Patent Application
20240092782
The invention relates to compounds of formula (I) or an agrochemically or verterinarily acceptable salt, stereoisomer, tautomer, or N-oxide thereof
wherein the variables are as defined below. The invention also relates to the use of compounds of formula (I) as an agrochemical pesticide; to pesticidal mixtures comprising a compound of formula (I) and another agrochemically active ingredient; to agrochemical or veterinary compositions comprising a compound of formula (I) or the pesticidal mixture and a liquid or solid carrier; and to seed comprising a compound of formula (I) or the pesticidal mixture. The invention also relates to methods for controlling invertebrate pests, infestation, or infection by invertebrate pests by application of the compounds of formula (I) or the pesticidal mixtures comprising them.
Invertebrate pests and in particular insects, arachnids and nematodes destroy growing and harvested crops and attack wooden dwelling and commercial structures, thereby causing large economic loss to the food supply and to property. Accordingly, there is an ongoing need for new agents for combating invertebrate pests.
WO2017/167832A1 discloses bicyclic compounds and their use as agrochemical pesticides, whereas tricyclic compounds are not described.
Due to the ability of target pests to develop resistance to pesticidally active agents, there is an ongoing need to identify further compounds, which are suitable for combating invertebrate pests such as insects, arachnids and nematodes. Furthermore, there is a need for new compounds having a high pesticidal activity and showing a broad activity spectrum against a large number of different invertebrate pests, especially against difficult to control insects, arachnids and nematodes. There is furthermore a need to find compounds that display a higher efficacy as compared with known pesticides, which reduces the application rates and costs for the applicant, and decreases the environmental effects on soil and ground water.
It is therefore an object of the present invention to identify and provide compounds, which exhibit a high pesticidal activity and have a broad activity spectrum against invertebrate pests.
It has been found that these objects can be achieved by substituted tricyclic compounds of formula I as depicted and defined below, including their stereoisomers, their salts, in particular their agriculturally or veterinarily acceptable salts, their tautomers and their N-oxides.
Therefore, the invention provides in a first aspect compounds of formula (I), or an agrochemically or veterinarily acceptable salt, stereoisomer, tautomer, or N-oxide thereof
Compounds of formula (I), or an agrochemically or veterinarily acceptable salt, stereoisomer, tautomer, or N-oxide thereof
wherein the variables in formula (I) have the following meaning
The tricyclic compounds of the formula (I), and their agriculturally acceptable salts are highly active against animal pest, i.e. harmful arthropodes and nematodes, especially against insects and acaridae which are difficult to control by other means.
Moreover, the present invention relates to and includes the following embodiments:
All the compounds of formula (I) if applicable their stereoisomers, their tautomers, their salts or their N-oxides as well as compositions thereof are particularly useful for controlling invertebrate pests, in particular for controlling arthropods and nematodes and especially insects. Therefore, the invention relates to the use of a compound of formula (I) as an agrochemical pesticide, preferably for combating or controlling invertebrate pests, in particular invertebrate pests of the group of insects, arachnids or nematodes.
The term “compound(s) according to the invention” or “compound(s) of formula (I)” as used in the present invention refers to and comprises the compound(s) as defined herein and/or stereoisomer(s), salt(s), tautomer(s) or N-oxide(s) thereof. The term “compound(s) of the present invention” is to be understood as equivalent to the term “compound(s) according to the invention”, therefore also comprising stereoisomer(s), salt(s), tautomer(s) or N-oxide(s) of compounds of formula (I).
Ther terms “tricyclic scaffold” or “tricyclic moiety” relate to the following moiety of formula (I)
wherein “#” means the remainder of formula (I) and wherein the other variables have a meaning a as defined form formula (I). For the avoidance of doubt, the circles in the three adjoined rings mean that the tricyclic scaffold is fully unsaturated, typically aromatic
The term “composition(s) according to the invention” or “composition(s) of the present invention” encompasses composition(s) comprising at least one compound of formula (I) according to the invention as defined above, therefore also including a stereoisomer, an agriculturally or veterinary acceptable salt, tautomer or an N-oxide of the compounds of formula (I).
The compounds of the present invention may be amorphous or may exist in one or more different crystalline states (polymorphs) or modifications which may have a different macroscopic properties such as stability or show different biological properties such as activities. The present invention includes both amorphous and crystalline compounds of the formula (I), mixtures of different crystalline states or modifications of the respective compound of formula ( )), as well as amorphous or crystalline salts thereof.
The compounds of the formula (I) have one or, depending on the substitution pattern, more centers of chirality, in which case they are present as mixtures of enantiomers or diastereomers. The invention provides both the single pure enantiomers or pure diastereomers of the compounds of formula (I), and their mixtures and the use according to the invention of the pure enantiomers or pure diastereomers of the compound of formula (I) or its mixtures. Suitable compounds of the formula (I) also include all possible geometrical stereoisomers (cis/trans isomers) and mixtures thereof. Cis/trans isomers may be present with respect to an alkene, carbon-nitrogen double-bond or amide group. The term “stereoisomer(s)” encompasses both optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one center of chirality in the molecule, as well as geometrical isomers (cis/trans isomers). The present invention relates to every possible stereoisomer of the compounds of formula (I), i.e. to single enantiomers or diastereomers, as well as to mixtures thereof.
Depending on the substitution pattern, the compounds of the formula (I) may be present in the form of their tautomers. Hence the invention also relates to the tautomers of the formula (I) and the stereoisomers, salts, tautomers and N-oxides of said tautomers.
Salts of the compounds of the formula (I) are preferably agriculturally and/or veterinary acceptable salts. They can be formed in a customary method, e.g. by reacting the compound with an acid of the anion in question if the compound of formula (I) has a basic functionality or by reacting an acidic compound of formula (I) with a suitable base.
Suitable agriculturally or veterinary useful salts are especially the salts of those cations or the acid addition salts of those acids whose cations and anions, respectively, do not have any adverse effect on the action of the compounds according to the present invention. Suitable cations are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, zinc and iron, and also ammonium (NH4+) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, hydroxy-C1-C4-alkoxy-C1-C4-alkyl, phenyl or benzyl. Examples of substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2-hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore phosphonium ions, sulfonium ions, preferably tri(C1-C4-alkyl)sulfonium, and sulfoxonium ions, preferably tri(C1-C4-alkyl)sulfoxonium.
Anions of useful acid addition salts are primarily chloride, bromide, fluoride, hydrogen sulfate, sulfate, dihydrogen phosphate, hydrogen phosphate, phosphate, nitrate, hydrogen carbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate. They can be formed by reacting the compounds of the formulae I with an acid of the corresponding anion, preferably of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid.
The term “N-oxide” includes any compound of the present invention which has at least one tertiary nitrogen atom that is oxidized to an N-oxide moiety.
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. “Halogen” will be taken to mean F, Cl, Br, and I, preferably F.
The term “substituted with”, e.g. as used in “partially, or fully substituted with” means that one or more, e.g. 1, 2, 3, 4 or 5 or all of the hydrogen atoms of a given radical have been replaced by one or more, same or different substituents, such as a halogen, in particular F. Accordingly, for substituted cyclic moieties, e.g. 1-cyanocyclopropyl, one or more of the hydrogen atoms of the cyclic moiety may be replaced by one or more, same or different substituents.
Likewise, the term “halogenated” means that one or more, e.g. 1, 2, 3, 4, or 5 or all of the hydrogen atoms of a given radical have been replaced by one or more, same or different halogen atoms, such as F.
The term “Cn-Cm-alkyl” as used herein (and also in Cn-Cm-alkylamino, di-Cn-Cm-alkylamino, Cn-Cm-alkylaminocarbonyl, di-(Cn-Cm-alkylamino)carbonyl, Cn-Cm-alkylthio, Cn-Cm-alkylsulfinyl and Cn-Cm-alkylsulfonyl) refers to a branched or unbranched saturated hydrocarbon group having n to m, e.g. 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 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, 1-ethyl-2-methylpropyl, heptyl, octyl, 2-ethylhexyl, nonyl and decyl and their isomers. C1-C4-alkyl means for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
The term “Cn-Cm-haloalkyl” as used herein (and also in Cn-Cm-haloalkylsulfinyl and Cn-Cm-haloalkylsulfonyl) refers to a straight-chain or branched alkyl group having n to m carbon atoms, e.g. 1 to 10 in particular 1 to 6 carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example C1-C4-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like. The term C1-C10-haloalkyl in particular comprises C1-C2-fluoroalkyl, which is synonym with methyl or ethyl, wherein 1, 2, 3, 4 or 5 hydrogen atoms are substituted with fluorine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl and pentafluoromethyl.
Similarly, “Cn-Cm-alkoxy” and “Cn-Cm-alkylthio” (or Cn-Cm-alkylsulfenyl, respectively) refer to straight-chain or branched alkyl groups having n to m carbon atoms, e.g. 1 to 10, in particular 1 to 6 or 1 to 4 carbon atoms (as mentioned above) bonded through oxygen (or sulfur linkages, respectively) at any bond in the alkyl group. Examples include C1-C4-alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy and tert-butoxy, further C1-C4-alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, and n-butylthio.
Accordingly, the terms “Cn-Cm-haloalkoxy” and “Cn-Cm-haloalkylthio” (or Cn-Cm-haloalkyl-sulfenyl, respectively) refer to straight-chain or branched alkyl groups having n to m carbon atoms, e.g. 1 to 10, in particular 1 to 6 or 1 to 4 carbon atoms (as mentioned above) bonded through oxygen or sulfur linkages, respectively, at any bond in the alkyl group, where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example C1-C2-haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy and pentafluoroethoxy, further C1-C2-haloalkylthio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichlorofluoromethylthio, chlorodifluoromethylthio, 1-chloroethylthio, 1-bromoethylthio, 1-fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2-trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2-fluoroethylthio, 2,2,2-trichloroethylthio and pentafluoroethylthio and the like. Similarly, the terms C1-C2-fluoroalkoxy and C1-C2-fluoroalkylthio refer to C1-C2-fluoroalkyl which is bound to the remainder of the molecule via an oxygen atom or a sulfur atom, respectively.
The term “C2-Cm-alkenyl” as used herein intends a branched or unbranched unsaturated hydrocarbon group having 2 to m, e.g. 2 to 10 or 2 to 6 carbon atoms and a double bond in any position, such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl, 1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.
The term “C2-Cm-alkynyl” as used herein refers to a branched or unbranched unsaturated hydrocarbon group having 2 to m, e.g. 2 to 10 or 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like.
The term “Cn-Cm-alkoxy-Cn-Cm-alkyl” as used herein refers to alkyl having n to m carbon atoms, e.g. like specific examples mentioned above, wherein one hydrogen atom of the alkyl radical is replaced by an Cn-Cm-alkoxy group; wherein the value of n and m of the alkoxy group are independently chosen from that of the alkyl group.
The suffix “-carbonyl” in a group or “C(═O)” denotes in each case that the group is bound to the remainder of the molecule via a carbonyl C═O group. This is the case e.g. in alkylcarbonyl, haloalkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, haloalkoxycarbonyl.
The term “aryl” as used herein refers to a mono-, bi- or tricyclic aromatic hydrocarbon radical such as phenyl or naphthyl, in particular phenyl (also referred as to C6H5 as subsitituent).
The term “C3-Cm-cycloalkyl” as used herein refers to a monocyclic ring of 3- to m-membered saturated cycloaliphatic radicals, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.
The term “alkylcycloalkyl” denotes as well as the term “alkyl which may be substituted with cycloalkyl” an alkyl group which is substituted with a cycloalkyl ring, wherein alkyl and cycloakyl are as herein defined.
The term “cycloalkylalkyl” denotes as well as the term “cycloalkyl which may be substituted with alkyl” a cycloalkyl ring which is substituted with an alkyl group, wherein alkyl and cycloakyl are as herein defined.
The term “alkylcycloalkylalkyl” denotes as well as the term “alkylcycloalkyl which may be substituted with alkyl” an alkylcycloalkyl group which is substituted with an alkyl, wherein alkyl and alkylcycloakyl are as herein defined.
The term “C3-Cm-cycloalkenyl” as used herein refers to a monocyclic ring of 3- to m-membered partially unsaturated cycloaliphatic radicals.
