Patent Application
20240292840
The invention relates to compounds of formula I
The invention also provides agricultural compositions comprising at least one compound of formula I, a stereoisomer thereof and/or an agriculturally acceptable salt thereof and at least one liquid and/or solid carrier, especially at least one inert liquid and/or solid agriculturally acceptable carrier.
The invention also provides a veterinary composition comprising at least one compound of formula I, a stereoisomer thereof and/or a veterinarily acceptable salt thereof and at least one liquid and/or solid carrier, especially at least one inert veterinarily liquid and/or solid acceptable carrier.
The invention also provides a method for controlling invertebrate pests which method comprises treating the pests, their food supply, their habitat or their breeding ground or a cultivated plant, plant propagation materials (such as seed), soil, area, material or environment in which the pests are growing or may grow, or the materials, cultivated plants, plant propagation materials (such as seed), soils, surfaces or spaces to be protected from pest attack or infestation with a pesticidally effective amount of a compound of formula I or a salt thereof as defined herein.
The invention also relates to plant propagation material, in particular seed, comprising at least one compound of formula I and/or an agriculturally acceptable salt thereof.
The invention further relates to a method for treating or protecting an animal from infestation or infection by parasites which comprises bringing the animal in contact with a parasiticidally effective amount of a compound of formula I or a veterinarily acceptable salt thereof. Bringing the animal in contact with the compound I, its salt or the veterinary composition of the invention means applying or administering it to the animal.
WO 2017/192385, WO 2019/197468, WO 2019/202077, WO 2019/201835, WO 2019/206799, WO 2020/002563, WO 2020/053364, WO 2020/053365, WO 2020/070049, and WO 2020/079198 describe structurally closely related active compounds. These compounds are mentioned to be useful for combating invertebrate pests.
Nevertheless, there remains a need for highly effective and versatile agents for combating invertebrate pests. It is therefore an object of the invention to provide compounds having a good pesticidal activity and showing a broad activity spectrum against a large number of different invertebrate pests, especially against difficult to control pests, such as insects.
It has been found that these objects can be achieved by compounds of formula I as depicted and defined below, and by their stereoisomers, salts, tautomers and N-oxides, in particular their agriculturally acceptable salts.
Compounds I can be obtained by reaction of a compound II with 1 to 1.5 equivalents of a suitable electrophile Ill in the presence of 1 to 2 equivalents of a base, such as Na2CO3, K2CO3, Cs2CO3, NaHCO3, KHCO3, NaH, KH, triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 1,8-diazabicylo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or 1,4-diazabicyclo[2.2.2]octane (DABCO), or a salt, such as CsF, in a solvent such as dimethylformamide (DMF), ethyl acetate (EtOAc), tetrahydrofuran (THF), 1,4-dioxane, methanol, ethanol, 2-propanol, dichloromethane (DCM), dichloroethane (DCE), chloroform, benzene, toluene, xylenes, or mesitylene, at temperatures from 0° C. to 200° C., preferably from 25° C. to the boiling point of the solvent, as known from literature (cf. Chernikova et al, Russian Journal of Organic Chemistry 2019, 55, 325-329; Wang et al, Journal of Medicinal Chemistry 2011, 54, 8541-8554; Plenkiewicz et al, Bulletin des Societes Chimiques Belges 1987, 96, 675-709; Korff et al, Journal of Medicinal Chemistry 2020, 63, 13159-13186; J. R. Shroff et al, Journal of Medicinal Chemistry 1981, 24, 1521-1525).
Further, compounds I, in which X is NOR15, can be obtained by alkylation of the corresponding compounds I, in which X is NOH, with alkylating reagents such as alkyl halides, alkyl tosylates, or alkyl mesylates, following procedures known from literature (cf. Kurbanli et al, Synthetic Communications 2004, 34, 1663-1675; Khomutov et al, Amino Acids 2010, 38, 509-517; Abele et al, Synthetic Communications 1998, 28, 2621-2633; Kocak et al, Synthetic Communications 2007, 37, 1155-1165; Faisal et al, Synthetic Communications 2010, 40, 3101-3108).
Compounds Ill with X being NOH or NOR15 can be obtained by reaction of the corresponding aldoxime(ether)s with 1 to 1.5 equivalents of a chlorinating agent such as N-chlorosuccinimide, optionally in the presence of 0.01 to 0.2 equivalents of a base such as pyridine, 2,6-lutidine, triethylamine, or diisopropylethylamine, or a chlorinating agent such as chlorine, optionally in the presence of 0.5 to 5 equivalents of hydrochloric acid, in a solvent such as DMF, ethyl acetate, chloroform, DCM, DCE, methanol, ethanol, ethylene glycol, 2-propanol, or water, at temperatures from −20° C. to 100° C., preferably from 0° C. to 60° C., as described in Jiang et al, Tetrahedron Letters 2016, 57, 712-714; Martsynkevich et al, Russian Chemical Bulletin, International Edition 2011, 60, 521-525, or G. Zinner, Chemische Berichte 1965, 98, 1353-1354.
Other compounds Ill can be obtained from the corresponding carboxylic acid (X═O) or secondary amide (X is NR5 with R5 other than O) following established literature procedures, e.g. Schaefer et al, Organic Syntheses 1929, 9, 32 and Detty et al, Journal of Organic Chemistry 1980, 45, 80-89, resp.
Alternatively, compounds II can be obtained from compounds IV by reaction with 1 to 1.5 equivalents of hydrazine hydrate in acetic acid (AcOH) as solvent, optionally using an alcohol as cosolvent such as methanol, ethanol, or 2-propanol, at temperatures from 25° C. to 110° C. as known from literature (cf. Lin et al, Journal of Organic Chemistry 1979, 44, 4160-4164; Wrobleski et al, Journal of Medicinal Chemistry 2019, 62, 8973-8995).
Compounds IV are known from WO 2020/094363 and can be obtained according to WO 2020/094363 from commercially available starting materials.
The reaction mixtures are worked up in a customary manner, for example by mixing with water, extracting with an appropriate organic solvent, separating the phases and, if appropriate, chromatographic purification of the crude products. Some of the intermediates and end products are obtained in the form of colourless or slightly brownish viscous oils which are purified or freed from volatile components under reduced pressure and at moderately elevated temperature. If the intermediates and end products are obtained as solids, purification can also be carried out by recrystallization or digestion.
If individual compounds I cannot be obtained by the routes described above, they can be prepared by derivatization of other compounds I.
However, if the synthesis yields mixtures of isomers, a separation is generally not necessarily required since in some cases the individual isomers can be interconverted during work-up for use or during application (for example under the action of light, acids or bases). Such conversions may also take place after use, for example in the treatment of plants in the treated plant, or in the pest to be controlled.
The organic moieties groups mentioned in the above definitions of the variables are—like the term halogen—collective terms for individual listings of the individual group members. The prefix Cn-Cm indicates in each case the possible number of carbon atoms in the group.
The term “partially or fully substituted” by a radical means that in general the group is substituted with same or different radicals.
The term “halogen” denotes in each case fluorine, bromine, chlorine, or iodine, in particular fluorine, chlorine, or bromine.
