NZ614662B2 - Isoxazole derivatives - Google Patents

Abstract

The disclosure relates to isoxazoline compounds of formula (I) wherein the variables are defined within the specification and optionally the enantiomers and geometrical isomers thereof. The disclosure also relates to their use in the control of parasites, in particular ectoparasites, in and on vertebrates. Example compounds include: N-{5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylthiophen-3-ylmethyl}-propionamide; cyclopropanecarboxylic acid {2-methyl-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thiophen-3-ylmethyl}-amide; cyclopropanecarboxylic acid {2-methyl-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide; cyclopropanecarboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yf]-furan-3-ylmethyl}-amide. brates. Example compounds include: N-{5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methylthiophen-3-ylmethyl}-propionamide; cyclopropanecarboxylic acid {2-methyl-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thiophen-3-ylmethyl}-amide; cyclopropanecarboxylic acid {2-methyl-5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-furan-3-ylmethyl}-amide; cyclopropanecarboxylic acid {2-methyl-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yf]-furan-3-ylmethyl}-amide.

Description

ISQXAZQLEDLBNAIMES FIELD OF THE lON This invention relates to novel isoxazoiines, their N—oxides, es and salts, processes for their manufacture, their use in the control of ectoparasites, especially insects and acari, on non—human animals, especially productive livestock and domestic animals, and furthermore pesticidai compositions which contain one or more of these compounds.

BACKGROUND OF THE INVENTION PCT Patent Publication W0 200?1075459 discloses oline derivatives of Formula (A) as plant insecticides (R2)n wherein, inter alia, each of A1, A: and 31-83 are C(Ra), A3 is N, R1 is haloalkyi and Q is a heterocyciic l.

The nds are mainly used in the control of invertebrate pests in agronomic environments. Many products are commercially avaiiabie for these purposes, but the need continues for new compounds that are more effective, less costiy, less toxic, environmentally safer or have different modes of action. it now has been surprisingly found that novei derivatives with a ed heterocyclic side chain have superior properties in the control of pests.

SUMMARY OF THE lNVENTiON This t invention is directed to a compound of formuia including all geometric and isomers, N-oxides, S-oxides and salts thereof, and compositions containing them and their use for lling parasites, wherein X is S(O)m, O or NR; and X1 and X; are each ndently of the other CR3 or N. m is an integer from 0 to 2; R5‘ is H, C1—C5—alkyl, C1-Ce-h'aloalkyl, Cvaalkylcarbonyl or C1wCS-alkoxycarbonyl; each R3 is independently H, halogen, Cl-Cs-aikyi, C1-Ce-haloalkyl, C3-Ce-oycloalkyl, Cg-Ce- halocycioalkyl, C1-Ce-alkoxy, C1~CB-haloalkoxy, Ci-Cyalkylthio, C1—Ce-haloalkylthio, 01 alkyl—sulfinyl, C1-Ce—haloalkylsulfinyl, C1-Ca-alkylsulfo-nyl, C1-Cs-haloalkylsulfonyl, amino, N—mono— or N,N~diaC1-Ca—alkylamino, C1-Ce—alkoxycarbonyl, cyano, nitro or unsubstituted or halogen—, a|kyl~, C1-Cs—haloalkyl~, alkoxy—, Ci—Ce-haloalkoxya amino~, cyano- or substituted phenyl, l or pyrimidyt; B and B’ are each independently a group CR5; Bi, 82 and E33 are each independently selected from the group consisting of CR; and N; each R2‘ is independently of the other H or R2; each R2 is independently halogen, Ci-Ce-alkyl, Ci-Cs-haloalkyl, C1-C5-alkoxy, (31 haloalkoxy. C1-Cs-alkylthio, C1-Cs—haloalkylthio, Cq-Cralkylsulfinyl, Ct—Ce-haloalkylsulfinyl, C1-Ce-alkylsulfonyl, C1-Ce-haloalkylsulfonyl, N-mono- or N,N—di-Ct-Cs-alkylamino, C1—C6— alkoxycarbonyl, cyano (-CN) or nitro (-NOZ); R1 is Ci-Ce-alkyl, Cz-Ce-alkenyl, Cz-Ce—aikynyl, Cs-Ca~cycloalkyl, C4-C7—alkylcycloalkyl or C4— Cy—cycioaikylalkyl, each unsubstituted or substituted with one or more substituents independently selected from R4; R4 is halogen, hydroxy, C1-Ca-alkoxy, alkylthio, C1—Cs~alkylsulfinyl, alkylsulfonyl, cyano or nitro; R5 is H. C1~Cs-alkyl, C1~Cs-haloalkyl, halogen or oyano; or R5 and X2 together with the intermediate C-atoms form a 5- or 6~membered carbocyclic ring; or R5 and X1 together with the intermediate C-atoms form a 5- or 6«membered carbocyclic ring; R6 is H; C1-Cs-alkyl. which is unsubstituted or substituted by C1—C4-alkoxy, cyano, phenyl, ethenyl or ethynyi; 02alkylcarbonyl; (lg-Crhaloalkylcarbonyl; or C2-Cralkoxycarbonyk Z is alkyl, a group -—C(O)—Q, a group -C(S)-Q or a group ,—Q; t is 1 or 2; Q is C1-Ce-alkoxy; C1-Cs-haloalkoxy; C1—Ce-alkylthio; C1—Ce-haloalkylthio; NR7R8; C(O)OR7; C(0)R7; C1-Ce—alkyl which is unsubstituted or substituted by Ca-Cs-cycloalkyl, halogen, cyano‘ nitro, hydroxy, C1-C5-aikoxy, C1~Cs~haloali<oxy, Cq~Cs-alkylthio, C1-Ce-haloalkylthio, Ci-Ce-alkylsulfinyl, Ci-Ce-haloalkylsulfinyl, C1-Ce-alkylsulfonyl. haloalkylsulfonyl, NHC(O)R7, C1-Ce—alkoxycarbonyl, sulfonamido, N-mono~ or N,N, di—C1~C4-alkylsulfonamido, C(O)NR7R3, C2-Cs-alkanoyl, unsubstituted or C1'C2'aikyl-, C1—C2-haloalkyl-, C1~Cz~alkoxy—, C1~Cz—haloalkoxy-, halogen-, cyano- or C1-C4-alkoxyoarbonyl-substituted Cs-Cio-aryl, or unsubstituted or C1—Cz-alkyl—, C1—Cg-haioalkyl-, alkoxy-, loalkoxyn n-, cyano- or C1alkoxycarbonyl—substituted 4— to 6-membered heterocyclyl; Cz~C5-alkenyl; Cg—Ce—aikynyl; Cg-Ce-oycloalkyl which is unsubstituted or tuted by n, C1-Cg—alkyl or C1-Cz-haloalkyl; Cs-Cm-aryl unsubstituted or substituted by C1-Cg—alkyl, C1-Cz—haloalkyl, alkoxy, Cq—Cz—haloalkoxy, halogen, cyano or CrCralkoxycarbonyl; or 4— to 6— membered heterocyclyl unsubstituted or substituted by C1~Cg~alkyl, C1-Cz~haloalkyl, Ceca- alkoxy, haloalkoxy, halogen, cyano or Cecil-alkoxycarbonyl; and R7 and R8 are each independently of the other H, Ci-Cs-alkyl, CrCs-haloalkyl, unsubstituted or C1—Ca—alkyl-substituted Cg~Ce—cycloalkyi, Cz~05~alkenyi or Cg-Ca-alkynyl.

This invention also provides a composition sing a compound of a (i), an N-oxide or a salt thereof, and at least one additional component selected from the group consisting of a tant, a solid diluent and a liquid diluent. in one embodiment, this invention also provides a composition for controlling parasites, in particular ectoparasites, comprising a biologically effective amount of a compound of a (I), an N—oxide, S—oxide or a salt thereof, and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid t, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent.

This invention further provides the composition described above in the form of a bait ition n the solid diluent andior the liquid diluent comprises one or more food materials, said composition optionally comprising an attractant andlor a humectant.

This invention further provides a trap device for controlling parasites, in particular ectoparasites, comprising said bait composition and a housing adapted to e said bait composition, wherein the housing has at least one opening sized to permit the parasites to pass through the opening. so the invertebrate pest can gain access to said bait composition from a location outside the housing, and wherein the housing is further adapted to be placed in or near a locus of potential or known activity for the parasites pest.

This invention also provides a method for controlling parasites comprising contacting the tes or their environment with a biologically effective amount of a compound of formula (I), an N-oxide, S—oxide or a salt f, (e.g., as a composition described herein). This invention also relates to such method wherein the tes or their environment are contacted with a composition comprising a biologically effective amount of a compound of formula (I), an e, S—oxlde or a salt thereof. and at least one additional component selected from the group consisting of a surfactant, a solid diluent and a liquid diluent, said composition optionally further comprising a biologically effective amount of at least one additional biologically active compound or agent.

This invention also provides a composition for protecting an animal from an parasitic pest sing a parasiticidally effective amount of a compound of formula (i) an N-oxide or a salt thereof, and at least one carrier. The present invention further provides the composition described above in a form for oral administration. This invention also es a method for protecting an animal from a parasitic pest comprising administering to the animal a parasiticidally effective amount of a compound of formula (i), an N-oxide or a salt thereof.

DETAlLS OF THE lNVENTlON in the above tions, the term ”alkyl", used either alone or in com pound words such "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, , ethyl, n~ propyl, i~propyl, or the different butyl, pentyl or hexyl isomers.

The radical (alk) denotes, for example, straight~chain or ed Ci-Ce—alkyiene, for example methylene, 1.1— or Liz-ethyleneor straight—chain or branched propylene, butylene, pentylene or ne. (alk) is preferably straight—chain or branched C1-C4-alkylene, more preferably alkylene, most preferably ene, or 1,2—ethylene and in particular ene.

"Alkenyl“ includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2- propenyl, and the ent butenyl, pentenyl and hexenyl isomers. "Alkenyl" also includes polyenes such as 1,2—propadienyl and 2,4-hexadienyl.

"Alkynyl" es straight-chain or branched alkynes such as ethynyl. ynyl, 2—propynyl and the different l, pentynyl and hexynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.

"Aikoxy" es, for example, methoxy, ethoxy, n—propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyioxy isomers. "Aikylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.

"Alkylsuifinyl" includes both enantiomers of an alkylsultinyi group. es of "alkylsulfinyl" include )-, CH30H28(O)-, CHSCHZCHZSQ): (CH3)QCHS(O)— and the different butylsulfinyl, pentyisulfinyl and hexylsulfinyl isomers.

Examples ot"‘alkylsulfonyi“ include CH38(0)2-. CH30H28(O)2~. CH30H20H28(O)2-, (CH3)ZCHS(O)2-, and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.

"N—alkylamino", i-alkyamino", and the like, are defined ously to the above examples.

"Cycioalkyl" inciudes, for example, cyciopropyl, cyclobutyl, entyl and cyciohexyl. The term "alkylcycloalkyi" denotes aikyi substitution on a cycloalkyl moiety and es, for example, ethylcyciopropyl, ylcyclobutyl, 3~methyicyclopentyl and emethylcyclohexyl.

The term "cycioalkylalkyl" denotes cycloalkyi substitution on an alkyl moiety. Examples of "cycioalkyialky " include cyciopropyimethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.

