Patent Application
20240287047
The present invention relates to pesticidally active, in particular insecticidally active compounds, to processes for their preparation, to compositions comprising those compounds, and to their use for controlling animal pests, including arthropods and in particular insects or representatives of the order Acarina.
WO 2020/070049, WO 2020/201398 and WO 2021/068179 describe certain diazine-amide compounds.
There have now been found novel pesticidally active bis pyrazine amide compounds.
The present invention accordingly relates, in a first aspect, to a compound of the formula I
Compounds of formula I which have at least one basic centre can form, for example, acid addition salts, for example with strong inorganic acids such as mineral acids, for example perchloric acid, sulfuric acid, nitric acid, nitrous acid, a phosphorus acid or a hydrohalic acid, with strong organic carboxylic acids, such as C1-C4alkanecarboxylic acids which are unsubstituted or substituted, for example by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid or phthalic acid, such as hydroxycarboxylic acids, for example ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or such as benzoic acid, or with organic sulfonic acids, such as C1-C4alkane- or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluenesulfonic acid. Compounds of formula I which have at least one acidic group can form, for example, salts with bases, for example mineral salts such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower-alkylamine, for example ethyl-, diethyl-, triethyl- or dimethylpropylamine, or a mono-, di- or trihydroxy-lower-alkylamine, for example mono-, di- or triethanolamine.
In each case, the compounds of formula I according to the invention are in free form, in oxidized form as a N-oxide or in salt form, e.g. an agronomically usable salt form.
N-oxides are oxidized forms of tertiary amines or oxidized forms of nitrogen containing heteroaromatic compounds. They are described for instance in the book “Heterocyclic N-oxides” by A. Albini and S. Pietra, CRC Press, Boca Raton 1991.
The compounds of formula I according to the invention also include hydrates which may be formed during the salt formation.
The term “C1-Cnalkyl” as used herein refers to a saturated straight-chain or branched hydrocarbon radical attached via any of the carbon atoms having 1 to n carbon atoms, for example, any one of the radicals methyl, ethyl, n-propyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, n-pentyl, 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, or 1-ethyl-2-methylpropyl.
The term “C1-Cnhaloalkyl” as used herein refers to a straight-chain or branched saturated alkyl radical attached via any of the carbon atoms having 1 to n carbon atoms (as mentioned above), where some or all of the hydrogen atoms in these radicals may be replaced by fluorine, chlorine, bromine and/or iodine, i.e., for example, any one of chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 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, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl. According a term “C1-C2fluoroalkyl” would refer to a C1-C2alkyl radical which carries 1, 2, 3, 4, or 5 fluorine atoms, for example, any one of difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2-tetrafluoroethyl or pentafluoroethyl.
The term “C1-Cnalkoxy” as used herein refers to a straight-chain or branched saturated alkyl radical having 1 to n carbon atoms (as mentioned above) which is attached via an oxygen atom, i.e., for example, any one of the radicals methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. The term “haloC1-Cnalkoxy” as used herein refers to a C1-Cnalkoxy radical where one or more hydrogen atoms on the alkyl radical is replaced by the same or different halo atom(s)—examples include trifluoromethoxy, 2-fluoroethoxy, 3-fluoropropoxy, 3,3,3-trifluoropropoxy, 4-chlorobutoxy.
The term “C1-Cncyanoalkyl” as used herein refers to a straight chain or branched saturated C1-Cnalkyl radical having 1 to n carbon atoms (as mentioned above), where one of the hydrogen atoms in these radicals is be replaced by a cyano group: for example, cyanomethyl, 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-ethyl, 1-(methyl)-2-cyanoethyl, 4-cyanobutyl, and the like.
The term “C3-Cncycloalkyl” as used herein refers to 3-n membered cycloalkyl groups such as cyclopropane, cyclobutane, cyclopentane and cyclohexane.
The term “C3-C4cycloalkyl-C1-C2alkyl” as used herein refers to 3 or 4 membered cycloalkyl group with either a methylene or ethylene group, which methylene or ethylene group is connected to the rest of the molecule. In the instance, the C3-C4cycloalkyl-C1-C2alkyl- group is substituted, the substituent(s) can be on the cycloalkyl group and/or on the alkyl group.
The term “aminocarbonylC1-Cnalkyl” as used herein refers to an alkyl radical where one of the hydrogen atoms in the radical is replaced by CONH2 group.
The term “hydroxycarbonylC1-Cnalkyl” as used herein refers to an alkyl radical where one of the hydrogen atoms in the radical is replaced by COOH group.
The term “C1-Cnalkylsulfanyl” as used herein refers to a C1-Cnalkyl moiety linked through a sulfur atom.
Similarly, the term “C1-Cnhaloalkylthio” or “C1-Cnhaloalkylsulfanyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through a sulfur atom. Similarly, the term “C3-Cncycloalkylsulfanyl” refers to 3-n membered cycloalkyl moiety linked through a sulfur atom.
The term “C1-Cnalkylsulfinyl” as used herein refers to a C1-Cnalkyl moiety linked through the sulfur atom of the S(═O) group. Similarly, the term “C1-Cnhaloalkylsulfinyl” or “C1-Cnhaloalkylsulfinyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through the sulfur atom of the S(═O) group. Similarly, the term “C3-Cncycloalkylsulfinyl” refers to 3-n membered cycloalkyl moiety linked through the sulfur atom of the S(═O) group.
The term “C1-Cnalkylsulfonyl” as used herein refers to a C1-Cnalkyl moiety linked through the sulfur atom of the S(═O)2 group. Similarly, the term “C1-Cnhaloalkylsulfonyl” or “C1-Cnhaloalkylsulfonyl” as used herein refers to a C1-Cnhaloalkyl moiety linked through the sulfur atom of the S(═O)2 group. Similarly, the term “C3-Cncycloalkylsulfonyl” refers to 3-n membered cycloalkyl moiety linked through the sulfur atom of the S(═O)2 group
The term “trimethylsilylC1-Cnalkyl” as used herein refers to an C1-Cnalkyl radical where one of the hydrogen atoms in the radical is replaced by a —Si(CH3)3 group.
The term “C2-Cnalkenyl” as used herein refers to a straight or branched alkenyl chain having from two to n carbon atoms and one or two double bonds, for example, ethenyl, prop-1-enyl, but-2-enyl.
The term “C2-Cnhaloalkenyl” as used herein refers to a C2-Cnalkenyl moiety substituted with one or more halo atoms which may be the same or different.
The term “C2-Cnalkynyl” as used herein refers to a straight or branched alkynyl chain having from two to n carbon atoms and one triple bond, for example, ethynyl, prop-2-ynyl, but-3-ynyl,
The term “C2-Cnhaloalkynyl” as used herein refers to a C2-Cnalkynyl moiety substituted with one or more halo atoms which may be the same or different.
The term “heterocyclyl” as used herein in connection with R4aa and R4ab can be 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-3-azabicyclo[3.1.1]heptan-3-yl, 1,4-oxazepan-4-yl, thiomorpholin-4-yl, 1,1-dioxidothiomorpholin-4-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, 3-oxopiperazin-1-yl, 4-methyl-3-oxo-piperazin-1-yl, 3,5-dioxopiperazin-1-yl, 3,3-dimethyl-1,3-azasilinan-1-yl, thiomorpholin-4-yl, wherein the morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl and azetidin-1-yl are optionally substituted with one to four substituents selected from the group consisting of fluorine, hydroxy, methyl, methoxy, 1,2,4-oxadiazolyl, and 2-methylpyrazolyl.
Halogen or “halo” is generally fluorine, chlorine, bromine or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl
As used herein, the term “controlling” refers to reducing the number of pests, eliminating pests and/or preventing further pest damage such that damage to a plant or to a plant derived product is reduced.
The staggered line as used herein, for example, in R4 and K-1, represent the point of connection/attachment to the rest of the compound.
As used herein, the term “pest” refers to insects and molluscs that are found in agriculture, horticulture, forestry, the storage of products of vegetable origin (such as fruit, grain and timber); and those pests associated with the damage of man-made structures. The term pest encompasses all stages in the life cycle of the pest.
As used herein, the term “effective amount” refers to the amount of the compound, or a salt thereof, which, upon single or multiple applications provides the desired effect.
An effective amount is readily determined by the skilled person in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered including, but not limited to: the type of plant or derived product to be applied; the pest to be controlled & its lifecycle; the particular compound applied; the type of application; and other relevant circumstances.
As one of ordinary skill in the art will appreciate, compounds of formula I contain a stereogenic centre which is indicated with an asterisk in the structure below:
where A, X, R1, R2a, R2b, R3, R4, R5a, and R5b are as defined in the first aspect.
The present invention contemplates both racemates and individual enantiomers. Compounds having preferred stereochemistry are set out below.
Particularly preferred compounds of the present invention are compounds of formula I′a: where A, X, R1, R2a, R2b, R3, R4, R5a, and R5b are as defined in the first aspect, and stereoisomers, enantiomers, tautomers and N-oxides of the compounds of formula (I′a), and agrochemically acceptable salts thereof.
The term “optionally substituted” as used herein means that the group referenced is either unsubstituted or is substituted by a designated substituent, for example, “C3-C4cycloalkyl is optionally substituted with 1 or 2 halo atoms” means C3-C4cycloalkyl, C3-C4cycloalkyl substituted with 1 halo atom and C3-C4cycloalkyl substituted with 2 halo atoms.
Embodiments according to the invention are provided as set out below.
In an embodiment of each aspect of the invention, X is O.
In an embodiment of each aspect of the invention, R1 is
In an embodiment of each aspect of the invention, A is
In an embodiment of each aspect of the invention, R2a is
In an embodiment of each aspect of the invention, R2b is
In an embodiment of each aspect of the invention, R3 is
In an embodiment of each aspect of the invention, R4a is
In an embodiment of each aspect of the invention, R4b is
In an embodiment of each aspect of the invention, R4c is
In an embodiment of each aspect of the invention, with reference to table Z below, R4 is
In an embodiment of each aspect of the invention, R5a and R5b, independent of each other and independent of Q1 to Q4, are
In an embodiment of each aspect of the invention, R5a is methyl and R5b is hydrogen.
In an embodiment of each aspect of the invention, R5a is hydrogen and R5b is hydrogen.
The present invention, accordingly, makes available a compound of formula I having the substituents R1, R2a, R2b, R3, R4a, R4b, R4c, R5a, R5b, X, and A as defined above in all combinations/each permutation. Accordingly, made available, for example, is a compound of formula I with A being of the first aspect (i.e. A is N or C—R2c, where R2c is H, halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy); X being O or S; R1 being embodiment B (i.e. hydrogen, methyl, or cyclopropylmethyl); R2a being an embodiment C (i.e. halogen, C1-C3haloalkyl, C1-C3haloalkylthio, C1-C3haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or two substituents independently selected from C1-C3haloalkyl, cyano, C1-C3alkoxy and halogen, C3-C6cycloalkylC1-C4alkyl, C3-C6cycloalkylC1-C4alkyl substituted with one to three substituents independently selected from C1-C3haloalkyl, cyano, and halogen, C1-C6cyanoalkyl, C1-C4alkylsulfonyl, C1-C4haloalkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfinyl, C3-C6cycloalkylsulfanyl, C3-C6cycloalkylsulfinyl, or C3-C6cycloalkylsulfonyl); R2b being embodiment B (i.e. halogen, C1-C3haloalkyl, or C1-C3haloalkoxy); R3 being embodiment B (i.e. methyl); R4a, R4b, and R4c being, independent of each other, of the first aspect (i.e. R4a, R4b, and R4c are, independently of each other, selected from hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, and C1-C3haloalkoxy); and R5a being embodiment A (i.e. selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy); and R5b being embodiment C (i.e. selected from hydrogen, Cl, methyl, methoxy, and OCF2H).
In an embodiment, the compound of formula I can be represented as
In an embodiment of each aspect of the invention, the R2 (the cyclic group containing A and the substituents R2a and R2b) is
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl or HCH≡CCH2—; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkylthio, C1-C3haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or two substituents independently selected from C1-C3haloalkyl, cyano, C1-C3alkoxy and halogen, C3-C6cycloalkylC1-C4alkyl, C3-C6cycloalkylC1-C4alkyl substituted with one to three substituents independently selected from C1-C3haloalkyl, cyano, and halogen, C1-C6cyanoalkyl, C1-C4alkylsulfonyl, C1-C4haloalkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfinyl, C3-C6cycloalkylsulfanyl, C3-C6cycloalkylsulfinyl, or C3-C6cycloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A: N, CCl, CBr, CF, Cl or CH; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkylthio, C1-C3haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or two substituents independently selected from C1-C3haloalkyl, cyano, C1-C3alkoxy and halogen, C3-C6cycloalkylC1-C4alkyl, C3-C6cycloalkylC1-C4alkyl substituted with one to three substituents independently selected from C1-C3haloalkyl, cyano, and halogen, C1-C5cyanoalkyl, C1-C4alkylsulfonyl, C1-C4haloalkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfinyl, C3-C6cycloalkylsulfanyl, C3-C6cycloalkylsulfinyl, or C3-C6cycloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkylthio, C1-C3haloalkoxy, C3-C6cycloalkyl, C3-C6cycloalkyl substituted with one or two substituents independently selected from C1-C3haloalkyl, cyano, C1-C3alkoxy and halogen, C3-C6cycloalkylC1-C4alkyl, C3-C6cycloalkylC1-C4alkyl substituted with one to three substituents independently selected from C1-C3haloalkyl, cyano, and halogen, C1-C5cyanoalkyl, C1-C4alkylsulfonyl, C1-C4haloalkylsulfonyl, C1-C4alkylsulfinyl, C1-C4haloalkylsulfinyl, C3-C6cycloalkylsulfanyl, C3-C6cycloalkylsulfinyl, or C3-C6cycloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, Cl, methyl, methoxy, and OCF2H.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C5cyanoalkyl, or C1-C4haloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, C, methyl, methoxy, and OCF2H.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C5cyanoalkyl, or C1-C4haloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, CF3, O—CF3, or O—CHF2; and as R5a and R5b, independently of each other, selected from hydrogen, C, methyl, methoxy, and OCF2H.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C5cyanoalkyl, or C1-C4haloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, C, Br, CN, or CF3; and as R5a and R5b, independently of each other, selected from hydrogen, C, methyl, methoxy, and OCF2H.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C5cyanoalkyl, or C1-C4haloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4b and R4c each hydrogen and as R4a hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, C, methyl, methoxy, and OCF2H.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as R1 hydrogen, methyl, or cyclopropylmethyl; as R2a halogen, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C5cyanoalkyl, or C1-C4haloalkylsulfonyl; as R2b halogen or C1-C3haloalkyl; as A N or CH; as R3 methyl; as R4b and R4c each hydrogen and as R4a hydrogen, halogen, CN, CF3, O—CF3, or O—CHF2; and as R5a and R5b, independently of each other, selected from hydrogen, C, methyl, methoxy, and OCF2H.
In an embodiment of each aspect of the invention, the compound of formula I-1 or I-1′a has as R1 hydrogen, methyl, ethyl, n-propyl, isobutyl, cyclopropylmethyl or HCH≡CCH2—; as R2 one of K-1 to K-24; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I-1 or I-1′a has as R1 hydrogen, methyl, or cyclopropylmethyl; as R2 one of K-1 to K-24; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I-1 or I-1′a has as R1 hydrogen, methyl, or cyclopropylmethyl; as R2 one of K-1 to K-24; as R3 methyl; as R4a, R4b, and R4c, independently of each other, hydrogen, halogen, CN, CF3, O—CF3, or O—CHF2; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I-1 or I-1′a has as R1 hydrogen, methyl, or cyclopropylmethyl; as R2 one of K-1 to K-24; as R3 methyl; as R4b and R4c each hydrogen and as R4a hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy, or C1-C3haloalkoxy; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I-1 or I-1′a has as R1 hydrogen, methyl, or cyclopropylmethyl; as R2 one of K-1 to K-24; as R3 methyl; as R4b and R4c each hydrogen and as R4a hydrogen, halogen, CN, CF3, O—CF3, or O—CHF2; and as R5a and R5b, independently of each other, selected from hydrogen, halogen C1-C3alkyl, C1-C3alkoxy, and C1-C3haloalkoxy.
Also, for example, a compound of formula I is made available, wherein A is CH or N; X is O; R1 is hydrogen or methyl; R2a is bromine, chlorine, iodine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 1-cyano-1-methylethyl, 1-cyanocyclopropyl, methylsulfonyl, or difluoromethylsulfonyl; R2b is bromine, chlorine, iodine, trifluoromethyl, difluoromethoxy, or trifluoromethoxy; R3 is methyl; R4a is H, Cl or cyano; R4b, R4c, R5a and R5b are each hydrogen.
Also for example, a compound of formula I is made available, wherein A is CH; X is O; R1 is hydrogen; R2a is bromine, chlorine, iodine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 1-cyano-1-methylethyl, 1-cyanocyclopropyl, methylsulfonyl, or difluoromethylsulfonyl; R2b is chlorine, trifluoromethyl, difluoromethoxy, or trifluoromethoxy; R3 is methyl; R4a is H, Cl or cyano, such as R4a is H; R4b, R4c, R5a and R5b are each hydrogen.
Also for example, a compound of formula I is made available, wherein A is CH; X is O; R1 is hydrogen; R2a is chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, 1-cyano-1-methylethyl, 1-cyanocyclopropyl, methylsulfonyl, or difluoromethylsulfonyl; R2b is chlorine, trifluoromethyl, difluoromethoxy, or trifluoromethoxy; R3 is methyl; R4a is H; R4b, R4c, R5a and R5b are each hydrogen.
Also for example, a compound of formula I is made available, wherein A is N; X is O; R1 is hydrogen or methyl; R2a is chlorine, 1-cyano-1-methylethyl, or 1-cyanocyclopropyl; R2b is bromine, chlorine, or trifluoromethyl; R3 is methyl; R4a is H; R4b, R4c, R5a and R5b are each hydrogen.
Also for example, a compound of formula I is made available, wherein A is N; X is O; R1 is hydrogen; R2a is 1-cyano-1-methylethyl, or 1-cyanocyclopropyl; R2b is bromine, chlorine, or trifluoromethyl; R3 is methyl; R4a is H; R4b, R4c, R5a and R5b are each hydrogen.
Also for example, a compound of formula I is made available, wherein A is N; X is O; R1 is hydrogen; R2a is difluoromethyl, or trifluoromethyl; R2b is bromine, chlorine, or trifluoromethyl; R3 is methyl; R4a is H; R4b, R4c, R5a and R5b are each hydrogen.
Also for example, a compound of formula I is made available, wherein A is N; X is O; R1 is hydrogen; R2a is difluoromethyl, or trifluoromethyl; R2b is bromine, or trifluoromethyl; R3 is methyl; R4a is H; R4b, R4c, R5a and R5b are each hydrogen.
In a second aspect, the present invention makes available a composition comprising a compound of formula I as defined in the first aspect, one or more auxiliaries and diluent, and optionally one or more other active ingredient.
In a third aspect, the present invention makes available a method of combating and controlling insects, acarines, nematodes or molluscs which comprises applying to a pest, to a locus of a pest, or to a plant susceptible to attack by a pest an insecticidally, acaricidally, nematicidally or molluscicidally effective amount of a compound as defined in the first aspect or a composition as defined in the second aspect.