The term “alkyl” as used herein and in the alkyl moieties of alkylamino, alkylcarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl and alkoxyalkyl denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, more preferably from 1 to 3 carbon atoms. Examples of an alkyl group are methyl (Me), ethyl (Et), n-propyl (n-Pr), iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl.
The term “haloalkyl” as used herein and in the haloalkyl moieties of haloalkylcarbonyl, haloalkoxycarbonyl, haloalkylthio, haloalkylsulfonyl, haloalkylsulfinyl, haloalkoxy and haloalkoxyalkyl, denotes in each case a straight-chain or branched alkyl group having usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from C1-C4-haloalkyl, more preferably from C1-C3-haloalkyl or C1-C2-haloalkyl, in particular from C1-C2-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, and the like.
The term “alkoxy” as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like.
The term “alkoxyalkyl” as used herein refers to alkyl usually comprising 1 to 10, frequently 1 to 4, preferably 1 to 2 carbon atoms, wherein 1 carbon atom carries an alkoxy radical usually comprising 1 to 4, preferably 1 or 2 carbon atoms as defined above. Examples are CH2OCH3, CH2—OC2H5, 2-(methoxy)ethyl, and 2-(ethoxy)ethyl.
The term “haloalkoxy” as used herein denotes in each case a straight-chain or branched alkoxy group having from 1 to 10 carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms, in particular fluorine atoms. Preferred haloalkoxy moieties include C1-C4-haloalkoxy, in particular C1-C2-fluoroalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoro-ethoxy, 2,2dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy and the like.
The term “alkylthio “(alkylsulfanyl: alkyl-S—)” as used herein refers to a straight-chain or 30 branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (═C1-C4-alkylthio), more preferably 1 to 3 carbon atoms, which is attached via a sulfur atom.
The term “haloalkylthio” as used herein refers to an alkylthio group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
The term “alkylsulfinyl” (alkylsulfoxyl: C1-C6-alkyl-S(═O)—), as used herein refers to a straight-chain or branched saturated alkyl group (as mentioned above) having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (═C1-C4-alkylsulfinyl), more preferably 1 to 3 carbon atoms bonded through the sulfur atom of the sulfinyl group at any position in the alkyl group.
The term “haloalkylsulfinyl” as used herein refers to an alkylsulfinyl group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
The term “alkylsulfonyl” (alkyl-S(═O)2—) as used herein refers to a straight-chain or branched saturated alkyl group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms (═C1-C4-alkylsulfonyl), preferably 1 to 3 carbon atoms, which is bonded via the sulfur atom of the sulfonyl group at any position in the alkyl group.
The term “haloalkylsulfonyl” as used herein refers to an alkylsulfonyl group as mentioned above wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
The term “alkylcarbonyl” refers to an alkyl group as defined above, which is bonded via the carbon atom of a carbonyl group (C═O) to the remainder of the molecule.
The term “haloalkylcarbonyl” refers to an alkylcarbonyl group as mentioned above, wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
The term “alkoxycarbonyl” refers to an alkylcarbonyl group as defined above, which is bonded via an oxygen atom to the remainder of the molecule.
The term “haloalkoxycarbonyl” refers to an alkoxycarbonyl group as mentioned above, wherein the hydrogen atoms are partially or fully substituted by fluorine, chlorine, bromine and/or iodine.
The term “alkenyl” as used herein denotes in each case a singly unsaturated hydrocarbon radical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. vinyl, allyl (2-propen-1-yl), 1-propen-1-yl, 2-propen-2-yl, methallyl (2-methylprop-2-en-1-yl), 2-buten-1-yl, 3-buten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 4-penten-1-yl, 1-methylbut-2-en-1-yl, 2-ethylprop-2-en-1-yl and the like.
The term “haloalkenyl” as used herein refers to an alkenyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
The term “alkynyl” as used herein denotes in each case a singly unsaturated hydrocarbon radical having usually 2 to 10, frequently 2 to 6, preferably 2 to 4 carbon atoms, e.g. ethynyl, propargyl (2-propyn-1-yl), 1-propyn-1-yl, 1-methylprop-2-yn-1-yl), 2-butyn-1-yl, 3-butyn-1-yl, 1-pentyn-1-yl, 3-pentyn-1-yl, 4-pentyn-1-yl, 1-methylbut-2-yn-1-yl, 1-ethylprop-2-yn-1-yl and the like.
The term “haloalkynyl” as used herein refers to an alkynyl group as defined above, wherein the hydrogen atoms are partially or totally replaced with halogen atoms.
The term “cycloalkyl” as used herein and in the cycloalkyl moieties of cycloalkoxy and cycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl (cC3H5 or cC3H5), cyclobutyl (c-C4H7 or cC4H7), cyclopentyl (c-C5He or cC5He), cyclohexyl (c-C6H11 or cC6H11), cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term “halocycloalkyl” as used herein and in the halocycloalkyl moieties of halocycloalkoxy and halocycloalkylthio denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 C atoms or 3 to 6 C atoms, wherein at least one, e.g. 1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are 1- and 2-fluorocyclopropyl, 1,2-, 2,2- and 2,3-difluorocyclopropyl, 1,2,2-trifluorocyclopropyl, 2,2,3,3-tetrafluorocyclpropyl, 1- and 2-chlorocyclopropyl, 1,2-, 2,2- and 2,3-dichlorocyclopropyl, 1,2,2-trichlorocyclopropyl, 2,2,3,3-tetrachlorocyclpropyl, 1-,2- and 3-fluorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-difluorocyclopentyl, 1-,2- and 3-chlorocyclopentyl, 1,2-, 2,2-, 2,3-, 3,3-, 3,4-, 2,5-dichlorocyclopentyl and the like.
The term “halocycloalkenyl” as used herein and in the halocycloalkenyl moieties of halocycloalkenyloxy and halocycloalkenylthio denotes in each case a monocyclic singly unsaturated nonaromatic radical having usually from 3 to 10, e.g. 3 or 4 or from 5 to 10 carbon atoms, preferably from 3- to 8 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 or 5 of the hydrogen atoms, are replaced by halogen, in particular by fluorine or chlorine. Examples are 3,3-difluorocyclopropen-1-yl and 3,3-dichlorocyclopropen-1-yl.
The term “cycloalkenylalkyl” refers to a cycloalkenyl group as defined above which is bonded via an alkyl group, such as a C1-C6-alkyl group or a C1-C4-alkyl group, in particular a methyl group (=cycloalkenylmethyl), to the remainder of the molecule.
The term “carbocycle” or “carbocyclyl” includes in general a 3- to 12-membered, preferably a 3- to 8-membered or a 5- to 8-membered, more preferably a 5- or 6-membered mono-cyclic, non-aromatic ring comprising 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above.
