WO2022255463A1 - Benzimidazole compound or salts thereof, canine heartworm disease control agent containing said compound, and method for using same - Google Patents
Benzimidazole compound or salts thereof, canine heartworm disease control agent containing said compound, and method for using same Download PDFInfo
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- WO2022255463A1 WO2022255463A1 PCT/JP2022/022539 JP2022022539W WO2022255463A1 WO 2022255463 A1 WO2022255463 A1 WO 2022255463A1 JP 2022022539 W JP2022022539 W JP 2022022539W WO 2022255463 A1 WO2022255463 A1 WO 2022255463A1
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- halo
- alkyl
- alkoxy
- alkyl group
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- -1 Benzimidazole compound Chemical class 0.000 title claims abstract description 120
- 150000003839 salts Chemical class 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims abstract description 23
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- 150000001875 compounds Chemical class 0.000 title abstract description 16
- 208000003917 Dirofilariasis Diseases 0.000 title abstract 4
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 30
- 125000005843 halogen group Chemical group 0.000 claims description 206
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 139
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 81
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 66
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 57
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 11
- 241000243988 Dirofilaria immitis Species 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
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- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 235000010374 vitamin B1 Nutrition 0.000 description 1
- 239000011691 vitamin B1 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019164 vitamin B2 Nutrition 0.000 description 1
- 239000011716 vitamin B2 Substances 0.000 description 1
- 235000019158 vitamin B6 Nutrition 0.000 description 1
- 239000011726 vitamin B6 Substances 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 235000015099 wheat brans Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 229910000368 zinc sulfate Inorganic materials 0.000 description 1
- 229960001763 zinc sulfate Drugs 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/14—Ectoparasiticides, e.g. scabicides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to a benzimidazole compound or a salt thereof, a dog heartworm control agent for animals containing the compound as an active ingredient, and a method for using the same.
- Heartworm infections are caused by mosquito-borne heartworms and occur in many animal species and pets.
- the mechanism is that when a mosquito ingests microfilariae (neonatal larval stage), they repeatedly molt inside the body and develop into infected larvae (L3).
- the infected larvae reach the host's skin when the mosquito feeds on the animal, and the larvae begin to invade and grow inside the animal's body.
- Infected larvae molt within 3 to 12 days and enter the fourth stage (L4), remaining in the subcutaneous tissue, abdomen and thorax for about 2 months, after which the L4 larvae undergo a final molt to become young adults. It reaches the host's heart and pulmonary arteries about 70 to 120 days after initial infection.
- melarsomin dihydrochloride is known as a canine heartworm control agent, and it is effective against both mature (adult) and immature heartworm.
- heartworm infection can be prevented by macrolide prophylactic drugs, but year-round prevention is recommended regardless of the breeding conditions of animals.
- Such long-term use in animals raises concerns about the potential development of resistance to existing drugs, and it is active against heartworm and can be used to treat infections caused by it. There is a need to provide new drugs.
- a benzimidazole compound having an isoxazoline group at the 2-position represented by the general formula (1) or a salt thereof has an excellent control effect on heartworm in dogs.
- the present inventors have found that the above problems can be solved in addition to having the above, and have completed the present invention.
- R is (a1) a hydrogen atom; (a2) a ( C1 - C6 ) alkyl group; (a3) a ( C1 - C6 ) alkylsulfonyl group; (a4) a ( C1 - C6 ) alkoxy ( C1 (a5) (C1 - C6)alkoxycarbonyl ( C1- C6 )alkyl group; ( a6 ) aryl( C1 - C6 )alkoxy( C1 - C6 )alkyl group (a7) ( C2 - C6 ) alkenyl group; (a8) ( C2 - C6 ) alkynyl group; (a9) ( C3 - C6 ) cycloalkyl ( C1 - C6 ) alkyl group; (a10) halo ( C 1 -C 6 )alkyl group; (a11) aryl (
- Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 )alkyl group.
- Y 2 and Y 3 may be the same or different, (f1) hydrogen atom; (f2) halogen atom; (f3) (C 1 -C 6 ) alkyl group; (f4) halo (C 1 -C 6 ) (f5) a ( C1 - C6 )alkoxy group; or (f6) a halo( C1 - C6 )alkoxy group; ⁇
- R is (a1) hydrogen atom; (a2) ( C1 - C6 ) alkyl group; (a3) ( C1 - C6 ) alkylsulfonyl group; (a4) ( C1 - C6 ) alkoxy ( C1 - C6 ) alkyl group
- the benzimidazole compound or its salt having an isoxazoline group bonded to the 2-position of the present invention has an excellent effect as an agent for controlling heartworm in dogs.
- halo means a "halogen atom” and is a fluorine atom, a chlorine atom, a bromine atom, or Indicates an iodine atom.
- (C 1 -C 6 )alkyl group means, for example, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, secondary butyl group, tertiary butyl group, normal pentyl group, isopentyl group , tertiary pentyl group, neopentyl group, 2,3-dimethylpropyl group, 1-ethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, normal hexyl group, isohexyl group, 2-hexyl group, 3-hexyl group, linear or branched C 1-6 alkyl groups such as 2-methylpentyl group, 3-methylpentyl group, 1,1,2-trimethylpropyl group and 3,3-dimethylbutyl group; , “(C 2 -C 6 )alkenyl group” means, for example, vinyl group, allyl group,
- Examples of "(C 1 -C 6 )alkoxy group” include methoxy group, ethoxy group, normal propoxy group, isopropoxy group, normal butoxy group, secondary butoxy group, tertiary butoxy group, normal pentyloxy group, isopentyl Linear or branched chain such as oxy group, tertiary pentyloxy group, neopentyloxy group, 2,3-dimethylpropyloxy group, 1-ethylpropyloxy group, 1-methylbutyloxy group, normal hexyloxy group, etc. represents an alkoxy group having 1 to 6 carbon atoms.
- Examples of the "(C 1 -C 6 )alkylthio group” include methylthio, ethylthio, normal-propylthio, isopropylthio, normal-butylthio, secondary-butylthio, tertiary-butylthio, normal-pentylthio group, isopentylthio group, tertiary pentylthio group, neopentylthio group, 2,3-dimethylpropylthio group, 1-ethylpropylthio group, 1-methylbutylthio group, normal hexylthio group, isohexylthio group , 1,1,2-trimethylpropylthio group and the like .
- methylsulfinyl group ethylsulfinyl group, normal-propylsulfinyl group, isopropylsulfinyl group, normal-butylsulfinyl group, secondary-butylsulfinyl group, tertiary-butylsulfinyl group, normal-pentylsulfinyl group, isopentylsulfinyl group, tertiary-pentylsulfinyl group, neo Straight groups such as pentylsulfinyl group, 2,3-dimethylpropylsulfinyl group, 1-ethylpropylsulfinyl group, 1-methylbutylsulfinyl group, normal hexylsulfinyl group, isohexylsulfinyl group and 1,1,2-trimethylpropylsulfinyl group.
- a chain or branched alkylsulfinyl group having 1 to 6 carbon atoms, and "(C 1 -C 6 )alkylsulfonyl group” includes, for example, methylsulfonyl group, ethylsulfonyl group, normal-propylsulfonyl group, isopropylsulfonyl group, normal butylsulfonyl group, secondary butylsulfonyl group, tertiary butylsulfonyl group, normal pentylsulfonyl group, isopentylsulfonyl group, tertiary pentylsulfonyl group, neopentylsulfonyl group, 2,3-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group, 1-methylbutylsulfonyl group, normal-hexylsulf
- the "(C 1 -C 6 ) alkylenedioxy group” includes linear or branched alkylenedioxy groups having 1 to 6 carbon atoms such as methylenedioxy, ethylenedioxy and propylenedioxy groups. indicates a group.
- halo(C 1 -C 6 )alkylenedioxy group includes linear or branched haloalkylenedioxy groups having 1 to 6 carbon atoms such as difluoromethylenedioxy group and tetrafluoroethylenedioxy group. indicates a group.
- ( C1 - C6 ) alkyl group "( C2 - C6 ) alkenyl group”, “( C2 - C6 ) alkynyl group”, “(C1 - C6 ) alkoxy group”, " one or more halogen atoms at substitutable positions of the (C 1 -C 8 )alkylthio group, "(C 1 -C 6 )alkylsulfinyl group” or "(C 1 -C 6 )alkylsulfonyl group”; may be substituted, and when two or more halogen atoms are substituted, the halogen atoms may be the same or different.
- Halo ( C1 - C6 ) alkyl group "Halo ( C2 - C6 ) alkenyl group”, “Halo ( C2 - C6 ) alkynyl group”, “Halo ( C1 - C6 ) alkoxy group”, “halo( C1 - C6 )alkylthio group”, “halo( C1 - C6 )alkylsulfinyl group” or “halo( C1 - C6 )alkylsulfonyl group”.
- (C 3 -C 6 )cycloalkyl group refers to a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- ( C1 - C6 )alkylcarbonyl group includes, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, normal butylcarbonyl group, isobutylcarbonyl group, secondary butylcarbonyl group, tertiary butylcarbonyl group, normal pentyl carbonyl group, isopentylcarbonyl group, tertiary pentylcarbonyl group, neopentylcarbonyl group, 2,3-dimethylpropylcarbonyl group, 1-ethylpropylcarbonyl group, 1-methylbutylcarbonyl group, 2-methylbutylcarbonyl group, normal hexylcarbonyl group, isohexylcarbonyl group, 2-hexylcarbonyl group, 3-hexylcarbonyl group, 2-methylpentylcarbonyl group, 3-methylpentylcarbonyl group, 1,1,2-trimethylpropylcarbon
- Examples of the "(C 1 -C 6 )alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a normal propoxycarbonyl group, an isopropoxycarbonyl group, a normal butoxycarbonyl group, a secondary butoxycarbonyl group and a tertiary butoxycarbonyl group.
- normal pentyloxycarbonyl group isopentyloxycarbonyl group, tertiary pentyloxycarbonyl group, neopentyloxycarbonyl group, 2,3-dimethylpropyloxycarbonyl group, 1-ethylpropyloxycarbonyl group, 1-methylbutyloxycarbonyl straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms such as normal hexyloxycarbonyl group, isohexyloxycarbonyl group, 1,1,2-trimethylpropyloxycarbonyl group, and carbonyl group represents an alkoxycarbonyl group.
- Aryl group refers to, for example, an aromatic hydrocarbon group having 6 to 10 carbon atoms such as a phenyl group, 1-naphthyl group, and 2-naphthyl group.
- Aromatic heterocyclic group includes, for example, nitrogen such as furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.
- a 5- or 6-membered monocyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from an atom, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized), etc.
- quinolyl isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyrazinyl, pyrazolopyridinyl 8- to 10-membered aromatic having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom (sulfur atom may be oxidized), etc. group condensed heterocyclic group, etc.
- Salts of the benzimidazole compound represented by the general formula (1) of the present invention include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, fumarate, maleate and oxalic acid. Salts, organic acid salts such as methanesulfonate, benzenesulfonate, and paratoluenesulfonate, salts with inorganic or organic bases such as sodium ion, potassium ion, calcium ion, and trimethylammonium can be exemplified. .
- the benzimidazole compound represented by the general formula (1) of the present invention or a salt thereof may have one asymmetric center in its structural formula, and the present invention provides each optical isomer and any ratio thereof All included mixtures are also included.
- the benzimidazole compound represented by the general formula (1) of the present invention and its salt may have two geometric isomers derived from a carbon-carbon double bond in its structural formula.
- the invention includes all geometric isomers and mixtures thereof in any proportion.
- the benzimidazole compound represented by the general formula (1) of the present invention or a salt thereof may have tautomers in its structural formula. It also includes all mixtures in any proportion.
- benzimidazole compound represented by the general formula (1) or a salt thereof which is an active ingredient of the dog heartworm control agent of the present invention, (a1) hydrogen atom; (a2) ( C1 - C6 ) alkyl group; (a3) ( C1 - C6 ) alkylsulfonyl group; (a4) ( C1 - C6 ) alkoxy ( ( C1 - C6 ) alkyl group; (a5) ( C1 - C6 ) alkoxycarbonyl ( C1 - C6 ) alkyl group; (a6) aryl( C1 - C6 ) alkoxy( C1 - C6 ) (a10) halo( C1 - C6 )alkyl group; (a14) ( C1 - C6 )alkoxycarbonyl group; (a16) trimethylsilyl( C1 - C6 )alkoxy( C1 - C6 ) Alkyl Group; (a17) (
- X 2 and X 3 are preferably (d1) a hydrogen atom; Y 1 and Y 4 are preferably (e1) hydrogen atom; (e2) halogen atom; or (e3) (C 1 -C 6 ) alkyl group; ( f1 ) hydrogen atom; (f2) halogen atom; (f3) (C1-C6 ) alkyl group; (f4) halo( C1 - C6 ) alkyl group; or ( f6) a halo( C1 - C6 )alkoxy group;
- the benzimidazole compound represented by the general formula (1) or a salt thereof, which is the active ingredient of the dog heartworm control agent of the present invention can be produced, for example, by the following production method, but the present invention is not limited thereto. not something.
- the amide compound represented by the general formula (2-1) is obtained by condensing the carboxylic acid represented by the general formula (2) and the phenylenediamine compound represented by the general formula (3). It can be produced by reacting in the presence of an agent, a base and an inert solvent.
- Condensing agents used in this reaction include, for example, diethyl cyanophosphate (DEPC), carbonyldiimidazole (CDI), 1,3-dicyclohexylcarbodiimide (DCC), chlorocarbonates, and 2-chloro-1-methylpyridinium iodide.
- DEPC diethyl cyanophosphate
- CDI carbonyldiimidazole
- DCC 1,3-dicyclohexylcarbodiimide
- chlorocarbonates 2-chloro-1-methylpyridinium iodide.
- EDC/HCl 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
- the amount used is 1 times the carboxylic acid represented by the general formula (2). It may be used by appropriately selecting from the range of mol to 10 times mol.
- Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; acetates such as sodium acetate and potassium acetate; - alkali metal alkoxides such as butoxide, sodium methoxide, sodium ethoxide; tertiary amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); Nitrogen-containing aromatic compounds such as pyridine and dimethylaminopyridine (DMAP) can be mentioned, and the amount used is usually 0.1 to 10 times the mol of the carboxylic acid represented by the general formula (2). used in the range of
- the inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction.
- examples include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons; chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Amides such as formamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ketones such as acetone and methyl ethyl ketone, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI ) and inert solvents such as nitrogen-containing aromatic compounds such as pyridine, and these inert solvents can be used alone
- reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography, or the like, if necessary.
- the next step may be performed without isolating the intermediate from the reaction system. Manufacturing method of step [B]
- the benzimidazole compound represented by general formula (1-1) can also be produced by reacting an amide compound represented by general formula (2-1) in the presence or absence of an acid and an inert solvent. be able to.
- acids used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and benzoic acid; and sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid. , phosphoric acid and the like can be exemplified.
- the inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction.
- examples include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons; chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Amides such as formamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ketones such as acetone and methyl ethyl ketone, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI ) can be exemplified, and these inert solvents can be used alone or in combination of two or more.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and if necessary, the target product can be produced by recrystallization, column chromatography, or the like.
- the benzimidazole compound represented by the general formula (1) is obtained by combining the benzimidazole compound represented by the general formula (1-1) and the compound represented by the general formula (4) with a base and an inorganic compound. It can be produced by reacting in the presence of an active solvent.
- Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium acetate, and acetic acid.
- inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium acetate, and acetic acid.
- Acetates such as potassium, alkali metal alkoxides such as potassium t-butoxide, sodium methoxide, sodium ethoxide; triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) tertiary amines such as pyridine, nitrogen-containing aromatic compounds such as dimethylaminopyridine (DMAP), etc., and the amount used is usually for the compound represented by the general formula (1-1) It is used in the range of 1-fold molar to 10-fold molar.
- DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
- the inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction.
- Hydrogens, diethyl ether, methyl tertiary butyl ether, dioxane, linear or cyclic ethers such as tetrahydrofuran (THF), amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), Ketones such as acetone and methyl ethyl ketone, polar solvents such as dimethylsulfoxide (DMSO) and 1,3-dimethyl-2-imidazolidinone (DMI), inert solvents such as alcohols such as methanol, ethanol, propanol, and isopropyl alcohol can be exemplified, and these inert solvents can be used alone or in combination of two or more.
- reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and the compound of the present invention can be produced by recrystallization, column chromatography, or the like, if necessary.
- step [D] The oxime represented by the general formula (6-1) is obtained by reacting an easily available aldehyde represented by the general formula (6-2) with hydroxylamines and a base in an inert solvent. It can be manufactured by
- hydroxylamines used in this reaction for example, hydroxylamine hydrochloride, hydroxylamine sulfate, etc. can be exemplified. It may be used by appropriately selecting from the range of 1-fold molar to 3-fold molar.
- Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium acetate, and acetic acid.
- inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium acetate, and acetic acid.
- Acetates such as potassium and the like can be mentioned, and the amount thereof to be used may generally be in the range of 1 to 10 mol per mol of the aldehyde represented by the general formula (6-2).
- the inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction.
- Linear or cyclic ethers, dimethylformamide (DMF), dimethylacetamide (DMA), inert solvents such as N-methylpyrrolidone (NMP) and other amides can be exemplified.
- two or more kinds can be mixed and used.
- reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary.
- the next step may be performed without isolating the intermediate from the reaction system.
- step [E] The imidoyl chloride represented by the general formula (6) is obtained by reacting the oxime represented by the general formula (6-1) produced in the previous step with a halogenating agent in an inert solvent. It can be manufactured by
- halogenating agent used in this reaction examples include halogens such as chlorine, bromine, and iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin. , 1,3-diiodo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, etc., and the amount used is represented by the general formula (6-1). It may be appropriately selected from the range of 1 to 5 times the molar amount of the oxime to be used.
- the inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction.
- aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons, chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Formamide (DMF), dimethylacetamide (DMA), amides such as N-methylpyrrolidone (NMP), polar solvent inert solvents such as 1,3-dimethyl-2-imidazolidinone (DMI) can be exemplified.
- aromatic hydrocarbons such as benzene, toluene, and xylene
- Halogenated hydrocarbons chlorobenzene, dichlorobenzene
- reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary.
- the next step may be performed without isolating the intermediate from the reaction system.
- step [D] and step [E] may be continuously performed in one pot.
- the carboxylic acid ester represented by the general formula (2-1) is the imidoyl chloride represented by the general formula (6) produced in the previous step and the acrylic represented by the general formula (5). It can be produced by reacting acid esters with metals in an inert solvent.
- metals used in this reaction include copper sulfate pentahydrate, copper nitrate, copper hydrochloride, and copper powder. It may be used by appropriately selecting from the range of 0.01 to 1 mol per mol.
- the inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction.
- aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons, chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl
- formamide DMF
- dimethylacetamide DMA
- amides such as N-methylpyrrolidone (NMP)
- polar solvents such as 1,3-dimethyl-2-imidazolidinone (DMI)
- inert solvents such as water.
- reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary.
- the next step may be performed without isolating the intermediate from the reaction system.
- step [D] to step [F] may be continuously performed in one pot.
- the carboxylic acid compound represented by the general formula (2) can be produced by reacting the ester compound represented by the general formula (2-1) with a base in an inert solvent. .
- Examples of the base used in this reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and the like. It is usually used in an amount of 1 to 10 times the molar amount of the compound represented by 2-1).
- the inert solvent that can be used in this reaction may be any one that does not significantly inhibit this reaction.
- examples include water, alcohols such as methanol, ethanol, propanol, and isopropyl alcohol, diethyl ether, tetrahydrofuran (THF), dioxane, and the like. and inert solvents such as water and the like, and these inert solvents can be used alone or in combination of two or more.
- reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
- the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary.
- Me is a methyl group
- Et is an ethyl group
- t-Bu is a tertiary butyl group
- n-Pen is a normal pentyl group
- n-Hex is a normal hexyl group
- c-Hex is a cyclohexyl group
- Ph is a phenyl group
- Bn is a benzyl group
- Ts is a paratoluenesulfonyl group
- E is a trans form.
- Physical properties are indicated by melting point (°C), refractive index (°C) or 1 H-NMR. 1 H-NMR data are shown in Table 6.
- the dog heartworm control agent of the present invention contains a benzimidazole compound represented by general formula (1) or a salt thereof as an active ingredient.
- the target animals of the canine heartworm control agent of the present invention are domestic animals such as cows, pigs, rabbits and birds, or pets such as dogs, rabbits and cats (hereinafter target animals, excluding humans). , preferably dogs, but not limited to these.
- control includes prevention and treatment.
- Canine filariasis refers to nematodes of the order Spirurida, in particular (a) nematodes of the family Onchocercidae, e.g., of the genus Brugia spp. Brugia malayi, Brugia pahangi, Brugia patei; Dipetalonema reconditum, of Dipetalonema spp.; Dirofilaria spp. Filaria spp., Filaria oculi; Onchocerca spp., Onchocerca cervicalis, Gibson Onchocerca gibsoni, Onchocerca gutturosa; (b) nematodes of the Setariidae family, e.g.
- Setaria spp. Setaria digitata, horse thread Setaria equina, Setaria labiatopapillosa, Setaria marshalli; Wuchereria spp., Wuchereria bancrofti; Filariidae nematodes, such as Parafilaria spp., Parafilaria multipapillosa; Stephanofilaria spp., Stephanofilaria assamensis, Stefano For Stephanofilaria dedoesi, Stephanofilaria kaeli, Stephanofilaria okinawaensis, Stephanofilaria stilesi, etc. However, it is not limited to these.