In a fourth aspect, the present invention makes available a method for the protection of plant propagation material from the attack by insects, acarines, nematodes or molluscs, which comprises treating the propagation material or the site, where the propagation material is planted, with an effective amount of a compound of formula I as defined in the first aspect or a composition as defined in the second aspect.
In a fifth aspect, the present invention makes available a plant propagation material, such as a seed, comprising, or treated with or adhered thereto, a compound of formula I as defined in the first aspect or a composition as defined in the second aspect.
The present invention in a further aspect provides a method of controlling parasites in or on an animal in need thereof comprising administering an effective amount of a compound of the first aspect. The present invention further provides a method of controlling ectoparasites on an animal in need thereof comprising administering an effective amount of a compound of formula I as defined om the first aspect.
The present invention further provides a method for preventing and/or treating diseases transmitted by ectoparasites comprising administering an effective amount of a compound of formula I as defined in the first aspect, to an animal in need thereof.
Compounds of formula I can be prepared by those skilled in the art following known methods. More specifically compounds of formulae I, and I′a, and intermediates therefor can be prepared as described below in the schemes and examples. Certain stereogenic centers have been left unspecified for the clarity and are not intended to limit the teaching of the schemes in any way.
The process according to the invention for preparing compounds of formula I is carried out by methods known to those skilled in the art.
Compounds of formula I
In Scheme 1 compounds of formula III, wherein R2a, R2b and A are as defined in formula I, are activated to compounds of formula IIIa by methods known to those skilled in the art and described for example in Tetrahedron, 61 (46), 10827-10852, 2005. For example, compounds wherein X0 is halogen are formed by treatment of compounds of formula III with for example, oxalyl chloride or thionyl chloride in the presence of catalytic quantities of DMF in inert solvents such as dichloromethane (DCM) or tetrahydrofuran (THF) at temperatures between 20° C. to 100° C., preferably 25° C. Treatment of IIIa with compounds of formula II, wherein R1, R3, R4, R5a and R5b are as defined in formula I, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), optionally in the presence of a base, for instance sodium, potassium or cesium carbonate, or e.g. triethylamine, diisopropylethylamine or pyridine leads to compounds of formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance ethyl acetate, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide, or mixtures thereof, in a temperature range of −100 to +300° C., preferably between 0° C. and 100° C.
Alternatively, a biphasic mixture involving for example ethyl acetate and an aqueous sodium or potassium bicarbonate or carbonate solution can also be used. Alternatively, compounds of formula I can be prepared by treatment of compounds of formula III with dicyclohexyl carbodiimide (DCC) or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to give the activated species IIIa, wherein X0 is X01 or X02, in an inert solvent, e.g. pyridine, or THE optionally in the presence of a base, e.g. triethylamine, at temperatures between 50-180° C. In addition, an acid of the formula III can also be activated by reaction with a coupling reagent such as propanephosphonic acid anhydride (T3P®) or O-(7-Aza-1-benzotriazolyl)-N,N,N′,N′-tetramethyluronium-hexafluorophosphate (HATU) to provide compounds of formula IIIa, wherein X0 is X03 or X04 as described for example in Synthesis 2013, 45, 1569 and Journal Prakt. Chemie 1998, 340, 581. Subsequent reaction with an amine of the formula II provides compounds of formula I.
Intermediates of formula II, wherein R1, R3, R4, R5a and R5b are as defined in formula I, can be prepared according to Scheme 2.
Compounds IVm (wherein M is a metal and R3, R5a and R5b are as defined in formula I) and compounds Vm (wherein M is a metal and R4a, R4b and R4c are defined as above) are known, or they can be prepared by known metalation reactions from compounds IV (wherein X05 is a leaving group such as chlorine, bromine, iodine, arysulfonate, alkylsulfonate or trifluoromethanesulfonate and R3, R5a and R5b are as defined in formula I) or compounds V (wherein X05 is a leaving group such as chlorine, bromine, iodine, arysulfonate, alkylsulfonate or trifluoromethanesulfonate and R4a, R4b and R4c are defined as above), respectively. Such compounds and transformations are found in the literature, for instance where M is zinc (for instance ZnCl), see WO2008019357, where M is magnesium (for instance MgCl), see Angewandte Chemie, International Edition (2020), 59(19), 7372-7376, where M is boron (for instance B(OH)2), see Bioorganic & Medicinal Chemistry Letters (2010), 20(7), 2326-2329. Such metalation reactions can be done, for instance, by treatment of a heteroaromatic halide, such as a bromide by treatment with butyllithium, or with magnesium, or with isopropylmagnesium chloride, or with pinacolborane, or bispinacolborane, in the presence or absence of a transition metal catalyst, such as a palladium catalyst, in the presence of a base or without a base, in a solvent, such as tetrahydrofurane, for examples, at a temperature between −100° C. and 200° C., preferably in a range between −78° C. and 100° C., heated by microwave or not. Many such transformations are known to a person skilled in the art.
Compounds of formula VI, wherein R3, R4, R5a and R5b are as defined in formula I, can be made by a C—C-coupling reaction of compounds of the formula IV with compounds of the formula Vm, or by a C—C-coupling reaction of compounds of the formula IVm with compounds of the formula V. Usually, such C—C-coupling reactions are done in the presence of a catalyst, for instance in the presence of a palladium catalyst. The C—C-coupling reactions can be achieved in the presence of a base, such as cesium carbonate or sodium tert-butoxide, optionally in the presence of a copper salt such as copper(I) iodide in an inert solvent, such as DMF, acetonitrile, or dioxane at temperatures between 20 and 180° C., preferably at 60-120° C. Additional methods including transition metal-catalyzed methods can be found in the literature. Many such transformations are known to a person skilled in the art.
Compounds of formula VI can be treated with compounds of formula VII (wherein R1 is as defined in formula I), e.g. in the presence of NaBH(OAc)3 or NaBH3CN, preferably with NaBH3CN as reducing reagent, in a suitable solvent, preferable in acetic acid at room temperature analogously to WO2002/088073, p. 35 to form compounds of formula II (wherein R1, R3, R4, R5a and R5b are as defined in formula I). Another reagent system for the reductive amination uses a combination of Ti(OiPr)4 and NaBH4 in the presence of an amine of formula VII to provide compounds of formula II (see Synthesis 2003 (14), 2206).
Alternatively, intermediates of formula II, wherein R1, R3, R4, R5a and R5b are as defined in formula I, can be prepared according to Scheme 3.
In an alternative process (Scheme 3), ketones of formula VI (wherein R3, R4, R5a and R5b are as defined in formula I) can be reduced to alcohols of formula VIII by reduction, for example with NaBH4 in the usual manner (see e.g. WO2012/082997, page 141), preferably in MeOH as solvent. Subsequent activation of the alcohols of formula VIII with compounds of formula X, YSO2Cl, wherein Y is CH3, CF3 or p-CH3-C6H4, in an inert solvent, preferable in dichloromethane or tetrahydrofuran, and in the presence of a base, e.g. triethylamine, affords compounds of formula IX, wherein X07 is OMs (OSO2CH3), OTs (OSO2C6H4-p-CH3) or OTf (OSO2CF3). Alcohols of formula VIII may be also be activated to alkyl halides IX (wherein X07 is Cl or Br) by treatment with phosphorous compounds, e.g. P(X0)3, wherein X0 is chlorine or bromine, by methods known to those skilled in the art. Such general functional group transformations are described for example in Organische Chemie. 4. Auflage, Wiley-VCH Verlag, Weinheim 2005, p. 393ff and Chem Commun. 2014, 50, 5756. Finally, nucleophilic substitution reaction of compound of formula IX with amines of formula VII, wherein R1 is as defined in formula I, furnishes compounds of formula II, wherein R1, R3, R4, R5a and R5b are as defined in formula I.
In yet another alternative process (Scheme 3), alcohols of formula VIII can be made from silyl ethers of formula VIIISi by deprotection, for instance by treatment with fluoride, for example with tetrabutylammonium fluoride, in an inert solvent, such as for example tetrahydrofuran. The reaction can be done in a temperature range of −10° C. to 80° C., for instance between 0° C. and 30° C. Such deprotection reactions are known to a person skilled in the art, and described in the literature, for instance in: Protective Groups in Organic Synthesis, 3rd Edition Theodora W. Green (The Rowland Institute for Science) and Peter G. M. Wuts (Pharmacia and Upjohn Company). John Wiley & Sons, Inc., New York, NY. 1999, ISBN 0-471-16019-9.
Silyl ethers of the formula VIIISi can be made from compounds of the formula VIIIA1, wherein XA1 is a halogen such as iodine or bromine, by metalation, such as by treatment with a Turbo Grignard reagent (iPrMgCl·LiCl) or with butyl lithium. Such metalations are known to a person skilled in the art, and described in the literature, for instance in Carey, Francis A. (2007). “Organometallic compounds of Group I and II metals”. Advanced Organic Chemistry: Reaction and Synthesis Pt. B (Kindle ed.). Springer. ISBN 978-0-387-44899-2. The lithium- or magnesium species thus generated can be transmetalated, for instance with a zinc halide, for example zinc chloride, and subsequently coupled with a compound of the formula VIIA1, wherein R4 has the meaning given above in formula I, and XC1 is a halogen, for example iodine or bromine, in the presence of a catalyst, for instance a palladium catalyst, for example tris(dibenzylideneacetone)dipalladium(0), and of a ligand, for instance a phosphine ligand, such as for example tri(2-furyl)phosphine, in an inert solvent, such as for example tetrahydrofuran. The reaction can be done in a temperature range of −100° C. to 100° C., for instance between −78° C. and 80° C. This transformation is known to a person skilled in the art, for instance as Negishi cross-coupling reaction, and described in the literature, for example in: Jie Jack Li, Name Reactions, A Collection of Detailed Mechanisms and Synthetic Applications, Springer, ISBN: 978-3-030-50865-4.
Compounds of the formula VIIIA1 can be made from compounds of the formula VIIIB1, by treatment with a silylating agent of the formula VIIB1, wherein (RA1)3Si is trialkylsilyl, for instance dimethyl-tert-butylsilyl, and XB1 is a leaving group, such as for example chloride, bromide, iodide or triflate, in the presence of a base, such as an amine base, for instance imidazole, in an inert solvent, such as for example tetrahydrofuran. In compound VIIB1, RA1 is a straight or branched C1-C4alkyl, such as methyl or tert-butyl.
The reaction can be done in a temperature range of 0° C. to 100° C., for instance between 10° C. and 80° C. Such silylation reactions are known to a person skilled in the art, and described in the literature, such as for example in: Protective Groups in Organic Synthesis, 3rd Edition Theodora W. Green (The Rowland Institute for Science) and Peter G. M. Wuts (Pharmacia and Upjohn Company). John Wiley & Sons, Inc., New York, NY. 1999, ISBN 0-471-16019-9.
Compounds of the formula VIIIB1 can be made from compounds of the formula VIIIC1, wherein R5a, R5b and XA1 have the same meaning as given above, by treatment with a base, such as a lithium amide base, for instance lithium 2,2,6,6-tetramethylpiperidide, followed by reaction of the lithiated species with an aldehyde of the formula VIIC1, wherein R3 has the same meaning as given above in formula I. This reaction can be done neat or in a solvent, for instance in an organic solvent, such as for example in tetrahydrofuran as a solvent. The reaction can be done in a temperature range of −100° C. to 100° C., for instance between −80° C. and 0° C., for example at 0° C. or at −78° C.
Compound of the formulas VIIC1 and VIIIC1 are known or commercially available. Ketones of formula IV (wherein R3, R4, R5a and R5b are as defined in formula I and X05 is defined as above) are either commercially available or can be prepared as shown in Scheme 4.
As shown in Scheme 4, compounds of formula XI (wherein R5a and R5b are as defined in formula I, Z1 is C1-C4alkyl, and X05 is a leaving group as defined in formula IV) can be converted to compounds of formula XII (wherein R5a, R5b and Z1 are as defined in formula XI) by a three step sequence: conversion to carboxylic acids by methods known in the art (see e.g. WO2011/143365, page 138), activation (see Scheme 1) of the carboxylic acids and treatment with N-methoxy-N-methylamine (according to Weinreb et al. Tetrahedron Lett. 1981, 39, 3815). Treatment of compounds of formula XII with a Grignard reagent R3MgBr, wherein R3 is as defined in formula I, e.g. MeMgBr, at lower temperatures, preferably at 0 to 25° C., gives alkyl ketones of formula IV (wherein R3, X05, R5a and R5b are defined as above).
Compounds of formula IV can also be used for preparation of compounds of formula XIII (Scheme 4), wherein R1, R3, R5a and R5b are defined as in formula I and X05 is a leaving group, preferably Cl or Br, using reagents of formula VII, wherein R1 is as defined in formula I, under reductive amination methods as described for the conversion of compounds of formula VI to compounds of formula II (see Scheme 2, above).
Compounds of formula XIII, wherein R1, R3, R5a and R5b are defined as in formula I and X05 is a leaving group, preferably Cl or Br, can be subsequently used as starting materials for an alternative synthetic sequence to obtain compounds of formula I, as shown in Scheme 5.
Compounds of formula XIII can be reacted with activated carboxylic acids of general formula IIIa to furnish amides of general formula XIV, wherein A, R1, R2a, R2b, R3, R5a and R5b are defined as in formula I and X05 is a leaving group such as halogen F, Br, Cl, I, or OTf, preferably Cl or Br. Methods for this transformation have been described in Scheme 1 above. Compounds of formula XIV can be converted into compounds of formula I by a C—C-coupling reaction with a compound of the formula Vm (substituents as defined in scheme 2), following methods described above for Scheme 2.
An additional method to prepare a particular subclass of compounds of general formula of II, namely compounds IIa, wherein R3, R4, R5a and R5b are as defined for formula II and R1 is hydrogen, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), is outlined in Scheme 6.
Compounds of formula II suited with a protecting group, e.g. R1 is benzyl, can be subjected to hydrogenolysis using hydrogen in the presence of a palladium catalyst such as palladium on charcoal in a solvent, e.g. MeOH or EtOH, to give compounds of formula IIa, wherein R3, R4, R5a and R5b are defined as in formula I (see e.g. Synlett, 2010, (18), page 2708). Alternatively, compounds of formula II, wherein R1 is allyl, and R3, R4, R5a and R5b are as defined in formula I can also be converted to compounds of formula IIa by reaction with N,N′-dimethylbarbituric acid in the presence of a Pd-catalyst, preferable tetrakis(triphenylphosphine)palladium(0), in a suitable solvent, for example CH2Cl2 to provide compounds of formula IIa according to J. Org. Chem. 1993, 58, 6109.
Alternatively, compounds of formula IIa, wherein R3, R4, R5a and R5b are as defined in formula I, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt) can be prepared (scheme 6a) from intermediates of formula VIIIZ3, wherein R3, R4, R5a and R5b are as described in formula I and Z3 is —NPhth (N-phthalimide group) or —NBoc2 (N-bis(tert-butyloxycarbonyl) group), typically by treatment with either hydrazine (preferably hydrazine hydrate or hydrazine monohydrate) in an alcohol solvent such as ethanol or isopropanol (Z3 is —NPhth), or with an acid such as trifluoroacetic acid or hydrochloric acid in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane (Z3 is —NBoc2), under deprotection conditions known to a person skilled in the art, and described in the literature, such as for example in: Protective Groups in Organic Synthesis, 3rd Edition Theodora W. Green (The Rowland Institute for Science) and Peter G. M. Wuts (Pharmacia and Upjohn Company), John Wiley & Sons, Inc., New York, NY. 1999, ISBN 0-471-16019-9.
Compounds of formula VIIIZ3, wherein R3, R4, R5a and R5b are as described in formula I and Z3 is —NPhth (N-phthalimide group) or —NBoc2 (N-bis(tert-butyloxycarbonyl) group), can be prepared from alcohol compounds of formula VIII, wherein R3, R4, R5a and R5b are as described in formula I, by a Mitsunobu reaction. Such a reaction involves treating alcohols of formula VIII with an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, in the presence of a phosphine, such as triphenylphosphine or tributylphosphine, and of an amine such as phthalimide (HNPhth) or bis(tert-butoxycarbonyl)amine (HNBoc2). Mitsunobu reactions (and conditions to perform them) are known by those skilled in the art and described for instance in Chem. Rev. 2009, 109, 2551-2651.
Carboxylic acids of formula III are known or can be prepared by methods described in the following schemes.
Accordingly, compounds of formula IIIb (Scheme 7), wherein R2b and A are as defined in formula I, can be prepared by reaction of compounds of formula XXI (wherein R2b and A are as defined in formula I and Z1 is C1-C4alkyl) with a suitable base such as sodium or lithium hydroxide, in a suitable solvent like MeOH, THF, and water or a mixture of them, usually upon heating at temperatures between room temperature and reflux. Compounds of formula XXI are prepared through oxidation of compounds of formula XXa, e.g. with mCPBA or NaIO4/RuCl3, in a solvent, preferable CH2Cl2, or CHCl3 or a mixture of H2O, MeCN and CCl4. Such transformations are known to those skilled in the art and described for example in J. Med. Chem. 2008, 51, 6902 or WO2004/9086, pages 24-25. Finally, compounds of formula XXa, wherein R2b and A are as defined in formula I and Z1 is C1-C4alkyl, may be prepared by reaction of compounds of formula XVIIIa with a suitable trifluoromethylthiolation copper reagent of formula XIX (wherein R2b and A are as defined in formula I and X08 is Br or Cl), ligands being e.g. 1,10-phenanthroline or 4,4′-di-tert-butylbipyridine, in suitable solvents, for example, acetonitrile or DMF, usually upon heating at temperatures between 20 to 150° C., preferably between 40° C. to the boiling point of the reaction mixture. Such processes have been described previously, for example, in Angew. Chem. Int. Ed. 2013, 52, 1548-1552, Angew. Chem. Int. Ed. 2011, 50, 3793, Org. Lett. 2014, 16, 1744, J. Org. Chem. 2017, 82, 11915.
Further intermediates of formula XX, wherein R2a, R2b, and A are as defined in formula I and Z1 is C1-C4alkyl, are generally known or can be easily prepared by those skilled in the art. A typical example of such a synthesis of compounds of formula XX is shown in Scheme 8.
For example, compounds of formula XX may be prepared by reaction of compounds of formula XVIIIb, wherein R2b and A are as defined for formula I and X05 is chlorine, bromine, iodine, OMs, OTs or OTf, with compounds of formula XXIII, wherein R2a is as defined in formula I, in the presence of a palladium catalyst, for example, Pd(PPh3)4, in suitable solvents, for example, toluene/water, 1,4-dioxane/water, in the presence of a suitable base, such as sodium, potassium or caesium carbonate or tripotassium phosphate usually upon heating at temperatures between room temperature and 20000, preferably between 2000 to the boiling point of the reaction mixture, optionally under microwave heating conditions. Such processes have been described previously, for example, in Tetrahedron Letters 2002, 43, 6987-6990.