The term “heterocycle” or “heterocyclyl” includes in general 3- to 12-membered, preferably 3- to 6-membered, in particular 6-membered monocyclic heterocyclic non-aromatic radicals. The heterocyclic non-aromatic radicals usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O, and S as ring members, wherein S-atoms as ring members may be present as S, SO, or SO2. Examples of 5- or 6-membered heterocyclic radicals comprise saturated or unsaturated, non-aromatic heterocyclic rings, such as oxiranyl, oxetanyl, thietanyl, thietanyl-S-oxide (S-oxothietanyl), thietanyl-S-dioxide (S-dioxothiethanyl), pyrrolidinyl, pyrrolinyl, pyrazolinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxolanyl, thiolanyl, S-oxothiolanyl, S-dioxothiolanyl, dihydrothienyl, S-oxodihydrothienyl, S-dioxodihydrothienyl, oxazolidinyl, oxazolinyl, thiazolinyl, oxathiolanyl, piperidinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 1,3- and 1,4-dioxanyl, thiopyranyl, S-oxothiopyranyl, S-dioxothiopyranyl, dihydrothiopyranyl, S-oxodihydrothiopyranyl, S-dioxodihydrothiopyranyl, tetrahydrothiopyranyl, S-oxotetrahydrothiopyranyl, S-dioxotetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S-dioxothiomorpholinyl, thiazinyl and the like. Examples for heterocyclic rings that contain 1 or 2 carbonyl groups as ring members comprise pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, imidazolidin-2-onyl, oxazolidin-2-onyl, thiazolidin-2-only, and the like.
The term “hetaryl” includes monocyclic 5- or 6-membered heteroaromatic radicals comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O, and S. Examples of 5- or 6-membered heteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl, pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e. 3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2- or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or 5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3,4-thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g. 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl. The term “hetaryl” also includes bicyclic 8 to 10-membered heteroaromatic radicals comprising as ring members 1, 2 or 3 heteroatoms selected from N, O, and S, wherein a 5- or 6-membered heteroaromatic ring is fused to a phenyl ring or to a 5- or 6-membered heteroaromatic radical. Examples of a 5- or 6-membered heteroaromatic ring fused to a phenyl ring or to a 5- or 6-membered heteroaromatic radical include benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxathiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzoxazinyl, chinolinyl, isochinolinyl, purinyl, 1,8-naphthyridyl, pteridyl, pyrido[3,2-d]pyrimidyl or pyridoimidazolyl and the like. These fused hetaryl radicals may be bonded to the remainder of the molecule via any ring atom of 5- or 6-membered heteroaromatic ring or via a carbon atom of the fused phenyl moiety.
The terms “heterocyclylalkyl” and “hetarylalkyl” refer to heterocyclyl or hetaryl, respectively, as defined above which are bonded via a C1-C6-alkyl group or a C1-C4-alkyl group, in particular a methyl group (=heterocyclylmethyl or hetarylmethyl, respectively), to the remainder of the molecule.
The term “arylalkyl” and “phenylalkyl” refer to aryl as defined above and phenyl, respectively, which are bonded via C1-C6-alkyl group or a C1-C4-alkyl group, in particular a methyl group (=arylmethyl or phenylmethyl), to the remainder of the molecule, examples including benzyl, 1-phenylethyl, 2-phenylethyl, 2-phenoxyethyl etc.
The terms “alkylene”, “cycloalkylene”, “heterocycloalkylene”, “alkenylene”, “cycloalkenylene”, “heterocycloalkenylene” and “alkynylene” refer to alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl and alkynyl as defined above, respectively, which are bonded to the remainder of the molecule, via two atoms, preferably via two carbon atoms, of the respective group, so that they represent a linker between two moieties of the molecule.
In a particular embodiment, the variables of the compounds of the formula I have the following meanings, these meanings, both on their own and in combination with one another, being particular embodiments of the compounds of the formula I.
Embodiments and preferred compounds of the invention for use in pesticidal methods and for insecticidal application purposes are outlined in the following paragraphs.
With respect to the variables, the particularly preferred embodiments of the intermediates correspond to those of the compounds of the formula I.
In a preferred embodiment, the compounds I are present in form of a mixture of compounds I.A and I.B, wherein compound I.A with S-configuration of the carbon atom neighboring the nitrogen is present in an amount of more than 50% by weight, in particular of at least 70% by weight, more particularly of at least 85% by weight, specifically of at least 90% by weight, based on the total weight of compounds I.A and I.B.
In one particularly preferred embodiment of the invention, the method comprises the step of contacting the plant, parts of it, its propagation material, the pests, their food supply, habitat or breeding grounds with a pesticidally effective amount of a compound of formula I.A.
Preferably R1 is H, C1-C6-alkyl, C3-C6-cycloalkyl, or C1-C4-alkyl-C3-C6-cycloalkyl.
Preferably R2 is CH3.
R3 is preferably halogen, CN, C1-C4-haloalkyl, C1-C4-haloalkoxy, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, S(O)m—C1-C4-alkyl, S(O)m—C1-C4-haloalkyl, S(O)m—C3-C4-cyclo¬alkyl, S(O)m—C3-C4-halocyclo¬alkyl. Index m in R3 is preferably 2. Index n is preferably 2.
R3 groups stand preferably in positions 3 and 5. R3 groups stand preferably in meta positions.
In another embodiment R3 is preferably halogen, CN, C1-C4-haloalkyl, C1-C4-haloalkoxy, C3-C4-cycloalkyl, C3-C4-halocycloalkyl, S(O)m—C1-C4-alkyl, S(O)m—C1-C4-haloalkyl, S(O)m—C3-C4-cycloalkyl, S(O)m—C3-C4-halocycloalkyl, or
S(O)—R14, wherein R14 is phenyl, which is partially substituted with R3a.
In another embodiment R3 is S(O)m—R14, wherein R14 is phenyl or hetaryl, such as pyridine, which rings are partially substituted with R3a.
In another embodiment of formula I compounds R3 is halogen, CN, NO2, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C6-haloalkyl, C1-C6-halocycloalkyl, OR14, S(O)m—R14; wherein rings are unsubstituted or substituted with R11.
R4 is preferably H, C1-C3-alkyl, or C1-C3-haloalkyl.
In another embodiment R4 is preferably H, C1-C3-alkyl, or C1-C3-haloalkyl, or NR12R13, wherein R12 and R13 are preferably selected from H and CH3.
X is preferably NR5.
X is preferably NR5, with R5 being OH, C1-C3-alkoxy, or C1-C3-haloalkoxy.
In another embodiment X is O.
In a preferred embodiment, the compounds I.1 wherein X is NR5 are present in form of a mixture of compounds E-I.1 and Z-I.1, wherein compound E-I.1 with E-geometry of the C═N double bond is present in an amount of at least 50% by weight, in particular of at least 70% by weight, more particularly of at least 85% by weight, specifically of at least 90% by weight, based on the total weight of compounds E-I.1 and Z-I.1.
In a preferred embodiment of formula I compounds Q is CH or CR3.
in another embodiment of formula I compounds Q is N.
In preferred embodiment the triazole is a 1,5-disubstituted 1,2,4-triazole. Such compounds correspond to formula I.1.
In another embodiment the triazole is a 1,3-disubstituted 1,2,4-triazole. Such compounds correspond to formula I.2.
In another embodiment the triazole is a 1,2-disubstituted 1,3,4-triazole. Such compounds correspond to formula I.3.
In formulae I.1, I.2, and I.3, resp., the variables are as defined and preferred for formula I.