- the benzimidazole compound may be used as it is without adding any other ingredients.
- Excipients that are solid carriers include, for example, lactose, sucrose, glucose, corn starch, gelatin, casein, starch, gum arabic, cellulose derivatives, alginic acid and the like.
- Excipients that are liquid carriers include, for example, water, glycerin, vegetable oils, fatty acids, fatty acid esters, sorbitol and the like.
- control agent of the present invention examples include organic minerals such as peptide zinc and peptide iron, inorganic minerals such as zinc carbonate, manganese carbonate, iron sulfate, and magnesium carbonate, vitamin A, vitamin B, vitamin C, vitamin D, and vitamin E. , vitamin K, folic acid, pantothenic acid, and nicotinic acid, alfalfa meal, pressed corn, and the like.
- a flavor or the like may be provided at the same time.
- conventional additives such as antibacterial agents, antifungal agents, anthelmintics, antioxidants, pigments, flavoring agents, flavoring agents, and enzymes may be mixed, and powders and granules are prepared by conventional methods. , liquid medicine, tablets and the like. These preparations may contain a benzimidazole compound or a salt thereof as an active ingredient, usually in an amount of about 0.01 to 95% by weight.
- control agent of the present invention formulated in this way can be used as it is or after being diluted with water or the like.
- other antibacterial agents, antifungal agents, anthelmintic agents, antioxidants, pigments, flavoring agents, flavoring agents, ordinary additives such as enzymes, etc. may be mixed or used simultaneously or not at the same time.
- the dosage is an amount effective for the control effect of canine heartworm in the target animal, that is, when other conditions are equal, the control agent of the present invention is administered to the target animal compared to when it is not administered. It is an amount that enhances the canine heartworm control effect.
- the method of mixing and gelling the active ingredients of the control agent of the present invention to be administered to target animals and allowing them to freely ingest can be carried out at both hatcheries and farms. It can also be carried out during transportation of the subject animals from the hatchery to the farm.
- a preparation for gelling is prepared by blending a predetermined amount of water-soluble polysaccharide powder with the active ingredient of the control agent of the present invention, and diluted with water to form a gel-like solid when used in hatcheries and farms.
- a method of administering to the target animal of interest ie, ad libitum, direct administration in the crochet
- the formulated control agent is usually used alone, but it can be diluted with water and used as a formulation diluent (i.e., diluted administration in drinking water).
- the active ingredient concentration in the formulation diluent is generally preferably in the range of about 10 to 10000 ppm, more preferably in the range of about 35 to 5000 ppm.
- a method for administering the diluted formulation a method of dissolving about 0.01 to 500 g of the pesticide in 1 L of water and processing the solution to be administered can be mentioned.
- a preferred method includes a method of dissolving about 0.035 to 350 g in 1 L of water and administering.
- the formulation dilution may be administered using a drinking water addition device or the like.
- the volume of the diluent to be administered may be appropriately determined according to the size of the target animal, growth conditions, rearing density, administration method, etc., but is usually about 300 to 2000 liters per 10,000 birds. is preferred.
- the timing and implementation period of the administration of the control agent of the present invention, in egg-producing species and meat-producing species, continue for the entire period of the target animal, preferably in the larval stage (chicken 0 to 5 weeks old after hatching) or 0 to 0 years old. Dosing at 5 weeks.
- the dosage of the control agent may be appropriately determined according to the type and size of the target animal, but generally the total dosage is preferably in the range of 0.005 to 2 g. It is more preferably in the range of 0.005 to 1 g.
- the control agent composition of the present invention is made by adding the control agent to animal feed, drinking water, physiological electrolyte solution, or the like.
- the amount of the control agent to be added is preferably in the range of about 0.005 to 10.0% by weight based on the total amount of the control agent composition.
- the target animal feed, drinking water, or physiological electrolyte solution used in the control agent composition of the present invention is not particularly limited as long as it is generally used.
- examples of these include corn, rice, barley, milo, soybean meal, wheat bran, skimmed rice bran, fish meal, skimmed milk powder, dried whey, oil, alfalfa meal, North Sea meal, soybean oil, powdered refined beef tallow, wheat flour, rapeseed oil, meat.
- Bone meal (feather meal), animal fat, calcium phosphate, corn gluten meal, molasses, corn germ meal, calcium carbonate, tricalcium phosphate, sodium chloride, choline chloride, vitamins (vitamin A, vitamin B1, vitamin B2, vitamin B6 , vitamin B12, vitamin D, vitamin E, calcium pantothenate, nicotinamide, folic acid, etc.), amino acids (lysine, methionine, etc.), trace inorganic salts (magnesium sulfate, iron sulfate, copper sulfate, zinc sulfate, potassium iodide) , cobalt sulfate, etc.), feeds prepared by appropriately mixing probiotic agents, and the like.
- vitamins vitamin A, vitamin B1, vitamin B2, vitamin B6 , vitamin B12, vitamin D, vitamin E, calcium pantothenate, nicotinamide, folic acid, etc.
- amino acids lysine, methionine, etc.
- control agent composition of the present invention includes, for example, organic minerals such as peptide zinc and peptide iron, inorganic minerals such as zinc carbonate, manganese carbonate, iron sulfate, and magnesium carbonate, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, pantothenic acid, vitamins such as nicotinic acid, alfalfa meal, pressed corn and the like may be further contained.
- a flavor or the like may be given at the same time.
- control agent composition of the present invention there is no particular limitation on the method of administering the control agent composition of the present invention to the target animal, and it can be applied by a feeding method using an appropriate method such as spraying or mixing with feed as described later.
- the dose of the control agent composition is, in short, an amount effective for the effect of controlling canine heartworm in the target animal, that is, when the other conditions are equal, the control agent composition of the present invention is more effective. It is an amount that enhances the canine heartworm-controlling effect of the subject animal compared to when it is not administered.
- the timing and implementation period of the administration of the control agent composition of the present invention should be continued for the entire period of the target animal in egg-producing species and meat-producing species, preferably in the larval stage (chickens aged 0 to 5 weeks after hatching) or after birth. Administer from 0-5 weeks. More preferably, administration is continued for 0 to 21 days after hatching or 0 to 21 days after birth.
- control agent composition of the present invention When used as a feed for target animals, it contains a benzimidazole compound or a salt thereof in an amount of about 0.0005 to 5% by weight, preferably about 0.05 to 2% by weight. can be used in When used by adding to drinking water or a physiological electrolyte solution, the benzimidazole compound or a salt thereof is added at a rate of about 0.035 to 3.5% by weight, preferably about 0.035 to 1.4% by weight. can be used.
- the control method of the present invention comprises the step of administering an effective amount of the control agent of the present invention or the control agent composition of the present invention to a target animal.
- the control agent composition can be given to the animal in a conventional manner.
- the above effective amount varies depending on the type of formulation, target animal, ingestion period, and other circumstances, and can be appropriately selected by increasing or decreasing regardless of the above range.
- the control agent of the present invention is diluted with water to a concentration suitable for administration to a target animal, and the obtained diluted solution is administered to the target animal.
- the dilution factor may be applied according to the conventional drinking water dilution administration method, and for example, a diluted solution of about 5 to 10 times is preferably used.
- the control agent of the present invention is diluted with water to a predetermined concentration, and the water-soluble polysaccharide is added and mixed with stirring to make a uniform solution, which is left at room temperature or in a cold place (eg, refrigerator). ) to obtain a gel-like solid.
- the gelling agent when using a gelling agent that dissolves at high temperature and solidifies at low temperature (e.g., agar, gelatin, etc.), the gelling agent is added in advance to the medium for preparing the control agent of the present invention, and the medium is pressurized. After steam sterilization, the product is cooled and left at room temperature or stored in a cool place (for example, a refrigerator) to obtain a gel-like solid product.
- the gel-like solid thus obtained may be administered to a subject animal.
- the appropriate gel strength when gelled is approximately 200 to 2000 g/cm 2 , and when agar is used, it corresponds to a concentration of approximately 0.5 to 3.0%, depending on the type of agar. do.
- Polysaccharides used for gelling the control agent of the present invention in an aqueous medium include, for example, agar, carrageenan, carboxymethylcellulose, starch, mannan, gelatin, sodium alginate, gum arabic, roast bean gum, xanthan gum, chitosan, guar gum, pectin, propyl glycol alginate, arabinogalactan, gati gum, tamarind seed gum, pullulan, morpholine fatty acid salt, curdlan, tragacanth gum and the like.
- agar, carrageenan, carboxymethylcellulose, starch, mannan, gelatin sodium alginate, gum arabic, roast bean gum, xanthan gum, chitosan, guar gum, pectin, propyl glycol alginate, arabinogalactan, gati gum, tamarind seed gum, pullulan, morpholine fatty acid salt, curdlan, tragacanth gum and the like
- the gel-like solid when the gel-like solid is administered to poultry, if it is administered to poultry of approximately 0 to 7 days of age with a small amount of drinking water and feed intake, the poultry that tries to ingest the solid on the floor by poking with its beak
- This genetic program allows the plant to ingest the necessary amount of the control agent of the present invention in a short period of time while saving labor.
- live bacteria, vaccines, drugs, nutrients, etc. which have been difficult to administer to young poultry as described above, are optionally mixed with the control agent of the present invention to form a water-soluble polysaccharide.
- When gelled it can be efficiently administered to poultry at the same time as the control agent of the present invention.
- the supply of water and nutrients during the chicks stage is extremely important for subsequent productivity.
- Carbohydrates such as disaccharides, proteins such as skim milk, lipids, vitamins, minerals and the like can be mentioned.
- an existing canine heartworm control agent can be used in combination for the purpose of reinforcing or complementing the effect of the dog heartworm control agent of the present invention.
- a formulation in which two or more active ingredients are mixed before administration may be used, or two or more different formulations may be administered separately.
- the aqueous layer was neutralized with 1N hydrochloric acid, and ethyl acetate was added to separate the layers.
- the organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the target product (450 mg, yield 42% (from the previous step)) was obtained.
- Formulation example 1 Powder After thoroughly mixing 25 parts of the benzimidazole compound and 25 parts of lactose in a mortar, the mixture is sufficiently stirred to obtain a powder.
- Formulation example 2 Granules 25 parts of benzimidazole compound and 25 parts of lactose are added and well stirred and mixed. Next, an appropriate amount of water is added to the mixture, and the mixture is stirred, granulated with a granulator, and air-dried to obtain granules.
- Wettable powder A wettable powder is obtained by uniformly mixing 25 parts of a benzimidazole compound, 65 parts of diatomaceous earth, 5 parts of a higher alcohol sulfate and 5% of an alkylnaphthalene sulfonate and pulverizing them finely.
- Test Example 1 Evaluation test of influence on larval movement of Dirofilaria immitis 500 L-1 stage larvae of Dirofilaria immitis diluted in a predetermined preparation solution were inoculated in each hole of a 96-well plate, and the test of the present invention was performed. A DMSO diluted solution of the benzimidazole compound represented by the general formula (1) or a salt thereof was added to a final concentration of 50 ppm. Then, it was left still for 3 days, and its exercise ability was investigated. Based on the inhibitory power of the DMSO solution alone, the motility inhibition rate of each treatment group was corrected and calculated, and judged according to the following criteria.
- Test example 2 Influence evaluation test on the development of Dirofilaria immitis A predetermined preparation solution, 8 to 20 L-3 stage larvae of Dirofilaria immitis and a DMSO diluted solution of the benzimidazole compound of the present invention were added to each hole of a 24-well plate. In addition, the final concentration was 50 ppm. Seven days later, the larvae that had grown to the L-4 stage were counted, and the growth inhibition rate from L3-stage larvae to L4-stage larvae was calculated.
- compound numbers 1-17, 1-23, 1-25, 2-1, 2-7, 2-8, and 2-9 showed a growth inhibition rate of 50% or more.
- the present invention it is possible to provide a canine heartworm control agent for target animals that exhibits excellent effects when administered to target animals, and a method for using the canine heartworm control agent for target animals using the same.
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Abstract
The present invention addresses the problem of providing a canine heartworm disease control agent for animals, said agent exhibiting an excellent effect when administered to a target animal, and a method for using a canine heartworm disease control agent on a target animal using the same. The present invention provides, inter alia: a benzimidazole compound expressed by general formula (1) {in the formula, R represents a hydrogen atom, an alkylsulfonyl group, or the like, X2, X3, Y4, Y1, Y2, Y3, and Y4 represent a hydrogen atom or the like, and X1 represents a substituted phenyl group.) or salts thereof; a canine heartworm disease control agent for animals, said agent using said compound or salts thereof as an active component; and a method for using the same.
Description
本願発明は、ベンゾイミダゾール化合物又はその塩類及び該化合物を有効成分とする動物用の犬糸状虫症防除剤並びに該使用方法に関する。
The present invention relates to a benzimidazole compound or a salt thereof, a dog heartworm control agent for animals containing the compound as an active ingredient, and a method for using the same.
犬糸状虫感染は、蚊が媒介する犬糸状虫によって引き起こされ、多くの動物種、及びペット類に起こる。そのメカニズムは、蚊がミクロフィラリア(新生幼虫段階)を摂取すると、それらは体内で脱皮を繰り返して感染幼虫(L3)に成長する。その感染幼虫は、蚊が動物を摂食する際に、宿主皮膚に到達し、幼虫は動物体内に侵入・成長を開始する。感染幼虫は3から12日以内に脱皮して第4段階(L4)に入り、皮下組織、腹部および胸部に約2ヶ月間程度留まった後、L4幼虫は最終の脱皮をして若い成虫となり、初期感染後約70日から120日で宿主の心臓および肺動脈に到達する。
Heartworm infections are caused by mosquito-borne heartworms and occur in many animal species and pets. The mechanism is that when a mosquito ingests microfilariae (neonatal larval stage), they repeatedly molt inside the body and develop into infected larvae (L3). The infected larvae reach the host's skin when the mosquito feeds on the animal, and the larvae begin to invade and grow inside the animal's body. Infected larvae molt within 3 to 12 days and enter the fourth stage (L4), remaining in the subcutaneous tissue, abdomen and thorax for about 2 months, after which the L4 larvae undergo a final molt to become young adults. It reaches the host's heart and pulmonary arteries about 70 to 120 days after initial infection.
一方で、ベンゾイミダゾール化合物の2位にピリジル基を有するベンゾイミダゾール化合物が、動物用の外部寄生虫又は内部寄生虫の防除に効果があることが報告されているが(例えば特許文献1参照)、かかる文献中には、イソキサゾリン基を有するベンゾイミダゾール化合物及び該化合物の犬糸状虫に対する殺虫効果に関する記載は一切開示されていない。
On the other hand, it has been reported that a benzimidazole compound having a pyridyl group at the 2-position of the benzimidazole compound is effective in controlling ectoparasites or endoparasites for animals (see, for example, Patent Document 1). This document does not disclose any description of a benzimidazole compound having an isoxazoline group and the insecticidal effect of this compound on heartworm.
従来、犬糸状虫症防除剤としてはメラルソミン・2塩酸塩が知られており、それは成熟(成体)および未成熟犬糸状虫に対しても有効である。また犬糸状虫感染は、マクロライド系予防薬により予防可能であるが、動物の飼育状況とは無関係に、通年予防が勧められている。このような動物への長期間の使用によって、既存薬剤に対する抵抗性発達の可能性が危惧されており、犬糸状虫に対して活性を有し、それによる感染を治療するのに用いることができる新たな薬剤の提供が求められている。
Conventionally, melarsomin dihydrochloride is known as a canine heartworm control agent, and it is effective against both mature (adult) and immature heartworm. In addition, heartworm infection can be prevented by macrolide prophylactic drugs, but year-round prevention is recommended regardless of the breeding conditions of animals. Such long-term use in animals raises concerns about the potential development of resistance to existing drugs, and it is active against heartworm and can be used to treat infections caused by it. There is a need to provide new drugs.
本願発明者等は、上記の課題を解決すべく鋭意検討した結果、一般式(1)で表される2位にイソキサゾリン基を有するベンゾイミダゾール化合物、又はその塩類が優れた犬糸状虫症防除効果を有するだけでなく、前記課題を解決し得ることを見出し、本願発明に至った。
即ち、本願発明は、
[1]一般式(1)
{式中、
Rは、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a7) (C2‐C6)アルケニル基;(a8) (C2‐C6)アルキニル基;(a9) (C3‐C6)シクロアルキル(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a11) アリール(C2‐C6)アルケニル基;(a12) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C2‐C6)アルケニル基;(a13) (C1-C6)アルキルカルボニル基;(a14) (C1-C6)アルコキシカルボニル基;(a15) (C1-C6)アルコキシカルボニルカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a22) R1(R2)Nカルボニル基(式中、R1及びR2は同一又は異なっても良く水素原子、(C1-C6)アルキル基、(C3-C6)シクロアルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基を示す。);(a23) R1(R2)Nチオカルボニル基(式中、R1及びR2は前記に同じ。);(a24) R1(R2)Nスルホニル基(式中、R1及びR2は前記に同じ。);(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;(a27) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール基;(a28) アリール(C1‐C6)アルキル基;又は(a29) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示す。
X1は、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、 (k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b6) (C2‐C6)アルケニル基;(b7) (C2‐C6)アルキニル基;(b8) (C3‐C6)シクロアルキル基;(b9) ハロ(C1‐C6)アルキル基;又は(b10) 3-テトラヒドロフリル基;を示す。
X4は、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;(c5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール基;(c6) アリール(C1‐C6)アルキル基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、 (i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示す。
X2及びX3は、同一又は異なってもよく、(d1) 水素原子;又は(d2)(C1‐C6)アルキル基;を示す。
Y1及びY4は、同一又は異なってもよく、(e1) 水素原子;(e2) ハロゲン原子;又は(e3)(C1‐C6)アルキル基;を示す。
Y2及びY3は、同一又は異なってもよく、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;(f5) (C1‐C6)アルコキシ基;又は(f6) ハロ(C1‐C6)アルコキシ基;を示す。}
で表されるベンゾイミダゾール化合物又はその塩類、
[2]Rが、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a14) (C1-C6)アルコキシカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;又は(a28) アリール(C1‐C6)アルキル基;を示し、
X1が、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b8)(C3‐C6)シクロアルキル基;又は(b10) 3-テトラヒドロフリル基;を示し、
X4が、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示し、
X2及びX3が、(d1)水素原子;を示し、
Y1及びY4が、同一又は異なってもよく、(e1) 水素原子;(e2) ハロゲン原子;又は(e3)(C1‐C6)アルキル基;を示し、
Y2及びY3が、同一又は異なってもよく、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;又は(f6) ハロ(C1‐C6)アルコキシ基;を示す、
[1]に記載のベンゾイミダゾール化合物またはその塩類、
[3][1]~[2]のいずれか1つに記載のベンゾイミダゾール化合物またはその塩類を有効成分として含有することを特徴とする動物用の犬糸状虫症防除剤、
[4][1]~[2]のいずれか1つに記載のベンゾイミダゾール化合物またはその塩類の有効量を動物に投与することを特徴とする動物用の犬糸状虫症防除剤の使用方法、に関する。 As a result of intensive studies to solve the above problems, the inventors of the present application have found that a benzimidazole compound having an isoxazoline group at the 2-position represented by the general formula (1) or a salt thereof has an excellent control effect on heartworm in dogs. The present inventors have found that the above problems can be solved in addition to having the above, and have completed the present invention.