The term "halogen", either alone or in compound words such as "haloaikyl", includes fluorine, ne, e or iodine. Further, when used in compound words such as "haloaikyi", said alkyl may be partially or fully substituted with n atoms which may be the same or different. Examples of ”haloaikyi" include F30, ClCH2-, CFchz- and CFacCl2-.

The terms "halocycioalkyl", "haloalkoxy", "haloalkylthio", and the like, are defined analogously to the term "haloalkyl". Examples of "haioalkoxy" include CF30, CCl30H20-, HCFchZCHZO- and CF30H20-. Examples of "haloalkylthio" e CCl38-, CF39», CCl3CH28- and CICHZCHZCHZS: Examples of "haioaikyisulfinyl" include CF38(O)-, CCI38(O)-, CF38H28(O)— and CF;CFZS(O)-. Examples of "haioaikyisuifonyi" e )2-, CCI3$(O)2-, CF30H28(O)2- and CF3CF25(O)2-.

"Aikylcarbonyl" denotes a straight-chain or branched alkyl moieties bonded to a C(=O) moiety. Examples of "alkyicarbonyi" inciude O)—, CH3CHZCH2C(=O)- and (CH3)ZCHC(=O)-. Examples of "alkoxycarbonyi" include CH30C(=O)-, CHsCHZOC(=O), CHacHZCHZOC(=O)-, (CH3)ZCHOC(=O)- and the different butoxy— or pentoxycarbonyl isomers, for example tart-butoxycarbonyi (Boo).

The totai number of carbon atoms in a substituent group is indicated by the " prefix where i andj are integers. For example, 01-04 aikyisuifonyl ates methylsultonyi through butylsulfonyi; Cz—aikoxyalkyl designates CHaocHg; Cg-alkoxyalkyi designates, for example, CH30H(OCH3), CHgoCHQCHg or CchHQOCHz; and C4~aikoxyaikyi designates the various isomers of an alkyl group substituted with an aikoxy group containing a total of four carbon atoms, examples inciuding CH30H20H200H2 and CH3CHQOCH2CHT.

When a compound is substituted with a substituent bearing a subscript that tes the number of said substituents can exceed 1, said tuents (when they exceed 1) are independently selected from the group of defined substituents, e.g_, (Ran, n is 1 or 2- "Aromatic" indicates that each of the ring atoms is essentially in the same plane and has l dicular to the ring plane, and in which (4n + 2) 1r eiectrons, where n is a positive integer, are associated with the ring to comply with Hiickel‘s rule.

The terms "heterocyciic ring", "heterocycie" or “heterocyclyl” denote a ring in which at least one atom forming the ring backbone is not carbon, e.g., nitrogen, oxygen or suifur. Typicaily a heterocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs. Unless ise indicated, a heterocyclic ring can be a saturated, partially unsaturated, or fully unsaturated ring. When a fulty unsaturated heterocyclic ring satisfies Hiickei's rule, then said ring is also netted a "heteroaromatic ring", "aromatic cyclic ring". Unless otherwise indicated. heterocyciic rings and ring systems can be attached through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.

When Q is a 4~ to 6-membered nitrogen-containing heterocyclic ring, it may be attached to the remainder of a (l) though any available carbon or nitrogen ring atom, unless otherwise bed.

Each R2 is independently of the other preferably halogen, C1-Cs-haloalkyl, 01-06 koxy or cyano, more preferably halogen, CF3, OCR», or cyano, especially halogen, for example chlorine or fluorine, and in particular chlorine.

B and B‘ are each independently preferably a radical OH or CR2, wherein R2 is halogen, in particular each a radical CH.

B1, Ba and B3 are each independently of the other preferably a group CR5, wherein R; is H or R2, and for R2 the above—given meanings and preferences apply. One preferred embodiment relates to a nd of formula (l), n one of the radicals B1, [32 and E33 is CH and the two other ones are each independently a radical CR2, n R2 is halogen, for example chlorine or fluorine, and in particular chlorine; within this embodiment it is particularly preferred, that 82 is CH and B1 and Ba are each independently CCl or CF.

Another preferred embodiment relates to a nd of formula (l), wherein all three radicals Br, Bz and B3 are each ndentiy a radical CR2, wherein R2 is halogen, for example chlorine or fluorine, and in particular each chlorine.

R4 is preferably halogen, Cr-Cz—alkoxy, cyano or nitro, more preferably n, cyano or nitro, and in: particular halogen.

R1 is preferably C1~C5-alkyl ally substituted with one or more substituents independently selected from R4, more preferably Ci—Cg-alkyl optionally substituted with halogen, even more preferably halo-CrCa-alkyl, especially preferably C1-C2-alkyl tuted with F, and in particular CF3.

Each R3 is ndently of the other preferably H, halogen,<C1—C4-alkyl, C1-C4-haloalkyl, Cs- Cg-cycloalkyl, C1-Cq—alkoxy, 01—64—haloalkoxy, N—mono~ or N,N—di—C1-C5-alkylamino, cyano or nitro, more preferably H, halogen, C1-Cz-alkyl, C1—Cz—haloalkyl, cyclopropyl, C1-CZ-alkoxy, cyano or nitro, even more preferably H, halogen, Cl-Cz-alkyl, C1-Cg-alkoxy, cyano or nitro, and in particular H or C1-Cg-alkyl.

According to a further preferred embodiment of the invention, R3 is phenyl, pyridyl or pyrimidyl, which is unsubstituted or substituted by halogen, alkyl, C1~Ce—haloalkyl, Cl- Ce-alkoxy, Ci-Cs—haloaikoxy, amino, cyano or nitro; ably phenyl, pyridyl or pyrimidyl which is unsubstituted or tuted by fluorine, chlorine, methyl, trifluoromethyl, methoxy, trifluoromethoxy, amino, cyano or nitro; and in particular phenyl which is unsubstituted or substituted by chlorine, fluorine, methyl or trifluoromethyl.

X1 or X: are each independently preferably a group CR3, n for R3 the above~given meanings and preferences apply. X1 or X2 are each independently most preferabiy a radical CR3, wherein R3 is H or Cl—Cz-alkyl. X1 is particularly preferably CH and X2 is particularly ably C(C1-Cz-alkyi), ally C(CHS).

R5’ is preferably H or Ci-CZ-alkyl. m is, for example 0, 1 or 2, in particular 0.

X is ably 8(0)m or O , wherein for m the above—given meanings and preferences apply, in particular 8 or O, and especially 8. A further particularly preferred meaning of X is 0.

According to one embodiment of the invention X is 8(0)m or O, m is O, 1 or 2, one of X1 and X2 is CR3 and the other one is N or independently another CR3, and R3 is H or C1—Cg-alkyl.

Preferably X is S or O, and X1 and X2 are each independently a radical CR3, wherein for R3 the above given meanings and preferences apply. More preferably, X is -S or 0, X1 is CH, and X2 is CR3 , n for R3 the above given meanings and preferences apply. Most preferably X is 3, X1 is CH and X2 is C(Ci-Cz-alkyl) or in particular C(CHa). Also very ably X is 0, X1 is CH and X2 is g—alkyi) or in particular .

R5 is preferably H or C1~Cz-alkyl or cyano, more preferably H or methyl, and in particular H.

According to a further embodiment of the invention, R5, X1 or X2 and the intermediate 0 atoms form a saturated, partially saturated or unsaturated 5— or 6-membered carbocyclic ring. The compounds of this embodiment are, for example, of the formula (l*) or wherein the les each have the meanings and ences as indicated above and below.

R5 is preferably H, C1-C4~alkyl, cyanomethyi. benzyl, propenyl or propynyl , in particular H.

Z is preferably a group Q or a group «S(O)t—Q, in particular a group -C(O)-Q, wherein t is an integer of O, 1 or 2, in particular 2, and for Q each the above given meanings and the preferences as given below apply.

Q as alkoxy is preferably Cir-Grammy, in particular methoxy, ethoxy or n- or isopropoxy.

Q as haloalkoxy is preferably Cl-Cz-haloalkyl, in particular 2,2,2-trifluoroethoxy or trifluoro- methoxy.

Q as alkylthio is preferably methylthio or hio.

Q as haloaikylthio is preferably trifluoromethylthio. ‘10- Q as radical -NR7R8 is preferably, N-mono- or N,N-di—C1—C4—alkylamino, N-C1—Cg-halo alkylamino, e-cycloalkylamino or N-C1-Cg-alkyl,N-Cg-C5~cycloalkyiamino. in particular N—mono- or N,N~di-C1-Cz-alkyiamino or N-Ca~Cs—cycloalkylamino. if Q is Ci-Cs-alkyl substituted by Ca-Cm-aryl , said aryl is, for e phenyl, naphthyl, tetrahydronaphthyl, indanyi or indenyl, in particular phenyi. The Cs-Cm-aryl is each unsubstituted or substituted by one or more same or different substituents, for example selected from the group consisting of C1-Cg-alkyl, C1-Cz-haloalkyl, alkoxy, C1432- koxy, halogen, cyano and 01alkoxycarbonyl, A preferred aryl substituent of the C1- Cs-alkyl radical Q is phenyl, which is substituted by 1 to 3, in particular 1 or 2, same or different substituentsselected from the group ting of halogen, C1«C2-alkyl, C1‘C2* haloaikyl, C1-Cz-alkoxy, C1—Cg—haloalkoxy, cyano and C1—C4-alkoxycarbonyl. if Q is C1-C5~alkyl substituted by 4~ to 6~membered heterocyclyl, said heterocyclyl is, for example, a heteroaromatic or heteroaliphatic ring radical which is unsubstituted or further substituted.

Preferred substituents of the heterocyclyl are, for example, halogen, C1-Cz—alkyl. 01 haloalkyl, C1—Cg-alkoxy, Ci—Cz—haloalkoxy, cyano and Ci-C4-alkoxycarbonyl.

A le heterocyciic substituent of the C1—Caealkyl radical Q is, for e, a 5— or 6- membered aromatic radical having from 1 to 4, preferably from 1 to 3 same or different heteroatoms selected from the group ting of N, O and S, which is further unsubstituted or substituted by one or more substituents as defined above for heterocyclic rings including the ences given therefore. The heteroaromatic radical is preferably substituted by 0 to 3, in particular 0, “l or 2 substituents from the group as defined above.

Examples of a 5« or 6-membered heteroaromatic substituent of the C1-Ca-alkyl radical Q include a thienyl, furyl, oxazolyl, thiazolyl, pyridyl or pyrimidinyl radical which is unsubstituted or substituted by C1-CZ-alkyl, haloalkyl or CT-C4Talkoxycarbonyl. Especially preferred aromatic substituents of the Ci-Cs—alkyl radical Q are 2-, 3- or 4-pyridyl, 2- or 4— pyrimidinyl. 2-thiazolyl or 2-thienyl. -11..

A further suitable heterocyciic substituent of the C1-Cs-aikyl radical Q is. for example, e 4 to 6~membered heteroaliphatic ring having from 1 to 4, preferably from 1 to 3 same or different atoms selected from the group consisting of N, O and S, which is further tituted or tuted by one or more substituents as defined before for heterocyciic rings including the preferences given ore.

Examples of heteroaiiphatic ring substituents of the Ci-CS-alkyi radicai Q include a thietanyl, for exampie thietan—S—yi, oxo-thietanyi, dioxc~thiethanyl, oxetanyl, for exampie oxetan-3~yl, azetidinyl, pyrroiidinyi, tetrahydrcfuranyi, tetrahydrothiophenyi, piperidinyi, piperazinyl, morphoiinyi, tetrahydropyranyi, thianyi, dioxanyl or dioxolanyi radical which is each unsubstituted or substituted by Ci—Cz-alkyl, C1-Cg~haloalkyl or C1—C4-alkoxycarbonyi.