The term “cycloalkylcycloalkyl” denotes as well as the term “cycloalkyl which may be substituted with cycloalkyl” a cycloalkyl substitution on another cycloalkyl ring, wherein each cycloalkyl ring independently has from 3 to 7 carbon atom ring members and the cycloalkyls are linked through one single bond or have one common carbon atom. Examples of cycloalkylcycloalkyl include cyclopropylcyclopropyl (e.g. 1,1′-bicyclopropyl-2-yl), cyclohexylcyclohexyl wherein the two rings are linked through one single common carbon atom (e.g. 1,1′-bicyclohexyl-2-yl), cyclohexylcyclopentyl wherein the two rings are linked through one single bond (e.g. 4-cyclopentylcyclohexyl) and their different stereoisomers such as (1R,2S)-1,1′-bicyclopropyl-2-yl and (1R,2R)-1,1′-bicyclopropyl-2-yl. The term “carbocycle” or “carbocyclyl” includes, unless otherwise indicated, 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, ring comprising 3 to 12, preferably 3 to 8 or 5 to 8, more preferably 5 or 6 carbon atoms.
The carbocyclic radicals may be saturated, partially unsaturated, or fully unsaturated. Preferably, the term “carbocycle” covers cycloalkyl and cycloalkenyl groups as defined above, for example cyclopropane, cyclobutane, cyclopentane and cyclohexane rings. When it is referred to “fully unsaturated” carbocycles, this term also includes “aromatic” carbocycles. In certain preferred embodiments, a fully unsaturated carbocycle is an aromatic carbocycle as defined below, preferably a 6-membered aromatic carbocycle.
The term “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” 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 “heteroaryl” 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 heteroaryl 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 “heterocycle”, “heterocyclyl” or “heterocyclic ring” includes, unless otherwise indicated, in general 3- to 12-membered, preferably 3- to 8-membered, 3- to 7-membered, or 5- to 8-membered, more preferably 5- or 6-membered, in particular 6-membered monocyclic heterocyclic radicals. The heterocyclic radicals may be saturated, partially unsaturated, or fully unsaturated. As used in this context, the term “fully unsaturated” also includes “aromatic”. In a preferred embodiment, a fully unsaturated heterocycle is thus an aromatic heterocycle, preferably a 5- or 6-membered aromatic heterocycle comprising one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members. Examples of aromatic heterocycles are provided above in connection with the definition of “heteroaryl”. Unless otherwise indicated, “heteroaryls” are thus covered by the term “heterocycles”. 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, where 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-oxid (S-oxothietanyl), thietanyl-S-dioxid (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 ring also comprising 1 or 2 carbonyl groups as ring members comprise pyrrolidin-2-onyl, pyrrolidin-2,5-dionyl, imidazolidin-2-onyl, oxazolidin-2-onyl, thiazolidin-2-onyl and the like.
The terms “alkylene”, “alkenylene”, and “alkynylene” refer to alkyl, alkenyl, 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 particular, the term “alkylene” may refer to alkyl chains such as CH2CH2, —CH(CH3)—, CH2CH2CH2, CH(CH3)CH2, CH2CH(CH3), CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2, and CH2CH2CH2CH2CH2CH2CH2. Similarly, “alkenylene” and “alkynylene” may refer to alkenyl and alkynyl chains, respectively.
The term “5- to 6-membered carbocyclic ring” as used herein refers to cyclopentane and cyclohexane rings.
Examples of 5- or 6-membered saturated heterocyclic rings include: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 1,2,4-oxadiazolidin-3-yl, 1,2,4-oxadiazolidin 5 yl, 1,2,4-thiadiazolidin-3-yl, 1,2,4-thiadiazolidin-5-yl, 1,2,4-triazolidin-3-yl, -1,3,4-oxadiazolidin-2-yl, 1,3,4-thiadiazolidin-2-yl, 1,3,4-triazolidin-2-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, 1,3,5-hexahydrotriazin-2-yl and 1,2,4-hexahydrotriazin-3-yl, 2-morpholinyl, 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 1-oxothiomorpholin-2-yl, 1-oxothiomorpholin-3-yl, 1,1-dioxothiomorpholin-2-yl, 1,1-dioxothiomorpholin-3-yl.
Examples of 5- or 6-membered partially unsaturated heterocyclyl or heterocyclic rings include: 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3-dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin 3 yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3 dihydropyrazol-1-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3-dihydropyrazol-5-yl, 3,4-dihydropyrazol-1-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4-dihydropyrazol-5-yl, 4,5-dihydropyrazol-1-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5-dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4-dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2-, 3-, 4-, 5- or 6-di- or tetrahydropyridinyl, 3-di- or tetrahydropyridazinyl, 4-di- or tetrahydropyridazinyl, 2-di- or tetrahydropyrimidinyl, 4-di- or tetrahydropyrimidinyl, 5-di- or tetrahydropyrimidinyl, di- or tetrahydropyrazinyl, 1,3,5-di- or tetrahydrotriazin-2-yl.
Examples of 5- or 6-membered fully unsaturated heterocyclic (heteroaryl) or heteroaromatic rings are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, 1,3,4-triazol-2-yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.
A “C2-Cm-alkylene” is divalent branched or preferably unbranched saturated aliphatic chain having 2 to m, e.g. 2 to 7 carbon atoms, for example CH2CH2, —CH(CH3)—, CH2CH2CH2, CH(CH3)CH2, CH2CH(CH3), CH2CH2CH2CH2, CH2CH2CH2CH2CH2, CH2CH2CH2CH2CH2CH2, and CH2CH2CH2CH2CH2CH2CH2.
The compounds of formula (I) can be prepared by standard methods of organic chemistry. If certain derivatives cannot be prepared by the processes outlined below, they can be obtained by derivatization of other compounds of formula (I) that are accessible by these methods. The definition of variable for the following compounds and intermediates is—unless otherwise provided—as defined for formula (I). The preferred meanings of variables according as defined herein is also valid for the following formulae (1) to (20).
Compounds of formula (11) are generally very useful building blocks for the synthesis of certain compounds of formula (I). Such compounds are accessible via a cascade of preparation steps as displayed under General Scheme 1 below:
In a first step, compounds of formula (1) may be reacted with NH3 to yield compounds of formula (2). The reaction is typically carried out in a polar solvent at a temperature of from 50 to 120° C. Suitable solvents include halogenated hydrocarbons, preferably halogenated aliphatic C1-C6-alkanes, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, preferably C1-C6-cycloalkyl ethers, C1-C6-alkyl-C1-C6-alkyl ethers and C1-C6-alkyl-C6-C10-aryl ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, CH3OC(CH3)3 (MTBE), CH3OCH3 (DME), CH3OCH2CH2OCH3, dioxane, anisole, and tetrahydrofurane (THF); nitriles, preferably C1-C6-nitriles, such as CH3CN, and CH3CH2CN; alcohols, preferably C1-C4-alcohols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH, and C(CH3)3OH; amides and urea derivatives, preferably dimethyl formamide (DMF), N-methyl-2-pyrrolidone (NMP), dimethyl acetamide (DMA), 1,3-dimethyl-2-imidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphamide (HMPA); moreover dimethyl sulfoxide (DMSO), sulfolane, H2O, and mixtures thereof.
Compounds of formula (3) may then be reacted first with a compound of formula (4) at a temperature of from 50 to 120° C. in a polar solvent. Suitable solvents include halogenated hydrocarbons, preferably halogenated aliphatic C1-C6-alkanes, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, preferably C1-C6-cycloalkyl ethers, C1-C6-alkyl-C1-C6-alkyl ethers and C1-C6-alkyl-C6-C10-aryl ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, MTBE, DME, CH3OCH2CH2OCH3, dioxane, anisole, and THF; nitriles, preferably C1-C6-nitriles, such as CH3CN, and CH3CH2CN; alcohols, preferably C1-C4-alcohols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH, and C(CH3)3OH; amides and urea derivatives, preferably DMF, NMP, DMA, DMI, DMPU, HMPA; moreover DMSO, sulfolane, H2O, and mixtures thereof. Second, NH2OH may be added to the reaction mixture to yield compounds of formula (4). Typically, NH2OH is added at a temperature of from 0 to 40° C., which temperature may then be raised to 60 to 120° C.
Compounds of formula (4) may then be converted to compounds of formula (5) in a condensation reaction in the presence of a catalyst at a temperature of from 80 to 150° C. in a polar solvent. Suitable solvents include halogenated hydrocarbons, preferably halogenated aliphatic C1-C6-alkanes, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, preferably C1-C6-cycloalkyl ethers, C1-C6-alkyl-C1-C6-alkyl ethers and C1-C6-alkyl-C6-C10-aryl ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, MTBE, DME, CH3OCH2CH2OCH3, dioxane, anisole, and THF; esters, preferably esters of aliphtic C1-C6-alcohols with aliphatic C1-C6-carboxylic acids, esters of aromatic C6-C10-alcohols with aromatic C6-C10-carboxylic acids, cyclic esters of ω-hydroxy-C1-C6-carboxylic acids, such as CH3C(O)OCH2CH3, CH3C(O)OCH3, CH3C(O)OCH2CH2CH2CH3, CH3C(O)OCH(CH3)CH2CH3, CH3C(O)OC(CH3), CH3CH2CH2C(O)OCH2CH3, CH3CH(OH)C(O)OCH2CH3, CH3CH(OH)C(O)OCH3, CH3C(O)OCH2CH(CH3)2, CH3C(O)OCH(CH3)2, CH3CH2C(O)OCH3, benzyl benzoate, and γ-butyrolactone; carbonates, such as ethylene carbonate, propylene carbonate, CH3CH2OC(O)OCH2CH3, and CH3OC(O)OCH3; nitriles, preferably C1-C6-nitriles, such as CH3CN, and CH3CH2CN; ketones, preferably C1-C6-alkyl-C1-C6-alkyl ketones, such as CH3C(O)CH3, CH3C(O)CH2CH3, CH3CH2C(O)CH2CH3, and CH3C(O)C(CH3)3 (MTBK); alcohols, preferably C1-C4-alcohols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH, and C(CH3)3OH; amides and urea derivatives, preferably DMF,NMP, DMA, DMI, DMPU, HMPA; moreover DMSO, sulfolane, and H2O. Suitable catalysts in include strong inorganic acids like polyphosphoric acid, H2SO4.
Compounds of formula (5) may then be hydrated with H2 in the presence of a catalyst in an inert solvent. Typical catalysts include Pd on C. Suitable solvents include halogenated hydrocarbons, preferably halogenated aliphatic C1-C6-alkanes, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, preferably C1-C6-cycloalkyl ethers, C1-C6-alkyl-C1-C6-alkyl ethers and C1-C6-alkyl-C6-C10-aryl ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, MTBE, DME, CH3OCH2CH2OCH3, dioxane, anisole, and THF; alcohols, preferably C1-C4-alcohols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH, and C(CH3)3OH; H2O, and mixtures thereof.
Compounds of formula (6) may then be methylated by introducing a suitable protection group at the primary amine, such as an acetate group (compounds of formula (7)), followed by a methylation step (to yield compounds of formula (8) and a hydrolysis step to yield compounds of formula (9). Such reactions are known to the skilled person and may be carried out under reaction conditions known in prior art.
Compounds of formula (9) are then nitrated under routine conditions, e.g. by addition of HNO3 in H2SO4 to yield compounds of formula (10).
Compounds of formula (10) may finally be converted to compounds of formula (11) by addition of a reducing agent in an inert solvent. Suitable reducing agents include LiAlH4, LiBH4, BH3, or SnCl2 in a protic solvent. Such reaction conditions are equally routine methods for the skilled person.
Compounds of formula (11) are then be reacted with a carbonic acid compound of formula (12) in the presence of a coupling agent to yield compounds of formula (13)
Typical Coupling Agents are hexafluorophosphate azabenzotriazole tetramethyl uronium (HA-TU), 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexafluorophosphate (HBTU), or O-(1H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU). The reaction may be carried out in a polar aprotic solvent, such as DMF, in the presence of a base. Compounds of formula (12) are commercially available or may be prepared by methods as inter alia described in WO2016/071214A1, EP Application Number 2115353132.2, and EP Application Number 20168197.0.
Compounds of formula (13) are then treated with an Acid Catalyst, such as CH3COOH, or toluene sulfonic acid, to produce compounds of formula (14), which fall under the definition of compounds of formula (I), in a condensation reaction:
The reaction is typically carried out at elevated temperatures of from 60 to 180° C. in a polar solvent. Typically, the Acid Catalyst also serves as the solvent for the reaction.