Compounds of formula I.1 with the preferences above and below are particularly preferred.
In particular with a view to their use, preference is given to the compounds of formula I compiled in the tables below, which compounds correspond to formulae I.1A, I.2A, and I.3A, resp.
Each of the groups mentioned for a substituent in the tables is furthermore per se, independently of the combination in which it is mentioned, a particularly preferred aspect of the substituent in question.
Compounds of formula I.1A* in which R4 is H, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is CN, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is CH2CH2CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is CH(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is c-C3H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)NHCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)NHC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)N(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)N(CH3)C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)OCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is C(═O)OC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1A* in which R4 is 4,5-dihydrooxazol-2-yl, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is H, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is CN, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is CH2CH2CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is CH(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is c-C3H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)NHCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)NHC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)N(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)N(CH3)C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)OCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is C(═O)OC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.2A* in which R4 is 4,5-dihydrooxazol-2-yl, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is H, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is CN, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is CH2CH2CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is CH(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is c-C3H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)NHCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)NHC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)N(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)N(CH3)C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)OCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is C(═O)OC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.3A* in which R4 is 4,5-dihydrooxazol-2-yl, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is H, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is CN, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is CH2CH2CH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is CH(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is c-C3H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)NH2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)NHCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)NHC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)N(CH3)2, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)N(CH3)C2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)OCH3, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is C(═O)OC2H5, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
Compounds of formula I.1nA* in which R4 is 4,5-dihydrooxazol-2-yl, and the combination of X and (R3)n for a compound corresponds in each case to one row of Table A
The term “compound(s) of the invention” refers to compound(s) of formula 1, or “compound(s) I”, and includes their salts, tautomers, stereoisomers, and N-oxides.
The invention also relates to agrochemical compositions comprising an auxiliary and at least one compound I.
An agrochemical composition comprises a pesticidally effective amount of a compound I.
An agrochemical composition comprises a pesticidally effective amount of a compound I.
The compounds I can be converted into customary types of agro-chemical compositions, e.g. solutions, emulsions, suspensions, dusts, powders, pastes, granules, pressings, capsules, and mixtures thereof. Examples for composition types are suspensions (e.g. SO, OD, FS), emulsifiable concentrates (e.g. EC), emulsions (e.g. EW, EO, ES, ME), capsules (e.g. OS, ZC), pastes, pastilles, wettable powders or dusts (e.g. WP, SP, WS, DP, DS), pressings (e.g. BR, TB, DT), granules (e.g. WG, SG, GR, FG, GG, MG), insecticidal articles (e.g. LN), as well as gel formulations for the treatment of plant propagation materials e.g. seeds (e.g. GF). These and further compositions types are defined in the “Catalogue of pesticide formulation types and international coding system”, Technical Monograph No. 2, 6th Ed. May 2008, CropLife International.
Suitable auxiliaries are solvents, liquid carriers, solid carriers or fillers, surfactants, dispersants, emulsifiers, wetters, adjuvants, solubilizers, penetration enhancers, protective colloids, adhesion agents, thickeners, humectants, repellents, attractants, feeding stimulants, compatibilizers, bactericides, anti-freezing agents, anti-foaming agents, colorants, tackifiers and binders.
Suitable solvents and liquid carriers are water and organic solvents. Suitable solid carriers or fillers are mineral earths.
Suitable surfactants are surface-active compounds, e.g. anionic, cationic, nonionic, and amphoteric surfactants, block polymers, polyelectrolytes. Such surfactants can be used as emulsifier, dispersant, solubilizer, wetter, penetration enhancer, protective colloid, or adjuvant. Surfactants are listed in McCutcheon's, Vol. 1: Emulsifiers & Detergents, McCutcheon's Directories, Glen Rock, USA, 2008 (International or North American Ed.). Suitable anionic surfactants are alkali, alkaline earth, or ammonium salts of sulfonates, sulfates, phosphates, carboxylates. Suitable nonionic surfactants are alkoxylates, N-subsituted fatty acid amides, amine oxides, esters, sugar-based surfactants, polymeric surfactants. Suitable cationic surfactants are quaternary surfactants.
The agrochemical compositions generally comprise between 0.01 and 95%, preferably between 0.1 and 90%, and most preferably between 0.5 and 75%, by weight of active substance.
The active substances are employed in a purity of from 90% to 100%, preferably from 95% to 100%.
Various types of oils, wetters, adjuvants, or fertilizer may be added to the active substances or the compositions comprising them as premix or, if appropriate not until immediately prior to use (tank mix). These agents can be admixed with the compositions according to the invention in a weight ratio of 1:100 to 100:1.
The user applies the composition according to the invention usually from a predosage device, a knapsack sprayer, a spray tank, a spray plane, or an irrigation system. Usually, the agrochemical composition is made up with water, buffer, and/or further auxiliaries to the desired application concentration and the ready-to-use spray liquor or the agrochemical composition according to the invention is thus obtained. Usually, 20 to 2000 liters of the ready-to-use spray liquor are applied per hectare of agricultural useful area.
The compounds I are suitable for use in protecting crops, plants, plant propagation materials, e.g. seeds, or soil or water, in which the plants are growing, from attack or infestation by animal pests. Therefore, the invention also relates to a plant protection method, which comprises contacting crops, plants, plant propagation materials, e.g. seeds, or soil or water, in which the plants are growing, to be protected from attack or infestation by animal pests, with a pesticidally effective amount of a compound I.
The compounds I are also suitable for use in combating or controlling animal pests. Therefore, the invention also relates to a method of combating or controlling animal pests, which comprises contacting the animal pests, their habitat, breeding ground, or food supply, or the crops, plants, plant propagation materials, e.g. seeds, or soil, or the area, material or environment in which the animal pests are growing or may grow, with a pesticidally effective amount of a compound I.
The compounds I are effective through both contact and ingestion to any and all developmental stages, such as egg, larva, pupa, and adult.
The compounds I can be applied as such or in form of compositions comprising them.
The application can be carried out both before and after the infestation of the crops, plants, plant propagation materials by the pests.
The term “contacting” includes both direct contact (applying the compounds/compositions directly on the animal pest or plant) and indirect contact (applying the compounds/compositions to the locus).
The term “animal pest” includes arthropods, gastropods, and nematodes. Preferred animal pests according to the invention are arthropods, preferably insects and arachnids, in particular insects.
