WO2013015429A1 - Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent - Google Patents

Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent Download PDF

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Publication number
WO2013015429A1
WO2013015429A1 PCT/JP2012/069263 JP2012069263W WO2013015429A1 WO 2013015429 A1 WO2013015429 A1 WO 2013015429A1 JP 2012069263 W JP2012069263 W JP 2012069263W WO 2013015429 A1 WO2013015429 A1 WO 2013015429A1
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group
alkyl
optionally substituted
haloalkyl
halogen
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PCT/JP2012/069263
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French (fr)
Inventor
Yasuhiro Endo
Yuichi Shirai
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OAT Agrio Co Ltd
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Otsuka Agritechno Co Ltd
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Priority to US14/128,807 priority Critical patent/US20140148477A1/en
Priority to KR1020147004951A priority patent/KR20140049574A/en
Priority to RU2014107002/15A priority patent/RU2014107002A/en
Priority to CA2842644A priority patent/CA2842644A1/en
Priority to MX2014000856A priority patent/MX2014000856A/en
Priority to PH1/2014/500048A priority patent/PH12014500048A1/en
Priority to EP12746402.2A priority patent/EP2736511A1/en
Priority to JP2013544048A priority patent/JP2014521590A/en
Application filed by Otsuka Agritechno Co Ltd filed Critical Otsuka Agritechno Co Ltd
Priority to CN201280036626.7A priority patent/CN103732228A/en
Priority to BR112014001866A priority patent/BR112014001866A2/en
Publication of WO2013015429A1 publication Critical patent/WO2013015429A1/en
Priority to ZA2014/00180A priority patent/ZA201400180B/en
Anticipated expiration legal-status Critical
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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

