Triazolylpyridine compound, parasite control agent for animals, method for controlling animal parasite, and method for preventing and treating parasitic disease

Abstract

Provided is a compound represented by formula (I) or a salt thereof. [In formula (I), R1 represents a substituted or unsubstituted C1-6 alkyl group; X represents a sulfur atom, a sulfinyl group, a sulfonyl group, or the like; each R2 independently represents a substituted or unsubstituted C1-6 alkyl group, a halogeno group, or the like; n denotes the number of R2 units and is 0, 1, or 2; R3 represents a substituted or unsubstituted C2-6 alkenyl group; and R4 represents a substituted or unsubstituted C1-6 alkyl group.]

Description

Triazolylpyridine compound, animal parasite control agent, method for controlling animal parasites, and method for preventing and treating parasitic diseases

[0001] The present invention relates to a triazolylpyridine compound, an animal parasite control agent, a method for controlling animal parasites, and a method for preventing and treating parasitic diseases.This application claims priority to Japanese Patent Application No. 2024-101835, filed on June 25, 2024, the contents of which are incorporated herein by reference.

[0002] Ectoparasites such as fleas, lice, flies, mosquitoes, ticks, and mites, as well as endoparasites such as gastrointestinal nematodes, trematodes, and heartworms, are targets for the healthy raising of animals. These parasites, at the egg, larval, pupal, nymph, and adult stages, can reduce the weight gain of the host, impair its health, and even cause death. These parasites also contribute to the spread of disease and discomfort in the host. In particular, ectoparasites are known to harbor and transmit a variety of microbial pathogens, including bacteria, viruses, and parasitic protozoa. Many of these parasites are pathogenic to humans, other warm-blooded mammals, and birds. Diseases associated with ectoparasites include, but are not limited to, malaria, lymphatic and blood-borne filariasis, trachoma, trypanosomiasis, leishmaniasis, Rocky Mountain spotted fever, Lyme disease, babesiosis, Salmonella, E. coli, and Campylobacter foodborne diseases.

[0003] A key focus in medical treatment of parasiticide infestations is to foster the development of agents capable of controlling them. For example, commonly encountered methods for controlling parasiticide infestations generally focus on the use of agricultural pesticides, which are often unsuccessful or inadequate for at least one of the following reasons: (1) lack of compliance by owners or applicators (requiring frequent administration), (2) behavioral or physiological intolerance of animals to the pesticide product or administration method, (3) development of ectoparasite resistance to the agent, and (4) negative environmental and / or toxicological effects.

[0004] Specifically, ticks and fleas infest wild animals, as well as domestic animals and humans, and are known or suspected to be involved in the transmission of pathogens, including bacteria, viruses, and protozoan parasites. Currently, ticks are thought to be the second most common vector of human disease worldwide, after mosquitoes, but are considered the most important pathogen in North America. Effective control of ectoparasite infestations, such as fleas, in the domestic environment is difficult and often impractical, as it is often necessary to simultaneously treat environmental reservoirs along with the direct host.

[0005] While the use of insecticides and pesticides is beneficial for controlling ectoparasites, alternative or improved compounds, formulations, and methods are needed. Desired compounds, formulations, and methods would not only provide alternative treatments but also overcome at least some of the limitations of current methods. Such limitations include (but are not limited to) toxicity and animal and user / owner safety, efficacy limitations (potency, duration of activity, kill rate), and resistance issues. Also affecting the beneficial use of insecticides and pesticides are administration obstacles, including dosage regimens, user / owner compliance issues with treatment recommendations, and repeated administration. For example, excessive and repeated treatment of animals is often tedious and difficult for users / owners, and therefore, reducing the number of administrations while maintaining efficacy is desirable. Incidentally, Patent Document 1 discloses the following compounds (Nos. 4-10):

[0006]

[0007] International Publication No. 2017 / 104741

[0008] The compounds of the present invention overcome at least some of the limitations of the use of currently used insecticides and repellents, particularly with regard to speed of kill, long duration of effectiveness, and control of ectoparasites such as mites and fleas, or endoparasites such as nematodes.

[0009] As a result of intensive research aimed at solving the above problems, the present inventors have found that a triazolylpyridine compound having a specific structure or a salt thereof is useful for controlling ectoparasites or endoparasites of animals. Based on these findings, the present invention has been completed through further research.

[0010] That is, the present invention is as follows: [1] A compound represented by formula (I) or a salt thereof:

[0011]

[0012] In formula (I), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group, R ２ are each independently a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group, or a halogeno group, and n is R ２ represents the number of ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group.

[0013] [2] An animal parasite control agent containing at least one compound selected from the compound represented by formula (I) described in [1] above and a salt thereof. [3] The animal parasite control agent according to [2], which is a systemically administered drug. [4] The animal parasite control agent according to [2], which is an orally administered drug. [5] The animal parasite control agent according to [2], which is a parenterally administered drug. [6] The animal parasite control agent according to [2], which is a topically administered drug. [7] The animal parasite control agent according to [2], wherein the animal is a companion animal. [8] The animal parasite control agent according to [2], wherein the parasite is an ectoparasite. [9] The animal parasite control agent according to [2], wherein the parasite is an endoparasite.

[10] The animal parasite control agent according to [2], further containing at least one other active ingredient.

[0014]

[11] A method for controlling parasitic infestation inside or on the body surface of an animal in need thereof, the method comprising administering to the animal at least one compound selected from the compound represented by formula (I) according to [1] and a salt thereof.

[12] The method according to

[11] , wherein the administration is systemic.

[13] The method according to

[11] , wherein the administration is oral.

[14] The method according to

[11] , wherein the administration is parenteral.

[15] The method according to

[11] , wherein the administration is topical.

[16] The method according to

[11] , wherein the animal is a companion animal.

[17] The method according to

[11] , wherein the parasite is an ectoparasite.

[18] The method according to

[11] , wherein the parasite is an endoparasite.

[19] The method according to

[11] , wherein at least one other active ingredient is further administered.

[0015]

[20] A method for preventing and treating a disease transmitted through a parasite, comprising administering at least one compound selected from the compounds represented by formula (I) according to [1] and salts thereof to an animal in need thereof.

[21] The method according to

[20] , wherein the administration is systemic administration.

[22] The method according to

[20] , wherein the administration is oral administration.

[23] The method according to

[20] , wherein the administration is parenteral administration.

[24] The method according to

[20] , wherein the administration is topical administration.

[25] The method according to

[20] , wherein the animal is a companion animal.

[26] The method according to

[20] , wherein the parasite is an ectoparasite.

[27] The method according to

[20] , wherein the parasite is an endoparasite.

[28] The method according to

[20] , wherein at least one other active ingredient is further administered.

[0016]

[29] A method for producing a compound represented by formula (im-1), comprising chemically reacting a compound represented by formula (im-5) with a compound represented by formula (im-6) in the presence of a base, and chemically reacting the product of the chemical reaction with a halogenating agent.

[0017] In formula (im-5), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group. ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group.

[0018]

[0019]

[0020] In formula (im-1), R 1 , R ３ , R ４ , and X are the same as those in formula (im-5). １ is a halogeno group.

[0021]

[30] A method for producing a compound represented by formula (IA), comprising chemically reacting a compound represented by formula (im-1) with a compound represented by formula (im-3) in the presence of a base, and reducing the product of the chemical reaction.

[0022]

[0023] In formula (im-1), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group. ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group. １ is a halogeno group.

[0024]

[0025]

[0026] In formula (IA), R 1 , R ３ , R ４ , and X are the same as those in formula (im-1).

[0027] The present invention includes an agent for controlling parasites in or on the body surface of an animal, a method for controlling parasites in or on the body surface of an animal, and provides an option for dealing with parasite control, particularly ectoparasite control for pet animals.In addition, the compound of the present invention can overcome at least some of the limitations of currently used insecticides and insecticides, particularly limitations regarding kill speed, long effective period, and control of ectoparasites such as mites and fleas, or endoparasites such as nematodes.

[0028] The triazolylpyridine compound of the present invention is a compound represented by the following formula (I) (hereinafter, may be referred to as compound (I)) or a salt of compound (I).

[0029]

[0030] In the present invention, the term "unsubstituted" refers to only the core group. When the name of the core group alone is used without the term "substituted," it means "unsubstituted" unless otherwise specified. On the other hand, the term "substituted" means that any hydrogen atom in the core group has been replaced with a group (substituent) of the same or different structure as the core group. Therefore, a "substituent" is another group bonded to the core group. The number of substituents may be one or more. The two or more substituents may be the same or different. A term such as "C1-6" indicates that the core group has 1 to 6 carbon atoms, for example. This number of carbon atoms does not include the number of carbon atoms in the substituent. For example, a butyl group having an ethoxy group as a substituent is classified as a C2 alkoxy C4 alkyl group. The "substituent" is not particularly limited as long as it is chemically permissible and provides the effects of the present invention.

[0031] Examples of groups that can serve as "substituents" include: C1-6 alkyl groups such as methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl; C2-6 alkenyl groups such as vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, and 2-methyl-2-propenyl; C2-6 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and 1-methyl-2-propynyl;

[0032] C3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; phenyl and naphthyl groups; phenyl C1-6 alkyl groups such as benzyl and phenethyl groups; 3- to 6-membered heterocyclyl groups; 3- to 6-membered heterocyclyl C1-6 alkyl groups;

[0033] hydroxyl groups; C1-6 alkoxy groups such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, and t-butoxy groups; C2-6 alkenyloxy groups such as vinyloxy, allyloxy, propenyloxy, and butenyloxy groups; C2-6 alkynyloxy groups such as ethynyloxy and propargyloxy groups; phenoxy and naphthoxy groups; phenyl C1-6 alkoxy groups such as benzyloxy and phenethyloxy groups; 5- to 6-membered heteroaryloxy groups such as thiazolyloxy and pyridyloxy groups; 5- to 6-membered heteroaryl C1-6 alkyloxy groups such as thiazolylmethyloxy and pyridylmethyloxy groups;

[0034] a formyl group; a C1-6 alkylcarbonyl group such as an acetyl group or a propionyl group; a formyloxy group; a C1-6 alkylcarbonyloxy group such as an acetyloxy group or a propionyloxy group; a benzoyl group; a C1-6 alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group or a t-butoxycarbonyl group; a C1-6 alkoxycarbonyloxy group such as a methoxycarbonyloxy group, an ethoxycarbonyloxy group, an n-propoxycarbonyloxy group, an i-propoxycarbonyloxy group, an n-butoxycarbonyloxy group or a t-butoxycarbonyloxy group; a carboxyl group;