The term “plant” includes cereals, e.g. durum and other wheat, rye, barley, triticale, oats, rice, or maize (fodder maize and sugar maize/sweet and field corn); beet, e.g. sugar beet, or fodder beet; fruits, e.g. pomes, stone fruits, or soft fruits, e.g. apples, pears, plums, peaches, nectarines, almonds, cherries, papayas, strawberries, raspberries, blackberries or gooseberries; leguminous plants, e.g. beans, lentils, peas, alfalfa, or soybeans; oil plants, e.g. rapeseed (oilseed rape), turnip rape, mustard, olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms, ground nuts, or soybeans; cucurbits, e.g. squashes, pumpkins, cucumber or melons; fiber plants, e.g. cotton, flax, hemp, or jute; citrus fruit, e.g. oranges, lemons, grapefruits or mandarins; vegetables, e.g. eggplant, spinach, lettuce (e.g. iceberg lettuce), chicory, cabbage, asparagus, cabbages, carrots, onions, garlic, leeks, tomatoes, potatoes, cucurbits or sweet peppers; lauraceous plants, e.g. avocados, cinnamon, or camphor; energy and raw material plants, e.g. corn, soybean, rapeseed, sugar cane or oil palm; tobacco; nuts, e.g. walnuts; pistachios; coffee; tea; bananas; vines; hop; sweet leaf (Stevia); natural rubber plants or ornamental and forestry plants, shrubs, broad-leaved trees or evergreens, eucalyptus; turf; lawn; grass. Preferred plants include potatoes, sugar beets, tobacco, wheat, rye, barley, oats, rice, corn, cotton, soybeans, rapeseed, legumes, sunflowers, coffee, or sugar cane; fruits; vines; ornamentals; or vegetables, e.g. cucumbers, tomatoes, beans or squashes.
The term “seed” embraces seeds and plant propagules including true seeds, seed pieces, suckers, corms, bulbs, fruit, tubers, grains, cuttings, cut shoots, and means preferably true seeds.
“Pesticidally effective amount” means the amount of active ingredient needed to achieve an observable effect on growth, including the effects of necrosis, death, retardation, prevention, and removal, destruction, or otherwise diminishing the occurrence and activity of the target organism. The pesticidally effective amount can vary for the various compounds/compositions used in the invention. A pesticidally effective amount of the compositions will also vary according to the prevailing conditions e.g. desired pesticidal effect and duration, weather, target species, locus, mode of application.
For use in treating crop plants, e.g. by foliar application, the rate of application of the active ingredients of this invention may be in the range of 0.0001 g to 4000 g per hectare, e.g. from 1 g to 2 kg per hectare or from 1 g to 750 g per hectare, desirably from 1 g to 100 g per hectare.
The compounds I are also suitable for use against non-crop insect pests. For use against said non-crop pests, compounds I can be used as bait composition, gel, general insect spray, aerosol, as ultra-low volume application and bed net (impregnated or surface applied).
The term “non-crop insect pest” refers to pests, which are particularly relevant for non-crop targets, e.g. ants, termites, wasps, flies, fleas, ticks, mosquitoes, bed bugs, crickets, or cockroaches, such as: Aedes aegypti, Musca domestica, Tribolium spp.; termites such as Reticulitermes flavipes, Coptotermes formosanus; roaches such as Blatella germanica, Periplaneta Americana; ants such as Solenopsis invicta, Linepithema humile, and Camponotus pennsylvanicus; stored product pests such as Tribolium confusum, Plodia interpunctella; turf pests such as Popillia japonica, Blissus leucopterus, Neocapteriscus vicinus.
The bait can be a liquid, a solid or a semisolid preparation (e.g. a gel). For use in bait compositions, the typical content of active ingredient is from 0.001 wt % to 15 wt %, desirably from 0.001 wt % to 5 wt % of active compound.
The compounds I and its compositions can be used for protecting wooden materials such as trees, board fences, sleepers, frames, artistic artifacts, etc. and buildings, but also construction materials, furniture, leathers, fibers, vinyl articles, electric wires and cables etc. from ants, termites and/or wood or textile destroying beetles, and for controlling ants and termites from doing harm to crops or human beings (e.g. when the pests invade into houses and public facilities or nest in yards, orchards or parks).
Customary application rates in the protection of materials are, e.g., from 0.001 g to 2000 g or from 0.01 g to 1000 g of active compound per m2 treated material, desirably from 0.1 g to 50 g per m2.
Insecticidal compositions for use in the impregnation of materials typically contain from 0.001 to 95 wt %, preferably from 0.1 to 45 wt %, and more preferably from 1 to 25 wt % of at least one repellent and/or insecticide.
The compounds of the invention are especially suitable for efficiently combating animal pests e.g. arthropods, and nematodes including:
The compounds I are suitable for use in treating or protecting animals against infestation or infection by parasites. Therefore, the invention also relates to the use of a compound of the invention for the manufacture of a medicament for the treatment or protection of animals against infestation or infection by parasites. Furthermore, the invention relates to a method of treating or protecting animals against infestation and infection by parasites, which comprises orally, topically or parenterally administering or applying to the animals a parasiticidally effective amount of a compound I.
The invention also relates to the non-therapeutic use of compounds of the invention for treating or protecting animals against infestation and infection by parasites. Moreover, the invention relates to a non-therapeutic method of treating or protecting animals against infestation and infection by parasites, which comprises applying to a locus a parasiticidally effective amount of a compound I.
The compounds of the invention are further suitable for use in combating or controlling parasites in and on animals. Furthermore, the invention relates to a method of combating or controlling parasites in and on animals, which comprises contacting the parasites with a parasitically effective amount of a compound I.
The invention also relates to the non-therapeutic use of compounds I for controlling or combating parasites. Moreover, the invention relates to a non-therapeutic method of combating or controlling parasites, which comprises applying to a locus a parasiticidally effective amount of a compound I.
The compounds I can be effective through both contact (via soil, glass, wall, bed net, carpet, blankets, or animal parts) and ingestion (e.g. baits). Furthermore, the compounds I can be applied to any and all developmental stages.
The compounds I can be applied as such or in form of compositions comprising them.
The term “locus” means the habitat, food supply, breeding ground, area, material or environment in which a parasite is growing or may grow outside of the animal.
As used herein, the term “parasites” includes endo- and ectoparasites. In some embodiments of the invention, endoparasites can be preferred. In other embodiments, ectoparasites can be preferred. Infestations in warm-blooded animals and fish include lice, biting lice, ticks, nasal bots, keds, biting flies, muscoid flies, flies, myiasitic fly larvae, chiggers, gnats, mosquitoes and fleas.
The compounds of the invention are especially useful for combating the following parasites: Cimex lectularius, Rhipicephalus sanguineus, and Ctenocephalides felis.
As used herein, the term “animal” includes warm-blooded animals (including humans) and fish.
Preferred are mammals, such as cattle, sheep, swine, camels, deer, horses, pigs, poultry, rabbits, goats, dogs and cats, water buffalo, donkeys, fallow deer and reindeer, and also in furbearing animals such as mink, chinchilla and raccoon, birds such as hens, geese, turkeys and ducks and fish such as fresh- and salt-water fish such as trout, carp and eels. Particularly preferred are domestic animals, such as dogs or cats.
The compounds I may be applied in total amounts of 0.5 mg/kg to 100 mg/kg per day, preferably 1 mg/kg to 50 mg/kg per day.
For oral administration to warm-blooded animals, the compounds I may be formulated as animal feeds, animal feed premixes, animal feed concentrates, pills, solutions, pastes, suspensions, drenches, gels, tablets, boluses and capsules. For oral administration, the dosage form chosen should provide the animal with 0.01 mg/kg to 100 mg/kg of animal body weight per day of the compounds I, preferably with 0.5 mg/kg to 100 mg/kg of animal body weight per day.