Definitions

  • the present invention relates to an animal
  • ectoparasite-controlling agent comprising an N-pyridylpiperidine compound as an active ingredient, and to a method for preventing or treating infection in animals caused by parasites by using the controlling agent.
  • N-pyridylpiperidine compound which is an active ingredient of the present invention, has already been reported ( see PTL 1 ) .
  • This document discloses that the N- pyridylpiperidine compound exhibits miticidal activity against plant-parasitic mites.
  • insecticidal effect of the N- pyridylpiperidine compound on animal ectoparasites was not known at all.
  • the present invention has been made in view of the above circumstances, and an object of the present invention is to provide an animal ectoparasite-controlling agent, and a method for preventing or treating infection in animals caused by
  • the present inventors conducted extensive research to achieve the above object and found that the compound disclosed in PTL 1 having a pyrazole ring at the 4-position of the piperidine ring also exhibited excellent insecticidal activity against animal ectoparasites.
  • the present invention has been accomplished based on this finding.
  • the present invention provides an animal ectoparasite-controlling agent, and a method for
  • An animal ectoparasite-controlling agent comprising an N- pyridylpiperidine compound, an N-oxide thereof, or salts of these compounds, the N-pyridylpiperidine compound being represented by Formula ( 1 ) :
  • R 1 is a halogen atom, a Ci- 4 haloalkyl group, a cyano group, a nitro group, or a Ci- 4 alkoxycarbonyl group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each a hydrogen atom or a Ci- 4 alkyl group
  • each pair of R 2 and R 8 , and R 4 and R 6 may join to form a Ci-4 alkylene group
  • R 10 is a hydrogen atom; a Ci_ 2 o alkyl group; a C 3 . 8 cycloalkyl group; a C 2 -6 alkenyl group; a C 2 -e alkynyl group; a Ci- 6 haloalkyl group; a C 2 -6 haloalkenyl group; a Ci_ 6 alkylcarbonyl group; a Ci_ 6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with one to five halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci- 4 alkyl, and Ci_ 4 haloalkyl; a
  • heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each independently selected from the group consisting of halogen, Ci_ 4 alkyl, Ci_ 4 haloalkyl, and optionally substituted heterocyclic groups; or a Ci_ 4 alkyl group optionally substituted with one or more substituents each independently selected from the group consisting of optionally halogen-substituted C 3 .
  • R 11 is a halogen atom; a Ci_ 6 alkyl group; a Ci- 4 haloalkyl group; a Ci_ 4 hydroxyalkyl group; a Ci- 4 alkoxycarbonyl group; a Ci_ 4 alkylcarbonyl group; a mono or di(Ci_ 4
  • R 14 is a hydrogen atom or a Ci_ 4 alkyl group
  • R 15 is a hydrogen atom, a Ci_ alkyl group, or a benzyl group
  • X is an oxygen atom, a sulfur atom, or -S0 2 -;
  • m is an integer of 1 to 4, and when m is an integer of 2 or more, the R ⁇ s, the number of which is represented by m, may be the same or different; and
  • n is an integer of 1 or 2 , and when n is 2 , the two R u 's may be the same or different.
  • Item 2 The animal ectoparasite-controlling agent according to Item 1 , wherein the N-pyridylpiperidine compound is represented by Formula ( 1 ) in which R 1 is a halogen atom, a Ci- 4 haloalkyl group, a cyano group, or a nitro group.
  • R 1 is a halogen atom, a Ci- 4 haloalkyl group, a cyano group, or a nitro group.
  • Item 3 The animal ectoparasite-controlling agent according to Item 1 , wherein the N-pyridylpiperidine compound is represented by Formula ( 1 ) in which R 10 is a hydrogen atom; a Ci- 2 o alkyl group; a C 2 . 6 alkenyl group; a Ci- 6 haloalkyl group; a Ci- 6
  • alkylcarbonyl group a Ci- 6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with one to five halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci- 4 alkyl, and Ci- haloalkyl; a heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each
  • heterocyclic groups optionally substituted on the heterocyclic ring with one or more Ci- 4 alkyl groups.
  • Item 4 The animal ectoparasite-controlling agent according to Item 1 , wherein the N-pyridylpiperidine compound is represented by Formula ( 1 ) in which R 11 is a halogen atom; a Ci- 6 alkyl group; a Ci_ haloalkyl group; a Ci- hydroxyalkyl group; a Ci- 4
  • Item 5 The animal ectoparasite-controlling agent according to Item 1, wherein the N-pyridylpiperidine compound is represented by Formula (1) in which X is an oxygen atom.
  • Item 6 A method for preventing or treating infection in an animal caused by parasites, the method comprising administrating the animal ectoparasite-controlling agent according to any one of Items 1 to 5 to the animal.
  • the present invention can provide an animal ectoparasite-controlling agent having an excellent control effect on animal ectoparasites, such as mites.
  • R 1 is a halogen atom, a Ci- 4 haloalkyl group, a cyano group, a nitro group, or a Ci- alkoxycarbonyl group;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each a hydrogen atom or a Ci- 4 alkyl group
  • each pair of R 2 and R 8 , and R 4 and R 6 may join to form a Ci-4 alkylene group
  • R 10 is a hydrogen atom; a Cj.- 2 o alkyl group; a C 3 -e cycloalkyl group; a C 2 -6 alkenyl group; a C 2 -6 alkynyl group; a Ci- 6 haloalkyl group; a C 2 -e haloalkenyl group; a Ci- 6 alkylcarbonyl group; a Ci- 6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with 1 to 5 halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci_ 4 alkyl, and Ci- haloalkyl; a
  • heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each independently selected from the group consisting of halogen, Ci- 4 alkyl, Ci_ haloalkyl, and optionally substituted heterocyclic groups; or a Ci- 4 alkyl group optionally substituted with one or more substituents each independently selected from the group consisting of optionally halogen-substituted C 3 .
  • R 14 is a hydrogen atom or a Ci- alkyl group
  • R 15 is a hydrogen atom, a Ci- 4 alkyl group, or a benzyl group
  • X is an oxygen atom, a sulfur atom, or -S0 2 - ;
  • m is an integer of 1 to 4, and when m is an integer of 2 or more, the l ⁇ 's, the number of which is represented by m, may be the same or different;
  • n is an integer of 1 or 2 , and when n is 2 , the two R u 's may be the same or different.
  • halogen atom examples include fluorine, chlorine, bromine, and iodine atoms.
  • Ci- 4 haloalkyl group examples include linear or branched alkyl groups having 1 to 4 carbon atoms and substituted with 1 to 9 , preferably 1 to 5 , halogen atoms. Specific examples thereof include fluoromethyl, chloromethyl, bromomethyl,
  • Ci- 4 alkoxycarbonyl group examples include groups formed by the bonding of a linear or branched alkoxy group having 1 to 4 carbon atoms to a carbonyl group. Specific examples thereof include methoxycarbonyl , ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, see- butoxycarbonyl, tert-butoxycarbonyl, and like groups.
  • Ci_ 4 alkyl group examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • Ci- 4 alkylene group examples include linear or branched alkylene groups having 1 to 4 carbon atoms, such as methylene, ethylene, trxmethylene, tetramethylene, propylene, and ethylethylene .
  • Ci- 6 alkyl group examples include linear or branched alkyl groups having 1 to 6 carbon atoms, such as n- pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, xsohexyl, and 2-ethyl-n-butyl, in addition to those mentioned as examples of the Ci-4 alkyl group.
  • Ci- 2 o alkyl group examples include linear or branched alkyl groups having 1 to 20 carbon atoms, such as n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl, in addition to those mentioned as examples of the Ci- 4 alkyl group and Ci_ 6 alkyl group.
  • Examples of the C 3 . 8 cycloalkyl group include cyclic alkyl groups having 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Examples of the C 2 -6 alkenyl group include linear or branched alkenyl groups containing 2 to 6 carbon atoms and having at least one double bond at any position. Specific examples thereof include vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl,
  • Examples of the C 2 . 6 alkynyl group include linear or branched alkynyl groups containing 2 to 6 carbon atoms and having at least one triple bond at any position. Specific examples thereof include ethynyl, 2-propynyl, 1-methyl-2-propynyl, 1,1- dimethyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
  • Ci_ 6 haloalkyl group examples include linear or branched alkyl groups having 1 to 6 carbon atoms and substituted with 1 to 13, preferably 1 to 7, halogen atoms. Specific examples thereof include 5-chloropentyl, 5-fluoropentyl, 6-chlorohexyl, and 6-fluorohexyl, in addition to those mentioned as examples of the Ci-4 haloalkyl group.
  • Examples of the C 2 . 6 haloalkenyl group include C 2 -6 linear or branched alkenyl groups having at least one double bond at any position and substituted with 1 to 13, preferably 1 to 7, halogen atoms. Specific examples thereof include 2,2- dichlorovinyl, 2,2-dibromovinyl, 3-chloro-2-propenyl, 3,3- difluoro-2-allyl, 3,3-dichloro-2-allyl, 4-chloro-2-butenyl,
  • heterocyclic group examples include thienyl, furyl, tetrahydrofuryl, dioxolanyl, dioxanyl, pyrrolyl,
  • dihydropyrxmidinyl tetrahydropyrimidinyl, hexahydropyrxmidinyl , pyrazinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahydrotriazinyl,
  • heterocyclic groups include those substituted at any substitutable position with an oxo or thioketone group.
  • heterocyclic groups further include those optionally substituted at any substitutable position with 1 to 5 (preferably 1 to 3) substituents , such as halogen atoms, Ci- 4 alkyl groups, Ci- 4 haloalkyl groups, or substituted heterocyclic groups (e.g., 3-chloropyridin-2-yl, 4-trifluoromethyl-l,3- thiazol-2-yl, and 5-trifluoromethylpyridin-2-yl) .
  • substituents such as halogen atoms, Ci- 4 alkyl groups, Ci- 4 haloalkyl groups, or substituted heterocyclic groups (e.g., 3-chloropyridin-2-yl, 4-trifluoromethyl-l,3- thiazol-2-yl, and 5-trifluoromethylpyridin-2-yl) .
  • thienyl, furyl, tetrahydrofuryl, dioxolanyl, dioxanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, and piperidyl are preferable.
  • Thienyl, tetrahydrofuryl, dioxolanyl, dioxanyl, thiazolyl, and pyridyl are particularly preferable .
  • Examples of the optionally halogen-substituted C 3 . 8 cycloalkyl group include cyclic alkyl groups having 3 to 8 carbon atoms, such as the above-mentioned C 3 - 8 cycloalkyl groups that are optionally substituted at any position with one to the maximum substitutable number of (preferably 1 to 5, and more preferably 1 to 3) halogen atoms.
  • Ci- 6 alkoxy group examples include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy, and isohexyloxy.
  • linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy, and isohexyloxy.
  • Ci_ 4 haloalkoxy group examples include linear or branched alkoxy groups having 1 to 4 carbon atoms and substituted with 1 to 9, preferably 1 to 5, halogen atoms. Specific examples thereof include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, dichloromethoxy, trichloromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, dichlorofluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2- chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 1-fluoroisopropoxy, 3- fluoropropoxy, 3-chloropropoxy, 3-bromopropoxy, 4-fluorobutoxy, 4-chlorobutoxy, and like groups.
  • Examples of the C 1 -4 alkylthio group include linear or branched alkylthio groups having 1 to 4 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, and tert- butylthio.
  • Examples of the C 2 -7 alkylene group include ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, and the like. These alkylene groups may contain an optionally substituted nitrogen, oxygen, or sulfur atom, or a phenylene group.
  • alkylene groups include - CH 2 NHCH 2 -, -CH 2 NHCH 2 CH 2 - , -CH 2 NH HCH 2 - , -CH 2 CH 2 NHCH 2 CH 2 - , - CH 2 NH HCH 2 CH 2 - , -CH 2 HCH 2 NHCH 2 - , -CH 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 - , -CH 2 OCH 2 CH 2 - , - - , -CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - , -CH 2 CH 2 SCH 2 CH 2 - ,
  • alkylene groups may be substituted at any position or on the nitrogen atom.
  • substituents include Ci_ 4 alkyl, Ci- 6 alkoxycarbonyl, hydroxy, and like groups.
  • Examples of the C 1 .4 alkylcarbonyl group include linear or branched alkylcarbonyl groups having 1 to 4 carbon atoms, such as methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n- propylcarbonyl (butyryl), isopropylcarbonyl (isobutyryl) , n- butylcarbonyl (valeryl), isobutylcarbonyl ( isovaleryl) , sec- butylcarbonyl, and tert-butylcarbonyl.
  • linear or branched alkylcarbonyl groups having 1 to 4 carbon atoms such as methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n- propylcarbonyl (butyryl), isopropylcarbonyl (isobutyryl) , n- butylcarbonyl (valeryl), isobutylcarbonyl ( isovaleryl)
  • Examples of the mono- or di(Ci_ 4 alkyl)aminocarbonyl group include alkylaminocarbonyl groups in which nitrogen atoms of the aminocarbonyl groups are mono- or di-substituted with linear or branched alkyl groups having 1 to 4 carbon atoms, such as methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, n- propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocaxbonyl, and
  • Ci- 4 hydroxyalkyl group examples include linear or branched alkyl groups having 1 to 4 carbon atoms and
  • hydroxy groups such as hydroxymethyl, 2- hydroxyethyl, 1-hydroxy-2-propyl, 3-hydroxypropyl, 4-hydroxybutyl, and 3, 4-dihydroxybutyl.
  • the N-pyridylpiperidine compound represented by Formula (1) includes N-pyridylpiperidine compounds represented by the followin Formulas (la), (lb), and (lc):
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , X, m, and n are as defined above.
  • N-pyridylpiperidine compound of Formula ( 1 ) wherein R 2 and R 8 join to form a Ci- 4 alkylene group may exist as, for example, cis-trans isomers represented by the following Formulas (Id) and (le).
  • the N-pyridylpiperidine compound of the invention represented by Formula (1) includes such isomers.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , X, m, and n are as defined above, and Y is a Ci_ 4 alkylene group.
  • N-pyridylpiperidine compound of Formula ( 1 ) wherein R 4 and R 6 join to form a Ci- 4 alkylene group may exist as, for example, cis-trans isomers represented by the following Formulas (If) and (lg).
  • the N-pyridylpiperidine compound of the invention represented by Formula (1) includes such isomers.
  • N-pyridylpiperidine compound of Formula ( 1 ) wherein at least one of R 2 . R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 is a Ci- 4 alkyl group may exist as stereoisomers in relation to the 4- position of the piperidine ring.
  • the N-pyridylpiperidine compound of the invention represented by Formula ( 1 ) includes such isomers.
  • the N-pyridylpiperidine compound represented by Formula ( 1 ) may exist as N-oxides formed by oxidation of the nitrogen atom of the pyridine ring or piperidine ring of the N- pyridylpiperidine compound.