[0035] halogeno groups such as a fluoro group, a chloro group, a bromo group, and an iodo group; C1-6 haloalkyl groups such as a chloromethyl group, a chloroethyl group, a trifluoromethyl group, a 1,2-dichloro-n-propyl group, a 1-fluoro-n-butyl group, and a perfluoro-n-pentyl group; C2-6 haloalkenyl groups such as a 2-chloro-1-propenyl group and a 2-fluoro-1-butenyl group; C2-6 haloalkynyl groups such as a 4,4-dichloro-1-butynyl group, a 4-fluoro-1-pentynyl group, and a 5-bromo-2-pentynyl group; C1-6 haloalkoxy groups such as a trifluoromethoxy group, a 2-chloro-n-propoxy group, and a 2,3-dichlorobutoxy group; C2-6 haloalkenyloxy groups such as a 2-chloropropenyloxy group and a 3-bromobutenyloxy group; C1-6 haloalkylcarbonyl groups such as a chloroacetyl group, a trifluoroacetyl group, or a trichloroacetyl group;

[0036] amino groups; C1-6 alkyl-substituted amino groups such as methylamino, dimethylamino, and diethylamino; anilino and naphthylamino groups; phenyl C1-6 alkylamino groups such as benzylamino and phenethylamino; formylamino groups; C1-6 alkylcarbonylamino groups such as acetylamino, propanoylamino, butyrylamino, and i-propylcarbonylamino; C1-6 alkoxycarbonylamino groups such as methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, and i-propoxycarbonylamino; unsubstituted or substituted aminocarbonyl groups such as aminocarbonyl, dimethylaminocarbonyl, phenylaminocarbonyl, and N-phenyl-N-methylaminocarbonyl; imino C1-6 alkyl groups such as iminomethyl, (1-imino)ethyl, and (1-imino)-n-propyl; Substituted or unsubstituted N-hydroxyimino C1-6 alkyl groups such as an N-hydroxy-iminomethyl group, a (1-(N-hydroxy)-imino)ethyl group, a (1-(N-hydroxy)-imino)propyl group, an N-methoxy-iminomethyl group, or a (1-(N-methoxy)-imino)ethyl group; an aminocarbonyloxy group; a C1-6 alkyl-substituted aminocarbonyloxy group such as an ethylaminocarbonyloxy group or a dimethylaminocarbonyloxy group;

[0037] a mercapto group; a C1-6 alkylthio group such as a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group, an n-butylthio group, an i-butylthio group, an s-butylthio group, or a t-butylthio group; a C1-6 haloalkylthio group such as a trifluoromethylthio group or a 2,2,2-trifluoroethylthio group; a phenylthio group or a naphthylthio group; a 5- or 6-membered heteroarylthio group such as a thiazolylthio group or a pyridylthio group;

[0038] C1-6 alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, and t-butylsulfinyl groups; C1-6 haloalkylsulfinyl groups such as trifluoromethylsulfinyl and 2,2,2-trifluoroethylsulfinyl groups; phenylsulfinyl groups; 5- to 6-membered heteroarylsulfinyl groups such as thiazolylsulfinyl and pyridylsulfinyl groups;

[0039] C1-6 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, and t-butylsulfonyl groups; C1-6 haloalkylsulfonyl groups such as trifluoromethylsulfonyl and 2,2,2-trifluoroethylsulfonyl groups; phenylsulfonyl groups; 5- to 6-membered heteroarylsulfonyl groups such as thiazolylsulfonyl and pyridylsulfonyl groups; C1-6 alkylsulfonyloxy groups such as methylsulfonyloxy, ethylsulfonyloxy, and t-butylsulfonyloxy groups; C1-6 haloalkylsulfonyloxy groups such as trifluoromethylsulfonyloxy and 2,2,2-trifluoroethylsulfonyloxy groups;

[0040] Tri-C1-6 alkyl-substituted silyl groups such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl; triphenylsilyl group; cyano group; and nitro group.

[0041] In addition, any hydrogen atom in these "substituents" may be substituted with a group of a different structure. In this case, examples of the "substituent" include a C1-6 alkyl group, a C1-6 haloalkyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a halogeno group, a cyano group, and a nitro group.

[0042] Furthermore, the above-mentioned "3- to 6-membered heterocyclyl group" contains 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms as ring-constituting atoms. The heterocyclyl group may be either monocyclic or polycyclic. In a polycyclic heterocyclyl group, as long as at least one ring is a heterocycle, the remaining rings may be saturated alicyclic, unsaturated alicyclic, or aromatic. Examples of the "3- to 6-membered heterocyclyl group" include 3- to 6-membered saturated heterocyclyl groups, 5- to 6-membered heteroaryl groups, and 5- to 6-membered partially unsaturated heterocyclyl groups.

[0043] Examples of the "3- to 6-membered saturated heterocyclyl group" include an aziridinyl group, an epoxy group, a pyrrolidinyl group, a tetrahydrofuranyl group, a thiazolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group, a dioxolanyl group, and a dioxanyl group.

[0044] Examples of "5-membered heteroaryl groups" include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl groups. Examples of "6-membered heteroaryl groups" include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and triazinyl groups. Examples of "5- to 6-membered partially unsaturated heterocyclyl groups" include 5-membered partially unsaturated heterocyclyl groups such as pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, imidazolinyl, pyrazolinyl, oxazolinyl, isoxazolinyl, thiazolinyl, and isothiazolinyl groups; and 6-membered partially unsaturated heterocyclyl groups such as dihydropyranyl.

[0045] In formula (I), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group, R ２are each independently a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group, or a halogeno group, and n is R ２ represents the number of , which is 0, 1 or 2. ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group.

[0046] R １ The "C1-6 alkyl group" in the above may be a straight chain or a branched chain. Examples of the "C1-6 alkyl group" include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an i-propyl group, an i-butyl group, an s-butyl group, an t-butyl group, an i-pentyl group, a neopentyl group, a 2-methylbutyl group, and an i-hexyl group.

[0047] R １ Preferred substituents on the "C1-6 alkyl group" in the formula (I) are a halogeno group, a hydroxyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a C3-6 cycloalkyl group, a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, and a cyano group; a phenyl group substituted with one or more substituents of a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; a 5-membered heteroaryl group substituted with one or more substituents of a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; or a 6-membered heteroaryl group substituted with one or more substituents of a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group. １ is preferably an ethyl group.

[0048] R a The "substituted or unsubstituted C1-6 alkyl group" in the above R １X is preferably a sulfonyl group.

[0049] R ２ The "substituted or unsubstituted C1-6 alkyl group" in the above R １ Examples of the compounds include the same compounds as those exemplified in R ２ Examples of the "C3-6 cycloalkyl group" in the formula (R) include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. ２ As the substituent on the "C3-6 cycloalkyl group" in R, a halogeno group is preferred. ２ Examples of the "C1-6 alkoxycarbonyl group" in the formula (R) include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, and a t-butoxycarbonyl group. ２ Preferred substituents on the "C1-6 alkoxycarbonyl group" in R are a halogeno group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a C3-6 cycloalkyl group, a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, and a cyano group. ２ Examples of the "halogeno group" in the above formula include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0050] R ３ Examples of the "C2-6 alkenyl group" in the above formula include vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, and 5-hexenyl group.

[0051] R ３Preferred substituents on the "C2-6 alkenyl group" in the above formula are: a halogeno group, a hydroxyl group, a C1-6 alkoxy group, a C1-6 haloalkoxy group, a C3-6 cycloalkyl group, a phenyl group, a 5-membered heteroaryl group, a 6-membered heteroaryl group, or a cyano group; a phenyl group substituted with one or more substituents of a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; a 5-membered heteroaryl group substituted with one or more substituents of a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group; or a 6-membered heteroaryl group substituted with one or more substituents of a C1-6 alkyl group, a C1-6 alkoxy group, a halogeno group, a C1-6 haloalkyl group, or a C1-6 haloalkoxy group.

[0052] R ３ As R, a "C2-6 alkenyl group substituted with a halogeno group (sometimes referred to as a C2-6 haloalkenyl group)" is preferred. Examples of a "C2-6 haloalkenyl group" include a 2,3,3,3-tetrafluoro-1-propenyl group, a 3,3,3-trifluoro-1-propenyl group, a 2-chloro-3,3,3-trifluoro-1-propenyl group, a 2-bromo-3,3,3-trifluoro-1-propenyl group, a 3,3,3-trifluoro-2-trifluoromethyl-1-propenyl group, a 3,3,4,4,4-pentafluoro-1-butenyl group, a 2,3,3,4,4,4-hexafluoro-1-butenyl group, and a 2-chloro-3,3,4,4,4-pentafluoro-1-butenyl group. ３ In the formula (I), the C2-6 haloalkenyl group may be a mixture of E / Z, or may be solely Z or solely E in terms of stereoisomerism.

[0053] R ３ is preferably a group represented by the following formula (II-1), a group represented by the following formula (II-2), or a group represented by the following formula (II-3).

[0054]

[0055] The arrow in the formula indicates the bonding position to the imidazole ring in formula (I). ３ａ R each independently represents a C1-4 haloalkyl group or a halogeno group. ３ｂ R each independently represents a hydrogen atom or a halogeno group. ３ｃ each independently represents a hydrogen atom or a halogeno group. Examples of a "C1-4 haloalkyl group" include a chloromethyl group, a dichloromethyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a perfluoroethyl group, a perfluoropropyl group, and a perfluorobutyl group. Examples of a "halogeno group" include a fluoro group, a chloro group, a bromo group, and an iodo group.

[0056] R ４ The "substituted or unsubstituted C1-6 alkyl group" in the above R １ Examples of the compounds include the same compounds as those exemplified in R ４ is preferably a methyl group.

[0057] The triazolylpyridine compound of the present invention is preferably a compound represented by the following formula (IA) (hereinafter, may be referred to as compound (IA)) or a salt of compound (IA).

[0058]

[0059] R in the formula １ , R ３ , R ４ and X have the same meanings as those in formula (I).

[0060] The salt of Compound (I) is not particularly limited as long as it is a veterinarily acceptable salt. Examples of the salt of Compound (I) include salts of inorganic acids such as hydrochloric acid and sulfuric acid; salts of organic acids such as acetic acid and lactic acid; salts of alkali metals such as lithium, sodium, and potassium; salts of alkaline earth metals such as calcium and magnesium; salts of transition metals such as iron and copper; ammonia; and salts of organic bases such as triethylamine, tributylamine, pyridine, and hydrazine.