Preferred aliphatic tuents of the C1—Cssaikyi radical Q include pyrroiidinyl, tetrahydrofuranyl, ydrothiophenyl, piperidinyL piperazinyi, morphoiinyi‘ tetrahydropyranyi or thianyl which are each tituted or substituted by C1—C2—alkyl, C1- 02—haloalkyl or C1-C4—alkoxycarbonyi, as weli as dioxanyl or dioxoianyl and in particular pyrroiidineyi, tetrahydrofuran-Z-yl, tetrahydrofuran—3-yl, dine—‘l-yi, morpholineyl, thianeyl, 1,3-dioxan—2—yi and 1,3—dioxoian—2-yi, in particular tetrahydrofuran—2~yl, tetrahydrofuran-B-yi, lineyi, —4-yl and 1,3-dioxolan-2—yi.

Q as optionally substituted alkyl is preferabiy straight-chain or branched Ct-C4-aikyi, which is each unsubstituted or substituted by Casca-«cycloalkyi, halogen, cyano, C1—Ca—aikoxy, 01—02— haloaikoxy, C1~C4—alkylthic, C1—C2-haioaikylthio, C1-C4—aikylsulfinyi, C1—C4-haioalkyisuifinyl, alkyleulfonyl, C1~C4-haioalkyisuifonyl, 01-Cz-alkylcarbonyiamino, C1-Cz—haloaikyi- carbonylamino or dioxolanyi. Especialiy preferred alkyi radicals Q are straight—chain or branched C1—C4—alkyl or 01—04-alkyi which is substituted by C3—C4—cycloalkyl, halogen, cyano, Ci-Cz-aikoxy, Ci-Cyalkylthio, C1-Czealkylsulfinyi, Ci-Cz—aikyisuifonyi, C1-Cg—haioalkyl~ carbonyiamino or dioxoianyl. Particularly preferred aikyl radicais Q are ht-chain or branched Ci-C4-aikyi. C1-C4-haloalkyi or C1-Cz-aikyi which is substituted by cyano, Cj‘Cz' alkoxy, C1—Cz-aikylthio, C1-C2—alkyisuifonyi C1~Cg-haloaikylcarbonyiamino or oxolan-2yl.

Q as alkyl is especially preferred straight-chain or branched C1-C4-atkyl, C1-Cg-haloalkyl, cyano—C1-Cz-alkyl, Ci-Cz—alkoxy-C1»Cz-aii<yl, Ct-Cg-aikylthio-C1-Cg-alkyl, C1-Cg-alkyisulfinyl- C1~Cz-alkyl, C1—Cz—alkylsulfonyI-C1-Cz~alkyi, Ci—Czshaloalkylcarbonylaminc-C1-C2—alkyl or 2 (1,3—dioxolan-2yi)-propyl.

A preferred alkenyl l Q is Cg-Cg—aikenyl, in particular 2-propenyl. A preferred aikynyl radical Q is CZ-Cg-alkynyi, in particular 2—propynyl.

A red cycloalkyl radicai Q is preferably cyclopropyl, cyclobutyi, cyclopentyl or cyclohexyl, which is in each case unsubstituted or substituted, for example by Ci—Cz—alkyl or halogen, in ular by one or more methyl groups. Q as Cg-Ce~cycloalkyl is preferably cyclopropyl or cyclobutyl. if Q denotes Ce-Cw-aryl, the meanings and preferences as given before for the CG-Cw—aryt substituent of the Ci-Cyalkyl radical Q apply. if Q denotes heterocyclyl, the meanings and ences as given before for the heterocyclic substituent of the CrCs-alkyl radical Q apply. 0 is preferably straightochain or branched alkyl, which is each unsubstituted or substituted by Ca—Cg—cycioalkyl. n, cyano, hydroxy, C1-C4-alkoxy, C1—C4—haioalkoxy, CT- C4-alkylthio, C1~C4—haloalkylthio, Ci~C4—alkylsulfinyl, 01-04—alkylsulfonyl, CrCz-aikW" carbonyiamino, Ci~C2-haloalkylcarbonylamino or dioxolanyl; unsubstituted or methyt- substituted Cg-Ca—cycloalkyl; , which is tituted or substituted by halogen, (31—02- alkyl, C1-C2—haloalkyl, C1-Cz—alkoxy, C1—Cg-haloalkoxy, cyano or 01alkoxycarbonyl; thienyl, furyl, oxazolyl, thiazolyi. pyridyl or pyrimidinyl. which are each unsubstituted or substituted by C1-Cg-aikyl, C1—Cz-haloaikyl or 01alkoxycarbonyl; 1,3-dioxanyl or t ,3~ an~2—yl; or pyrroiidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dinyt, piperazinyl, morpholinyl. tetrahydrcpyranyl or thianyl which are each unsubstituted or substituted by 01— Cz-alkyl, haloaikyl or 01—04-alkoxycarbonyl.

Q is in particular straight—chain or branched C1~C4~aii<yl, cyclopropyl, cyclobutyl, haio-Ci-Ca- alkyi, cyano-C1-Cg—alkyl, C1—Cz-alkoxy-Ci-Cz-alkyl, CinCZ-alkylthio-Ci—Cz-alkyl, C1—Cz- alkylsulfinyl-C1-Cz-alkyl, C1—Cz—alkyisulfonyl—C1—Cg-alkyl, Ci-Cz—haloalkylcarbonylamino— C1— Cg-alkyl, tetrahydrofuran—Z—yl, tetrahydrofuran-3—yl or 2-(1,3—dioxolan-2yl)-n-propyl.

If 2 is a group —S(O)t-Q, t is preferably an integer 2; in addition, all the gs and ences given aboven for 0 apply. According to a preferred embodiment, Z is a group —S(O)t-Q, t is 2 and Q is Ci-Cralkyl, in particular methyl or ethyl.

According to a preferred embodiment of the ion there is provided a compound of formula (Rain F30 0w orig-MHZ (Ia) including all geometric and stereoisomers, N'oxides, S—oxides and saits thereof, wherein for R2, X, X1, X2 and Z each the above-given gs and preferences apply, and n is an integer of from O to 4, preferably of from i to 3, and in particular of 2 or 3. ln particular, n is an integer from i to 3; each R2 is independently selected from the group consisting of halogen, Ci-CB-haloalkyl, C1—Ca-haloalkoxy and cyano; X is S(O)m, O or NRS’; m is an integer from O to 2; R5’ is H or alkyl; one of X1 and X2 is CR5 and the other one is N or independently CR5; R3’ is H or Grog-33KB”; Z is a group —S(O)2-Ci~cz~aikyi or a group —C(O)—Q; and Q is straight-chain or ed CVCi—aikyl, which is each unsubstituted or tuted by Cg—Ce—cycloalkyl, halogen, cyano, Ci-C‘i-alkoxy, C1-C4-haloalkoxy, 01 alkylthio, C1—C4-haloalkylthio, C1-C4aaikylsulfinyl, Ci-Cg-alkylsulfonyl, C1-Cz-alkyl- carbonylamino, C1—Cz-haloaikylcarbonylamino or dioxanyl ; unsubstituted or methyl- substituted Ca-Ce-cycloalkyl; phenyl, which is tituted or substituted by halogen, Ci'Cg" ,aikyl, C1—Cz-haloalkyl, Ci-Cg—aikoxy, C1—Cz—haioalkoxy, cyano or CvCraikoxycarbonyl; furyl, thienyl, oxazolyl, thiazolyl, pyridyl or dinyl, which are each unsubstituted or substituted by C1-Cz-alkyl, Ci-Cg-haloalkyl or 01alkoxycarbonyl; or pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl. piperazinyl, morpholinyl, tetrahydropyranyl or thianyl which is each unsubstituted or substituted by ikyl‘ Ci-Cg—haloalkyl or 01—04-alkoxycarbonyl.

According to a particularly preferred ment of the invention there is provided a compound of formula R; CHg—m~—z including all geometric and etereoisomers, N-oxides, and salts thereof, wherein the ls R; are each independently of the other H, halogen or trifluoromethyl, subject to the proviso that at least 2 radicals R2‘ are not H ; R3 is hydrogen or ; Z is a radical -Q; and Q is straight-chain or branched C1-C4-alkyl, ropyl, cyclobutyl, C1-Ca-haloalkyl, cyano- Ci-Cz—alkyl, alkoxy-Ci-C2~alkyl, C1-Cg-aikylthio—C,«Cg-alkyi, C1-C2~aikylsulfinyl~C1~Cg- alkyl, C1—Cz-alkylsulfonyl—C1-Cz—a!kyl, C1-C2-haloalkylcarbonylaminc—C1-Cz-alkyl, tetrahydrofuranyl or 2-(1,3-dioxolan—Zyl)-n—propyl.

Particularly preferred members of this embodiment are N—{5—{5-(3,5-dichloro—phenyl) trifluoromethyl—4,5-dihydro-isoxazol—3-yl]—2—methyl~thiophen—3-ylmethyl}-propionamide; N-{5— [5-(3,4,5-trichloro~phenyl)trifluoromethyl-4,5-dihydro-isoxazol-S-yl]~2~methyl-thiophen-S— ylmethyl}-propionamide; cyclopropanecarboxylio acid {2-methyl[5-(3,5-dichloro-phenyl)-5— trifluoromethyl—4,5-di—hydro~isoxazoi-3~yl]-thiophen~3-ylmethylHamide; cyclopropane~ carboxylic acid hyl[5u(3,4,5-trichloro~phenyi)—5»trifluoromethyl-4,5-di-hydro~isoxazol— 3-yl]~thiophenyimethyl}—amide; tetrahydro—furan-3—carboxylic acid {2—methyl-5[5-(3.5— dichloro—phenyl)w5—trifluoromeihyl-4,5~dihydro-isoxazolle-thiophenylmethyl}—amide; and tetrahydro—furancarboxylic acid {thethyl—S-[S-(3A,5-trichloro~phenyl)—5-trifluoromethyl— 4,5-dihydro-isoxazol-B—yll-thiophen—3~y|methyl}-amide.

According to a further ularly preferred embodiment of the invention there is provided a compound of formuia R; CH;—N~—z (Io) including all geometric and stereoisomers, N’oxides, and salts thereof, wherein the radicals R2‘ are each independently of the other H, halogen or trifluoromethyl, subject to the proviso that at least 2 radicals R2‘ are not H ; R3 is hydrogen or methyl; Z is a radical «C(O)-Q; and Q is straight-chain or branched 01-04—alkyl, cyclopropyl, utyl, haloalkyi, cyano- C1-C2-alkyl, C1—C2—alkoxy—C1—Cz—alkyi, 01-Cg—alkylthio—01—Cz~alkyl, Ci-Cz-alkylsulfinyl—Ct—Cz- alkyl, C1-C2—alkylsuIfonyl~C1—Cg-alkyl, C1~C2-haloalkylcarbonylamino-Q~Cz-alkyi, tetrahydrofuranyl or dloxolan—2yl)-napropyl.