  • the N-pyridylpiperidine compound of the invention represented by Formula ( 1 ) includes these N-oxides.
  • N-oxide formed by oxidation of the nitrogen atom on the pyridine ring is called N-pyridyl oxide
  • N-oxide formed by oxidation of the nitrogen atom on the piperidine ring is called N-piperidyl oxide.
  • ( 1 ) has basic properties, and therefore can form salts with, for example, inorganic acids, such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic acids, such as formic acid, acetic acid, fumaric acid, oxalic acid, and sulfonic acid; and acid salts, such as sodium hydrogen sulfate and potassium
  • N-pyridylpiperidine compounds represented by Formula ( 1 ) those wherein R 1 is a C 1 .4 haloalkyl group, a cyano group, or a nitro group are preferable, and those wherein R 1 is a Ci-4 haloalkyl group are more preferable. Specifically, those wherein R 1 is a trifluoromethyl group are particularly preferable.
  • N-pyridylpiperidine compounds represented by Formula ( 1 ) are those wherein R 10 is a Ci- 2 o alkyl group; a C 2 -6 alkenyl group; a Ci- 6 haloalkyl group; a Ci_ 6
  • alkylcarbonyl group a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group
  • heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group consisting of C 1 -4 alkyl and Ci_ 4 haloalkyl) ; or a Ci_ 4 alkyl group substituted with one or more, and preferably one or two substituents each
  • Ci- 6 alkoxy independently selected from the group consisting of Ci- 6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms ) , and heterocyclic groups. More preferable are those wherein R 10 is a Ci_ 6 alkyl group; a C 2 -6 alkenyl group; a phenyl group (optionally
  • Ci_ 4 alkyl groups substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci_ 4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more, and preferably one or two C x . alkyl groups); or a Ci- alkyl group substituted with one or two substituents each independently selected from the group consisting of Ci_ 6 alkoxy, phenyl
  • R 10 is a Ci- 6 alkyl group, a pyridyl group, a 2 , 2-dimethoxyethyl group, or a (l, 3-dioxolan-2-yl)methyl group.
  • N-pyridylpiperidine compounds of the invention represented by Formula ( 1 ) are those wherein R 11 is a Ci-6 alkyl group, a Ci_ 4 haloalkyl group, a phenyl group
  • R u is a trifluoromethyl group or a phenyl group (optionally substituted on the phenyl ring with one to three halogen atoms ) .
  • N-pyridylpiperidine compounds of the invention represented by Formula ( 1 ) are those wherein X is an oxygen atom. More preferable are compounds of Formula ( 1 ) wherein R 1 is a Ci-4 haloalkyl group, a cyano group, or a nitro group; R 10 is a Ci-20 alkyl group; a C 2 -6 alkenyl group; a Ci- 6 haloalkyl group; a Ci-6 alkylcarbonyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group
  • heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group consisting of C 1 -4 alkyl and C 1 -4 haloalkyl); or a Ci_ 4 alkyl group substituted with one or more, and preferably one or two substituents each
  • R 11 is a Ci- 6 alkyl group, a C 1 -4 haloalkyl group, a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one to three substituents each independently selected from the group consisting of halogen, C 1 -4 alkyl, nitro, Ci-4 haloalkyl, and C 1 -4 haloalkoxy) , or a heterocyclic group
  • X is an oxygen atom
  • R 1 is a C 1 -4 haloalkyl group
  • R 10 is a Ci-6 alkyl group
  • a C 2 -e alkenyl group a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci_ 4 alkyl groups )
  • a pyridyl group (optionally substituted on the pyridine ring with one or more C 1 -4 alkyl groups); or a C 1 -4 alkyl group substituted with one or two substituents each independently selected from the group
  • R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , R 9 , R 10 , R 11 , X, Y, m, and n are as defined above.
  • R 10 is a Ci- 2 o alkyl group; a C 2 -6 alkenyl group; a Ci- 6 haloalkyl group; a Ci_ 6 alkylcarbonyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group consisting of halogen, Ci_ 4 alkyl, and Ci- 4
  • haloalkyl a heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group
  • Ci_ 4 alkyl and Ci- 4 haloalkyl consisting of Ci_ 4 alkyl and Ci- 4 haloalkyl); or a Ci- 4 alkyl group substituted with one or more, and preferably one or two substituents each independently selected from the group
  • Ci- 6 alkoxy consisting of Ci- 6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms ) , and heterocyclic groups . More preferable are those wherein R 10 is a Ci_ 6 alkyl group; a C 2 -6 alkenyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci_ 4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more, and preferably one or two Ci- 4 alkyl groups ) ; or a Ci_ 4 alkyl group substituted with one or two substituents each independently selected from the group consisting of Ci_ 6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms
  • R 10 is a Ci_ 6 alkyl group, a pyridyl group, a 2,2-dimethoxyethyl group, or a ( 1 , 3-dioxolan-2-yl)methyl .
  • N-pyridylpiperidine compounds of the invention represented by Formulas (la) and (If), preferable are those wherein R 11 is a Ci_ 6 alkyl group, a Ci- 4 haloalkyl group, a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one to three substituents each
  • halogen independently selected from the group consisting of halogen, Ci- 4 alkyl, nitro, Ci- 4 haloalkyl, and C x . 4 haloalkoxy) , or a
  • heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two halogen atoms). More preferable are compounds wherein R 11 is a trifluoromethyl group or a phenyl group (optionally substituted on the phenyl ring with one to three halogen atoms ) .
  • N-pyridylpiperidine compounds of the invention represented by Formulas (la) and (If), those wherein X is an oxygen atom are preferable.
  • R 1 is a Ci- haloalkyl group or a cyano group
  • R 10 is a Ci- 20 alkyl-group
  • C 2 _ 6 alkenyl group a Ci- 6 haloalkyl group
  • Ci. 6 alkylcarbonyl group a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group
  • heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group consisting of Cj.. 4 alkyl and Ci_ 4 haloalkyl); or a C 1 -4 alkyl group substituted with one or more, and preferably one or two substituents each
  • R 11 is a Ci- 6 alkyl group, a C 1 -4 haloalkyl group, a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably 1 to 3 substituents each independently selected from the group consisting of halogen, C 1 -4 alkyl, nitro, Ci_ 4 haloalkyl, and Ci- 4 haloalkoxy) , or a heterocyclic group
  • X is an oxygen atom
  • R 1 is a Ci- 4 haloalkyl group
  • R 10 is a Ci-6 alkyl group; a C 2 -6 alkenyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci- 4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more, and preferably one or two C 1 -4 alkyl groups); or a Ci- alkyl group substituted with one or two substituents each independently selected from the group consisting of Ci- 6 alkoxy, phenyl
  • R 11 is a trifluoromethyl group or a phenyl group (optionally
  • N-pyridylpiperidine compounds of the invention represented by Formula (la) preferable are those wherein any one of R 4 , R 5 , R 6 , and R 7 is a Ci_ alkyl group that is positioned trans to the X on the 4-position of the piperidine ring.
  • Particularly preferable are compounds wherein the d-4 alkyl group is a methyl group.
  • N-pyridylpiperidine compound represented by Formula (1) can be produced, for example, by the method described in WO 2008/026658.
  • the animal ectoparasite-controlling agent of the present invention characteristically comprises the N- pyridylpiperidine compound represented by Formula (1) as an active ingredient.
  • the controlling agent of the present invention is effective against fleas, mites, lice (cattle lice, horse lice, sheep lice, linognathus vituli, head lice, etc.), biting lice (Trichodectes canis , etc . ) , and the like that live in the body surface of host animals.
  • the controlling agent of the present invention has the beneficial effect of preventing mites.
  • the controlling agent of the present invention has the beneficial effect of preventing mites.
  • invention is effective against blood-sucking dipteran insects, such as flies, biting midges, black flies, and stable flies.
  • Fleas refer to ectoparasitic wingless insects belonging to Siphonaptera, specifically fleas belonging to Pulicidae,
  • Pulicidae include Ctenocephalides canis, Ctenocephalides fells, Pulex irritans , Echidnophaga gallinacea, Xenopsylla cheopis , Monopsyllus anisus, Nosopsyllus fasciatus , etc.
  • Mites are, for example, ticks. Examples thereof include Haemaphysalls longicomis, Haemaphysalls japonica,
  • Dermacentor reticulatus Dermacentor taiwanesis , Haemaphysalls flava, Ixodes ovatus , Ixodes persulcatus , Boophilus microplus , etc.
  • Examples of host animals for which the controlling agent of the present invention is effective include pets, such as dogs, cats, mice, rats, hamsters, guinea pigs, squirrels, rabbits, ferrets, and birds (e.g., pigeons, parrots, myna birds, paddy birds, parakeets, lovebirds, and canaries); livestock, such as cattle, horses, pigs, and sheep; poultry, such as ducks and chicken; and the like.
  • Ectoparasites are parasitic and live on the back, infra-axillary region, lower abdominal region, inner thigh region, etc., of these host animals.
  • the controlling agent of the present invention may be used as it is, without the addition of any other components.
  • controlling agent can be mixed with various suitable carriers in the form of liquids, solids, or gases, optionally followed by addition of surfactants and other
  • the amount of the compound of the present invention as an active ingredient in such formulations can be suitably provided.
  • Such formulations usually contain the compound in an amount of about 0.01 to 95 wt.%, and preferably about 0.1 to 50 wt.%.
  • the aforementioned suitable carriers may be those generally used in animal feed drugs. Examples thereof are lactose, sucrose, glucose, starch, wheat flour, corn flour, soybean oil cake, defatted rice bran, calcium carbonate, and other
  • surfactant examples include anionic surfactants (e.g., alkali stearate, sodium abietate, alkyl sulfate, sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate, and fatty acids), cationic surfactants (e.g., water-soluble quaternary ammonium), nonionic surfactants (optionally selected from anionic surfactants (e.g., alkali stearate, sodium abietate, alkyl sulfate, sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate, and fatty acids), cationic surfactants (e.g., water-soluble quaternary ammonium), nonionic surfactants (optionally selected from anionic surfactants (e.g., alkali stearate, sodium abietate, alkyl sulfate, sodium dodecylbenzene
  • polyoxyethylenated sorbitan esters polyoxyethylenated alkyl ethers, polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters,
  • amphoteric surfactants e.g., lauryl-substituted betaine
  • auxiliary materials for preparation of formulations include fixing agents, dispersing agents, thickeners, preservatives, anti-freezing agents, stabilizers, adjuvants, and the like.
  • fixing agents and dispersing agents include casein, gelatin, polysaccharides (e.g., starch, gum arable, cellulose derivatives, and alginic acid), lignin derivatives, bentonite, sugars, water-soluble synthetic polymers (e.g.,
  • polyvinyl alcohol polyvinylpyrrolidone , and polyacrylic acids ) , and the like.
  • thickeners examples include water-soluble polymer compounds, such as xanthan gum and carboxymethyl cellulose, high- purity bentonite, white carbon, and the like.
  • preservatives examples include sodium benzoate, p- hydroxybenzoic acid ester, and the like.
  • anti-freezing agents examples include ethylene glycol, diethylene glycol, and the like.
  • stabilizers examples include PAP (acidic isopropyl phosphate), BHT (2, 6-di-tert-butyl-4-methylphenol) , BHA (a)
  • adjuvants examples include soybean oil, corn oil, and like vegetable oils, machine oil, glycerin, polyethylene glycol, and the like.
  • Such formulations may be colored with an organic or inorganic dye.
  • the thus-obtained formulations can be used as they are or after being diluted with water or the like. However, fine granules, granules, etc., are generally used as they are, without being diluted.
  • the active ingredient concentration is generally 0.0001 to 50 wt.%, and preferably about 0.001 to 10 wt.%.
  • controlling agent of the present invention may be previously mixed with other agents, such as insecticides, nematocides, acaricides, fungicides, antifungals, antibacterial agents, anti-inflammatory agents, antiprotozoan drugs, synergists (e.g., piperonyl butoxide), or the like, and then formulated.
  • agents such as insecticides, nematocides, acaricides, fungicides, antifungals, antibacterial agents, anti-inflammatory agents, antiprotozoan drugs, synergists (e.g., piperonyl butoxide), or the like.
  • the formulations of the present invention and other such agents may be used in combination when used.
  • the controlling agent of the present invention may generally be administered to a host animal in a dose of 0.01 mg or more and 100 g or less, and preferably 0.1 mg or more and 10 g or less, per kg of body weight of the host animal.
  • the controlling agent of the present invention is orally or parenterally administered to a host.
  • the controlling agent of the present invention When orally administered, for example, the controlling agent of the present invention is mixed with feed of a host animal, and then administered together with the feed; or tablets, solutions, capsules, wafers, biscuits, minced meat, etc., containing the controlling agent of the present invention are administered.
  • the controlling agent of the present invention When parenterally administered, for example, the controlling agent of the present invention is formed into suitable formulations, and then incorporated into the body by intravenous infusion administration, intramuscular administration, intracutaneous administration, subcutaneous administration, spot- on treatment, pore-on treatment, or the like; or resin pieces, etc . , containing the controlling agent of the present invention are implanted under the skin of a host animal.
  • Test Example Mortality of Ixodid Ticks by Filter Paper Clipping Method
  • Acetone was added to each of Test Compounds 1 to 17 so that the concentration was 0.5 mg/ml, thereby preparing solutions.
  • Test Compound 15 which was not dissolved in acetone, formed a heterogeneous suspension, the suspension was used as it was .
  • Each of the above prepared solutions was added dropwise in an amount of 1 ml to a square filter paper (5 x 10 cm; area: 50 cm 2 ), and dried on aluminum foil at room temperature for 24 hours. Then, each filter paper was folded double on the long side. and both sides were secured with bulldog clips into a bag shape. About 20 ixodid ticks were placed in the bag-like filter paper, and the opening was sealed with a bulldog clip. After 72 hours, the number of dead ticks was calculated. Thereafter, the