Alternatively, the compounds I may be administered to animals parenterally, e.g., by intraruminal, intramuscular, intravenous or subcutaneous injection. The compounds I may be dispersed or dissolved in a physiologically acceptable carrier for subcutaneous injection. Alternatively, the compounds I may be formulated into an implant for subcutaneous administration. In addition, the compounds I may be transdermally administered to animals. For parenteral administration, the dosage form chosen should provide the animal with 0.01 mg/kg to 100 mg/kg of animal body weight per day of the compounds 1.
The compounds I may also be applied topically to the animals in the form of dips, dusts, powders, collars, medallions, sprays, shampoos, spot-on and pour-on formulations and in ointments or oil-in-water or water-in-oil emulsions. For topical application, dips and sprays usually contain 0.5 ppm to 5,000 ppm and preferably 1 ppm to 3,000 ppm of the compounds 1. In addition, the compounds I may be formulated as ear tags for animals, particularly quadrupeds e.g. cattle and sheep.
Oral solutions are administered directly.
Solutions for use on the skin are trickled on, spread on, rubbed in, sprinkled on or sprayed on.
Gels are applied to or spread on the skin or introduced into body cavities.
Pour-on formulations are poured or sprayed onto limited areas of the skin, the active compound penetrating the skin and acting systemically. Pour-on formulations are prepared by dissolving, suspending, or emulsifying the active compound in suitable skin-compatible solvents or solvent mixtures.
Emulsions can be administered orally, dermally or as injections.
Suspensions can be administered orally or topically/dermally.
Semi-solid preparations can be administered orally or topically/dermally.
For the production of solid preparations, the active compound is mixed with suitable excipients, if appropriate with addition of auxiliaries, and brought into the desired form.
The compositions which can be used in the invention can comprise generally from about 0.001 to 95% of the compound I.
Ready-to-use preparations contain the compounds acting against parasites, preferably ectoparasites, in concentrations of 10 ppm to 80% by weight, preferably from 0.1 to 65% by weight, more preferably from 1 to 50% by weight, most preferably from 5 to 40% by weight.
Preparations which are diluted before use contain the compounds acting against ectoparasites in concentrations of 0.5 to 90% by weight, preferably of 1 to 50% by weight.
Furthermore, the preparations comprise the compounds of formula I against endoparasites in concentrations of 10 ppm to 2% by weight, preferably of 0.05 to 0.9% by weight, very particularly preferably of 0.005 to 0.25% by weight.
Solid formulations which release compounds of the invention may be applied in total amounts of 10 mg/kg to 300 mg/kg, preferably 20 mg/kg to 200 mg/kg, most preferably 25 mg/kg to 160 mg/kg body weight of the treated animal in the course of three weeks.
The compounds were characterized by melting point determination, by NMR spectroscopy or by the mass-to-charge ratio ([m/z]) and retention time (RT; [min.]), as determined by mass spectrometry (MS) coupled with HPLC analysis (HPLC-MS=high performance liquid chromatography-coupled mass spectrometry) or LC analysis (LC-MS=liquid chromatography-coupled mass spectrometry).
To a solution of 3,5-bis(trifluoromethyl)benzoic acid (5 g, 19.37 mmol) in MeCN (50 mL) was added Chloro-N,N,N′,N′-tetramethylformamidinium-hexafluorophosphate (8.15 g, 29.05 mmol), N-methylimidazole (6.36 g, 77.48 mmol), and 2-aminopropanamide (2.41 g, 19.37 mmol) at 20° C. and the mixture stirred at 20° C. for 16 h until completion was determined by thin layer chromatographs (TLC; PE: EtOAc=1:1, Rf=0.5). The mixture was poured into H2O (30 mL) and extracted with ethyl acetate (EtOAc; 3×30 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The crude product was triturated with H2O (50 mL) and filtered to give N-(2-amino-1-methyl-2-oxo-ethyl)-3,5-bis(trifluoromethyl)benzamide (5.3 g, 79% yield) as a white solid.
1H-NMR (400 MHz, DMSO-d6): δ=9.06 (d, J=7.4 Hz, 1H), 8.56 (s, 2H), 8.32 (s, 1H), 7.49 (brs, 1H), 7.04 (br s, 1H), 4.44 (dq, J=7.2 Hz, J=7.4 Hz, 1H), 1.36 (d, J=7.3 Hz, 3H).
To a solution of N-(2-amino-1-methyl-2-oxo-ethyl)-3,5-bis(trifluoromethyl)benzamide (1 g, 3.1 mmol) in DCM (10 mL) was added DMF-DMA (730 mg, 6.2 mmol) at 30° C. The mixture was stirred at 50° C. for 2 h until completion was determined by TLC (PE:EtOAc=1:1, Rf=0.5) and LCMS. The mixture was concentrated to give N-[2-[dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide (1.2 g, crude) as yellow oil. The crude product was directly employed in the next step.
To a solution of N-[2-[dimethylaminomethyleneamino]-1-methyl-2-oxo-ethyl]-3,5-bis(trifluoromethyl)benzamide (19.4 g, 50.6 mmol) in AcOH (10 mL) was added N2H4×H2O (5.1 g, 101.2 mmol) and the resulting mixture stirred at 20° C. for 5 min, then at 90° C. for 2 h until completion was determined by TLC (PE:EtOAc=1:1, Rf=0.6) and LCMS. The reaction mixture was concentrated. The residue was dissolved with EtOAc (5 mL), poured into aq. sat. NaHCO3 (30 mL) and the mixture extracted with EtOAc (3×10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was triturated with DCM (15 mL) and filtered to deliver N-[1-(1H-1,2,4-triazol-5-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (14 g, 78% yield) as yellow solid.
1H-NMR (400 MHz, DMSO-d6): δ=13.92-13.82 (m, 1H), 9.50-9.35 (m, 1H), 8.56 (brs, 2H), 8.33 (br d, J=9.9 Hz, 1H), 7.89 (s, 1H), 5.33 (dq, J=6.9 Hz, 1H), 1.57 (dd, J=7.1, 13.3 Hz, 3H).
To a solution of acetaldehyde oxime (200 mg, 3.39 mmol) in DMF (2 mL) was added N-chlorosuccinimide (497.3 mg, 3.72 mmol) at 0° C. under N2 atmosphere and the resulting mixture allowed to warm up to 20° C. within 10 min, at which time reaction completion was determined by TLC (PE:EtOAc=1:1, Rf=0.5). This DMF solution of N-hydroxyacetimidoyl chloride (3 mL) was directly employed in the next step.
To a mixture of N-[1-(1H-1,2,4-triazol-5-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide (715 mg, 2.03 mmol) and Cs2CO3 (1.7 g, 5.08 mmol) in DMF (7 mL) was added N-hydroxyacetimidoyl chloride (3 mL DMF solution) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 20° C. for 16 h, until completion was determined by LCMS. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (TFA) to deliver N-[1-[2-[(Z)—N-hydroxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (1.1-1, 80 mg, 9.8% yield) and N-[1-[2-[(E)-N-hydroxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (I.1-76, 150 mg, 18% yield) as white solids.