Other suitable building blocks for the preparation of compounds of formula (I) are compounds of formula (15), which are accessible as depicted under General Scheme 2 below:
In a first step, compounds of formula (15) are reacted with compounds of formula (17) to yield compounds of formula (18). Such reactions have been described in Journal of Chemistry (2019), 43(25), 9961-9968. The reaction is typically carried out in a two-step approach. In a first step, compounds of formula (16) and compounds of formula (17) are reacted in an inert polar solvent at a temperature of from 60 to 150° C. Typical solvents include halogenated hydrocarbons, preferably halogenated aliphatic C1-C6-alkanes, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, preferably C1-C6-cycloalkyl ethers, C1-C6-alkyl-C1-C6-alkyl ethers and C1-C6-alkyl-C6-C10-aryl ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, MTBE, DME, CH3OCH2CH2OCH3, dioxane, anisole, and THF, and mixtures thereof. Typically, the reaction is carried out in a microwave reactor.
In a second step, a base is added to the reaction mixture at 20 to 30° C. to yield compounds of formula (18). Suitable bases include inorganic bases, such as alkali metal and alkaline earth metal hydroxides, such as LiOH, NaOH, KOH, and Ca(OH)2; alcoholates, such as alkali methanolate, alkali ethanolate, alkali isopropanolate, alkali tert-butanolate, and mixtures thereof.
Subsequently, compounds of formula (18) may be reacted with an aminating agent to yield compounds of formula (15). Reactions of this kind have are routine for the skilled person and may for example be carried out as described in Org. Lett. 2020, 22, 16, 6547-6551; Org. Lett. 2006, 8, 11, 2425-2428 and U.S. Pat. No. 6,046,211A, Example 310.
Compounds of formula (15) may then be reacted with compounds of formula (19) to yield compounds of formula (20) falling under the definition of compounds of formula (I)
Reactions of this type have been described in EP3257853A1 and WO2018206479. The reaction is typically carried out under elevated temperatures of from 50-160° C. in an inert solvent. Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane, or petrol ether; aromatic hydrocarbons, such as benzene, toluene, o-, m-, and p-xylene; halogenated hydrocarbons, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, MTBE, DME, CH3OCH2CH2OCH3, CH3OC(CH3)2CH2CH3, dioxane, anisole, 2-methyltetrahydrofuran, THF, and diethylene glycol; nitriles, such as CH3CN, and CH3CH2CN; alcohols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH, and C(CH3)3OH, CH2(OH)CH2(OH), CH3CH(OH)CH2OH; amides and urea derivatives, such as DMF, NMP, DMA, DMI, DMPU, HMPA; moreover DMSO, sulfolane, and H2O. Mixtures of the above solvents are also possible.
The reaction may be carried out in the presence of a catalyst, such as an acid or a base, preferably a base. Suitable bases are, in general, inorganic bases, such as LiOH, NaOH, KOH, and Ca(OH)2; alkali metal and alkaline earth metal oxides, such as Li2O, Na2O, CaO, and MgO; alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH and CaH2; alkali metal and alkaline earth metal carbonates, such as Li2CO3, K2CO3 and CaCO3; alkali metal bicarbonates, such as NaHCO3; organic bases, such as pyrrolidine; tertiary amines, such as diisopropylethyl-amine, trimethylamine, triethylamine, triisopropylamine and N-methylpiperidine, imidazol, pyridine; substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and polycyclic amides and amidines, such as 1,8-diazabicycloundec-7-ene (DBU), 1,4-Diazabicyclo[2.2.2]octane (DABCO); alkali metal salts of secondary amines, such as alkali diisopropylamide, alkali bis(trimethylsilyl)amide, alkali tetramethylpiperidene; alcoholates, such as alkali methanolate, alkali ethanolate, alkali isopropanolate, alkali tert-butanolate; alkali metal-alkyl, and alkali metal-aryl salts, such as n-butyl lithium, tert-butyl lithium, phenyl lithium. Mixtures of the aforementioned bases are also possible. The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts, in excess or, if appropriate, as solvent.
Compounds of formula (15) and compounds of formula (19) are typically reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of compounds of formula (19).
Compounds of formula (19) are accessible by a variety of synthetic methods, such as described in EP Application Number 2115353132.2, EP Application Number 20168197.0, WO2016/071214A1, and WO2018/206479A1.
By other way of example, compounds of formula (22), falling under the definition of compounds of formula (I), may be obtained as depicted in General Scheme 3
PG means protective group, e.g. benzyl.
In a first step, compounds of formula (23) are reacted with compounds (19) to obtain compounds (24). Reactions of this type have been described in EP3257853A1 and WO2018206479. The reaction is typically carried out under elevated temperatures of from 50-160° C. in an inert solvent. Suitable solvents are aliphatic hydrocarbons, such as pentane, hexane, cyclohexane, or petrol ether; aromatic hydrocarbons, such as benzene, toluene, o-, m-, and p-xylene; halogenated hydrocarbons, or halogenated aromatic C6-C10-hydrocarbons, such as CH2Cl2, CHCl3, CCl4, CH2ClCH2Cl, CCl3CH3, CHCl2CH2Cl, CCl2CCl2, or chlorobenzene; ethers, such as CH3CH2OCH2CH3, (CH3)2CHOCH(CH3)2, MTBE, DME, CH3OCH2CH2OCH3, CH3OC(CH3)2CH2CH3, dioxane, anisole, 2-methyltetrahydrofuran, THF, and diethylene glycol; nitriles, such as CH3CN, and CH3CH2CN; alcohols, such as CH3OH, CH3CH2OH, CH3CH2CH2OH, CH3CH(OH)CH3, CH3(CH2)3OH, and C(CH3)3OH, CH2(OH)CH2(OH), CH3CH(OH)CH2OH; amides and urea derivatives, such as DMF, NMP, DMA, DMI, DMPU, HMPA; moreover DMSO, sulfolane, and H2O. Mixtures of the above solvents are also possible.
The reaction may be carried out in the presence of a catalyst, such as an acid or a base, preferably a base. Suitable bases are, in general, inorganic bases, such as LiOH, NaOH, KOH, and Ca(OH)2; alkali metal and alkaline earth metal oxides, such as Li2O, Na2O, CaO, and MgO; alkali metal and alkaline earth metal hydrides, such as LiH, NaH, KH and CaH2; alkali metal and alkaline earth metal carbonates, such as Li2CO3, K2CO3 and CaCO3; alkali metal bicarbonates, such as NaHCO3; organic bases, such as pyrrolidine; tertiary amines, such as diisopropylethylamine, trimethylamine, triethylamine, triisopropylamine and N-me19etramethridine, imidazol, pyridine; substituted pyridines, such as collidine, lutidine and 4-dimethylaminopyridine, and polycyclic amides and amidines, such as 1,8-diazabicycloundec-7-ene (DBU), 1,4-Diazabicyclo[2.2.2]octane (DABCO); alkali metal salts of secondary amines, such as alkali diisopropylamide, alkali bis(trimethylsilyetramethylpiperidinemethylpiperidene; alcoholates, such as alkali methanolate, alkali ethanolate, alkali isopropanolate, alkali tert-butanolate; alkali metal-alkyl, and alkali metal-aryl salts, such as n-butyl lithium, tert-butyl lithium, phenyl lithium. Mixtures of the aforementioned bases are also possible. The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts, in excess or, if appropriate, as solvent.
Compounds (23) can be prepared as described in WO2017/167832A1, e.g. Example C-1. Compounds (23) and compounds (19) are typically reacted with one another in equimolar amounts. In terms of yield, it may be advantageous to employ an excess of compounds (2).
In a second step, protective group “PG” is removed. This may be achieved by standard methods as described in “Greene's Protective Groups in Organic Synthesis”, Wiley, 2006.
In a third step, the carbonyl group in compounds (25) is converted into an enamine group in compounds (26). Typically, compounds (25) are first reacted with a suitable activating agent, such as triflateanhydride, followed by reaction with NH3. The activation reaction is typically carried out in a suitable inert, aprotic solvent, such as a hydrocarbon, or a halogenated hydrocarbon, at a temperature of from −10 to 25° C. in the presence of a base, such as organic bases, especially pyridine. The subsequent reaction with NH3 is then typically carried out in an organic polar solvent, such as halogenated hydrocarbons and alcohols, at a temperature of from 10 to 50° C.
Finally, compounds (26) are reacted with compounds (27) to obtain compounds (22). The reaction is typically carried out in a polar solvent in the presence of a base. Suitable solvents include H2O, ethers, alcohols, nitriles, amides and urea derivatives, DMSO, and sulfolane. Suitable bases are inorganic bases, preferably alkali metal and alkaline earth metal carbonates, such as Li2CO3, K2CO3 and CaCO3. Typically, compounds (27) are applied in excess compared to compounds (26). They may, however, also be applied in equimolar amounts.
The reaction mixtures are worked up in a customary manner, for example by mixing with water, 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 colorless 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.
The N-oxides may be prepared from the inventive compounds according to conventional oxidation methods, e. g. by treating compounds of formula (I) with an organic peracid such as metachloroperbenzoic acid (cf. WO03/64572 or J. Med. Chem. 38(11), 1892-903, 1995); or with inorganic oxidizing agents such as hydrogen peroxide (cf. J. Heterocyc. Chem. 18(7), 1305-8, 1981) or oxone (cf. J. Am. Chem. Soc. 123(25), 5962-5973, 2001). The oxidation may lead to pure mono-N-oxides or to a mixture of different N-oxides, which can be separated by conventional methods such as chromatography.
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 harmful fungus to be controlled.
A skilled person will readily understand that the preferences for the substituents, also in particular the ones given in the tables below for the respective substituents, given herein in connection with compounds of formula (I) apply for the intermediates accordingly. Thereby, the substituents in each case have independently of each other or more preferably in combination the meanings as defined herein.
Embodiments and preferred compounds of the present invention for use in pesticidal methods and for insecticidal application purposes are outlined in the following paragraphs. The remarks made below concerning preferred embodiments of the variables of compounds of formula (I) are valid both on their own in combination with each other. The variables of the compounds of 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).
The variable A is CH, N, or NH. In one embodiment, A is N. In another embodiment, A is NH. The variable E is N, NH, O, S, or CRE. In one embodiment, E is NRE or CRE. In another embodiment, A is N or NH, and E is NRE or CRE. In another embodiment, A is N and E is NRE. In another embodiment, A is N and E is CRE
The variables G and J are independently C or N, provided that only one of E or G is N. Typically, both G and J are C. In one embodiment, G is N and J is C.
The variable L is N or CRL. In one embodiment, the variable L is N. In another embodiment, the variable L is CRL, preferably wherein RL is H, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy, more preferably wherein RL is H, C1-C3-fluoroalkyl, or C1-C3-fluoroalkoxy, most preferably wherein RL is H, CF3 or OCF3, especially preferably wherein RL is H.
The variable M is N or CRM. In one embodiment, the variable M is N. In another embodiment, the variable M is CRM, preferably wherein RM is H, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy, more preferably wherein RM is H, C1-C3-fluoroalkyl, or C1-C3-fluoroalkoxy, most preferably wherein RM is H, or OCF3, especially preferably wherein RM is H or CF3.
The variable Q is N or CRQ. In one embodiment, the variable Q is N. In another embodiment, the variable Q is CRQ, preferably wherein RQ is H, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy, more preferably wherein RQ is H, C1-C3-fluoroalkyl, or C1-C3-fluoroalkoxy, most preferably wherein RQ is H, CF3, OCHF2, or OCF3, especially preferably wherein RQ is H, CF3, or OCF3, such as CF3.
The variable T is N or CRT. In one embodiment, the variable Q is N. In another embodiment, the variable T is CRT, preferably wherein RT is H, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy, more preferably wherein RT is H, C1-C3-fluoroalkyl, or C1-C3-fluoroalkoxy, most preferably wherein RT is H, or CF3, especially H.
Typically, only one of the variables Q and T is N. In one embodiment, both Q and T are C. In another embodiment, Q is N and T is CRT.
Preferred combinations of variables A, E, G, J, L, M, Q, and T are presented below as formulae (I-A) to (I-M), wherein the variables have a meaning as defined for formula (I).
In one embodiment, compounds of formula (I) are compounds of formula (I-A). In another embodiment, compounds of formula (I) are compounds of formula (I-B). In another embodiment, compounds of formula (I) are compounds of formula (I-A) or (I-B). In another embodiment, compounds of formula (I) are compounds of formula (I-G). In another embodiment, compounds of formula (I) are compounds of formula (I-A), (I-B), or (I-G).