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Abstract

The present invention provides an animal ectoparasite-controlling agent and a method for preventing or treating infection in animals caused by parasites by using the controlling agent. An animal ectoparasite-controlling agent exhibiting excellent insecticidal activity, and a method for preventing or treating infection in animals caused by parasites by using the controlling agent are obtained by using a compound having a pyrazole ring at the 4-position of the piperidine ring as an active ingredient.

Description

DESCRIPTION
Title of Invention: ANIMAL ECTOPARASITE-CONTROLLING AGENT AND METHOD FOR PREVENTING OR TREATING INFECTION IN ANIMALS CAUSED BY PARASITES BY USING THE CONTROLLING AGENT
Technical Field
The present invention relates to an animal
ectoparasite-controlling agent comprising an N-pyridylpiperidine compound as an active ingredient, and to a method for preventing or treating infection in animals caused by parasites by using the controlling agent.
Background Art
Various controlling agents and repellents for ectoparasites of animals have been developed so far; however, there is always the possibility that a species having resistance to the active ingredients of such agents may appear. For this reason, there is a constant demand for research and development of novel active ingredients.
Meanwhile, an N-pyridylpiperidine compound, which is an active ingredient of the present invention, has already been reported ( see PTL 1 ) . This document discloses that the N- pyridylpiperidine compound exhibits miticidal activity against plant-parasitic mites. However, the insecticidal effect of the N- pyridylpiperidine compound on animal ectoparasites was not known at all.
Citation List
Patent Literature
PTL 1: WO 2008/026658
Summary of Invention
Technical Problem
The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an animal ectoparasite-controlling agent, and a method for preventing or treating infection in animals caused by
parasites by using the controlling agent.
Solution to Problem
The present inventors conducted extensive research to achieve the above object and found that the compound disclosed in PTL 1 having a pyrazole ring at the 4-position of the piperidine ring also exhibited excellent insecticidal activity against animal ectoparasites. The present invention has been accomplished based on this finding.
More specifically, the present invention provides an animal ectoparasite-controlling agent, and a method for
preventing or treating infection in animals caused by parasites by using the controlling agent, as summarized below.
Item 1. An animal ectoparasite-controlling agent comprising an N- pyridylpiperidine compound, an N-oxide thereof, or salts of these compounds, the N-pyridylpiperidine compound being represented by Formula ( 1 ) :
Figure imgf000003_0001
wherein R1 is a halogen atom, a Ci-4 haloalkyl group, a cyano group, a nitro group, or a Ci-4 alkoxycarbonyl group;
R2 , R3 , R4 , R5 , R6 , R7 , R8 , and R9 are each a hydrogen atom or a Ci-4 alkyl group;
each pair of R2 and R8 , and R4 and R6 , may join to form a Ci-4 alkylene group;
R10 is a hydrogen atom; a Ci_2o alkyl group; a C3.8 cycloalkyl group; a C2-6 alkenyl group; a C2-e alkynyl group; a Ci-6 haloalkyl group; a C2-6 haloalkenyl group; a Ci_6 alkylcarbonyl group; a Ci_6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with one to five halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci-4 alkyl, and Ci_4 haloalkyl; a
heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each independently selected from the group consisting of halogen, Ci_4 alkyl, Ci_4 haloalkyl, and optionally substituted heterocyclic groups; or a Ci_4 alkyl group optionally substituted with one or more substituents each independently selected from the group consisting of optionally halogen-substituted C3.8 cycloalkyl, cyano, nitro, formyl, Ci_6 alkoxy, Ci-4 haloalkoxy, benzyloxy, phenoxy, -CON(R12) (R13) , phenyl optionally substituted on the phenyl ring with one or more halogen atoms, and heterocyclic groups optionally substituted on the heterocyclic ring with one or more Ci_4 alkyl groups; wherein R12 and R13 are each a C1-4 alkyl group, or R12 and R13 may join to form a C2-7 alkylene group;
R11 is a halogen atom; a Ci_6 alkyl group; a Ci-4 haloalkyl group; a Ci_4 hydroxyalkyl group; a Ci-4 alkoxycarbonyl group; a Ci_4 alkylcarbonyl group; a mono or di(Ci_4
alkyl)aminocarbonyl group; a nitro group; a cyano group; a formyl group; -C(R14) =NO(R15) ; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci-6 alkyl, Ci-4 haloalkyl, Ci-6 alkoxy, Ci-4 haloalkoxy, Ci_4 alkylthio, cyano, and nitro; or a heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each
independently selected from the group consisting of halogen, Ci-4 alkyl, and Ci_4 haloalkyl; wherein R14 is a hydrogen atom or a Ci_4 alkyl group, and R15 is a hydrogen atom, a Ci_ alkyl group, or a benzyl group;
X is an oxygen atom, a sulfur atom, or -S02-; m is an integer of 1 to 4, and when m is an integer of 2 or more, the R^s, the number of which is represented by m, may be the same or different; and n is an integer of 1 or 2 , and when n is 2 , the two Ru's may be the same or different.
Item 2 . The animal ectoparasite-controlling agent according to Item 1 , wherein the N-pyridylpiperidine compound is represented by Formula ( 1 ) in which R1 is a halogen atom, a Ci-4 haloalkyl group, a cyano group, or a nitro group.
Item 3 . The animal ectoparasite-controlling agent according to Item 1 , wherein the N-pyridylpiperidine compound is represented by Formula ( 1 ) in which R10 is a hydrogen atom; a Ci-2o alkyl group; a C2.6 alkenyl group; a Ci-6 haloalkyl group; a Ci-6
alkylcarbonyl group; a Ci-6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with one to five halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci-4 alkyl, and Ci- haloalkyl; a heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each
independently selected from the group consisting of halogen, Ci-4 alkyl, Ci_4 haloalkyl, and optionally substituted heterocyclic groups; or a C1-4 alkyl group substituted with one or more substituents each independently selected from the group
consisting of formyl, Ci-6 alkoxy, phenyl optionally substituted on the phenyl ring with one or more halogen atoms, and
heterocyclic groups optionally substituted on the heterocyclic ring with one or more Ci-4 alkyl groups.
Item 4. The animal ectoparasite-controlling agent according to Item 1 , wherein the N-pyridylpiperidine compound is represented by Formula ( 1 ) in which R11 is a halogen atom; a Ci-6 alkyl group; a Ci_ haloalkyl group; a Ci- hydroxyalkyl group; a Ci-4
alkoxycarbonyl group; a formyl group; -C(R14)=NO(R15) wherein R14 is a hydrogen atom, and R15 is a hydrogen atom or a Ci-4 alkyl group; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci-6 alkyl, Ci-4 haloalkyl, Ci_6 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, cyano, and nitro; or a heterocyclic group optionally substituted on the heterocyclic ring with one or more halogen atoms.
Item 5. The animal ectoparasite-controlling agent according to Item 1, wherein the N-pyridylpiperidine compound is represented by Formula (1) in which X is an oxygen atom.
Item 6. A method for preventing or treating infection in an animal caused by parasites, the method comprising administrating the animal ectoparasite-controlling agent according to any one of Items 1 to 5 to the animal.
Advantageous Effect of Invention
The present invention can provide an animal ectoparasite-controlling agent having an excellent control effect on animal ectoparasites, such as mites.
Description of Embodiments
The present invention is described in detail below. N-pyridylpiperidine Compound
The controlling agent of the present invention
comprises, as an active ingredient, a compound represented by the following Formula (1) and having pyrazole bonded to the 4- position of the piperidine ring via an oxygen or sulfur atom.
Figure imgf000006_0001
wherein R1 is a halogen atom, a Ci-4 haloalkyl group, a cyano group, a nitro group, or a Ci- alkoxycarbonyl group;
R2, R3, R4, R5, R6, R7, R8, and R9 are each a hydrogen atom or a Ci-4 alkyl group;
each pair of R2 and R8, and R4 and R6, may join to form a Ci-4 alkylene group;
R10 is a hydrogen atom; a Cj.-2o alkyl group; a C3-e cycloalkyl group; a C2-6 alkenyl group; a C2-6 alkynyl group; a Ci-6 haloalkyl group; a C2-e haloalkenyl group; a Ci-6 alkylcarbonyl group; a Ci-6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with 1 to 5 halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci_4 alkyl, and Ci- haloalkyl; a
heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each independently selected from the group consisting of halogen, Ci-4 alkyl, Ci_ haloalkyl, and optionally substituted heterocyclic groups; or a Ci-4 alkyl group optionally substituted with one or more substituents each independently selected from the group consisting of optionally halogen-substituted C3.8 cycloalkyl, cyano, nitro, formyl, Ci-6 alkoxy, Ci- haloalkoxy, benzyloxy, phenoxy, -CON( R12 ) ( R13 ) , phenyl optionally substituted on the phenyl ring with one or more halogen atoms, and heterocyclic groups optionally substituted on the heterocyclic ring with one or more Ci_4 alkyl groups; wherein R12 and R13 are each a €χ. alkyl group, or R12 and R13 may join to form a C2-7 alkylene group;
R11 is a halogen atom; a Ci_6 alkyl group; a Ci_4 haloalkyl group; a Ci-4 hydroxyalkyl group; a Ci-4 alkoxycarbonyl group; a Ci-4 alkylcarbonyl group; a mono or di(Ci- alkyl)aminocarbonyl group; a nitro group; a cyano group; a formyl group; -C (R1 ) =NO(R15 ) ; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci_6 alkyl, Ci-4 haloalkyl, Ci_6 alkoxy, Ci-4 haloalkoxy, Ci_4 alkylthio, cyano, and nitro; or a heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each
independently selected from the group consisting of halogen, d- alkyl, and Ci_ haloalkyl; wherein R14 is a hydrogen atom or a Ci- alkyl group, and R15 is a hydrogen atom, a Ci-4 alkyl group, or a benzyl group;
X is an oxygen atom, a sulfur atom, or -S02- ; m is an integer of 1 to 4, and when m is an integer of 2 or more, the l^'s, the number of which is represented by m, may be the same or different; and