That is, the present invention is
[1] General formula (1)
{In the formula,
R is (a1) a hydrogen atom; (a2) a ( C1 - C6 ) alkyl group; (a3) a ( C1 - C6 ) alkylsulfonyl group; (a4) a ( C1 - C6 ) alkoxy ( C1 (a5) (C1 - C6)alkoxycarbonyl ( C1- C6 )alkyl group; ( a6 ) aryl( C1 - C6 )alkoxy( C1 - C6 )alkyl group (a7) ( C2 - C6 ) alkenyl group; (a8) ( C2 - C6 ) alkynyl group; (a9) ( C3 - C6 ) cycloalkyl ( C1 - C6 ) alkyl group; ( (a10) halo ( C 1 -C 6 )alkyl group; (a11) aryl (C 2 -C 6 )alkenyl group; C6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl group, (i) halo( C1 - C6 )alkyl aryl ( C 2 -C 6 ) alkenyl group; (a13) ( C1 - C6 ) alkylcarbonyl group; (a14) ( C1 - C6 ) alkoxycarbonyl group; (a15) ( C1 - C6 ) alkoxycarbonylcarbonyl group; (a16) (a17 ) ( C1 - C6 )alkylthio( C1 - C6 )alkyl groups; (a18) (C1- C6 ) trimethylsilyl( C1 -C6)alkoxy( C1 - C6 )alkyl groups; ) alkylsulfinyl (C 1 -C 6 ) alkyl group; (a19) (C 1 -C 6 ) alkylsulfonyl (C 1 -C 6 ) alkyl group; (a20) arylsulfonyl group; (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy (e) a halo( C1 - C6 )alkoxy group; (f) a ( C1 - C6 )alkylthio group; (g) a halo( C1 -C6)alkylthio group; (h) (C1- C6 ) alkylthio group; -C6 ) alkylsulfinyl group, (i) halo( C1 - C6 )alkylsulfinyl group, (j) ( C1 - C6 )alkylsulfonyl group, and (k) halo( C1 - C6 )alkyl an arylsulfonyl group having 1 to 5 substituents selected from sulfonyl groups; (a22) R 1 (R 2 )N carbonyl group (wherein R 1 and R 2 may be the same or different hydrogen atoms C 1 -C 6 )alkyl group, (C 3 -C 6 )cycloalkyl group, (C 2 -C 6 )alkenyl group and (C 2 -C 6 )alkynyl group. ); (a23) R 1 (R 2 )N thiocarbonyl group (wherein R 1 and R 2 are the same as above); (a24) R 1 (R 2 )N sulfonyl group (wherein R 1 and (a25) 2 - tetrahydrofurylmethyl group ; (a26) aryl group; ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) a (C 1 -C 6 ) alkylsulfonyl group, and (k) a halo (C 1 -C 6 ) alkylsulfonyl group; (a28) an aryl group having 1 to 5 substituents; or ( a29 ), which may be the same or different, (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) (d) ( C1 - C6 ) alkoxy group; (e) halo ( C1 - C6 ) alkoxy group; (f) ( C1 - C6 ) alkylthio group; (g) halo ( C1 -C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, (j) ( C1 - C6 ) alkylsulfonyl group, and (k) an aryl(C 1 -C 6 )alkyl group having 1 to 5 substituents selected from halo(C 1 -C 6 )alkylsulfonyl groups;
X 1 is (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo (C 1 —C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; (b5) which may be the same or different, ( a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) a halo ( C1 - C6 ) alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) a halo( C1 - C6 )alkylsulfinyl group, (j) a ( C1 - C6 )alkylsulfonyl group, (k) a halo( C1 - C6 )alkylsulfonyl group, and (l) a phenoxy group (b6) (C 2 -C 6 ) alkenyl group; (b7) (C 2 -C 6 ) alkynyl group; (b8) (C 3 - C6 ) cycloalkyl group; (b9) halo( C1 - C6 ) alkyl group; or (b10) 3-tetrahydrofuryl group;
(c1) a hydrogen atom; (c2) a ( C1 - C6 ) alkyl group ; (c3) a halo( C1 - C6 ) alkyl group; (c4) an aryl group; (c5) the same or different (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, ( e) halo( C1 - C6 )alkoxy groups, (f) ( C1 - C6 )alkylthio groups, (g) halo( C1 - C6 )alkylthio groups, (h) ( C1 - C6 ) selected from alkylsulfinyl groups, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups; (c6) an aryl (C 1 -C 6 )alkyl group; or (c7), which may be the same or different, (a) a halogen atom, (b) (C 1 -C6 ) alkyl group, (c) halo ( C1 - C6 ) alkyl group, (d) ( C1 - C6 ) alkoxy group, (e) halo ( C1 - C6 ) alkoxy group, (f ) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl group, (i) halo( C1 - C6 ) aryl ( C 1 - C 6 ) alkyl group;
X 2 and X 3 may be the same or different and represent (d1) a hydrogen atom; or (d2) a (C 1 -C 6 )alkyl group.
Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 )alkyl group.
Y 2 and Y 3 may be the same or different, (f1) hydrogen atom; (f2) halogen atom; (f3) (C 1 -C 6 ) alkyl group; (f4) halo (C 1 -C 6 ) (f5) a ( C1 - C6 )alkoxy group; or (f6) a halo( C1 - C6 )alkoxy group; }
A benzimidazole compound or salts thereof represented by
[2] R is (a1) hydrogen atom; (a2) ( C1 - C6 ) alkyl group; (a3) ( C1 - C6 ) alkylsulfonyl group; (a4) ( C1 - C6 ) alkoxy ( C1 - C6 ) alkyl group; (a5) ( C1 - C6 ) alkoxycarbonyl ( C1 - C6 ) alkyl group; (a6) aryl( C1 - C6 ) alkoxy( C1 - C6) (a10) halo( C1 - C6 )alkyl group; (a14) ( C1 - C6 )alkoxycarbonyl group; (a16) trimethylsilyl( C1 - C6 )alkoxy( C1 - C6) (a17) (C1 - C6 )alkylthio( C1 - C6 )alkyl group; (a18) ( C1 - C6 )alkylsulfinyl( C1 - C6 )alkyl group; (a19) (C 1 -C 6 ) alkylsulfonyl ( C 1 -C 6 ) alkyl group; (a20) arylsulfonyl group; 6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl (j) (C 1 -C 6 )alkylsulfonyl groups, and (k) halo(C 1 -C 6 )alkylsulfonyl groups; (a25) 2-tetrahydrofurylmethyl group; (a26) aryl group; or (a28) aryl(C 1 -C 6 )alkyl group;
X 1 is (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo (C 1 —C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; (b5) which may be the same or different, ( a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) a halo ( C1 - C6 ) alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups, and (l) phenoxy (b8) a ( C3 - C6 ) cycloalkyl group; or (b10) a 3-tetrahydrofuryl group;
(c1) a hydrogen atom; (c2) a ( C1 - C6 ) alkyl group ; (c3) a halo( C1 - C6 ) alkyl group; (c4) an aryl group; or (c7) the same or different (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1 - C6 )alkylthio groups, (g) halo( C1 - C6 )alkylthio groups, (h) ( C1 - C6 ) ) alkylsulfinyl groups, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups; an aryl(C 1 -C 6 )alkyl group with 1 to 5 selected substituents;
X 2 and X 3 are (d1) hydrogen atoms;
Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 ) alkyl group;
( f1 ) hydrogen atom; ( f2 ) halogen atom; (f3) ( C1 - C6 ) alkyl group; (f4) halo ( C1 - C6 ) an alkyl group; or (f6) a halo(C1 - C6 )alkoxy group;
The benzimidazole compound or salts thereof according to [1],
[3] A canine heartworm control agent for animals, characterized by containing the benzimidazole compound or a salt thereof according to any one of [1] to [2] as an active ingredient,
[4] A method of using a canine heartworm control agent for animals, which comprises administering an effective amount of the benzimidazole compound or salt thereof according to any one of [1] to [2] to the animal; Regarding.
即ち、本願発明は、
[1]一般式(1)
Rは、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a7) (C2‐C6)アルケニル基;(a8) (C2‐C6)アルキニル基;(a9) (C3‐C6)シクロアルキル(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a11) アリール(C2‐C6)アルケニル基;(a12) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C2‐C6)アルケニル基;(a13) (C1-C6)アルキルカルボニル基;(a14) (C1-C6)アルコキシカルボニル基;(a15) (C1-C6)アルコキシカルボニルカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a22) R1(R2)Nカルボニル基(式中、R1及びR2は同一又は異なっても良く水素原子、(C1-C6)アルキル基、(C3-C6)シクロアルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基を示す。);(a23) R1(R2)Nチオカルボニル基(式中、R1及びR2は前記に同じ。);(a24) R1(R2)Nスルホニル基(式中、R1及びR2は前記に同じ。);(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;(a27) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール基;(a28) アリール(C1‐C6)アルキル基;又は(a29) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示す。
X1は、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、 (k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b6) (C2‐C6)アルケニル基;(b7) (C2‐C6)アルキニル基;(b8) (C3‐C6)シクロアルキル基;(b9) ハロ(C1‐C6)アルキル基;又は(b10) 3-テトラヒドロフリル基;を示す。
X4は、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;(c5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール基;(c6) アリール(C1‐C6)アルキル基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、 (i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示す。
X2及びX3は、同一又は異なってもよく、(d1) 水素原子;又は(d2)(C1‐C6)アルキル基;を示す。
Y1及びY4は、同一又は異なってもよく、(e1) 水素原子;(e2) ハロゲン原子;又は(e3)(C1‐C6)アルキル基;を示す。
Y2及びY3は、同一又は異なってもよく、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;(f5) (C1‐C6)アルコキシ基;又は(f6) ハロ(C1‐C6)アルコキシ基;を示す。}
で表されるベンゾイミダゾール化合物又はその塩類、
[2]Rが、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a14) (C1-C6)アルコキシカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;又は(a28) アリール(C1‐C6)アルキル基;を示し、
X1が、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b8)(C3‐C6)シクロアルキル基;又は(b10) 3-テトラヒドロフリル基;を示し、
X4が、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示し、
X2及びX3が、(d1)水素原子;を示し、
Y1及びY4が、同一又は異なってもよく、(e1) 水素原子;(e2) ハロゲン原子;又は(e3)(C1‐C6)アルキル基;を示し、
Y2及びY3が、同一又は異なってもよく、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;又は(f6) ハロ(C1‐C6)アルコキシ基;を示す、
[1]に記載のベンゾイミダゾール化合物またはその塩類、
[3][1]~[2]のいずれか1つに記載のベンゾイミダゾール化合物またはその塩類を有効成分として含有することを特徴とする動物用の犬糸状虫症防除剤、
[4][1]~[2]のいずれか1つに記載のベンゾイミダゾール化合物またはその塩類の有効量を動物に投与することを特徴とする動物用の犬糸状虫症防除剤の使用方法、に関する。 As a result of intensive studies to solve the above problems, the inventors of the present application have found that a benzimidazole compound having an isoxazoline group at the 2-position represented by the general formula (1) or a salt thereof has an excellent control effect on heartworm in dogs. The present inventors have found that the above problems can be solved in addition to having the above, and have completed the present invention.
That is, the present invention is
[1] General formula (1)
R is (a1) a hydrogen atom; (a2) a ( C1 - C6 ) alkyl group; (a3) a ( C1 - C6 ) alkylsulfonyl group; (a4) a ( C1 - C6 ) alkoxy ( C1 (a5) (C1 - C6)alkoxycarbonyl ( C1- C6 )alkyl group; ( a6 ) aryl( C1 - C6 )alkoxy( C1 - C6 )alkyl group (a7) ( C2 - C6 ) alkenyl group; (a8) ( C2 - C6 ) alkynyl group; (a9) ( C3 - C6 ) cycloalkyl ( C1 - C6 ) alkyl group; ( (a10) halo ( C 1 -C 6 )alkyl group; (a11) aryl (C 2 -C 6 )alkenyl group; C6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl group, (i) halo( C1 - C6 )alkyl aryl ( C 2 -C 6 ) alkenyl group; (a13) ( C1 - C6 ) alkylcarbonyl group; (a14) ( C1 - C6 ) alkoxycarbonyl group; (a15) ( C1 - C6 ) alkoxycarbonylcarbonyl group; (a16) (a17 ) ( C1 - C6 )alkylthio( C1 - C6 )alkyl groups; (a18) (C1- C6 ) trimethylsilyl( C1 -C6)alkoxy( C1 - C6 )alkyl groups; ) alkylsulfinyl (C 1 -C 6 ) alkyl group; (a19) (C 1 -C 6 ) alkylsulfonyl (C 1 -C 6 ) alkyl group; (a20) arylsulfonyl group; (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy (e) a halo( C1 - C6 )alkoxy group; (f) a ( C1 - C6 )alkylthio group; (g) a halo( C1 -C6)alkylthio group; (h) (C1- C6 ) alkylthio group; -C6 ) alkylsulfinyl group, (i) halo( C1 - C6 )alkylsulfinyl group, (j) ( C1 - C6 )alkylsulfonyl group, and (k) halo( C1 - C6 )alkyl an arylsulfonyl group having 1 to 5 substituents selected from sulfonyl groups; (a22) R 1 (R 2 )N carbonyl group (wherein R 1 and R 2 may be the same or different hydrogen atoms C 1 -C 6 )alkyl group, (C 3 -C 6 )cycloalkyl group, (C 2 -C 6 )alkenyl group and (C 2 -C 6 )alkynyl group. ); (a23) R 1 (R 2 )N thiocarbonyl group (wherein R 1 and R 2 are the same as above); (a24) R 1 (R 2 )N sulfonyl group (wherein R 1 and (a25) 2 - tetrahydrofurylmethyl group ; (a26) aryl group; ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) a (C 1 -C 6 ) alkylsulfonyl group, and (k) a halo (C 1 -C 6 ) alkylsulfonyl group; (a28) an aryl group having 1 to 5 substituents; or ( a29 ), which may be the same or different, (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) (d) ( C1 - C6 ) alkoxy group; (e) halo ( C1 - C6 ) alkoxy group; (f) ( C1 - C6 ) alkylthio group; (g) halo ( C1 -C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, (j) ( C1 - C6 ) alkylsulfonyl group, and (k) an aryl(C 1 -C 6 )alkyl group having 1 to 5 substituents selected from halo(C 1 -C 6 )alkylsulfonyl groups;
X 1 is (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo (C 1 —C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; (b5) which may be the same or different, ( a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) a halo ( C1 - C6 ) alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) a halo( C1 - C6 )alkylsulfinyl group, (j) a ( C1 - C6 )alkylsulfonyl group, (k) a halo( C1 - C6 )alkylsulfonyl group, and (l) a phenoxy group (b6) (C 2 -C 6 ) alkenyl group; (b7) (C 2 -C 6 ) alkynyl group; (b8) (C 3 - C6 ) cycloalkyl group; (b9) halo( C1 - C6 ) alkyl group; or (b10) 3-tetrahydrofuryl group;
(c1) a hydrogen atom; (c2) a ( C1 - C6 ) alkyl group ; (c3) a halo( C1 - C6 ) alkyl group; (c4) an aryl group; (c5) the same or different (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, ( e) halo( C1 - C6 )alkoxy groups, (f) ( C1 - C6 )alkylthio groups, (g) halo( C1 - C6 )alkylthio groups, (h) ( C1 - C6 ) selected from alkylsulfinyl groups, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups; (c6) an aryl (C 1 -C 6 )alkyl group; or (c7), which may be the same or different, (a) a halogen atom, (b) (C 1 -C6 ) alkyl group, (c) halo ( C1 - C6 ) alkyl group, (d) ( C1 - C6 ) alkoxy group, (e) halo ( C1 - C6 ) alkoxy group, (f ) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl group, (i) halo( C1 - C6 ) aryl ( C 1 - C 6 ) alkyl group;
X 2 and X 3 may be the same or different and represent (d1) a hydrogen atom; or (d2) a (C 1 -C 6 )alkyl group.
Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 )alkyl group.
Y 2 and Y 3 may be the same or different, (f1) hydrogen atom; (f2) halogen atom; (f3) (C 1 -C 6 ) alkyl group; (f4) halo (C 1 -C 6 ) (f5) a ( C1 - C6 )alkoxy group; or (f6) a halo( C1 - C6 )alkoxy group; }
A benzimidazole compound or salts thereof represented by
[2] R is (a1) hydrogen atom; (a2) ( C1 - C6 ) alkyl group; (a3) ( C1 - C6 ) alkylsulfonyl group; (a4) ( C1 - C6 ) alkoxy ( C1 - C6 ) alkyl group; (a5) ( C1 - C6 ) alkoxycarbonyl ( C1 - C6 ) alkyl group; (a6) aryl( C1 - C6 ) alkoxy( C1 - C6) (a10) halo( C1 - C6 )alkyl group; (a14) ( C1 - C6 )alkoxycarbonyl group; (a16) trimethylsilyl( C1 - C6 )alkoxy( C1 - C6) (a17) (C1 - C6 )alkylthio( C1 - C6 )alkyl group; (a18) ( C1 - C6 )alkylsulfinyl( C1 - C6 )alkyl group; (a19) (C 1 -C 6 ) alkylsulfonyl ( C 1 -C 6 ) alkyl group; (a20) arylsulfonyl group; 6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl (j) (C 1 -C 6 )alkylsulfonyl groups, and (k) halo(C 1 -C 6 )alkylsulfonyl groups; (a25) 2-tetrahydrofurylmethyl group; (a26) aryl group; or (a28) aryl(C 1 -C 6 )alkyl group;
X 1 is (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo (C 1 —C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; (b5) which may be the same or different, ( a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) a halo ( C1 - C6 ) alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups, and (l) phenoxy (b8) a ( C3 - C6 ) cycloalkyl group; or (b10) a 3-tetrahydrofuryl group;
(c1) a hydrogen atom; (c2) a ( C1 - C6 ) alkyl group ; (c3) a halo( C1 - C6 ) alkyl group; (c4) an aryl group; or (c7) the same or different (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1 - C6 )alkylthio groups, (g) halo( C1 - C6 )alkylthio groups, (h) ( C1 - C6 ) ) alkylsulfinyl groups, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups; an aryl(C 1 -C 6 )alkyl group with 1 to 5 selected substituents;
X 2 and X 3 are (d1) hydrogen atoms;
Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 ) alkyl group;
( f1 ) hydrogen atom; ( f2 ) halogen atom; (f3) ( C1 - C6 ) alkyl group; (f4) halo ( C1 - C6 ) an alkyl group; or (f6) a halo(C1 - C6 )alkoxy group;
The benzimidazole compound or salts thereof according to [1],
[3] A canine heartworm control agent for animals, characterized by containing the benzimidazole compound or a salt thereof according to any one of [1] to [2] as an active ingredient,
[4] A method of using a canine heartworm control agent for animals, which comprises administering an effective amount of the benzimidazole compound or salt thereof according to any one of [1] to [2] to the animal; Regarding.
本願発明の2位にイソキサゾリン基が結合したベンゾイミダゾール化合物又はその塩類は犬糸状虫症防除剤として優れた効果を有する。
The benzimidazole compound or its salt having an isoxazoline group bonded to the 2-position of the present invention has an excellent effect as an agent for controlling heartworm in dogs.
本願発明の2位にイソキサゾリン基が結合したベンゾイミダゾール化合物又はその塩類の一般式(1)の定義において、「ハロ」とは「ハロゲン原子」を意味し、フッ素原子、塩素原子、臭素原子、又はヨウ素原子を示す。
In the definition of the general formula (1) of the benzimidazole compound having an isoxazoline group bonded to the 2-position of the present invention or a salt thereof, "halo" means a "halogen atom" and is a fluorine atom, a chlorine atom, a bromine atom, or Indicates an iodine atom.
「(C1‐C6)アルキル基」とは、例えばメチル基、エチル基、ノルマルプロピル基、イソプロピル基、ノルマルブチル基、イソブチル基、セカンダリーブチル基、ターシャリーブチル基、ノルマルペンチル基、イソペンチル基、ターシャリーペンチル基、ネオペンチル基、2,3‐ジメチルプロピル基、1‐エチルプロピル基、1‐メチルブチル基、2‐メチルブチル基、ノルマルヘキシル基、イソヘキシル基、2‐ヘキシル基、3‐ヘキシル基、2‐メチルペンチル基、3‐メチルペンチル基、1,1,2‐トリメチルプロピル基、3,3‐ジメチルブチル基等の直鎖又は分岐鎖状の炭素原子数1~6個のアルキル基を示し、「(C2‐C6)アルケニル基」とは、例えばビニル基、アリル基、イソプロペニル基、1‐ブテニル基、2‐ブテニル基、2‐メチル‐2‐プロペニル基、1‐メチル‐2‐プロペニル基、2‐メチル‐1‐プロペニル基、ペンテニル基、1‐ヘキセニル基、3,3‐ジメチル‐1‐ブテニル基等の直鎖又は分鎖状の炭素原子数2~6個のアルケニル基を示し、「(C2‐C6)アルキニル基」とは、例えばエチニル基、1‐プロピニル基、2‐プロピニル基、1‐ブチニル基、2‐ブチニル基、3‐ブチニル基、3‐メチル‐1‐プロピニル基、2‐メチル‐3‐プロピニル基、ペンチニル基、1‐ヘキシニル基等の直鎖又は分鎖状の炭素原子数2~6個のアルキニル基を示す。
“(C 1 -C 6 )alkyl group” means, for example, methyl group, ethyl group, normal propyl group, isopropyl group, normal butyl group, isobutyl group, secondary butyl group, tertiary butyl group, normal pentyl group, isopentyl group , tertiary pentyl group, neopentyl group, 2,3-dimethylpropyl group, 1-ethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, normal hexyl group, isohexyl group, 2-hexyl group, 3-hexyl group, linear or branched C 1-6 alkyl groups such as 2-methylpentyl group, 3-methylpentyl group, 1,1,2-trimethylpropyl group and 3,3-dimethylbutyl group; , “(C 2 -C 6 )alkenyl group” means, for example, vinyl group, allyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 2-methyl-2-propenyl group, 1-methyl-2 -propenyl group, 2-methyl-1-propenyl group, pentenyl group, 1-hexenyl group, 3,3-dimethyl-1-butenyl group, and other linear or branched alkenyl groups having 2 to 6 carbon atoms and "( C2 - C6 ) alkynyl group" includes, for example, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 3-methyl- It represents a linear or branched alkynyl group having 2 to 6 carbon atoms such as 1-propynyl group, 2-methyl-3-propynyl group, pentynyl group and 1-hexynyl group.
「(C1‐C6)アルコキシ基」としては、例えば、メトキシ基、エトキシ基、ノルマルプロポキシ基、イソプロポキシ基、ノルマルブトキシ基、セカンダリーブトキシ基、ターシャリーブトキシ基、ノルマルペンチルオキシ基、イソペンチルオキシ基、ターシャリーペンチルオキシ基、ネオペンチルオキシ基、2,3‐ジメチルプロピルオキシ基、1‐エチルプロピルオキシ基、1‐メチルブチルオキシ基、ノルマルヘキシルオキシ基、等の直鎖又は分岐鎖状の炭素原子数1~6個のアルコキシ基を示す。
Examples of "(C 1 -C 6 )alkoxy group" include methoxy group, ethoxy group, normal propoxy group, isopropoxy group, normal butoxy group, secondary butoxy group, tertiary butoxy group, normal pentyloxy group, isopentyl Linear or branched chain such as oxy group, tertiary pentyloxy group, neopentyloxy group, 2,3-dimethylpropyloxy group, 1-ethylpropyloxy group, 1-methylbutyloxy group, normal hexyloxy group, etc. represents an alkoxy group having 1 to 6 carbon atoms.