I.1-1: 1H-NMR (400 MHz, DMSO-d6): δ=11.65 (s, 1H), 9.50 (d, J=6.9 Hz, 1H), 8.51 (s, 2H), 8.33 (s, 1H), 8.09 (s, 1H), 5.18 (dq, J=6.9 Hz, J=6.9 Hz, 1H), 2.27 (s, 3H), 1.61 (d, J=6.9 Hz, 3H).
I.1-76: 1H-NMR (400 MHz, DMSO-d6): δ=11.60 (s, 1H), 9.57 (d, J=7.2 Hz, 1H), 8.53 (s, 2H), 8.33 (s, 1H), 8.06 (s, 1H), 5.63-5.55 (m, 1H), 2.33 (s, 3H), 1.59 (d, J=6.9 Hz, 3H).
To a solution of N-[1-[2-[N-hydroxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (140 mg, 0.34 mmol) in DMF (2 mL) were added and K2CO3 (94.55 mg, 0.68 mmol) and CH3I (97.1 mg, 0.68 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 16 h, until completion was determined by LCMS. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (TFA) to deliver N-[1-[2-[(Z)—N-methoxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (1.1-2, 163 mg, 56% yield) as a yellow solid.
1H-NMR (400 MHz, DMSO-d6): δ=9.54 (d, J=6.8 Hz, 1H), 8.51 (s, 2H), 8.34 (s, 1H), 8.13 (s, 1H), 5.13 (dq, J=6.9 Hz, J=6.8 Hz, 1H), 3.81 (s, 3H), 2.29 (s, 3H), 1.61 (d, J=7.0 Hz, 3H). 13C-NMR (125.7 MHz, CDCl3): δ=163.62, 157.56, 151.42, 141.97, 135.37, 132.17, 132.17, 127.36, 127.36, 125.29, 122.74, 122.74, 62.65, 42.87, 19.65, 18.90.
To a solution of N-[1-[2-[N-hydroxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (160 mg, 0.39 mmol) in DMF (2 mL) were added K2CO3 (108 mg, 0.78 mmol) and CH3I (111 mg, 0.78 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 16 h, until completion was determined by LCMS. The mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC (TFA) to deliver N-[1-[2-[(E)-N-methoxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-3,5-bis(trifluoromethyl)benzamide (1.1-3, 90 mg, 42% yield) as a yellow solid.
1H-NMR (400 MHz, DMSO-d6): δ=9.56 (d, J=7.0 Hz, 1H), 8.52 (s, 2H), 8.34 (s, 1H), 8.12 (s, 1H), 5.62 (dq, J=7.0 Hz, J=6.9 Hz, 1H), 3.86 (s, 3H), 2.34 (s, 3H), 1.61 (d, J=6.9 Hz, 3H).
13C-NMR (125.7 MHz, CDCl3): δ=163.43, 157.18, 150.32, 149.62, 135.77, 132.12, 132.12, 127.39, 127.39, 125.17, 122.80, 122.80, 63.04, 43.92, 20.30, 13.29.
To a solution of 3-chloro-N-[1-[2-[N-hydroxy-C-methyl-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (200 mg, 0.53 mmol) in DCE (10 ml) was added phenylboronic acid (130 mg, 1.06 mmol), pyridine (83 mg, 1.06 mmol) and Cu(OAc)2 (211 mg, 1.06 mmol) at 20° C. The reaction mixture was stirred at 50° C. for 16 h under O2 atmosphere, until completion was determined by LC-MS. The reaction mixture was filtered. The filtrate was diluted with water (10 ml), extracted with EtOAc (3×20 ml) and washed with brine (10 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (NH4HCO3, ACN-water) to give 3-chloro-N-[1-[2-[C-methyl-N-phenoxy-carbonimidoyl]-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (I.1-13, 50 mg, 21% yield) as a white solid.
1H-NMR (400 MHz, CDCl3) δ=8.03 (s, 1H), 7.88 (d, J=14.4 Hz, 2H), 7.74 (s, 1H), 7.37-7.30 (m, 2H), 7.13-7.06 (m, 1H), 6.78-6.67 (m, 1H), 5.44-5.28 (m, 1H), 2.62 (s, 3H), 1.73 (d, J=6.9 Hz, 3H).
To a solution of phenoxyammonium chloride (2 g, 18 mmol) and NaHCO3 (4.62 g, 55 mmol) in THF (20 ml) was added dropwise acetyl chloride (2.5M, 1.43 g, 18 mmol) at 0° C. under N2 atmosphere. The resulting mixture was stirred at 20° C. for 16 h. TCL (PE:EtOAc=3:1) showed the reaction was completed. The reaction mixture was quenched with NH4Cl (aqueous, 30 ml) and extracted with EtOAc (2×30 ml). The organic layer was washed with brine (30 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column (PE:EtOAc=3:1) to give N-phenoxyacetamide (1.5 g, 56% yield) as a yellow oil.
1H-NMR (400 MHz, CDCl3) δ=7.28-7.34 (m, 2H), 7.16-7.22 (m, 2H), 7.05 (t, J=7.25 Hz, 1H), 2.39 (s, 3H).
To a solution of N-phenoxyacetamide (1 g, 6.6 mmol) in toluene (15 ml) was added phosphoroxy chloride (5 g, 33 mmol) at 20° C. The mixture was stirred at 80° C. for 16 h, TLC (PE:EtOAc=10:1) showed that the reaction was completed. The reaction mixture was concentrated under reduced pressure and purified by column (PE-PE:EtOAc=80:1) to give N-phenoxyacetimidoyl chloride (800 mg, 73% yield) as a grey solid.
1H-NMR (400 MHz, CDCl3) δ=7.31-7.36 (m, 2H), 7.20-7.24 (m, 2H), 7.08 (br d, J=7.25 Hz, 1H), 2.41 (s, 3H)
To a solution of N-phenoxyacetimidoyl chloride (500 mg, 3 mmol) and 3-chloro-N-[1-1H-1,2,4-triazol-3-yl)ethyl]-5-(trifluoromethyl)benzamide (1.24 g, 3.9 mmol) in THF (10 ml) was added CsF (762 mg, 3.77 mmol) at 20° C. The mixture was stirred at 20° C. for 16 h until TLC (PE:EtOAc=3:1) showed the reaction was completed. The reaction mixture was quenched with NH4Cl (aqueous, 20 ml) and extracted with EtOAc (2×30 ml). The organic layer was washed with brine (20 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column (PE-PE:EtOAc=5:1) to give 3-chloro-N-[1-[1-(C-methyl-N-phenoxy-carbonimidoyl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (1.2-6, 300 mg, 23% yield) as a yellow solid.
1H-NMR (400 MHz, CDCl3) δ=9.38 (s, 1H), 7.99 (d, J=13.55 Hz, 2H), 7.76 (s, 1H), 7.35-7.42 (m, 2H), 7.29 (br d, J=1.00 Hz, 2H), 7.10-7.15 (m, 1H), 6.98 (br d, J=7.53 Hz, 1H), 5.54 (quin, J=7.12 Hz, 1H), 2.60 (s, 3H), 1.70 (d, J=6.90 Hz, 3H).