[0061] The method for producing compound (I) or a salt of compound (I) is not particularly limited. For example, compound (I) or a salt of compound (I) can be obtained by a known production method described in the Examples, etc. Furthermore, a salt of compound (I) can be obtained from compound (I) by a known method.

[0062] Methods for Producing Compound (I) Production Method 1 The compound of formula (I) can be produced by a method comprising a step of reacting a compound of formula (im-1) with a compound of formula (im-2), as shown in Scheme 1.

[0063]

[0064] The compound of formula (im-1) is X １ is a halogeno group, and the other symbols are the same as defined in the compound of formula (I). The compound of formula (im-1) can be prepared by one or more of the methods described herein (see Preparation Method 3). The compound of formula (im-2) is a compound in which the symbols are the same as defined in the compound of formula (I). The compound of formula (im-2) may be commercially available or may be prepared by a well-known method. The compound of formula (I) can be prepared by reacting the compound of formula (im-1) with the compound of formula (im-2) by a well-known method. The reaction may be carried out in the presence of a base. Examples of the base include common inorganic bases and organic bases, and alkali metal carbonates, alkaline earth metal acetates, tertiary amines, or aromatic amines are preferably used. is preferably used. In some cases, the compound of formula (im-2) does not bond to the compound of formula (im-1) at the 2-position of the triazole, resulting in a compound with a different substitution position. In this case, the compound can be purified by a general purification method such as crystallization, chromatography, etc. Examples of the compound of formula (im-1) include the following compounds.

[0065]

[0066] Preparation Method 2 Among the compounds of formula (I), a compound having no substituent on the triazole ring (sometimes referred to as a compound of formula (IA)) can be prepared by a method including a reaction step of reacting a compound of formula (im-1) with a compound of formula (im-3) to obtain a compound of formula (im-4), and a subsequent reduction step, as shown in Scheme 2.

[0067]

[0068] The compound of formula (IA) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-3) may be commercially available or may be prepared by known methods. The compound of formula (im-4) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-4) can be prepared by reacting the compound of formula (im-1) with the compound of formula (im-3) in the presence of a base. Examples of the base include common organic bases, and tertiary amines or aromatic amines are preferably used. The compound of formula (IA) can be prepared by reducing the compound of formula (im-4). The reduction is preferably catalytic hydrogenation using a heterogeneous catalyst such as Pd / C.

[0069] Preparation Method 3 The compound of formula (im-1) can be prepared by a method comprising the steps of reacting a compound of formula (im-5) with a compound of formula (im-6) to give a compound of formula (im-7a) or a compound of formula (im-7b), and subsequently reacting the compound with a halogenating agent, as shown in Scheme 3.

[0070]

[0071] The compound of formula (im-5) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-5) can be prepared by one or more of the methods described herein (see Preparation Method 4). The compound of formula (im-6) may be commercially available or may be prepared by known methods. For example, it can be prepared by reacting a propiolic acid ester with ammonia gas or aqueous ammonia. The compound of formula (im-7a) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-7b) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-7a) and the compound of formula (im-7b) are tautomers. The compound of formula (im-7a) or the compound of formula (im-7b) can be prepared by reacting the compound of formula (im-5) with the compound of formula (im-6) in the presence of a base. Examples of the base include general inorganic bases and organic bases, and alkali metal salts, alkaline earth metal salts, tertiary amines, or aromatic amines are preferably used. The compound of formula (im-1) can be produced by reacting the compound of formula (im-7a) or the compound of formula (im-7b) with a halogenating agent. Preferred examples of the halogenating agent include phosgene, oxalyl chloride, and thionyl chloride. Examples of the compound of formula (im-5) include the following compounds:

[0072]

[0073] Preparation Method 4 The compound of formula (im-5) can be prepared by a method comprising the steps of reacting a compound of formula (im-8) with a compound of formula (im-9) to give a compound of formula (im-10), and subsequently reacting the compound with a compound of formula (im-11), as shown in Scheme 4.

[0074]

[0075] The compound of formula (im-8) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-8) can be prepared by one or more of the methods described herein (see Preparation Method 5). R in formula (im-9) ａ is a C1-6 alkyl group. The compound of formula (im-9) may be commercially available. The compound of formula (im-10) is a compound in which the symbols are the same as those defined in the compound of formula (I). R ａ are the same as those in formula (im-9). The compound of formula (im-11) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-11) can be produced by a well-known method. The compound of formula (im-10) can be produced by reacting the compound of formula (im-9) in the presence of an organic base. Preferred examples of the organic base include tertiary amines such as triethylamine and diisopropylethylamine. The compound of formula (im-5) can be produced by reacting the compound of formula (im-10) with the compound of formula (im-11). Examples of the compound of formula (im-8) include the following compounds.

[0076]

[0077] Preparation Method 5 The compound of formula (im-8) can be prepared by a method comprising a step of reacting the compound of formula (im-12) with p-toluenesulfonylmethyl isocyanide (TosMIC), as shown in Scheme 5.

[0078]

[0079] The compound of formula (im-12) is a compound in which the symbols are the same as those defined in the compound of formula (I). The compound of formula (im-12) may be commercially available or may be prepared by a known method. The compound of formula (im-8) can be prepared by reacting the compound of formula (im-12) with TosMIC in the presence of a base. Examples of the base include general inorganic bases and organic bases, and alkali metal salts, alkaline earth metal salts, tertiary amines, and aromatic amines are preferably used. Specific examples of the base include tertiary amines such as triethylamine, tributylamine, and diisopropylethylamine; alkylanilines such as N,N-dimethylaniline; heterocyclic amines such as 1,4-diazabicyclo[2.2.2]octane and 1,8-diazabicyclo[5.4.0]-7-undecene; aromatic amines such as pyridine and N,N-dimethylaminopyridine; sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Examples of the compound of formula (im-12) include the following compounds.

[0080]

[0081] The triazolylpyridine compounds and salts thereof of the present invention (hereinafter referred to as "compounds of the present invention") are highly effective in controlling ectoparasites and endoparasites that are harmful to humans and animals. Furthermore, they are highly safe substances due to their low toxicity to fish and warm-blooded animals. Furthermore, the compounds of the present invention are effective against all developmental stages of target organisms, and exhibit excellent control effects against, for example, eggs, nymphs, larvae, pupae, and adults of mites, insects, and the like.

[0082] [Parasite Control Agent, Control Method, and Method for Preventing and Treating Infectious Diseases] The present invention provides a parasite control agent for an animal in need of control of parasitic infestation, which contains at least one compound selected from the compounds of the present invention. The parasite control agent may further contain at least one other active ingredient. The animal may be a mammal, a human, a pet animal such as a dog or a cat, a food-producing animal such as a cow or a sheep, or a bird such as a chicken or a turkey. The present invention provides a control method for an animal in need of control of parasitic infestation, which comprises administering to the animal an effective amount of at least one compound selected from the compounds of the present invention. The method may further comprise administering to the animal at least one other active ingredient. The present invention provides a method for preventing and treating diseases transmitted through parasites, which comprises administering to an animal in need thereof at least one compound selected from the compounds of the present invention. The present invention provides a method for controlling parasites, comprising applying at least one compound selected from the compounds of the present invention to the parasites and / or their habitat. The present invention provides the use of at least one compound selected from the compounds of the present invention for controlling parasites. The present invention provides at least one compound selected from the compounds of the present invention for use in treatment. The present invention further provides at least one compound selected from the compounds of the present invention for use in suppressing parasitic infestation. The present invention also provides the use of at least one compound selected from the compounds of the present invention for producing a formulation or drug for suppressing parasitic infestation.

[0083] [Ectoparasite Control Agent and Ectoparasite Control Method] The ectoparasite control agent of the present invention contains at least one compound selected from the compounds of the present invention as an active ingredient. The ectoparasite control method of the present invention uses at least one compound selected from the compounds of the present invention as an active ingredient. The ectoparasites to be controlled are typically insect and acarid pests that parasitize or infect animals, including their egg, larval, pupal, nymph, and adult stages. Such pests include ticks, fleas, lice, mosquitoes, mites, beetles, and blood-sucking, biting, or harmful flies. The habitat of these pests is primarily the surface of the animal's body. In the case of botflies, they can also be found inside the body. The host animal against which the ectoparasite control agent or control method of the present invention is effective may be a mammal or a non-mammal, such as a bird (turkey, chicken) or fish. When the host animal is a mammal, it may be a human or a non-human mammal. Non-human mammals include livestock animals, such as farm animals and companion animals. Farm animals include cattle, camelids, pigs, sheep, goats, and horses. Companion animals include dogs, rabbits, cats, and other pets that are kept and cared for in close proximity to humans as part of the human-animal bond.

[0084] The mites (Acari) that are the target of control include the following pests. (1) Mites of the order Mesostigmata (a) Mites of the family Dermanyssidae, for example, Dermanyssus gallinae of the genus Dermanyssus; (b) Mites of the family Macronyssidae, for example, Ornithonyssus spp., Ornithonyssus sylviarum, Ornithonyssus bursa, Ornithonyssus bacoti of the genus Ornithonyssus; (c) Mites of the family Laelapidae, for example, Laelaps spp., Laelaps echidninus, Laelaps (d) mites from the family Varroidae, for example, from the genus Varroa, such as Varroa destructor, Varroa jacobsoni, Varroa underwoodi.

[0085] (2) Metastigmata ticks (a) Argasidae ticks, for example, Argas persicus, Argas reflexus, Ornithodoros moubata ... cinnabarina), Haemaphysalis otophila, Haemaphysalis leachi, Haemaphysalis longicornis, Haemaphysalis mageshimaensis, Haemaphysalis yeni, Haemaphysalis campanulata, Haemaphysalis pentalagi, Haemaphysalis flava, Haemaphysalis megaspinosa, Haemaphysalis japonica, Haemaphysalis douglasi; for example, Amblyomma spp.) such as Amblyomma americanum, Amblyomma variegatum, Amblyomma maculatum, Amblyomma hebraeum, Amblyomma cajennense, Amblyomma testudinarium; for example, from Ixodes spp. such as Ixodes ricinus, Ixodes hexagonus, Ixodes canisuga, Ixodes pilosus, Ixodes rubicundus, Ixodes scapularis scapularis, Ixodes holocyclus, Ixodes ovatus, Ixodes persulcatus, Ixodes nipponensis; for example, Boophilus spp.from the genus Rhipicephalus, for example Rhipicephalus (Boophilus) microplus, Rhipicephalus (Boophilus) decoloratus, Rhipicephalus (Boophilus) annulatus, Rhipicephalus (Boophilus) calceratus; from the genus Rhipicephalus, for example Rhipicephalus evertsi, Rhipicephalus sanguineus, Rhipicephalus bursa, Rhipicephalus appendiculatus, Rhipicephalus capensis capensis, Rhipicephalus turanicus, Rhipicephalus zambeziensis; Dermacentor spp., for example, Dermacentor marginatus, Dermacentor reticulatus, Dermacentor pictus, Dermacentor albipictus, Dermacentor andersoni, Dermacentor variabilis.

