidiosis control agents may be used in combination. When used in combination, the preparation may be a mixture of two or more active ingredients before administration, or two or more different preparations may be administered separately.

[0230] Example

[0231] Hereinafter, the production examples, formulation examples, and test examples of the present invention will be described in more detail, but the present invention is not limited to these examples.

[0232] Manufacturing Example 1.

[0233] Preparation Example of Intermediate (2-2)

[0234] Method for producing 5-cyano-2-(2,2,3,3,3-pentafluoropropoxy)pyridine

[0235] [Chemical formula 11]

[0236]

[0237] 2-Chloro-5-cyanopyridine (4.16 g, 30 mmol) was dissolved in NMP (60 mL), and 2,2,3,3,3-pentafluoropropanol (6.77 g, 1.5 equivalents) and potassium carbonate (12.4 g, 3.0 equivalents) were added, and the mixture was heated at 100°C for 2 hours to react. After cooling to room temperature, water and ethyl acetate were added and the liquid was separated. The organic layer was washed with saturated brine and dried over sodium sulfate. After evaporating the solvent, the product was purified by column chromatography to obtain the target product (7.03 g, yield 93%).

[0238] Manufacturing Example 2.

[0239] Method for producing 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid

[0240] [Chemical formula 12]

[0241]

[0242] 5-cyano-2-(2,2,3,3,3-pentafluoropropoxy)pyridine (6.02 g, 24 mmol) obtained by the above process was dissolved in ethanol (30 mL), and water (30 mL) and sodium hydroxide (9.60 g, 10 equivalents) were added, followed by reflux for 2 hours. After cooling to room temperature, 10% hydrochloric acid water was added dropwise under an ice bath to neutralize it, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated to obtain a mixture containing the target product as the main component (6.40 g).

[0243] Manufacturing Example 3.

[0244] Method for producing 2-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)benzimidazole (intermediate compound 11-6)

[0245] [Chemical formula 13]

[0246]

[0247] 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid (1.47 g, 5.4 mmol) was dissolved in pyridine (10 mL), and phenylenediamine (0.70 g, 1.2 equivalents), DMAP (0.13 g, 0.2 equivalents), and EDC·HCl (1.54 g, 1.5 equivalents) were added, and the mixture was reacted at room temperature for 3 hours. Water and ethyl acetate were added, and the mixture was separated. The organic layer was washed with 10% hydrochloric acid water, potassium carbonate aqueous solution, and saturated brine in sequence, and dried over sodium sulfate. The solvent was evaporated. The residue was dissolved in NMP (10 mL), and p-toluenesulfonic acid monohydrate (3.08 g, 3 equivalents) was added, and the mixture was reacted at 140°C for 1 hour. After cooling to room temperature, potassium carbonate aqueous solution and ethyl acetate were added, and the mixture was separated. The organic layer was washed with saturated brine and dried over sodium sulfate. After evaporating the solvent, the residue was purified by column chromatography to obtain the target product (0.67 g, melting point: 234-239° C., yield 36% (based on the previous step)).

[0248] Manufacturing Example 4.

[0249] Method for producing 2-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)-1-ethylsulfonylbenzimidazole (Compound No. 1-7)

[0250] [Chemical formula 14]

[0251]

[0252] 2-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)benzimidazole (610 mg, 1.8 mmol) obtained by the above process was dissolved in THF (10 mL), and 60% sodium hydride (108 mg, 1.5 equivalents) was added at room temperature with stirring. After reacting for 10 minutes, ethanesulfonyl chloride (463 mg, 2.0 equivalents) was added and reacted for 1 hour. Water and ethyl acetate were added in sequence for separation. The organic layer was washed with potassium carbonate aqueous solution and brine in sequence, and dried over sodium sulfate. After the solvent was distilled off, the concentrated residue was purified by column chromatography to obtain the target product (695 mg, yield 89%).

[0253] Manufacturing Example 5

[0254] Method for producing 5,6-dibromo-2-(6-(2,2,3,3,3-pentafluoropropoxy)pyridin-3-yl)benzimidazole (intermediate compound 11-5)

[0255] [Chemical formula 15]

[0256]

[0257] 6-(2,2,3,3,3-pentafluoropropoxy)nicotinic acid (1.47 g, 5.4 mmol) was dissolved in pyridine (10 mL), and 4,5-dibromophenylenediamine (1.72 g, 1.2 equivalents), DMAP (0.13 g, 0.2 equivalents), and EDC·HCl (1.54 g, 1.5 equivalents) were added, and the mixture was reacted at room temperature for 3 hours. Water and ethyl acetate were added for separation, and the organic layer was washed with 10% hydrochloric acid water, potassium carbonate aqueous solution, and brine in sequence, and dried over sodium sulfate. The solvent was distilled off. The residue was dissolved in acetic acid (10 mL) and reacted under heating reflux for 1 hour. After cooling to room temperature, the mixture was neutralized with sodium hydroxide aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was distilled off, and then purified by column chromatography to obtain the target product (0.43 g, melting point: 218-220°C, yield 16% (from the previous step)).