n is an integer of 1 or 2 , and when n is 2 , the two Ru's may be the same or different.
Examples of the halogen atom include fluorine, chlorine, bromine, and iodine atoms.
Examples of the Ci-4 haloalkyl group include linear or branched alkyl groups having 1 to 4 carbon atoms and substituted with 1 to 9 , preferably 1 to 5 , halogen atoms. Specific examples thereof include fluoromethyl, chloromethyl, bromomethyl,
iodomethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, bromodifluoromethyl, dichlorofluoromethyl, 1-fluoroethyl, 2- fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2 , 2 , 2- trifluoroethyl, 2 , 2 , 2-trichloroethyl, pentafluoroethyl, 1- fluoroisopropyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl, 4-fluorobutyl, 4-chlorobutyl, 4,4,4-trifluorobutyl, and like groups .
Examples of the Ci-4 alkoxycarbonyl group include groups formed by the bonding of a linear or branched alkoxy group having 1 to 4 carbon atoms to a carbonyl group. Specific examples thereof include methoxycarbonyl , ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, see- butoxycarbonyl, tert-butoxycarbonyl, and like groups.
Examples of the Ci_4 alkyl group include linear or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
Examples of the Ci-4 alkylene group include linear or branched alkylene groups having 1 to 4 carbon atoms, such as methylene, ethylene, trxmethylene, tetramethylene, propylene, and ethylethylene .
Examples of the Ci-6 alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms, such as n- pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, xsohexyl, and 2-ethyl-n-butyl, in addition to those mentioned as examples of the Ci-4 alkyl group.
Examples of the Ci-2o alkyl group include linear or branched alkyl groups having 1 to 20 carbon atoms, such as n- heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n- tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, and n-icosyl, in addition to those mentioned as examples of the Ci-4 alkyl group and Ci_6 alkyl group.
Examples of the C3.8 cycloalkyl group include cyclic alkyl groups having 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Examples of the C2-6 alkenyl group include linear or branched alkenyl groups containing 2 to 6 carbon atoms and having at least one double bond at any position. Specific examples thereof include vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl,
3-butenyl, 1-methyl-2-propenyl, 1,3-butadienyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 1,1-dimethyl-2-propenyl, 1- ethyl-2-propenyl, 1-methyl-2-butenyl, 1-methyl-3-butenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,1- dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, and like groups .
Examples of the C2.6 alkynyl group include linear or branched alkynyl groups containing 2 to 6 carbon atoms and having at least one triple bond at any position. Specific examples thereof include ethynyl, 2-propynyl, 1-methyl-2-propynyl, 1,1- dimethyl-2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,
2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl-
3-butynyl, 1, 1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1- methyl-3-pentynyl, 1-methyl-4-pentynyl, and like groups.
Examples of the Ci_6 haloalkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms and substituted with 1 to 13, preferably 1 to 7, halogen atoms. Specific examples thereof include 5-chloropentyl, 5-fluoropentyl, 6-chlorohexyl, and 6-fluorohexyl, in addition to those mentioned as examples of the Ci-4 haloalkyl group.
Examples of the C2.6 haloalkenyl group include C2-6 linear or branched alkenyl groups having at least one double bond at any position and substituted with 1 to 13, preferably 1 to 7, halogen atoms. Specific examples thereof include 2,2- dichlorovinyl, 2,2-dibromovinyl, 3-chloro-2-propenyl, 3,3- difluoro-2-allyl, 3,3-dichloro-2-allyl, 4-chloro-2-butenyl,
4,4,4-trifluoro-2-butenyl, 4,4,4-trichloro-3-butenyl , 5-chloro-3- pentenyl, 6-fluoro-2-hexenyl, and like groups.
Examples of the heterocyclic group include thienyl, furyl, tetrahydrofuryl, dioxolanyl, dioxanyl, pyrrolyl,
pyrrolinyl, pyrrolidinyl, oxazolyl, isoxazolyl, oxazolinyl, oxazolxdinyl, xsoxazolxnyl, thxazolyl, xsothxazolyl, thxazolinyl, thiazolidinyl, isothiazolinyl, pyrazolyl, pyrazolidinyl ,
imidazolyl, xmidazolinyl, imidazolidxnyl, oxadiazolyl,
oxadiazolinyl, thiadiazolinyl, triazolyl, triazolinyl,
triazolidinyl, tetrazolyl, tetrazolxnyl, pyrxdyl, dxhydropyrxdyl, tetrahydropyridyl, piperidyl, oxazinyl, dihydroxazinyl,
morpholino, thiazinyl, dihydrothiazinyl, thiamorpholino,
pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl,
hexahydropyridazinyl, oxadiaziny1, dihydrooxadiazinyl ,
tetrahydrooxadiazinyl, thiadiazolyl , thiadiazinyl,
dihydrothiadiazinyl , tetrahydrothiadiazinyl, pyrimidinyl,
dihydropyrxmidinyl, tetrahydropyrimidinyl, hexahydropyrxmidinyl , pyrazinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, triazinyl, dihydrotriazinyl, tetrahydrotriazinyl,
hexahydrotriazinyl, tetrazinyl, dihydrotetrazinyl, indolyl, indolinyl, isoindolyl, indazolyl, quinazolinyl, dihydroquinazolyl , tetrahydroquinazolyl , carbazolyl, benzoxazolyl, benzoxazolinyl, benzisoxazolyl, benzisoxazolinyl, benzothiazolyl,
benzisothiazolyl, benzisothiazolinyl, benzimidazolyl, indazolinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinolinyl,
isoquinolinyl, dihydroisoquinolinyl , tetrahydroisoquinolinyl, pyrxdoindolyl, dihydrobenzoxazinyl, cinnolinyl, dihydrocinnolinyl, tetrahydrocinnolinyl, phthalazinyl, dihydrophthalazinyl,
tetrahydrophthalazinyl , quinoxalinyl, dihydroquinoxalxnyl,
tetrahydroquinoxalinyl, purinyl, dihydrobenzotriazinyl, dihydrobenzotetrazinyl, phenothiazinyl, furanyl, benzofuranyl , benzothienyl , and like groups. These heterocyclic groups include those substituted at any substitutable position with an oxo or thioketone group. These heterocyclic groups further include those optionally substituted at any substitutable position with 1 to 5 (preferably 1 to 3) substituents , such as halogen atoms, Ci-4 alkyl groups, Ci-4 haloalkyl groups, or substituted heterocyclic groups (e.g., 3-chloropyridin-2-yl, 4-trifluoromethyl-l,3- thiazol-2-yl, and 5-trifluoromethylpyridin-2-yl) .
Among these heterocyclic rings, thienyl, furyl, tetrahydrofuryl, dioxolanyl, dioxanyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, pyridyl, and piperidyl are preferable.
Thienyl, tetrahydrofuryl, dioxolanyl, dioxanyl, thiazolyl, and pyridyl are particularly preferable .
Examples of the optionally halogen-substituted C3.8 cycloalkyl group include cyclic alkyl groups having 3 to 8 carbon atoms, such as the above-mentioned C3-8 cycloalkyl groups that are optionally substituted at any position with one to the maximum substitutable number of (preferably 1 to 5, and more preferably 1 to 3) halogen atoms.
Examples of the Ci-6 alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, cyclopropyloxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, n-hexyloxy, and isohexyloxy.
Examples of the Ci_4 haloalkoxy group include linear or branched alkoxy groups having 1 to 4 carbon atoms and substituted with 1 to 9, preferably 1 to 5, halogen atoms. Specific examples thereof include fluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, dichloromethoxy, trichloromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, dichlorofluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2- chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, 1-fluoroisopropoxy, 3- fluoropropoxy, 3-chloropropoxy, 3-bromopropoxy, 4-fluorobutoxy, 4-chlorobutoxy, and like groups.
Examples of the C1-4 alkylthio group include linear or branched alkylthio groups having 1 to 4 carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, and tert- butylthio.
Examples of the C2-7 alkylene group include ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, and the like. These alkylene groups may contain an optionally substituted nitrogen, oxygen, or sulfur atom, or a phenylene group. Examples of such alkylene groups include - CH2NHCH2-, -CH2NHCH2CH2- , -CH2NH HCH2- , -CH2CH2NHCH2CH2- , - CH2NH HCH2CH2- , -CH2 HCH2NHCH2- , -CH2CH2CH2NHCH2CH2CH2- , -CH2OCH2CH2- , - - , -CH2SCH2CH2- , -CH2CH2SCH2CH2- ,
Figure imgf000012_0001
and like groups. These alkylene groups may be substituted at any position or on the nitrogen atom. Examples of such substituents include Ci_4 alkyl, Ci-6 alkoxycarbonyl, hydroxy, and like groups.
Examples of the C1.4 alkylcarbonyl group include linear or branched alkylcarbonyl groups having 1 to 4 carbon atoms, such as methylcarbonyl (acetyl), ethylcarbonyl (propionyl), n- propylcarbonyl (butyryl), isopropylcarbonyl (isobutyryl) , n- butylcarbonyl (valeryl), isobutylcarbonyl ( isovaleryl) , sec- butylcarbonyl, and tert-butylcarbonyl.
Examples of the mono- or di(Ci_4 alkyl)aminocarbonyl group include alkylaminocarbonyl groups in which nitrogen atoms of the aminocarbonyl groups are mono- or di-substituted with linear or branched alkyl groups having 1 to 4 carbon atoms, such as methylaminocarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, n- propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocaxbonyl, and
dibutylaminocarbonyl .
Examples of the Ci-4 hydroxyalkyl group include linear or branched alkyl groups having 1 to 4 carbon atoms and
substituted with 1 or 2 hydroxy groups, such as hydroxymethyl, 2- hydroxyethyl, 1-hydroxy-2-propyl, 3-hydroxypropyl, 4-hydroxybutyl, and 3, 4-dihydroxybutyl.
The N-pyridylpiperidine compound represented by Formula (1) includes N-pyridylpiperidine compounds represented by the followin Formulas (la), (lb), and (lc):
Figure imgf000013_0001
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X, m, and n are as defined above.
The N-pyridylpiperidine compound of Formula ( 1 ) , wherein R2 and R8 join to form a Ci-4 alkylene group may exist as, for example, cis-trans isomers represented by the following Formulas (Id) and (le). The N-pyridylpiperidine compound of the invention represented by Formula (1) includes such isomers.
Figure imgf000014_0001
wherein R1, R3, R4, R5, R6, R7, R9, R10, R11, X, m, and n are as defined above, and Y is a Ci_4 alkylene group.
The N-pyridylpiperidine compound of Formula ( 1 ) , wherein R4 and R6 join to form a Ci-4 alkylene group may exist as, for example, cis-trans isomers represented by the following Formulas (If) and (lg). The N-pyridylpiperidine compound of the invention represented by Formula (1) includes such isomers.