Particularly preferred members of this ment are N-{5~[5-(3,5—dichloro-phenyl) tritluoromethyl-4,5~dihydro-isoxazol—B—yl]—2-methyl-furan—3—ylmethyl}—propionamide; N-{S-[S-(3,4,5-trichloro—phenyi)~5—tritiuoromethyl~4,5-dihydro—isoxazol-3~yl]—2-methyl—furan—3- ylmethyI}-propionamide; cyclopropanecarboxylic acid {2-methyl[5—(3,5-dichloro-phenyl)—5~ trifluoromethyl—4,5—di—hydro—isoxazol~3-yl}-furan~3~ylmethyl}~amide; cyclopropanecarboxylic acid {2-methyl[5-(3,4,5-trichloro—phenyl)trifluoromethyl—4,5-di—hydro-isoxazol—B—ylj—furan- 3-ylmethyl}-amide; tetrahydro-furan—S-carboxylic acid thyl—5-[5—(3,5-dichioro-phenyl) trifluoromethyl-4,5-dihydro~isoxazol-B—yl]~furan~3vylmethyl}-amide; and tetrahydro-turan~3- carboxylic acid {2-methyl[5—(3,4,5-trichtoro-phenyl)-5~trifluoromethyl-4,S—dihydro-isoxazoi- 3—yli-furanylmethyl}-amide.

Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.

One skilled in the art will iate that one stereoisomer may be more active and/or exhibit beneficial effects when enriched relative to the other isomer(s) or when ted from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, , andlor to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.

One skilled in the art will appreciate that not all nitrogen containing heterocyclic rings form N—oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocyclic rings which form N-oxides. One skilled in the art will also recognize that tertiary amines can form N- oxides. tic methods for the preparation of N-oxides of heterocyclic rings and tertiary amines are very well known by one skilled in the art ing the oxidation of heterocyclic rings and tertiary amines with peroxy acids such as peracetio and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as t-butyl hydroperoxide, sodium perborate, and anes such as dimethyl dioxirane These methods for the preparation of N-oxides have been extensively described and reviewed in the literature. The manufacture of suitable S-oxides may be performed in an ous manner using, for example, the same kind of oxidants as mentioned above for the es.

One skilled in the art recognizes that because of the nment and under physiological conditions salts of al compounds are in equilibrium with their corresponding t forms, saits share the biological utility of the nonsalt forms. Thus a wide variety of salts of the compounds of formula (l) are useful for l of invertebrate pests (is. are veterinarily or agriculturally suitable). The salts of the compounds of formula (1) include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4— toluenesulfonic "or valeric acids. When a compound of formula (I) contains an acidic moiety such as a carboxylic acid or phenol, salts aiso include those formed with organic or inorganic bases such as pyridine, triethylamine or ammonia. or amides, hydrides, hydroxides or carbonates of sodium, potassium, m, m, magnesium or barium. Accordingly, the present invention comprises compounds selected from formula (I), N-oxides and nary acceptable and agriculturally suitable salts thereof.

The compounds of the present ion may be prepared, for example, by reacting a compound of formula with a compound of formula Z — LG (ill), wherein Z is C1—Cs-alkyl or a l C(O)-Q or 8(O)i-Q, LG is a leaving group, for example halogen, hydroxy or C1-C4-alkoxy, and the further les are defined as described above, and, if R6 is hydrogen, optionally further reacting the resulting compound of formula (l’) with a compound of formula R6~LG’ (IV), wherein R6 is as defined above with the exception of H, and LG’ is a leaving group, for example halogen. The reactions of the compounds of formula (ll) and (ill) on the one hand and of a (l’) and (N) on the other hand each may be med by methods known per se, for example, from textbooks of Organic Chemistry.

A r synthetic route for the manufacture of the compounds of formula (I’) wherein Z is a radical C(O)Q comprises subjecting a compound of formula R1 O\N 31/ \ X\ M 2 33” Xi—A (/0 to a triethyisilane-promoted reductive amination with a compound of formula HzN—J‘l—‘Q (Vi) wherein Q is as d above. The on of the compounds of formula (V) and (Vi) takes place, for example, at elevated ature in an inert solvent such as toluene or the like in the presence of a strong acid, for example trifluoroacetic acid. Typical reaction conditions can be found in Tetrahedron Letters 1999, 2295.

The compounds of formula (V) may be prepared from a compound of formula W0 201 2/1 20135 —18~ wherein (alk) is, for example. straight-chain or branched alkyl, by converting said compound to the respective aldehyde of formula (V). it may be advisable to first reduce the compound of formula (VII) to the respective alcohol (~CH2—OH) and then oxidizing said alcohol to the de of a (V), for example, with MHOz.

The compounds of formula (Vll) may be prepared from a compound of formula (VIII) n Y is an halogen, in particular bromine or iodine. The reaction of a compound of formula (VIII) takes place, for e. by lithium halogen exchange or by converting compound (VIII) into a Grignard t and further reaction with alkyicyanoformate or COZ and additional treatment with an alcohol (alk)—OH. r process for the preparation of compounds of the formula (VII) includes the alkoxyoarbonyiation of an aryibromide oder iodide of the above formula (VIII), wherein Y is Br or I, with an alcohol (alk)—OH and carbon monoxide. The reaction is typically d out in the presence of a palladium catalyst under CO atmosphere. Many catalysts are useful for this type of transformation; a typical catalyst is tetrakis(tripheny|phosphine)pailadium(0), Solvents such as 1,2.dimethoxyethane, N,N—dimethylacetamide or toluene are suitable. The method can be ted over a wide range of temperatures, for example from about 25°C to about 150°C, especially from 60 to 110°C.

The compounds of formula (VII) and (VIII) may also be prepared, for example, by cycloaddition of a compound of formula Ft1 H 8/ WP! BL|\B¢B‘ (IX) with a nitriie oxide derived from an oxime of formula O'ialk) (Xe) or Y (Xb) wherein B, B’, 81-83, R, X, X1. X2, Y and (alk) each have the above-given meaning, to yield a compound of formula (Vii) or (Viti), respectivety.

The reaction typically proceeds through the intermediacy of an in situ generated hydroxamyl chioride. in a typical procedure a chlorinattng reagent such as sodium hypochiorite, N- chiorosuccinimidet or chloramine-T is combined with the oxime in the presence of the styrene. Depending on the conditions amine bases such as pyridine or triethyiamine may be necessary. The reaction can be run in a wide variety of solvents inciuding tetrahydrofuran, diethyl ether, methyiene chloride, dioxane, and toluene with m temperatures ranging from room temperature to the reflux ature of the t.

The nds of formula (1X) are known, for example, from or may be prepared in analogy to the methods disclosed therein. Likewise, the compounds of formula (Xa) and (Xb) are known or may be prepared by methods known per se.

The compounds of formula (Vii) and (Vill), respectively, may also be prepared by a process in analogy of W020091025983, wherein a compound of formula (Xla) below is contacted with hydroxylamine and a base to form an oie of formula (Xl) R1 hydroxylamine 0——N x (NHZOH) R1 \ \x x \ _..._.. \ B /e / 2 base 81 \‘ \ X2 81/ \ X1‘< / solvent 8' I X1 \\ f/B' W 2\B? W area (Xla) (XI) wherein 81—83, R, R2 X, X1, X2 and h each have the above—given meaning and W is a l O(alk) or Y. The reaction may be performed as described in W02009l025983 on pages 29-31. In addition, synthetic routes to prepare the intermediate of formula (Xla) are se disclosed inW02009/025983 on pages 31—34. ”20- The compounds of formula (Ii) above may be ed. for example, from a compound of formula (VIII) above, wherein Y is halogen, In particular Br, by suitable conversion of the halogen group Y to a cyano group Y and its subsequent reduction to an amino group —CH2NH2.

Another synthetic route for the ation of the compounds of formulation (ll), wherein R5 and R5 are hydrogen comprises reacting an aldehyde nd of the formula (V) with compound of formula.

HQN OtBu The ing compound is then deprotected by methods known per se in the literature for example with a strong acid like trifluroacetic acid to form an amine of formula (ll) wherein R5 and R6 are hydrogen.

A further tic route for the preparation of the compounds of formula (II) comprises subjecting an aldehyde compound of the formula (V) to a Grignard reaction with a compound R5MgHal, wherein R5 is as defined above and Hal is halogen. in particular e. and converting the OH group in the resulting compound of the formula R1 O\N 31/ \ X\ (Xll) BLI\ 2 /’ Bl 33/ X1 OH to the respective amino compound by methods known per se.

The reaction of an aldehyde compound of formula (V) in a medium of an inorganic cyanide, for example KCN. s ammonia and ammonium chloride yleids a compound of formula (Xi!) above, wherein R5 is cyano, which in turn may be further converted to the corresponding aminomethyl group.

The compounds of the formula (ill) above are known and commercially available in part or may be prepared according to ses well-known in the art.

WO 20135 l The compounds of the formula (l) ing to the invention are notable for their broad activity spectrum and are valuable active ingredients for use in pest control. They are particularly suitable in the control of ectoparasites and to a certain extent also for controlling endoparasites on and in animals and in the e field, whilst being well tolerated by vertebrates such as warm—blooded s and fishes.

Animals in the context of the invention are understood to include vertebrates. The term vertebrate in this context is understood to comprise, for example fishes, amphibians, reptiles, birds, and mammals including humans. One preferred group of vertebrates ing to the invention comprises warm~blooded animals including farm animals, such as cattle, horses, pigs, sheep and goats, y such as chickens, turkeys, guinea fowls and geese, fur— bearing animals such as mink, foxes, chinchillas, rabbits and the like, as well as companion s such as ferrets, guinea pigs, rats, hamster, cats and dogs, and also humans. A further group of preferred vertebrates according to the invention comprises fishes including salmons.

In the context of the present invention, ectoparasites are understood to be in ular s, acari (mites and ticks), and crustaceans (sea lice). These include insects of the following orders: ptera, Coleoptera, Homoptera, Hemiptera, Heteroptera, Diptera, Dictyoptera, Thysanoptera, Orthoptera, Anoplura, Siphonaptera, Mallophaga, Thysanura, lsoptera, Psocoptera and Hymenoptera. However, the ectoparasites which may be mentioned in particular are those which trouble humans or animals and carry pathogens, for example flies such as Musca domestica, Musca vetustissima, Musca autumnalis, Fannie canicularis, Sarcophaga carnaria, Lucilia cuprina, Lucilia sericata. Hypoderma bovis, Hypoderma lineatum, Chrysomyia chloropyga, Dermatobia hominis, Cochliomyia hominivorax, Gasterophilus inalis, Oestrus ovis, biting flies such as Haematobia irritans irritans, Haematobia irritans , Stomoxys calcitrans, flies (Tabanids) with the subfamilies of Tabanidae such as Haematopota spp. (eg. Haematopota pluvialis) and s spp, (e.g.Tabanus nigrovittatus) and Chrysopsinae such as Chrysops spp. (eg.

Chrysops caecutiens); oscids such as Melophagus ovinus (sheep keel); tsetse files, such as Glossinia spp,; other biting insects like midges, such as Ceratopogonidae (biting midges), Simuliidae (Blackflies), Psychodidae ies); but also blood—sucking insects, for example mosquitoes, such as Anopheles spp, Aedes spp and Culex spp, fleas, such as Ctenocephalides felis and Ctenocephaiides canis (cat and dog fleas), Xenopsylla cheopis, WO 20135 Pulex irritans, Ceratophyllus gallinae, Dermatophiius penetrans, blood-sucking lice (Anoplura) such as Linognathus spp, Haematopinus spp, Solenopotes spp, Pediculus humanis; but also chewing lice (Mallophaga) such as Bovicola (Damalinia) ovis, Bovicola (Damalinia) bovis and other Bovicola spp. . Ectcparasites also include s of the order Acarina, such as mites (eg. Chorioptes bouts, Cheyietielia spp., Dermanyssus gallinae, Ortnithonyssus spp., Demodex canis, Sarcoptes scabiei, Pscroptes ovis and Pscrergates app. and ticks. Known representatives of ticks are, for example, lus, Amblyomma, Anocentor, Dermacentor, Haemaphysalis, Hyalomma, , Rhipicentor, Margaropus, Rhipicephalus, Argas, Otobius and Ornithodoros and the like, which preferably infest vertebrates, for example warm—blooded animals including farm s, such as cattle, horses, pigs, sheep and goats, pouitry such as chickens, turkeys, guineatowls and geese, fur—bearing animals such as mink, foxes, chinchillas, s and the like, as well as companion animals such as ferrets, guinea pigs, rats, hamster, cats and dogs, but also humans and fishes.