「(C1‐C6)アルキルチオ基」としては、例えば、メチルチオ基、エチルチオ基、ノルマルプロピルチオ基、イソプロピルチオ基、ノルマルブチルチオ基、セカンダリーブチルチオ基、ターシャリーブチルチオ基、ノルマルペンチルチオ基、イソペンチルチオ基、ターシャリーペンチルチオ基、ネオペンチルチオ基、2,3‐ジメチルプロピルチオ基、1‐エチルプロピルチオ基、1‐メチルブチルチオ基、ノルマルヘキシルチオ基、イソヘキシルチオ基、1,1,2‐トリメチルプロピルチオ基等の直鎖又は分岐鎖状の炭素原子数1~6個のアルキルチオ基を示し、「(C1‐C6)アルキルスルフィニル基」としては、例えば、メチルスルフィニル基、エチルスルフィニル基、ノルマルプロピルスルフィニル基、イソプロピルスルフィニル基、ノルマルブチルスルフィニル基、セカンダリーブチルスルフィニル基、ターシャリーブチルスルフィニル基、ノルマルペンチルスルフィニル基、イソペンチルスルフィニル基、ターシャリーペンチルスルフィニル基、ネオペンチルスルフィニル基、2,3‐ジメチルプロピルスルフィニル基、1‐エチルプロピルスルフィニル基、1‐メチルブチルスルフィニル基、ノルマルヘキシルスルフィニル基、イソヘキシルスルフィニル基、1,1,2‐トリメチルプロピルスルフィニル基等の直鎖又は分岐鎖状の炭素原子数1~6個のアルキルスルフィニル基を示し、「(C1‐C6)アルキルスルホニル基」としては、例えば、メチルスルホニル基、エチルスルホニル基、ノルマルプロピルスルホニル基、イソプロピルスルホニル基、ノルマルブチルスルホニル基、セカンダリーブチルスルホニル基、ターシャリーブチルスルホニル基、ノルマルペンチルスルホニル基、イソペンチルスルホニル基、ターシャリーペンチルスルホニル基、ネオペンチルスルホニル基、2,3‐ジメチルプロピルスルホニル基、1‐エチルプロピルスルホニル基、1‐メチルブチルスルホニル基、ノルマルヘキシルスルホニル基、イソヘキシルスルホニル基、1,1,2‐トリメチルプロピルスルホニル基等の直鎖又は分岐鎖状の炭素原子数1~6個のアルキルスルホニル基を示す。
Examples of the "(C 1 -C 6 )alkylthio group" include methylthio, ethylthio, normal-propylthio, isopropylthio, normal-butylthio, secondary-butylthio, tertiary-butylthio, normal-pentylthio group, isopentylthio group, tertiary pentylthio group, neopentylthio group, 2,3-dimethylpropylthio group, 1-ethylpropylthio group, 1-methylbutylthio group, normal hexylthio group, isohexylthio group , 1,1,2-trimethylpropylthio group and the like . methylsulfinyl group, ethylsulfinyl group, normal-propylsulfinyl group, isopropylsulfinyl group, normal-butylsulfinyl group, secondary-butylsulfinyl group, tertiary-butylsulfinyl group, normal-pentylsulfinyl group, isopentylsulfinyl group, tertiary-pentylsulfinyl group, neo Straight groups such as pentylsulfinyl group, 2,3-dimethylpropylsulfinyl group, 1-ethylpropylsulfinyl group, 1-methylbutylsulfinyl group, normal hexylsulfinyl group, isohexylsulfinyl group and 1,1,2-trimethylpropylsulfinyl group. A chain or branched alkylsulfinyl group having 1 to 6 carbon atoms, and "(C 1 -C 6 )alkylsulfonyl group" includes, for example, methylsulfonyl group, ethylsulfonyl group, normal-propylsulfonyl group, isopropylsulfonyl group, normal butylsulfonyl group, secondary butylsulfonyl group, tertiary butylsulfonyl group, normal pentylsulfonyl group, isopentylsulfonyl group, tertiary pentylsulfonyl group, neopentylsulfonyl group, 2,3-dimethylpropylsulfonyl group, 1-ethylpropylsulfonyl group, 1-methylbutylsulfonyl group, normal-hexylsulfonyl group, isohexylsulfonyl group, 1,1,2-trimethylpropylsulfonyl group, or other linear or branched chain having 1 to 6 carbon atoms; represents an alkylsulfonyl group.
「(C1-C6)アルキレンジオキシ基」としては、メチレンジオキシ基、エチレンジオキシ基、プロピレンジオキシ基等の直鎖又は分岐鎖状の炭素原子数1~6個のアルキレンジオキシ基を示す。
The "(C 1 -C 6 ) alkylenedioxy group" includes linear or branched alkylenedioxy groups having 1 to 6 carbon atoms such as methylenedioxy, ethylenedioxy and propylenedioxy groups. indicates a group.
「ハロ(C1-C6)アルキレンジオキシ基」としては、ジフルオロメチレンジオキシ基、テトラフルオロエチレンジオキシ基等の直鎖又は分岐鎖状の炭素原子数1~6個のハロアルキレンジオキシ基を示す。
The “halo(C 1 -C 6 )alkylenedioxy group” includes linear or branched haloalkylenedioxy groups having 1 to 6 carbon atoms such as difluoromethylenedioxy group and tetrafluoroethylenedioxy group. indicates a group.
上記「(C1‐C6)アルキル基」、「(C2‐C6)アルケニル基」、「(C2‐C6)アルキニル基」、「(C1‐C6)アルコキシ基」、「(C1‐C8)アルキルチオ基」、「(C1‐C6)アルキルスルフィニル基」、又は「(C1‐C6)アルキルスルホニル基」の置換し得る位置に1又は2以上のハロゲン原子が置換されていても良く、置換されるハロゲン原子が2以上の場合は、ハロゲン原子は同一又は異なっても良い。それぞれ、「ハロ(C1‐C6)アルキル基」、「ハロ(C2‐C6)アルケニル基」、「ハロ(C2‐C6)アルキニル基」、「ハロ(C1‐C6)アルコキシ基」、「ハロ(C1‐C6)アルキルチオ基」、「ハロ(C1‐C6)アルキルスルフィニル基」、又は「ハロ(C1‐C6)アルキルスルホニル基」と示す。
The above "( C1 - C6 ) alkyl group", "( C2 - C6 ) alkenyl group", "( C2 - C6 ) alkynyl group", "(C1 - C6 ) alkoxy group", " one or more halogen atoms at substitutable positions of the (C 1 -C 8 )alkylthio group, "(C 1 -C 6 )alkylsulfinyl group" or "(C 1 -C 6 )alkylsulfonyl group"; may be substituted, and when two or more halogen atoms are substituted, the halogen atoms may be the same or different. "Halo ( C1 - C6 ) alkyl group", "Halo ( C2 - C6 ) alkenyl group", "Halo ( C2 - C6 ) alkynyl group", "Halo ( C1 - C6 ) alkoxy group", "halo( C1 - C6 )alkylthio group", "halo( C1 - C6 )alkylsulfinyl group" or "halo( C1 - C6 )alkylsulfonyl group".
「(C1‐C6)」、「(C2‐C6)」、等の表現は各種置換基の炭素原子数の範囲を示す。更に、上記置換基が連結した基についても上記定義を示すことができ、例えば、「(C1‐C6)アルコキシ(C1‐C6)アルキル基」の場合は直鎖又は分岐鎖状の炭素数1~6個のアルコキシ基が直鎖又は分岐鎖状の炭素数1~6個のアルキル基に結合していることを示す。
The expressions "(C 1 -C 6 )", "(C 2 -C 6 )", etc. indicate the range of carbon atoms of the various substituents. Furthermore, the above definitions can also be shown for groups to which the above substituents are linked. It indicates that an alkoxy group having 1 to 6 carbon atoms is bonded to a linear or branched alkyl group having 1 to 6 carbon atoms.
「(C3‐C6)シクロアルキル基」としては、例えばシクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等の炭素原子数3~6個の環状のアルキル基を示す。
The “(C 3 -C 6 )cycloalkyl group” refers to a cyclic alkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
「(C1‐C6)アルキルカルボニル基」とは、例えばアセチル基、プロピオニル基、ブチリル基、イソブチリル基、ノルマルブチルカルボニル基、イソブチルカルボニル基、セカンダリーブチルカルボニル基、ターシャリーブチルカルボニル基、ノルマルペンチルカルボニル基、イソペンチルカルボニル基、ターシャリーペンチルカルボニル基、ネオペンチルカルボニル基、2,3-ジメチルプロピルカルボニル基、1-エチルプロピルカルボニル基、1-メチルブチルカルボニル基、2-メチルブチルカルボニル基、ノルマルヘキシルカルボニル基、イソヘキシルカルボニル基、2-ヘキシルカルボニル基、3-ヘキシルカルボニル基、2-メチルペンチルカルボニル基、3-メチルペンチルカルボニル基、1,1,2-トリメチルプロピルカルボニル基、3,3-ジメチルブチル基カルボニル等の直鎖又は分岐鎖状の炭素原子数1~6個のアルキル基とカルボニル基とから構成されるアルキルカルボニル基を示す。
"( C1 - C6 )alkylcarbonyl group" includes, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, normal butylcarbonyl group, isobutylcarbonyl group, secondary butylcarbonyl group, tertiary butylcarbonyl group, normal pentyl carbonyl group, isopentylcarbonyl group, tertiary pentylcarbonyl group, neopentylcarbonyl group, 2,3-dimethylpropylcarbonyl group, 1-ethylpropylcarbonyl group, 1-methylbutylcarbonyl group, 2-methylbutylcarbonyl group, normal hexylcarbonyl group, isohexylcarbonyl group, 2-hexylcarbonyl group, 3-hexylcarbonyl group, 2-methylpentylcarbonyl group, 3-methylpentylcarbonyl group, 1,1,2-trimethylpropylcarbonyl group, 3,3- An alkylcarbonyl group composed of a linear or branched alkyl group having 1 to 6 carbon atoms such as dimethylbutyl group carbonyl and a carbonyl group.
「(C1‐C6)アルコキシカルボニル基」としては、例えば、メトキシカルボニル基、エトキシカルボニル基、ノルマルプロポキシカルボニル基、イソプロポキシカルボニル基、ノルマルブトキシカルボニル基、セカンダリーブトキシカルボニル基、ターシャリーブトキシカルボニル基、ノルマルペンチルオキシカルボニル基、イソペンチルオキシカルボニル基、ターシャリーペンチルオキシカルボニル基、ネオペンチルオキシカルボニル基、2,3-ジメチルプロピルオキシカルボニル基、1-エチルプロピルオキシカルボニル基、1-メチルブチルオキシカルボニル基、ノルマルヘキシルオキシカルボニル基、イソヘキシルオキシカルボニル基、1,1,2-トリメチルプロピルオキシカルボニル基等の直鎖又は分岐鎖状の炭素原子数1~6個のアルコキシ基とカルボニル基とから構成されるアルコキシカルボニル基を示す。
Examples of the "(C 1 -C 6 )alkoxycarbonyl group" include a methoxycarbonyl group, an ethoxycarbonyl group, a normal propoxycarbonyl group, an isopropoxycarbonyl group, a normal butoxycarbonyl group, a secondary butoxycarbonyl group and a tertiary butoxycarbonyl group. , normal pentyloxycarbonyl group, isopentyloxycarbonyl group, tertiary pentyloxycarbonyl group, neopentyloxycarbonyl group, 2,3-dimethylpropyloxycarbonyl group, 1-ethylpropyloxycarbonyl group, 1-methylbutyloxycarbonyl straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms such as normal hexyloxycarbonyl group, isohexyloxycarbonyl group, 1,1,2-trimethylpropyloxycarbonyl group, and carbonyl group represents an alkoxycarbonyl group.
「アリール基」とは、例えば、フェニル基、1-ナフチル基、2-ナフチル基等の炭素数6~10個の芳香族炭化水素基を示す。
"Aryl group" refers to, for example, an aromatic hydrocarbon group having 6 to 10 carbon atoms such as a phenyl group, 1-naphthyl group, and 2-naphthyl group.
「芳香族複素環基」とは、例えば、フリル、チエニル、ピリジル、ピリミジニル、ピリダジニル、ピラジニル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、トリアジニル等の窒素原子、酸素原子、硫黄原子(硫黄原子はオキシド化されていてもよい)等から選ばれる1~4個のヘテロ原子を有する5又は6員の単環式芳香族複素環基、キノリル、イソキノリル、キナゾリル、キノキサリル、ベンゾフラニル、ベンゾチエニル、ベンズオキサゾリル、ベンズイソオキサゾリル、ベンゾチアゾリル、ベンズイミダゾリル、ベンゾトリアゾリル、インドリル、インダゾリル、ピロロピラジニル、イミダゾピリジニル、イミダゾピラジニル、ピラゾロピリジニル、ピラゾロチエニル、ピラゾロトリアジニル等の窒素原子、酸素原子、硫黄原子(硫黄原子はオキシド化されていてもよい)等から選ばれる1~4個のヘテロ原子を有する8~10員の芳香族縮合複素環基等を示す。
"Aromatic heterocyclic group" includes, for example, nitrogen such as furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc. a 5- or 6-membered monocyclic aromatic heterocyclic group having 1 to 4 heteroatoms selected from an atom, an oxygen atom, a sulfur atom (the sulfur atom may be oxidized), etc., quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyrazinyl, imidazopyridinyl, imidazopyrazinyl, pyrazolopyridinyl 8- to 10-membered aromatic having 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom, sulfur atom (sulfur atom may be oxidized), etc. group condensed heterocyclic group, etc.
本願発明の一般式(1)で表されるベンゾイミダゾール化合物の塩類としては、例えば塩酸塩、硫酸塩、硝酸塩、燐酸塩等の無機酸塩類、酢酸塩、フマル酸塩、マレイン酸塩、シュウ酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン酸塩等の有機酸塩類、ナトリウムイオン、カリウムイオン、カルシウムイオン、トリメチルアンモニウム等の無機又は有機の塩基との塩類を例示することができる。
Salts of the benzimidazole compound represented by the general formula (1) of the present invention include, for example, inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, fumarate, maleate and oxalic acid. Salts, organic acid salts such as methanesulfonate, benzenesulfonate, and paratoluenesulfonate, salts with inorganic or organic bases such as sodium ion, potassium ion, calcium ion, and trimethylammonium can be exemplified. .
本願発明の一般式(1)で表されるベンゾイミダゾール化合物又はその塩類は、その構造式中に1つの不斉中心を有する場合があり、本願発明は各光学異性体及びそれらが任意の割合で含まれる混合物をも全て包含するものである。また本発明の一般式(1)で表されるベンゾイミダゾール化合物及びその塩は、その構造式中に炭素-炭素二重結合に由来する2種の幾何異性体が存在する場合もあるが、本発明は各々の幾何異性体及びそれらが任意の割合で含まれる混合物をも全て包含するものである。更に本願発明の一般式(1)で表されるベンゾイミダゾール化合物又はその塩類は、その構造式中に互変異性体が存在する場合もあるが、本発明は各々の互変異性体及びそれらが任意の割合で含まれる混合物をも全て包含するものである。
The benzimidazole compound represented by the general formula (1) of the present invention or a salt thereof may have one asymmetric center in its structural formula, and the present invention provides each optical isomer and any ratio thereof All included mixtures are also included. In addition, the benzimidazole compound represented by the general formula (1) of the present invention and its salt may have two geometric isomers derived from a carbon-carbon double bond in its structural formula. The invention includes all geometric isomers and mixtures thereof in any proportion. Furthermore, the benzimidazole compound represented by the general formula (1) of the present invention or a salt thereof may have tautomers in its structural formula. It also includes all mixtures in any proportion.
本願発明の犬糸状虫症防除剤の有効成分である一般式(1)で表されるベンゾイミダゾール化合物又はその塩類において、
Rとして好ましくは、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a14) (C1-C6)アルコキシカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;又は(a28) アリール(C1‐C6)アルキル基;であり、
X1として好ましくは、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b8)(C3‐C6)シクロアルキル基;又は(b10) 3-テトラヒドロフリル基;であり、
X4として好ましくは、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;であり、
X2及びX3として好ましくは、(d1) 水素原子;であり、
Y1及びY4として好ましくは、(e1) 水素原子;(e2) ハロゲン原子;又は(e3) (C1‐C6)アルキル基;であり、
Y2及びY3として好ましくは、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;又は(f6) ハロ(C1‐C6)アルコキシ基;である。 In the benzimidazole compound represented by the general formula (1) or a salt thereof, which is an active ingredient of the dog heartworm control agent of the present invention,
(a1) hydrogen atom; (a2) ( C1 - C6 ) alkyl group; (a3) ( C1 - C6 ) alkylsulfonyl group; (a4) ( C1 - C6 ) alkoxy ( ( C1 - C6 ) alkyl group; (a5) ( C1 - C6 ) alkoxycarbonyl ( C1 - C6 ) alkyl group; (a6) aryl( C1 - C6 ) alkoxy( C1 - C6 ) (a10) halo( C1 - C6 )alkyl group; (a14) ( C1 - C6 )alkoxycarbonyl group; (a16) trimethylsilyl( C1 - C6 )alkoxy( C1 - C6 ) Alkyl Group; (a17) ( C1 - C6 ) Alkylthio( C1 - C6 ) Alkyl Group; (a18) ( C1 - C6 ) Alkylsulfinyl( C1 - C6 ) Alkyl Group; (a19) ( C1 - C6 ) alkylsulfonyl ( C1 - C6 ) alkyl group; (a20) arylsulfonyl group; (a21) which may be the same or different, (a) a halogen atom, (b) ( C1 - C6) ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) (C 1 -C 6 )alkylsulfonyl groups, and (k) halo(C 1 -C 6 )alkylsulfonyl groups; - a tetrahydrofurylmethyl group; (a26) an aryl group; or (a28) an aryl( C1 - C6 )alkyl group;
X 1 is preferably (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo ( C 1 -C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; , (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl (i) a halo( C1 - C6 )alkylsulfinyl group, (j) a ( C1 - C6 )alkylsulfonyl group, and (k) a halo( C1 - C6 )alkylsulfonyl group, and (l (b8) a ( C3 - C6 ) cycloalkyl group; or (b10) a 3-tetrahydrofuryl group;
(c1) hydrogen atom; (c2) ( C1 - C6 )alkyl group; (c3) halo( C1 - C6 )alkyl group; ( c4 ) aryl group; or (c7) the same or may be different, (a) halogen atom, (b) ( C1 - C6 ) alkyl group, (c) halo( C1 - C6 ) alkyl group, (d) ( C1 - C6 ) alkoxy (e) a halo( C1 - C6 )alkoxy group; (f) a ( C1 - C6 )alkylthio group; (g) a halo( C1 - C6 )alkylthio group; (h) a (C1- C6 )alkylthio group; (i) a halo( C1 - C6 )alkylsulfinyl group; (j ) a ( C1 - C6 )alkylsulfonyl group; and (k) a halo( C1 - C6 )alkylsulfonyl group. an aryl(C 1 -C 6 )alkyl group having 1 to 5 substituents selected from the group;
X 2 and X 3 are preferably (d1) a hydrogen atom;
Y 1 and Y 4 are preferably (e1) hydrogen atom; (e2) halogen atom; or (e3) (C 1 -C 6 ) alkyl group;
( f1 ) hydrogen atom; (f2) halogen atom; (f3) (C1-C6 ) alkyl group; (f4) halo( C1 - C6 ) alkyl group; or ( f6) a halo( C1 - C6 )alkoxy group;
Rとして好ましくは、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a14) (C1-C6)アルコキシカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;又は(a28) アリール(C1‐C6)アルキル基;であり、
X1として好ましくは、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b8)(C3‐C6)シクロアルキル基;又は(b10) 3-テトラヒドロフリル基;であり、
X4として好ましくは、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;であり、
X2及びX3として好ましくは、(d1) 水素原子;であり、
Y1及びY4として好ましくは、(e1) 水素原子;(e2) ハロゲン原子;又は(e3) (C1‐C6)アルキル基;であり、
Y2及びY3として好ましくは、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;又は(f6) ハロ(C1‐C6)アルコキシ基;である。 In the benzimidazole compound represented by the general formula (1) or a salt thereof, which is an active ingredient of the dog heartworm control agent of the present invention,
(a1) hydrogen atom; (a2) ( C1 - C6 ) alkyl group; (a3) ( C1 - C6 ) alkylsulfonyl group; (a4) ( C1 - C6 ) alkoxy ( ( C1 - C6 ) alkyl group; (a5) ( C1 - C6 ) alkoxycarbonyl ( C1 - C6 ) alkyl group; (a6) aryl( C1 - C6 ) alkoxy( C1 - C6 ) (a10) halo( C1 - C6 )alkyl group; (a14) ( C1 - C6 )alkoxycarbonyl group; (a16) trimethylsilyl( C1 - C6 )alkoxy( C1 - C6 ) Alkyl Group; (a17) ( C1 - C6 ) Alkylthio( C1 - C6 ) Alkyl Group; (a18) ( C1 - C6 ) Alkylsulfinyl( C1 - C6 ) Alkyl Group; (a19) ( C1 - C6 ) alkylsulfonyl ( C1 - C6 ) alkyl group; (a20) arylsulfonyl group; (a21) which may be the same or different, (a) a halogen atom, (b) ( C1 - C6) ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) (C 1 -C 6 )alkylsulfonyl groups, and (k) halo(C 1 -C 6 )alkylsulfonyl groups; - a tetrahydrofurylmethyl group; (a26) an aryl group; or (a28) an aryl( C1 - C6 )alkyl group;
X 1 is preferably (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo ( C 1 -C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; , (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl (i) a halo( C1 - C6 )alkylsulfinyl group, (j) a ( C1 - C6 )alkylsulfonyl group, and (k) a halo( C1 - C6 )alkylsulfonyl group, and (l (b8) a ( C3 - C6 ) cycloalkyl group; or (b10) a 3-tetrahydrofuryl group;
(c1) hydrogen atom; (c2) ( C1 - C6 )alkyl group; (c3) halo( C1 - C6 )alkyl group; ( c4 ) aryl group; or (c7) the same or may be different, (a) halogen atom, (b) ( C1 - C6 ) alkyl group, (c) halo( C1 - C6 ) alkyl group, (d) ( C1 - C6 ) alkoxy (e) a halo( C1 - C6 )alkoxy group; (f) a ( C1 - C6 )alkylthio group; (g) a halo( C1 - C6 )alkylthio group; (h) a (C1- C6 )alkylthio group; (i) a halo( C1 - C6 )alkylsulfinyl group; (j ) a ( C1 - C6 )alkylsulfonyl group; and (k) a halo( C1 - C6 )alkylsulfonyl group. an aryl(C 1 -C 6 )alkyl group having 1 to 5 substituents selected from the group;
X 2 and X 3 are preferably (d1) a hydrogen atom;
Y 1 and Y 4 are preferably (e1) hydrogen atom; (e2) halogen atom; or (e3) (C 1 -C 6 ) alkyl group;
( f1 ) hydrogen atom; (f2) halogen atom; (f3) (C1-C6 ) alkyl group; (f4) halo( C1 - C6 ) alkyl group; or ( f6) a halo( C1 - C6 )alkoxy group;
本願発明の犬糸状虫症防除剤の有効成分である一般式(1)で表されるベンゾイミダゾール化合物又はその塩類は、例えば下記製造方法によって製造することができるが、本願発明はこれらに限定されるものではない。
The benzimidazole compound represented by the general formula (1) or a salt thereof, which is the active ingredient of the dog heartworm control agent of the present invention, can be produced, for example, by the following production method, but the present invention is not limited thereto. not something.