Figure imgf000014_0002
wherein R1, R2, R3, R5, R7, R8, R9, R10, R11, X, Y, m, and n are as defined above. The N-pyridylpiperidine compound of Formula ( 1 ) , wherein at least one of R2. R3 , R4 , R5 , R6 , R7 , R8 , and R9 is a Ci-4 alkyl group may exist as stereoisomers in relation to the 4- position of the piperidine ring. The N-pyridylpiperidine compound of the invention represented by Formula ( 1 ) includes such isomers.
The N-pyridylpiperidine compound represented by Formula ( 1 ) may exist as N-oxides formed by oxidation of the nitrogen atom of the pyridine ring or piperidine ring of the N- pyridylpiperidine compound. The N-pyridylpiperidine compound of the invention represented by Formula ( 1 ) includes these N-oxides.
In this specification, for convenience, N-oxide formed by oxidation of the nitrogen atom on the pyridine ring is called N-pyridyl oxide, whereas N-oxide formed by oxidation of the nitrogen atom on the piperidine ring is called N-piperidyl oxide.
The N-pyridylpiperidine compound represented by Formula
( 1 ) has basic properties, and therefore can form salts with, for example, inorganic acids, such as hydrochloric acid, sulfuric acid, and phosphoric acid; organic acids, such as formic acid, acetic acid, fumaric acid, oxalic acid, and sulfonic acid; and acid salts, such as sodium hydrogen sulfate and potassium
hydrogen sulfate. The N-pyridylpiperidine compound of the
invention represented by Formula ( 1 ) includes these salts.
Among the N-pyridylpiperidine compounds represented by Formula ( 1 ) , those wherein R1 is a C1.4 haloalkyl group, a cyano group, or a nitro group are preferable, and those wherein R1 is a Ci-4 haloalkyl group are more preferable. Specifically, those wherein R1 is a trifluoromethyl group are particularly preferable.
Preferable among the N-pyridylpiperidine compounds represented by Formula ( 1 ) are those wherein R10 is a Ci-2o alkyl group; a C2-6 alkenyl group; a Ci-6 haloalkyl group; a Ci_6
alkylcarbonyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group
consisting of halogen, Ci-4 alkyl, and C1.4 haloalkyl); a
heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group consisting of C1-4 alkyl and Ci_4 haloalkyl) ; or a Ci_4 alkyl group substituted with one or more, and preferably one or two substituents each
independently selected from the group consisting of Ci-6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms ) , and heterocyclic groups. More preferable are those wherein R10 is a Ci_6 alkyl group; a C2-6 alkenyl group; a phenyl group (optionally
substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci_4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more, and preferably one or two Cx. alkyl groups); or a Ci- alkyl group substituted with one or two substituents each independently selected from the group consisting of Ci_6 alkoxy, phenyl
(optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms), and l, 3-dioxolan-2-yl.
Particularly preferable are the compounds wherein R10 is a Ci-6 alkyl group, a pyridyl group, a 2 , 2-dimethoxyethyl group, or a (l, 3-dioxolan-2-yl)methyl group.
Preferable among the N-pyridylpiperidine compounds of the invention represented by Formula ( 1 ) are those wherein R11 is a Ci-6 alkyl group, a Ci_4 haloalkyl group, a phenyl group
(optionally substituted on the phenyl ring with one or more, and preferably one to three substituents each independently selected from the group consisting of halogen, Ci-4 alkyl, nitro, Ci-4 haloalkyl, and Ci- haloalkoxy) , or a heterocyclic group
(optionally substituted on the heterocyclic ring with one or more, and preferably one or two halogen atoms). More preferable are those wherein Ru is a trifluoromethyl group or a phenyl group (optionally substituted on the phenyl ring with one to three halogen atoms ) .
Preferable among the N-pyridylpiperidine compounds of the invention represented by Formula ( 1 ) are those wherein X is an oxygen atom. More preferable are compounds of Formula ( 1 ) wherein R1 is a Ci-4 haloalkyl group, a cyano group, or a nitro group; R10 is a Ci-20 alkyl group; a C2-6 alkenyl group; a Ci-6 haloalkyl group; a Ci-6 alkylcarbonyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group
consisting of halogen, Ci-4 alkyl, and C1-4 haloalkyl); a
heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group consisting of C1-4 alkyl and C1-4 haloalkyl); or a Ci_4 alkyl group substituted with one or more, and preferably one or two substituents each
independently selected from the group consisting of Ci-6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms), and heterocyclic groups; R11 is a Ci-6 alkyl group, a C1-4 haloalkyl group, a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one to three substituents each independently selected from the group consisting of halogen, C1-4 alkyl, nitro, Ci-4 haloalkyl, and C1-4 haloalkoxy) , or a heterocyclic group
(optionally substituted on the heterocyclic ring with one or more, and preferably one or two halogen atoms); and X is an oxygen atom.
Among these preferable compounds, particularly preferable are those wherein R1 is a C1-4 haloalkyl group; R10 is a Ci-6 alkyl group; a C2-e alkenyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci_4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more C1-4 alkyl groups); or a C1-4 alkyl group substituted with one or two substituents each independently selected from the group
consisting of Ci-4 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms), and l, 3-dioxolan-2-yl; Ru is a trifluoromethyl group or a phenyl group (optionally substituted on the phenyl ring with one to three halogen atoms); and X is an oxygen atom. Among the N-pyridylpiperidine compounds of the
invention represented by Formula ( 1 ) , those represented by
Formulas (la), (lb), and (If) are preferable, and those
represented by Formulas (la) and (If) are more preferable.
Figure imgf000018_0001
wherein R1, R2, R3, R5, R7, R8, R9, R10, R11, X, Y, m, and n are as defined above.
Among the N-pyridylpiperidine compounds of the
invention represented by Formulas (la) and (If), those wherein R1 is a Ci-4 haloalkyl group or a cyano group are preferable, and those wherein R1 is a Ci-4 haloalkyl group are more preferable. Specifically, the compounds wherein R1 is a trifluoromethyl group are particularly preferable.
Among the N-pyridylpiperidine compounds of the
invention represented by Formulas (la) and (If), preferable are those wherein R10 is a Ci-2o alkyl group; a C2-6 alkenyl group; a Ci- 6 haloalkyl group; a Ci_6 alkylcarbonyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group consisting of halogen, Ci_4 alkyl, and Ci-4
haloalkyl); a heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group
consisting of Ci_4 alkyl and Ci-4 haloalkyl); or a Ci-4 alkyl group substituted with one or more, and preferably one or two substituents each independently selected from the group
consisting of Ci-6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms ) , and heterocyclic groups . More preferable are those wherein R10 is a Ci_6 alkyl group; a C2-6 alkenyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci_4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more, and preferably one or two Ci-4 alkyl groups ) ; or a Ci_ 4 alkyl group substituted with one or two substituents each independently selected from the group consisting of Ci_6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms), and 1,3-dioxolan- 2-yl. Particularly preferable are compounds wherein R10 is a Ci_6 alkyl group, a pyridyl group, a 2,2-dimethoxyethyl group, or a ( 1 , 3-dioxolan-2-yl)methyl .
Among the N-pyridylpiperidine compounds of the invention represented by Formulas (la) and (If), preferable are those wherein R11 is a Ci_6 alkyl group, a Ci-4 haloalkyl group, a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one to three substituents each
independently selected from the group consisting of halogen, Ci-4 alkyl, nitro, Ci-4 haloalkyl, and Cx.4 haloalkoxy) , or a
heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two halogen atoms). More preferable are compounds wherein R11 is a trifluoromethyl group or a phenyl group (optionally substituted on the phenyl ring with one to three halogen atoms ) .
Among the N-pyridylpiperidine compounds of the invention represented by Formulas (la) and (If), those wherein X is an oxygen atom are preferable.
More preferable are compounds of Formulas (la) and (If) wherein R1 is a Ci- haloalkyl group or a cyano group; R10 is a Ci-20 alkyl-group; a C2_6 alkenyl group; a Ci-6 haloalkyl group; a Ci.6 alkylcarbonyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two substituents each independently selected from the group
consisting of halogen, C1-4 alkyl, and Ci_4 haloalkyl); a
heterocyclic group (optionally substituted on the heterocyclic ring with one or more, and preferably one or two substituents each independently selected from the group consisting of Cj..4 alkyl and Ci_4 haloalkyl); or a C1-4 alkyl group substituted with one or more, and preferably one or two substituents each
independently selected from the group consisting of Ci_6 alkoxy, phenyl (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms) , and heterocyclic groups; R11 is a Ci-6 alkyl group, a C1-4 haloalkyl group, a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably 1 to 3 substituents each independently selected from the group consisting of halogen, C1-4 alkyl, nitro, Ci_4 haloalkyl, and Ci-4 haloalkoxy) , or a heterocyclic group
(optionally substituted on the heterocyclic ring with one or more, and preferably one or two halogen atoms); and X is an oxygen atom.
Among these preferable compounds, particularly preferable are those wherein R1 is a Ci-4 haloalkyl group, R10 is a Ci-6 alkyl group; a C2-6 alkenyl group; a phenyl group (optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms or Ci-4 alkyl groups ) ; a pyridyl group (optionally substituted on the pyridine ring with one or more, and preferably one or two C1-4 alkyl groups); or a Ci- alkyl group substituted with one or two substituents each independently selected from the group consisting of Ci-6 alkoxy, phenyl