The variable Y is SRY1, S(O)RY1, S(O)2RY1, S(═O)(═NRY2)RY1, or S(═NRY2)(═NRY3)RY1. In one embodiment, the variable Y is S(O)2RY1. In another embodiment, the variable Y is S(═O)(═NRY2)RY1. In another embodiment, the variable Y is S(═NRY2)(═NRY3)RY1.
Each RY1, RY2, RY3 is independently selected from H, C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-cycloalkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl-C1-C3-alkyl, which groups are unsubstituted, or substituted with one or more, same or different substituents selected from halogen and CN;
In another embodiment, each RY1, RY2, RY3 is independently selected from H, C1-C3-alkyl, which is unsubstituted, or substituted with one or more, same or different substituents selected from halogen; phenyl, which is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, CN, C1-C3-alkyl, and C1-C3-haloalkyl; or two substituents selected from RY1, RY2, RY3 form, together with the heteroatoms atom to which they are bound, a 5- or 6-membered partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with halogen, and wherein said heterocycle comprises no, one or more, same or different heteroatoms O, N, or S in addition to the heteroatoms to which the substituents selected from RY1, RY2, and RY3 are bound to.
Typically, each RY1, RY2, RY3 is selected from H, C1-C3-alkyl and C1-C3-haloalkyl. Preferably, RY1 is selected from C1-C3-alkyl and C1-C3-haloalkyl, and RY2 is selected from H, C1-C3-alkyl, and C1-C3-haloalkyl.
Accordingly, Y is preferably SO2RY1, or S(═O)(═NRY2)RY1, wherein RY1 is C1-C3-alkyl or C1-C3-haloalkyl, and RY2 is H, C1-C3-alkyl, or C1-C3-haloalkyl. More preferably, Y is SO2RY1.
The index n is 0, 1, 2, 3, or 4, if X is phenyl, or a 6-membered heteroaryl, or 0, 1, 2, or 3 if X is a 5-membered heteroaryl. Typically, n is 1. In one embodiment, n is 0. In another embodiment, n is 2. In another embodiment, n is 3.
RE, RL, RM, RQ, and RT are independently H, halogen, N3, CN, NO2, SCN, SF5; C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, tri-C1-C6-alkylsilyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxyx-C1-C4-alkyl, which groups are halogenated or non-halogenated; C(═O)OR1, NR2R3, C1-C6-alkylen-NR2R3, O—C1-C6-alkylen-NR2R3, C1-C6-alkylen-CN, NH—C1-C6-alkylen-NR2R3, C(═O)NR2R3, C(═O)R4, SO2NR2R3, S(═O)mR5, OR6, C(═O)R6, SR6, or CH2R6; or phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11.
RE is typically H, halogen; C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C5-cycloalkyl, which groups are halogenated or non-halogenated. In one embodiment, RE is H, C1-C1-C3-alkyl, or C1-C3-haloalkyl. In another embodiment, RE is H or CH3. In another embodiment, RE is CH3.
RL is typically H, halogen; C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C5-cycloalkyl, which groups are halogenated or non-halogenated. In one embodiment, RL is H, C1-C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy. In another embodiment, RL is H or CF3. In another embodiment, RL is H.
RM is typically H, halogen; C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C5-cycloalkyl, which groups are halogenated or non-halogenated. In one embodiment, RM is H, C1-C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy. In another embodiment, RM is H or CF3.
RQ is typically H, halogen; C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C5-cycloalkyl, which groups are halogenated or non-halogenated. In one embodiment, RQ is H, C1-C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy. In another embodiment, RQ is H, CF3, or OCF3. In another embodiment, RQ is H, CF3 or OCF3. In another embodiment, RQ is H. In another embodiment, RQ is CF3.
RT is typically H, halogen; C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C5-cycloalkyl, which groups are halogenated or non-halogenated. In one embodiment, RT is H, C1-C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy. In another embodiment, RT is H, CF3, or OCF3. In another embodiment, RT is H, C1-C3-haloalkyl, or C1-C3-haloalkoxy. In another embodiment, RT is H.
In one embodiment, RM, RQ, and RT are independently H; or C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, or C1-C6-alkyl-S(O)m, which groups are halogenated or non-halogenated.
In another embodiment, RM, RQ, and RT are independently H; or C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C6-cycloalkyl, or C3-C6-cycloalkoxy, which groups are halogenated or non-halogenated. In another embodiment, RM, RQ, and RT are independently H; or C1-C3-alkyl, or C1-C3-alkoxy, which groups are halogenated or non-halogenated.
In another embodiment, RM, RQ, and RT are independently H; or C1-C3-haloalkyl, or C1-C3-haloalkoxy. In another embodiment, RM, RQ, and RT are independently H; or C1-C3-fluoroalkyl, or C1-C3-fluoroalkoxy, wherein at least one substituent RM, RQ, RT, and RV is not H.
In one embodiment, RL, RM, RQ, and RT are independently H; or C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, or C1-C6-alkyl-S(O)m, which groups are halogenated or non-halogenated.
In another embodiment, RL, RM, RQ, and RT are independently H; or C1-C3-alkyl, C1-C3-alkoxy, C2-C3-alkenyl, C2-C3-alkynyl, C3-C6-cycloalkyl, or C3-C6-cycloalkoxy, which groups are halogenated or non-halogenated. In another embodiment, RL, RM, RQ, and RT are independently H; or C1-C3-alkyl, or C1-C3-alkoxy, which groups are halogenated or non-halogenated.
In another embodiment, RL, RM, RQ, and RT are independently H; or C1-C3-haloalkyl, or C1-C3-haloalkoxy. In another embodiment, RL, RM, RQ, and RT are independently H; or C1-C3-fluoroalkyl, or C1-C3-fluoroalkoxy, wherein at least one substituent RL, RM, RQ, RT, and RV is not H.
In one embodiment, RE and RL are independently H, halogen; C1-C4-alkyl, C1-C4-alkoxy, C2-C4-alkenyl, or C2-C4-alkynyl, which groups are halogenated or non-halogenated. In another embodiment, RE and RL are independently H, C1-C3-alkyl, or C1-C3-haloalkyl. In another embodiment, RE and RL are independently H, or C1-C3-alkyl. In another embodiment, RL is H and RE is H or C1-C3-alkyl.
The cycle X is phenyl, or a 5- or 6-membered heteroaryl, preferably phenyl or 2-pyridyl. For the avoidance of doubt, the cycle X is substituted with n substituents RX. Also, for the avoidance of doubt, X is connected to Y and to the tricyclic system by direct chemical bonds to two adjacent ring members of X.
In one embodiment, X is phenyl. In another embodiment, X is a 5-membered heteroaryl. In another embodiment, X is a 6-membered hetary. In another embodiment, X is a 5-membered heteroaryl comprising one N-atom. In another embodiment, X is a 6-membered heteroaryl comprising at least one N-atom. In another embodiment, X is a 6-membered heteroaryl comprising two N-atoms.
Preferred 5- or 6-membered heteroaryls X are depicted below as formulae A-1 to A-48, wherein “&” stands for the connection to the trycyclic scaffold of compounds of formula (I). For the avoidance of doubt, the formulae A-1 to A-48 are preferred embodiments on their own and in combination for the following moiety of formula (I)
wherein “&” stands for the connection to the tricyclic scaffold in formula (I). In other words, the substituents Y and (RX)n in formulae A1 to A48 are mere illustrations but are not part of the heteroaryl G.
In one embodiment, X is selected from formulae A-1 to A-14. In one embodiment, X is selected from formulae A-1 to A-3. In another embodiment, X is A-1. In another embodiment, X is A-2. In another embodiment, X is A-3.
R1 is H; C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, or C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are halogenated or non-halogenated; C1-C6-alkylen-NR2R3, C1-C6-alkylen-CN, or CH2R6; or phenyl, which is unsubstituted, or substituted with one or more, same or different substituents R11.
In one embodiment, R1 is phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11. In another embodiment, R1 is H; C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-Calkyl-C1-C4-alkyl, or C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are halogenated or non-halogenated. In another embodiment, R1 is H; C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkynyl, which groups are halogenated or non-halogenated. In another embodiment, R1 is C1-C3-alkyl or C1-C3-haloalkyl.
R11 is halogen, N3, OH, CN, NO2, SCN, SF5; C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are halogenated or non-halogenated.
In one embodiment, R11 is halogen, OH, CN, SF5; C1-C3-alkyl, C1-C3-alkoxy, which groups are halogenated or non-halogenated. In one embodiment, R11 is halogen; C1-C3-alkyl, or C1-C3-haloalkyl.
R2 is H; C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are halogenated or non-halogenated; C(═O)R21, C(═O)OR21, C(═O)NR21, C1-C6-alkylen-CN, or CH2R6; or phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11. In one embodiment, R2 is H; C1-C3-alkyl, C2-C3-alkenyl, C2-C3-alkynyl, which groups are halogenated or non-halogenated. In another embodiment, R2 is H. In another embodiment, R2 is H; C1-C3-alkyl, or C1-C3-haloalkyl.
R21 is H; C1-C6-alkyl, C1-C6-haloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl; C3-C6-cycloalkoxy-C1-C4-alkyl, phenyl, or a saturated, partially-, or fully unsaturated 5- or 6-membered heterocycle, wherein the cyclic moieties are unsubstituted or substituted with one or more, same or different substituents R11. In one embodiment, R21 is H; C1-C3-alkyl, C1-C3-haloalkyl, or phenyl. In another embodiment, R21 is C1-C3-alkyl.
R3 is H; C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are halogenated or non-halogenated; C1-C6-alkylen-CN, or CH2R6; phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11; or NR2R3 may also form an N-bound, saturated 3- to 8-membered heterocycle, which in addition to the nitrogen atom may have 1 or 2 further heteroatoms or heteroatom moieties selected from O, S(═O)m, NH, and N—C1-C6-alkyl, and wherein the N-bound heterocycle is unsubstituted or substituted with one or more, same or different substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy. In one embodiment, R3 is H, C1-C3-alkyl, C1-C3-haloalkyl, or phenyl. In another embodiment, R3 is phenyl. In another embodiment, R3 is H. In another embodiment, R2 is H and R3 is C1-C3-alkyl or phenyl.
R4 is selected from H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which are unsubstituted or substituted with halogen; CH2R6, or phenyl, which is unsubstituted, or substituted with one or more, same or different substituents R11. In one embodiment, R4 is H, C1-C3-alkyl, C1-C3-haloalkyl, or phenyl. In another embodiment, R4 is H. In another embodiment, R4 is C1-C3-alkyl, or C1-C3-haloalkyl. In another embodiment, R4 is C3-C6-cycloalkyl, which is unsubstituted or substituted with CN, preferably 1-cyanocyclopropyl.
R5 C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, or C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are halogenated or non-halogenated; C1-C6-alkylen-NR2R3, C1-C6-alkylen-CN, CH2R6; or phenyl, which is unsubstituted, or substituted with one or more, same or different substituents R11. In one embodiment, R5 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, or phenyl, which groups are unhalogenated or halogenated. In another embodiment, R5 is C1-C3-alkyl or C1-C3-haloalkyl.
R6 is phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11. In one embodiment, R6 is phenyl. In another embodiment, R6 is phenyl that is unsubstituted or substituted with halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, or C1-C3-haloalkoxy.
Each RX is independently halogen, N3, OH, CN, NO2, SCN, SF5;
C1-C6-alkyl, C1-C6-alkoxy, C2-C6-alkenyl, tri-C1-C6-alkylsilyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are unsubstituted or substituted with CN or halogen;
C(═O)OR1, NR2R3, C(═O)NR2R3, C(═O)R4, SO2NR2R3, S(═O)mR1, OR6, SR6, CH2R6, OC(═O)R4, NR3C(═O)R4, OC(═O)OR1, OC(═O)NR2R3, OC(═O)SR1, OC(═S)NR2R3, OC(═S)SR1, ONR2R3, ON═CR1R4, N═CR1R4, NNR2, NR3C(═O)R7, SC(═O)SR1, SC(═O)NR2R3, C(═S)R6, C(═S)OR4, C(═NR2)R4, C(R8)═N—O(R9);
phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11.
a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms O, N, or S, and is unsubstituted, or substituted with one or more, same or different substituents R31, and wherein said N- and S-atoms are independently oxidized, or non-oxidized; or
a group of formula (S)
wherein each RS1, RS2 is independently selected from C1-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C3-C6-cycloalkenyl, C2-C6-alkynyl, C3-C6-cycloalkyl-C1-C3-alkyl, which groups are unsubstituted, or halogenated;
a 3- to 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring or ring system, wherein said heterocyclic ring or ring system comprises one or more, same or different heteroatoms O, N, or S, and is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein said N- and S-atoms are independently oxidized, or non-oxidized;
phenyl, which is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy;
or two substituents RS1, RS2 form, together with the sulfur atom to which they are bound, a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein said heterocycle comprises no, one or more, same or different heteroatoms O, N, or S in addition to the sulfur atom to which RS1 and RS2 are bound to.