工程[A]の製造方法
一般式(2-1)で表されるアミド化合物は、一般式(2)で表されるカルボン酸と一般式(3)で表されるフェニレンジアミン化合物とを、縮合剤、塩基及び不活性溶媒の存在下反応することにより製造することができる。 Production method of step [A] The amide compound represented by the general formula (2-1) is obtained by condensing the carboxylic acid represented by the general formula (2) and the phenylenediamine compound represented by the general formula (3). It can be produced by reacting in the presence of an agent, a base and an inert solvent.
一般式(2-1)で表されるアミド化合物は、一般式(2)で表されるカルボン酸と一般式(3)で表されるフェニレンジアミン化合物とを、縮合剤、塩基及び不活性溶媒の存在下反応することにより製造することができる。 Production method of step [A] The amide compound represented by the general formula (2-1) is obtained by condensing the carboxylic acid represented by the general formula (2) and the phenylenediamine compound represented by the general formula (3). It can be produced by reacting in the presence of an agent, a base and an inert solvent.
本反応で使用する縮合剤としては、例えばシアノリン酸ジエチル(DEPC)、カルボニルジイミダゾール(CDI)、1,3‐ジシクロヘキシルカルボジイミド(DCC)、クロロ炭酸エステル類、ヨウ化2‐クロロ‐1‐メチルピリジニウム、1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド塩酸塩(EDC・HCl)等を例示することができ、その使用量は一般式(2)で表されるカルボン酸に対して1倍モル~10倍モルの範囲から適宜選択して使用すれば良い。
Condensing agents used in this reaction include, for example, diethyl cyanophosphate (DEPC), carbonyldiimidazole (CDI), 1,3-dicyclohexylcarbodiimide (DCC), chlorocarbonates, and 2-chloro-1-methylpyridinium iodide. , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC/HCl) and the like can be exemplified, and the amount used is 1 times the carboxylic acid represented by the general formula (2). It may be used by appropriately selecting from the range of mol to 10 times mol.
本反応で使用する塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基類、酢酸ナトリウム、酢酸カリウム等の酢酸塩類、カリウムt‐ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド等のアルカリ金属アルコキシド類;トリエチルアミン、ジイソプロピルエチルアミン、1,8‐ジアザビシクロ[5.4.0]ウンデック‐7‐エン(DBU)等の第三級アミン類、ピリジン、ジメチルアミノピリジン(DMAP)等の含窒素芳香族化合物等を挙げることができ、その使用量は一般式(2)で表されるカルボン酸に対して通常0.1倍モル~10倍モルの範囲で使用される。
Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; acetates such as sodium acetate and potassium acetate; - alkali metal alkoxides such as butoxide, sodium methoxide, sodium ethoxide; tertiary amines such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); Nitrogen-containing aromatic compounds such as pyridine and dimethylaminopyridine (DMAP) can be mentioned, and the amount used is usually 0.1 to 10 times the mol of the carboxylic acid represented by the general formula (2). used in the range of
本反応で使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類;クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、ジエチルエーテル、メチルターシャリーブチルエーテル、ジオキサン、テトラヒドロフラン(THF)等の鎖状又は環状エーテル類、酢酸エチル等のエステル類、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N-メチルピロリドン(NMP)等のアミド類、アセトン、メチルエチルケトン等のケトン類、ジメチルスルホキシド(DMSO)、1,3‐ジメチル‐2‐イミダゾリジノン(DMI)等の極性溶媒、ピリジン等の含窒素芳香族化合物等の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することができる。
The inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction. Examples include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons; chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Amides such as formamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ketones such as acetone and methyl ethyl ketone, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI ) and inert solvents such as nitrogen-containing aromatic compounds such as pyridine, and these inert solvents can be used alone or in combination of two or more.
本反応は等モル反応であるので、各反応剤を等モル使用すれば良いが、いずれかの反応剤を過剰に使用することもできる。反応温度は室温から使用する不活性溶媒の沸点域で行うことができ、反応時間は反応規模、反応温度により一定しないが、数分~48時間の範囲で行えば良い。
Since this reaction is an equimolar reaction, it is sufficient to use an equimolar amount of each reactant, but it is also possible to use an excess of either reactant. The reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
反応終了後、目的物を含む反応系から常法により目的物を単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより目的物を製造することができる。また反応系から中間体を単離せずに、次工程を行ってもよい。
工程[B]の製造方法 After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography, or the like, if necessary. Alternatively, the next step may be performed without isolating the intermediate from the reaction system.
Manufacturing method of step [B]
工程[B]の製造方法 After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by purification by recrystallization, column chromatography, or the like, if necessary. Alternatively, the next step may be performed without isolating the intermediate from the reaction system.
Manufacturing method of step [B]
一般式(1-1)で表されるベンゾイミダゾール化合物は、一般式(2-1)で表されるアミド化合物を酸及び不活性溶媒の存在下又は非存在下、反応させることによっても製造することができる。
The benzimidazole compound represented by general formula (1-1) can also be produced by reacting an amide compound represented by general formula (2-1) in the presence or absence of an acid and an inert solvent. be able to.
反応で使用する酸としては、例えば、塩酸、硫酸、硝酸等の無機酸、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、安息香酸等の有機酸、メタンスルホン酸、トリフルオロメタンスルホン酸等のスルホン酸、リン酸等を例示することができ、その使用量は一般式(2)で表されるアミド化合物に対して0.01倍モル~200倍モルの範囲から適宜選択して使用すれば良い。
Examples of acids used in the reaction include inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid and benzoic acid; and sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid. , phosphoric acid and the like can be exemplified.
本反応で使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類;クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、ジエチルエーテル、メチルターシャリーブチルエーテル、ジオキサン、テトラヒドロフラン(THF)等の鎖状又は環状エーテル類、酢酸エチル等のエステル類、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N-メチルピロリドン(NMP)等のアミド類、アセトン、メチルエチルケトン等のケトン類、ジメチルスルホキシド(DMSO)、1,3‐ジメチル‐2‐イミダゾリジノン(DMI)等の極性溶媒等の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することができる。
The inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction. Examples include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons; chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Amides such as formamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), ketones such as acetone and methyl ethyl ketone, dimethyl sulfoxide (DMSO), 1,3-dimethyl-2-imidazolidinone (DMI ) can be exemplified, and these inert solvents can be used alone or in combination of two or more.
反応終了後、目的物を含む反応系から目的物を常法により単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより目的物を製造することができる。
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and if necessary, the target product can be produced by recrystallization, column chromatography, or the like.
工程[C]の製造方法
一般式(1)で表されるベンゾイミダゾール化合物は、一般式(1-1)で表されるベンゾイミダゾール化合物と一般式(4)で表される化合物を塩基及び不活性溶媒の存在下、反応させることにより製造することができる。 Production method of step [C] The benzimidazole compound represented by the general formula (1) is obtained by combining the benzimidazole compound represented by the general formula (1-1) and the compound represented by the general formula (4) with a base and an inorganic compound. It can be produced by reacting in the presence of an active solvent.
一般式(1)で表されるベンゾイミダゾール化合物は、一般式(1-1)で表されるベンゾイミダゾール化合物と一般式(4)で表される化合物を塩基及び不活性溶媒の存在下、反応させることにより製造することができる。 Production method of step [C] The benzimidazole compound represented by the general formula (1) is obtained by combining the benzimidazole compound represented by the general formula (1-1) and the compound represented by the general formula (4) with a base and an inorganic compound. It can be produced by reacting in the presence of an active solvent.
本反応で使用する塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、水素化ナトリウム、水素化カリウム等の無機塩基類、酢酸ナトリウム、酢酸カリウム等の酢酸塩類、カリウムt-ブトキシド、ナトリウムメトキシド、ナトリウムエトキシド等のアルカリ金属アルコキシド類;トリエチルアミン、ジイソプロピルエチルアミン、1,8-ジアザビシクロ[5.4.0]ウンデック-7-エン(DBU)等の第三級アミン類、ピリジン、ジメチルアミノピリジン(DMAP)等の含窒素芳香族化合物等を挙げることができ、その使用量は一般式(1-1)で表される化合物に対して通常1倍モル~10倍モルの範囲で使用される。
Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium acetate, and acetic acid. Acetates such as potassium, alkali metal alkoxides such as potassium t-butoxide, sodium methoxide, sodium ethoxide; triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) tertiary amines such as pyridine, nitrogen-containing aromatic compounds such as dimethylaminopyridine (DMAP), etc., and the amount used is usually for the compound represented by the general formula (1-1) It is used in the range of 1-fold molar to 10-fold molar.
本反応で使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、ジエチルエーテル、メチルターシャリーブチルエーテル、ジオキサン、テトラヒドロフラン(THF)等の鎖状又は環状エーテル類、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N-メチルピロリドン(NMP)等のアミド類、アセトン、メチルエチルケトン等のケトン類、ジメチルスルホキシド(DMSO)、1,3-ジメチル-2-イミダゾリジノン(DMI)等の極性溶媒、メタノール、エタノール、プロパノール、イソプロピルアルコール等のアルコール類等の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することができる。
The inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction. Hydrogens, diethyl ether, methyl tertiary butyl ether, dioxane, linear or cyclic ethers such as tetrahydrofuran (THF), amides such as dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidone (NMP), Ketones such as acetone and methyl ethyl ketone, polar solvents such as dimethylsulfoxide (DMSO) and 1,3-dimethyl-2-imidazolidinone (DMI), inert solvents such as alcohols such as methanol, ethanol, propanol, and isopropyl alcohol can be exemplified, and these inert solvents can be used alone or in combination of two or more.
本反応は等モル反応であるので、各反応剤を等モル使用すれば良いが、いずれかの反応剤を過剰に使用することもできる。反応温度は室温から使用する不活性溶媒の沸点域で行うことができ、反応時間は反応規模、反応温度により一定しないが、数分~48時間の範囲で行えば良い。
Since this reaction is an equimolar reaction, it is sufficient to use an equimolar amount of each reactant, but it is also possible to use an excess of either reactant. The reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
反応終了後、目的物を含む反応系から常法により目的物を単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより本発明化合物を製造することができる。
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the compound of the present invention can be produced by recrystallization, column chromatography, or the like, if necessary.
工程[D]の製造方法
一般式(6‐1)で表されるオキシムは、入手容易な一般式(6-2)で表わされるアルデヒド類を不活性溶媒下、ヒドロキシルアミン類、及び塩基と反応させることにより製造することができる。 Production method of step [D] The oxime represented by the general formula (6-1) is obtained by reacting an easily available aldehyde represented by the general formula (6-2) with hydroxylamines and a base in an inert solvent. It can be manufactured by
一般式(6‐1)で表されるオキシムは、入手容易な一般式(6-2)で表わされるアルデヒド類を不活性溶媒下、ヒドロキシルアミン類、及び塩基と反応させることにより製造することができる。 Production method of step [D] The oxime represented by the general formula (6-1) is obtained by reacting an easily available aldehyde represented by the general formula (6-2) with hydroxylamines and a base in an inert solvent. It can be manufactured by
本反応で使用するヒドロキシルアミン類としては、例えば、ヒドロキシルアミン塩酸塩、ヒドロキシルアミン硫酸塩等を例示することができ、その使用量は一般式(6-2)で表されるアルデヒド類に対して1倍モル~3倍モルの範囲から適宜選択して使用すれば良い。
As hydroxylamines used in this reaction, for example, hydroxylamine hydrochloride, hydroxylamine sulfate, etc. can be exemplified. It may be used by appropriately selecting from the range of 1-fold molar to 3-fold molar.
本反応で使用する塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム、水素化ナトリウム、水素化カリウム等の無機塩基類、酢酸ナトリウム、酢酸カリウム等の酢酸塩類等を挙げることができ、その使用量は一般式(6-2)で表されるアルデヒド類に対して通常1倍モル~10倍モルの範囲で使用すればよい。
Examples of the base used in this reaction include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydride, potassium hydride, sodium acetate, and acetic acid. Acetates such as potassium and the like can be mentioned, and the amount thereof to be used may generally be in the range of 1 to 10 mol per mol of the aldehyde represented by the general formula (6-2).
本反応で使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えばメタノール、エタノール等のアルコール類、ジエチルエーテル、メチルターシャリーブチルエーテル、ジオキサン、テトラヒドロフラン(THF)等の鎖状又は環状エーテル類、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N-メチルピロリドン(NMP)等のアミド類等の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することができる。
The inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction. Linear or cyclic ethers, dimethylformamide (DMF), dimethylacetamide (DMA), inert solvents such as N-methylpyrrolidone (NMP) and other amides can be exemplified. Alternatively, two or more kinds can be mixed and used.
本反応は等モル反応であるので、各反応剤を等モル使用すれば良いが、いずれかの反応剤を過剰に使用することもできる。反応温度は室温から使用する不活性溶媒の沸点域で行うことができ、反応時間は反応規模、反応温度により一定しないが、数分~48時間の範囲で行えば良い。
Since this reaction is an equimolar reaction, it is sufficient to use an equimolar amount of each reactant, but it is also possible to use an excess of either reactant. The reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
反応終了後、目的物を含む反応系から常法により目的物を単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより目的物を製造することができる。また反応系から中間体を単離せずに、次工程を行ってもよい。
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary. Alternatively, the next step may be performed without isolating the intermediate from the reaction system.
工程[E]の製造方法
一般式(6)で表されるイミドイルクロリドは、前工程で製造した一般式(6-1)で表わされるオキシム類を不活性溶媒下、ハロゲン化剤と反応させることにより製造することができる。 Production method of step [E] The imidoyl chloride represented by the general formula (6) is obtained by reacting the oxime represented by the general formula (6-1) produced in the previous step with a halogenating agent in an inert solvent. It can be manufactured by
一般式(6)で表されるイミドイルクロリドは、前工程で製造した一般式(6-1)で表わされるオキシム類を不活性溶媒下、ハロゲン化剤と反応させることにより製造することができる。 Production method of step [E] The imidoyl chloride represented by the general formula (6) is obtained by reacting the oxime represented by the general formula (6-1) produced in the previous step with a halogenating agent in an inert solvent. It can be manufactured by
本反応で使用するハロゲン化剤としては、例えば、塩素、臭素、ヨウ素等のハロゲン類、N-クロロスクシンイミド、N-ブロモスクシンイミド、N-ヨードスクシンイミド、1,3-ジブロモ-5,5-ジメチルヒダントイン、1,3-ジヨ-ド-5,5-ジメチルヒダントイン、1,3-ジクロロ-5,5-ジメチルヒダントイン等を例示することができ、その使用量は一般式(6-1)で表されるオキシム類に対して1倍モル~5倍モルの範囲から適宜選択して使用すれば良い。
Examples of the halogenating agent used in this reaction include halogens such as chlorine, bromine, and iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin. , 1,3-diiodo-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin, etc., and the amount used is represented by the general formula (6-1). It may be appropriately selected from the range of 1 to 5 times the molar amount of the oxime to be used.
本反応で使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、ジエチルエーテル、メチルターシャリーブチルエーテル、ジオキサン、テトラヒドロフラン(THF)等の鎖状又は環状エーテル類、酢酸エチル等のエステル類、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N‐メチルピロリドン(NMP)等のアミド類、1,3-ジメチル-2-イミダゾリジノン(DMI)等の極性溶媒の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することができる。
The inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction. Examples include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons, chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Formamide (DMF), dimethylacetamide (DMA), amides such as N-methylpyrrolidone (NMP), polar solvent inert solvents such as 1,3-dimethyl-2-imidazolidinone (DMI) can be exemplified. These inert solvents can be used alone or in combination of two or more.
本反応は等モル反応であるので、各反応剤を等モル使用すれば良いが、いずれかの反応剤を過剰に使用することもできる。反応温度は室温から使用する不活性溶媒の沸点域で行うことができ、反応時間は反応規模、反応温度により一定しないが、数分~48時間の範囲で行えば良い。
Since this reaction is an equimolar reaction, it is sufficient to use an equimolar amount of each reactant, but it is also possible to use an excess of either reactant. The reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
反応終了後、目的物を含む反応系から常法により目的物を単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより目的物を製造することができる。また反応系から中間体を単離せずに、次工程を行ってもよい。又は、工程[D]及び工程[E]を連続して、ワンポットで製造してもよい。
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary. Alternatively, the next step may be performed without isolating the intermediate from the reaction system. Alternatively, step [D] and step [E] may be continuously performed in one pot.
工程[F]の製造方法
一般式(2‐1)で表されるカルボン酸エステル類は、前工程で製造した一般式(6)で表わされるイミドイルクロリドと一般式(5)で表わされるアクリル酸エステル類とを不活性溶媒下、及び金属類と反応させることにより製造することができる。 Production method of step [F] The carboxylic acid ester represented by the general formula (2-1) is the imidoyl chloride represented by the general formula (6) produced in the previous step and the acrylic represented by the general formula (5). It can be produced by reacting acid esters with metals in an inert solvent.
一般式(2‐1)で表されるカルボン酸エステル類は、前工程で製造した一般式(6)で表わされるイミドイルクロリドと一般式(5)で表わされるアクリル酸エステル類とを不活性溶媒下、及び金属類と反応させることにより製造することができる。 Production method of step [F] The carboxylic acid ester represented by the general formula (2-1) is the imidoyl chloride represented by the general formula (6) produced in the previous step and the acrylic represented by the general formula (5). It can be produced by reacting acid esters with metals in an inert solvent.
本反応で使用する金属類としては、硫酸銅5水和物、硝酸銅、塩酸銅、及び銅粉末等を例示することができ、その使用量は一般式(6)で表されるイミドイルクロリドに対して0.01倍モル~1倍モルの範囲から適宜選択して使用すれば良い。
Examples of metals used in this reaction include copper sulfate pentahydrate, copper nitrate, copper hydrochloride, and copper powder. It may be used by appropriately selecting from the range of 0.01 to 1 mol per mol.
本反応で使用する不活性溶媒としては、本反応の進行を著しく阻害しないものであれば良く、例えばベンゼン、トルエン、キシレン等の芳香族炭化水素類、塩化メチレン、クロロホルム、四塩化炭素等のハロゲン化炭化水素類、クロロベンゼン、ジクロロベンゼン等のハロゲン化芳香族炭化水素類、ジエチルエーテル、メチルターシャリーブチルエーテル、ジオキサン、テトラヒドロフラン(THF)等の鎖状又は環状エーテル類、酢酸エチル等のエステル類、ジメチルホルムアミド(DMF)、ジメチルアセトアミド(DMA)、N‐メチルピロリドン(NMP)等のアミド類、1,3-ジメチル-2-イミダゾリジノン(DMI)等の極性溶媒及び水等の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することができる。
The inert solvent used in this reaction may be one that does not significantly hinder the progress of this reaction. Examples include aromatic hydrocarbons such as benzene, toluene, and xylene; Halogenated hydrocarbons, chlorobenzene, dichlorobenzene and other halogenated aromatic hydrocarbons, diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF) and other chain or cyclic ethers, ethyl acetate and other esters, dimethyl Examples include formamide (DMF), dimethylacetamide (DMA), amides such as N-methylpyrrolidone (NMP), polar solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), and inert solvents such as water. These inert solvents can be used alone or in combination of two or more.