Compounds of formula XX may also be prepared by reaction of compounds of formula XXIV, wherein R2b and A and Z1 are as defined in formula XX, and compounds of formula XXV, wherein R2a is as defined in formula I, and X05 is a leaving group, for example, bromine or iodine, in the presence of a palladium catalyst, for example, PdCl2(dppf), in suitable solvents that may include, for example, toluene/water, 1,4-dioxane/water, in the presence of a suitable base, such as sodium, potassium or cesium carbonate or tripotassium phosphate usually upon heating at temperatures between room temperature and 20000, preferably between 2000 to the boiling point of the reaction mixture, optionally under microwave heating conditions. Such processes have been described previously, for example, in WO12139775, page 73.
Compounds of formula XXIV, wherein R2b and A and Z1 are as defined in formula I, may be prepared by reaction of compounds of formula XVIIIb, wherein R2b and A and Z1 are as defined in formula XXIV, and X05 is Cl, Br, I, OMs, OTs or OTf, with compound of formula XXII, e.g. bis(pinacolato)diboron (Bpin)2, in the presence of a palladium catalyst, for example, PdCl2(dppf), in suitable solvents that may include, for example, toluene/water, 1,4-dioxane/water, in the presence of a suitable base, such as sodium, potassium or cesium carbonate or potassium acetate, usually upon heating at temperatures between room temperature and 200° C., preferably between 20° C. to the boiling point of the reaction mixture, optionally under microwave heating conditions. Such processes have been described previously, for example, in Bioorg. Med. Chem. Lett. 2015, 25, 1730, and WO12139775, page 67.
Carboxylic acids of formula III may be prepared from compound of formula XXVIII as outlined in Scheme 7, by treatment with, for example aqueous LiOH, NaOH or KOH, in suitable solvents that may include, for example, THF/MeOH mixture, usually upon heating at temperatures between room temperature and 100° C., preferably between 20° C. to the boiling point of the reaction mixture (see also Scheme 9).
Compounds of formula XXVIII (Scheme 9), wherein, R2b and A are defined in formula I and Z1 is C1-C4alkyl, may be prepared by treatment of compounds of formula XXVII, which are either commercially available or can be prepared by methods known to those skilled in the art (see e.g. Angew. Chem. Int. Ed. 2004, 43, 1132 and Pure Appl. Chem. 1985, 57, 1771) with compound of formula XXVI, e.g. (trifluoroethyl)-diphenyl-sulfonium triflate (Ph2S+CH2CF3−OTf) in the presence of an Fe-catalyst and a base, preferable CsF at temperatures between 0 to 50° C., preferable 20° C. in DMA as solvent (analog to Org. Lett. 2016, 18, 2471). Compounds of formula XXVIII are obtained as mixture of stereoisomers with the trans isomer being the major isomer.
Yet another methodology to prepare compounds of formula XXVIII uses trifluoroethylamine hydrochloride/NaNO2/NaOAc in the presence of an Fe-catalyst; this reaction is conducted at room temperature in H2O; or in a mixture of CH2Cl2 and H2O, see e.g. Angew. Chem. Int. Ed. 2010, 49, 938 and Chemm. Commun. 2018, 54, 5110.
Carboxylic acids of formula IIIc, wherein R2b and A are as defined in formula I, may be prepared in quite a similar manner as already shown in Scheme 7.
Compounds of formula XXIX, wherein R2b and A are as defined in formula I, and Z1 is C1-C4alkyl, are prepared by reaction of compounds of formula XXVII (synthesized analog to ACS Med. Chem. Lett. 2013, 4, 514 or Tetrahedron Lett. 2001, 42, 4083) with (bromodifluoromethyl)-trimethylsilane in the presence of NH4Br in a suitable solvent, preferably in THE or toluene at temperatures between 70 to 110° C. Subsequent saponification of the ester intermediates XXIX provide compounds of formula IIId (Scheme 10).
Carboxylic acids of formula IIIe, wherein R2b and A are as defined in formula I, can be prepared according to reaction Scheme 11. Thus, compounds of formula XVIIIa, wherein R2b and A are defined as in formula I, Z1 is C1-C4alkyl and X08 is bromine or iodine, are treated with iPrMgCl/LiCl-complex; subsequent reaction with CuCN and quenching with cyclopropane carbonyl chlorides such as formula XXX provides compounds of formula XXXI (analog to WO2006/067445, page 148). Following fluorination with 2,2-difluoro-1,3-dimethylimidazoline either in a solvent, e.g. in 1,2-dimethoxyethane or in the absence of a solvent (see Chem. Commun. 2002, (15), 1618) affords compounds of formula XXXII. Subsequent hydrolysis using e.g. LiOH has already described gives carboxylic acids of formula IIIe.
A particular group of compounds III can be obtained by hydrolysis from the corresponding esters of type XXXVI, wherein A and R2b are defined as in formula I and Z1 is C1-C4alkyl. Synthetic methods to obtain compounds of formula XXXVI are shown in Scheme 12 below.
Treatment of compounds of formula XVIIIc, wherein R2b and A are as defined in formula I, X09 is a leaving group, for example a halogen or a sulfonate, preferably chlorine, bromine, iodine or trifluoromethanesulfonate, and Z1 is C1-C4alkyl, with trimethylsilyl acetonitrile (Me3SiCH2CN) in the presence of zinc(II)fluoride (ZnF2), and a palladium(0)catalyst such as tris(dibenzylideneacetone)di-palladium(0) chloroform adduct (Pd2(dba)3 CHCl3), with a ligand, for example Xantphos or BINAP, in an inert solvent, such as N,N-dimethylformamide (DMF) at temperatures between 100-180° C., optionally under microwave heating, leads to compounds of formula XXXV, wherein R2b. Z1 and A are as defined in formula XVIIIc. Such methods have been described in the literature, e.g. in Org. Lett. 16(24), 6314-6317, 2014. Alternatively, reaction of compounds of formula XVIIIc with 4-isoxazoleboronic acid or 4-isoxazoleboronic acid pinacol ester, in the presence of potassium fluoride (KF), and a palladium catalyst such as bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), in an inert solvent, such as dimethylsulfoxide DMSO, optionally in mixture with water, at temperatures between 40-150° C., optionally under microwave heating, leads to compounds of formula XXXVII, wherein R2b, A are as defined in formula I and Z1 is C1-C4alkyl. Reaction of compounds of formula XXXVII with aqueous potassium fluoride (KF concentration between 0.5 and 3M, preferably 1M), in an inert solvent, such as dimethylsulfoxide DMSO or methanol, at temperatures between 20-150° C., optionally under microwave heating, leads to compounds of formula XXXV, wherein R2b, Z1 and A are as defined in formula XVIIIc. Such chemistry has been described in the literature, e.g. in J. Am. Chem. Soc. 2011, 133, 6948-6951.
Compounds of formula XXXV, wherein R2b and A are as defined in formula I and Z1 is C1-C4alkyl, can be further treated with compounds of formula XXXIV, in which X10 is a leaving group, such as halogen (preferably chlorine, bromine or iodine), in the presence of a base such as sodium hydride, sodium carbonate, potassium carbonate, or cesium carbonate, in an inert solvent such as N,N-dimethylformamide (DMF), acetone, or acetonitrile, at temperatures between 0-120° C., to give compounds of formula XXXVI, wherein R2b, and A are as defined in formula I above and Z1 is C1-C4alkyl.
Alternatively, compounds of formula XXXVI can be prepared directly from compounds of formula XVIIIc by treatment with compounds of formula XXXVIII, in presence of a catalyst such as Pd2(dba)3, with a ligand, such as BINAP, a strong base such as lithium hexamethyldisilazane (LiHMDS), in an inert solvent such as tetrahydrofuran (THF), at temperatures between 30-80° C. Such chemistry has been described in, for example, J. Am. Chem. Soc. 127(45), 15824-15832, 2005.
In yet another method to prepare compounds of formula XXXV, compounds of formula XVIIIc, wherein R2b, and A are as defined in formula I, Z1 is C1-C4alkyl and X05 is a leaving group, for example a halogen or a sulfonate, preferably chlorine, bromine, iodine or trifluoromethanesulfonate, are reacted with reagents of the formula XXXVIII, wherein Z2 is C1-C4alkyl, in the presence of a base, such as sodium carbonate, potassium carbonate or cesium carbonate, or sodium hydride, sodium methoxide or ethoxide, potassium tert-butoxide, optionally in the presence of a transition metal catalyst such as palladium (for example involving Pd(PPh3)2Cl2) or copper (for example involving CuI) catalysis, in an appropriate solvent such as for example toluene, dioxane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone (NMP) or dimethylsulfoxide (DMSO), optionally in presence of a phase transfer catalyst PTC, such as for example tetrabutyl ammonium bromide or triethyl benzyl ammonium chloride TEBAC, at temperatures between room temperature and 180° C., gives compounds of formula XXXIX, wherein R2b, and A are as defined in formula I and Z1 and Z2 are each independently of the other C1-C4alkyl. Compounds of formula XXXIX can be decarboxylated using conditions such as heating in wet DMSO optionally in the presence of lithium or sodium chloride at temperatures between 50° C. and 180° C. to afford compounds of formula XXXV. Similar chemistry has been described in, for example, Synthesis 2010, No. 19, 3332-3338.
Compounds of formula I′a
The chemistry is described in more detail in Scheme 14 where X is oxygen.
Compounds of formula IIIa, wherein A, R2a, R2b and X0 are as described in Scheme 1, can be treated with compounds of formula IIb, wherein R1, R3, R4, R5a, and R5b are as described in formula I, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), under the conditions described in detail in Scheme 1. The formation of compounds of formula IIIa from compounds of formula III is described in Scheme 1.
Alternatively, compounds of formula I′a may also be prepared by coupling of compounds of formula XL, wherein A, R1, R2a, R2b, R3, R5a, and R5b are defined in formula I and X05 is a leaving group such as chlorine, bromine, iodine, arysulfonate, alkylsulfonate or trifluoromethanesulfonate, with compounds of formula V (as defined above in Scheme 2), as shown in Scheme 15.
Such C—C coupling reactions can be achieved in the presence of a base, such as cesium carbonate or sodium tert-butoxide, optionally in the presence of a copper salt such as copper(I) iodide in an inert solvent, such as DMF, acetonitrile, or dioxane at temperatures between 20 and 180° C., preferably at 60-120° C. Additional methods including transition metal-catalyzed methods can be found in the literature, e.g. J. Paradies in Metal-Catalyzed Cross-Coupling Reactions and More (E ds. A. de Meijere, S. Bräse, and M. Oestreich), Wiely-VCH (Weinheim), 2014, Vol. 3., p. 995. Compounds of formula XL can be synthesized by coupling between amines of formula XIIIa, wherein R1, R3, R5a, and R5b are defined in formula I and X05 is a leaving group such as chlorine, bromine, iodine, arysulfonate, alkylsulfonate or trifluoromethanesulfonate, and compounds of formula IIIa following the conditions detailed in Scheme 1.
The formation of compounds of formula IIb is outlined in Scheme 16.
Compounds of formula IIb can be prepared by treatment of compounds of formula IIc, wherein R3, R4, R5a, and R5b are described in formula I, with compounds of formula XLI (wherein R1 is defined in formula I), e.g. in the presence of NaBH(OAc)3 or NaBH3CN, in a suitable solvent, preferably in acetic acid at room temperature analog to WO2002/088073, page 35. Alternatively, another reagent system for the reductive amination uses a combination of Ti(i-OiPr)4 and NaBH4 (see Synthesis 2003 (14), 2206). Amines of formula IIc may be obtained by biocatalyzed deracemization of amines of formula IIa. This may be done for instance using a lipase, e.g. Candida Antarctica lipase B or Pseudomonas fluorescens lipase, eventually in immobilized form (e.g. Novozym® 435) in presence of an acyl donor. e.g. ethyl methoxyacetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert-butyl ether at temperatures between 20° C. to 100° C. Such processes are described for instance in J. Org. Chem. 2007, 72, 6918-6923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical outcome of such enzymatic deracemization are known of those skilled in the art and are documented in the literature, for instance in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.
In an alternative process, compounds of formula IIc, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be obtained from VIIIa, wherein R3, R4, R5a, and R5b are as described in formula I, following the synthesis described in Scheme 17.
Amines of formula IIc may be obtained from intermediates of formula XLII, wherein R3, R4, R5a, and R5b are described in formula I and Z3 is NPhth or NBoc2. Such intermediates can be obtained from alcohols of formula XIIa by a Mitsunobu reaction, which involves treating alcohols of formula VIIIa by diisopropyl azodicarboxylate in the presence of a phosphine such as triphenylphosphine or tributylphosphine and of an amine such as phthalimide or bis(tert-butoxycarbonyl)amine. Mitsunobu reactions are known by those skilled in the art to proceed with inversion of the stereocenter, as described for instance in Chem. Rev. 2009, 109, 2551-2651. Amines of formula XLII can then be transformed into amines of formula IIc by treatment with hydrazine if Z3=NPhth or with TFA if Z3=NBoc2.
Alternatively, amines of formula IIc may be obtained by reduction of azides of formula XLIII, wherein R3, R4, R5a, and R5b are described in formula I, by treatment with triphenylphosphine and water (Staudinger reaction) or by hydrogenation for example using a palladium catalyst in the presence of hydrogen. Azides of formula XLIII may be obtained by treatment of alcohols of formula VIIIa, wherein R3, R4, R5a, and R5b are as described in formula I, with an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THE in presence of a base such as DBU. Such processes are known by those skilled in the art to proceed with inversion of the stereocenter and are described in the literature for instance in Adv. Synth. Catal. 2018, 360, 2157-2165.
Alcohols of formula VIIIa may be obtained by enantioselective reduction of ketones of formula VI. Such reductions can be done using a catalyst, for instance a ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF4[(R,R)-TsDPEN](p-cymene) in the presence of a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4. Such processes are described in the literature for instance in J. Org. Chem. 2017, 82, 5607.
Alternatively, compounds of formula IIc may also be prepared as outlined in Scheme 18.
Amines of formula IIc, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be prepared by deprotection of amines of formula XLIX, wherein R3, R4, R5a and R5b are described in formula I, for instance using an acid such as trifluoroacetic acid or hydrochloric acid, optionally in the presence of a suitable solvent such as dichloromethane, tetrahydrofuran or dioxane. Amines of formula XLIX can be obtained by condensation of diamines of formula XLVIII, wherein R5a, and R5b are as described in formula I, on diketones of formula XLVII, wherein R3 and R4 is as described in formula I. This condensation can take place in the presence of a suitable solvent such as ethanol or isopropanol, in presence of an oxidant such as air or DDQ. Diketones of formula XLVII may be formed by oxidation of hydroxyketones of formula XLVI wherein R3 and R4 is as described in formula I. This oxidation can involve for instance SO3-pyridine in presence of solvents such as dichloromethane or dimethyl sulfoxide DMSO, or mixtures thereof, and a base, for instance triethylamine or N,N-diisopropylethylamine, or alternatively sodium hypochlorite in presence of a catalyst such as TEMPO/Bu4NHSO4. Examples of such oxidations can be found in the literature, for instance in Synlett, 2014, 25, 596 or J. Am. Chem. Soc. 1990, 112, 5290-5313. Hydroxyketones of formula XLVI may be synthesized by cross-benzoin condensation between aldehydes of formula XLIV, wherein R4 is as described in formula I, and aldehydes of formula XLV, wherein R3 is as described in formula I. Aldehydes of formula XLIV are commercially available in chiral form, like for instance Boc-L-alaninal (CAS 79069-50-4) or tert-butyl N-[(1S)-1-(cyclopropylmethyl)-2-oxo-ethyl]carbamate (CAS 881902-36-9). Cross-benzoin condensations are done in the usual way by employing an organocatalyst such as a triazolium salt or a thiazolium salt in the presence of a base such as potassium tert-butoxide or N,N-diisopropylethylamine in a suitable solvent such as dichloromethane or tetrahydrofuran at a temperature between −20° C. and the boiling point of the solvent. Examples of catalysts for such transformations have been described in the literature for instance in J. Am. Chem. Soc. 2014, 136, 7539-7542 or in Org. Lett. 2016, 18, 4518-4521.
Amines of formula XIIIa can be prepared by deracemization procedure method, which involves for example, a selective acylation of one enantiomer. Such an example is described more in details in Scheme 19.
Amines of formula XIIIa may be obtained by biocatalyzed deracemization of amines of formula XIII. This may be done for instance using a lipase, e.g. Candida Antarctica lipase B or Pseudomonas fluorescens lipase, eventually in immobilized form (e.g. Novozym® 435) in presence of an acyl donor, e.g. ethyl methoxyacetate or vinyl acetate, in a suitable solvent such as acetonitrile or methyl tert-butyl ether at temperatures between 20° C. to 100° C. Such processes are described for instance in J. Org. Chem. 2007, 72, 6918-6923 or Adv. Synth. Catal. 2007, 349, 1481-1488. The expected stereochemical outcome of such enzymatic deracemization are known of those skilled in the art and are documented in the literature, for instance in J. Org. Chem. 1991, 56, 2656-2665 or J. Am. Chem. Soc. 2015, 137, 3996-4009.
Amines of formula XIII may be formed by reductive amination of ketone IV, which can occur for instance by treating ketones of formula IV with a nitrogen source, e.g. ammonium acetate or ammonia, in the presence of a hydride donor, e.g. in the presence of NaBH(OAc)3 or NaBH3CN.
Alternatively, resolution of amines of formula XIIIb, wherein R3, R5a, and R5b are described in formula I, may be achieved using a chiral auxiliary, as described in Scheme 20.
Amines of formula XIIIc, wherein R3, R5a, and R5b are described in Scheme 1 and X05 is a leaving group such as bromine, chlorine, iodine, mesylate, tosylate or triflate, can be prepared from intermediates of formula L, wherein R3, R5a, and R5b are described in Scheme 1, X05 is a leaving group such as bromine, chlorine, iodine, mesylate, tosylate or triflate and X12* is a chiral auxiliary, by treatment with acids such as HCl or bases such as NaOH. Chiral auxiliaries of formula LI, wherein X11* is a chiral auxiliary and X0 is as described in Scheme 1, are for instance mandelic acid or (1R)-menthylchloroformate. Amines of formula L can be formed by coupling of a chiral auxiliary of formula LI with amines of formula XIIIb following the conditions detailed in Scheme 1. Examples of such deracemization are reported in the literature for instance in J. Org. Chem. 2007, 72, 485-493.
Alternatively, amines of formula XIIIc, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be formed as described in Scheme 21.
Amines of formula XIIIc may be obtained from intermediates of formula LIII, wherein R3, R5a, and R5b are as described in formula I, X05 is a leaving group described above and Z3 is NPhth or NBoc2. Such intermediates can be obtained from alcohols of formula LII, wherein R3, R5a, and R5b are as described in formula I and X05 is a leaving group described above, by a Mitsunobu reaction, which involves treating alcohols of formula LII by diisopropyl azodicarboxylate in the presence of a phosphine such as triphenylphosphine or tributylphosphine and of an amine such as phthalimide or bis(tert-butoxycarbonyl)amine. Mitsunobu reactions are known by those skilled in the art to proceed with inversion of the stereocenter, as described for instance in Chem. Rev. 2009, 109, 2551-2651. Amines of formula LIII can then be transformed into amines of formula XIIIc by treatment with hydrazine if Z3=NPhth or with TFA if Z3=NBoc2.