Typically, each RX is independently halogen, CN;
C1-C3-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkyl, which groups are unsubstituted or substituted with CN or halogen;
NR3C(═O)R7, C(R8)═N—O(R9);
phenyl, which is unsubstituted or substituted with one or more, same or different substituents R11;
a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms O, N, or S, and is unsubstituted, or substituted with one or more, same or different substituents R31, and wherein said N- and S-atoms are independently oxidized, or non-oxidized; or
a group of formula (S),
wherein each RS1, RS2 is independently selected from C1-C6-alkyl, C3-C6-cycloalkyl, which groups are unsubstituted, or halogenated;
or two substituents RS1, RS2 form, together with the sulfur atom to which they are bound, a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein said heterocycle comprises no, one or more, same or different heteroatoms O, N, or S in addition to the sulfur atom to which RS1 and RS2 are bound to.
In another embodiment, each RX is independently halogen;
C1-C3-alkyl, C1-C3-alkoxy, which groups are unsubstituted or substituted with CN or halogen;
NR3C(═O)R7, C(R8)═N—O(R9);
phenyl, which is unsubstituted or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy;
a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms O, N, or S, and is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, CN, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein two substituents may form together with the carbon-atom to which they are bound a group (C═O), and wherein said N- and S-atoms are independently oxidized, or non-oxidized; or
a group of formula (S),
wherein each RS1, RS2 is independently selected from C1-C3-alkyl, which groups are unsubstituted, or halogenated;
or two substituents RS1, RS2 form, together with the sulfur atom to which they are bound, a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein said heterocycle comprises no, one or more, same or different heteroatoms O, N, or S in addition to the sulfur atom to which RS1 and RS2 are bound to.
In another embodiment, each RX is independently halogen;
C1-C3-alkyl, C1-C3-alkoxy, which groups are unsubstituted or substituted with CN or halogen (such as 1-cyanoisopropyl);
NR3C(═O)R7, C(R8)═N—O(R9);
phenyl, which is unsubstituted or halogenated;
a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms O, N, or S, and is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, CN, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein two substituents may form together with the carbon-atom to which they are bound a group (C═O), and wherein said N- and S-atoms are independently oxidized, or non-oxidized; or a group of formula (S),
wherein each RS1, RS2 is independently selected from C1-C3-alkyl, which groups are unsubstituted, or halogenated;
or two substituents RS1, RS2 form, together with the sulfur atom to which they are bound, a 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein said heterocycle comprises no, one or more, same or different heteroatoms O, N, or S in addition to the sulfur atom to which RS1 and RS2 are bound to.
In another embodiment, each RX is independently halogen; C1-C3-alkyl, which groups are unsubstituted or substituted with halogen; phenyl, which is unsubstituted or halogenated.
In another embodiment, each RX is independently halogen;
C1-C3-alkyl, C3-C6-cycloalkyl, or C1-C3-alkoxy, which groups are unsubstituted or substituted with CN;
NR3C(═O)R7;
phenyl, which is unsubstituted or halogenated;
a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms O, N, or S, and is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein two substituents may form together with the carbon-atom to which they are bound a group (C═O), and wherein said N- and S-atoms are independently oxidized, or non-oxidized; or
a group of formula (S),
wherein each RS1, RS2 is independently selected from C1-C3-alkyl, which groups are unsubstituted, or halogenated;
or two substituents RS1, RS2 form, together with the sulfur atom to which they are bound, a 5- or 6-membered saturated, partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy, and wherein said heterocycle comprises no, one or more, same or different heteroatoms O, N, or S in addition to the sulfur atom to which RS1 and RS2 are bound to.
In another embodiment, each RX is independently halogen;
C1-C3-alkyl, C3-C6-cycloalkyl, or C1-C3-alkoxy, which groups are unsubstituted or substituted with CN;
phenyl, which is unsubstituted or halogenated;
a 6-membered saturated, partially unsaturated, or fully unsaturated heterocyclic ring, wherein said heterocyclic ring comprises one or more, same or different heteroatoms O, N, or S, and wherein two substituents may form together with the carbon-atom to which they are bound a group (C═O); or
a group of formula (S),
wherein each RS1, RS2 is independently selected from C1-C3-alkyl, which groups are unsubstituted, or halogenated;
or two substituents RS1, RS2 form, together with the sulfur atom to which they are bound, a 5-membered saturated, partially unsaturated, or fully unsaturated heterocycle, which heterocycle is unsubstituted, or substituted with one or more, same or different substituents selected from halogen, C1-C3-alkyl, C1-C3-alkoxy, C1-C3-haloalkyl, and C1-C3-haloalkoxy.
R31 is halogen, N3, OH, CN, NO2, SCN, SF5; C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkoxy, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkoxy, C1-C6-alkoxycarbonyl, C3-C6-cycloalkyl; C3-C6-cycloalkoxy, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4 alkyl, phenyl, or a saturated, partially-, or fully unsaturated 5- or 6-membered heterocycle, wherein the cyclic moieties are unsubstituted or substituted with one or more, same or different substituents R11; or two geminal substituents R31 form together with the atom to which they are bound a group ═O or ═S.
In one embodiment, R31 is halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxycarbonyl, or two geminal substituents form together with the atom to which they are bound a group ═O. In one embodiment, R31 is halogen, C1-C3-alkyl, C1-C3-haloalkyl, or two geminal substituents form together with the atom to which they are bound a group ═O.
In one embodiment, R31 is halogen, C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxycarbonyl, or two geminal substituents form together with the atom to which they are bound a group ═O. In one embodiment, R31 is halogen, C1-C3-haloalkyl, or two geminal substituents form together with the atom to which they are bound a group ═O.
The index m is 0, 1, or 2. Typically, m is 0 or 2. In one embodiment, m is 2. In another embodiment, m is 0.
Each R7 is independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are unsubstituted or substituted with one or more, same or different substituents selected from CN and halogen. In one embodiment, each R9 is independently C1-C3-alkyl, or C3-C6-cycloalkyl, which groups are unsubstituted or substituted with one or more, same or different substituents selected from CN and halogen. In another embodiment, each R9 is independently C3-C6-cycloalkyl, which is unsubstituted or substituted with one or more, same or different substituents selected from CN. In another embodiment, R9 is 1-cyanocyclopropyl.
Each R8 is independently H, CN, OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are unsubstituted or substituted with halogen;
phenyl or benzyl, wherein the phenyl ring is unsubstituted or substituted with one or more, same or different substituents R11. In one embodiment, R8 is H, CN, C1-C3-alkyl, or C1-C3-haloalkyl. In another embodiment, R8 is CN.
Each R9 is independently H, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy-C1-C4-alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-C1-C4-alkyl, C3-C6-cycloalkoxy-C1-C4-alkyl, which groups are unsubstituted or substituted with one or more, same or different substituents selected from halogen and CN; phenyl or benzyl, wherein the phenyl ring is unsubstituted or substituted with one or more, same or different substituents R11. In one embodiment, each R9 is independently H, C1-C3-alkyl, or C1-C3-haloalkyl. In another embodiment, each R9 is independently C1-C3-alkyl.
Preferably, compounds of formula (I) are compounds of formulae (II.1), or (III.1)
wherein all variables have a meaning as defined for formula (I).
In another embodiment, compounds of formula (I) are compounds of formulae (II.1), (III.1), or (IV.1)
wherein all variables have a meaning as defined for formula (I).
Table A below contains combinations of meanings for variables RE, Y, and RX in lines S-1 to S-68. The resective numbering S-1 to S-80 of the lines of Table A is used herein below as an abbreviation for the specific combination of meanings of the variables RE, Y and RX in this line.
Table B below contains combinations of meanings for variables RL, RM, RQ, and RT in lines T-1 to T-29. The resective numbering T-1 to T-29 of the lines of Table B is used herein below as an abbreviation for the specific combination of meanings of the variables RL, RM, RQ, and RT in the line of Table B. Moreover, the meanings mentioned for the individual variables in Table A and Table B are per se, independently of the combination in which they are mentioned, a particularly preferred embodiment of the substituents in question.
The following Tables 1 to 58 represent preferred embodiments of combinations of variables RL, RM, RQ, RT, RE, Y and RX with formulae (II.1), or (III.1). In case the variable does not occur in the respective formula, the respective definition of the variable is void.
In one embodiment, the compounds of formula (I) are compounds of formula (I-A), or (I-B) wherein
In another embodiment, the compounds of formula (I) are compounds of formula (I-A), or (I-B) wherein
In another embodiment, the compounds of formula (I) are compounds of formula (I-A), or (I-B) wherein
In one embodiment, the compounds of formula (I) are compounds of formula (II.1), (II.1), or (IV.1)
In one embodiment, the compounds of formula (I) are compounds of formula (II.1), (II.1), or (IV.1)
In another embodiment, the compounds of formula (I) are compounds of formula (I-A), wherein RE, RL, RM, RQ, and RT are independently H; or
The term “compound(s) of the invention” refers to compound(s) of formula (I), 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).
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. SC, OD, FS), emulsifiable concentrates (e.g. EC), emulsions (e.g. EW, EO, ES, ME), capsules (e.g. CS, 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. The compositions are prepared in a known manner, e.g. described by Mollet and Grubemann, Formulation technology, Wiley VCH, Weinheim, 2001; or Knowles, New developments in crop protection product formulation, Agrow Reports DS243, T&F Informa, London, 2005.
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-substituted 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. There-fore, 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, grape-fruits 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, 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.
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 I.
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 I. 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 following examples illustrate the invention.
Materials: Unless otherwise noted, reagents and solvents were purchased at highest commercial quality and used without further purification. Dry tetrahydrofuran (THF), ethylacetate (EtOAc), dimethylsulfoxide (DMSO), acetone, ethanol (EtOH), benzene, dimethylformamide (DMF), diisopropylethylamine (DIPEA), hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), pyridine, and CH2Cl2 were purchased from commercial providers.
All reactions were monitored by thin-layer chromatography (TLC) using Merck silica gel 60 F254 pre-coated plates (0.25 mm). Flash chromatography was carried out with Kanto Chemical silica gel (Kanto Chemical, silica gel 60N, spherical neutral, 0.040-0.050 mm, Cat.-No. 37563-84). If not otherwise indicated, 1H NMR spectra were recorded on JEOL JNM-ECA-500 (500 MHz). Chemical shifts are expressed in ppm downfield from the internal solvent peaks for acetone-d6 (1H; δ=2.05 ppm) and CD3OD (1H; δ=3.30 ppm), and J values are given in Hertz. The following abbreviations were used to explain the multiplicities: s=singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, dt=double triplet, m=multiplet, br=broad. High-resolution mass spectra were measured on a JEOL JMS-T100LP.
Step 1: Preparation of 3-nitro-6-(trifluoromethyl)pyridin-2-amine:
A composition containing 2-chloro-3-nitro-6-(trifluoromethyl)pyridine (43.3 mmol), an aqueous solution of NH3 (30% in H2O, 13 mL) and CH3CN (40 mL) was stirred at 80° C. for 16 hours. The reaction mixture was then cooled down to 20 to 25° C. and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford give 3-nitro-6-(trifluoromethyl)pyridin-2-amine (8.34 g). 1H-NMR (400 MHz, CDCl3): δ 8.60 (d, J=8.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H).