To a solution of 3-chloro-N-[1-[2-(N-hydroxy-C-methyl-carbonimidoyl)-1,2,4-triazol-3-yl]-5-(trifluoromethyl)benzamide (400 mg, 1.06 mmol) in DMF (5 ml) was added iodoethane (250 mg, 1.60 mmol) and Cs2CO3 (691 mg, 2.12 mmol) at 20° C. The mixture was stirred at 20° C. for 16 h until TLC showed the reaction was completed. The reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3×10 ml). The organic layer was washed with brine (3×10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 3-chloro-N-[1-[2-(N-ethoxy-C-methyl-carbonimidoyl)-1,2,4-triazol-3-yl]ethyl]-5-(trifluoromethyl)benzamide (I.1-12, 60 mg, 14% yield) as a white solid.
1H-NMR (400 MHz, CDCl3) δ=7.97 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 7.75 (s, 1H), 6.83 (br d, J=7.1 Hz, 1H), 5.35 (t, J=7.1 Hz, 1H), 4.23-4.15 (m, 2H), 4.43 (s, 3H), 1.67 (d, J=6.9 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H).
The geometry of the C═N double bond (E/Z-isomerism) was assigned by NMR as described in G. E. Hawkes et al, The Journal of Organic Chemistry 1974, 39, 1017-1028.
With appropriate modification of the starting materials, the procedures given in the synthesis descriptions were used to obtain further compounds 1. The compounds obtained in this manner are listed in the table that follows, together with physical data.
If not otherwise specified, the test solutions were prepared as follow:
The active compound was dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acetone. The test solution was prepared on the day of use.
The activity of the compounds of formula I of the present invention can be demonstrated and evaluated by the following biological tests.
B.1 Diamond Back Moth (Plutella xylostella)
The active compound was dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acetone. Surfactant (Kinetic HV) was added at a rate of 0.01% (vol/vol). The test solution was prepared on the day of use.
Leaves of cabbage were dipped in test solution and air-dried. Treated leaves were placed in petri dishes lined with moist filter paper and inoculated with ten 3rd instar larvae. Mortality was recorded 72 hours after treatment. Feeding damages were also recorded using a scale of 0-100%.
In this test, compounds I.1-1, I.1-2, I.1-3, I.1-4, I.1-5, I.1-8, I.1-11, and I.1-76, resp., at 300 ppm showed at least 75% mortality in comparison with untreated controls.
B.2 Green Peach Aphid (Myzus persicae)
For evaluating control of green peach aphid (Myzus persicae) through systemic means, the test unit consisted of 96-well-microtiter plates containing liquid artificial diet under an artificial mem brane.
The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were pipetted into the aphid diet, using a custom built pipetter, at two replications.
After application, 5-8 adult aphids were placed on the artificial membrane inside the microtiter plate wells. The aphids were then allowed to suck on the treated aphid diet and incubated at about 23±1° C. and about 50±5% relative humidity for 3 days. Aphid mortality and fecundity was then visually assessed.
In this test, compounds I.1-1, I.1-2, I.1-3, I.1-11, I.1-14, I.1-23, I.1-32, I.1-38, I.1-41, I.1-46, I.1-50, I.1-55, I.1-62, I.1-76, and I.1-99, resp., at 2500 ppm showed at least 75% mortality in comparison with untreated controls.
B.4 Tobacco Budworm (Heliothis virescens)
For evaluating control of tobacco budworm (Heliothis virescens), the test unit consisted of 96-well-microtiter plates containing an insect diet and 15-25 H. virescens eggs.
The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 10 μl, using a custom-built micro atomizer, at two replications.
After application, microtiter plates were incubated at about 28±1° C. and about 80±5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.
In this test, compounds I.1-1, I.1-2, I.1-3, I.1-4, I.1-33, I.1-41, I.1-50, I.1-59, and I.1-76, resp., at 2500 ppm showed at least 75% mortality in comparison with untreated controls.
B.5 Boll Weevil (Anthonomus grandis)
For evaluating control of boll weevil (Anthonomus grandis), the test unit consisted of 96-well-microtiter plates containing an insect diet and 5-10 A. grandis eggs.
The compounds were formulated using a solution containing 75% v/v water and 25% v/v DMSO. Different concentrations of formulated compounds were sprayed onto the insect diet at 5 μl, using a custom-built micro atomizer, at two replications.
After application, microtiter plates were incubated at about 25±1° C. and about 75±5% relative humidity for 5 days. Egg and larval mortality was then visually assessed.
In this test, compounds I.1-1, I.1-2, I.1-3, I.1-4, I.1-11, I.1-12, I.1-16, I.1-21, I.1-23, I.1-26, I.1-31, I.1-32, I.1-33, I.1-38, I.1-40, I.1-41, I.1-46, I.1-50, I.1-55, I.1-59, I.1-62, I.1-76, I.1-99, and 1.2-4, resp., at 2500 ppm showed at least 75% mortality in comparison with untreated controls.
B.7 Orchid Thrips (Dichromothrips corbetti)
Dichromothrips corbetti adults used for bioassay were obtained from a colony maintained continuously under laboratory conditions. For testing purposes, the test compound is diluted in a 1:1 mixture of acetone:water (vol:vol), plus Kinetic HV at a rate of 0.01% v/v.
Thrips control potency of each compound was evaluated by using a floral-immersion technique. All petals of individual, intact orchid flowers were dipped into treatment solution and allowed to dry in Petri dishes. Treated petals were placed into individual re-sealable plastic along with about 20 adult thrips. All test arenas were held under continuous light and a temperature of about 28° C. for duration of the assay. After 3 days, the numbers of live thrips were counted on each petal. The percent mortality was recorded 72 hours after treatment.
In this test, compounds I.1-2, I.1-3, and I.1-11, resp., at 300 ppm showed at least 75% mortality in comparison with untreated controls.
B.8 Yellow Fever Mosquito (Aedes aegypti)
For evaluating control of yellow fever mosquito (Aedes aegypti) the test unit consisted of 96-well-microtiter plates containing 200 μl of tap water per well and 5-15 freshly hatched A. aegypti larvae.
The active compounds were formulated using a solution containing 75% (v/v) water and 25% (v/v) DMSO. Different concentrations of formulated compounds or mixtures were sprayed onto the insect diet at 2.5 μl, using a custom-built micro atomizer, at two replications.
After application, microtiter plates were incubated at 28±1° C., 80±5% RH for 2 days. Larval mortality was then visually assessed.
In this test, compounds I.1-1, I.1-2, I.1-3, I.1-4, I.1-5, I.1-8, I.1-11, I.1-12, I.1-13, I.1-14, I.1-16, 1.1-21, I.1-23, I.1-26, I.1-27, I.1-31, I.1-32, I.1-33, I.1-35, I.1-38, I.1-39, I.1-40, I.1-41, I.1-46, I.1-48, I.1-50, I.1-58, I.1-59, I.1-60, I.1-62, I.1-63, I.1-76, I.1-99, 1.2-4, and 1.3-5, resp., at 2500 ppm showed at least 75% mortality in comparison with untreated controls.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21185074.8 | Jul 2021 | EP | regional |
| 21185079.7 | Jul 2021 | EP | regional |
| 21215021.3 | Dec 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/068368 | 7/4/2022 | WO |