[0086] (3) Acaridida of the order Astigmata (a) mites of the family Psoroptidae, for example, Psoroptidae spp., Psoroptes ovis, Psoroptes cuniculi, Psoroptes equi; for example, Chorioptes spp., Chorioptes bovis; Otodectes spp., Otodectes cynotis; (b) Sarcoptidae mites, for example, Sarcoptes spp. (c) Mites of the family Knemidokoptidae, for example Knemidokoptes mutans of the genus Knemidokoptes.

[0087] (4) Prostigmata (Actinedida) (a) Demodex mites (Demodixidae), for example, Demodex spp., Demodex canis, Demodex bovis, Demodex ovis, Demodex caprae, Demodex equi, Demodex caballi, Demodex suis, Demodex cati; (b) Trombiculidae mites, for example, Trombicula spp., Trombicula alfreddugesi, Trombicula akamushi.

[0088] The fleas (Siphonaptera) that are the target of control include the following pests. (a) fleas of the Tungidae family, for example, Tunga penetrans of the Tunga spp.; (b) fleas of the Pulicidae family, for example, Ctenocephalides canis and Ctenocephalides felis of the Ctenocephalides spp.; for example, Archaeopsylla erinacei of the Archaeopsylla spp.; for example, Xenopsylla cheopis of the Xenopsylla spp.; for example, Pulex irritans of the Pulex spp.; for example, Echidnophaga (c) fleas of the family Ceratophyllidae, for example, from the genus Ceratophyllus, the chicken flea (Ceratophyllus gallinae), the Japanese rat flea (Ceratophyllus anisus); from the genus Nosopsyllus, for example, the European rat flea (Nosopsyllus fasciatus); (d) fleas of the family Leptopsyllidae, for example, from the genus Leptopsylla, the mole rat flea (Leptopsylla segnis).

[0089] Other ectoparasites that can be controlled include pests of the order Hemiptera.

[0090] Pests of the Hemiptera order include the following pests: (a) insects of the family Cimicidae, such as the Taiwanese bed bug (Cimex hemipterus) and the bed bug (Cimex lectularius) of the genus Cimex; (b) insects of the family Reduviidae, including the Triatominae subfamily, such as Panstrongylus spp.; Rhodnius spp., such as the Venezuelan assassin bug (Rhodnius prolixus); and Triatoma spp., such as the assassin bug (Triatoma infestans).

[0091] It is also effective against Diptera pests, which are biting insects (chewing flies, adult blood-sucking flies, migratory dipteran larvae, and parasitic fly maggots).

[0092] Pests of flies (Diptera) include the following pests: (1) Nematocera (a) Culicidae mosquitoes, for example, Culex spp., Culex quinquefasciatus, Culex pipiens pallens, Culex tarsalis, Culex pipiens molestus, Culex pipiens fatigans, Culex tritaeniorhynchus summorosus; for example, Armigeres spp., Armigeres subalbatus; for example, Anopheles spp., Anopheles gambiae, Anopheles maculipennis, Anopheles (b) blackflies of the family Simuliidae, for example, from the genus Simuliidae, Simulium reptans, Simulium ornatum, Simulium venustum, Simulium lesteri, Aedes spp., Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Aedes togoi, Aedes vexans nipponii; (c) blackflies of the family Simuliidae, for example, from the genus Simuliidae, Simulium reptans, Simulium ornatum, Simulium venustum, Simulium lesteri, Aedes spp., Aedes aegypti, Aedes albopictus, Aedes taeniorhynchus, Aedes togoi, Aedes vexans nipponii, Aedes vexans nipponii, Aedes spp. ... salopiense; for example, Prosimulium spp., Prosimulium yezoense; (c) midges of the family Ceratopogonidae, for example, Culicoides spp.) Chicken midge (Culicoides arakawae), pale midge (Culicoides pictimargo), yellow midge (Culicoides kibunensis), second-spotted midge (Culicoides homotomus), cow midge (Culicoides oxystoma), Japanese midge (Culicoides nipponensis), spotted midge (Culicoides punctatus), mountain midge (Culicoides maculatus), and Matsuzawa midge (Culicoides matsuzawai).

[0093] (2) Brachycephalus suborder (a) Tabanidae, for example, Tabanus spp., Tabanus bromius, Tabanus spodopterus, Tabanus atratus, Tabanus sudeticus, Tabanus trigonus, Tabanus chrysurus, Tabanus trigeminus, Tabanus fulvimedioides, Tabanus iyoensis; for example, Chrysops spp., Chrysops caecutiens, Chrysops relictus (b) flies of the family Muscidae, for example, of the genus Muscina, such as the house fly Musca domestica, the black house fly Musca bezzii, the common house fly Musca hervei, the light house fly Musca conducens, the big house fly Musca stabulans; of the genus Stomoxys, such as the stable fly Stomoxys calcitrans; of the genus Haematobia, such as the horn fly Haematobia irritans, Haematobia irritans exigua exigua), Haematobia stimulans; of the genus Fannia, for example Fannia canisularis; (c) of the family Glossinidae, for example Glossina spp.; (e) flies of the family Hippoboscidae, for example Melophagus spp.(d) flies of the Calliphoridae family, for example, the blowfly Calliphora lata of the Calliphora genus; for example, the blowfly Lucilia (Phaenicia) cuprina, the blowfly Lucilia (Phaenicia) sericata, the blowfly Lucilia illustris of the Lucilia genus; for example, the screwworm Chrysomya hominivorax, Chrysomya chloropyga, Chrysomya bezziana of the Chrysomyia genus; (e) Flies of the family Oestridae, for example, Cuterebrinae subfamily Cuterebrinae's Cuterebrinae's Cuterebrinae's Cuterebrinae's Cuterebrinae's Cuterebrinae's Cuterebrinae's Cuterebrinae's Hypoderma bovis and Hypoderma lineatum; for example, Gasterophilinae subfamily Gasterophilinae's Gasterophilus spp.'s Gasterophilus intestinalis, Gasterophilus haemorroidalis, Gasterophilus inermis, Gasterophilus spp.'s Gasterophilus nasalis, Gasterophilus nigricornis, Gasterophilus pecorum; for example, the sheep fly Oestrus ovis, from the subfamily Oestrinae and also from the genus Oestrus.

[0094] By administering the compound of the present invention to an animal and controlling the above-mentioned ectoparasites, it is possible to prevent diseases transmitted through parasites and other pathological conditions, or damage directly caused by parasites (hereinafter sometimes referred to as parasitic diseases). By administering the compound of the present invention to an animal and controlling the above-mentioned ectoparasites, it is possible to partially or completely inhibit the occurrence of parasitic diseases in animals susceptible to parasitic diseases, reduce or eliminate the symptoms of parasitic diseases, and partially or completely cure or treat parasitic diseases.

[0095] Diseases transmitted by external parasites include bacterial, viral, and protozoan-borne diseases. Some, like flies, carry pathogens to other locations by attaching them to their sticky legs, while others are pests whose pathogens develop and multiply inside their bodies, becoming the source of infection. Specific examples are listed below.

[0096] (1) Viral diseases (a) Akabane disease, which is transmitted by Culicoides oxystoma through the Akabane virus of the Bunyaviridae family; Aino virus disease, which is transmitted through the Aino virus; Ibaraki disease, which is transmitted through the Ibaraki virus of the Reoviridae family; Chuzan disease, which is transmitted through the Chuzan virus; Bluetongue disease, which is transmitted through the Bluetongue virus of the Orbivirus genus of the Reoviridae family; Other arboviruses, such as Peaton virus, Sathuperi virus, D'Aguilar virus, and Shamonda virus, are transmitted through arboviruses; (b) swine cholera, which is transmitted by Culex quinquefasciatus through the swine cholera virus of the Flaviviridae family; (c) Japanese encephalitis, which is transmitted by Culex tritaeniorhynchus summorosus and Culex pipiens pallens via the Japanese encephalitis virus of the Flaviviridae family; (d) Newcastle disease in birds, which is transmitted by the little house fly Fannia canisularis via the Newcastle disease virus (NDV); and (e) equine infectious anemia, which is transmitted by blood-sucking insects such as horseflies (Tabanidae) via the equine infectious anemia virus of the Retroviridae family, Lentivirus genus.

[0097] (2) Bacterial diseases (a) Japanese scarlet fever, or rickettsiosis, in dogs, transmitted by the long-spined tick (Haemaphysalis longicornis) through Richettsia japonica, a Rickettsia spp.; (b) Tularemia, transmitted by the flava tick (Haemaphysalis flava) through Francisella tularensis; (c) Feline infectious anemia, transmitted by the ovine tick (Ixodes ovatus) through Candidatus Mycoplasma haemominutum; (d) Anaplasmosis, transmitted by the cow tick (Rhipicephalus (Boophilus) microplus) through Anaplasma marginale; (e) Anaplasmosis, transmitted by the brown dog tick (Rhipicephalus sanguineus) through Anaplasma canine anaplasmosis, transmitted via Haemobartonella platys; canine hemobartonellosis, transmitted via Haemobartonella canis.

[0098] (3) Protozoan-borne diseases: (a) Bovine piroplasmosis, transmitted by the long-spined tick (Haemaphysalis longicornis) through the large piroplasm (Babesia ovata); canine piroplasmosis, transmitted by the Gibson's dog Babesia (Babesia gibsoni); (b) Bovine babesiosis, including Q fever, transmitted by the cow tick (Rhipicephalus (Boophilus) microplus) through the large piroplasm (Babesia bigemia) and the bovine Babesia (Babesia bovis); (c) Canine babesiosis, transmitted by the brown dog tick (Rhipicephalus sanguineus) through the canine Babesia (Babesia canis) and the Gibson's dog Babesia (Babesia gibsoni); canine hepatozoonosis, transmitted by the canine Hepatozoon canis; (d) leucocytozoonosis in chickens, transmitted by the chicken midge (Culicoides arakawae) through the blood sporozoan parasite (Leukocytozoon caulleryi); (e) trypanosomiasis, such as chronic sleeping sickness and acute sleeping sickness, transmitted by blood-sucking insects such as horseflies (Tabanidae) through Trypanosoma ssp.; (f) tapeworm disease in dogs and cats, transmitted by the cat flea (Ctenocephalides felis) through the tapeworm (Diphylidium caninum); (g) Aedes togoi, Aedes albopictus, Culex tritaeniorhynchus summorosus, and Culex pipiens Canine heartworm disease is transmitted by the canine heartworm (Dirofilaria immitis) caused by the canine parasite, Dirofilaria pallens.