The compounds of the formula (l) according to the invention are also active against all or individual pment stages of animal pests showing normal sensitivity, as well as those showing resistance to widely used parasiticides. This is especially true for resistant insects and members of the order Acarina. The insecticidal, al and/or acaricidal effect of the active substances of the ion can manifest itself ly, is. killing the pests either immediately or after some time has elapsed, for example when moulting occurs, or by destroying their eggs, or indirectly, eg. reducing the number of eggs laid and/or the hatching rate, good efficacy correSponding to a pesticide! rate (mortaiity) of at least 50 to 60%.

Compounds of the formula (I) can also be used against hygiene pests, especially of the order Diptera of the families ae, Sarcophagidae, Anophilidae and Cuiicidae; the orders Orthoptera, Dictyoptera (e.g. the family dae (cockroaches), such as Blatella germanica, Biatta orientalis, Periptaneta americana) and Hymenoptera (eg. the families Formicidae (ants) and Vespidae (wasps). singly, the compounds of formula (i) are also effective against ectoparasites of fishes, especially the sub—ciass of Copepoda (eg. order of ostomatoida (sea lice), whilst being well tolerated by fish.

The compounds of formula (1) can also be used t hygiene pests, especially of the order a of the families Sarcophagidae, Anophi/idae and Cu/icidae; the orders Orthoptera, Dictyoptera (e.g. the family Blattidae) and Hymenoptera (eg. the family Formicfdae).

Compounds of the formula (I) also have sustainable y on tic mites and insects of plants. l n the case of spider mites of the order Acarina, they are effective against eggs, nymphs and adults of Tetranychidae (Tetranychus spp. and Panonychus app).

They have high activity against sucking s of the order Homoprera, ally against pests of the families Aphididae, Defphacidae, Cicadeflidae, Psyliidae, Loccr'dae, Diaspia’idae and Eriophydidae (eg. rust mite on citrus fruits); the orders Hemiptera, Heteroptera and Thysanoptera, and on the plant-eating s of the orders Lepidoptera, Coleoptera, Diptera and Orthoptera They are similarly suitable as a soil insecticide against pests in the soil.

The compounds of formula (l) are therefore effective against all stages of development of sucking insects and eating insects on crops such as cereals, cotton, rice, maize, soya, potatoes, vegetables, fruit, tobacco, hops, ‘ avocados and other crops.

The compounds of formula l are also effective against plant nematodes of the species Meloidogyne, Heterodera, Pratyl‘enchus, Ditylenchus, Radopholus, Rizoglyphus etc.

Certain compounds of the formula (i) seem to be also effective against n species of helminths. Helminths are commercially important because they cause s diseases in mammals and poultry, egg. in sheep, pigs, goats, cattle, horses, donkeys, camels, dogs, cats, rabbits, —pigs, rs, chicken, turkeys, guinea fowls and other farmed birds, as wet! as exotic birds. Typical nematodes are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostonum, Oesophagostonum, Charbertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capiliaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris, Parascaris and Dirofilaria. The trematodes e, in uiar, the family of Fascioiideae, especially Fasciola ca.

The good pesticidal activity of the compounds of formula (3) according to the invention corresponds to a mortality rate of at least 50—60% of the pests mentioned, more preferably to a mortality rate over 90%, most preferably to 95-100%. The compounds of formula (l) are preferably employed internally and externally in fied form or preferably together with the adjuvants conventionally used in the art of formulation and may therefore be processed in a known manner to give, for example, liquid formulations (e.g. spot-on, pour-on, sprayson, emulsions, suspensions, solutions, emulsifiable concentrates, solution concentrates), semi- solid formulations (eg. creams, ointments, pastes, gels, liposomal ations) and soiid preparations (eg food ves tablets including e. g, es, s including soluble powders, granules, or embeddings of the active ient in polymeric substances, like impiants and microparticles). As with the compositions, the methods of application are selected in accordance with the intended objectives and the prevailing circumstances.

The formulation, Le. preparations containing the active ingredient of formula (I), or combinations of these active ingredients with other active ingredients, and optionally a solid, semi-solid or liquid adiuvant, are produced in a manner known per se, for example by intimately mixing, kneading or dispersing the active ients with compositions of excipients, whereby the physiological compatibility of the formulation excipients must be taken into consideration.

The solvents in question may be: alcohols atic and aromatic), such as benzylalcohol, ethanol, propanol, isopropanol or butanol, fatty alcohols, such as oleyl l and glycols and their ethers and esters, such as glycerin, propylene glycol, dipropylene glycol ether, ethylene glycol, ethylene glycol monomethyl or ethyl ether and butyi dioxytol, carbonates. such as propylene carbonate, ketones, such as cyclohexanone, isophorone or diacetanol alcohol and polyethylene glycols, such as PEG 300. In addition, the compositions comprise strong polar ts, such as N~methyl—2—pyrrolidone, dimethyl sulfoxide or dimethylforrnamide, or water, fatty acid esters, such as ethyl oieate or isopropylpalmitate, vegetable oils, such as rape, caster, coconut, or soybean oil, synthetic mono—, di~, triglycerides like e.g. giyceryl monostearate and medium chain triglycerides and also, if appropriate, silicone oils. The mentioned ingredients may also serve as carrier for particulate application froms.

As ointment base resp. structure ng ingredients the following ents may be used: Petroleum based substances, such as ne or paraffines, bases made from wool fat, like eg. lanolin or lanolin alcohols, polyethylene glycols like eg. macrogols and lipid bases like eg. olipids or triglyceride, such as hydrogenated ble cits.

The use of emulsifiers, wetting agents and spreading agents may also be required, in general, lecithins like soy lecithin, salts of fatty acids with alkaline earth and alkali , alkyl sulfates like sodium cetylstearyl sulphate, choiates, fatty alcohols like cetyl alcohol, stercls like cholestesterol, polyoxyethylene sorbitan fatty acid esters like polysorbate 20, sorbitan fatty acid esters like sorbitan mono laureate, fatty acid esters and fatty l ethers of polyoxyethylene like poloxyl oleyl ether, ypropylene polyoxyethylene block copolymers as eg. PluroniciM , saccharose esters like saccharose distearate, polygiyceryl fatty acid esters like polyglycerol oleate and fatty acid esters like e.g. ethyl oleate or isopropylmyristate, The formulations may also include gelifying and ning agents, like eg. polyacrylic acid derivatives, cellulose , polyvinyl alcohols, polyvinylpyrrolidons and fine disperse silicium dioxide.

As ric agents with controlled release properties, may be applied derivatives made by eg. polylactic acid, polylactic coglycolic acid, poly orthoester, polyethylene carbonate, poly anhydrids and starch and PVC based matrices.

The on of penetration enhancers like ketones, sultoxides, amides, fatty acid esters and fatty alcohols may be necessary.

Also preservatives like sorbic acid, benzyl alcohol and parabenes, and idants as alpha tocopherol may be added.

The active ingredient or combinations of the active ient may also applied in capsules, like hard gelatine capsules or soft capsules.

The binders for tablets and boll may be chemically modified polymeric natural substances that are soluble in water or in alcohol, such as starch, cellulose or protein derivatives (e.g. methyl cellulose, carboxymethyl cellulose, ethylhydroxyethyl cellulose, proteins such as zein, gelatin and the like), as well as synthetic rs, such as polyvinyl alcohol, polyvinyl pyrrolidone etc. The tablets also contain fillers (eg. starch, rystaliine cellulose, sugar, lactose etc). lubricants (eg. magnesium stearate). glidants (eg. colloidal silicon dioxide) and disintegrants (e.g. cellulose derivatives) and acid resistant coatings, like eg. acrylic acid esters.

The compounds of formula (I) according to the invention may be used alone or in combination with other biocides. They may be combined with ides having the same sphere of activity eg. to increase activity, or with nces having another sphere of activity eg. to broaden the range of activity. it can also be sensible to add so-called repellents. For e, in case of a compound of formula (l) having a particular efficacy as adulticide, is. since it is effective in particular against the adult stage of the target parasites, the addition of a pesticide which instead attack the juvenile stages of the tes may be very advantageous, or vice verse. in this way, the st part of those parasites that 2012/054161 produce great economic damage will be covered. Moreover, this action will contribute substantially to avoiding the formation of ance. Many combinations may also lead to synergistic effects, i.e. the total amount of active ingredient can be reduced, which is desirable from an ecological point of view. Preferred groups of combination partners and ally preferred combination partners are named in the following, whereby combinations may contain one or more of these partners in addition to a compound of a (l).

Suitable partners in the mixture may be es, eg. the insecticides and acaricides with a varying mechanism of activity, which are named in the following and have been known to the person skilled in the art for a long time, eg. chitin synthesis tors, growth regulators; active ingredients which act as juvenile hormones; active ingredients which act as adulticides; broad-band insecticides, band acaricides and nematicides; and also the well known anthelminthics and insect- and/or acarid—deterring substances, said repellents detachers. Non-limitative examples of suitable insecticides and acaricides are ned in , compounds Nos, 1-284 on pages 18'21t Non~limitative examples of suitable antheiminthics are mentioned in WC) 20091071500, compounds (A1) -— (A31) on page 21. Non~limitative examples of le repellents and detachers are mentioned in WO 2009/071500, compounds (R1) —(R3) on page 21 and 22. Non-limitative examples of suitable synergists are mentioned in WC 20091’071500, compounds (81) «(83) on page 22.

The said partners in the mixture are best known to specialists in this field. Most are described in various editions of the Pesticide Manual, The British Crop Protection Council.

London, and others in the various editions of The Merck index, Merck 8: Co, inc, Rahway, New Jersey, USA or in patent literature.

As a consequence of the above details, a further aspect of the present invention relates to combination preparation for the control of parasites on vertebrates, in ular on warm— blooded animals or on , characterised in that it contains, in addition to a compound of formula (l), at least one further active ingredient having the same or ent sphere of activity and at least one physiologically acceptable carrier. The present invention is not restricted to two-fold combinations.

As a rule. the insecticidal and acaricidal compositions according to the ion n 0.1 to 99 % by weight, ally 0.1 to 95 % by weight of one or more active ingredients of formula (I), 99.9 to 1 % by weight, especially 99.8 to 5 % by weight of a solid or liquid admixture, including 0 to 25 % by weight, especially 0.1 to 25 % by weight of a surfactant, Application of the compositions according to the ion to the animals to be treated may take place topically, lly, parenterally or subcutaneously, the composition being present, for example, in the form of solutions, emulsions, suspensions, hes), s, tablets, boli, capsules, chewable treats, collars. eartags and pour-on formulations.