(optionally substituted on the phenyl ring with one or more, and preferably one or two halogen atoms), and l, 3-dioxolan-2-yl; R11 is a trifluoromethyl group or a phenyl group (optionally
substituted on the phenyl ring with one to three halogen atoms ) ; and X is an oxygen atom.
Among the N-pyridylpiperidine compounds of the invention represented by Formula (la), preferable are those wherein any one of R4 , R5 , R6 , and R7 is a Ci_ alkyl group that is positioned trans to the X on the 4-position of the piperidine ring. Particularly preferable are compounds wherein the d-4 alkyl group is a methyl group.
Method of Producing N-pyridylpiperidine Compound
The N-pyridylpiperidine compound represented by Formula (1) can be produced, for example, by the method described in WO 2008/026658.
Ectoparasite-Controlling Agent
The animal ectoparasite-controlling agent of the present invention characteristically comprises the N- pyridylpiperidine compound represented by Formula (1) as an active ingredient.
The controlling agent of the present invention is effective against fleas, mites, lice (cattle lice, horse lice, sheep lice, linognathus vituli, head lice, etc.), biting lice (Trichodectes canis , etc . ) , and the like that live in the body surface of host animals. In particular, the controlling agent of the present invention has the beneficial effect of preventing mites. In addition, the controlling agent of the present
invention is effective against blood-sucking dipteran insects, such as flies, biting midges, black flies, and stable flies.
Fleas refer to ectoparasitic wingless insects belonging to Siphonaptera, specifically fleas belonging to Pulicidae,
Ceratophyllus , or the like. Examples of fleas belonging to
Pulicidae include Ctenocephalides canis, Ctenocephalides fells, Pulex irritans , Echidnophaga gallinacea, Xenopsylla cheopis , Monopsyllus anisus, Nosopsyllus fasciatus , etc.
Mites are, for example, ticks. Examples thereof include Haemaphysalls longicomis, Haemaphysalls japonica,
Dermacentor reticulatus, Dermacentor taiwanesis , Haemaphysalls flava, Ixodes ovatus , Ixodes persulcatus , Boophilus microplus , etc.
Examples of host animals for which the controlling agent of the present invention is effective include pets, such as dogs, cats, mice, rats, hamsters, guinea pigs, squirrels, rabbits, ferrets, and birds (e.g., pigeons, parrots, myna birds, paddy birds, parakeets, lovebirds, and canaries); livestock, such as cattle, horses, pigs, and sheep; poultry, such as ducks and chicken; and the like. Ectoparasites are parasitic and live on the back, infra-axillary region, lower abdominal region, inner thigh region, etc., of these host animals.
The controlling agent of the present invention may be used as it is, without the addition of any other components.
Alternatively, the controlling agent can be mixed with various suitable carriers in the form of liquids, solids, or gases, optionally followed by addition of surfactants and other
auxiliary materials for preparation of formulations, and then formulated into granules, fine granules, tablets, powders,
capsules, premix formulations, solutions, emulsions, and other dosage forms.
The amount of the compound of the present invention as an active ingredient in such formulations can be suitably
selected from a wide range, depending on various conditions including the type of formulation, place of application, etc.
Such formulations usually contain the compound in an amount of about 0.01 to 95 wt.%, and preferably about 0.1 to 50 wt.%.
The aforementioned suitable carriers may be those generally used in animal feed drugs. Examples thereof are lactose, sucrose, glucose, starch, wheat flour, corn flour, soybean oil cake, defatted rice bran, calcium carbonate, and other
commercially available feed raw materials.
Examples of the surfactant include anionic surfactants (e.g., alkali stearate, sodium abietate, alkyl sulfate, sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate, and fatty acids), cationic surfactants (e.g., water-soluble quaternary ammonium), nonionic surfactants (optionally selected from
polyoxyethylenated sorbitan esters, polyoxyethylenated alkyl ethers, polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters,
polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide, etc . ) ,
amphoteric surfactants (e.g., lauryl-substituted betaine
compounds ) , and the like .
Examples of auxiliary materials for preparation of formulations include fixing agents, dispersing agents, thickeners, preservatives, anti-freezing agents, stabilizers, adjuvants, and the like.
Examples of fixing agents and dispersing agents include casein, gelatin, polysaccharides (e.g., starch, gum arable, cellulose derivatives, and alginic acid), lignin derivatives, bentonite, sugars, water-soluble synthetic polymers (e.g.,
polyvinyl alcohol, polyvinylpyrrolidone , and polyacrylic acids ) , and the like.
Examples of thickeners include water-soluble polymer compounds, such as xanthan gum and carboxymethyl cellulose, high- purity bentonite, white carbon, and the like.
Examples of preservatives include sodium benzoate, p- hydroxybenzoic acid ester, and the like.
Examples of anti-freezing agents include ethylene glycol, diethylene glycol, and the like.
Examples of stabilizers include PAP (acidic isopropyl phosphate), BHT (2, 6-di-tert-butyl-4-methylphenol) , BHA (a
mixture of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4- methoxyphenol) , vegetable oils, mineral oils, surfactants, fatty acids and esters thereof, and the like.
Examples of adjuvants include soybean oil, corn oil, and like vegetable oils, machine oil, glycerin, polyethylene glycol, and the like.
Such formulations may be colored with an organic or inorganic dye.
The thus-obtained formulations can be used as they are or after being diluted with water or the like. However, fine granules, granules, etc., are generally used as they are, without being diluted. When emulsions, wettable powders, flowable formulations, etc., are used after being diluted with water or the like, the active ingredient concentration is generally 0.0001 to 50 wt.%, and preferably about 0.001 to 10 wt.%.
In addition, the controlling agent of the present invention may be previously mixed with other agents, such as insecticides, nematocides, acaricides, fungicides, antifungals, antibacterial agents, anti-inflammatory agents, antiprotozoan drugs, synergists (e.g., piperonyl butoxide), or the like, and then formulated. Alternatively, the formulations of the present invention and other such agents may be used in combination when used.
When the controlling agent of the present invention is mixed with other animal drugs, the proportion of N- pyridylpiperidine compound and other animal drugs is not
particularly limited, but is generally 100:0 to 1:99 (weight ratio).
Although the dose of the controlling agent of the present invention varies depending on the administration method, the purpose of administration, disease symptoms, etc., the controlling agent of the present invention may generally be administered to a host animal in a dose of 0.01 mg or more and 100 g or less, and preferably 0.1 mg or more and 10 g or less, per kg of body weight of the host animal.
The controlling agent of the present invention is orally or parenterally administered to a host.
When orally administered, for example, the controlling agent of the present invention is mixed with feed of a host animal, and then administered together with the feed; or tablets, solutions, capsules, wafers, biscuits, minced meat, etc., containing the controlling agent of the present invention are administered.
When parenterally administered, for example, the controlling agent of the present invention is formed into suitable formulations, and then incorporated into the body by intravenous infusion administration, intramuscular administration, intracutaneous administration, subcutaneous administration, spot- on treatment, pore-on treatment, or the like; or resin pieces, etc . , containing the controlling agent of the present invention are implanted under the skin of a host animal.
Examples
The present invention is described in more detail below with reference to test examples of the controlling agent of the present invention; however, the present invention is not limited thereto .
Test Example: Mortality of Ixodid Ticks by Filter Paper Clipping Method
( 1 ) Preparation of Drug
Among the compounds disclosed in WO 2008/026658,
Compound Nos. la-16, la-17, la-62, la-75, la-76, la-174, la-201, la-208, la-234, la-251, la-262, la-267, la-268, la-274, la-302. If-38, and If-39 were used as Test Compounds 1 to 17.
Figure imgf000025_0001
(Test Compound 1)
Figure imgf000025_0002
(Test Compound 2)
Figure imgf000026_0001
(Test Compound 3)
Figure imgf000026_0002
(Test Compound 4)
Figure imgf000026_0003
(Test Compound 5)
Figure imgf000026_0004
(Test Compound 6)
Figure imgf000026_0005
(Test Compound 7)
Figure imgf000026_0006
(Test Compound 8)
Figure imgf000027_0001
(Test Compound 9)
Figure imgf000027_0002
(Test Compound 10)
Figure imgf000027_0003
(Test Compound 11)
Figure imgf000027_0004
(Test Compound 12)
Figure imgf000027_0005
(Test Compound 13)
Figure imgf000028_0001
(Test Compound 14)
Figure imgf000028_0002
(Test Compound 15)
Figure imgf000028_0003
(Test Compound 16)
Figure imgf000028_0004
(Test Compound 17)
Acetone was added to each of Test Compounds 1 to 17 so that the concentration was 0.5 mg/ml, thereby preparing solutions. Although Test Compound 15, which was not dissolved in acetone, formed a heterogeneous suspension, the suspension was used as it was .
(2) Filter Paper Clipping Method
Each of the above prepared solutions was added dropwise in an amount of 1 ml to a square filter paper (5 x 10 cm; area: 50 cm2), and dried on aluminum foil at room temperature for 24 hours. Then, each filter paper was folded double on the long side. and both sides were secured with bulldog clips into a bag shape. About 20 ixodid ticks were placed in the bag-like filter paper, and the opening was sealed with a bulldog clip. After 72 hours, the number of dead ticks was calculated. Thereafter, the
surviving ticks were killed in a freezer, and the total number of ticks was calculated.
As a result, a mortality of 70% or more was achieved by all of Test Compounds 1 to 17.