[0099] (4) Horsefly larvae and bot fly larvae Some sanitary pests parasitize their hosts internally. For example, horsefly larvae parasitize under the skin of cattle, horsefly larvae parasitize the stomach walls of horses, and sheepfly larvae parasitize the nasal cavities of sheep. Horsefly larvae also parasitize under the skin on the backs of cattle, creating holes in the skin and significantly reducing the value of leather products. Some specific examples are given below.

[0100] (a) Hypoderma bovis, a disease caused by the larvae of the horse fly (Hypoderma bovis) and the yellow horse fly (Hypoderma lineatum); (b) Gasterophilus intestinalis, a disease caused by the larvae of the horse fly (Gasterophilus nasalis), and the red-breasted horse fly (Gasterophilus haemorroidalis); (c) Myiasis, a disease caused by the larvae of the green blowfly (Lucilia illustris).

[0101] (5) Injuries due to parasitism or bites Bites by mites such as Sarcoptes scabiei and Cheyletidae, or insects such as mosquitoes, horseflies, and lice cause severe itching and pain due to physical injury or the injection of venom, causing great stress to the host. Furthermore, secondary infections can occur when animals scratch the affected area. This can lead to insomnia and loss of appetite, and in livestock, reduced milk production, weight gain, and egg production, resulting in a decline in production efficiency and sometimes even death. Specific examples are given below.

[0102] (a) The intense itch caused by stable flies (Stomoxys calcitrans) and horn flies (Haematobia irritans) in cattle; (b) The intense itch caused by pig lice (Haematopinus suis) in pigs; (c) The itch caused by dog ​​fleas (Ctenocephalides canis) in dogs and cats; (d) The itch caused by chicken midge (Culicoides arakawae); and the intense itch caused by chicken bite lice (Menopon gallinae).

[0103] (6) Injuries such as blood-sucking, anemia, and bleeding Many sanitary pests bite and cause stress to their hosts while also sucking their blood. This can cause the host to suffer from anemia, resulting in weakness and poor growth. Specific examples are given below.

[0104] (a) Blood-sucking ticks on cattle, such as Haemaphysalis longicornis, Rhipicephalus (Boophilus) microplus, Ixodes ovatus, Ixodes nipponensis, and Ixodes persulcatus; (b) Blood-sucking ticks on dogs, such as Haemaphysalis longicornis, Rhipicephalus sanguineus, Haemaphysalis flava, Ixodes nipponensis, and Ixodes persulcatus; (c) Blood-sucking ticks, such as Dermanyssus gallinae and Ornithonyssus gallinae. (d) Black flies (Simuliidae) causing bleeding in cattle; (e) Horseflies (Tabanidae) causing anemia in cattle; (f) Cat fleas (Ctenocephalides felis) causing long-term anemia in cats; (g) Chicken midge (Culicoides arakawae) causing anemia in chickens.

[0105] (7) Skin Disorders Infestation and bites by sanitary pests can cause not only itching, redness, swelling, but also serious skin damage. Sarcoptes scabiei mites cause severe itching as well as hair loss, crust formation, and erosion, while Demodex mites cause hair loss and systemic erosion due to secondary infection. In addition, blood-sucking pests generally inject a large amount of saliva when sucking blood, which can cause an allergic reaction, resulting in severe itching as well as redness, swelling, papules, ulcers, and other symptoms. Specific examples are given below.

[0106] (a) Scabies of cattle, horses, and sheep caused by Sarcoptic mange and Sarcoptic mange of the genus Dermpathogens; Scabies of pigs and dogs caused by Sarcoptic mange of the genus Dermpathogens; Scabies of cats caused by Sarcoptic mange of the cat mite; Scabies of dogs and cats caused by Otodectes cynodontii; Scabies of chickens caused by Trichosanthes scabiei; (b) Flea allergy dermatitis caused by cat fleas; (c) Demodex mange caused by Demodex canis; (d) Papules, blisters, and edema caused by black flies.

[0107] [Endoparasite control agent and control method] The endoparasite control agent of the present invention contains at least one compound selected from the compounds of the present invention as an active ingredient. The endoparasite control method of the present invention uses at least one compound selected from the compounds of the present invention as an active ingredient. The parasites to be controlled are parasitic inside host animals, particularly warm-blooded animals and fish (endoparasites). Examples of host animals for which the control agent or method of the present invention is effective include warm-blooded animals such as humans, domestic mammals (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rats, gerbils, etc.), pet animals (e.g., hamsters, guinea pigs, dogs, cats, horses, squirrels, rabbits, ferrets, etc.), wild and zoo mammals (monkeys, foxes, deer, buffalo, etc.), poultry (turkeys, ducks, chickens, quails, geese, etc.), and pet birds (pigeons, parrots, mynah birds, Java sparrows, parakeets, Bengalese finches, canaries, etc.); or fish such as salmon, trout, and koi carp. Controlling and eliminating parasites can prevent or treat parasitic diseases transmitted by parasites.

[0108] Examples of parasites to be controlled include the following: (1) Nematodes of the order Dioctophymatida (a) kidney worms of the family Dioctophymatidae, for example, the kidney worm (Dioctophyma renale) of the genus Dioctophyma; (b) kidney worms of the family Soboliphymatidae, for example, the kidney worm (Soboliphyme abei) and the kidney worm (Soboliphyme baturini) of the genus Soboliphyme.

[0109] (2) Nematodes of the order Trichocephalidae (a) Trichinella of the family Trichinellidae, for example, Trichinella spiralis of the genus Trichinella; (b) Trichuridae whipworms, for example, Capillaria annulata, Capillaria contorta, Capillaria hepatica, Capillaria perforans, Capillaria plica, Capillaria suis of the genus Trichuris; Trichuris vulpis, Trichuris discolor, Trichuris ovis), Trichuris skrjabini, and Trichuris suis.

[0110] (3) Rhabditida Nematodes Strongyloides of the Strongyloididae family, for example, Strongyloides spp., Strongyloides papillosus, Strongyloides planiceps, Strongyloides ransomi, Strongyloides suis, Strongyloides stercoralis, Strongyloides tumefaciens, Strongyloides ratti.

[0111] (4) Strongylid nematodes Hookworms of the Ancylostomatidae family, for example, Ancylostoma spp., Ancylostoma braziliense, Ancylostoma caninum, Ancylostoma duodenale, Ancylostoma tubaeforme; Uncinaria stenocephala, Uncinaria stenocephala; Bunostomum spp., Bunostomum phlebotomum, Bunostomum trigonocephalum.

[0112] (5) Strongylidae nematodes (a) Angiostrongylidae nematodes, for example, Aelurostrongylus spp., cat lungworm (Aelurostrongylus abstrusus); Angiostrongylus spp., Angiostrongylus vasorum, Angiostrongylus cantonesis; (b) Crenosomatidae nematodes, for example, Crenosoma spp., Crenosoma aerophila, Crenosoma vulpis; (c) Filaroididae nematodes, for example, Filaroides spp., dog lungworm (Filaroides (d) lungworms of the family Metastrongylidae, for example, from the genus Metastrongylus, the pig lungworm (Metastrongylus apri), Metastrongylus asymmetricus, Metastrongylus pudendotectus, Metastrongylus salmi; (e) open-beaked worms of the family Syngamidae, for example, from the genus Cyathostoma, the waterfowl lungworm (Cyathostoma bronchialis); from the genus Syngamus, the scrijavin open-beaked worm (Syngamus skrjabinomorpha), chicken open-beak worm (Syngamus trachea).

[0113] (6) Strongylid nematodes (a) Molineidae nematodes, for example, Nematodirus spp., Nematodirus filicollis, Nematodirus spathiger; (b) Dictyocaulidae nematodes, for example, Dictyocaulus spp., Dictyocaulus filaria, Dictyocaulus viviparus; (c) Haemonchidae nematodes, for example, Haemonchus spp., Haemonchus contortus; Mecistocirrus (d) nematodes of the Haemonchidae family, for example, Ostertagia ostertagi of the Ostertagia spp.; (e) nematodes of the Heligmonellidae family, for example, Nippostrongylus braziliensis of the Nippostrongylus spp.; (f) nematodes of the Trichostrongylidae family, for example, Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus tenuis; Hyostrongylus spp., Hyostrongylus rubidus; Obeliscoides spp., Obeliscoides cuniculi.

[0114] (7) Strongylid nematodes (a) nematodes of the Chabertiidae family, for example, Chabertia spp., sheep nematode (Chabertia ovina); Oesophagostomum spp., Oesophagostomum brevicaudatum, Oesophagostomum columbianum, Oesophagostomum dentatum, Oesophagostomum georgianum, Oesophagostomum maplestonei, Oesophagostomum quadrispinulatum, Oesophagostomum radiatum, Oesophagostomum hymenoptera (b) nematodes of the Stephanuridae family, for example, Stephanurus spp., pig kidney worm (Stephanurus dentatus); (c) nematodes of the Strongylidae family, for example, Strongylus spp., donkey strongyle (Strongylus asini), toothless strongyle (Strongylus edentatus), horse strongyle (Strongylusequinus), common strongyle (Strongylus vulgaris).

[0115] (8) Nematodes of the Order Oxyurida Nematodes of the family Oxyuridae, for example, Enterobius spp., chimpanzee pinworm (Enterobius anthropopitheci), pinworm (Enterobius vermicularis); Oxyuris spp., horse pinworm (Oxyuris equi); Passalurus spp., rabbit pinworm (Passalurus ambiguus).

[0116] (9) Nematodes of the order Ascaridida (a) nematodes of the family Ascaridiidae, for example, Ascaridia spp., Ascaridia galli; (b) nematodes of the family Heterakidae, for example, Heterakis spp., Heterakis beramporia, Heterakis brevispiculum, Heterakis gallinarum, Heterakis pusilla, Heterakis putaustralis; (c) nematodes of the family Anisakidae, for example, Anisakis spp. (d) nematodes of the Ascarididae family, for example, Ascaris lumbricoides, Ascaris suum, of the Ascaris genus; Parascaris equorum, of the Parascaria genus; (e) nematodes of the Toxocara family, for example, Toxocara canis, Toxocara leonina, Toxocarasuum, Toxocara vitulorum, Toxocara cati, of the Toxocara genus.