Preferred l formulations are understood to refer to a ready-to-use solution in form of a spot-on, pour—on or spray—on formulation often consisting of a dispersion or suspoemulsion or a combination of active ingredient and spreading auxiliaries. The expression spot—on pour-on method is understood to refer to a ready-to—use concentrate intended to be applied topically and locally on the animal. This sort of ation is intended to be applied directly to a relatively small area of the animal, preferably on the animal's back and breech or at one or several points along the line of the back and breech. it is applied as a low volume of about 0.05 to 1 ml per kg, preferably about 0.1 ml per kg. with a total volume from 0.1 to 100 mi per animal, preferably limited to a maximum of about 50 ml. However, it goes without saying that the total volume has to be adapted to the animal that is in need of the treatment and will clearly be different, for example, in young cats and in cattle. These pour-on and spotson ations are designed to spread all around the animal giving protection or ent to almost any part of the animal. Even so the stration is carried out by applying a swab or spray of the pour-on or spot-on formulation to a relatively small area of the coat, one observes that from the active substance is sed almost tically over wide areas of the fur owing to the spreading nature of the components in the formulation and assisted by the animal's movements.

Pour—on or spot—on formulations suitably contain carriers, which promote rapid sement over the skin surface or in the coat of the host animal, and are generally regarded as spreading oils. Suitable carriers are eg. oily solutions; lic and isopropanolic ons such as solutions of 2~octyldodecanol or oleyl alcohol; solutions in esters of monocarboxylic acids, such as isopropyl myristate, lsopropyl palmitate, lauric acid oxalate, oleic acid oleyl ester, oleic acid decyl ester, hexyl laurate, oleyl oleate, decyl oleate, capric acid esters of saturated fat alcohols of chain length (312-618; solutions of esters of dicarboxylic acids, such as dibutyl phthalate, diisopropyl isophthalate, adipic acid diisopropyl ester, di-n-butyl adipate or also solutions of esters of aliphatic acids, eg. glycols. lt may be advantageous for a dispersing agent to be additionally present, such as one known from the pharmaceutical or cosmetic industry. es are 2—pyrrolidone, 2-(Nvalkyl)pyrrolidone, acetone, polyethylene glycol and the ethers and esters thereof, propylene glycol or synthetic triglycerides. ~28- The oily solutions include eg. ble oils such as olive oil, groundnut oil, sesame oil, pine oil, linseed oil or castor oil. The vegetable oils may also be present in epoxidised form.

Paraffins and silicone oils may also be used.

A pour-on or spot-on formulation generally ns 1 to 98.9 % by weight of a compound of formula (l), 0.1 to 80 % by weight of dispersing agent and 1 to 98.9 % by weight of solvent.

The pour—on or spotwon method is ally advantageous for use on herd animals such cattle, horses, sheep or pigs, in which it is difficult or time-consuming to treat all the animals orally or by injection. Because of its simplicity, this method can of course also be used for all other animals, including individual domestic animals or pets, and is greatly favoured by the keepers of the animals, as it can often be carried out without the specialist presence of the veterinarian.

Whereas it is preferred to formulate commercial products as concentrates, the end user will often use dilute formulations. However, this depends on the mode of administration. Orally administered products are most often used in diluted form or as feed ves, whereas commercial pour-on and spot-on formulations are normally ready~to~use concentrates.

Such compositions may also contain further additives, such as stabilisers, oaming agents, viscosity regulators, binding agents or tackifiers, as well as other active ingredients, in order to achieve special effects. insecticidal and acaricidal compositions of this type, which are used by the end user, similarly form a tuent of the t invention. in each of the ses according to the invention for pest control or in each of the pest control compositions ing to the invention, the active ingredients of formula (i) can be used in all of their steric configurations or in mixtures thereof.

The invention also es a method of prophylactically protecting animals, especially productive livestock, domestic animals and pets, against parasitic helminths, which is characterised in that the active ients of formula (I) or the active ient formulations prepared therefrom are administered to the animals as an additive to the feed, or to the drinks or also in solid or liquid form, orally or by injection or erally. The invention also includes the compounds of formula (l) according to the invention for usage in one of the said pnacesses.

The following examples serve merely to illustrate the invention without restricting it, the term active ingredient representing any substance as described in the preparation examples. in particular, preferred formulations are made up as follows: (% = percent by weight) Formulation examples 1. Granulate a) b) (i) active ingredient 5 % 10 % kaolin 94 % ~ highly dispersed silicic acid 1 % - attapulgite — 90 % The active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the t uently trated by evaporation under vacuum. Granulates of this kind can be mixed with the animal feed. (ii) active ient 3 % polyethylene glycol (mw 200) 3 % kaolin 94 % (mw = molecular weight) The finely ground active ient is evenly applied in a mixer to the kaolin which has been moistened with polyethylene glycol. In this way, dust-free coated granules are obtained. 2. Tablets or boli l active ingredient 33.00 % methylcellulose 0.80 % silicic acid, highly dispersed 0.80 % corn starch 8.40 % ll lactose. cryst. 22.50 % corn starch 17.00 % microcryst. cellulose 16.50 % magnesium stearate 1.00 % l Methyl cellulose is stirred into water. After the material has swollen, silicic acid is stirred in and the mixture homogeneously suspended. The active ingredient and the corn starch are mixed. The aqueous suspension is worked into this e and kneaded to a dough. The resulting mass is ated through a 12 M sieve and dried.

II All 4 excipients are mixed thoroughly. lit The preliminary mixes obtained according to l and ll are mixed and pressed into tablets or boli. 3. lnjectables A. Oily vehicle (slow release) (i) active ingredient 0.1-1.0 g nut oil ad 100 ml (ii) active ingredient 0.1-1.0 g sesame oil ad 100 ml Preparation: The active ingredient is dissolved in part of the oil whilst stirring and, if required with gentle heating then after g made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 pm.

B miscible solvent (average rate of release) (i) active ingredient 0.1-1.0 g 4~hydroxymethyl~i ,3~dioxoiane (glycerol formal) 40 g 1,2—propanediol ad 100 ml (ii) active ingredient 0.1—1.0 9 glycerol dimethyl ketal 40 g 1,2-propanedioi ad 100 mi Preparation: The active ient is dissolved in part of the solvent whilst stirring, made up to the desired volume and sterile-filtered through a suitable membrane filter with a pore size of 0.22 pm.

C. Aqueous solubilisate (rapid release) (i) active ingredient Cut—1,0 g polyethoxylated castor oil (40 ethylene oxide units) 10 g opanediol 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml (ii) active ingredient 0.1-1.0 g polyethoxylated sorbitan monooleate (20 ethylene oxide units) 8 g 4—hydroxymethyl—1,B-dioxolane (glycerol formal) 20 g benzyl alcohol 1 g aqua ad inject. ad 100 ml Preparation: The active ingredient is dissolved in the solvents and the tant, and made up with water to the d volume. Sterile filtration through an appropriate membrane filter of 0.22 pm pore size. 4. Pour on (i) active ient 5 g isopropyl myristate 10 g isopropanol ad 100 ml _ 31 - (ii) active ingredient 2 g hexyl iaurate 5 g medium-chained triglyceride 15 9 ethanol ad 100 mi (iii) active ingredient 2 g oleyi oleate 5 g N—methyl—pyrrolidone 40 g isopropanoi ad 100 ml . Spot on (i) active ient 0-15 9 diethyleneglycol monoethylether ad 100 ml (ii) active ingredient 10—1 5 g octyi palmitate 10 g isopropanol ad 100 mi (iii) active ingredient 10-15 g isopropanol 20 g benzyl alcohol ad 100 ml 6‘ Spray on (i) active ient 1 g panol 40 g propylene carbonate ad 100 ml (ii) active ingredient 1 g propylene glycol 10 g isopropanol ad 100 ml The aqueous systems may also preferably be used for oral andlor intraruminal application.

The itions may also n further additives, such as stabilisers, 63.9. where appropriate epoxidised vegetable oils (epoxidised coconut oil, rapeseed oil, or soybean oil); antifoams, ego silicone oil, preservatives, viscosity regulators, s, tackifiers, as welt as fertilisers or other active ingredients to e special effects.

Further biologically active substances or additives, which are neutral towards the compounds of a (I) and do not have a harmful effect on the host animal to be treated, as well as mineral salts or vitamins, may also be added to the described compositions.

The following examples serve to illustrate the invention. The letter ‘h‘ stands for hour. The starting materials are known and partially commercially available or may be produced in analogy to methods known per se.

Analysis of the purified samples is in each case done using a Waters Autopurification (HPLC/MS) system with a reversed phase column using either method A or B described beiow. The samples are characterized by milz and retention time. The above-given retention times relate in each case to the use of a solvent system comprising two different solvents, solvent A: H20 + 001% HCOOH, and solvent B: CHscN + 0.01% .

- Method A: coiumn Daisogel O-ODS-AP 5pm, 150x3mm) from Bischoff, Leonberg, Germany, flow rate of 2.00 mL/min with a time—dependent gradient as given in the Table: - Method B: column Waters XTerra MS (318 5pm, 50X4.6mm (Waters), flow rate of 3.00 lemin with a time-dependent nt as given in the Table: methyl-thioghenylmethylz-Qrogionamide gcomgound 1.6 in Table 1) Steg A: Bromine (9.7 ml) is added to a solution of 2—acetyl~5-methylthiophene (26.8 g) and NaOAc (17.2 g) in water (100 ml) at room temperature. After 12 hours at room temperature the reaction is quenched with a 1M aqueous solution of sodium thiosulfate (100 ml) and extracted three times with ethyl acetate (250 mt). The c phases are combined, washed with a saturated aqueous solution of NaCl, dried over M9804 and concentrated in vacuo to yield 1-(4-bromo—5—methyl-thiophenyi)-ethanone (41.8 g) as a brown oil. The crude product is used without further purification. §t_e_g_B_; LiH (3.2 g) is added to a solution of 1—(3,5-dichloro—phenyl)-2,2,2—tritluoro-ethanone (56 g) and 1-(4—bromomethyl-thiophen-Z-yl)—ethanone (41 g) in dry THF (500 ml). After 5h at 60°C under nitrogen atmosphere, ted-butylmethylether (500 mi) is added to the on mixture. The reaction is slowly quenched with water (500 ml) at 5°C and further extracted twice with tert—butylmethylether (500 ml). The organic phases are combined, washed with saturated aqueous solution of NaCl, dried over M9804 and concentrated in vacuo to yield 1— momethyl-thiophenyl)-3~(3,5-dichloro-phenyl)-4,4,4-trifluoro—3-hydroxy-butan-1 ~ one (110 g, 77% purity) as a brown oil. The crude product is used without further purification. _S_t_eg_£_); Triethylamine (53 ml) and trifluoracetic anhydride (38 ml) are added to a on of - (4-bromomethyl—thiophenyl)-3~(3,5-dichloro-phenyl)-4l4,4-trifiuorohydroxy-butan—i — one (110 g, 77% purity) at 0°C. After 12 hours at room temperature, the on is quenched with water (200 ml) and a saturated aqueous solution of NaHCOa. The aqueous phase is ted and further extracted with two times dichloromethane. The organic phases are combined, washed with water, dried over M9804 and concentrated in vacuo to yield 1 ~(4-bromo—5-methyl—thiophen—Z—yi)—3~(3,5-dichloro-phenyl)-4,4,4—trifluoro—buten-1— one (95 g, 71% purity) as a brown oil. The crude product is used without further purification. _S__t_e_p__l_2_); Hydroxylamine hydrochioride (13 g) and NaOH (18 g) are added to a solution of 1- (4-brcmo~5~methyl~thiophen-Z-yl)(3,5~dichloro-phenyi)~4,4,4~trifluorc~but—2-en—1—one (84 g, 71% purity) in EtOH (1000 ml) at room temperature. After 12 hours at room, the reaction mixture is concentrated in vacuo, diluted with lether and waters The aqueous phase is separated and further extracted two times with diethylether. The organic phases are combined, washed with a saturated aqueous soiution of NaCl, dried over M9804 and concentrated in vacuo. The crude product is purified by chromatography on silica get (1800 g) eluting with a e of heptane and dichloromethane (4:1) to yield 3-(4—bromo methyl-thiophen-2—yl)—5-(3,5-dichloro-phenyl)trifiuoromethyl-4,5-dihydro~isoxazoie (47 g) as a light brown ls.