Step 2: Preparation of N′-hydroxy-N-(3-nitro-6-(trifluoromethyl)pyridin-2-yl)formimidamide:
A solution of 3-nitro-6-(trifluoromethyl)pyridin-2-amine (40.2 mmol) and dimethylformamidimethylacetal (52.3 mmol) in (CH3)2CHOH (200 mL) was heated to 80° C. and stirred for 4 hours. The reaction mixture was then cooled to 20 to 25° C., upon which hydroxylamine hydrochloride (52.3 mmol) was added. After the resulting reaction mixture was stirred at 80° C. for 4 hours, the mixture was cooled to 20 to 25° C. The reaction was then quenched with H2O and the resulting composition was extracted. The combined organic layers were dried, filtered and concentrated under reduced pressure to afford N′-hydroxy-N-(3-nitro-6-(trifluoromethyl)pyridin-2-yl)formimidamide (9.85 g). 1H-NMR (400 MHz, DMSO-d6): δ 11.56 (s, 1H), 10.45 (d, J=9.2 Hz, 1H), 8.83 (d, J=8.4 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H).
Step 3: Preparation of 8-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine:
A solution of N′-hydroxy-N-(3-nitro-6-(trifluoromethyl)pyridin-2-yl)formimidamide (39.3 mmol) and polyphosphoric acid (268.0 mmol) in 1,4-dioxane (150 mL) was stirred at 100° C. for 16 hours. The reaction mixture was then cooled to 20 to 25° C. and concentrated to remove the contained 1,4-dioxane. The resulting residue was treated with H2O, and it the pH value was adjusted to 9 at a temperature of ° C. The resulting composition was extracted and the combined organic layers were dried, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford 8-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (5.93 g). 1H-NMR (400 MHz, CDCl3): δ 8.71 (s, 1H), 8.60 (d, J=8.2 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H). LCMS (ESI) m/z 233.0 [M+H]+.
Step 4: Preparation of 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine:
A solution of 8-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (25.5 mmol) in CH3CH2OH (100 mL) was added to a solution of Pd/C (593 mg, 10% w/w) in CH3CH2OH (20 mL). The resulting reaction mixture was stirred at 20 to 25° C. under H2 (1 atm) for 16 hours. The reaction mixture was then filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to afford crude 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (5.01 g). 1H-NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 6.59 (d, J=8.0 Hz, 1H), 5.00 (Br s, 2H).
To a solution of 5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (7.32 mmol) in 1,2-dichloroethane (50 mL) was added acetyl chloride (36.6 mmol) and pyridine (36.6 mmol) at 0° C. The resulting reaction mixture was stirred at 20 to 25° C. for 2 hours. The reaction mixture was quenched with H2O and the resulting composition was extracted. The combined organic layers were dried and concentrated under reduced pressure. The residue was purified by flash column chromatography to afford N-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetamide (1.54 g, 70% yield). 1H-NMR (400 MHz, CDCl3): δ 8.55 (d, J=8.2 Hz, 1H), 8.51 (br s, 1H), 8.39 (s, 1H), 7.46 (d, J=8.2 Hz, 1H), 2.35 (s, 3H). LCMS (ESI) m/z found, 245.1 [M+H]+.
Step 6: Preparation of N-methyl-N-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetamide:
To a solution of N-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetamide (30.3 mmol) in DMF (80 mL) was added NaH (60% in mineral oil, 1.45 g, 60.7 mmol) at 0° C. After the resulting composition was stirred at 0° C. for 1 hours, CH3I (46 mmol) was added. The resulting reaction mixture was stirred at 20 to 25° C. for another 1 hours. The reaction mixture was then quenched by H2O and the resulting composition was extracted. The combined organic layers were dried and concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography to afford N-methyl-N-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetamide (5.53 g). 1H-NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 7.55-7.50 (m, 2H), 3.48 (s, 3H), 2.10 (s, 3H). LCMS (ESI) m/z found, 259.1 [M+H]+.
Step 7: preparation of N-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine:
To a solution of N-methyl-N-(5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl)acetamide (21.4 mmol) in CH3OH (100 mL) was added HCl (6 N aqueous, 60 mL) at 20 to 25° C. After the resulting reaction mixture had been stirred at 50° C. for 16 hours, the reaction mixture was cooled to 20 to 25° C. The reaction mixture was then concentrated under reduced pressure, and the residue was treated with H2O, and the resulting composition was extracted. The combined organic layers were dried, filtered, and concentrated under reduced pressure to afford crude N-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (4.24 g). LCMS (ESI) m/z found, 217.1 [M+H]+.
Step 8: Preparation of N-methyl-7-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine:
To a solution of N-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (19.6 mmol) in sulfuric acid (30 mL) was added nitric acid (19.6 mmol) at 0° C. After the resulting reaction mixture had been stirred at 0° C. for 30 minutes, the reaction mixture was poured into ice water. The resulting composition was treated with H2O and extracted. The combined organic layers were dried and concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography to afford N-methyl-7-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (4.69 g). 1H-NMR (400 MHz, CDCl3): δ 8.69 (s, 1H), 8.18 (s, 1H), 3.95 (s, 3H).
Step 9: Preparation of N8-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7,8-diamine:
To a solution of N-methyl-7-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (17.9 mmol) in CH3CH2OH (100 mL) was added SnCl2·2H2O (71.8 mmol) at 20 to 25° C. After the resulting reaction mixture was stirred at 80° C. for 2 hours, the reaction was quenched with an aqueous saturated solution of NaHCO3. The resulting composition was filtered by a pad of Celite, and the filtrate was extracted. The combined organic layers were dried and concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography to afford N8-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7,8-diamine (1.66 g). 1H-NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 6.98 (s, 1H), 3.06 (s, 3H).
LCMS (ESI) m/z found, 232.1 [M+H]+.
Step 1: Preparation of methyl 5-bromo-3-chloropicolinate:
To a solution of 5-bromo-3-chloropicolinic acid (85.0 mmol) in CH3OH (200 mL) was added thionyl chloride (102 mmol) dropwise at 20 to 25° C. The resulting reaction mixture was stirred at 75° C. for 2.5 hours. The solvent was removed under reduced pressure to afford a residue. The residue was treated with CH2CL2 and and aqueous saturated solution of NaHCO3. The resulting mixture was extracted and the combined organic layers were dried, filtered and concentrated under reduced pressure to afford methyl 5-bromo-3-chloropicolinate (20.9 g) which was used to next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 8.63 (d, J=1.8 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 4.01 (s, 3H).
Step 2: methyl 5-bromo-3-(ethylthio)picolinate:
To a solution of methyl 5-bromo-3-chloropicolinate (59.9 mmol) in THF (260 mL) was added sodium ethanethiolate (59.9 mmol) at 0° C., and the resulting reaction mixture was stirred at 0° C. for 1 hour. Subsequently, the the reaction mixture was stirred at 20 to 25° C. for 16 hours. Then, the reaction mixture was concentrated under reduced pressure to afford a residue, which was treated with H2O and extracted. The combined organic layers were dried, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford methyl 5-bromo-3-(ethylthio)picolinate (2.58 g). 1H-NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 7.78 (s, 1H), 3.99 (s, 3H), 2.94 (q, J=7.4 Hz, 2H), 1.41 (t, J=7.4 Hz, 3H). LCMS (ESI) m/z 276.0 [M+H]+ and 298.0 [M+Na]+.
Step 3: methyl 5-bromo-3-(ethylsulfonyl)picolinate:
To a solution of methyl 5-bromo-3-(ethylthio)picolinate (7.31 mmol) in CH2Cl2 (50 mL) was added 3-chloroperbenzoic acid (16.8 mmol) at 0° C. After stirring the resulting reaction mixture at 0° C. for 1 hour, the reaction mixture was quenched, washed, and extracted. The combined organic layer was dried, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by silica gel column chromatography to afford methyl 5-bromo-3-(ethylsulfonyl)picolinate (2.61 g). 1H-NMR (400 MHz, CDCl3): δ 8.90 (d, J=2.0 Hz, 1H), 8.51 (d, J=2.0 Hz, 1H), 4.04 (s, 3H), 3.57 (q, J=7.6 Hz, 2H), 1.37 (t, J=7.6 Hz, 3H).
Step 4: 5-bromo-3-(ethylsulfonyl)picolinic Acid:
To a solution of methyl 5-bromo-3-(ethylsulfonyl)picolinate (8.47 mmol) in THF/H2O (80 mL, 3:1 (v/v)) was added LiOH (12.7 mmol) at 0° C. and the resulting reaction mixture was stirred at 20 to 25° C. for 1 hour. The pH of the reaction mixture was then adjusted with Dowex H+ (pH=6), which reaction mixture was then filtered, and concentrated under reduced pressure to afford 5-bromo-3-(ethylsulfonyl)picolinic acid (2.63 g), which was used to next step without further purification. 1H-NMR (400 MHz, DMSO-d6): δ 8.78 (d, J=2.4 Hz, 1H), 8.18 (d, J=2.4 Hz, 1H), 3.75 (q, J=7.6 Hz, 2H), 1.08 (t, J=7.6 Hz, 3H).
Step 1: 5-bromo-3-(ethylsulfonyl)-N-(8-(methylamino)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)picolinamide:
A solution of 5-bromo-3-(ethylsulfonyl)picolinic acid (3.24 mmol) in thionyl chloride (8 mL) was heated to 80° C. for 2 hours. The reaction mixture was then concentrated in vacuo to remove residual thionyl chloride. A solution of N8-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7,8-diamine (2.16 mmol) and (CH3CH2)3N (3.2 mmol) in CH2Cl2 (10 mL) was added to the reaction mixture at 0° C. After the resulting reaction mixture was stirred at 20 to 25° C. for 1 hour, the reaction was quenched with H2O and extracted. The combined organic layers were dried, filtered and concentrated under reduced pressure to afford crude 5-bromo-3-(ethylsulfonyl)-N-(8-(methylamino)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)picolinamide (1.3 g), which was used in the next step without purification.
Step 2: 8-(5-bromo-3-(ethylsulfonyl)pyridin-2-yl)-9-methyl-5-(trifluoromethyl)-9H-imidazo[4,5-c][1,2,4]triazolo[1,5-a]pyridine:
A solution of 5-bromo-3-(ethylsulfonyl)-N-(8-(methylamino)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)picolinamide (2.56 mmol) in CH3COOH (4 mL) was stirred at 110° C. for 16 hours. After the reaction mixture was cooled to 20 to 25° C., it was treated with H2O and extracted. The combined organic layers were dried, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography. The product was washed with CH3OH to afford 8-(5-bromo-3-(ethylsulfonyl)pyridin-2-yl)-9-methyl-5-(trifluoromethyl)-9H-imidazo[4,5-c][1,2,4]triazolo[1,5-a]pyridine (549 mg). 1H-NMR (400 MHz, CDCl3): δ 9.06 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 7.88 (s, 1H), 4.29 (s, 3H), 3.88 (q, J=7.6 Hz, 2H), 1.41 (t, J=7.6 Hz, 3H). LCMS (ESI) m/z found, 489.0 [M+H]+; HPLC purity: 99.53%, tR (retention time)=21.13 min.
Step-1: Preparation of 3-bromo-6-(trifluoromethyl)pyridin-2-amine (Compound I.8)
To a solution of 6-(trifluoromethyl)pyridin-2-amine (333 g) in CH2Cl2 (2.30 L) was added Br2 (344 g). The resulting reaction mixture was stirred at 0-25° C. for 2 hours. The reaction mixture was poured into water. Then the aqueous layer was washed with a saturated aqueous solution of NaHCO3. The organic layer was dried, and concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford a crude product. The crude product was triturated with n-hexane:2-methoxy-2-methylpropane=10:1 (500 mL) at 5° C. for 1 hour to afford 3-bromo-6-(trifluoromethyl)pyridin-2-amine (708 g) as a white solid. 1H-NMR: (400 MHz, CDCl3) δ 7.78-7.96 (m, 1H), 6.88-6.91 (m, 1H), 5.26-5.48 (s, 2H).
Step-2: Preparation of N-[3-bromo-6-(trifluoromethyl)-2-pyridyl]-N′-hydroxy-formamidine
To a solution of 3-bromo-6-(trifluoromethyl)pyridin-2-amine (354 g) in (CH3)2CHOH (2.40 L) was added dimethylformamide-dimethylacetal (350 g) at 25° C. The resulting mixture was stirred at 85° C. for 3 hours. The mixture was then cooled to 50° C., upon which hydroxylamine; hydrochloride (204 g) was added. Subsequently, the mixture was stirred at 90° C. for 9 hours. The solvent was then evaporated under reduced pressure to afford a residue, to which water (2.00 L) was added. The resulting mixture was extracted and the combined organic phaseses dried. The solvent was evaporated under reduced pressure to afford N-[3-bromo-6-(trifluoromethyl)-2-pyridyl]-N′-hydroxy-formamidine (640 g) as a white solid. 1H-NMR: (400 MHz, CDCl3) δ 8.43-8.46 (d, J=12 Hz, 1H), 8.16-8.18 (d, J=8.0 Hz, 1H), 7.95-7.96 (d, J=4.0 Hz, 1H), 7.14-7.16 (d, J=8.0 Hz, 2H).