Alternatively, amines of formula XIIIc may be obtained by reduction of azides of formula LIV, wherein R3, R5a, and R5b are as described in formula I and X05 is a leaving group as described above, by treatment with triphenylphosphine and water (Staudinger reaction) or by hydrogenation for example using a palladium catalyst in the presence of hydrogen. Azides of formula LIV may be obtained by treatment of alcohols of formula LII with an azidation reagent such as diphenyl phosphoryl azide in a solvent such as toluene or THE in presence of a base such as DBU. Such processes are known by those skilled in the art to proceed with inversion of the stereocenter and are described in the literature for instance in Adv. Synth. Catal. 2018, 360, 21 57-2165.
Alcohols of formula LII may be obtained by enantioselective reduction of ketones of formula IV. Such reductions can be done using catalysts, for instance a ruthenium or a rhodium catalyst with a chiral ligand such as RuCl[(R,R)-TsDPEN](mesitylene) or RuBF4[(R,R)-TsDPEN](p-cymene) in the presence of a hydrogen donor system such as for example HCOOH/Et3N or HCO2NH4. Such processes are described in the literature for instance in J. Org. Chem. 2017, 82, 5607.
Alternatively, compounds of formula I wherein R1 is different from hydrogen, and in which X is oxygen, can be made, for example, as shown in Scheme 22.
A compound of the formula Ia, wherein A, R2a, R2b, R3, R4, R5a and R5b are as described in formula I, can be reacted with a compound of the formula R1-X3, wherein R1 is as defined in formula I but different from hydrogen and X3 is a leaving group, such as a halogen or a sulfonate, for instance a chloride, bromide, iodide or mesylate, to give a compound of formula I, wherein A, R2a, R2b, R1, R3, R4, R5a and R5b are as described in formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), or mixtures thereof, in a temperature range of −100 to +300° C., preferably between 0° C. and 200° C., with or without the addition of a base, such as an inorganic base, for instance sodium, potassium or cesium carbonate, or an organic base, such as, for example, triethylamine, diisopropylethylamine or pyridine. Such methods for the alkylation of amines, and the range of conditions to perform them, are well known to a person skilled in the art.
Compounds of the formula Ia, wherein A, R2a, R2b, R3, R4, R5a and R5b are as described in formula I, can be prepared by reaction of an amine of formula IIa, wherein R3, R4, R5a and R5b are as described in formula I, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), with a carboxylic acid derivative of formula IIIa, wherein A, R2a and R2b are described as above under formula I and wherein X0 is as defined in Scheme 1, under conditions described in detail in Scheme 1.
In analogy, compounds of formula I′a wherein R1 is different from hydrogen, and in which X is oxygen, can be made, for example, as shown in Scheme 23.
A compound of the formula I′aa, wherein A, R2a, R2b, R3, R4, R5a and R5b are as described in formula I, can be reacted with a compound of the formula R1-X3, wherein R1 is as defined in formula I but different from hydrogen and X3 is a leaving group, such as a halogen or a sulfonate, for instance a chloride, bromide, iodide or mesylate, to give a compound of formula I′a, wherein A, R2a, R2b, R1, R3, R4, R5a and R5b are as described in formula I, under conditions described in detail in Scheme 22.
Compounds of the formula I′aa, wherein A, R2a, R2b, R3, R4, R5a and R5b are as described in formula I, can be prepared by reaction of an amine of formula IIc, wherein R3, R4, R5a and R5b are as described in formula I, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), with a carboxylic acid derivative of formula IIIa, wherein A, R2a and R2b are described as above under formula I and wherein X0 is as defined in Scheme 1, under conditions described in detail in Scheme 1.
Compounds of formula Ia-CN, as shown in Scheme 24, correspond to compounds of Formula I, wherein X is oxygen, R1 is hydrogen and R4a is CN, and wherein A, R2a, R2b, R3, R4b, R4c, R5a and R5b are as defined in formula I. Compounds of formula Ia-CN can be prepared as shown in Scheme 24 from compounds of formula Ia-X, wherein A, R2a, R2b, R3, R4b, R4c, R5a and R5b are as defined in formula I, and wherein X4 is a halogen (or a pseudo-halogen leaving group, such as a triflate), preferably bromine or chlorine, even more preferably chlorine, via a cyanation reaction.
Such cyanation reactions can be carried out in the presence of a metal cyanide M1-CN, such as sodium cyanide NaCN, potassium cyanide KCN, copper cyanide CuCN, zinc cyanide Zn(CN)2 or potassium ferrocyanide K4[Fe(CN)6], amongst others, optionally in the presence of a palladium catalyst and ligand, and optionally under microwave irradiation. Examples of palladium catalyst include palladium(II) acetate Pd(OAc)2 or tris(dibenzylideneacetone)dipalladium(0) Pd2(dba)3, amongst others, and examples of ligands include 1,1′-bis(diphenylphosphino)ferrocene dppf, dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2-yl]phosphane XPhos or (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) Xantphos, amongst other phosphine based ligands. Other examples of catalyst/ligand combination include tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)4, [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium (PdCl2(dppf), 2nd generation XPhos precatalyst XPhos Pd G2 or 3rd generation XPhos precatalyst XPhos Pd G3, amongst others. The reaction can be carried out in the presence of solvents such as N,N-dimethylformamide DMF, dioxane, toluene, xylene, acetonitrile, and at temperature ranging between room temperature and the boiling point of the reaction mixture.
Compounds of formula Ia-X, wherein A, R2a, R2b, R3, R4b, R4c, R5a and R5b are as defined in formula I, and wherein X4 is a halogen (or a pseudo-halogen leaving group, such as a triflate), preferably bromine or chlorine, even more preferably chlorine, can be prepared by reaction of an amine of formula IIa-X, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and wherein X4 is a halogen (or a pseudo-halogen leaving group, such as a triflate), preferably bromine or chlorine, even more preferably chlorine, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), with a carboxylic acid derivative of formula IIIa, wherein A, R2a and R2b are described as above under formula I and wherein X0 is as defined in Scheme 1, under conditions described in detail in Scheme 1.
Compounds of formula IIa-X, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and wherein X4 is a halogen, preferably bromine or chlorine, even more preferably chlorine, or a salt thereof (such as a hydrohalide salt, preferably a hydrochloride or a hydrobromide salt, or a trifluoroacetic acid salt, or any other equivalent salt), can be prepared as shown in Scheme 25 from compounds of formula VIIIZ3-X, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and wherein X4 is a halogen, preferably bromine or chlorine, even more preferably chlorine, and Z3 is —NPhth (N-phthalimide group), under deprotection conditions already described in Scheme 6a.
Compounds of formula VIIIZ3-X, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and wherein X4 is a halogen, preferably bromine or chlorine, even more preferably chlorine, and Z3 is —NPhth (N-phthalimide group), can be prepared from compounds of formula VIIIZ3-2, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and Z3 is —NPhth (N-phthalimide group), by treatment with phosphorus reagents such as phosphorus oxychloride or phosphorus pentachloride, amongst others, in an inert solvent such as toluene or chlorobenzene, and at temperature ranging between room temperature and the boiling point of the reaction mixture.
Compounds of formula VIIIZ3-2, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and Z3 is —NPhth (N-phthalimide group), can be prepared from compounds of formula VIIIZ3-1, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and Z3 is —NPhth (N-phthalimide group), by a hydrolysis reaction, involving for example an acid such as hydrochloric acid, optionally in the presence of a suitable solvent such as tetrahydrofuran or dioxane, and at temperature ranging between room temperature and the boiling point of the reaction mixture.
Compounds of formula VIIIZ3-1, wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and Z3 is —NPhth (N-phthalimide group), define a particular subgroup of compounds of formula VIIIZ3 (described in Scheme 6a), wherein R3, R4b, R4c, R5a and R5b are as described in formula I, and in which Ra is C1-C3alkoxy and Z3 is —NPhth (N-phthalimide group). As such they can be prepared from compounds of formula VIII as detailed in scheme 6a.
Depending on the procedure or the reaction conditions, the reactants can be reacted in the presence of a base. Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines. Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium acetate, sodium carbonate, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, lithium diisopropylamide, potassium bis(trimethylsilyl)amide, calcium hydride, triethylamine, diisopropylethylamine, triethylenediamine, cyclohexylamine, N-cyclohexyl-N,N-dimethylamine, N,N-diethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, quinuclidine, N-methylmorpholine, benzyltrimethylammonium hydroxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
The reactants can be reacted with each other as such, i.e. without adding a solvent or diluent. In most cases, however, it is advantageous to add an inert solvent or diluent or a mixture of these. If the reaction is carried out in the presence of a base, bases which are employed in excess, such as triethylamine, pyridine, N-methylmorpholine or N,N-diethylaniline, may also act as solvents or diluents.
The reactions are advantageously carried out in a temperature range from approximately −80° C. to approximately +140° C., preferably from approximately −30° C. to approximately +100° C., in many cases in the range between ambient temperature and approximately +80° C.
Depending on the choice of the reaction conditions and starting materials which are suitable in each case, it is possible, for example, in one reaction step only to replace one substituent by another substituent according to the invention, or a plurality of substituents can be replaced by other substituents according to the invention in the same reaction step.
Salts of compounds of formula I can be prepared in a manner known per se. Thus, for example, acid addition salts of compounds of formula I are obtained by treatment with a suitable acid or a suitable ion exchanger reagent and salts with bases are obtained by treatment with a suitable base or with a suitable ion exchanger reagent.
Salts of compounds of formula I can be converted in the customary manner into the free compounds I, acid addition salts, for example, by treatment with a suitable basic compound or with a suitable ion exchanger reagent and salts with bases, for example, by treatment with a suitable acid or with a suitable ion exchanger reagent.
Salts of compounds of formula I can be converted in a manner known per se into other salts of compounds of formula I, acid addition salts, for example, into other acid addition salts, for example by treatment of a salt of inorganic acid such as hydrochloride with a suitable metal salt such as a sodium, barium or silver salt, of an acid, for example with silver acetate, in a suitable solvent in which an inorganic salt which forms, for example silver chloride, is insoluble and thus precipitates from the reaction mixture.
Depending on the procedure or the reaction conditions, the compounds of formula I, which have salt-forming properties can be obtained in free form or in the form of salts.
The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can be present in the form of one of the isomers which are possible or as a mixture of these, for example in the form of pure isomers, such as antipodes and/or diastereomers, or as isomer mixtures, such as enantiomer mixtures, for example racemates, diastereomer mixtures or racemate mixtures, depending on the number, absolute and relative configuration of asymmetric carbon atoms which occur in the molecule and/or depending on the configuration of non-aromatic double bonds which occur in the molecule; the invention relates to the pure isomers and also to all isomer mixtures which are possible and is to be understood in each case in this sense hereinabove and hereinbelow, even when stereochemical details are not mentioned specifically in each case.
Diastereomer mixtures or racemate mixtures of compounds of formula I, in free form or in salt form, which can be obtained depending on which starting materials and procedures have been chosen can be separated in a known manner into the pure diastereomers or racemates on the basis of the physicochemical differences of the components, for example by fractional crystallization, distillation and/or chromatography.
Enantiomer mixtures, such as racemates, which can be obtained in a similar manner can be resolved into the optical antipodes by known methods, for example by recrystallization from an optically active solvent, by chromatography on chiral adsorbents, for example high-performance liquid chromatography (HPLC) on acetyl cellulose, with the aid of suitable microorganisms, by cleavage with specific, immobilized enzymes, via the formation of inclusion compounds, for example using chiral crown ethers, where only one enantiomer is complexed, or by conversion into diastereomeric salts, for example by reacting a basic end-product racemate with an optically active acid, such as a carboxylic acid, for example camphor, tartaric or malic acid, or sulfonic acid, for example camphorsulfonic acid, and separating the diastereomer mixture which can be obtained in this manner, for example by fractional crystallization based on their differing solubilities, to give the diastereomers, from which the desired enantiomer can be set free by the action of suitable agents, for example basic agents.
Pure diastereomers or enantiomers can be obtained according to the invention not only by separating suitable isomer mixtures, but also by generally known methods of diastereoselective or enantioselective synthesis, for example by carrying out the process according to the invention with starting materials of a suitable stereochemistry.
N-oxides can be prepared by reacting a compound of the formula I with a suitable oxidizing agent, for example the H2O2/urea adduct in the presence of an acid anhydride, e.g. trifluoroacetic anhydride. Such oxidations are known from the literature, for example from J. Med. Chem., 32 (12), 2561-73, 1989 or WO 2000/15615.
It is advantageous to isolate or synthesize in each case the biologically more effective isomer, for example enantiomer or diastereomer, or isomer mixture, for example enantiomer mixture or diastereomer mixture, if the individual components have a different biological activity.
The compounds of formula I and, where appropriate, the tautomers thereof, in each case in free form or in salt form, can, if appropriate, also be obtained in the form of hydrates and/or include other solvents, for example those which may have been used for the crystallization of compounds which are present in solid form.
The compounds of formula I according to the following Tables A-1 to A-126 can be prepared according to the methods described above. The examples which follow are intended to illustrate the invention and show preferred compounds of formula I, in the form of a compound of formula Iaa.
Table A-1 provides 5 compounds A-1.001 to A-1.005 of formula Iaa wherein A is CH, R1 is H, R2a is Cl, R2b is Cl and R4 is as defined in table Z. For example, compound A-1.002 is
Table A-2 provides 5 compounds A-2.001 to A-2.005 of formula Iaa wherein A is CH, R1 is H, R2a is Cl, R2b is Br and R4 is as defined in table Z.
Table A-3 provides 5 compounds A-3.001 to A-3.005 of formula Iaa wherein A is CH, R1 is H, R2a is Cl, R2b is CF3 and R4 is as defined in table Z.
Table A-4 provides 5 compounds A-4.001 to A-4.005 of formula Iaa wherein A is CH, R1 is H, R2a is Br, R2b is Cl and R4 is as defined in table Z.
Table A-5 provides 5 compounds A-5.001 to A-5.005 of formula Iaa wherein A is CH, R1 is H, R2a is Br, R2b is Br and R4 is as defined in table Z.
Table A-6 provides 5 compounds A-6.001 to A-6.005 of formula Iaa wherein A is CH, R1 is H, R2a is Br, R2b is CF3 and R4 is as defined in table Z.
Table A-7 provides 5 compounds A-7.001 to A-7.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is C and R4 is as defined in table Z.
Table A-8 provides 5 compounds A-8.001 to A-8.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is Br and R4 is as defined in table Z.
Table A-9 provides 5 compounds A-9.001 to A-9.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-10 provides 5 compounds A-10.001 to A-10.005 of formula Iaa wherein A is CH, R1 is H, R2a is O—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-11 provides 5 compounds A-11.001 to A-11.005 of formula Iaa wherein A is CH, R1 is H, R2a is O—CF3, R2b is Br and R4 is as defined in table Z.
Table A-12 provides 5 compounds A-12.001 to A-12.005 of formula Iaa wherein A is CH, R1 is H, R2a is O—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-13 provides 5 compounds A-13.001 to A-13.005 of formula Iaa wherein A is CH, R1 is H, R2a is SO2—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-14 provides 5 compounds A-14.001 to A-14.005 of formula Iaa wherein A is CH, R1 is H, R2a is SO2—CF3, R2b is Br and R4 is as defined in table Z.
Table A-15 provides 5 compounds A-15.001 to A-15.005 of formula Iaa wherein A is CH, R1 is H, R2a is SO2—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-16 provides 5 compounds A-16.001 to A-16.005 of formula Iaa wherein A is CH, R1 is H, R2a is 1-cyano-cyclopropyl, R2b is Cl and R4 is as defined in table Z.
Table A-17 provides 5 compounds A-17.001 to A-17.005 of formula Iaa wherein A is CH, R1 is H, R2a is 1-cyano-cyclopropyl, R2b is Br and R4 is as defined in table Z.
Table A-18 provides 5 compounds A-18.001 to A-18.005 of formula Iaa wherein A is CH, R1 is H, R2a is 1-cyano-cyclopropyl, R2b is CF3 and R4 is as defined in table Z.
Table A-19 provides 5 compounds A-19.001 to A-19.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is Cl, R2b is C and R4 is as defined in table Z.
Table A-20 provides 5 compounds A-20.001 to A-20.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is Cl, R2b is Br and R4 is as defined in table Z.
Table A-21 provides 5 compounds A-21.001 to A-21.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is Cl, R2b is CF3 and R4 is as defined in table Z.
Table A-22 provides 5 compounds A-22.001 to A-22.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is Br, R2b is C and R4 is as defined in table Z.
Table A-23 provides 5 compounds A-23.001 to A-23.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is Br, R2b is Br and R4 is as defined in table Z.
Table A-24 provides 5 compounds A-24.001 to A-24.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is Br, R2b is CF3 and R4 is as defined in table Z.
Table A-25 provides 5 compounds A-25.001 to A-25.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is C and R4 is as defined in table Z.
Table A-26 provides 5 compounds A-26.001 to A-26.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is Br and R4 is as defined in table Z.
Table A-27 provides 5 compounds A-27.001 to A-27.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-28 provides 5 compounds A-28.001 to A-28.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is O—CF3, R2b is C and R4 is as defined in table Z.
Table A-29 provides 5 compounds A-29.001 to A-29.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is O—CF3, R2b is Br and R4 is as defined in table Z.
Table A-30 provides 5 compounds A-30.001 to A-30.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is O—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-31 provides 5 compounds A-31.001 to A-31.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is SO2—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-32 provides 5 compounds A-32.001 to A-32.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is SO2—CF3, R2b is Br and R4 is as defined in table Z.
Table A-33 provides 5 compounds A-33.001 to A-33.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is SO2—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-34 provides 5 compounds A-34.001 to A-34.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is 1-cyano-cyclopropyl, R2b is Cl and R4 is as defined in table Z.
Table A-35 provides 5 compounds A-35.001 to A-35.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is 1-cyano-cyclopropyl, R2b is Brand R4 is as defined in table Z.
Table A-36 provides 5 compounds A-36.001 to A-36.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is 1-cyano-cyclopropyl, R2b is CF3 and R4 is as defined in table Z.
Table A-37 provides 5 compounds A-37.001 to A-37.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is Cl, R2b is C and R4 is as defined in table Z.
Table A-38 provides 5 compounds A-38.001 to A-38.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is Cl, R2b is Br and R4 is as defined in table Z.
Table A-39 provides 5 compounds A-39.001 to A-39.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is Cl, R2b is CF3 and R4 is as defined in table Z.
Table A-40 provides 5 compounds A-40.001 to A-40.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is Br, R2b is C and R4 is as defined in table Z.
Table A-41 provides 5 compounds A-41.001 to A-41.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is Br, R2b is Br and R4 is as defined in table Z.
Table A-42 provides 5 compounds A-42.001 to A-42.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is Br, R2b is CF3 and R4 is as defined in table Z.
Table A-43 provides 5 compounds A-43.001 to A-43.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is CF3, R2b is C and R4 is as defined in table Z.
Table A-44 provides 5 compounds A-44.001 to A-44.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is CF3, R2b is Br and R4 is as defined in table Z.