Siege: isfiriphenylphosphine)palladium(0) (1.2 g) is added to a solution of Zn(CN)2 (1.2 g) and 3—(4~bromomethyl-thiophen—E—-yl)(3,5-dichioro~phenyl)trifluoromethylati,5~ dihydro-isoxazole (4.6 g) in DMF (12 mi). After 11': at 120°C in the ave, the reaction is quenched with water (150 ml) and ethyl acetate (100 ml) and filtered over ceiite. The aqueous phase is separated and further extracted two times with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of NaCi, dried over M9804 and concentrated in vacuo. The crude t is purified on a semi—preparative HPLC to yield 5-[5-(3,5-dichloro-phenyl)—5-trifluoromethyl-4,5—dihydro-isoxazoiyi1-2methyl— thiophene-3—carbonitrile (2.2 g) as a beige crystal.

MBorane dimethyl sulfide complex (0.73 mi) is added to a solution of 3,5~ dichloro-phenyi)—5-trifluoromethyl—4,5—dihydro—isoxazolyl1-2smethyl—thiophene-B—carbonitrile (2.8 g) in THF (21 mi) at . After 30 minutes at reflux, the reaction is cooled down to room temperature. HCl (6.2 ml, 1.25M in MeOH) is added and the reaction mixture is refluxed for 30 minutes. The mixture is then trated in vacuo to yield C—{S-{S-(3,5~ dichloro-phenyl)—5—trifluoromethyl~4,5-dihydro—isoxazol~3~yi]~2~methyI—thiophen-3—yl}* methylamine as a brown foam (2.9 g). The crude product is used without further purification.

Step G: Propionyl chioride (0.17 ml) is added to a solution of C—{5-[5-(3,5—dichloro-phenyl)-5~ trifluoromethyl-4,S—dihydro-isoxazol—3—yl]—2-methyi~thiophen—B-yl}-methylamine (816 mg) and DIPEA (1 mi) in dichloromethane (10 mi) at room temperature. After 3 hours at RT, the reaction is quenched with water. The aqueous phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over M9804 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC and by crystallization in a diethylether/petroleum ether mixture to yield N-{5—[5-(3,5-dichloro—phenyi)— luoromethyl-4,5—dihydro—isoxazol—S'yll—Z—methyl—thiophen-S—ylmethyi}-propionamide (compound 16, 122 mg) as white ls. MS (HPLC/MS): 465 (MW). Retention time: 1.98 min.

Example 2 Pre aration of 3-0 ano—N- 5— 5- ~5-trifiuorometh l-4 5-dih dro-isoxazol—3— 1|i-Z-methyi-thiophen-B-ylmethyli-grogionamide(Comgound 1.39 in Table 1) 3-Cyanopropionic acid (104 mg) and PyBOP (400 mg) are added to a solution of DiF’EA (0.36 ml) and C—{S—{S-(B,5~dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazol-S-yll-Z- methyl-thiophen-S-yl}methyiamine (286 mg, Example 1, step F) in dichloromethane (5 ml).

After 4 hours at RT, the reaction is ed with water, The s phase is separated and further extracted two times with dichloromethane. The organic phases are combined, dried over M9804 and concentrated in vacuo. The crude product is purified on a semi- preparative HPLC to yield 3-cyano-N-{5—[5-(3,5-dichloro-phenyl)tritluoromethyl-4,5- dihydro—isoxazol-3~yi]methyl-thiophenylmethy|}-propionamide (compound 1.39, 67 mg) as a beige resin. MS (HPLC/MS): 491 (MH+). Retention time: 1.90 min.

Example 3 Pre aration of tetrah dro-iuran-S-carbo trifluoromethyl—4,5-dihydro—isoxazol—3~yll-turan-B—ylmethyli—amide (Comgound 2.3 in Table 2) MPhosphorus oxychloride (33 ml) is added dropwise to a solution of 2-methyl—furan—3— carboxylic acid methyl ester (25.0 g) in DMF (75 ml) under nitrogen at 0°C. After 3 h 30 at 40°C, the reaction mixture is slowly poured onto water at 0°C and NaOH 5 N is added carefully. The mixture is extracted three times with diethyl ether. The combined organic phases are washed with a saturated s solution of Mal-1003, dried over NaZSCu and concentrated in vacuo. The crude product is ed by chromatography on silica gel eiuting with a mixture of diethyl ether and ethyl acetate (3:1) to yield 5—formyl-2~methyi—furan-3~ carboxyiic acid methyl ester (22.36 g) as a yellow solid. MS (HPLC/MS): 159 (MH*). gigs; Methylmagnesium bromide (370.5 mi, 1.4M in THF) is added over 30 minutes to a solution of 5-formyl-2—methyl-furan—S-carboxyiic acid methyl ester (87.2 g) in THF (1200 mi) under nitrogen at 0°C. After 1 hour at 0°C, the reaction is quenched with a saturated aqueous on of NH4Cl in water. The mixture is stirred 1 hour at 0°C and then is extracted three times with ethyl acetate. The organic phases are combined, dried over Na2804 and concentrated in vacuo to yield 5-(1-hydroxyethyl)-2—methyl-furan—s-carboxylic acid methyl ester (94.5 g) as a yellow solid. The crude product ed is used without r purification. MS (HPLC/MS): 185 (MW). m9; Manganese dioxide (669 g) is added portionwise to a solution of 5—(1—hydroxy—ethyl} 2-methyl-furan—3—carboxylic acid methyl ester (94.5 g) in dichloromethane (1000 mi). After 72 hours at room temperature, the reaction mixture is filtered through a plug of silica gel and the tion cake is washed several times with ethyl acetate. The filtrate is trated in vacuo to yield ylmethyl—furan—3~carboxylic acid methyl ester (7’8 g) as a yellow solid.

The crude product obtained is used without further purification. MS (HPLC/MS): 183 (MH‘). giggly; n-BuLi (16.5 ml, 2.5M in hexane) is added over 20 minutes to a solution of 5-bromo- 1,2,3-trichloro—benzene (10.2 g) in diethyl ether (150 ml) under nitrogen at -78°C. After 20 minutes at -78°C, a on of ethyl trifluoroacetate (5.15 ml) in diethyi ether (50 ml) is added over 15 minutes to the reaction mixture. After 40 s at -78°C, the on mixture is slowly warmed up to room temperature and then quenched with a saturated aqueous solution of NH4CI. The aqueous phase is extracted three times with diethyl ether.

The combined organic phases are dried over Na2804 and concentrated in vacuo. The crude product is purified by vacuum distillation to yield 2,2,2—trifluoro—1-(3,4,5—trichloro-phenyl)- ethanone (9.20 g) as a yellow solid. gap; LiH (1.76 g) is added to a solution of 2,2,2—trifluoro—1-(3,4,5-trichloro-phenyl)- ethanone (35.33 g) and ylmethyl-furan—3-carboxylic acid methyl ester (20 g) in THF (300 ml). After 1 hour 30 at 60°C MTBE is added (450 ml) and the reaction mixture is poured onto water (750 ml) at 0°C. The organic phase is washed with water and a saturated aqueous solution of NaCl, dried over M9804 and trated in vacuo to yield 62.3 g of 2- methyl-S—[4,4,4-trifluoro-3—hydroxy-3—(SA,5-trich|oro—phenyl)—butyryl]—furan—3—carboxylic acid methyl ester. The crude product is used without further purification. MS (HPLCIMS): 459 (MH"). $2.13.; Trifluoroacetic anhydride (21.5 ml) is added dropwise to a solution of 2—methyl—5- [4,4,4—trifluoro-S-hydroxy—3-(3,4,5-trichioro-phenyl)—butyryli-furan«3-carboxylic acid methyl ester (50.5 g) and triethylamine (30.6 ml) in dichloromethane (700 ml). After 30 minutes at room temperature, the reaction is diluted with water and the aqueous phase is extracted two times with dichloromethane. The combined organic phases are washed once with a saturated solution of NaHCOs, with water and with a saturated aqueous solution of NaCl, dried over Na2804 and concentrated in vacuo. The crude product is ed by chromatography on silica gel eluting with a mixture of heptane and ethyl acetate (95:5) to yield (E/Z)—2-methyl—5—[4,4,4—trifluoro(3,4,5-trichIoro-phenyl)-butenoyl]-furan—3» carboxylic acid methyl ester (29.1 g) as a yellow solid. MS MS): 441 (MH‘).

Step G: Cesium hydroxyde monohydrate (33.2 g) and hydroxylamine hydrochloride (9.16 g) are added to a on of (Em-Z—methyl-S-[A,4,4-trifluoro(3,4,5-trichloro-phenyl)—but—2— enoyli-furan-B-carboxylic acid methyl ester (29.1 g) in romethane (650 ml) at 0°C. The mixture is slowly warmed up to room temperature and stirred during 1 hour 30. The reaction mixture is quenched with water. The organic phase is separated and washed two times with HCI 2M, dried over N32804 and concentrated in vacuo. The crude product is purified by chromatography on silica gel (1400 g) eluting with a mixture of heptane and ethyl acetate (95:5 to 90:10) to yield 2-methyl[5-(3,4,5-trlchloro-phenyl)—5—trifluoromethyl-4,5-dihydro- isoxazol-B-yil-furan-Scarboxylic acid methyl ester (8.69 g) as a white solid. MS (HPLC/MS}: 456 (MH‘). _l_-l_:_ Diisobutylaluminium hydride (DlBAL-H, 21.9 ml, 1M in toluene) is added to a solution of 2—methyl~5-{5-(3,4,5—trlchIoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazoi-S—yli-furan PCT/EP201 2/0541 6] carboxylic acid methyl ester (5.0 g) in diethyl ether (100 ml) under nitrogen at -5°C. After 15 min at ~5°C, the cold bad is removed. After 20 hours at room temperature, the reaction mixture is diluted with ethyl acetate and is quenched with a saturated solution of .