Claims

[Claim 1]
An animal ectoparasite-controlling agent comprising an N-pyridylpiperidine compound, an N-oxide thereof, or salts of these compounds, the N-pyridylpiperidine compound being
represented by Formula ( 1 ) :
Figure imgf000030_0001
wherein R1 is a halogen atom, a Ci_4 haloalkyl group, a cyano group, a nitro group, or a Ci- alkoxycarbonyl group;
R2 , R3 , R4 , R5 , R6 , R7 , R8 , and R9 are each a hydrogen atom or a Ci-4 alkyl group;
each pair of R2 and R8 , and R4 and R6 , may join to form a Ci-4 alkylene group;
R10 is a hydrogen atom; a Ci-2o alkyl group; a C3-8 cycloalkyl group; a C2.6 alkenyl group; a C2.6 alkynyl group; a Ci-6 haloalkyl group; a C2-6 haloalkenyl group; a Ci-6 alkylcarbonyl group; a Ci-6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with one to five halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci-4 alkyl, and Ci_4 haloalkyl; a
heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each independently selected from the group consisting of halogen, Ci_4 alkyl, Ci_4 haloalkyl, and optionally substituted heterocyclic groups; or a Ci-4 alkyl group optionally substituted with one or more substituents each independently selected from the group consisting of optionally halogen-substituted C3-8 cycloalkyl, cyano, nitro, formyl, Ci-6 alkoxy, Ci_4 haloalkoxy, benzyloxy, phenoxy, -CON(R12 ) ( R13 ) , phenyl optionally substituted on the phenyl ring with one or more halogen atoms, and heterocyclic groups optionally substituted on the heterocyclic ring with one or more Ci-4 alkyl groups; wherein R12 and R13 are each a Ci_4 alkyl group, or R12 and R13 may join to form a C2-7 alkylene group;
R11 is a halogen atom; a Ci_6 alkyl group; a Ci.4
haloalkyl group; a Ci_ hydroxyalkyl group; a Ci_4 alkoxycarbonyl group; a Ci_4 alkylcarbonyl group; a mono or di(Ci_4
alkyl)aminocarbonyl group; a nitro group; a cyano group; a formyl group; -C(R14)=NO(R15) ; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci_6 alkyl, Ci-4 haloalkyl, Ci-6 alkoxy, Ci_4 haloalkoxy, Ci_4 alkylthio, cyano, and nitro; or a heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each
independently selected from the group consisting of halogen, Ci_4 alkyl, and Ci_ haloalkyl; wherein R14 is a hydrogen atom or a Ci_4 alkyl group, and R15 is a hydrogen atom, a Ci_4 alkyl group, or a benzyl group;
X is an oxygen atom, a sulfur atom, or -S02-; m is an integer of 1 to 4, and when m is an integer of 2 or more, the R^s, the number of which is represented by m, may be the same or different; and
n is an integer of 1 or 2, and when n is 2, the two R11' s may be the same or different.
[Claim 2]
The animal ectoparasite-controlling agent according to claim 1, wherein the N-pyridylpiperidine compound is represented by Formula (1) in which R1 is a halogen atom, a Ci_4 haloalkyl group, a cyano group, or a nitro group.
[Claim 3]
The animal ectoparasite-controlling agent according to claim 1, wherein the N-pyridylpiperidine compound is represented by Formula (1) in which R10 is a hydrogen atom; a Ci_2o alkyl group; a C2-6 alkenyl group; a Ci_6 haloalkyl group; a Ci-6
alkylcarbonyl group; a Ci_6 alkoxycarbonyl group; a benzoyl group optionally substituted on the phenyl ring with one to five halogen atoms; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, C1-4 alkyl, and Ci- haloalkyl; a heterocyclic group optionally substituted on the heterocyclic ring with one or more substituents each
independently selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 haloalkyl, and optionally substituted heterocyclic groups; or a Ci-4 alkyl group substituted with one or more substituents each independently selected from the group
consisting of formyl, Ci_6 alkoxy, phenyl optionally substituted on the phenyl ring with one or more halogen atoms, and
heterocyclic groups optionally substituted on the heterocyclic ring with one or more Ci_ alkyl groups.
[Claim 4 ]
The animal ectoparasite-controlling agent according to claim 1, wherein the N-pyridylpiperidine compound is represented by Formula (1) in which R11 is a halogen atom; a Ci-6 alkyl group; a Ci-4 haloalkyl group; a Ci_ hydroxyalkyl group; a Ci_4
alkoxycarbonyl group; a formyl group; -C(R14)=NO(R15) wherein R14 is a hydrogen atom, and R15 is a hydrogen atom or a Ci_4 alkyl group; a phenyl group optionally substituted on the phenyl ring with one or more substituents each independently selected from the group consisting of halogen, Ci_6 alkyl, Ci_4 haloalkyl, Ci-6 alkoxy, Ci_ haloalkoxy, Ci-4 alkylthio, cyano, and nitro; or a heterocyclic group optionally substituted on the heterocyclic ring with one or more halogen atoms.
[Claim 5]
The animal ectoparasite-controlling agent according to claim 1, wherein the N-pyridylpiperidine compound is represented by Formula (1) in which X is an oxygen atom. [Claim 6]
A method for preventing or treating infection in an animal caused by parasites, the method comprising administrating the animal ectoparasite-controlling agent according to any one of claims 1 to 5 to the animal.
PCT/JP2012/069263 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent Ceased WO2013015429A1 (en)

Priority Applications (11)

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EP12746402.2A EP2736511A1 (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent
RU2014107002/15A RU2014107002A (en) 2011-07-26 2012-07-19 MEANS FOR COMBATING AN ETHOPARASIS OF ANIMALS AND METHOD FOR PREVENTING OR TREATING INFECTIOUS INFECTION CAUSED BY PARASITIS IN ANIMALS USING THE SPECIFIED MEANS FOR COMBATING INFECTIONS
CA2842644A CA2842644A1 (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent
MX2014000856A MX2014000856A (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent.
PH1/2014/500048A PH12014500048A1 (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent
US14/128,807 US20140148477A1 (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent
BR112014001866A BR112014001866A2 (en) 2011-07-26 2012-07-19 animal ectoparasite control agent and method for preventing or treating parasite infection in animals using the control agent
JP2013544048A JP2014521590A (en) 2011-07-26 2012-07-19 Animal ectoparasite control agent, and method for preventing or treating animal infection caused by parasite using the control agent
CN201280036626.7A CN103732228A (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent
KR1020147004951A KR20140049574A (en) 2011-07-26 2012-07-19 Animal ectoparasite-controlling agent and method for preventing or treating infection in animals caused by parasites by using the controlling agent
ZA2014/00180A ZA201400180B (en) 2011-07-26 2014-01-09 Animal ectoparasite-controlling agent and method for preventing ot treating infection in animals caused by parasites by using the controlling agent

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WO2008034785A2 (en) * 2006-09-18 2008-03-27 Basf Se Pesticidal mixtures comprising an anthranilamide insecticide and a fungicide
JP2010138082A (en) * 2008-12-09 2010-06-24 Nippon Soda Co Ltd Cyclic amine compound or salt thereof, and noxious organism-controlling agent

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WO2008026658A1 (en) 2006-09-01 2008-03-06 Otsuka Chemical Co., Ltd. N-pyridylpiperidine compound, method for producing the same, and pest control agent
EP2050745A1 (en) * 2006-09-01 2009-04-22 Otsuka Chemical Co., Ltd. N-pyridylpiperidine compound, method for producing the same, and pest control agent
WO2008034785A2 (en) * 2006-09-18 2008-03-27 Basf Se Pesticidal mixtures comprising an anthranilamide insecticide and a fungicide
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US20140148477A1 (en) 2014-05-29
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BR112014001866A2 (en) 2017-02-21
ZA201400180B (en) 2015-06-24
MX2014000856A (en) 2014-04-30
CN103732228A (en) 2014-04-16
CA2842644A1 (en) 2013-01-31
JP2014521590A (en) 2014-08-28
RU2014107002A (en) 2015-09-10
AR087300A1 (en) 2014-03-12

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