Step-3: Preparation of 8-bromo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine
A mixture of N-[3-bromo-6-(trifluoromethyl)-2-pyridyl]-N′-hydroxy-formamidine (320 g) and polyphosphoric acid (761 g) in dioxane (2.24 L) was stirred at 100° C. for 12 hours. The mixture was then poured into ice water (1.50 L), then the mixture was adjusted to pH=8-9 with saturated aqueous solution of NaOH. Then, the resulting mixture was extracted, and the combined organic phases were washed, dried, filtered and concentrated to afford a crude product. The crude product was triturated with n-heptane (1.50 L) at 25° C. for 1 hour to afford 8-bromo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (490 g) as a brown solid. 1H-NMR:(400 MHz, CDCl3) δ 8.51 (s, 1H), 7.87-7.89 (d, J=8.0 Hz, 1H), 7.36-7.38 (d, J=8.0 Hz, 1H).
Step-4: Preparation of tert-butyl N-methyl-N-[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbamate
To a solution of 8-bromo-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine (245 g), tert-butyl N-methylcarbamate (181 g), and Cs2CO3 (450 g) in dioxane (1.70 L) was added (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane (53.2 g) and (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium (42.1 g,) at 25° C. The resulting reaction mixture was stirred at 100° C. for 12 hours under N2. The reaction mixture was then filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography to give tert-butyl N-methyl-N-[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbamate (380 g) as a yellow solid. 1H-NMR: (400 MHz, DMSO) δ 8.70 (s, 1H), 7.82-7.83 (d, J=4.0 Hz, 1H), 7.75-7.77 (d, J=4.0 Hz, 1H), 3.33 (s, 3H), 1.33 (s, 9H).
Step-5: Preparation of N-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine
A mixture of tert-butyl N-methyl-N-[5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-yl]carbamate (224 g) and CF3COOH (808 g) in CH2Cl2 (1.61 L) was stirred at 25° C. for 12 hours. The mixture was then poured into water (1.00 L), and the separated organic layer was further washed with water (1.00 L×2). Then, the organic phase was washed with saturated aqueous solution of NaHCO3 (about 1.00 L). The combined organic phases were washed with brine, dried, filtered and concentrated to N-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (133 g, 84.6% yield, 97.4% purity) as a yellow solid. 1H NMR: (400 MHz, DMSO) δ 8.52 (s, 1H), 7.52-7.54 (d, J=8.0 Hz, 1H), 7.35-7.36 (d, J=4.0 Hz, 1H), 6.37-6.39 (d, J=8.0 Hz, 1H), 2.89-2.91 (d, J=8.0 Hz, 3H).
Step-6: Preparation of N-methyl-7-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine
A composition was prepared comprising N-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (47.0 g) in dichloroethane (470 mL), to which was added H2 SO4 (127 g) at 20° C. Then, HNO3 (42.8 g, 68% purity) was added to the composition at 0-5° C., and the resulting reaction mixture was stirred at 0° C. for 1 hour. Then, HNO3 (6.00 g, 68% purity) was added to the reaction mixture at 0° C., which was subsequently stirred at 0° C. for 1 hour. Two parallel reactions were combined for work-up. The reaction mixture was poured into 1.50 kg iced water (1.00 kg ice+500 g water) with CH2Cl2 (300 mL). The resulting mixture was allowed to warm to 25° C. with stirring. The aqueous phase was extracted, the organic phases combined and concentrated to afford a crude product. The crude product was triturated with 2-methoxy-2-methylpropan/n-heptane=1/1 (300 mL) at 25° C. for 2 hours to give N-methyl-7-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (75.7 g) as a yellow solid. LC-MS: mass calculated for C8H7F3N5O2 [M]+ 262, found 263
Step-7: Preparation of N8-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7,8-diamine
To a solution of N-methyl-7-nitro-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-8-amine (55.0 g, 210 mmol) in EtOH (385 mL) was added SnCl2·2H2O (166 g, 737 mmol) and HCl (12 M, 165 mL) at 25° C. Then the mixture was stirred at 25-80° C. for 12 hrs. HPLC showed starting material was consumed completely. The reaction was quenched by addition of ice water (1.00 L), then the mixture was adjusted to pH=9-10 with NaOH (solid) at 5° C., and then the mixture was extracted with EtOAc (300 mL×3). The combined organic layers were washed with H2O (150 mL×2), concentrated under reduced pressure to give a residue (31.0 g crude). The crude product was purified by prep-HPLC (column: Phenomenex luna C18 (250*70 mm, 15 um); mobile phase: [water (TFA)-ACN]; B%: 5%-35%, 27 min) to give N8-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7,8-diamine (17.1 g, 33.5% yield, 95.6% purity) as a pink solid. 1H NMR: (400 MHz, CDCl3) δ 8.21 (s, 1H), 6.97 (s, 1H), 7.35-7.36 (d, J=4.0 Hz, 1H), 3.07 (s, 3H).
Step-8: Preparation of 4-bromo-2-ethylsulfonyl-N-[8-(methylamino)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]benzamide
To a solution of N8-methyl-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridine-7,8-diamine (2.00 g) and diisopropylamine (1.79 g) in dimethylformamide (100 mL) was added 4-bromo-2-ethylsulfonyl-benzoic acid (2.53 g) (synthesized as described in WO2016/023954, p. 86) followed by HATU (4.27 g, 11.25 mmol) in small portions. The resulting reaction mixture was stirred at 20 to 25° C. for 24 hours. The reaction mixture was then poured into water (50.0 mL) and a brown solution was obtained, which was extracted with dichloromethane, then concentrated and purified with column chromatography to give 4-bromo-2-ethylsulfonyl-N-[8-(methylamino)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]benzamide (4.2 g, 96% yield). LC-MS: mass calculated for C17H15BrF3N5O3S [M+2]+ 508, found 508 at 1.106 mins (Method B)
Step-9: Preparation of 11-(4-bromo-2-ethylsulfonyl-phenyl)-12-methyl-7-(trifluoromethyl)-3,5,6,10,12-pentazatricyclo[7.3.0.0{circumflex over ( )}{2,6}]dodeca-1(9),2,4,7,10-pentaene (Compound I.8)
A mixture of 4-bromo-2-ethylsulfonyl-N-[8-(methylamino)-5-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]benzamide (2 g) in CH3COOH (20 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110° C. for 12 hours under N2 atmosphere. The reaction mixture was then poured into H2O (50 mL). Formed crystalline solid was separated by suction filtration. The collected filter cake was purified by column chromatography to give compound I.8 (0.8 g, 41.4% yield, 98% purity) as an off-white solid. LC-MS: mass calculated for C17H13BrF3N5O2S [M+1]+ 489, found 489 at 1.093 mins with Method B
Accordingly, by the above Synthesis Examples 1-2, or by analogous procedures to the procedure described above, the following examples of formula I-A.1 were prepared,
wherein wherein the variables RM, RT, RX, and Z have a meaning as defined in Table E:
1H-NMR (δ); Sol-
(a)is HPLC Method A;
(c)is HPLC Method C
Step-1: Preparation of 7-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one
A composition was prepared comprising 1H-1,2,4-triazol-3-amine (1 g) in dioxane (10 mL). Ethyl 4,4,4-trifluorobut-2-ynoate (2.37 g) was added to the composition, which was subsequently stirred at 110° C. for 2 hours. The reaction was then quenched with water, the aqueous layer was extracted with ethylacetate. The combined organic layers were washed, dried, and concentrated to afford a crud product. The crude product was purified by HPLC to give 7-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (375 mg) as yellow solid. 1H-NMR: (400 MHz, DMSO-d6) δ=8.24 (s, 1H), 6.87 (s, 1H)
Step-2: Preparation of 4-[2-(5-bromo-3-ethylsulfonyl-2-pyridyl)-2-oxo-ethyl]-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-one
A composition was prepared comprising 7-(trifluoromethyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (3.1 g) in CH3CN (150 mL). 2-bromo-1-(5-bromo-3-ethylsulfonyl-2-pyridyl)ethenone (6.2 g) (synthesized as described in WO2021204577, page 79) and K2CO3 (5.2 g) were added to the composition, which was subsequently stirred at 60° C. for 3 hours. The reaction was quenched with water, and the resulting composition extracted with EtOAc. The combined organic layers were washed, dried, and concentrated to afford a crude product. The crude product was purified by column to give 4-[2-(5-bromo-3-ethylsulfonyl-2-pyridyl)-2-oxo-ethyl]-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (3 g) as yellow solid. 1H-NMR:(400 MHz, CDCl3) δ=9.01 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.03 (s, 1H), 6.74 (s, 1H), 5.87 (s, 2H), 3.60 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.4 Hz, 3H).
Step-3: Preparation of 11-(5-bromo-3-ethylsulfonyl-2-pyridyl)-7-(trifluoromethyl)-1,3,5,6,10-pentazatricyclo[7.3.0.0{circumflex over ( )}{2,6}]dodeca-2,4,7,9,11-pentaene
To a solution of 4-[2-(5-bromo-3-ethylsulfonyl-2-pyridyl)-2-oxo-ethyl]-7-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-5-one (500 mg) in CH3CH2CH2CH2OH (2.5 mL) was added NH4(CF3COO) (1.3 g), CH3COOH (600 mg) and a molecular sieve (4A-MS; 500 mg), and the resulting mixture was stirred at 145° C. for 8 hours. The reaction was quenched with water, and extracted with EtOAc. The combined organic layers were washed, dried, and concentrated to afford a crude product. The crude product was purified by column to give compound I.20 (60 mg) as yellow solid. 1H-NMR: (400 MHz, CDCl3) δ=8.96 (d, J=2.0 Hz, 1H), 8.72 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.32 (s, 1H), 7.69 (s, 1H), 4.03 (q, J=7.4 Hz, 2H), 1.43 (t, J=7.4 Hz, 3H).
Accordingly, by the above Synthesis Example 3 or by analogous procedures to the procedure described above, the following examples of formula I-G.1 were prepared,
wherein wherein the variables RM, RT, RX, and Z have a meaning as defined in Table F:
(a)is HPLC Method A;
(b)is HPLC Method B;
(d)is HPLC Method D;
Step 1: Preparation of 1-benzyl-3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyppyrimidine-2,4-dione
To the stirred solution of 3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione (20 g) (prepared as described in WO2018206479, page 65) and K2CO3 (18.41 g) in DMF (150 mL), chloromethylbenzene (12.64 g) was added dropwise at 0° C. The resulting reaction mixture was heated to 95° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled and diluted with ice water (300 mL). Formed precipitate was filtered through buckner funnel and dried over high vacuum to afford 1-benzyl-3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)pyrimidine-2,4-dione as a white solid (20 g). 1H-NMR (300 MHz, DMSO-d6) δ 7.45 (d, J=8 Hz, 2H), 7.1-7.4 (m, 5H), 6.85 (d, J=8 Hz, 2H), 6.35 (s, 1H), 5.2 (s, 2H), 5.25 (s, 2H), 3.82 (s, 3H), 1.21 (t, J=7.4 Hz, 3H).
Step-2: Preparation of 1-benzyl-6-(trifluoromethyl)pyrimidine-2,4-dione
To a stirred solution of 1-benzyl-3-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)pyrimidine-2,4-dione (20 g) in 20% H2O in CH3CN (100 mL) was added ceric ammonium nitrate (35.11 g). The resultant reaction mixture was stirred at 25° C. for 12 hours. After the completion of the reaction, the reaction mixture was diluted with water, and extracted. The organic layers from the extraction were dried, and concentrated dryness under reduced pressure. The obtained crude product was purified by flash column chromatography to afford 1-benzyl-6-(trifluoromethyl)pyrimidine-2,4-dione as white solid (6 g). 1H-NMR (300 MHz, DMSO-d6) δ 11.63 (s,1H), 7.31-7.09 (m, 2H), 7.03-6.94 (m, 2H), 6.83-6.73 (m, 1H), 4.61 (s, 1H), 3.36 (d, J=2.7 Hz, 2H).