The organic phase is separated and washed with a saturated solution of NaHCOa and with saturated aqueous solution of NaCi, dried over Na2804 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield {2-methyl-5»[5~(3.4,5strichloro- phenyl)—5—trifluoromethyl-4,5-dihydro—isoxazoi~3—yl]-furanyl}-methanoi (3.88 g) as a white foam. MS (HPLC/MS): 428 (Ml-f). giggl; Manganese e (9.64 g) is added portion‘wise to a solution of {2nmethyl—5~[5- (3,4,5~trichloro—phenyl)-5~trifiuoromethylc4,S—dihydro-isoxazol—S—yl]—furan~3—yl}-methanol (3.88 g) in dichloromethane (100 ml). After 18 hours at room temperature, the reaction mixture is filtered through a plug of celite and the filtration cake is washed with dichloromethane. The filtrate is concentrated in vacuo to yield 2—methyl—S-[S—(3,4,5—trich|oro~phenyl)—5~ trifluoromethyl-4,5-dihydro-isoxazol~3-yl]—furan—3—carbaldehyde (3.16 g) as a white foam. The crude product obtained is used without further cation. MS MS): 426 (MH‘). @9941: A mixture of 2-methyl[5-(3A,5-inchloro—phenyl)trifluoromethyl4,5~dihydro- isoxazol—3-yl];furancarbaldehyde (2.15 g), tert-butylcarbamate (1.80 g), trifluoroacetic acid (0.78 ml) and triethylsilane (2.48 ml) in acetonitrile (23 ml) is stirred at room ature for hours. After diluting with ethyl e, the reaction mixture is quenched with a saturated solution of NaHCOa. The organic phase is separated and the aqueous phase is extracted once with ethyl acetate. The combined organic phases are washed with a ted solution of NaHCOa and with a saturated aqueous solution of NaCl, dried over M9304 and concentrated in vacuo. The crude product is purified on a semi'preparative HPLC to yield {2— methyl—S-[S-(B,4,5-trichIoro—phenyl)-5»triftuoromethyl»4,5—dihydro-isoxazola3—yll—furan-3» ylmethyl}-carbamic acid ten-butyl ester (2.10 9, compound 2.4 in Table 2) as a light yeiiow foam. MS MS); 527 (MW). _S_t_gp__lg: oroacetic acid (6.0 ml) is added to a solution of {2—methyl—5~[5—(3,4,5-trichloro~ phenyl)—5-trifluoromethyl-4,5-dihydro-isoxazoi—3~yl]-iuran~3~ylmethyl}-carbamic acid tert—butyl ester (2.05 g) in dichloromethane (20 ml). After 45 min at room ature, an aqueous solution of NaOH (2M) is added untii pH = 12 is reached and the on mixture is extracted three times with dichlorcmethane. The combined organic phases are washed with a saturated solution of NaCl, dried over Na2804 and concentrated in vacuo to yield C—{Z- methyl[5-(3,4,5—trichlcro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyII-furanyl}- methylamine (1.64 9, compound 2.5 in Table 2) as a light yellow foam. The crude product obtained is used without further purification. MS (HPLC/MS): 410 (Ml-F). ion time: 1.27 min. _S_t_ep__L_: Tetrahydro-furan-B-carboxyiic acid (81 mg), PyBOP (268 mg) and DIPEA (0.244 ml) are added to a solution of C—{2—methyl~5—[5»(3,4,5-trichloro-phenyi)trifiuoromethyi-4,5- dihydro-isoxazol-3~yi]-furan—3-yi}-methyiamine (200 mg) in dichloromethane (4 ml). After 24 hours at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are washed with a saturated solution of NaH003 and with a saturated aqueous solution of NaCl, dried over NazSO4 and concentrated in vacuo. The crude t is purified on a semi—preparative HPLC to yield tetrahydro-turan—3-carboxyiic acid {2-methyl{5-(3,4,5-triohloro-phenyi)—5- trifluoromethyi-4,5~dihydro~isoxazo|—3-yl]~furan—3~yimethyl}-amide (189 mg, compound 2.3 in Table 2) as a white foam. MS (HPLC/MS): 525 (MW). ion time: 1.97 min.

Preparation of cyclogroganecarboxylic acid 32-methyl15-(3 4 hloro-Qhenyl)—5- orometh l-4 5-dih dro—isoxazol-3~ l ‘ A mixture of yi[5-(3,4,5-trichloro-phenyi)trifluoromethyl-4,5-dihydro-isoxazoI yl]-furan-3~carbaldehyde (250 mg, Example 3, step i), cyclopropanecarboxylic acid amide (160 mg), oroacetic acid (0.142 ml) and triethylsilane (0.301 mi) in toluene (4 ml) is refluxed overnight. After 23 hours the reaction mixture is concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield cyclopropanecarboxylic acid {2- methyl-5—[5~(3,4,5—triohloro—phenyl)—5-trifiuoromethyl—4,5-dihydro—isoxazol-3—yl1—furan—3- ylmethyl}—amide (251 mg, compound 2.2 in Table 2) as a yellowish foam. MS (HPLC/MS): 495 (Mi-F”). Retention time: 2.02 min.

The substances named in the following Table 'l are prepared analogously to the above- described methods. The compounds are of formula F30 O\N Ci CH(R5)-N(R6)-Z wherein the meaning of the variables is given in Table 1.

The following physical data are obtained according to the above-described HPLC/MS characterization s. The values of the melting point are indicated in °C.

Table 1: WO 20135 WO 20135 WO 20135 The nces named in the following Table 2 are prepared analogously to the above- described methods. The compounds are of formula F30 O\N Cl CH(R5)-N(R6)—Z wherein the meaning of the variables is given in Table 2.

The following al data are obtained according to the above-described HPLC/MS characterization process. The values of the melting point are indicated in °C. 2012/054161 Table 2: Compound No. Analy'ticai EMcalcd Rt *1) 483 2.00 .N —8 524 525 1 ,97 N A.

.N c» N. (D M . £0 493 494 2.00 _..l__ 507 508 1 .98 2.12 498 499 2.03 2.13 536 537 2.13 WO 20135 Biological Examples: 1. Activit in vitro 3 ainst Ctenoce halides felis Cat flea .

A mixed adult population of fleas is placed in a suitably formatted 96-well plate allowing fleas to access and feed on treated blood via an artificial g system. Fleas are fed on treated blood for 24 hours, after which the compound effect is recorded. insecticidal activity is ined on the basis of the number of dead fleas recovered from the feeding system. in this test the following examples showed more than 80% (ECao) cy at 100ppm: Compound 1.1—1.3, 1.5,1.6, 1.8,1.12,1.18,1.20,1.21,1.26, 1.28, 130,1.32, 1.36-1.39, 1.44, 1.51. 1.55-1.58, 21-222 and 2.24-2.28. 2. Activity in who against Rhigiceghaius sanguineus (Dgg tick).

A clean adult tick tion is used to seed a suitably formatted 96-well plate containing the test substances to be evaluated for antiparasitic activity. Each compound is tested by serial dilution in order to determine its minimal effective dose (MED). Ticks are left in contact with the test compound for 10 minutes and are then incubated at 28°C and 80% relative ty for 7 days, during which the test compound effect is monitored. Acaricidal ty is confirmed if adult ticks are dead. in this test the ing examples showed more than 80% (E880) y at 640ppm: 1.1- 1.3, 1.5, 1.6, 1.8, 1.12, 1.28, 1.30, 1.32, 1.36-1.39, 1.44, 1.55-1.58, 2.1-2.4, 2.65-2.22 and 2.24-2.27. 3. Activity in vivo against Rhigiceghalus sanguineus nymphs on Mongolian gerbils (Meriones un uiculatus er orala lication One day before treatment, gerbils are infested with nymphs of Rsanguineus. On day 0, the animals are treated orally by gavage with the test compound formulated at a given dose.

Ticks are left on the animals until full repletion. Seven days after infestation nymphs dropped off fully engorged are collected and d. Efficacy in killing is expressed as a tick number reduction in comparison with a placebo treated group, using the Abbot’s formula. in this test the following examples showed more than 90% (E090) y at 100 mg/kg: 12, 2.1. 4. Activity in viva t Rhipiceghalus neus nymphs on Mongolian gerbils lMeriones unguicuiatus} (spray agpiication) On day 0, gerbils are treated with the test compound at a given dose by spray application.

On day +1 (+2), the animals are infested with nymphs of Rsanguineus. Ticks are left on the s until full repletion. Seven days after infestation nymphs dropped off fully engorged are collected and counted. Efficacy in kiliing is expressed as a tick number reduction in comparison with a o treated group, using the Abbot’s formula. in this test the following examples showed more than 80% (E080) efficacy at 10 mg/kg; 1.8, 1.36, 1.55, 1.56, 2.1, 2.7, 2.8. 2.11, 2.14 and 2.15.

. Activity in viva t Ctenoceghalides falls (cat flea) on Mongolian gerbils (Men‘ones u/atusi (spray application) On day 0, gerbils are treated with the test compound at a given dose by spray or spot-on application. On day +1 , the animals are infested with a mixed adult population of cat fleas.

Evaluation of efficacy is performed 24h and 48h infestation by counting the numbers of live fleas recovered from the gerbils. Efficacy is expressed as ison with a placebo treated group using the Abbot’s formula. in this test the following examples showed more than 80% (E050) efficacy at 100 mg/kg: 1.44, 1.57, 2.1, 2.3, 2.9, 2.12 and 2.14.

Claims (1)

What is claimed

1. A compound of formula R1 O\N e l 3/ \ X\ B” /B' \ /X2 2\Ba/’ xr—_.< R Hl‘:-—~N——-Z including all geometric and isomers, N-oxides, S-oxidee and salts thereof, n X is , 0 or NR5’ and X1 and X2 are each independently of the other CR3 or N, m is an integer from O to 2; R5’ is H, C1—Ce-aikyl, Ceca-haloalkyl, C1-Ce—alkylcarbonyl or C1-Ce~alkoxycarbonyl; each R3 is independently H, halogen, Ci-Cs-alkyl, C1—05-haioalkyi, Cs-Cs~cycloalkyl, 03—06- halocycloalkyl, CrCe—alkoxy, C1—Cs-haloalkoxy, CrCe—aikylthio, C1—Cs»haloalkylthio, 01—05— alkyl-sulfinyl, C1-Ce-haloalkylsulfinyl, Ci-Cs—alkylsulfonyl, C1-Cs-haloalkylsulfonyl, amino, N-mono- or N,N-di—Ci-Cs-alkylamino, Ci-Cs-alkoxycarbonyl, cyano, nitro or unsubstituted er halogen~, Ci-Csvalkqu Ci-Cs-haloalkyl-, alkoxyn haloalkoxy-, amino~, cyano~ or nine-substituted phenyl, l or pyrimidyl; B and B' are each independently a group CR5; B1, 82 and Ba are each independently selected from the group consisting of CR5 and N; each R2’ is independently of the other H or R2; each R2 is independently halogen, (31»06—alkyl, Cece—haloaikyl, C1-Cs—alkoxy, (Si—Cs- haloalkoxy, Ci-Ce-alkylthio, haloalkylthio, C1-Cs~alkylsulfinyl, ClaCS-haloalkylsulfinyl, alkylsulfonyl, C1-CB-haloalkylsulfonyl, N—mono— or N,N-di-C1—Cs-alkylamino, C1~C6—— alkoxycarbonyl, cyano (-CN) or nitro ; R1 is C1—C6~alkyl, CzaCe-alkenyl, C2-C6~alkynyl, C3—Ce~cycloalkyl, C4-C7-alkylcycloalkyl or C4- Cy-cycloalkylalkyl, each unsubstituted or substituted with one or more substituents independently selected from R4; R4 is halogen, hydroxy, Ci—Cs-alkoxy, Ci—Cs—alkylthio, Cq—Cyalkylsulfinyl, C1—Ca—alkylsulfonyl, cyano or nitro; R5 is H, Ci-Ce-alkyl, C1—Ce-haloalkyl, halogen or cyano; or R5 and X2 together with the intermediate C-atoms form a 5- or 6~membered carbocyclic ring; or R5 and X1 together with the ediate C-atoms form a 5- or 6-membered carbocyclic ring; PCT/EP201