[0117] (10) Nematodes of the order Spirurida (a) Nematodes of the family Onchocercidae, for example, Brugia spp., such as Brugia malayi, Brugia pahangi, and Brugia patei; Dipetalonema spp., such as Dipetalonema reconditum; Dirofilaria spp., such as Dirofilaria immitis; Filaria spp., such as Filaria oculi; Onchocerca spp., such as Onchocerca cervicalis. (b) nematodes of the family Setariidae, for example, from the genus Setaria, Setaria digitata, Setaria equina, Setaria labiatopapillosa, Setaria marshalli; from the genus Wuchereria, Wuchereria bancrofti; (c) nematodes of the family Filariidae, for example, from the genus Parafilaria, Parafilaria multipapillosa; spp.), including Stephanofilaria assamensis, Stephanofilaria dedoesi, Stephanofilaria kaeli, Stephanofilaria okinawaensis, and Stephanofilaria stilesi.

[0118] (11) Nematodes of the order Spirurida (a) nematodes of the family Gnathostomatidae, for example, Gnathostoma doloresi, Gnathostoma spinigerum, of the genus Gnathostoma; (b) nematodes of the family Habronematidae, for example, Habronema majus, Habronema microstoma, Habronema muscae, of the genus Habronema; Draschia megastoma, of the genus Draschia; (c) Physalopteridae nematodes, for example, Physaloptera spp., dog stomach worm (Physaloptera canis), fox stomach worm (Physaloptera cesticillata), Physaloptera erdocyona, Physaloptera felidis, Egyptian cat stomach worm (Physaloptera gemina), Physaloptera papilloradiata, cat stomach worm (Physaloptera praeputialis), Physaloptera pseudopraerutialis, Rara stomach worm (Physaloptera rara), Physaloptera sibirica, Physaloptera vulpinius (Physaloptera (d) nematodes of the family Gongylonematidae, for example, Gongylonema spp., Gongylonema pulchrum; (e) nematodes of the family Spirocercidae, for example, Ascarops spp.(f) Nematodes of the family Thelaziidae, for example, Thelazia spp., such as Thelazia callipaeda, Thelazia gulosa, Thelazia lacrymalis, Thelazia rhodesi, and Thelazia skrjabini.

[0119] When the compound of the present invention is administered, it can penetrate into the body of the parasite or be near the parasite, resulting in a repellent effect due to the presence of the compound of the present invention. For application on or inside the body of an animal, the dosage of the compound of the present invention in this method ranges from 0.01 to 1000 mg / kg of the animal's body weight, more preferably 0.1 to 100 mg / kg. The frequency of administration also depends on several factors and can be a single administration for the necessary period as determined by the attending physician, veterinarian, or other appropriately trained person. Additional active ingredients may be administered in conjunction with the compound of the present invention. The term "pharmaceutically acceptable" as used in this application encompasses the meanings of "dermatologically acceptable" and "veterinarily acceptable," and therefore includes individual application to animals. "Controlling" refers to ameliorating or eliminating ongoing infestation or preventing infestation in or on the body of an animal host by administering at least one compound selected from the compounds of the present invention. "Effective amount" refers to an amount of at least one compound selected from the compounds of the present invention sufficient to control ectoparasite infestations, including measurably reducing ectoparasite populations, which itself will depend on several factors.

[0120] In the control agent or control method of the present invention, at least one additional active ingredient may be used simultaneously by mixing, combining, etc. The additional active ingredient may be in the form of a pharmaceutical formulation or a veterinary drug formulation.

[0121] Additional active ingredients include: (1B) Acetylcholinesterase (AChE) inhibitors (organophosphates): Acephate, Azamethiphos, Azinphos-ethyl, Azinphosmethyl, Cadusafos, Chlorethoxyfos, Chlorfenvinphos, Chlormephos, Chlorpyrifos, Chlorpyrifos-methyl, Coumaphos, Cyanophos, Demeton-S-methyl, Diazinon, Dichlorvos DDVP), Dicrotophos, Dimethoate, Dimethylvinphos, Disulfoton, EPN, Ethion, Ethoprophos, Famphur, Fenamiphos, Fenitrothion, Fenthion, Fosthiazate, Heptenophos, Imicyafos, Isofenphos, Isopropyl O-(methoxyaminothio-phosphoryl) salicylatesalicylate, Isoxathion, Malathion, Mecarbam, Methamidophos, Methidathion, Mevinphos, Monocrotophos, Naled, Omethoate, Oxydemeton-methyl, Parathion, Parathion-methyl, Phenthoate, Phorate, Phosalone, Phosmet, Phosphamidon, Phoxim, Pirimiphos-methyl methyl), Profenofos, Propetamphos, Prothiofos, Pyraclofos, Pyridaphenthion, Quinalphos, Sulfotep, Tebupirimfos, Temephos, Terbufos, Tetrachlorvinphos, Thiometon, Triazophos, Trichlorfon, Vamidothion, Bromophos-e, Cyanofenphos, Demeton-S-methylsulfone), Dialifos, Dichlofenthion, Dioxabenzofos, Etrimfos, Fensulfothion, Fonofos, Formothion, Iodofenphos, Isazofos, Isocarbofos, Methacrifos, Phosphocarb, Pirimiphos-ethyl, Propaphos, Prothoate, Sulprofos.

[0122] (2) GABAergic chloride channel blockers: Chlordane, Endosulfan, Ethiprole, Fipronil, Acetoprole, Camphechlor, Dienochlor, Heptachlor, Pyrafluprole, Pyriprole, Flufiprole. (3A) Sodium channel modulators (pyrethroids) Acrinathrin, Allethrin, d-cis-trans-Allethrin, d-trans-Allethrin, Bifenthrin, Bioallethrin, Bioallethrin-S-cyclopentenyl-isomer S-cyclopentenyl-isomer), Bioresmethrin, Cycloprothrin, Cyfluthrin, beta-cyfluthrin, Cyhalothrin, lambda-cyhalothrin, gamma-cyhalothrin, Cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, Cyphenothrin [(1R)-trans-isomers] ), Deltamethrin, Empenthrin [(EZ)-(1R)-isomers]), Esfenvalerate, Etofenprox, Fenpropathrin, Fenvalerate, Flucythrinate, Flumethrin, tau-Fluvalinate, Halfenprox, Imiprothrin, Kadethrin, Permethrin, Phenothrin [(1R)-trans-isomer] ), Prallethrin, Pyrethrins, Resmethrin, Silafluofen, Tefluthrin, Tetramethrin, Tetramethrin [(1R)-isomers], Tralomethrin, Transfluthrin.κ-Bifenthrin, Biopermethrin, Chloroprallethrin, Dimefluthrin, Fenfluthrin, Fenpirithrin, Flufenprox, Heptafluthrin, Meperfluthrin, ε-Metofluthrin ), Momfluorothrin, ε-Momfluorothrin, trans-Permethrin, Profluthrin, Protrifenbute, κ-Tefluthrin, Terallethrin, Tetramethylfluthrin; Bioethanomethrin. (3B) Sodium channel modulators (DDTs) DDT, Methoxychlor.

[0123] (4) Nicotinic acetylcholine receptor (nAChR) competitive modulators: acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, thiamethoxam; nicotine; sulfoxaflor; flupyradifurone; triflumezopyrim; nithiazine; dichloromezotiazol; flupyrimin. (5) Nicotinic acetylcholine receptor (nAChR) allosteric modulators: spinetoram, spinosad. (6) Glutamate-gated chloride channel (GluCl) allosteric modulators: Abamectin, Emamectin, Emamectin-benzoate, Lepimectin, Milbemectin, Milbemycin oxime, Doramectin, Eprinomectin, Ivermectin, Moxidectin, Selamectin.

[0124] (7) Juvenile hormone mimetics Hydroprene, Kinoprene, Methoprene, Fenoxycarb, Pyriproxifen, Diofenolan, Epophenonane, Triprene. (8) Other nonspecific (multi-site) inhibitors: methyl bromide, alkyl halides; chloropicrin; sodium aluminum fluoride, sulfuryl fluoride; borax, boric acid, disodium octaborate, sodium borate, sodium metaborate; tartar emetic; dazomet, metam, metam sodium, metam potassium. (9) Chordotonal TRPV channel modulators: pymetrozine, pyrifluquinazon, afidopyropen. (10) Mite growth inhibitors Clofentezine, Diflovidazin, Hexythiazox; Etoxazole.

[0125] (11) Microbial midgut membrane disruptors for insects: Bt subsp. israelensis, Bt subsp. aizawai, Bt subsp. kurstaki, Bt subsp. tenebrionis; Bt crop proteins: Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1 / Cry35Ab1; Bacillus sphaericus. (12) Mitochondrial ATP synthase inhibitors: diafenthiuron, azocyclotin, cyhexatin, fenbutatin oxide, propargite, tetradifon. (13) Oxidative phosphorylation uncouplers that disrupt the proton gradient: Chlorfenapyr, DNOC (4,6-dinitro-o-cresol), sulfluramid, binapacryl, dinobuton, dinocap. (14) Nicotinic acetylcholine receptor (nAChR) channel blockers: Bensultap, cartap hydrochloride, thiocyclam, thiosultap-sodium.

[0126] (15) Chitin biosynthesis inhibitors, type 0: Bistrifluron, Chlorfluazuron, Diflubenzuron, Flucycloxuron, Flufenoxuron, Hexaflumuron, Lufenuron, Novaluron, Noviflumuron, Teflubenzuron, Triflumuron. Fluazuron. (16) Chitin biosynthesis inhibitors, type 1: Buprofezin. (17) Molting inhibitors: Cyromazine. (18) Molting hormone (ecdysone) receptor agonists Chromafenozide, halofenozide, methoxyfenozide, tebufenozide.

[0127] (19) Octopamine receptor agonists: Amitraz; Chlordimeform. (20) Mitochondrial electron transport chain complex III inhibitors: Hydramethylnon; Acequinocyl; Fluacrypyrim; Bifenazate. (21) Mitochondrial electron transport chain complex I inhibitors (METI): Fenazaquin, Fenpyroximate, Pyridaben, Pyrimidifen, Tebufenpyrad, Tolfenpyrad; Rotenone. (22) Voltage-dependent sodium channel blockers: Indoxacarb; Metaflumizone. (23) Acetyl-CoA carboxylase inhibitors: spirodiclofen, spiromesifen, spirotetramat. Spiropidione. (24) Mitochondrial electron transport chain complex IV inhibitors: aluminum phosphide, calcium phosphide, zinc phosphide, phosphine; calcium cyanide, sodium cyanide, potassium cyanide. (25) Mitochondrial electron transport chain complex II inhibitors: cyenopyrafen, cyflumetofen, pyflubumide.