本反応は等モル反応であるので、各反応剤を等モル使用すれば良いが、いずれかの反応剤を過剰に使用することもできる。反応温度は室温から使用する不活性溶媒の沸点域で行うことができ、反応時間は反応規模、反応温度により一定しないが、数分~48時間の範囲で行えば良い。
Since this reaction is an equimolar reaction, it is sufficient to use an equimolar amount of each reactant, but it is also possible to use an excess of either reactant. The reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
反応終了後、目的物を含む反応系から常法により目的物を単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより目的物を製造することができる。また反応系から中間体を単離せずに、次工程を行ってもよい。又は、工程[D]~工程[F]を連続して、ワンポットで製造してもよい。
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary. Alternatively, the next step may be performed without isolating the intermediate from the reaction system. Alternatively, step [D] to step [F] may be continuously performed in one pot.
工程[G]の製造方法
一般式(2)で表わされるカルボン酸化合物は、一般式(2-1)で表わされるエステル化合物を、不活性溶媒中、塩基と反応させることにより製造することができる。 Production method of step [G] The carboxylic acid compound represented by the general formula (2) can be produced by reacting the ester compound represented by the general formula (2-1) with a base in an inert solvent. .
一般式(2)で表わされるカルボン酸化合物は、一般式(2-1)で表わされるエステル化合物を、不活性溶媒中、塩基と反応させることにより製造することができる。 Production method of step [G] The carboxylic acid compound represented by the general formula (2) can be produced by reacting the ester compound represented by the general formula (2-1) with a base in an inert solvent. .
本反応で使用する塩基としては、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等を挙げることができ、その使用量は一般式(2-1)で表される化合物に対して通常1倍モル~10倍モルの範囲で使用される。
Examples of the base used in this reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and the like. It is usually used in an amount of 1 to 10 times the molar amount of the compound represented by 2-1).
本反応で使用できる不活性溶媒としては、本反応を著しく阻害しないものであれば良く、例えば、水、メタノール、エタノール、プロパノール、イソプロピルアルコール等のアルコール類、ジエチルエーテル、テトラヒドロフラン(THF)、ジオキサン等の鎖状又は環状エーテル類及び水等の不活性溶媒を例示することができ、これらの不活性溶媒は単独で又は2種以上混合して使用することもできる。
The inert solvent that can be used in this reaction may be any one that does not significantly inhibit this reaction. Examples include water, alcohols such as methanol, ethanol, propanol, and isopropyl alcohol, diethyl ether, tetrahydrofuran (THF), dioxane, and the like. and inert solvents such as water and the like, and these inert solvents can be used alone or in combination of two or more.
本反応は等モル反応であるので、各反応剤を等モル使用すれば良いが、いずれかの反応剤を過剰に使用することもできる。反応温度は室温から使用する不活性溶媒の沸点域で行うことができ、反応時間は反応規模、反応温度により一定しないが、数分~48時間の範囲で行えば良い。
Since this reaction is an equimolar reaction, it is sufficient to use an equimolar amount of each reactant, but it is also possible to use an excess of either reactant. The reaction temperature can be from room temperature to the boiling point range of the inert solvent used, and the reaction time varies depending on the reaction scale and reaction temperature, but may be carried out in the range of several minutes to 48 hours.
反応終了後、目的物を含む反応系から常法により目的物を単離すれば良く、必要に応じて再結晶、カラムクロマトグラフィー等で精製することにより目的物を製造することができる。
After completion of the reaction, the target product may be isolated from the reaction system containing the target product by a conventional method, and the target product can be produced by recrystallization, column chromatography, or the like, if necessary.
次に、本願発明化合物及びその中間体の具体例を以下に示す。下記の表において、Meはメチル基、Etはエチル基、t‐Buはターシャリーブチル基、n‐Penはノルマルペンチル基、n‐Hexはノルマルヘキシル基、c‐Hexはシクロへキシル基、Phはフェニル基、Bnはベンジル基、Tsはパラトルエンスルホニル基、Eは、トランス体を示す。物性は融点(℃)、屈折率(℃)又は1H‐NMRを示す。1H‐NMRデータは第6表に示す。
Specific examples of the compounds of the present invention and intermediates thereof are shown below. In the table below, Me is a methyl group, Et is an ethyl group, t-Bu is a tertiary butyl group, n-Pen is a normal pentyl group, n-Hex is a normal hexyl group, c-Hex is a cyclohexyl group, Ph is a phenyl group, Bn is a benzyl group, Ts is a paratoluenesulfonyl group, and E is a trans form. Physical properties are indicated by melting point (°C), refractive index (°C) or 1 H-NMR. 1 H-NMR data are shown in Table 6.
本願発明の犬糸状虫症防除剤は、一般式(1)で表されるベンゾイミダゾール化合物またはその塩類を有効成分として含有する。
本願発明の犬糸状虫症防除剤の対象となる動物は、牛、豚、ウサギ、鳥類などの家畜、または犬、ウサギ又は猫等のペット類(以後対象動物、ただし人間を除く。)であり、好ましくは犬であるが、これらに限定されるものではない。なお、本願発明において、防除とは予防および治療を含むものである。 The dog heartworm control agent of the present invention contains a benzimidazole compound represented by general formula (1) or a salt thereof as an active ingredient.
The target animals of the canine heartworm control agent of the present invention are domestic animals such as cows, pigs, rabbits and birds, or pets such as dogs, rabbits and cats (hereinafter target animals, excluding humans). , preferably dogs, but not limited to these. In the present invention, control includes prevention and treatment.
本願発明の犬糸状虫症防除剤の対象となる動物は、牛、豚、ウサギ、鳥類などの家畜、または犬、ウサギ又は猫等のペット類(以後対象動物、ただし人間を除く。)であり、好ましくは犬であるが、これらに限定されるものではない。なお、本願発明において、防除とは予防および治療を含むものである。 The dog heartworm control agent of the present invention contains a benzimidazole compound represented by general formula (1) or a salt thereof as an active ingredient.
The target animals of the canine heartworm control agent of the present invention are domestic animals such as cows, pigs, rabbits and birds, or pets such as dogs, rabbits and cats (hereinafter target animals, excluding humans). , preferably dogs, but not limited to these. In the present invention, control includes prevention and treatment.
犬糸状虫症とは、旋尾線虫目(Spirurida)の線虫類、詳細には、(a)オンコセルカ科(Onchocercidae)の線虫、例えば、ブルギア属種(Brugia spp.)の、マレー糸状虫(Brugia malayi)、ブルギア・パハンギィ(Brugia pahangi)、ブルギア・パティ(Brugia patei);ディペタロネーマ属種(Dipetalonema spp.)の、ディペタロネーマ・リコンディトゥム(Dipetalonema reconditum);イヌ糸状虫属種(Dirofilaria spp.)の、イヌ糸状虫(Dirofilaria immitis);フィラリア属種(Filaria spp.)の、フィラリア・オクリィ(Filaria oculi);オンコセルカ属種(Onchocerca spp.)の、頸部糸状虫(Onchocerca cervicalis)、ギブソン糸状虫(Onchocerca gibsoni)、咽頭糸状虫(Onchocerca gutturosa);(b)セタリア科(Setariidae)の線虫、例えば、セタリア属種(Setaria spp.)の、指状糸状虫(Setaria digitata)、馬糸条虫(Setaria equina)、唇乳頭糸状虫(Setaria labiatopapillosa)、マーシャル糸状虫(Setaria marshalli);ブケレリア属種(Wuchereria spp.)の、バンクロフト糸状虫(Wuchereria bancrofti);(c)糸状虫科(Filariidae)の線虫、例えば、パラフィラリア属種(Parafilaria spp.)の、多乳頭糸状虫(Parafilaria multipapillosa);ステファノフィラリア属種(Stephanofilaria spp.)の、ステファノフィラリア・アッサムエンシス(Stephanofilaria assamensis)、ステファノフィラリア・デドエシー(Stephanofilaria dedoesi)、ステファノフィラリア・カエリー(Stephanofilaria kaeli)、沖縄糸状虫(Stephanofilaria okinawaensis)、ステファノフィラリア・スティレシー(Stephanofilaria stilesi)等によって引き起こされる事が知られているがこれらに限定されるものではない。
Canine filariasis refers to nematodes of the order Spirurida, in particular (a) nematodes of the family Onchocercidae, e.g., of the genus Brugia spp. Brugia malayi, Brugia pahangi, Brugia patei; Dipetalonema reconditum, of Dipetalonema spp.; Dirofilaria spp. Filaria spp., Filaria oculi; Onchocerca spp., Onchocerca cervicalis, Gibson Onchocerca gibsoni, Onchocerca gutturosa; (b) nematodes of the Setariidae family, e.g. Setaria spp., Setaria digitata, horse thread Setaria equina, Setaria labiatopapillosa, Setaria marshalli; Wuchereria spp., Wuchereria bancrofti; Filariidae nematodes, such as Parafilaria spp., Parafilaria multipapillosa; Stephanofilaria spp., Stephanofilaria assamensis, Stefano For Stephanofilaria dedoesi, Stephanofilaria kaeli, Stephanofilaria okinawaensis, Stephanofilaria stilesi, etc. However, it is not limited to these.
本願発明の防除剤を用いる場合には、他に何らの成分も加えず、そのままベンゾイミダゾール化合物を使用してもよいが、通常はベンゾイミダゾール化合物又はその塩類にさらに固体坦体、液体坦体等の賦形剤を加え、通常の方法(例えば「製剤学」大塚昭信ら編、1995年、南江堂に記載される方法等)に準じて錠剤、粉末剤、顆粒剤、カプセル剤、水溶剤、液剤、水和剤及び懸濁剤等に製剤化してから使用するのが好ましい。固体坦体である賦形剤としては例えば、乳糖、ショ糖、ブドウ糖、コーンスターチ、ゼラチン、カゼイン、澱粉、アラビアガム、セルロース誘導体、アルギン酸等が挙げられる。また液体担体である賦形剤としては例えば、水、グリセリン、植物油、脂肪酸、脂肪酸エステル、ソルビトール等が挙げられる。
When the control agent of the present invention is used, the benzimidazole compound may be used as it is without adding any other ingredients. Add excipients, tablets, powders, granules, capsules, aqueous solutions, liquids according to the usual method (e.g., "Pharmaceutical Science" Akinobu Otsuka et al., 1995, Nankodo, etc.) , wettable powders and suspensions before use. Excipients that are solid carriers include, for example, lactose, sucrose, glucose, corn starch, gelatin, casein, starch, gum arabic, cellulose derivatives, alginic acid and the like. Excipients that are liquid carriers include, for example, water, glycerin, vegetable oils, fatty acids, fatty acid esters, sorbitol and the like.
本願発明の防除剤には、例えば、ペプチド亜鉛、ペプチド鉄等の有機ミネラル、炭酸亜鉛、炭酸マンガン、硫酸鉄、炭酸マグネシウム等の無機ミネラル、ビタミンA、ビタミンB、ビタミンC、ビタミンD、ビタミンE、ビタミンK、葉酸、パントテン酸、ニコチン酸等のビタミン類、アルファルファミール、圧ペントウモロコシ等をさらに含有させてもよい。また、嗜好性を高めるために、フレーバー等を同時に給与してもよい。必要により、抗菌剤、防カビ剤、駆虫剤、抗酸化剤、色素、着香料、呈味料、酵素のような通常の添加物を混合してもよく、通常の方法により、散剤、顆粒剤、液剤、錠剤等の形態に製剤化して用いるのが好ましい。これらの製剤には、有効成分としてベンゾイミダゾール化合物又はその塩類を、通常、重量比で約0.01~95重量%含有させてもよい。
Examples of the control agent of the present invention include organic minerals such as peptide zinc and peptide iron, inorganic minerals such as zinc carbonate, manganese carbonate, iron sulfate, and magnesium carbonate, vitamin A, vitamin B, vitamin C, vitamin D, and vitamin E. , vitamin K, folic acid, pantothenic acid, and nicotinic acid, alfalfa meal, pressed corn, and the like. Moreover, in order to enhance palatability, a flavor or the like may be provided at the same time. If necessary, conventional additives such as antibacterial agents, antifungal agents, anthelmintics, antioxidants, pigments, flavoring agents, flavoring agents, and enzymes may be mixed, and powders and granules are prepared by conventional methods. , liquid medicine, tablets and the like. These preparations may contain a benzimidazole compound or a salt thereof as an active ingredient, usually in an amount of about 0.01 to 95% by weight.
このようにして製剤化された本願発明の防除剤は、そのままで、あるいは水等で希釈して使用することができる。また、さらに他の抗菌剤、防カビ剤、駆虫剤、抗酸化剤、色素、着香料、呈味料、酵素のような通常の添加物等が混用又は同時若しくは非同時に併用されてもよい。
The control agent of the present invention formulated in this way can be used as it is or after being diluted with water or the like. In addition, other antibacterial agents, antifungal agents, anthelmintic agents, antioxidants, pigments, flavoring agents, flavoring agents, ordinary additives such as enzymes, etc. may be mixed or used simultaneously or not at the same time.
本願発明の防除剤の対象動物への投与について特別の制限はなく、後述のような飼料へ撒布、混合など従来公知の方法によることができる。投与量は、対象動物の犬糸状虫症防除効果に有効な量、即ち、他の条件を等しくした場合において、本願発明の防除剤を投与したときの方が投与しないときに較べて対象動物の犬糸状虫症防除効果が増進される量である。
There are no particular restrictions on the administration of the control agent of the present invention to target animals, and conventionally known methods such as spraying or mixing with feed as described later can be used. The dosage is an amount effective for the control effect of canine heartworm in the target animal, that is, when other conditions are equal, the control agent of the present invention is administered to the target animal compared to when it is not administered. It is an amount that enhances the canine heartworm control effect.
対象動物に投与しようとする本願発明の防除剤の有効成分を混合、ゲル化し自由摂取させる方法は、孵化場及び農場のいずれでも実施することができる。また、孵化場から農場への対象動物の輸送中にも実施することができる。
The method of mixing and gelling the active ingredients of the control agent of the present invention to be administered to target animals and allowing them to freely ingest can be carried out at both hatcheries and farms. It can also be carried out during transportation of the subject animals from the hatchery to the farm.
また、本願発明の防除剤の有効成分に所定量の水溶性多糖類の粉末を配合したゲル化用調製物を用意し、孵化場及び農場で使用する際に水で希釈しゲル状固形物とし、対象とする対象動物に投与する方法(即ち、自由摂取、そ嚢内直接投与)も実施することができる。
In addition, a preparation for gelling is prepared by blending a predetermined amount of water-soluble polysaccharide powder with the active ingredient of the control agent of the present invention, and diluted with water to form a gel-like solid when used in hatcheries and farms. Alternatively, a method of administering to the target animal of interest (ie, ad libitum, direct administration in the crochet) can also be carried out.
製剤化した防除剤は通常は単独で用いるが、水で希釈して製剤希釈液として使用することができる(即ち、飲水希釈投与)。当該製剤希釈液中の有効成分濃度としては、通常、約10~10000ppmの範囲が好ましく、より好ましくは約35~5000ppmの範囲である。当該製剤希釈液の投与方法としては、通常、水1Lに対して防除剤を約0.01~500g溶解して、投与液量に処理する方法等が挙げられる。好ましくは、水1Lに対して約0.035~350gを溶解し投与する方法等が挙げられる。
The formulated control agent is usually used alone, but it can be diluted with water and used as a formulation diluent (i.e., diluted administration in drinking water). The active ingredient concentration in the formulation diluent is generally preferably in the range of about 10 to 10000 ppm, more preferably in the range of about 35 to 5000 ppm. As a method for administering the diluted formulation, a method of dissolving about 0.01 to 500 g of the pesticide in 1 L of water and processing the solution to be administered can be mentioned. A preferred method includes a method of dissolving about 0.035 to 350 g in 1 L of water and administering.
このようにして調製した製剤希釈液を対象動物に投与するには、飲水添加装置等を用いて当該製剤希釈液を投与すればよい。当該製剤希釈液の投与液量は、対象となる対象動物の大きさ、生育状況、飼育密度及び投与方法等に応じて適宜決定すればよいが、通常10,000羽当たり約300~2000リットル程度が好ましい。
In order to administer the formulation dilution prepared in this way to the target animal, the formulation dilution may be administered using a drinking water addition device or the like. The volume of the diluent to be administered may be appropriately determined according to the size of the target animal, growth conditions, rearing density, administration method, etc., but is usually about 300 to 2000 liters per 10,000 birds. is preferred.
本願発明の防除剤の投与の時期及び実施期間は、採卵用種及び肉用種において、対象動物の全期間継続して、好ましくは幼雛期(孵化後0~5週令の鶏)又は生後0~5週に投与することである。
The timing and implementation period of the administration of the control agent of the present invention, in egg-producing species and meat-producing species, continue for the entire period of the target animal, preferably in the larval stage (chicken 0 to 5 weeks old after hatching) or 0 to 0 years old. Dosing at 5 weeks.
防除剤の投与量は、対象動物の種類や大きさ等により適宜決定すればよいが、一般に投与総量として0.005~2gの範囲が好ましい。より好ましくは0.005~1gの範囲である。
The dosage of the control agent may be appropriately determined according to the type and size of the target animal, but generally the total dosage is preferably in the range of 0.005 to 2 g. It is more preferably in the range of 0.005 to 1 g.
本願発明の防除剤組成物は、前記防除剤を動物用飼料又は飲料水若しくは生理電解質溶液等に添加して防除剤組成物とされる。防除剤の添加量としては、防除剤組成物全量に対して約0.005~10.0重量%の範囲が好ましい。
The control agent composition of the present invention is made by adding the control agent to animal feed, drinking water, physiological electrolyte solution, or the like. The amount of the control agent to be added is preferably in the range of about 0.005 to 10.0% by weight based on the total amount of the control agent composition.
本願発明の防除剤組成物に用いられる対象動物用飼料又は飲料水若しくは生理電解質溶液は、一般に使用されているものであればよく特に限定されるものではない。これらの一例としては、とうもろこし、米、麦、マイロ、大豆粕、ふすま、脱脂米ぬか、魚粉、脱脂粉乳、乾燥ホエー、油脂、アルファルファミール、北洋ミール、大豆油脂、粉末精製牛脂、小麦粉、なたね油脂、肉骨粉(フェザーミール)、動物性油脂、リン酸カルシウム、コーングルテンミール、糖蜜、コーンジャームミール、炭酸カルシウム、リン酸三カルシウム、塩化ナトリウム、塩化コリン、ビタミン類(ビタミンA、ビタミンB1、ビタミンB2、ビタミンB6、ビタミンB12、ビタミンD、ビタミンE、パントテン酸カルシウム、ニコチン酸アミド、葉酸等)、アミノ酸類(リジン、メチオニン等)、微量無機塩類(硫酸マグネシウム、硫酸鉄、硫酸銅、硫酸亜鉛、ヨウ化カリウム、硫酸コバルト等)、生菌剤等を適宜混合して調製した飼料等が挙げられる。
The target animal feed, drinking water, or physiological electrolyte solution used in the control agent composition of the present invention is not particularly limited as long as it is generally used. Examples of these include corn, rice, barley, milo, soybean meal, wheat bran, skimmed rice bran, fish meal, skimmed milk powder, dried whey, oil, alfalfa meal, North Sea meal, soybean oil, powdered refined beef tallow, wheat flour, rapeseed oil, meat. Bone meal (feather meal), animal fat, calcium phosphate, corn gluten meal, molasses, corn germ meal, calcium carbonate, tricalcium phosphate, sodium chloride, choline chloride, vitamins (vitamin A, vitamin B1, vitamin B2, vitamin B6 , vitamin B12, vitamin D, vitamin E, calcium pantothenate, nicotinamide, folic acid, etc.), amino acids (lysine, methionine, etc.), trace inorganic salts (magnesium sulfate, iron sulfate, copper sulfate, zinc sulfate, potassium iodide) , cobalt sulfate, etc.), feeds prepared by appropriately mixing probiotic agents, and the like.
本願発明の防除剤組成物には、その他に例えば、ペプチド亜鉛、ペプチド鉄等の有機ミネラル、炭酸亜鉛、炭酸マンガン、硫酸鉄、炭酸マグネシウム等の無機ミネラル、ビタミンA、ビタミンB、ビタミンC、ビタミンD、ビタミンE、ビタミンK、葉酸、パントテン酸、ニコチン酸等のビタミン類、アルファルファミール、圧ペントウモロコシ等がさらに含有されていてもよい。また、嗜好性を高める為、同時にフレーバー等を給与してもよい。
In addition, the control agent composition of the present invention includes, for example, organic minerals such as peptide zinc and peptide iron, inorganic minerals such as zinc carbonate, manganese carbonate, iron sulfate, and magnesium carbonate, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, folic acid, pantothenic acid, vitamins such as nicotinic acid, alfalfa meal, pressed corn and the like may be further contained. In addition, in order to enhance palatability, a flavor or the like may be given at the same time.
本願発明の防除剤組成物の対象動物への投与方法に特に制限はなく、後述のような飼料へ撒布、混合等適宜の方法を利用した給与法によることができる。なお防除剤組成物の投与量は、要するに対象動物の犬糸状虫症防除効果に有効な量、即ち、他の条件を等しくした場合において、本願発明の防除剤組成物を投与したときの方が投与しないときに較べて対象動物の犬糸状虫症防除効果が増進される量である。
There is no particular limitation on the method of administering the control agent composition of the present invention to the target animal, and it can be applied by a feeding method using an appropriate method such as spraying or mixing with feed as described later. The dose of the control agent composition is, in short, an amount effective for the effect of controlling canine heartworm in the target animal, that is, when the other conditions are equal, the control agent composition of the present invention is more effective. It is an amount that enhances the canine heartworm-controlling effect of the subject animal compared to when it is not administered.