Step-3: Preparation of 4-amino-1-benzyl-6-(trifluoromethyl)pyrimidin-2-one
To a composition of 1-benzyl-6-(trifluoromethyl)-3H-pyrimidine-2,4-dione (2 g, 7.407 mmol) in CH2Cl2 (20 V) at 0° C., pyridine (1.733 g) was added and stirred for 10 minutes. Then, trifluoromethanesulfonic anhydride (4.17 g) was added drop wise to the composition over a period of 20 minutes. The resultant reaction mixture was stirred at 20-25° C. for 4 hours. Subsequently, a solution of NH3 in CH3OH (7 N) was added to the reaction mixture, and the resulting mixture was continued to stir for another 4-5 hours. The reaction mixture was then partitioned between CH2Cl2 (250 mL×2) and brine solution (100 mL), Organic layer was separated, dried and concentrated under reduced pressure to get a crude product. The crude product was purified by column chromatography to afford 4-amino-1-benzyl-6-(trifluoromethyl)pyrimidin-2-one as an off white solid (1.0 g, 50% yield). 1H-NMR (300 MHz, DMSO-d6) δ 7.8 (s, 1H), 7.9 (s, 1H), 7.1-7.5 (m, 5H), 6.4 (s, 1H), 5.1 (s, 2H). LC-MS: mass calculated C12H10F3N3O [M−H]1− 269, found 269.
Step-4: Preparation of 6-benzyl-2-(5-bromo-3-ethylsulfonyl-2-pyridyl)-7-(trifluoromethypimidazo-[1,2-c]pyrimidin-5-one
To a stirred solution of 2-bromo-1-(4-bromo-2-ethylsulfonyl-phenyl)ethanone (1.64 g) in (CH3)3COH (2 V) was added 4-amino-1-benzyl-6-(trifluoromethyl)pyrimidin-2-one (1 g). A Molecular sieve was added to the obtained reaction mixture (0.4 g) and the resultant composition was heated to 120° C. for 24 hours. After the completion of the reaction, the composition was filtered through a celite bed, and celite bed was washed with EtOAc. The obtained filtrate was collected and concentrated under reduced pressure to get crude product, which was purified by flash column chromatography to afford 6-benzyl-2-(5-bromo-3-ethylsulfonyl-2-pyridyl)-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-one as a yellow solid (0.65 g). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (d, J=2.2 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H), 8.37 (s, 1H), 7.67 (s, 1H), 7.39-7.19 (m, 5H), 5.30 (s, 2H), 4.08 (q, J=7.4 Hz, 2H), 1.25 (t, J=7.4 Hz, 3H).
Step 5: Preparation of 6-benzyl-2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-one
To the stirred solution of 6-benzyl-2-(5-bromo-3-ethylsulfonyl-2-pyridyl)-7-(trifluoromethyl)-imidazo[1,2-c]pyrimidin-5-one (0.5 g) in dioxane (5 mL) was added imino-dimethyl-oxo-λ6-sulfane (0.129 g) and Cs2CO3 (0.451 g)). The resulting composition stirred under continuous purging of N2 for a period of 5 minutes. Under continued inert condition, tris-(dibenzylidenaceton)-dipalladium(0) (0.042 g) was added to the composition, followed by Xantphos (0.053 g), and the resulting reaction mixture was stirred at 120° C. for a period of 3-4 hours. After completion of the reaction, the reaction mixture was cooled and filtered through a celite followed by washing with 5% CH3OH in CH2Cl2. The obtained filtrate was concentrated to get a brown colored crude residue, which was purified by column chromatography to afford 6-benzyl-2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-one as a pale yellow solid (0.282 g , 52% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.90 (d, J=2.5 Hz, 1H), 7.62 (s, 1H), 7.39-7.18 (m, 5H), 5.30 (s, 2H), 3.96 (q, J=7.4 Hz, 2H), 3.37 (s, 6H), 1.21 (t, J=7.4 Hz, 3H).
Step-6: Preparation of 2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)-6H-imidazo[1,2-c]pyrimidin-5-one
A composition of 6-benzyl-2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-one (0.25 g) in CH3OH (3 mL) was produced. Ammonium formate (0.285 g) was then added to the composition, followed by 10% Pd/C (0.020 g, 0.0226 mmol) at 20 to 25° C. under inert conditions. The mixture was stirred at 25° C. for 12 hours. The reaction mixture was then filtered through a celite bed at 25° C. The celite bed was subsequently washed with CH3OH, and the filtrate containing the reaction mass was concentrated under reduced pressure to dryness, The obtained crude mass was purified by column chromatography to afford 2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)-6H-imidazo[1,2-c]pyrimidin-5-one as a pale yellow solid (0.190 g). 1H NMR (500 MHz, DMSO-d6) δ 12.92 (s, 1H), δ 8.48 (d, J=2.5 Hz, 1H), 8.14 (s, 1H), 7.91 (d, J=2.5 Hz, 1H), 7.35 (s, 1H), 3.94 (s, 2H), 3.40 (s, 6H), 1.19 (dt, J=10.9, 7.2 Hz, 3H).
Step-7: Preparation of 2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethypimidazo[1,2-c]pyrimidin-5-amine
To a solution of 2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)-6H-imidazo[1,2-c]pyrimidin-5-one (0.05 g) in CH2Cl2 (2 mL) and pyridine (0.026 g) was added dropwise trifluoromethanesulfonic anhydride (0.061 g) at 0° C. The resulting mixture was then stirred at 0° C. to 25° C. for 3 hours. A solution of NH3 in CH3OH (7 N) was added to the mixture for 10 minutes at 0° C. The resulting mixture was then stirred at 25° C. for 12 hours, upon which the mixture was concentrated under reduced pressure. The remaining residue was purified by column chromatography to give 2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-amine (0.03 g, 60%) as yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44-8.34 (m, 2H), 8.19 (s, 2H), 7.85 (d, J=2.5 Hz, 1H), 7.30 (s, 1H), 4.06 (q, J=6.4, 5.3 Hz, 2H), 3.41(s, 6H), 1.21-1.14 (m, 3H). LC-MS: mass calculated C16H17F3N6O3S2 [M+H]+ 463, found 463 at 1.851 mins (method A).
Step-8: Preparation of [5-ethylsulfonyl-6-[7-(trifluoromethyl)-1,3,6,10-tetrazatricyclo[7.3.0.02,6]dodeca-2,4,7,9,11-pentaen-11-yl]-3-pyridyl]imino-dimethyl-oxo-λ6-sulfane (compound I.24)
2-[5-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-3-ethylsulfonyl-2-pyridyl]-7-(trifluoromethyl)-imidazo[1,2-c]pyrimidin-5-amine (0.1 g) was dissolved in CH3CH2OH (1 mL) in a 10 mL microwave vial with a magnetic stir bar. Then, a 50% solution of 2-chloroacetaldehyde in H2O (0.034 g) and NaHCO3 (0.036 g) were added to the above mixture. The obtained reaction mixture was heated to 120° C. for 2 hours in microwave. The reaction mixture was then concentrated in vacuo, and the residue was purified by flash chromatography to obtain [5-ethylsulfonyl-6-[7-(trifluoromethyl)-1,3,6,10-tetrazatricyclo[7.3.0.02,6]dodeca-2,4,7,9,11-pentaen-11-yl]-3-pyridyl]imino-dimethyl-oxo-λ6-sulfane. (0.06 g, 56%). 1H-NMR (300 MHz, DMSO-d6) δ 8.56-8.47 (m, 2H), 8.05 (s, 1H), 7.91 (dd, J=19.5, 2.2 Hz, 2H), 7.50 (d, J=1.7 Hz, 1H), 4.02 (q, J=7.4 Hz, 2H), 3.41 (s, 6H), 1.24 (t, J=7.4 Hz, 3H).
The activity of the compounds of formula (I) of the present invention could be demonstrated and evaluated in biological tests described in the following. If not otherwise specified, the test solutions are prepared as follows: The active compound of formula ( ))s dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acteone. The test solution is prepared at the day of use. Test solutions are prepared in general at concentrations of 1000 ppm, 500 ppm, 300 ppm, 100 ppm and 30 ppm (wt/vol).
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 of formula I.2, I.3, and I.4 at 10 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I. 6, I.7, I.8, I.9, I.11, I.12, I.13, I.16, I.20, I.21, I.22 at 800 ppm showed over 70% mortality in comparison with untreated controls.
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 of formula I.2 at 30 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I.3 and I.4 at 30 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I.6, I.7, I.8, I.9, I.10, I.11, I.12, I.13, I.14, I.20, I.21, I.22, I.24, at 800 ppm showed over 70% mortality in comparison with untreated controls.
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 of formula I.2, I.3, and I.4 at 10 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I.5, I.7, I.8, I.9, I.11, I.12, I.13, I.14, I.15, I.16, I.20, I.21, I.22 at 800 ppm showed over 70% mortality in comparison with untreated controls.
Green Peach Aphid (Myzus persicae)
The active compounds were formulated by a Tecan liquid handler in 100% cyclohexanone as a 10,000 ppm solution supplied in tubes. The 10,000 ppm solution was serially diluted in 100% cyclohexanone to make interim solutions. These served as stock solutions for which final dilutions were made by the Tecan in 50% acetone:50% water (v/v) into 10 or 20 ml glass vials. A nonionic surfactant (Kinetic®) was included in the solution at a volume of 0.01% (v/v). The vials were then inserted into an automated electrostatic sprayer equipped with an atomizing nozzle for application to plants/insects. Bell pepper plants at the first true-leaf stage were infested prior to treatment by placing heavily infested leaves from the main colony on top of the treatment plants. Aphids were allowed to transfer overnight to accomplish an infestation of 30-50 aphids per plant and the host leaves were removed. The infested plants were then sprayed by an automated electrostatic plant sprayer equipped with an atomizing spray nozzle. The plants were dried in the sprayer fume hood, removed, and then maintained in a growth room under fluorescent lighting in a 14:10 light:dark photoperiod at about 25° C. and about 20-40% relative humidity. Aphid mortality on the treated plants, relative to mortality on untreated control plants, was determined after 5 days. In this test, compound of formula I.1 at 10 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I.2, I.3, and I.4 at 10 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I.5, I.6, I.7, I.8, I.9, I.10, I.11, I.12, I.13, I.14, I.15, I.16, I.20, I.21, and I.22, at 800 ppm showed over 70% mortality in comparison with untreated controls.
Red Spider Mite (Tetranychus kanzawai)
The active compound of formula ( ))s dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:acetone. Add surfactant (Kinetic) is added at a rate of 0.01% (vol/vol).The test solution is prepared at the day of use. Potted cowpea beans of 4-5 days of age are cleaned with tap water and sprayed with 1-2 ml of the test solution using air driven DeVilbiss® hand atomizer at 20-30 psi (≈1.38 to 2.07 bar). The treated plants are allowed to air dry and afterwards inoculated with 30 or more mites by clipping a cassava leaf section from rearing population. Treated plants are placed inside a holding room at about 25-26° C. and about 65-70% relative humidity. Estimate percent mortality is assessed 72 hours after treatment. In this test, compounds of formula I.2, I.3 and I.4 at 10 ppm showed over 70% mortality in comparison with untreated controls. In this test, compounds of formula I.5, I.6, I.7, I.8, I.9, I.10, I.12, I.13, I.14, I.16, I.20, I.24 at 800 ppm showed over 70% mortality in comparison with untreated controls.
Green Soldier Stink Bug (Nezara viridula)
The active compound is dissolved at the desired concentration in a mixture of 1:1 (vol:vol) distilled water:aceteone. Surfactant (Kinetic) is added at a rate of 0.01% (vol/vol).The test solution is prepared at the day of use. Soybean pods are placed in 90×50 mm glass Petri dishes lined with moistened filter paper and inoculated with ten late 3rd instar N. viridula. Using a hand atomizer, an approximately 2 ml solution is sprayed into each Petri dish. Treated set-up is kept at about 25-26° C. and relative humidity of about 65-70%. Percent mortality is recorded after 5 days. In this test, compounds I.5, I.6 at 300 ppm showed over 70% mortality in comparison with untreated controls.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202121009837 | Mar 2021 | IN | national |
| 21169545.7 | Apr 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/055029 | 3/1/2022 | WO |