[0258] Preparation Example 1. Powder

[0259] After 25 parts of a benzimidazole compound and 25 parts of lactose were thoroughly mixed in a mortar, the mixture was thoroughly stirred and mixed to obtain a powder.

[0260] Preparation Example 2. Granules

[0261] 25 parts of a benzimidazole compound and 25 parts of lactose were added and stirred thoroughly to mix. Then, an appropriate amount of water was added to the mixture, and after further stirring, the mixture was granulated with a granulator and air-dried to obtain granules.

[0262] Formulation Example 3. Wettable Powder

[0263] 25 parts of a benzimidazole compound, 65 parts of diatomaceous earth, 5 parts of a higher alcohol sulfate, and 5 parts of an alkylnaphthalenesulfonate were uniformly mixed and pulverized into a fine state to obtain a wettable powder.

[0264] Test Example 1. Evaluation test on the development inhibition of chicken coccidia (Eimeria tenella)

[0265] The benzimidazole compound represented by the general formula (1) of the present invention or its salt is diluted to a given concentration by a conditioning solution and placed in a microtiter plate, and mammalian cells infected with sporozoites of chicken coccidia are incubated therein. After 48 hours, the degree of inhibition of the development of chicken coccidia into mature schizonts is investigated by indirect immunofluorescence, and the EC 50 value.

[0266] As a result, the EC values ​​of compound numbers 1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 2-1, 3-1, 4-1, 11-1, 11-3, 11-4 and 11-5 of the compounds of the present invention were 50 The EC values ​​of compound numbers 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 3-1 and 4-1 were less than 20 μM. 50 The value was below 1 μM.

[0267] It should be noted that it has been confirmed that the compounds of the present application are rapidly hydrolyzed in the presence of water and are transformed into corresponding intermediates. In addition, in the subject animals, when the blood after administration of the compounds of the present application is analyzed, the corresponding intermediates are detected, so the activity against coccidiosis may depend on the intermediates, and the compounds of the present application are more likely to be prodrugs.

[0268] Industrial Applicability

[0269] The present invention can provide a coccidiosis control agent for a target animal that exhibits an excellent effect when administered to the target animal, and a method for using the coccidiosis control agent for a target animal using the coccidiosis control agent.

Claims

1. Use of a benzimidazole compound represented by the following general formula (1) or its salt in the preparation of a coccidiosis control agent, General formula (1) [Chemical formula 1] In the formula, R represents a methyl group or an ethyl group, R 1 represents (b1) (C1-C8) alkyl; (b2) CF3CF2CH2, CF3CH2, CHF2CF2CH2 or CF3CF2CF2CH2; (b3) (C3-C8) cycloalkyl; or (b6) an aryl group having the same or different substituents selected from (e) a halo (C1-C6) alkoxy group, (g) a halo (C1-C6) alkylthio group, (i) a halo (C1-C6) alkylsulfinyl group, (k) a halo (C1-C6) alkylsulfonyl group and (l) a trimethylsilyl group, X represents O, S, SO, SO2, N(n-Pro) or Y represents a (c1) halogen atom, m represents 0 or 1, Z represents the same or different (d1) halogen atoms; or (d2) methyl groups, n represents 0, 1 or 2, where There are no (C1-C8)alkylsulfonyl groups, (C1-C8)alkoxy(C1-C8)alkylsulfonyl groups, (C3-C8)cycloalkylsulfonyl groups, or halogenated (C1-C8)alkylsulfonyl groups at the 2-position and 4-position of the pyridine ring.

2. The use according to claim 1, wherein R represents a methyl group or an ethyl group, R 1 represents (b1) (C1-C8) alkyl; (b2) CF3CF2CH2, CF3CH2, CHF2CF2CH2 or CF3CF2CF2CH2; (b3) (C3-C8) cycloalkyl; or (b6) an aryl group having the same or different substituents selected from (e) a halo (C1-C6) alkoxy group, (g) a halo (C1-C6) alkylthio group, (i) a halo (C1-C6) alkylsulfinyl group, (k) a halo (C1-C6) alkylsulfonyl group and (l) a trimethylsilyl group, Y represents a (c1) halogen atom, m represents 0 or 1, Z are the same or different and represent (d1) a halogen atom; or a methyl group, n represents 0, 1, or 2.

3. The use according to claim 1, wherein R represents a methyl group or an ethyl group, R 1 represents (b1) a halogenated (C1-C8) alkyl group, m means 0.

4. The use according to claim 1, wherein R represents a methyl group or an ethyl group, R 1 represents (b1) a halogenated (C1-C8) alkyl group, m represents 0, Z are the same or different and represent (d1) a halogen atom; or a methyl group, n means 2.

5. The use according to any one of claims 1 to 4, wherein The coccidiosis control agent is used for target animals other than humans.

6. The use according to claim 5, wherein The target animals are birds.

7. The use according to claim 5, wherein The target animals are chickens.

8. The use according to claim 1, wherein The benzimidazole compound represented by the general formula (1) or a salt thereof is a benzimidazole compound represented by the following general formula (1a), (1c) or (1aa), wherein the compound number is 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-11, 1-12, 1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22, 1-23, 1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 3-1 or 4-1, or a salt thereof;

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