本願発明の防除剤組成物の投与の時期及び実施期間は、採卵用種及び肉用種において、対象動物の全期間継続して、好ましくは幼雛期(孵化後0~5週令の鶏)又は生後0~5週に投与する。より好ましくは孵化後0~21日間又は生後0~21日間継続して投与する。
The timing and implementation period of the administration of the control agent composition of the present invention should be continued for the entire period of the target animal in egg-producing species and meat-producing species, preferably in the larval stage (chickens aged 0 to 5 weeks after hatching) or after birth. Administer from 0-5 weeks. More preferably, administration is continued for 0 to 21 days after hatching or 0 to 21 days after birth.
本願発明の防除剤組成物は、対象動物用飼料に配合して用いる場合には、ベンゾイミダゾール化合物又はその塩類を約0.0005~5重量%、好ましくは約0.05~2重量%の割合で用いることができる。また、飲料水若しくは生理電解質溶液に添加して用いる場合には、ベンゾイミダゾール化合物又はその塩類を約0.035~3.5重量%、好ましくは約0.035~1.4重量%の割合で用いることができる。
When the control agent composition of the present invention is used as a feed for target animals, it contains a benzimidazole compound or a salt thereof in an amount of about 0.0005 to 5% by weight, preferably about 0.05 to 2% by weight. can be used in When used by adding to drinking water or a physiological electrolyte solution, the benzimidazole compound or a salt thereof is added at a rate of about 0.035 to 3.5% by weight, preferably about 0.035 to 1.4% by weight. can be used.
本願発明の防除方法は、本願発明の防除剤又は本願発明の防除剤組成物の有効量を対象動物に投与する工程を有する。当該方法において、防除剤組成物は前記動物に通常の方法で与えることができる。上記の有効量は、いずれも製剤の種類、対象動物、摂取させる期間等の状況によって異なり、上記の範囲に関わることなく増減して適宜選択することができる。
The control method of the present invention comprises the step of administering an effective amount of the control agent of the present invention or the control agent composition of the present invention to a target animal. In the method, the control agent composition can be given to the animal in a conventional manner. The above effective amount varies depending on the type of formulation, target animal, ingestion period, and other circumstances, and can be appropriately selected by increasing or decreasing regardless of the above range.
具体的には例えば、本願発明の防除剤を対象動物に投与するのに適した濃度になるように水で希釈し、得られた希釈液を対象動物に投与する。尚、希釈倍率は従来の飲水希釈投与法に準じて適用すればよく、例えば、5~10倍程度の希釈液が好ましく使用される。また、本願発明の防除剤を所定濃度になるように水で希釈し、これに攪拌下水溶性多糖類を添加混合し、均一な溶液とし、常温で放置するか、若しくは冷所(例えば、冷蔵庫等)に保管することによりゲル状固形物を得る。または高温で溶解し低温で凝固するゲル化剤(例えば、寒天、ゼラチン等)を用いる場合には、本願発明の防除剤を作成するための培地にあらかじめゲル化剤を加えておき、培地を高圧蒸気殺菌後冷却して、これを常温で放置するか、若しくは冷所(例えば、冷蔵庫等)に保管することによってゲル状固形物を得る。このようにして得られたゲル状固形物を対象動物に投与してもよい。尚、ゲル化した場合のゲル強度は、概ね200~2000g/cm2 が適当であり、寒天を用いた場合には寒天の種類により異なるが、概ね0.5~3.0%の濃度に相当する。
Specifically, for example, the control agent of the present invention is diluted with water to a concentration suitable for administration to a target animal, and the obtained diluted solution is administered to the target animal. The dilution factor may be applied according to the conventional drinking water dilution administration method, and for example, a diluted solution of about 5 to 10 times is preferably used. In addition, the control agent of the present invention is diluted with water to a predetermined concentration, and the water-soluble polysaccharide is added and mixed with stirring to make a uniform solution, which is left at room temperature or in a cold place (eg, refrigerator). ) to obtain a gel-like solid. Alternatively, when using a gelling agent that dissolves at high temperature and solidifies at low temperature (e.g., agar, gelatin, etc.), the gelling agent is added in advance to the medium for preparing the control agent of the present invention, and the medium is pressurized. After steam sterilization, the product is cooled and left at room temperature or stored in a cool place (for example, a refrigerator) to obtain a gel-like solid product. The gel-like solid thus obtained may be administered to a subject animal. The appropriate gel strength when gelled is approximately 200 to 2000 g/cm 2 , and when agar is used, it corresponds to a concentration of approximately 0.5 to 3.0%, depending on the type of agar. do.
本願発明の防除剤を水媒体中でゲル化させるのに使用される多糖類しては、例えば、寒天、カラギーナン、カルボキシメチルセルロース、澱粉、マンナン、ゼラチン、アルギン酸ナトリウム、アラビアガム、ロウストビーンガム、キサンタンガム、キトサン、グアーガム、ペクチン、アルギン酸プロピルグリコールエステル、アラビノガラクタン、ガティガム、タマリンドシードガム、プルラン、モルホリン脂肪酸塩、カードラン、トラガントガム等が挙げられる。これらの多糖類の中でも、安価且つ容易に入手し得る点から、特に寒天、澱粉、マンナン、ゼラチンを用いることが好ましい。
Polysaccharides used for gelling the control agent of the present invention in an aqueous medium include, for example, agar, carrageenan, carboxymethylcellulose, starch, mannan, gelatin, sodium alginate, gum arabic, roast bean gum, xanthan gum, chitosan, guar gum, pectin, propyl glycol alginate, arabinogalactan, gati gum, tamarind seed gum, pullulan, morpholine fatty acid salt, curdlan, tragacanth gum and the like. Among these polysaccharides, it is particularly preferable to use agar, starch, mannan, and gelatin because they are inexpensive and readily available.
例えば、前記のゲル状固形物を家禽に投与する場合、飲料水量及び飼料摂取量の少ない概ね0~7日令の家禽に投与すると、床面の固形物を嘴で突っついて摂取しようとする家禽の遺伝的プログラム(習性)によって短時間に本願発明の防除剤の必要量を省力的に摂取させることができる。この際、前記のような若令期の家禽に投与することが困難であった生菌剤、ワクチン、薬剤、栄養等も必要に応じて本願発明の防除剤と共に混合して水溶性多糖類でゲル化させておくと、本願発明の防除剤と同時に効率よく家禽に投与することもできる。また、雛鶏の時期における水分及び栄養の補給はその後の生産性にとって極めて重要であり、栄養を投与する場合には、グルコース、マンノース、フラクトース等の単糖類及びこれらのオリゴ体、シュークロース等の二糖類の糖類等の炭水化物、スキムミルク等の蛋白質、脂質に加えてビタミン、ミネラル等が挙げられる。
For example, when the gel-like solid is administered to poultry, if it is administered to poultry of approximately 0 to 7 days of age with a small amount of drinking water and feed intake, the poultry that tries to ingest the solid on the floor by poking with its beak This genetic program (habit) allows the plant to ingest the necessary amount of the control agent of the present invention in a short period of time while saving labor. At this time, live bacteria, vaccines, drugs, nutrients, etc., which have been difficult to administer to young poultry as described above, are optionally mixed with the control agent of the present invention to form a water-soluble polysaccharide. When gelled, it can be efficiently administered to poultry at the same time as the control agent of the present invention. In addition, the supply of water and nutrients during the chicks stage is extremely important for subsequent productivity. Carbohydrates such as disaccharides, proteins such as skim milk, lipids, vitamins, minerals and the like can be mentioned.
また、本願発明の犬糸状虫症防除剤の効果を補強又は補完する目的で既存の犬糸状虫症防除剤を併用することもできる。併用にあたっては投与前に2種以上の有効成分を混合した製剤でもよく、異なる2種以上の製剤を別々に投与してもよい。
In addition, an existing canine heartworm control agent can be used in combination for the purpose of reinforcing or complementing the effect of the dog heartworm control agent of the present invention. For combined use, a formulation in which two or more active ingredients are mixed before administration may be used, or two or more different formulations may be administered separately.
以下で、本願発明の製造例、製剤例及び試験例によりさらに詳しく説明するが、本願発明はこれらの例に何ら限定されるものではない。
Below, the present invention will be explained in more detail with production examples, formulation examples, and test examples, but the present invention is not limited to these examples.
製造例1.2-(3-(1,1-ジメチルエチル)-5-メチル-4、5-ジヒドロ-イソキサゾール-5-イル)ベンゾイミダゾール(化合物番号1-5)の製造方法
3-(1,1-ジメチルエチル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-カルボン酸(300mg、1.41mmol)をピリジン(5mL)に溶解し、フェニレンジアミン(183mg、1.2当量)、DMAP(34mg、0.2当量)、EDC・HCl(405mg、1.5当量)を添加した後、室温で2時間反応した。水、酢酸エチルを加えて分液し、有機層を10%塩酸水、炭酸カリウム水溶液、ブラインで順に洗浄した。有機層を硫酸ナトリウムで乾燥させ、溶媒を留去した。残渣を酢酸(10mL)に溶解させた後、130℃で1時間反応した。反応終了後、反応溶液を室温まで冷却し、炭酸カリウム水溶液、酢酸エチルを加えて分液した。有機層をブラインで洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、カラムクロマトグラフィーで精製し、目的物(198mg、融点:193‐194℃、収率55%)を得た。
Preparation Example 1. Preparation of 2-(3-(1,1-dimethylethyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)benzimidazole (Compound No. 1-5)
3-(1,1-Dimethylethyl)-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid (300 mg, 1.41 mmol) was dissolved in pyridine (5 mL) and phenylenediamine (183 mg, 1.5 mL) was added. 2 eq.), DMAP (34 mg, 0.2 eq.) and EDC.HCl (405 mg, 1.5 eq.) were added and reacted at room temperature for 2 hours. Water and ethyl acetate were added to separate the layers, and the organic layer was washed with 10% aqueous hydrochloric acid, an aqueous potassium carbonate solution and brine in this order. The organic layer was dried over sodium sulfate and evaporated. The residue was dissolved in acetic acid (10 mL) and reacted at 130° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and an aqueous potassium carbonate solution and ethyl acetate were added to separate the layers. The organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the product was purified by column chromatography to obtain the desired product (198 mg, melting point: 193-194°C, yield 55%).
製造例2.2-(3-(1,1-ジメチルエチル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-イル)-1-エタンスルホニル-ベンゾイミダゾール(化合物番号1-6)の製造方法
前記工程で得られた3-((1,1-ジメチルエチル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-イル)-ベンゾイミダゾール(198mg、0.770mmol)をTHF(8mL)に溶解し、60%水素化ナトリウム(88mg、2.0当量)を室温、撹拌下で加えた。10分間反応した後、エタンスルホニルクロリド(298mg、3.0当量)を添加し、1時間反応した。反応終了後、飽和塩化アンモニウム水溶液、酢酸エチルを順に加えて分液した。有機層をブラインで洗浄し、硫酸ナトリウムで乾燥させた。溶媒留去後、濃縮残渣をカラムクロマトグラフィーで精製し、目的物(214mg、屈折率:1.556(21.2℃)、収率80%)を得た。
Production Example 2. 2-(3-(1,1-Dimethylethyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-1-ethanesulfonyl-benzimidazole (Compound No. 1-6) Production method
3-((1,1-dimethylethyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-benzimidazole (198 mg, 0.770 mmol) obtained in the above step was dissolved in THF (8 mL). Dissolved and 60% sodium hydride (88 mg, 2.0 eq) was added under stirring at room temperature. After reacting for 10 minutes, ethanesulfonyl chloride (298 mg, 3.0 eq) was added and reacted for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution and ethyl acetate were added in order to separate the layers. The organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the concentrated residue was purified by column chromatography to obtain the desired product (214 mg, refractive index: 1.556 (21.2°C), yield 80%).
製造例3.2‐(3‐(3,5‐ジクロロフェニル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-イル)-5,6-ジブロモベンゾイミダゾール(化合物番号1-23)の製造方法
3‐(3,5‐ジクロロフェニル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-カルボン酸(3.20g、11.7mmol)をピリジン(40mL)に溶解し、4,5-ジブロモフェニレンジアミン(3.09g、1.0当量)、DMAP(285mg、0.2当量)、EDC・HCl(3.38g、1.5当量)を添加した後、室温で2時間反応した。水、酢酸エチルを加えて分液し、有機層を10%塩酸水、炭酸カリウム水溶液、ブラインで順に洗浄した。有機層を硫酸ナトリウムで乾燥させ、溶媒を留去した。残渣を酢酸(70mL)に溶解させた後、130℃で1時間反応した。反応終了後、反応溶液を室温まで冷却し、炭酸カリウム水溶液、酢酸エチルを加えて分液した。有機層をブラインで洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、カラムクロマトグラフィーで精製し、目的物(3.87g、融点:188‐191℃、収率66%)を得た。
Preparation 3. Preparation of 2-(3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-5,6-dibromobenzimidazole (Compound No. 1-23) Method
3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid (3.20 g, 11.7 mmol) was dissolved in pyridine (40 mL) and 4,5-dibromophenylene Diamine (3.09 g, 1.0 eq.), DMAP (285 mg, 0.2 eq.), EDC.HCl (3.38 g, 1.5 eq.) were added, followed by reaction at room temperature for 2 hours. Water and ethyl acetate were added to separate the layers, and the organic layer was washed with 10% aqueous hydrochloric acid, an aqueous potassium carbonate solution and brine in this order. The organic layer was dried over sodium sulfate and evaporated. The residue was dissolved in acetic acid (70 mL) and reacted at 130° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, and an aqueous potassium carbonate solution and ethyl acetate were added to separate the layers. The organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the product was purified by column chromatography to obtain the desired product (3.87 g, melting point: 188-191°C, yield 66%).
製造例4.2‐(3‐(3,5‐ジクロロフェニル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-イル)-1-エタンスルホニル-5,6-ジブロモベンゾイミダゾール(化合物番号1-24)の製造方法
前記工程で得られた2‐(3‐(3,5‐ジクロロフェニル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-イル)-5,6-ジブロモベンゾイミダゾール(180mg、0.360mmol)をTHF(4mL)に溶解し、60%水素化ナトリウム(29mg、2.0当量)を室温、撹拌下で加えた。10分間反応した後、エタンスルホニルクロリド(139mg、3.0当量)を添加し、1時間反応した。反応終了後、飽和塩化アンモニウム水溶液、酢酸エチルを順に加えて分液した。有機層をブラインで洗浄し、硫酸ナトリウムで乾燥させた。溶媒留去後、濃縮残渣をカラムクロマトグラフィーで精製し、目的物(96mg、融点:87‐91℃、収率45%)を得た。
Preparation 4. 2-(3-(3,5-Dichlorophenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-1-ethanesulfonyl-5,6-dibromobenzimidazole (Compound No. 1 -24) manufacturing method
2-(3-(3,5-dichlorophenyl)-5-methyl-4,5-dihydro-isoxazol-5-yl)-5,6-dibromobenzimidazole (180 mg, 0.360 mmol) obtained in the previous step was dissolved in THF (4 mL) and 60% sodium hydride (29 mg, 2.0 eq) was added under stirring at room temperature. After reacting for 10 minutes, ethanesulfonyl chloride (139 mg, 3.0 eq) was added and reacted for 1 hour. After completion of the reaction, a saturated aqueous ammonium chloride solution and ethyl acetate were added in order to separate the layers. The organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the concentrated residue was purified by column chromatography to obtain the desired product (96 mg, melting point: 87-91°C, yield 45%).
中間体製造例1.3-(1,1-ジメチルエチル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-カルボン酸エチルの製造方法
2,2-ジメチルプロパナール(1.00g、11.6mmol)をジメチルホルムアミド(100mL)に溶解し、ヒドロキシルアミン塩酸塩(0.883g、1.1当量)、酢酸ナトリウム(1.05g、1.1当量)を順に撹拌下で添加し、室温で2時間反応した。撹拌中の反応溶液にN‐クロロスクシンイミド(1.70g、1.1当量)を添加し、室温でさらに2時間撹拌した。撹拌中の反応溶液にメタクリル酸エチル(1.72g、1.3当量)、硫酸銅(II)五水和物(87mg、0.03当量)、粉末銅(30mg、0.04当量)、水(30mL)を順に添加し、室温でさらに5時間撹拌した。反応終了後、水、酢酸エチルを加えて分液した。有機層をブラインで洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、目的物の残渣(3.22g)を得た。
Intermediate Preparation Example 1. Preparation of ethyl 3-(1,1-dimethylethyl)-5-methyl-4,5-dihydro-isoxazole-5-carboxylate
2,2-Dimethylpropanal (1.00 g, 11.6 mmol) was dissolved in dimethylformamide (100 mL), hydroxylamine hydrochloride (0.883 g, 1.1 eq), sodium acetate (1.05 g, 1.0 eq). 1 equivalent) was added in turn under stirring and reacted at room temperature for 2 hours. N-Chlorosuccinimide (1.70 g, 1.1 eq) was added to the stirring reaction solution and stirred at room temperature for an additional 2 hours. Ethyl methacrylate (1.72 g, 1.3 eq.), copper (II) sulfate pentahydrate (87 mg, 0.03 eq.), powdered copper (30 mg, 0.04 eq.), water were added to the stirring reaction solution. (30 mL) was added sequentially and stirred at room temperature for an additional 5 hours. After completion of the reaction, water and ethyl acetate were added to separate the layers. The organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the desired residue (3.22 g) was obtained.
中間体製造例2.3-(1,1-ジメチルエチル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-カルボン酸の製造方法
前記工程で得られた3-(1,1-ジメチルエチル)-5-メチル-4,5-ジヒドロ-イソキサゾール-5-カルボン酸エチルの残渣(1.61g)をTHF(30mL)、水(15mL)に溶解し、水酸化リチウム一水和物(1.22g、5.0当量)を室温撹拌下で加え、同温で3時間撹拌した。反応終了後、反応溶液に水を加えメチル-ターシャリーブチルエーテルで洗浄した。水層を1規定塩酸で中和し、酢酸エチルを加えて分液した。有機層をブラインで洗浄し、硫酸ナトリウムで乾燥した。溶媒を留去後、目的物(450mg、収率42%(前行程から))を得た。
Intermediate Preparation 2. Preparation of 3-(1,1-dimethylethyl)-5-methyl-4,5-dihydro-isoxazole-5-carboxylic acid
The residue (1.61 g) of ethyl 3-(1,1-dimethylethyl)-5-methyl-4,5-dihydro-isoxazole-5-carboxylate obtained in the above step was dissolved in THF (30 mL) and water (15 mL). ), lithium hydroxide monohydrate (1.22 g, 5.0 equivalents) was added under stirring at room temperature, and stirred at the same temperature for 3 hours. After completion of the reaction, water was added to the reaction solution and washed with methyl-tert-butyl ether. The aqueous layer was neutralized with 1N hydrochloric acid, and ethyl acetate was added to separate the layers. The organic layer was washed with brine and dried over sodium sulfate. After distilling off the solvent, the target product (450 mg, yield 42% (from the previous step)) was obtained.
製剤例1. 散剤
ベンゾイミダゾール化合物25部と、乳糖25部とを乳鉢でよく混合した後、当該混合物を充分攪拌混合することにより、散剤を得る。 Formulation example 1. Powder After thoroughly mixing 25 parts of the benzimidazole compound and 25 parts of lactose in a mortar, the mixture is sufficiently stirred to obtain a powder.
ベンゾイミダゾール化合物25部と、乳糖25部とを乳鉢でよく混合した後、当該混合物を充分攪拌混合することにより、散剤を得る。 Formulation example 1. Powder After thoroughly mixing 25 parts of the benzimidazole compound and 25 parts of lactose in a mortar, the mixture is sufficiently stirred to obtain a powder.
製剤例2. 顆粒剤
ベンゾイミダゾール化合物25部と乳糖25部とを加え、よく攪拌混合する。次いで、これらの混合物に適当量の水を加え、さらに攪拌した後、これを造粒機で製粒し、通風乾燥することにより、顆粒剤を得る。 Formulation example 2. Granules 25 parts of benzimidazole compound and 25 parts of lactose are added and well stirred and mixed. Next, an appropriate amount of water is added to the mixture, and the mixture is stirred, granulated with a granulator, and air-dried to obtain granules.
ベンゾイミダゾール化合物25部と乳糖25部とを加え、よく攪拌混合する。次いで、これらの混合物に適当量の水を加え、さらに攪拌した後、これを造粒機で製粒し、通風乾燥することにより、顆粒剤を得る。 Formulation example 2. Granules 25 parts of benzimidazole compound and 25 parts of lactose are added and well stirred and mixed. Next, an appropriate amount of water is added to the mixture, and the mixture is stirred, granulated with a granulator, and air-dried to obtain granules.
製剤例3. 水和剤
ベンゾイミダゾール化合物25部、珪藻土65部、高級アルコール硫酸エステル 5部、アルキルナフタレンスルホン酸塩5%を均一に混合して微細に粉砕することにより、水和剤を得る。 Formulation example 3. Wettable powder A wettable powder is obtained by uniformly mixing 25 parts of a benzimidazole compound, 65 parts of diatomaceous earth, 5 parts of a higher alcohol sulfate and 5% of an alkylnaphthalene sulfonate and pulverizing them finely.