[0128] (28) Ryanodine receptor modulators: Chlorantraniliprole, Cyantraniliprole, Cyclaniliprole, Flubendiamide. Cyhalodiamide, Tetrachlorantraniliprole, Tetraaniliprole. (29) Chordotonal organ modulators: Target site unidentified: Flonicamid. (30) GABA-gated chloride channel allosteric modulators: Broflanilide, Fluxametamide. Isocycloseram; Afoxolaner, Fluralaner, Lotilaner, Sarolaner.

[0129] (31) Other insecticides and acaricides: Azadirachtin, Benzoximate, Bromopropylate, Chinomethionate, Dicofol, Lime sulfur, Mancozeb, Pyridalyl, Sulfur. Acynonapyr, Amidoflumet, Benzomate, Benzpyrimoxan, Chlorobenzilate, Dicyclanil, Fenoxacrim, Fentrifanil, Flometoquin, Flubenzimine, Flufenzine, Fluhexafon, Fluopyram, Metaflumizone, Metoxadiazone, Oxazosulfyl, Tetrasul, Triarathene, Tyclopyrazoflor, Tigolaner, Nicofluprole.

[0130] Specific examples of active ingredients for anthelmintics that can be mixed or used in combination are shown below. (a) Benzimidazoles: Fenbendazole, Albendazole, Triclabendazole, Oxibendazole, Mebendazole, Oxfendazole, Parabendazole, Flubendazole; Febantel, Netobimin, Thiophanate; Thiabendazole, Cambendazole; (b) Salicylanilides: Closantel, Oxyclozanide, Rafoxanide, Niclosamide; (c) Substituted phenols: Nitroxynil, Nitroscanate; (d) Pyrimidines: Pyrantel, Morantel; (e) Imidazothiazoles: Levamisole, Tetramisole; (f) Tetrahydropyrimidines: Praziquantel, Epsiprantel; (g) Organophosphates: Trichlorphon, Haloxon, Dichlorvos, Naphthalophos; (h) Other anthelmintics: Cyclodien, Rhiania, Clorulon, Metronidazole, Demiditraz; Piperazine, Diethylcarbamazine, Dichlorophen, Monepantel, Tribendimidin, Amidantel;Thiacetarsamide, Melorsamine, Arsenamide; Phenothiazine; Emodepside; Derquantel;

[0131] The combination of the compound of the present invention with other active ingredients is expected to produce a synergistic effect in terms of insecticidal, acaricidal, and nematicidal activities. The synergistic effect can be confirmed by Colby's formula (Colby, SR; Calculating Synergistic and Antagonistic Responses of Herbicide Combinations; Weeds, 15, pp. 20-22, 1967) in accordance with a conventional method.

[0132] [Application Method] When the compound of the present invention is applied to livestock such as cows and pigs, or pets such as dogs and cats, it can be applied in an amount (effective amount) that provides 0.01 to 1,000 mg of the compound of the present invention per 1 kg of the host animal. The compound of the present invention can be applied by known veterinary methods (systemic administration, oral administration, parenteral administration, topical administration, or subcutaneous administration). Examples of such methods include oral administration to animals via tablets, capsules, or incorporation into feed; administration to animals via immersion, suppositories, or injection (intramuscular, subcutaneous, intravenous, intraperitoneal, etc.); topical administration of an oily or aqueous liquid formulation by spraying, pour-on, spot-on, or the like; and topical administration by kneading the agent into a resin, molding the kneaded product into an appropriate shape such as a collar or ear tag, and attaching the resulting product to the animal. Here, oral administration can be difficult due to the taste and smell of the tablets used, whereas topical administration is a simple and useful administration method because the effect can be obtained simply by applying it to the skin, such as the neck, of the animal to be administered.

[0133] Due to the excellent durability of activity of the compounds of the present invention, a single administration even at a low dose enables long-term control of parasites. Specifically, a single administration provides control for about three weeks to about one month. Therefore, the compounds of the present invention may be administered weekly, every other week, monthly, or at longer intervals. That is, the present invention may further include the following: (1) A method for suppressing parasitic infestation in or on the body of an animal in need thereof, the method comprising topically administering to the animal an effective amount of at least one compound selected from the compounds of the present invention at monthly or longer intervals; (2) A method for controlling ectoparasites that gather in and on warm-blooded animals, comprising topically administering at least one compound selected from the compounds of the present invention as an active ingredient at monthly or longer intervals; (3) Topical use of at least one compound selected from the compounds of the present invention at monthly or longer intervals to suppress ectoparasite infestation.

[0134] Next, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the following examples. Example 1 Synthesis of (Z)-2-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-3-(ethylsulfonyl)-6-(2H-1,2,3-triazol-2-yl)pyridine (Compound No. 1) (Step 1) Synthesis of (Z)-6-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-5-(ethylsulfonyl)pyridin-2-ol

[0135]

[0136] 25% Aqueous ammonia (7.5 ml) was cooled to -10°C, and methyl propiolate (4.0 g) was added dropwise thereto, followed by stirring at 5°C for 1 hour. To this was added (Z)-1-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-2-ethylsulfonyl)ethan-1-one (9.3 g), 1,2-dimethoxyethane (47 mL), and 25% aqueous potassium hydroxide solution (6.3 g), followed by stirring at 60°C overnight. The resulting solution was washed with toluene. The resulting aqueous layer was adjusted to pH 4 with 2N hydrochloric acid and extracted with dichloromethane. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was used in the next step without purification. (Step 2) Synthesis of (Z)-6-chloro-2-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-3-(ethylsulfonyl)pyridine

[0137]

[0138] Thionyl chloride (29 mL) and N,N-dimethylformamide (0.34 mL) were added to the (Z)-6-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-5-(ethylsulfonyl)pyridin-2-ol obtained in step 1, and the mixture was stirred at 70°C overnight. The resulting solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The resulting solution was poured into water, and extracted with dichloromethane. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 7.2 g of the target product (yield 62%, 2 steps). 1The H-NMR is shown below. 1 H-NMR (400 MHz, CDCl3): δ 8.42 (d, 1H), 8.08 (s, 1H), 7.62 (d, 1H), 7.18 - 7.07 (m, 1H), 3.85 (q, 2H), 3.68 (s, 3H), 1.35 (t, 3H). (Step 3) Synthesis of (Z)-2-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-6-(4,5-dibromo-2H-1,2,3-triazol-2-yl)-3-(ethylsulfonyl)pyridine

[0139]

[0140] Toluene (4.3 mL), 4,5-dibromo-1H-1,2,3-triazole (1.0 g), triethylamine (0.60 mL), and N,N-dimethyl-4-aminopyridine (0.03 g) were added to (Z)-6-chloro-2-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-3-(ethylsulfonyl)pyridine (1.0 g), and the mixture was stirred at 100°C overnight. The resulting liquid was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 1.3 g (yield 92%) of the target product. 1 The H-NMR is shown below. 1H-NMR (400 MHz, CDCl3): δ 8.68 (d, 1H), 8.24 (d, 1H), 8.08 (s, 1H), 7.14 (s, 1H), 3.93 (q, 2H), 3.75 (s, 3H), 1.38 (t, 3H). (Step 4) Synthesis of (Z)-2-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-3-(ethylsulfonyl)-6-(2H-1,2,3-triazol-2-yl)pyridine

[0141]

[0142] Methanol (34 mL) and 10% palladium / carbon (0.22 g) were added to (Z)-2-(5-(2-chloro-3,3,4,4,4-pentafluorobut-1-en-1-yl)-1-methyl-1H-imidazol-2-yl)-6-(4,5-dibromo-2H-1,2,3-triazol-2-yl)-3-(ethylsulfonyl)pyridine (4.5 g), and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The resulting solution was filtered through Celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 2.3 g (yield 67%) of the target product. 1 The H-NMR is shown below. 1 H-NMR(400 MHz, CDCl3): δ 8.66 (d, 1H), 8.36 (d, 1H), 8.08 (s, 1H), 7.99 (s, 2H), 7.13 (s, 1H), 3.90 (q, 2H), 3.74 (s, 3H), 1.38 (t, 3H).

[0143] The compounds of the present invention were synthesized in the same manner as in Example 1. Some of them are shown in Table 1. The physical properties column lists the melting point or LCMS retention time.

[0144]

[0145]

[0146]

[0147] LCMS retention times were determined as follows. A system consisting of an ultra-high-performance, high-resolution liquid chromatograph (ACQUITY UPLC H-Class, manufactured by Waters), an HPLC / UHPLC detector (ACQUITY UPLC Photodiode Array (PDA) eλ Detector, manufactured by Waters), and a single quadrupole MS detector (LC / MS) (SQ Detector 2 detector, positive and negative ion electrospray mode and atmospheric pressure chemical ionization mode) was equipped with a CORTECS UPLC C18 column (manufactured by Waters, 2.1 x 50 mm, 1.6 μm). Measurements were performed at 40°C, with a flow rate of 0.6 mL / min and a 2 μL injection. Water containing 0.1% formic acid was used as mobile phase (A), and acetonitrile was used as mobile phase (B). The concentration of mobile phase (B) was maintained at 30% by mass for 0.15 minutes, then the concentration of mobile phase (B) was increased at a constant rate from 30% by mass to 95% by mass over 1.35 minutes, maintained at 95% by mass for 0.5 minutes, then the concentration of mobile phase (B) was immediately decreased to 30% by mass, and finally the concentration of mobile phase (B) was maintained at 30% by mass for 0.50 minutes.

[0148] Test Example 1: Efficacy Test Against Cat Fleas The compound of the present invention was dissolved in isopropanol to prepare a drug solution of a predetermined concentration. 100 μL of this drug solution was applied to the inner bottom surface of a glass vial (φ330 mm) and air-dried to form a thin film of the compound of the present invention. Four adult cat fleas (Ctenocephalides felis) (male and female mixed) were released into the vial. The vial was then capped and placed in a thermostatic chamber at 25°C. Four days after release, the cat fleas were counted for survival and death, and the insecticidal rate was calculated. This was repeated twice.