Table A-45 provides 5 compounds A-45.001 to A-45.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-46 provides 5 compounds A-46.001 to A-46.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is O—CF3, R2b is C and R4 is as defined in table Z.
Table A-47 provides 5 compounds A-47.001 to A-47.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is O—CF3, R2b is Br and R4 is as defined in table Z.
Table A-48 provides 5 compounds A-48.001 to A-48.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is O—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-49 provides 5 compounds A-49.001 to A-49.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is SO2—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-50 provides 5 compounds A-50.001 to A-50.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is SO2—CF3, R2b is Br and R4 is as defined in table Z.
Table A-51 provides 5 compounds A-51.001 to A-51.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is SO2—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-52 provides 5 compounds A-52.001 to A-52.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is 1-cyano-cyclopropyl, R2b is Cl and R4 is as defined in table Z.
Table A-53 provides 5 compounds A-53.001 to A-53.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is 1-cyano-cyclopropyl, R2b is Brand R4 is as defined in table Z.
Table A-54 provides 5 compounds A-54.001 to A-54.005 of formula Iaa wherein A is CH, R1 is CH2-cyclopropyl, R2a is 1-cyano-cyclopropyl, R2b is CF3 and R4 is as defined in table Z.
Table A-55 provides 5 compounds A-55.001 to A-55.005 of formula Iaa wherein A is N, R1 is H, R2a is Cl, R2b is Cl and R4 is as defined in table Z.
Table A-56 provides 5 compounds A-56.001 to A-56.005 of formula Iaa wherein A is N, R1 is H, R2a is Cl, R2b is Br and R4 is as defined in table Z.
Table A-57 provides 5 compounds A-57.001 to A-57.005 of formula Iaa wherein A is N, R1 is H, R2a is Cl, R2b is CF3 and R4 is as defined in table Z.
Table A-58 provides 5 compounds A-58.001 to A-58.005 of formula Iaa wherein A is N, R1 is H, R2a is Br, R2b is Cl and R4 is as defined in table Z.
Table A-59 provides 5 compounds A-59.001 to A-59.005 of formula Iaa wherein A is N, R1 is H, R2a is Br, R2b is Br and R4 is as defined in table Z.
Table A-60 provides 5 compounds A-60.001 to A-60.005 of formula Iaa wherein A is N, R1 is H, R2a is Br, R2b is CF3 and R4 is as defined in table Z.
Table A-61 provides 5 compounds A-61.001 to A-61.005 of formula Iaa wherein A is N, R1 is H, R2a is CF3, R2b is Cl and R4 is as defined in table Z.
Table A-62 provides 5 compounds A-62.001 to A-62.005 of formula Iaa wherein A is N, R1 is H, R2a is CF3, R2b is Br and R4 is as defined in table Z.
Table A-63 provides 5 compounds A-63.001 to A-63.005 of formula Iaa wherein A is N, R1 is H, R2a is CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-64 provides 5 compounds A-64.001 to A-64.005 of formula Iaa wherein A is N, R1 is H, R2a is O—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-65 provides 5 compounds A-65.001 to A-65.005 of formula Iaa wherein A is N, R1 is H, R2a is O—CF3, R2b is Br and R4 is as defined in table Z.
Table A-66 provides 5 compounds A-66.001 to A-66.005 of formula Iaa wherein A is N, R1 is H, R2a is O—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-67 provides 5 compounds A-67.001 to A-67.005 of formula Iaa wherein A is N, R1 is H, R2a is SO2—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-68 provides 5 compounds A-68.001 to A-68.005 of formula Iaa wherein A is N, R1 is H, R2a is SO2—CF3, R2b is Br and R4 is as defined in table Z.
Table A-69 provides 5 compounds A-69.001 to A-69.005 of formula Iaa wherein A is N, R1 is H, R2a is SO2—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-70 provides 5 compounds A-70.001 to A-70.005 of formula Iaa wherein A is N, R1 is H, R2a is 1-cyano-cyclopropyl, R2b is Cl and R4 is as defined in table Z.
Table A-71 provides 5 compounds A-71.001 to A-71.005 of formula Iaa wherein A is N, R1 is H, R2a is 1-cyano-cyclopropyl, R2b is Br and R4 is as defined in table Z.
Table A-72 provides 5 compounds A-72.001 to A-72.005 of formula Iaa wherein A is N, R1 is H, R2a is 1-cyano-cyclopropyl, R2b is CF3 and R4 is as defined in table Z.
Table A-73 provides 5 compounds A-73.001 to A-73.005 of formula Iaa wherein A is N, R1 is CH3, R2a is Cl, R2b is Cl and R4 is as defined in table Z.
Table A-74 provides 5 compounds A-74.001 to A-74.005 of formula Iaa wherein A is N, R1 is CH3, R2a is Cl, R2b is Br and R4 is as defined in table Z.
Table A-75 provides 5 compounds A-75.001 to A-75.005 of formula Iaa wherein A is N, R1 is CH3, R2a is Cl, R2b is CF3 and R4 is as defined in table Z.
Table A-76 provides 5 compounds A-76.001 to A-76.005 of formula Iaa wherein A is N, R1 is CH3, R2a is Br, R2b is Cl and R4 is as defined in table Z.
Table A-77 provides 5 compounds A-77.001 to A-77.005 of formula Iaa wherein A is N, R1 is CH3, R2a is Br, R2b is Br and R4 is as defined in table Z.
Table A-78 provides 5 compounds A-78.001 to A-78.005 of formula Iaa wherein A is N, R1 is CH3, R2a is Br, R2b is CF3 and R4 is as defined in table Z.
Table A-79 provides 5 compounds A-79.001 to A-79.005 of formula Iaa wherein A is N, R1 is CH3, R2a is CF3, R2b is Cl and R4 is as defined in table Z.
Table A-80 provides 5 compounds A-80.001 to A-80.005 of formula Iaa wherein A is N, R1 is CH3, R2a is CF3, R2b is Br and R4 is as defined in table Z.
Table A-81 provides 5 compounds A-81.001 to A-81.005 of formula Iaa wherein A is N, R1 is CH3, R2a is CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-82 provides 5 compounds A-82.001 to A-82.005 of formula Iaa wherein A is N, R1 is CH3, R2a is O—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-83 provides 5 compounds A-83.001 to A-83.005 of formula Iaa wherein A is N, R1 is CH3, R2a is O—CF3, R2b is Br and R4 is as defined in table Z.
Table A-84 provides 5 compounds A-84.001 to A-84.005 of formula Iaa wherein A is N, R1 is CH3, R2a is O—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-85 provides 5 compounds A-85.001 to A-85.005 of formula Iaa wherein A is N, R1 is CH3, R2a is SO2—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-86 provides 5 compounds A-86.001 to A-86.005 of formula Iaa wherein A is N, R1 is CH3, R2a is SO2—CF3, R2b is Br and R4 is as defined in table Z.
Table A-87 provides 5 compounds A-87.001 to A-87.005 of formula Iaa wherein A is N, R1 is CH3, R2a is SO2—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-88 provides 5 compounds A-88.001 to A-88.005 of formula Iaa wherein A is N, R1 is CH3, R2a is 1-cyano-cyclopropyl, R2b is Cl and R4 is as defined in table Z.
Table A-89 provides 5 compounds A-89.001 to A-89.005 of formula Iaa wherein A is N, R1 is CH3, R2a is 1-cyano-cyclopropyl, R2b is Br and R4 is as defined in table Z.
Table A-90 provides 5 compounds A-90.001 to A-90.005 of formula Iaa wherein A is N, R1 is CH3, R2a is 1-cyano-cyclopropyl, R2b is CF3 and R4 is as defined in table Z.
Table A-91 provides 5 compounds A-91.001 to A-91.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is Cl, R2b is Cl and R4 is as defined in table Z.
Table A-92 provides 5 compounds A-92.001 to A-92.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is Cl, R2b is Br and R4 is as defined in table Z.
Table A-93 provides 5 compounds A-93.001 to A-93.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is Cl, R2b is CF3 and R4 is as defined in table Z.
Table A-94 provides 5 compounds A-94.001 to A-94.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is Br, R2b is Cl and R4 is as defined in table Z.
Table A-95 provides 5 compounds A-95.001 to A-95.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is Br, R2b is Br and R4 is as defined in table Z.
Table A-96 provides 5 compounds A-96.001 to A-96.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is Br, R2b is CF3 and R4 is as defined in table Z.
Table A-97 provides 5 compounds A-97.001 to A-97.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is CF3, R2b is Cl and R4 is as defined in table Z.
Table A-98 provides 5 compounds A-98.001 to A-98.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is CF3, R2b is Br and R4 is as defined in table Z.
Table A-99 provides 5 compounds A-99.001 to A-99.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-100 provides 5 compounds A-100.001 to A-100.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is O—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-101 provides 5 compounds A-101.001 to A-101.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is O—CF3, R2b is Br and R4 is as defined in table Z.
Table A-102 provides 5 compounds A-102.001 to A-102.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is O—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-103 provides 5 compounds A-103.001 to A-103.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is SO2—CF3, R2b is Cl and R4 is as defined in table Z.
Table A-104 provides 5 compounds A-104.001 to A-104.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is SO2—CF3, R2b is Br and R4 is as defined in table Z.
Table A-105 provides 5 compounds A-105.001 to A-105.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is SO2—CF3, R2b is CF3 and R4 is as defined in table Z.
Table A-106 provides 5 compounds A-106.001 to A-106.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is 1-cyano-cyclopropyl, R2b is Cl and R4 is as defined in table Z.
Table A-107 provides 5 compounds A-107.001 to A-107.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is 1-cyano-cyclopropyl, R2b is Brand R4 is as defined in table Z.
Table A-108 provides 5 compounds A-108.001 to A-108.005 of formula Iaa wherein A is N, R1 is CH2-cyclopropyl, R2a is 1-cyano-cyclopropyl, R2b is CF3 and R4 is as defined in table Z.
Table A-109 provides 5 compounds A-109.001 to A-109.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is CHF2 and R4 is as defined in table Z.
Table A-110 provides 5 compounds A-110.001 to A-110.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is 1-cyano-1-methyl-ethyl and R4 is as defined in table Z.
Table A-111 provides 5 compounds A-111.001 to A-111.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is I and R4 is as defined in table Z.
Table A-112 provides 5 compounds A-112.001 to A-112.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is SO2—CH3 and R4 is as defined in table Z.
Table A-113 provides 5 compounds A-113.001 to A-113.005 of formula Iaa wherein A is CH, R1 is H, R2a is CF3, R2b is OCHF2 and R4 is as defined in table Z.
Table A-114 provides 5 compounds A-114.001 to A-114.005 of formula Iaa wherein A is CH, R1 is H, R2a is OCHF2, R2b is OCHF2 and R4 is as defined in table Z.
Table A-115 provides 5 compounds A-115.001 to A-115.005 of formula Iaa wherein A is CH, R1 is H, R2a is I, R2b is I and R4 is as defined in table Z.
Table A-116 provides 5 compounds A-116.001 to A-116.005 of formula Iaa wherein A is CH, R1 is H, R2a is I, R2b is Br and R4 is as defined in table Z.
Table A-117 provides 5 compounds A-117.001 to A-117.005 of formula Iaa wherein A is CH, R1 is H, R2a is I, R2b is C and R4 is as defined in table Z.
Table A-118 provides 5 compounds A-118.001 to A-118.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is CHF2 and R4 is as defined in table Z.
Table A-119 provides 5 compounds A-119.001 to A-119.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is 1-cyano-1-methyl-ethyl and R4 is as defined in table Z.
Table A-120 provides 5 compounds A-120.001 to A-120.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is I and R4 is as defined in table Z.
Table A-121 provides 5 compounds A-121.001 to A-121.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is SO2—CH3 and R4 is as defined in table Z.
Table A-122 provides 5 compounds A-122.001 to A-122.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is CF3, R2b is OCHF2 and R4 is as defined in table Z.
Table A-123 provides 5 compounds A-123.001 to A-123.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is OCHF2, R2b is OCHF2 and R4 is as defined in table Z.
Table A-124 provides 5 compounds A-124.001 to A-124.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is I, R2b is I and R4 is as defined in table Z.
Table A-125 provides 5 compounds A-125.001 to A-125.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is I, R2b is Br and R4 is as defined in table Z.
Table A-126 provides 5 compounds A-126.001 to A-126.005 of formula Iaa wherein A is CH, R1 is CH3, R2a is I, R2b is C and R4 is as defined in table Z.
Also made available are certain intermediate compounds of formulae II, and IIb, some of which are novel. For example,
Also made available are certain intermediate compounds of formulae VIIIa, VIIIa′, and VIIISi, some of which are novel. For example,
Also made available are certain intermediate compounds of formulae VIIIa, VIIIa′, and VIIISi, as shown above, wherein:
Also made available are certain intermediate compounds of formulae XLII and XLII′, some of which are novel. For example,
Also made available are certain intermediate compounds of formulae XLII and XLII′, as shown above:
Also made available are certain intermediate compounds of formulae XLIX and XLIX′, some of which are novel. For example,
In further aspect, the present invention accordingly makes available compounds of formulae II and IIb, R1, R3, R4, R5a and R5b are as defined for formula I in the first aspect. Furthermore, the corresponding embodiments illustrated for formula I also apply to the compounds of formulae II and IIb.
In a further aspect, the present invention accordingly makes available compounds of formulae VIIIa, VIIIa′, and VIIISi, as shown above, wherein (RA1)3Si is a silyl-protecting group, such as tri(C1-C4alkyl)-silyl-; R3, R4a, R4b, R4c, R5a and R5b are as defined for formula I in the first aspect. Furthermore, the corresponding embodiments illustrated for formula I also apply to the compounds of formulae VIIIa, VIIIa′, and VIIISi.
In a further aspect, the present invention accordingly makes available compounds of formulae XLII and XLII′, as shown above, wherein R3, R4a, R4b, R4c, R5a and R5b are as defined for formula I in the first aspect. Furthermore, the corresponding embodiments illustrated for formula I also apply to the compounds of formulae XLII and XLII′.
In a further aspect, the present invention accordingly makes available compounds of formulae XLIX and XLIX′, as shown above, wherein R3, R4a, R4b, R4c, R5a and R5b are as defined for formula I in the first aspect. Furthermore, the corresponding embodiments illustrated for formula I also apply to the compounds of formulae XLIX and XLIX′.
The compounds of formula I according to the invention are preventively and/or curatively valuable active ingredients in the field of pest control, even at low rates of application, which have a very favorable biocidal spectrum and are well tolerated by warm-blooded species, fish and plants. The active ingredients according to the invention act against all or individual developmental stages of normally sensitive, but also resistant, animal pests, such as insects or representatives of the order Acarina. The insecticidal or acaricidal activity of the active ingredients according to the invention can manifest itself directly, i.e. in destruction of the pests, which takes place either immediately or only after some time has elapsed, for example during ecdysis, or indirectly, for example in a reduced oviposition and/or hatching rate.
Examples of the above mentioned animal pests are:
In a further aspect, the invention may also relate to a method of controlling damage to plant and parts thereof by plant parasitic nematodes (Endoparasitic-, Semiendoparasitic- and Ectoparasitic nematodes), especially plant parasitic nematodes such as root knot nematodes, Meloidogyne hapla, Meloidogyne incognita, Meloidogyne javanica, Meloidogyne arenaria and other Meloidogyne species; cyst-forming nematodes, Globodera rostochiensis and other Globodera species; Heterodera avenae, Heterodera glycines, Heterodera schachtii, Heterodera trifolii, and other Heterodera species; Seed gall nematodes, Anguina species; Stem and foliar nematodes, Aphelenchoides species; Sting nematodes, Belonolaimus longicaudatus and other Belonolaimus species; Pine nematodes, Bursaphelenchus xylophilus and other Bursaphelenchus species; Ring nematodes, Criconema species, Criconemella species, Criconemoides species, Mesocriconema species; Stem and bulb nematodes, Ditylenchus destructor, Ditylenchus dipsaci and other Ditylenchus species; Awl nematodes, Dolichodorus species; Spiral nematodes, Heliocotylenchus multicinctus and other Helicotylenchus species; Sheath and sheathoid nematodes, Hemicycliophora species and Hemicriconemoides species; Hirshmanniella species; Lance nematodes, Hoploaimus species; false rootknot nematodes, Nacobbus species; Needle nematodes, Longidorus elongatus and other Longidorus species; Pin nematodes, Pratylenchus species; Lesion nematodes, Pratylenchus neglectus, Pratylenchus penetrans, Pratylenchus curvitatus, Pratylenchus goodeyi and other Pratylenchus species; Burrowing nematodes, Radopholus similis and other Radopholus species; Reniform nematodes, Rotylenchus robustus, Rotylenchus reniformis and other Rotylenchus species; Scutellonema species; Stubby root nematodes, Trichodorus primitivus and other Trichodorus species, Paratrichodorus species; Stunt nematodes, Tylenchorhynchus claytoni, Tylenchorhynchus dubius and other Tylenchorhynchus species; Citrus nematodes, Tylenchulus species; Dagger nematodes, Xiphinema species; and other plant parasitic nematode species, such as Subanguina spp., Hypsoperine spp., Macroposthonia spp., Melinius spp., Punctodera spp., and Quinisulcius spp.
The compounds of the invention may also have activity against the molluscs. Examples of which include, for example, Ampullariidae; Arion (A. ater, A. circumscriptus, A. hortensis, A. rufus); Bradybaenidae (Bradybaena fruticum); Cepaea (C. hortensis, C. Nemoralis); ochlodina; Deroceras (D. agrestis, D. empiricorum, D. laeve, D. reticulatum); Discus (D. rotundatus); Euomphalia; Galba (G. trunculata); Helicelia (H. itala, H. obvia); Helicidae Helicigona arbustorum); Helicodiscus; Helix (H. aperta); Limax (L. cinereoniger, L. flavus, L. marginatus, L. maximus, L. tenellus); Lymnaea; Milax (M. gagates, M. marginatus, M. sowerbyi); Opeas; Pomacea (P. canaticulata); Vallonia and Zanitoides.
The active ingredients according to the invention can be used for controlling, i.e. containing or destroying, pests of the abovementioned type which occur in particular on plants, especially on useful plants and ornamentals in agriculture, in horticulture and in forests, or on organs, such as fruits, flowers, foliage, stalks, tubers or roots, of such plants, and in some cases even plant organs which are formed at a later point in time remain protected against these pests.
Suitable target crops are, in particular, cereals, such as wheat, barley, rye, oats, rice, maize or sorghum; beet, such as sugar or fodder beet; fruit, for example pomaceous fruit, stone fruit or soft fruit, such as apples, pears, plums, peaches, almonds, cherries or berries, for example strawberries, raspberries or blackberries; leguminous crops, such as beans, lentils, peas or soya; oil crops, such as oilseed rape, mustard, poppies, olives, sunflowers, coconut, castor, cocoa or ground nuts; cucurbits, such as pumpkins, cucumbers or melons; fibre plants, such as cotton, flax, hemp or jute; citrus fruit, such as oranges, lemons, grapefruit or tangerines; vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes or bell peppers; Lauraceae, such as avocado, Cinnamonium or camphor; and also tobacco, nuts, coffee, eggplants, sugarcane, tea, pepper, grapevines, hops, the plantain family and latex plants.