ベンゾイミダゾール化合物25部、珪藻土65部、高級アルコール硫酸エステル 5部、アルキルナフタレンスルホン酸塩5%を均一に混合して微細に粉砕することにより、水和剤を得る。 Formulation example 3. Wettable powder A wettable powder is obtained by uniformly mixing 25 parts of a benzimidazole compound, 65 parts of diatomaceous earth, 5 parts of a higher alcohol sulfate and 5% of an alkylnaphthalene sulfonate and pulverizing them finely.
試験例1. 犬糸状虫(Dirofilaria immitis)の幼虫運動に対する影響評価試験
所定の調製液に希釈した犬糸状虫のL-1ステージ幼虫500頭を96穴プレート1穴毎に接種し、本発明の一般式(1)で表されるベンゾイミダゾール化合物又はその塩類のDMSO希釈溶液を加えて最終濃度を50ppmとした。その後、3日間静置し、その運動能力を調査した。DMSO溶液のみによる阻害力を基準に各処理区の運動阻害率を補正、算出し、下記の判定基準に従って判定した。 Test Example 1. Evaluation test of influence on larval movement of Dirofilaria immitis 500 L-1 stage larvae of Dirofilaria immitis diluted in a predetermined preparation solution were inoculated in each hole of a 96-well plate, and the test of the present invention was performed. A DMSO diluted solution of the benzimidazole compound represented by the general formula (1) or a salt thereof was added to a final concentration of 50 ppm. Then, it was left still for 3 days, and its exercise ability was investigated. Based on the inhibitory power of the DMSO solution alone, the motility inhibition rate of each treatment group was corrected and calculated, and judged according to the following criteria.
所定の調製液に希釈した犬糸状虫のL-1ステージ幼虫500頭を96穴プレート1穴毎に接種し、本発明の一般式(1)で表されるベンゾイミダゾール化合物又はその塩類のDMSO希釈溶液を加えて最終濃度を50ppmとした。その後、3日間静置し、その運動能力を調査した。DMSO溶液のみによる阻害力を基準に各処理区の運動阻害率を補正、算出し、下記の判定基準に従って判定した。 Test Example 1. Evaluation test of influence on larval movement of Dirofilaria immitis 500 L-1 stage larvae of Dirofilaria immitis diluted in a predetermined preparation solution were inoculated in each hole of a 96-well plate, and the test of the present invention was performed. A DMSO diluted solution of the benzimidazole compound represented by the general formula (1) or a salt thereof was added to a final concentration of 50 ppm. Then, it was left still for 3 days, and its exercise ability was investigated. Based on the inhibitory power of the DMSO solution alone, the motility inhibition rate of each treatment group was corrected and calculated, and judged according to the following criteria.
判定基準
A・・・補正運動阻害率100%
B・・・補正運動阻害率99%~90%
C・・・補正運動阻害率89%~80%
D・・・補正運動阻害率79%~50% Judgment criteria A: Corrected motor inhibition rate 100%
B: Corrected movement inhibition rate 99% to 90%
C: Corrected motor inhibition rate 89% to 80%
D: Corrected motor inhibition rate 79% to 50%
A・・・補正運動阻害率100%
B・・・補正運動阻害率99%~90%
C・・・補正運動阻害率89%~80%
D・・・補正運動阻害率79%~50% Judgment criteria A: Corrected motor inhibition rate 100%
B: Corrected movement inhibition rate 99% to 90%
C: Corrected motor inhibition rate 89% to 80%
D: Corrected motor inhibition rate 79% to 50%
その結果、本願発明化合物の1-14、又は1-15は、Aの活性を示した。
As a result, 1-14 or 1-15 of the compound of the present invention showed the activity of A.
試験例2.犬糸状虫(Dirofilaria immitis)の発育に対する影響評価試験
24穴プレート1穴毎に所定の調製液、犬糸状虫のL‐3ステージ幼虫8~20頭及び本願発明のベンゾイミダゾール化合物のDMSO希釈溶液を加えて最終濃度を50ppmとした。その7日後にL‐4ステージに発育した幼虫を計数し、L3ステージ幼虫からL4‐ステージ幼虫への発育阻害率を算出した。 Test example 2. Influence evaluation test on the development of Dirofilaria immitis A predetermined preparation solution, 8 to 20 L-3 stage larvae of Dirofilaria immitis and a DMSO diluted solution of the benzimidazole compound of the present invention were added to each hole of a 24-well plate. In addition, the final concentration was 50 ppm. Seven days later, the larvae that had grown to the L-4 stage were counted, and the growth inhibition rate from L3-stage larvae to L4-stage larvae was calculated.
24穴プレート1穴毎に所定の調製液、犬糸状虫のL‐3ステージ幼虫8~20頭及び本願発明のベンゾイミダゾール化合物のDMSO希釈溶液を加えて最終濃度を50ppmとした。その7日後にL‐4ステージに発育した幼虫を計数し、L3ステージ幼虫からL4‐ステージ幼虫への発育阻害率を算出した。 Test example 2. Influence evaluation test on the development of Dirofilaria immitis A predetermined preparation solution, 8 to 20 L-3 stage larvae of Dirofilaria immitis and a DMSO diluted solution of the benzimidazole compound of the present invention were added to each hole of a 24-well plate. In addition, the final concentration was 50 ppm. Seven days later, the larvae that had grown to the L-4 stage were counted, and the growth inhibition rate from L3-stage larvae to L4-stage larvae was calculated.
その結果、本発願明の一般式(1)で表される化合物のうち、化合物番号1-17、1-23、1-25、2-1、2-7、2-8、及び2-9の化合物は、50%以上の発育阻害率を示した。
As a result, among the compounds represented by the general formula (1) of the present invention, compound numbers 1-17, 1-23, 1-25, 2-1, 2-7, 2-8, and 2-9 showed a growth inhibition rate of 50% or more.
本願発明により、対象動物に投与して優れた効果を発揮する対象動物用犬糸状虫症防除剤及びそれを用いる対象動物の犬糸状虫症防除剤の使用方法を提供することができる。
According to the present invention, it is possible to provide a canine heartworm control agent for target animals that exhibits excellent effects when administered to target animals, and a method for using the canine heartworm control agent for target animals using the same.
Claims (4)
- 一般式(1)
Rは、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a7) (C2‐C6)アルケニル基;(a8) (C2‐C6)アルキニル基;(a9) (C3‐C6)シクロアルキル(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a11) アリール(C2‐C6)アルケニル基;(a12) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C2‐C6)アルケニル基;(a13) (C1-C6)アルキルカルボニル基;(a14) (C1-C6)アルコキシカルボニル基;(a15) (C1-C6)アルコキシカルボニルカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a22) R1(R2)Nカルボニル基(式中、R1及びR2は同一又は異なっても良く水素原子、(C1-C6)アルキル基、(C3-C6)シクロアルキル基、(C2-C6)アルケニル基、(C2-C6)アルキニル基を示す。);(a23) R1(R2)Nチオカルボニル基(式中、R1及びR2は前記に同じ。);(a24) R1(R2)Nスルホニル基(式中、R1及びR2は前記に同じ。);(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;(a27) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール基;(a28) アリール(C1‐C6)アルキル基;又は(a29) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示す。
X1は、(b1) (C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、 (k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b6) (C2‐C6)アルケニル基;(b7) (C2‐C6)アルキニル基;(b8) (C3‐C6)シクロアルキル基;(b9) ハロ(C1‐C6)アルキル基;又は(b10) 3-テトラヒドロフリル基;を示す。
X4は、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;(c5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール基;(c6) アリール(C1‐C6)アルキル基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示す。
X2及びX3は、同一又は異なってもよく、(d1) 水素原子;又は(d2)(C1‐C6)アルキル基;を示す。
Y1及びY4は、同一又は異なってもよく、(e1) 水素原子;(e2) ハロゲン原子;又は(e3)(C1‐C6)アルキル基;を示す。
Y2及びY3は、同一又は異なってもよく、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;(f5) (C1‐C6)アルコキシ基;又は(f6) ハロ(C1‐C6)アルコキシ基;を示す。}
で表されるベンゾイミダゾール化合物またはその塩類。 General formula (1)
R is (a1) a hydrogen atom; (a2) a ( C1 - C6 ) alkyl group; (a3) a ( C1 - C6 ) alkylsulfonyl group; (a4) a ( C1 - C6 ) alkoxy ( C1 (a5) (C1 - C6)alkoxycarbonyl ( C1- C6 )alkyl group; ( a6 ) aryl( C1 - C6 )alkoxy( C1 - C6 )alkyl group (a7) ( C2 - C6 ) alkenyl group; (a8) ( C2 - C6 ) alkynyl group; (a9) ( C3 - C6 ) cycloalkyl ( C1 - C6 ) alkyl group; ( (a10) halo ( C 1 -C 6 )alkyl group; (a11) aryl (C 2 -C 6 )alkenyl group; C6 ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl group, (i) halo( C1 - C6 )alkyl aryl ( C 2 -C 6 ) alkenyl group; (a13) ( C1 - C6 ) alkylcarbonyl group; (a14) ( C1 - C6 ) alkoxycarbonyl group; (a15) ( C1 - C6 ) alkoxycarbonylcarbonyl group; (a16) (a17 ) ( C1 - C6 )alkylthio( C1 - C6 )alkyl groups; (a18) (C1- C6 ) trimethylsilyl( C1 -C6)alkoxy( C1 - C6 )alkyl groups; ) alkylsulfinyl (C 1 -C 6 ) alkyl group; (a19) (C 1 -C 6 ) alkylsulfonyl (C 1 -C 6 ) alkyl group; (a20) arylsulfonyl group; (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy (e) a halo( C1 - C6 )alkoxy group; (f) a ( C1 - C6 )alkylthio group; (g) a halo( C1 -C6)alkylthio group; (h) (C1- C6 ) alkylthio group; -C6 ) alkylsulfinyl group, (i) halo( C1 - C6 )alkylsulfinyl group, (j) ( C1 - C6 )alkylsulfonyl group, and (k) halo( C1 - C6 )alkyl an arylsulfonyl group having 1 to 5 substituents selected from sulfonyl groups; (a22) R 1 (R 2 )N carbonyl group (wherein R 1 and R 2 may be the same or different hydrogen atoms C 1 -C 6 )alkyl group, (C 3 -C 6 )cycloalkyl group, (C 2 -C 6 )alkenyl group and (C 2 -C 6 )alkynyl group. ); (a23) R 1 (R 2 )N thiocarbonyl group (wherein R 1 and R 2 are the same as above); (a24) R 1 (R 2 )N sulfonyl group (wherein R 1 and (a25) 2 - tetrahydrofurylmethyl group ; (a26) aryl group; ) alkyl group, (c) halo( C1 - C6 )alkyl group, (d) ( C1 - C6 )alkoxy group, (e) halo( C1 - C6 )alkoxy group, (f) (C 1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1- C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group , (j) a (C 1 -C 6 ) alkylsulfonyl group, and (k) a halo (C 1 -C 6 ) alkylsulfonyl group; (a28) an aryl group having 1 to 5 substituents; or ( a29 ), which may be the same or different, (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) (d) ( C1 - C6 ) alkoxy group; (e) halo ( C1 - C6 ) alkoxy group; (f) ( C1 - C6 ) alkylthio group; (g) halo ( C1 -C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, (j) ( C1 - C6 ) alkylsulfonyl group, and (k) an aryl(C 1 -C 6 )alkyl group having 1 to 5 substituents selected from halo(C 1 -C 6 )alkylsulfonyl groups;
X 1 is (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo (C 1 —C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; (b5) which may be the same or different, ( a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) a halo ( C1 - C6 ) alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) a halo( C1 - C6 )alkylsulfinyl group, (j) a ( C1 - C6 )alkylsulfonyl group, (k) a halo( C1 - C6 )alkylsulfonyl group, and (l) a phenoxy group (b6) (C 2 -C 6 ) alkenyl group; (b7) (C 2 -C 6 ) alkynyl group; (b8) (C 3 - C6 ) cycloalkyl group; (b9) halo( C1 - C6 ) alkyl group; or (b10) 3-tetrahydrofuryl group;
(c1) a hydrogen atom; (c2) a ( C1 - C6 ) alkyl group ; (c3) a halo( C1 - C6 ) alkyl group; (c4) an aryl group; (c5) the same or different (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, ( e) halo( C1 - C6 )alkoxy groups, (f) ( C1 - C6 )alkylthio groups, (g) halo( C1 - C6 )alkylthio groups, (h) ( C1 - C6 ) selected from alkylsulfinyl groups, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups; (c6) an aryl (C 1 -C 6 )alkyl group; or (c7), which may be the same or different, (a) a halogen atom, (b) (C 1 -C6 ) alkyl group, (c) halo ( C1 - C6 ) alkyl group, (d) ( C1 - C6 ) alkoxy group, (e) halo ( C1 - C6 ) alkoxy group, (f ) ( C1 - C6 )alkylthio group, (g) halo( C1 - C6 )alkylthio group, (h) ( C1 - C6 )alkylsulfinyl group, (i) halo( C1 - C6 ) aryl ( C 1 - C 6 ) alkyl group;
X 2 and X 3 may be the same or different and represent (d1) a hydrogen atom; or (d2) a (C 1 -C 6 )alkyl group.
Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 )alkyl group.
Y 2 and Y 3 may be the same or different, (f1) hydrogen atom; (f2) halogen atom; (f3) (C 1 -C 6 ) alkyl group; (f4) halo (C 1 -C 6 ) (f5) a ( C1 - C6 )alkoxy group; or (f6) a halo( C1 - C6 )alkoxy group; }
A benzimidazole compound represented by or a salt thereof. - Rが、(a1) 水素原子;(a2) (C1‐C6)アルキル基;(a3) (C1‐C6)アルキルスルホニル基;(a4) (C1‐C6)アルコキシ(C1‐C6)アルキル基;(a5) (C1‐C6)アルコキシカルボニル(C1‐C6)アルキル基;(a6) アリール(C1‐C6)アルコキシ(C1‐C6)アルキル基;(a10) ハロ(C1‐C6)アルキル基;(a14) (C1-C6)アルコキシカルボニル基;(a16) トリメチルシリル(C1-C6)アルコキシ(C1-C6)アルキル基;(a17) (C1-C6)アルキルチオ(C1-C6)アルキル基;(a18) (C1-C6)アルキルスルフィニル(C1-C6)アルキル基;(a19) (C1-C6)アルキルスルホニル(C1-C6)アルキル基;(a20) アリールスルホニル基;(a21) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリールスルホニル基;(a25) 2-テトラヒドロフリルメチル基;(a26) アリール基;又は(a28) アリール(C1‐C6)アルキル基;を示し、
X1が、(b1)(C1‐C6)アルキル基;(b2) アリール基;(b3) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、(k)ハロ(C1‐C6)アルキルスルホニル基、(l)(C1-C6)アルキレンジオキシ基、(m)ハロ(C1-C6)アルキレンジオキシ基、及び(n)フェノキシ基から選択される1~5の置換基を有するアリール基;(b4) 芳香族複素環基;(b5) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基、及び(l)フェノキシ基、から選択される1~3の置換基を有する芳香族複素環基;(b8)(C3‐C6)シクロアルキル基;又は(b10) 3-テトラヒドロフリル基;を示し、
X4が、(c1) 水素原子;(c2) (C1‐C6)アルキル基;(c3) ハロ(C1‐C6)アルキル基;(c4) アリール基;又は(c7) 同一又は異なっても良く、(a)ハロゲン原子、(b)(C1‐C6)アルキル基、(c)ハロ(C1‐C6)アルキル基、(d)(C1‐C6)アルコキシ基、(e)ハロ(C1‐C6)アルコキシ基、(f)(C1‐C6)アルキルチオ基、(g)ハロ(C1‐C6)アルキルチオ基、(h)(C1‐C6)アルキルスルフィニル基、(i)ハロ(C1‐C6)アルキルスルフィニル基、(j)(C1‐C6)アルキルスルホニル基、及び(k)ハロ(C1‐C6)アルキルスルホニル基から選択される1~5の置換基を有するアリール(C1‐C6)アルキル基;を示し、
X2及びX3が、 (d1)水素原子;を示し、
Y1及びY4が、同一又は異なってもよく、(e1) 水素原子;(e2) ハロゲン原子;又は(e3)(C1‐C6)アルキル基;を示し、
Y2及びY3が、同一又は異なってもよく、(f1) 水素原子;(f2) ハロゲン原子;(f3) (C1‐C6)アルキル基;(f4) ハロ(C1‐C6)アルキル基;又は(f6) ハロ(C1‐C6)アルコキシ基;を示す、
請求項1に記載のベンゾイミダゾール化合物またはその塩類。 (a1) a hydrogen atom; (a2) a ( C1 - C6 ) alkyl group; (a3) a ( C1 - C6 ) alkylsulfonyl group; (a4) a ( C1 - C6 ) alkoxy ( C1 (a5) (C1 - C6)alkoxycarbonyl ( C1- C6 )alkyl group; ( a6 ) aryl( C1 - C6 )alkoxy( C1 - C6 )alkyl group (a10) halo( C1 - C6 )alkyl group; (a14) ( C1 - C6 )alkoxycarbonyl group; (a16) trimethylsilyl( C1 - C6 )alkoxy( C1 - C6 )alkyl group (a17) (C1 - C6 )alkylthio( C1 - C6 )alkyl group; (a18) ( C1 - C6 )alkylsulfinyl( C1 - C6 )alkyl group; (a19) ( C1 -C6 ) alkylsulfonyl ( C1 - C6 ) alkyl group; (a20) arylsulfonyl group; (a21), which may be the same or different, (a) a halogen atom, (b) ( C1 - C6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( ( a25 ) 2 - tetrahydro (a26) an aryl group; or (a28) an aryl( C1 - C6 )alkyl group;
X 1 is (b1) (C 1 -C 6 ) alkyl group; (b2) aryl group; (b3) which may be the same or different, (a) halogen atom, (b) (C 1 -C 6 ) alkyl (c) halo( C1 - C6 )alkyl groups, (d) ( C1 - C6 )alkoxy groups, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1- C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 ) alkylsulfinyl group, ( j) (C 1 -C 6 ) alkylsulfonyl group, (k) halo (C 1 -C 6 ) alkylsulfonyl group, (l) (C 1 -C 6 ) alkylenedioxy group, (m) halo (C 1 —C 6 ) an alkylenedioxy group, and (n) an aryl group having 1 to 5 substituents selected from a phenoxy group; (b4) an aromatic heterocyclic group; (b5) which may be the same or different, ( a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo ( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) a halo ( C1 - C6 ) alkoxy group, (f) ( C1 - C6 ) alkylthio group, (g) halo( C1 - C6 ) alkylthio group, (h) ( C1 - C6 ) alkylsulfinyl group, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups, and (l) phenoxy (b8) a ( C3 - C6 ) cycloalkyl group; or (b10) a 3-tetrahydrofuryl group;
(c1) a hydrogen atom; (c2) a ( C1 - C6 ) alkyl group ; (c3) a halo( C1 - C6 ) alkyl group; (c4) an aryl group; or (c7) the same or different (a) a halogen atom, (b) a ( C1 - C6 ) alkyl group, (c) a halo( C1 - C6 ) alkyl group, (d) a ( C1 - C6 ) alkoxy group, (e) halo( C1 - C6 )alkoxy groups, (f) ( C1 - C6 )alkylthio groups, (g) halo( C1 - C6 )alkylthio groups, (h) ( C1 - C6 ) ) alkylsulfinyl groups, (i) halo( C1 - C6 )alkylsulfinyl groups, (j) ( C1 - C6 )alkylsulfonyl groups, and (k) halo( C1 - C6 )alkylsulfonyl groups; an aryl(C 1 -C 6 )alkyl group with 1 to 5 selected substituents;
X 2 and X 3 are (d1) a hydrogen atom;
Y 1 and Y 4 may be the same or different and represent (e1) a hydrogen atom; (e2) a halogen atom; or (e3) a (C 1 -C 6 ) alkyl group;
( f1 ) hydrogen atom; ( f2 ) halogen atom; (f3) ( C1 - C6 ) alkyl group; (f4) halo ( C1 - C6 ) an alkyl group; or (f6) a halo(C1 - C6 )alkoxy group;
The benzimidazole compound or salts thereof according to claim 1. - 請求項1~2の何れか一項に記載のベンゾイミダゾール化合物またはその塩類を有効成分として含有することを特徴とする動物用の犬糸状虫症防除剤。 A dog heartworm control agent for animals, characterized by containing the benzimidazole compound or a salt thereof according to any one of claims 1 and 2 as an active ingredient.
- 請求項1~2の何れか一項に記載のベンゾイミダゾール化合物またはその塩類の有効量を動物に投与することを特徴とする動物用の犬糸状虫症防除剤の使用方法。 A method of using a dog heartworm control agent for animals, which comprises administering an effective amount of the benzimidazole compound or salt thereof according to any one of claims 1 and 2 to the animal.
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GB1140397A (en) * | 1965-09-01 | 1969-01-15 | Merck & Co Inc | Treating animals for helminthiasis |
WO2018118781A1 (en) * | 2016-12-20 | 2018-06-28 | Fmc Corporation | Fungicidal oxadiazoles |
WO2020225143A1 (en) * | 2019-05-03 | 2020-11-12 | Intervet International B.V. | Injectable pharmaceutical compositions and uses thereof |
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