[0149] Compound No. 1 was tested for efficacy against cat fleas using a 0.06 ppm solution, and showed an insecticidal rate of 80% or more. Compounds Nos. 2, 3, and 4 were tested for efficacy against cat fleas using a 0.25 ppm solution, and all of the compounds showed an insecticidal rate of 80% or more.

[0150] Similar tests were conducted on compounds No. 4-10 and No. 4-12 listed in Table 4 of Patent Document 1. No. 4-10 showed an insecticidal rate of over 80% against cat fleas at a concentration of 4 ppm, and compound No. 4-12 showed an insecticidal rate of over 80% against cat fleas at a concentration of 16 ppm. The structures of both compounds are shown below.

[0151]

[0152] Test Example 2: Efficacy test against Haemophysalis longicornis The compound of the present invention was dissolved in isopropanol to prepare a drug solution of a predetermined concentration. 20 μL of this drug solution was applied to the inner bottom surface of a glass test tube (φ12 mm) and air-dried to form a thin film of the compound of the present invention. Four nymphs of Haemophysalis longicornis were released into the test tube. The tube was then capped and placed in a thermostatic chamber at 25°C. Four days after release, the live or dead Haemophysalis longicornis mites were determined, and the insecticidal rate was calculated. This was repeated twice.

[0153] Compound No. 1 was tested for efficacy against Haemaphysalis longicornis using a 0.016 ppm solution, and showed an insecticidal rate of 80% or more against the tick. Compound No. 2 was tested for efficacy against Haemaphysalis longicornis using a 0.06 ppm solution, and showed an insecticidal rate of 80% or more against the tick. Similarly, compound No. 3 and compound No. 4 showed insecticidal rates of 80% or more against Haemaphysalis longicornis at a concentration of 10 ppm and 0.25 ppm, respectively.

[0154] Similar tests were carried out on compounds No. 4-10 and No. 4-12 listed in Table 4 of Patent Document 1. No. 4-10 showed an insecticidal rate of over 80% against Haemaphysalis longicornis at a concentration of 4 ppm. Compound No. 4-12 showed a 0% insecticidal rate against Haemaphysalis longicornis even at a concentration of 16 ppm.

[0155] Since all of the compounds randomly selected from the compounds of the present invention exhibit the effects described above, it can be understood that the compounds of the present invention, including compounds not listed as examples, are also effective against parasites that are harmful to humans and animals, such as ectoparasites.

[0156] [Hemokinetics Test 1] An example of a hemokinetic test of the present compound (Compound No. 1) using rats is shown below. (1) Animals: Three female rats were prepared. They were 5 to 6 weeks old at the time of administration. No fasting was performed before administration. (2) Administration Method: Each rat was administered 2 mg / kg by single oral gavage using a stomach tube. The administration solution was prepared by pulverizing the present compound using a pestle and mortar, adding a small amount of 1% methylcellulose 100 aqueous solution, thoroughly kneading, and then adding a certain amount of the same solution to the powder, mixing, and homogenizing. (3) Preparation of Serum Extract: Approximately 0.2 mL of blood was collected from the external jugular vein of each rat 1, 3, 6, and 24 hours after administration of the administration solution, and then 3, 7, 10, and 14 days later. After coagulation, the collected blood was centrifuged (12,000 rpm, 1 minute) to obtain serum. A three-fold volume of acetonitrile was added to the serum, and the mixture was centrifuged (12,000 rpm, 1 minute) to remove proteins. The resulting supernatant was used as the serum extract. (4) Analysis Using LC-MS / MS The serum extract was analyzed using LC-MS / MS. The analysis was performed using the absolute calibration curve method with selected reaction monitoring (SRM). (A) LC Conditions Apparatus: Acquity (Waters) Column: L-column3 C18, 2.1 mm x 50 mm, particle size 2 μm (Chemicals Evaluation and Research Institute, Japan) Mobile phase: A: 0.1% formic acid aqueous solution, B: acetonitrile. The gradient conditions are shown in Table 2.

[0157]

[0158] Flow rate: 0.4 mL / min Column temperature: 40°C Injection volume: 2 μL (B) MS conditions Instrument: TQD (Waters) Ionization conditions: electrospray ionization (ESI) Scan type: selected reaction monitoring (SRM)

[0159] The time course of serum concentrations is shown in Table 3 below.

[0160]

[0161] The pharmacokinetic parameters are C max is 122.6⊥27.9(ng / mL), T max was 6.00 hours.

[0162] [Hemokinetics Test 2] An example of a hemokinetic test of the present compound (Compound No. 1) using rats is shown below. (1) Animals: Three female rats were prepared. They were 5 to 6 weeks old at the time of administration. No fasting was performed before administration. (2) Administration Method: Each rat was administered 25 mg / kg by single oral gavage using a stomach tube. The administration solution was prepared by pulverizing the present compound using a pestle and mortar, adding a small amount of 1% methylcellulose 100 aqueous solution, thoroughly kneading, and then adding a certain amount of the same solution to the powder, mixing, and homogenizing. (3) Preparation of Serum Extract: Approximately 0.2 mL of blood was collected from the external jugular vein of each rat 1, 3, 6, and 24 hours after administration of the administration solution, and then 3, 7, 10, and 14 days later. After coagulation, the collected blood was centrifuged (12,000 rpm, 1 minute) to obtain serum. A three-fold volume of acetonitrile was added to the serum, and the mixture was centrifuged (12,000 rpm, 1 minute) to remove proteins. The resulting supernatant was used as the serum extract. (4) Analysis Using LC-MS / MS The serum extract was analyzed using LC-MS / MS. Analysis was performed using the absolute calibration curve method with selected reaction monitoring (SRM). (A) LC Conditions: Apparatus: 1290 Infinity II (Agilent); Column: L-column3 C18, 2.1 mm x 50 mm, particle size 2 μm (Chemicals Evaluation and Research Institute, Japan); Mobile Phase: A: 0.1% formic acid aqueous solution; B: acetonitrile. The gradient conditions are shown in Table 4.

[0163]

[0164] Flow rate: 0.6 mL / min Column temperature: 50°C Injection volume: 1 μL (B) MS conditions Instrument: 6470B (Agilent) Ionization conditions: electrospray ionization (ESI) Scan type: selected reaction monitoring (SRM)

[0165] The time course of serum concentrations is shown in Table 5 below.

[0166]

[0167] The pharmacokinetic parameters are C max is 2066.2⊥330.3(ng / mL), T max was 4.33 hours.

[0168] The compound of the present invention (Compound No. 1) is expected to have a long-term sustained effect based on the above-described changes in serum concentration. Since compounds randomly selected from the compounds of the present invention exhibit the above-described effects, it can be understood that the compounds of the present invention, including compounds not exemplified above, are also effective in the long-term control of parasites harmful to humans and animals, such as ectoparasites.

[0169] The compounds of the present invention can overcome at least some of the limitations in the use of currently used insecticides and repellents, particularly with respect to speed of kill, long duration of effectiveness, and control of ectoparasites such as mites and fleas, or endoparasites such as nematodes.

Claims

1. A compound represented by formula (I) or a salt thereof: [In formula (I), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group, R ２ are each independently a substituted or unsubstituted C1-6 alkyl group, a substituted or unsubstituted C3-6 cycloalkyl group, a substituted or unsubstituted C1-6 alkoxycarbonyl group, an amino group, or a halogeno group, and n is R ２ represents the number of ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group.

2. An agent for controlling parasites in animals, which contains at least one compound selected from the compounds represented by formula (I) according to claim 1 and salts thereof.

3. The animal parasite control agent according to claim 2, which is a systemically administered drug.

4. The animal parasite control agent according to claim 2, which is an orally administered drug.

5. The animal parasite control agent according to claim 2, which is a parenteral drug.

6. The animal parasite control agent according to claim 2, which is a topically administered drug.

7. The parasite control agent for animals according to claim 2, wherein the animal is a pet.

8. The animal parasite control agent according to claim 2, wherein the parasite is an ectoparasite.

9. The animal parasite control agent according to claim 2, wherein the parasite is an endoparasite.

10. The animal parasite control agent according to claim 2, further comprising at least one other active ingredient.

11. A method for controlling parasitic infestation in or on the body of an animal in need thereof, which comprises administering to said animal at least one compound selected from the compounds represented by formula (I) and salts thereof according to claim 1.

12. The method of claim 11, wherein the administration is systemic.

13. The method of claim 11, wherein the administration is oral.

14. The method of claim 11, wherein the administration is parenteral.

15. The method of claim 11, wherein the administration is topical.

16. The method of claim 11, wherein the animal is a companion animal.

17. The method of claim 11, wherein the parasite is an ectoparasite.

18. The method of claim 11, wherein the parasite is an endoparasite.

19. The method of claim 11, further comprising administering at least one other active ingredient.

20. A method for the prevention and treatment of diseases transmitted through parasites, which comprises administering to an animal in need thereof at least one compound selected from the compounds of formula (I) and salts thereof as defined in claim 1.

21. The method of claim 20, wherein the administration is systemic.

22. The method of claim 20, wherein the administration is oral.

23. The method of claim 20, wherein the administration is parenteral.

24. The method of claim 20, wherein the administration is topical.

25. The method of claim 20, wherein the animal is a companion animal.

26. The method of claim 20, wherein the parasite is an ectoparasite.

27. The method of claim 20, wherein the parasite is an endoparasite.

28. The method of claim 20, further comprising administering at least one other active ingredient.

29. A method for producing a compound represented by formula (im-1), comprising chemically reacting a compound represented by formula (im-5) with a compound represented by formula (im-6) in the presence of a base, and chemically reacting the product of the chemical reaction with a halogenating agent. (In formula (im-5), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group. ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group. (In formula (im-1), R 1 , R ３ , R ４ , and X are the same as those in formula (im-5). １ is a halogeno group.) 30. A method for producing a compound represented by formula (IA), comprising chemically reacting a compound represented by formula (im-1) with a compound represented by formula (im-3) in the presence of a base, and reducing the product of the chemical reaction. (In formula (im-1), R １ is a substituted or unsubstituted C1-6 alkyl group, X is a sulfur atom, a sulfinyl group, a sulfonyl group, or a group of the formula: S(═O)(═N—R ａ ) is a group represented by R ａ is a hydrogen atom or a substituted or unsubstituted C1-6 alkyl group. ３ is a substituted or unsubstituted C2-6 alkenyl group, R ４ is a substituted or unsubstituted C1-6 alkyl group. １ is a halogeno group.) (In formula (IA), R 1 , R ３ , R ４ , and X are the same as those in formula (im-1).

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