The compositions and/or methods of the present invention may be also used on any ornamental and/or vegetable crops, including flowers, shrubs, broad-leaved trees and evergreens.
For example the invention may be used on any of the following ornamental species: Ageratum spp., Alonsoa spp., Anemone spp., Anisodontea capsenisis, Anthemis spp., Antirrhinum spp., Aster spp., Begonia spp. (e.g. B. elatior, B. semperflorens, B. tubereux), Bougainvillea spp., Brachycome spp., Brassica spp. (ornamental), Calceolaria spp., Capsicum annuum, Catharanthus roseus, Canna spp., Centaurea spp., Chrysanthemum spp., Cineraria spp. (C. maritime), Coreopsis spp., Crassula coccinea, Cuphea ignea, Dahlia spp., Delphinium spp., Dicentra spectabilis, Dorotheantus spp., Eustoma grandiflorum, Forsythia spp., Fuchsia spp., Geranium gnaphalium, Gerbera spp., Gomphrena globosa, Heliotropium spp., Helianthus spp., Hibiscus spp., Hortensia spp., Hydrangea spp., Hypoestes phyllostachya, Impatiens spp. (I. Walleriana), Iresines spp., Kalanchoe spp., Lantana camara, Lavatera trimestris, Leonotis leonurus, Lilium spp., Mesembryanthemum spp., Mimulus spp., Monarda spp., Nemesia spp., Tagetes spp., Dianthus spp. (carnation), Canna spp., Oxalis spp., Bellis spp., Pelargonium spp. (P. peltatum, P. Zonale), Viola spp. (pansy), Petunia spp., Phlox spp., Plecthranthus spp., Poinsettia spp., Parthenocissus spp. (P. quinquefolia, P. tricuspidata), Primula spp., Ranunculus spp., Rhododendron spp., Rosa spp. (rose), Rudbeckia spp., Saintpaulia spp., Salvia spp., Scaevola aemola, Schizanthus wisetonensis, Sedum spp., Solanum spp., Surfinia spp., Tagetes spp., Nicotinia spp., Verbena spp., Zinnia spp. and other bedding plants.
For example the invention may be used on any of the following vegetable species: Allium spp. (A. sativum, A. cepa, A. oschaninii, A. Porrum, A. ascalonicum, A. fistulosum), Anthriscus cerefolium, Apium graveolus, Asparagus officinalis, Beta vulgarus, Brassica spp. (B. Oleracea, B. Pekinensis, B. rapa), Capsicum annuum, Cicer arietinum, Cichorium endivia, Cichorum spp. (C. intybus, C. endivia), Citrillus lanatus, Cucumis spp. (C. sativus, C. melo), Cucurbita spp. (C. pepo, C. maxima), Cyanara spp. (C. scolymus, C. cardunculus), Daucus carota, Foeniculum vulgare, Hypericum spp., Lactuca sativa, Lycopersicon spp. (L. esculentum, L. lycopersicum), Mentha spp., Ocimum basilicum, Petroselinum crispum, Phaseolus spp. (P. vulgaris, P. coccineus), Pisum sativum, Raphanus sativus, Rheum rhaponticum, Rosemarinus spp., Salvia spp., Scorzonera hispanica, Solanum melongena, Spinacea oleracea, Valerianella spp. (V. locusta, V. eriocarpa) and Vicia faba.
Preferred ornamental species include African violet, Begonia, Dahlia, Gerbera, Hydrangea, Verbena, Rosa, Kalanchoe, Poinsettia, Aster, Centaurea, Coreopsis, Delphinium, Monarda, Phlox, Rudbeckia, Sedum, Petunia, Viola, Impatiens, Geranium, Chrysanthemum, Ranunculus, Fuchsia, Salvia, Hortensia, rosemary, sage, St. Johnswort, mint, sweet pepper, tomato and cucumber.
The active ingredients according to the invention are especially suitable for controlling Aphis craccivora, Diabrotica balteata, Heliothis virescens, Myzus persicae, Plutella xylostella and Spodoptera littoralis in cotton, vegetable, maize, rice and soya crops. The active ingredients according to the invention are further especially suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatoes) and Chilo supressalis (preferably in rice).
The compounds of formula I are particularly suitable for control of
The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known, for example, from toxin-producing bacteria, especially those of the genus Bacillus.
Toxins that can be expressed by such transgenic plants include, for example, insecticidal proteins, for example insecticidal proteins from Bacillus cereus or Bacillus popilliae; or insecticidal proteins from Bacillus thuringiensis, such as 6-endotoxins, e.g. Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), e.g. Vip1, Vip2, Vip3 or Vip3A; or insecticidal proteins of bacteria colonising nematodes, for example Photorhabdus spp. or Xenorhabdus spp., such as Photorhabdus luminescens, Xenorhabdus nematophilus; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins and other insect-specific neurotoxins; toxins produced by fungi, such as Streptomycetes toxins, plant lectins, such as pea lectins, barley lectins or snowdrop lectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin, papain inhibitors; ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3-hydroxysteroidoxidase, ecdysteroid-UDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors, HMG-COA-reductase, ion channel blockers, such as blockers of sodium or calcium channels, juvenile hormone esterase, diuretic hormone receptors, stilbene synthase, bibenzyl synthase, chitinases and glucanases.
In the context of the present invention there are to be understood by 6-endotoxins, for example Cry1Ab, Cry1Ac, Cry1F, Cry1Fa2, Cry2Ab, Cry3A, Cry3Bb1 or Cry9C, or vegetative insecticidal proteins (Vip), for example Vip1, Vip2, Vip3 or Vip3A, expressly also hybrid toxins, truncated toxins and modified toxins.
Hybrid toxins are produced recombinantly by a new combination of different domains of those proteins (see, for example, WO 02/15701). Truncated toxins, for example a truncated Cry1Ab, are known. In the case of modified toxins, one or more amino acids of the naturally occurring toxin are replaced. In such amino acid replacements, preferably non-naturally present protease recognition sequences are inserted into the toxin, such as, for example, in the case of Cry3A055, a cathepsin-G-recognition sequence is inserted into a Cry3A toxin (see WO 03/018810).
Examples of such toxins or transgenic plants capable of synthesising such toxins are disclosed, for example, in EP-A-0 374 753, WO 93/07278, WO 95/34656, EP-A-0 427 529, EP-A-451 878 and WO 03/052073.
The processes for the preparation of such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above. Cryl-type deoxyribonucleic acids and their preparation are known, for example, from WO 95/34656, EP-A-0 367 474, EP-A-0 401 979 and WO 90/13651.
The toxin contained in the transgenic plants imparts to the plants tolerance to harmful insects. Such insects can occur in any taxonomic group of insects, but are especially commonly found in the beetles (Coleoptera), two-winged insects (Diptera) and moths (Lepidoptera).
Transgenic plants containing one or more genes that code for an insecticidal resistance and express one or more toxins are known and some of them are commercially available. Examples of such plants are: YieldGard® (maize variety that expresses a Cry1Ab toxin); YieldGard Rootworm® (maize variety that expresses a Cry3Bb1 toxin); YieldGard Plus® (maize variety that expresses a Cry1Ab and a Cry3Bb1 toxin); Starlink® (maize variety that expresses a Cry9C toxin); Herculex I® (maize variety that expresses a Cry1 Fa2 toxin and the enzyme phosphinothricine N-acetyltransferase (PAT) to achieve tolerance to the herbicide glufosinate ammonium); NuCOTN 33B® (cotton variety that expresses a Cry1Ac toxin); Bollgard I® (cotton variety that expresses a Cry1Ac toxin); Bollgard II® (cotton variety that expresses a Cry1Ac and a Cry2Ab toxin); VipCot® (cotton variety that expresses a Vip3A and a Cry1Ab toxin); NewLeaf® (potato variety that expresses a Cry3A toxin); NatureGard®, Agrisure® GT Advantage (GA21 glyphosate-tolerant trait), Agrisure® CB Advantage (Bt11 corn borer (CB) trait) and Protecta®.
Further examples of such transgenic crops are:
Transgenic crops of insect-resistant plants are also described in BATS (Zentrum fur Biosicherheit und Nachhaltigkeit, Zentrum BATS, Clarastrasse 13, 4058 Basel, Switzerland) Report 2003, (http://bats.ch).
The term “crops” is to be understood as including also crop plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as, for example, the so-called “pathogenesis-related proteins” (PRPs, see e.g. EP-A-0 392 225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from EP-A-0 392 225, WO 95/33818 and EP-A-0 353 191. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.
Crops may also be modified for enhanced resistance to fungal (for example Fusarium, Anthracnose, or Phytophthora), bacterial (for example Pseudomonas) or viral (for example potato leafroll virus, tomato spotted wilt virus, cucumber mosaic virus) pathogens.
Crops also include those that have enhanced resistance to nematodes, such as the soybean cyst nematode.
Crops that are tolerance to abiotic stress include those that have enhanced tolerance to drought, high salt, high temperature, chill, frost, or light radiation, for example through expression of NF-YB or other proteins known in the art.
Antipathogenic substances which can be expressed by such transgenic plants include, for example, ion channel blockers, such as blockers for sodium and calcium channels, for example the viral KP1, KP4 or KP6 toxins; stilbene synthases; bibenzyl synthases; chitinases; glucanases; the so-called “pathogenesis-related proteins” (PRPs; see e.g. EP-A-0 392 225); antipathogenic substances produced by microorganisms, for example peptide antibiotics or heterocyclic antibiotics (see e.g. WO 95/33818) or protein or polypeptide factors involved in plant pathogen defence (so-called “plant disease resistance genes”, as described in WO 03/000906).
Further areas of use of the compositions according to the invention are the protection of stored goods and store rooms and the protection of raw materials, such as wood, textiles, floor coverings or buildings, and also in the hygiene sector, especially the protection of humans, domestic animals and productive livestock against pests of the mentioned type.
The present invention provides a compound of the first aspect for use in therapy. The present invention provides a compound of the first aspect, for use in controlling parasites in or on an animal. The present invention further provides a compound of the first aspect, for use in controlling ectoparasites on an animal. The present invention further provides a compound of the first aspect, for use in preventing and/or treating diseases transmitted by ectoparasites.
The present invention provides the use of a compound of the first aspect, for the manufacture of a medicament for controlling parasites in or on an animal. The present invention further provides the use of a compound of the first aspect, for the manufacture of a medicament for controlling ectoparasites on an animal. The present invention further provides the use of a compound of the first aspect, for the manufacture of a medicament for preventing and/or treating diseases transmitted by ectoparasites.
The present invention provides the use of a compound of the first aspect, in controlling parasites in or on an animal. The present invention further provides the use of a compound of the first aspect, in controlling ectoparasites on an animal.
The term “controlling” when used in context of parasites in or on an animal refers to reducing the number of pests or parasites, eliminating pests or parasites and/or preventing further pest or parasite infestation.
The term “treating” when used in context of parasites in or on an animal refers to restraining, slowing, stopping or reversing the progression or severity of an existing symptom or disease.
The term “preventing” when used in context of parasites in or on an animal refers to the avoidance of a symptom or disease developing in the animal.
The term “animal” when used in context of parasites in or on an animal may refer to a mammal and a non-mammal, such as a bird or fish. In the case of a mammal, it may be a human or non-human mammal. Non-human mammals include, but are not limited to, livestock animals and companion animals. Livestock animals include, but are not limited to, cattle, camelids, pigs, sheep, goats and horses. Companion animals include, but are not limited to, dogs, cats and rabbits.
A “parasite” is a pest which lives in or on the host animal and benefits by deriving nutrients at the host animal's expense. An “endoparasite” is a parasite which lives in the host animal. An “ectoparasite” is a parasite which lives on the host animal. Ectoparasites include, but are not limited to, acari, insects and crustaceans (e.g. sea lice). The Acari (or Acarina) sub-class comprises ticks and mites. Ticks include, but are not limited to, members of the following genera: Rhipicaphalus, for example, Rhipicaphalus (Boophilus) microplus and Rhipicephalus sanguineus; Amblyomrna; Dermacentor; Haemaphysalis; Hyalomma; Ixodes; Rhipicentor; Margaropus; Argas; Otobius; and Ornithodoros. Mites include, but are not limited to, members of the following genera: Chorioptes, for example Chorioptes bovis; Psoroptes, for example Psoroptes ovis; Cheyletiella; Dermanyssus; for example Dermanyssus gallinae; Ortnithonyssus; Demodex, for example Demodex canis; Sarcoptes, for example Sarcoptes scabiei; and Psorergates. Insects include, but are not limited to, members of the orders: Siphonaptera, Diptera, Phthiraptera, Lepidoptera, Coleoptera and Homoptera. Members of the Siphonaptera order include, but are not limited to, Ctenocephalides felis and Ctenocephatides canis. Members of the Diptera order include, but are not limited to, Musca spp.; bot fly, for example Gasterophilus intestinalis and Oestrus ovis; biting flies; horse flies, for example Haematopota spp. and Tabunus spp.; haematobia, for example haematobia irritans; Stomoxys; Lucilia; midges; and mosquitoes. Members of the Phthiraptera class include, but are not limited to, blood sucking lice and chewing lice, for example Bovicola Ovis and Bovicola Bovis.
The term “effective amount” when used in context of parasites in or on an animal refers to the amount or dose of the compound of the invention, or a salt thereof, which, upon single or multiple dose administration to the animal, provides the desired effect in or on the animal. The effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the parasite to be controlled and the degree of infestation; the specific disease or disorder involved; the degree of or involvement or the severity of the disease or disorder; the response of the individual; the particular compound administered: the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.
The compounds of the invention may be administered to the animal by any route which has the desired effect including, but not limited to topically, orally, parenterally and subcutaneously. Topical administration is preferred. Formulations suitable for topical administration include, for example, solutions, emulsions and suspensions and may take the form of a pour-on, spot-on, spray-on, spray race or dip. In the alternative, the compounds of the invention may be administered by means of an ear tag or collar.
Salt forms of the compounds of the invention include both pharmaceutically acceptable salts and veterinary acceptable salts, which can be different to agrochemically acceptable salts. Pharmaceutically and veterinary acceptable salts and common methodology for preparing them are well known in the art. See, for example, Gould, P. L., “Salt selection for basic drugs”, International Journal of Pharmaceutics, 33: 201-217 (1986); Bastin, R. J., et al. “Salt Selection and Optimization Procedures for Pharmaceutical New Chemical Entities”, Organic Process Research and Development, 4: 427-435 (2000); and Berge, S. M., et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Sciences, 66: 1-19, (1977). One skilled in the art of synthesis will appreciate that the compounds of the invention are readily converted to and may be isolated as a salt, such as a hydrochloride salt, using techniques and conditions well known to one of ordinary skill in the art. In addition, one skilled in the art of synthesis will appreciate that the compounds of the invention are readily converted to and may be isolated as the corresponding free base from the corresponding salt.
The present invention also provides a method for controlling pests (such as mosquitoes and other disease vectors; see also http://www.who.int/malaria/vector_control/irs/en/). In one embodiment, the method for controlling pests comprises applying the compositions of the invention to the target pests, to their locus or to a surface or substrate by brushing, rolling, spraying, spreading or dipping. By way of example, an IRS (indoor residual spraying) application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention. In another embodiment, it is contemplated to apply such compositions to a substrate such as non-woven or a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
In one embodiment, the method for controlling such pests comprises applying a pesticidally effective amount of the compositions of the invention to the target pests, to their locus, orto a surface or substrate so as to provide effective residual pesticidal activity on the surface or substrate. Such application may be made by brushing, rolling, spraying, spreading or dipping the pesticidal composition of the invention.
By way of example, an IRS application of a surface such as a wall, ceiling or floor surface is contemplated by the method of the invention so as to provide effective residual pesticidal activity on the surface. In another embodiment, it is contemplated to apply such compositions for residual control of pests on a substrate such as a fabric material in the form of (or which can be used in the manufacture of) netting, clothing, bedding, curtains and tents.
Substrates including non-woven, fabrics or netting to be treated may be made of natural fibres such as cotton, raffia, jute, flax, sisal, hessian, or wool, or synthetic fibres such as polyamide, polyester, polypropylene, polyacrylonitrile or the like. The polyesters are particularly suitable. The methods of textile treatment are known, e.g. WO 2008/151984, WO 2003/034823, U.S. Pat. No. 5,631,072, WO 2005/64072, WO2006/128870, EP 1724392, WO 2005113886 or WO 2007/090739.
Further areas of use of the compositions according to the invention are the field of tree injection/trunk treatment for all ornamental trees as well all sort of fruit and nut trees.
In the field of tree injection/trunk treatment, the compounds according to the present invention are especially suitable against wood-boring insects from the order Lepidoptera as mentioned above and from the order Coleoptera, especially against woodborers listed in the following tables A and B:
Agrilus planipennis
Anoplura glabripennis
Xylosandrus crassiusculus
X. mutilatus
Tomicus piniperda
Agrilus anxius
Agrilus politus
Agrilus sayi
Agrilus vittaticolllis
Chrysobothris femorata
Texania campestris
Goes pulverulentus
Goes tigrinus
Neoclytus acuminatus
Neoptychodes trilineatus
Oberea ocellata
Oberea tripunctata
Oncideres cingulata
Saperda calcarata
Strophiona nitens
Corthylus columbianus
Dendroctonus frontalis
Dryocoetes betulae
Monarthrum fasciatum
Phloeotribus liminaris
Pseudopityophthorus pruinosus
Paranthrene simulans
Sannina uroceriformis
Synanthedon exitiosa
Synanthedon pictipes
Synanthedon rubrofascia
Synanthedon scitula
Vitacea polistiformis
The present invention may be also used to control any insect pests that may be present in turfgrass, including for example beetles, caterpillars, fire ants, ground pearls, millipedes, sow bugs, mites, mole crickets, scales, mealybugs, ticks, spittlebugs, southern chinch bugs and white grubs. The present invention may be used to control insect pests at various stages of their life cycle, including eggs, larvae, nymphs and adults.
In particular, the present invention may be used to control insect pests that feed on the roots of turfgrass including white grubs (such as Cyclocephala spp. (e.g. masked chafer, C. lurida), Rhizotrogus spp. (e.g. European chafer, R. majalis), Cotinus spp. (e.g. Green June beetle, C. nitida), Popillia spp. (e.g. Japanese beetle, P. japonica), Phyllophaga spp. (e.g. May/June beetle), Ataenius spp. (e.g. Black turfgrass ataenius, A. spretulus), Maladera spp. (e.g. Asiatic garden beetle, M. castanea) and Tomarus spp.), ground pearls (Margarodes spp.), mole crickets (tawny, southern, and short-winged; Scapteriscus spp., Gryllotalpa africana) and leatherjackets (European crane fly, Tipula spp.).
The present invention may also be used to control insect pests of turfgrass that are thatch dwelling, including armyworms (such as fall armyworm Spodoptera frugiperda, and common armyworm Pseudaletia unipuncta), cutworms, billbugs (Sphenophorus spp., such as S. venatus verstitus and S. parvulus), and sod webworms (such as Crambus spp. and the tropical sod webworm, Herpetogramma phaeopteralis).
The present invention may also be used to control insect pests of turfgrass that live above the ground and feed on the turfgrass leaves, including chinch bugs (such as southern chinch bugs, Blissus insularis), Bermudagrass mite (Eriophyes cynodoniensis), rhodesgrass mealybug (Antonina graminis), two-lined spittlebug (Propsapia bicincta), leafhoppers, cutworms (Noctuidae family), and greenbugs.
The present invention may also be used to control other pests of turfgrass such as red imported fire ants (Solenopsis invicta) that create ant mounds in turf.
In the hygiene sector, the compositions according to the invention are active against ectoparasites such as hard ticks, soft ticks, mange mites, harvest mites, flies (biting and licking), parasitic fly larvae, lice, hair lice, bird lice and fleas.
Examples of such parasites are: Of the order Anoplurida: Haematopinus spp., Linognathus spp., Pediculus spp. and Phtirus spp., Solenopotes spp.
Of the order Mallophagida: Trimenopon spp., Menopon spp., Trinoton spp., Bovicola spp., Werneckiella spp., Lepikentron spp., Damalina spp., Trichodectes spp. and Felicola spp.
Of the order Diptera and the suborders Nematocerina and Brachycerina, for example Aedes spp., Anopheles spp., Culex spp., Simulium spp., Eusimulium spp., Phlebotomus spp., Lutzomyia spp., Culicoides spp., Chrysops spp., Hybomitra spp., Atylotus spp., Tabanus spp., Haematopota spp., Philipomyia spp., Braula spp., Musca spp., Hydrotaea spp., Stomoxys spp., Haematobia spp., Morellia spp., Fannia spp., Glossina spp., Calliphora spp., Lucilia spp., Chrysomyia spp., Wohlfahrtia spp., Sarcophaga spp., Oestrus spp., Hypoderma spp., Gasterophilus spp., Hippobosca spp., Lipoptena spp. and Melophagus spp.
Of the order Siphonapterida, for example Pulex spp., Ctenocephalides spp., Xenopsylla spp., Ceratophyllus spp.
Of the order Heteropterida, for example Cimex spp., Triatoma spp., Rhodnius spp., Panstrongylus spp.
Of the order Blattarida, for example Blatta orientalis, Periplaneta americana, Blattelagermanica and Supella spp.
Of the subclass Acaria (Acarida) and the orders Meta- and Meso-stigmata, for example Argas spp., Ornithodorus spp., Otobius spp., Ixodes spp., Amblyomma spp., Boophilus spp., Dermacentor spp., Haemophysalis spp., Hyalomma spp., Rhipicephalus spp., Dermanyssus spp., Raillietia spp., Pneumonyssus spp., Sternostoma spp. and Varroa spp.
Of the orders Actinedida (Prostigmata) and Acaridida (Astigmata), for example Acarapis spp., Cheyletiella spp., Ornithocheyletia spp., Myobia spp., Psorergates spp., Demodex spp., Trombicula spp., Listrophorus spp., Acarus spp., Tyrophagus spp., Caloglyphus spp., Hypodectes spp., Pterolichus spp., Psoroptes spp., Chorioptes spp., Otodectes spp., Sarcoptes spp., Notoedres spp., Knemidocoptes spp., Cytodites spp. and Laminosioptes spp.
The compositions according to the invention are also suitable for protecting against insect infestation in the case of materials such as wood, textiles, plastics, adhesives, glues, paints, paper and card, leather, floor coverings and buildings.
The compositions according to the invention can be used, for example, against the following pests: beetles such as Hylotrupes bajulus, Chlorophorus pilosis, Anobium punctatum, Xestobium rufovillosum, Ptilinuspecticornis, Dendrobium pertinex, Ernobius mollis, Priobium carpini, Lyctus brunneus, Lyctus africanus, Lyctus planicollis, Lyctus linearis, Lyctus pubescens, Trogoxylon aequale, Minthesrugicollis, Xyleborus spec., Tryptodendron spec., Apate monachus, Bostrychus capucins, Heterobostrychus brunneus, Sinoxylon spec. and Dinoderus minutus, and also hymenopterans such as Sirex juvencus, Urocerus gigas, Urocerus gigas taignus and Urocerus augur, and termites such as Kalotermes flavicollis, Cryptotermes brevis, Heterotermes indicola, Reticulitermes flavipes, Reticulitermes santonensis, Reticulitermes lucifugus, Mastotermes darwiniensis, Zootermopsis nevadensis and Coptotermes formosanus, and bristletails such as Lepisma saccharina.
The compounds of formulae I, and I′a, or salts thereof, are especially suitable for controlling one or more pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae, and Heteroderidae. In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-126 and Table P and Table E”) controls one or more of pests selected from the family: Noctuidae, Plutellidae, Chrysomelidae, Thripidae, Pentatomidae, Tortricidae, Delphacidae, Aphididae, Noctuidae, Crambidae, Meloidogynidae, and Heteroderidae.
The compounds of formulae I, and I′a, or salts thereof, are especially suitable for controlling one or more of pests selected from the genus: Spodoptera spp, Plutella spp, Frankliniella spp, Thrips spp, Euschistus spp, Cydia spp, Nilaparvata spp, Myzus spp, Aphis spp, Diabrotica spp, Rhopalosiphum spp, Pseudoplusia spp and Chilo spp. In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-126 and Table P and Table E”) controls one or more of pests selected from the genus: Spodoptera spp, Plutella spp, Frankliniella spp, Thrips spp, Euschistus spp, Cydia spp, Nilaparvata spp, Myzus spp, Aphis spp, Diabrotica spp, Rhopalosiphum spp, Pseudoplusia spp and Chilo spp.
The compounds of formulae I, and I′a, or salts thereof, are especially suitable for controlling one or more of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis includens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum padi, and Chilo suppressalis.
In a preferred embodiment of each aspect, a compound TX (where the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-126 and Table P and Table E”) controls one or more of Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis includens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum Padia, and Chilo Suppressalis, such as Spodoptera littoralis+TX, Plutella xylostella+TX; Frankliniella occidentalis+TX, Thrips tabaci+TX, Euschistus heros+TX, Cydia pomonella+TX, Nilaparvata lugens+TX, Myzus persicae+TX, Chrysodeixis includens+TX, Aphis craccivora+TX, Diabrotica balteata+TX, Rhopalosiphum Padi+TX, and Chilo suppressalis+TX.
In an embodiment, of each aspect, one compound from Tables A-1 to A-126 and Table P and Table E is suitable for controlling Spodoptera littoralis, Plutella xylostella, Frankliniella occidentalis, Thrips tabaci, Euschistus heros, Cydia pomonella, Nilaparvata lugens, Myzus persicae, Chrysodeixis includens, Aphis craccivora, Diabrotica balteata, Rhopalosiphum padia, and Chilo suppressalis in cotton, vegetable, maize, cereal, rice and soya crops.
In an embodiment, one compound from from Tables A-1 to A-126 and Table P and Table E is suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatoes) and Chilo supressalis (preferably in rice).
Compounds according to the invention may possess any number of benefits including, inter alia, advantageous levels of biological activity for protecting plants against insects or superior properties for use as agrochemical active ingredients (for example, greater biological activity, an advantageous spectrum of activity, an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability). In particular, it has been surprisingly found that certain compounds of formula I may show an advantageous safety profile with respect to non-target arthropods, in particular pollinators such as honey bees, solitary bees, and bumble bees. Most particularly, Apis mellifera.
The compounds according to the invention can be used as pesticidal agents in unmodified form, but they are generally formulated into compositions in various ways using formulation adjuvants, such as carriers, solvents and surface-active substances. The formulations can be in various physical forms, e.g. in the form of dusting powders, gels, wettable powders, water-dispersible granules, water-dispersible tablets, effervescent pellets, emulsifiable concentrates, microemulsifiable concentrates, oil-in-water emulsions, oil-flowables, aqueous dispersions, oily dispersions, suspo-emulsions, capsule suspensions, emulsifiable granules, soluble liquids, water-soluble concentrates (with water or a water-miscible organic solvent as carrier), impregnated polymer films or in other forms known e.g. from the Manual on Development and Use of FAO and WHO Specifications for Pesticides, United Nations, First Edition, Second Revision (2010). Such formulations can either be used directly or diluted prior to use. The dilutions can be made, for example, with water, liquid fertilisers, micronutrients, biological organisms, oil or solvents.
The formulations can be prepared e.g. by mixing the active ingredient with the formulation adjuvants in order to obtain compositions in the form of finely divided solids, granules, solutions, dispersions or emulsions. The active ingredients can also be formulated with other adjuvants, such as finely divided solids, mineral oils, oils of vegetable or animal origin, modified oils of vegetable or animal origin, organic solvents, water, surface-active substances or combinations thereof.
The active ingredients can also be contained in very fine microcapsules. Microcapsules contain the active ingredients in a porous carrier. This enables the active ingredients to be released into the environment in controlled amounts (e.g. slow-release). Microcapsules usually have a diameter of from 0.1 to 500 microns. They contain active ingredients in an amount of about from 25 to 95% by weight of the capsule weight. The active ingredients can be in the form of a monolithic solid, in the form of fine particles in solid or liquid dispersion or in the form of a suitable solution. The encapsulating membranes can comprise, for example, natural or synthetic rubbers, cellulose, styrene/butadiene copolymers, polyacrylonitrile, polyacrylate, polyesters, polyamides, polyureas, polyurethane or chemically modified polymers and starch xanthates or other polymers that are known to the person skilled in the art.
Alternatively, very fine microcapsules can be formed in which the active ingredient is contained in the form of finely divided particles in a solid matrix of base substance, but the microcapsules are not themselves encapsulated.
The formulation adjuvants that are suitable for the preparation of the compositions according to the invention are known per se. As liquid carriers there may be used: water, toluene, xylene, petroleum ether, vegetable oils, acetone, methyl ethyl ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone, amyl acetate, 2-butanone, butylene carbonate, chlorobenzene, cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol acetate, glycerol diacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropylbenzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol, propionic acid, propyl lactate, propylene carbonate, propylene glycol, propylene glycol methyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylenesulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol methyl ether, diethylene glycol methyl ether, methanol, ethanol, isopropanol, and alcohols of higher molecular weight, such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, ethylene glycol, propylene glycol, glycerol, N-methyl-2-pyrrolidone and the like.
Suitable solid carriers are, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, limestone, calcium carbonate, bentonite, calcium montmorillonite, cottonseed husks, wheat flour, soybean flour, pumice, wood flour, ground walnut shells, lignin and similar substances.
A large number of surface-active substances can advantageously be used in both solid and liquid formulations, especially in those formulations which can be diluted with a carrier prior to use. Surface-active substances may be anionic, cationic, non-ionic or polymeric and they can be used as emulsifiers, wetting agents or suspending agents or for other purposes. Typical surface-active substances include, for example, salts of alkyl sulfates, such as diethanolammonium lauryl sulfate; salts of alkylarylsulfonates, such as calcium dodecylbenzenesulfonate; alkylphenol/alkylene oxide addition products, such as nonylphenol ethoxylate; alcohol/alkylene oxide addition products, such as tridecylalcohol ethoxylate; soaps, such as sodium stearate; salts of alkylnaphthalenesulfonates, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryltrimethylammonium chloride, polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono- and di-alkylphosphate esters; and also further substances described e.g. in McCutcheon's Detergents and Emulsifiers Annual, MC Publishing Corp., Ridgewood New Jersey (1981).
Further adjuvants that can be used in pesticidal formulations include crystallisation inhibitors, viscosity modifiers, suspending agents, dyes, anti-oxidants, foaming agents, light absorbers, mixing auxiliaries, antifoams, complexing agents, neutralising or pH-modifying substances and buffers, corrosion inhibitors, fragrances, wetting agents, take-up enhancers, micronutrients, plasticisers, glidants, lubricants, dispersants, thickeners, antifreezes, microbicides, and liquid and solid fertilisers.
The compositions according to the invention can include an additive comprising an oil of vegetable or animal origin, a mineral oil, alkyl esters of such oils or mixtures of such oils and oil derivatives. The amount of oil additive in the composition according to the invention is generally from 0.01 to 10%, based on the mixture to be applied. For example, the oil additive can be added to a spray tank in the desired concentration after a spray mixture has been prepared. Preferred oil additives comprise mineral oils or an oil of vegetable origin, for example rapeseed oil, olive oil or sunflower oil, emulsified vegetable oil, alkyl esters of oils of vegetable origin, for example the methyl derivatives, or an oil of animal origin, such as fish oil or beef tallow. Preferred oil additives comprise alkyl esters of C8-C22 fatty acids, especially the methyl derivatives of C12-C18 fatty acids, for example the methyl esters of lauric acid, palmitic acid and oleic acid (methyl laurate, methyl palmitate and methyl oleate, respectively). Many oil derivatives are known from the Compendium of Herbicide Adjuvants, 10th Edition, Southern Illinois University, 2010.
The inventive compositions generally comprise from 0.1 to 99% by weight, especially from 0.1 to 95% by weight, of compounds of the present invention and from 1 to 99.9% by weight of a formulation adjuvant which preferably includes from 0 to 25% by weight of a surface-active substance. Whereas commercial products may preferably be formulated as concentrates, the end user will normally employ dilute formulations.
The rates of application vary within wide limits and depend on the nature of the soil, the method of application, the crop plant, the pest to be controlled, the prevailing climatic conditions, and other factors governed by the method of application, the time of application and the target crop. As a general guideline compounds may be applied at a rate of from 1 to 2000 I/ha, especially from 10 to 1000 I/ha.
Preferred formulations can have the following compositions (weight %):
The following Examples further illustrate, but do not limit, the invention.
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
Emulsions of any require dilution, which can be use in plant protection, can be obtained from this concentrate by dilution with water.
Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
28 parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
Formulation types include an emulsion concentrate (EC), a suspension concentrate (SC), a suspo-emulsion (SE), a capsule suspension (CS), a water dispersible granule (WG), an emulsifiable granule (EG), an emulsion, water in oil (EO), an emulsion, oil in water (EW), a micro-emulsion (ME), an oil dispersion (OD), an oil miscible flowable (OF), an oil miscible liquid (OL), a soluble concentrate (SL), an ultra-low volume suspension (SU), an ultra-low volume liquid (UL), a technical concentrate (TK), a dispersible concentrate (DC), a wettable powder (WP), a soluble granule (SG) or any technically feasible formulation in combination with agriculturally acceptable adjuvants.
“Mp” means melting point in ° C. 1H NMR measurements were recorded on a Brucker 400 MHz spectrometer, chemical shifts are given in ppm relevant to a TMS standard. Spectra measured in deuterated solvents as indicated. The following abbreviations are used: s=singlet; br s=broad singlet; d=doublet; br d=broad doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin=quintuplet, sept=septet; m=multiplet.
Either one of the LCMS methods below was used to characterize the compounds. The characteristic LCMS values obtained for each compound were the retention time (“Rt”, recorded in minutes) and the measured molecular ion (M+H)+ or (M−H)−.
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII or QDA Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 0.8-3.00 kV, Cone: 5-30 V, Source Temperature: 120-150° C., Desolvation Temperature: 350-600° C., Cone Gas Flow: 50-150 I/h, Desolvation Gas Flow: 650-1000 I/h, Mass range: 50 to 900 Da and an Acquity UPLC from Waters Corporation: Binary pump, heated column compartment, diode-array detector and ELSD. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 400, Runtime: 1.5 min; Solvents: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH; Flow (ml/min) 0.85, Gradient: 10% B isocratic for 0.2 min, then 10-100% B in 1.0 min, 100% B isocratic for 0.2 min, 100-10% B in 0.05 min, 10% B isocratic for 0.05 min.
Spectra were recorded on a ACQUITY Mass Spectrometer from Waters Corporations (SQD or SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.0 kV, Cone: 30V, Extractor: 3.00 V, Source Temperature: 150° C., Desolvation Temperature: 400° C., Cone Gas Flow: 60 L/hr, Desolvation Gas Flow: 700 L/hr, Mass range: 140 to 800 Da) and an ACQUITY UPLC from Waters Corporations with solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 400, Solvent Gradient: A=Water/Methanol 9:1+0.1% formic acid, B=Acetonitrile+0.1% formic acid, gradient: 0-100% B in 2.5 min; Flow (ml/min) 0.75.
Under an argon atmosphere, THE (35 mL) was cooled to 0° C. Then 2,2,6,6-tetramethylpiperidine (5.4 mL, 30.9 mmol, 1.34 equiv.) was added at 0° C. followed by a dropwise addition of 2.5M n-BuLi (12 mL, 29.98 mmol, 1.3 equiv.). The reaction mixture was cooled to −78° C., then a solution of 2-iodopyrazine (5.0 g, 23.06 mmol, 1.0 equiv.) in THE (5 mL) was added dropwise. After stirring for 1 hour, acetaldehyde (12 mL, 210 mmol, 9.2 equiv.) was added dropwise at −78° C. After addition, the reaction mixture was allowed to warm up to room temperature before it was quenched with saturated aqueous ammonium chloride solution. The reaction mixture was diluted with water and a mixture of TBME and ethyl acetate. The aqueous layer was acidified with 1M HCl to pH 1-2. The phases were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude extract was purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to afford 1-(3-iodopyrazin-2-yl)ethanol.
LC-MS (method 1): retention time 0.54 min, m/z 251 [M+H+].
1H NMR (400 MHz, CDCl3) δ ppm 8.47 (d, 1H) 8.31 (d, 1H) 5.10 (dd, 1H) 3.66-3.73 (m, 1H) 1.52 (d, 3H).
To a solution of 1-(3-iodopyrazin-2-yl)ethanol (1.20 g, 4.80 mmol, 1.0 equiv.) in THE (10 mL) was added imidazole (660 mg, 9.60 mmol, 2.0 equiv.) followed by tert-butyldimethylchlorosilane (1.1 mL, 5.76 mmol, 1.2 equiv.). The resulting reaction mixture was heated to 50° C. and was stirred at this temperature for 2 hours before it was allowed to cool down to room temperature. The reaction mixture was filtered. The filtration cake was washed with TBME and the filtrate way concentrated in vacuo. The crude extract was purified by flash chromatography (0-3% ethyl acetate in cyclohexane) to afford tert-butyl-[1-(3-iodopyrazin-2-yl)ethoxy]-dimethyl-silane.
LC-MS (method 1): retention time 1.30 min, m/z 365 [M+H+].
1H NMR (400 MHz, CDCl3) δ ppm 0.05 (s, 3H) 0.074 (s, 3H) 0.88 (s, 9H) 1.51 (d, 5H) 8.24 (d, 4H) 8.52 (d, 1H)
Under an argon atmosphere tert-butyl-[1-(3-iodopyrazin-2-yl)ethoxy]-dimethyl-silane (500 mg, 1.372 mmol, 1.0 equiv.) was dissolved in degassed THF (14 mL). The solution was cooled to −78° C., then Turbo Grignard 1.3 M in THF (1.7 mL, 2.1 mmol, 1.6 equiv.) was added dropwise (Turbo Grignard=2-butylmagnesium chloride lithium chloride complex). After aging for 30 minutes, zinc chloride (1.2 g, 2.2 mmol, 1.65 equiv.) was added at −78° C., then the reaction mixture was allowed to warm up to 0° C. After 40 minutes, a solution of tris(2-furyl)phosphine (40 mg, 0.16 mmol, 0.12 equiv.), Pd2(dba)3 (78 mg, 0.08 mmol, 0.06 equiv.) and 2-iodopyrazine (350 mg, 1.6 mmol, 1.2 equiv.) in degassed THF (14 mL) was added dropwise. The resulting reaction mixture was heated to 60° C. where it was stirred for 1 hour before it was diluted with water and a saturated aqueous ammonium chloride solution. After separation of the layers, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-5% ethyl acetate in cyclohexane) to afford tert-butyl-dimethyl-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethoxy]silane.
LC-MS (method 1): retention time 1.17 min, m/z 317 [M+H+].
1H NMR (400 MHz, CDCl3) δ ppm −0.18 (s, 3H) −0.15 (s, 3H) 0.73 (s, 10H) 1.66 (d, 3H) 5.67 (d, 1H) 8.60 (d, 1H) 8.64-8.69 (m, 2H) 8.72 (d, 1H) 9.22 (d, 1H) 9.62 (d, 1H).
To a solution of tert-butyl-dimethyl-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethoxy]silane (320 mg, 0.96 mmol, 1.0 equiv.) in THF (10 mL) was added tetrabutylammonium fluoride (1M in THF, 1.4 mL, 1.4 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature. After 2 hours, additional tetrabutylammonium fluoride (1M in THF, 0.1 mL, 0.1 mmol, 0.1 equiv.) was added and the reaction mixture was stirred for 30 minutes at room temperature before it was diluted with brine and ethyl acetate. Phases were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. This crude extract was purified by flash chromatography (15% ethyl acetate/ethanol (3/1) in cyclohexane) to afford 1-(3-pyrazin-2-ylpyrazin-2-yl)ethanol.
LC-MS (method 1): retention time 0.36 min, m/z 203 [M+H+].
1H NMR (400 MHz, CDCl3) δ ppm 0.92 (t, 1H) 1.24-1.35 (m, 1H) 1.38-1.47 (m, 1H) 1.59 (d, 3H) 1.73-1.77 (m, 1H) 2.38-2.50 (m, 1H) 5.02 (br d, 2H) 5.37 (quin, 2H) 8.63-8.69 (m, 5H) 8.71 (d, 2H) 9.47 (d, 1H).
Under an argon atmosphere 1-(3-pyrazin-2-ylpyrazin-2-yl)ethanol (179 mg, 0.79 mmol, 1.0 equiv.) was dissolved in THE (2 mL). Phthalimide (130 mg, 0.88 mmol, 1.1 equiv.) was added followed by triphenylphosphine (253 mg, 0.96 mmol, 1.2 equiv.). The resulting solution was cooled to 0° C., then diisopropyl azodicarboxylate (0.20 mL, 0.96 mmol, 1.2 equiv.) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 1 hour at this temperature before it was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography (0-35% ethyl acetate in cyclohexane) to afford the desired product 2-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]isoindoline-1,3-dione.
LC-MS (method 1): retention time 0.82 min, m/z 332 [M+H+].
1H NMR (400 MHz, CDCl3) δ ppm 1.91 (d, 3H) 6.52 (q, 2H) 7.63-7.69 (m, 2H) 7.70-7.77 (m, 2H) 8.52-8.56 (m, 1H) 8.59-8.62 (m, 2H) 8.62-8.65 (m, 1H) 9.20 (d, 1H).
To a solution of 2-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]isoindoline-1,3-dione (1.73 g, 5.22 mmol) in EtOH (52 mL) was added hydrazine monohydrate (0.30 mL, 6.27 mmol, 1.2 equiv.). The resulting suspension was heated to reflux and stirred at this temperature for 16 hours. The reaction mixture was then cooled to 20° C., diluted with H2O, and acidified with HCl 2N, then washed with EtOAc. The aqueous phase was then basified with NaOH 4N and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduce pressure to afford 1-(3-pyrazin-2-ylpyrazin-2-yl)ethanamine which was used without further purification.
LC-MS (method 1): retention time 0.19 min, m/z 202 [M+H+].
1H NMR (400 MHz, CDCl3) δ: 9.30 (d, 1H), 8.65-8.71 (m, 3H), 8.59 (d, 1H), 4.68-4.76 (m, 1H), 1.50 (d, 3H).
To a solution of 1-(3-pyrazin-2-ylpyrazin-2-yl)ethanamine (0.040 g, 0.20 mmol) and 2-chloro-6-(1-cyanocyclopropyl)pyridine-4-carboxylic acid (0.044 g, 0.20 mmol) in ethyl acetate (0.8 mL) was added T3P (0.18 mL, 0.30 mmol, 1.5 equiv.) and N-ethyl-N-isopropyl-propan-2-amine (0.14 mL, 0.79 mmol, 4.0 equiv.). The reaction mixture was stirred at 20° C. for 1 hour, pyridine (0.10 mL, 0.98 mmol) and additional T3P (0.12 mL, 0.2 mmol) were added and the reaction mixture was aged for additional 60 min at 20° C. The reaction mixture was then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc. And the combined organic layers were washed with NaHCO3, dried over MgSO4, filtered and concentrated under reduce pressure. The residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired product 2-chloro-6-(1-cyanocyclopropyl)-N-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]pyridine-4-carboxamide.
LC-MS (method 1): retention time 0.91 min, m/z 406/408 [M+H+].
1H NMR (400 MHz, CDCl3) δ: 9.46 (d, 1H), 8.78 (dd, 1H), 8.67-8.74 (m, 3H), 7.93 (d, 1H), 7.85 (br d, 1H), 7.57 (d, 1H), 6.32 (q, 1H), 1.87-1.92 (m, 2H), 1.79-1.84 (m, 2H), 1.67 (d, 3H).
To a suspension of 2-chloro-6-(1-cyanocyclopropyl)-N-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]pyridine-4-carboxamide (0.024 g, 0.059 mmol) and cesium carbonate (0.058 g, 0.177 mmol, 3.00 equiv.) in acetonitrile (0.4 mL) and DMA (0.3 mL) was added iodomethane (0.019 mL, 0.296 mmol, 5.00 equiv.) and the reaction mixture was stirred at RT for 20 h. The reaction was then partitioned between H2O and EtOAc. The organic phase was washed with saturated LiCl solution, dried over MgSO4, filtered and concentrated under reduce pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired product 2-chloro-6-(1-cyanocyclopropyl)-N-methyl-N-[1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]pyridine-4-carboxamide.
LC-MS (method 1): retention time 0.92 min, m/z 420/422 [M+H+].
1H NMR (400 MHz, CDCl3) 2 rotamers, chemical shifts provided for major rotamer δ: 9.33 (d, 1H), 8.66-8.72 (m, 3H), 8.56-8.60 (m, 1H), 7.45-7.50 (m, 1H), 6.99-7.03 (m, 1H), 6.40 (q, 1H), 2.98 (s, 3H), 1.65-1.88 (m, 7H).
2-[1-[3-(5-methoxypyrazin-2-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione (18) was prepared in 3 steps from tert-butyl-[1-(3-iodopyrazin-2-yl)ethoxy]-dimethyl-silane and 2-bromo-5-methoxy pyrazine in analogy to compound I3, as described in Example PE1.
LC-MS (method 1): retention time 0.95 min, m/z 362 [M+H+].
1H NMR (400 MHz, CDCl3) δ: 8.75 (d, 1H), 8.54-8.59 (t, 2H), 8.23 (d, 1H), 7.73-7.80 (m, 2H), 7.67-7.70 (m, 2H), 6.46-6.52 (q, 1H), 3.99 (s, 3H), 1.91 (d, 3H).
To a suspension of 2-[1-[3-(5-methoxypyrazin-2-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione (0.45 g, 1.25 mmol) in 1,4-dioxane (3 mL) was added HCl (4N in dioxane, 2.5 mL, 9.96 mmol, 8 equiv.) and the reaction mixture was stirred 80° C. for 40 hours. The reaction mixture was concentrated under reduced pressure and the residual solid was triturated with toluene. The solid was then dried in vacuo to afford 2-[1-[3-(5-hydroxypyrazin-2-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione which was used without further purification.
LC-MS (method 1): retention time 0.72 min, m/z 348 [M+H+].
1H NMR (400 MHz, CDCl3) δ: 11.07-11.61 (br s, 1H), 8.54 (d, 1H), 8.47 (d, 1H), 8.25 (d, 1H), 8.11 (d, 1H), 7.76-7.85 (m, 2H), 7.67-7.74 (m, 2H), 6.52 (q, 1H), 1.94 (d, 3H).
To a mixture of 2-[1-[3-(5-hydroxypyrazin-2-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione (0.47 g, 1.08 mmol) in chlorobenzene (4 mL) was added portionwise phosphorus pentachloride (0.34 g, 1.62 mmol, 1.5 equiv.) at RT. The resulting mixture was heated to reflux and aged for 2 hours at this temperature before cooling back to RT. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford 2-[1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione.
LC-MS (method 1): retention time 1.00 min, m/z 366/368 [M+H+].
1H NMR (400 MHz, CDCl3) δ=9.10-9.04 (m, 1H), 8.66 (d, 1H), 8.64-8.60 (m, 2H), 7.79-7.74 (m, 2H), 7.73-7.66 (m, 2H), 6.49 (q, 1H), 1.94 (d, 3H).
To a suspension of 2-[1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethyl]isoindoline-1,3-dione (0.357 g, 0.976 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.047 mL, 0.976 mmol, 1 equiv.). The mixture was warmed to 80° C. and stirred at this temperature for 16 hours. The reaction mixture was allowed to cool to RT, diluted with EtOAc and water. HCl 2M (2.5 mL) was added to acidify the mixture and the layers were separated. The aqueous layer was basicified with 4M NaOH (4 mL) then extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford 1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethanamine which was used without further purification.
LC-MS (method 1): retention time 0.39 min, m/z 236/238 [M+H+].
1H NMR (400 MHz, CDCl3) δ=9.15-9.09 (m, 1H), 8.68 (dd, 2H), 8.58 (d, 1H), 7.02-6.99 (m, 1H), 4.74 (q, 1H), 1.52-1.48 (d, 3H).
To a solution of 1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethanamine (0.063 g, 0.27 mmol), 3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethyl)benzoic acid (0.068 g, 0.27 mmol) and DMAP (1 small crystal) in pyridine (1 mL) was added T3P (0.236 mL, 0.4 mmol, 1.5 equiv.). The reaction mixture was stirred at RT for 3 h and then partitioned between EtOAc and water. The organic phase was washed with NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ethyl acetate in cyclohexane) to afford N-[1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethyl]-3-(1-cyano-1-methyl-ethyl)-5-(trifluoromethyl)benzamide.
LC-MS (method 1): retention time 1.10 min, m/z 475/477 [M+H+].
1H NMR (400 MHz, CDCl3) δ: 9.26 (d, 1H), 8.78 (d, 1H), 8.68-8.71 (m, 2H), 8.13 (m, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.66 (br d, 1H), 6.25-6.32 (m, 1H), 1.80 (d, 6H), 1.69 (d, 3H).
19F NMR (CDCl3) δ: −62.57 (s, 3F).
To a solution of N-[1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethyl]-3-methylsulfonyl-5-(trifluoromethyl) benzamide (0.020 g, 0.041 mmol; prepared in analogy to Example PE3 Step 5 from 1-[3-(5-chloropyrazin-2-yl)pyrazin-2-yl]ethanamine and 3-methylsulfonyl-5-(trifluoromethyl)benzoic acid) in N,N-dimethylacetamide (0.12 mL) was added Zn(CN)2 (0.005 g, 0.042 mmol). The solution was degassed with argon, then X-Phos Pd G2 (0.0015 g, 0.0019 mmol) was added and the vial placed in a microwave oven and stirred at 150° C. for 30 min. The resulting dark solution was cooled to RT and partitioned between ethyl acetate and aqueous NaHCO3. The organic phase was washed with water, dried over over sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate eluent) to afford N-[1-[3-(5-cyanopyrazin-2-yl)pyrazin-2-yl]ethyl]-3-methylsulfonyl-5-(trifluoromethyl)benzamide as a yellow solid.
LC-MS (method 1): retention time 0.95 min, m/z 477 [M+H+].
1H NMR (400 MHz, CDCl3) δ 9.68-9.61 (m, 1H), 9.09 (d, 1H), 8.75 (s, 2H), 8.53-8.48 (m, 1H), 8.40-8.33 (m, 2H), 7.69-7.64 (m, 1H), 6.42-6.27 (m, 1H), 3.16 (s, 3H), 1.74 (s, 3H).
19F NMR (CDCl3) δ −62.81 (s, 3F).
A 25 ml round bottom flask was charged with tert-butyl N-[(1S)-1-methyl-2-oxo-ethyl]carbamate (0.725 g), 3-benzyl-5-(3-hydroxyethyl)-4-methylthiazol-3-ium bromide (0.210 g), pyrazine-2-carbaldehyde (1.13 g) and dichloromethane (12 ml). Then N,N-diisopropylethylamine (1.46 ml) was added, and the mixture was stirred for 2 h at ambient temperature. The reaction was quenched by addition of saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC on a reversed phase C18 column, using water and acetonitrile as eluent. Thus, tert-butyl N-[(1S)-2-hydroxy-1-methyl-3-oxo-3-pyrazin-2-yl-propyl]carbamate was obtained as a mixture of diastereoisomers in the approximate ratio of 3:1. The diastereoisomeric mixture was used for the next step without further separation.
LC-MS (method 1): retention time 0.74 min, m/z 280 [M−H]− in the negative mode.
1H NMR (400 MHz, CDCl3) δ/ppm, signals of the major diastereoisomer: 9.20 (d, 1H), 8.80 (d, 1H), 8.65 (t, 1H), 5.27 (d, 1H), 4.63 (d, broad, 1H), 4.42 (m, 1H), 3.64 (d, 1H), 1.41 (d, 3H), 1.32 (s, 9H).
tert-butyl N-[(1S)-2-hydroxy-1-methyl-3-oxo-3-pyrazin-2-yl-propyl]carbamate (0.590 g) was dissolved in a mixture of dichloromethane (7 ml), dimethyl sulfoxide (1 ml) and N,N-diisopropylethylamine (1.08 ml). The mixture was cooled to 0° C. and then sulfur trioxide pyridine complex (688 mg) was added in a single portion to the orange solution. After 30 minutes at 0° C., the reaction was quenched with water, and diluted with dichloromethane and aqueous HCl (1N). The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, and concentrated under reduced pressure to give crude tert-butyl N-[(1S)-1-methyl-2,3-dioxo-3-pyrazin-2-yl-propyl]carbamate as a brown oil. The crude product was used for the next step without further purification.
1H NMR (400 MHz, CDCl3) δ/ppm 9.28 (d, 1H), 8.84 (d, 1H), 8.73 (s, 1H), 5.11 (s, broad, 1H), 4.88 (m, 1H), 1.50 (d, 3H), 1.36 (s, 9H).
To a solution of crude tert-butyl N-[(1S)-1-methyl-2,3-dioxo-3-pyrazin-2-yl-propyl]carbamate (570 mg) in ethanol (8 ml) was added ethane-1,2-diamine (1.39 ml). The resulting brown solution was stirred at ambient temperature open to air. After 48 hours, the orange solution was concentrated under vacuum and the residue purified by chromatography on silica gel, using cyclohexane and ethyl acetate as eluent. Thus, tert-butyl N-[(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]carbamate was obtained as a yellow gum.
LC-MS (method 1): retention time 0.86 min, m/z 302 [M+H+].
1H NMR (400 MHz, CDCl3) δ/ppm: 9.39 (d, 1H), 8.70 (m, 1H), 8.63 (m, 3H), 5.78 (m, 2H), 1.56 (d, 3H), 1.40 (s, 9H).
A solution of tert-butyl N-[(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]carbamate (282 mg) in dichloromethane (7 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred at ambient temperature for 20 hours. All volatiles were then removed under reduced pressure to give crude [(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]ammonium-2,2,2-trifluoroacetate as a thick oil which was used for the next step without further purification.
LC-MS (method 1): retention time 0.18 min, m/z 202 [M+H+] of the amine as free base.
1H NMR (400 MHz, CDCl3) δ/ppm: 9.62 (s, 1H), 9.40 (s, broad, 3H), 8.88 (d, 1H), 8.83 (d, 1H), 8.78 (d, 1H), 8.71 (d, 1H), 7.88 (s, broad, 2H), 5.68 (m, broad, 1H), 1.80 (d, 3H).
A solution of [(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]ammonium-2,2,2-trifluoroacetate (150 mg) in ethyl acetate (2 ml) was treated with 3,5-bis(trifluoromethyl)benzoyl chloride (160 mg) and sodium bicarbonate (1N in water, 2 ml). The biphasic mixture was stirred vigorously at ambient temperature. After 1.5 hours, the phases were separated, the aqueous phase extracted with ethyl acetate, and the combined organic phases were concentrated under reduced pressure. The residue was purified by chromatography on silica gel, using cyclohexane and ethyl acetate as eluent. Thus, N-[(1S)-1-(3-pyrazin-2-ylpyrazin-2-yl)ethyl]-3,5-bis(trifluoromethyl)benzamide was obtained.
LC-MS (method 1): retention time 1.05 min, m/z 442 [M+H+].
1H NMR (400 MHz, CDCl3) δ/ppm: 9.44 (d, 2H), 8.76 (d, 1H), 8.71 (m, 3H), 8.28 (s, 2H), 8.01 (s, 1H), 7.82, (d, broad, 1H), 6.33 (q, 1H), 1.69 (d, 3H).
19F NMR (377 MHz, CDCl3) δ/ppm: −62.87 (s, 6F).
[α]20D: +96.2 (c: 0.547, CHCl3)
The activity of the compositions according to the invention can be broadened considerably, and adapted to prevailing circumstances, by adding other insecticidally, acaricidally and/or fungicidally active ingredients. The mixtures of the compounds of formula I with other insecticidally, acaricidally and/or fungicidally active ingredients may also have further surprising advantages which can also be described, in a wider sense, as synergistic activity. For example, better tolerance by plants, reduced phytotoxicity, insects can be controlled in their different development stages or better behaviour during their production, for example during grinding or mixing, during their storage or during their use.
Suitable additions to active ingredients here are, for example, representatives of the following classes of active ingredients: organophosphorus compounds, nitrophenol derivatives, thioureas, juvenile hormones, formamidines, benzophenone derivatives, ureas, pyrrole derivatives, carbamates, pyrethroids, chlorinated hydrocarbons, acylureas, pyridylmethyleneamino derivatives, macrolides, neonicotinoids and Bacillus thuringiensis preparations.
The following mixtures of a compound of formula I with an active substances are preferred (the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-126 and Table P and Table E”):
The references in brackets behind the active ingredients, e.g. [3878-19-1] refer to the Chemical Abstracts Registry number. The above described mixing partners are known. Where the active ingredients are included in “The Pesticide Manual” [The Pesticide Manual—A World Compendium; Thirteenth Edition; Editor: C. D. S. TomLin; The British Crop Protection Council], they are described therein under the entry number given in round brackets hereinabove for the particular compound; for example, the compound “abamectin” is described under entry number (1). Where “[CCN]” is added hereinabove to the particular compound, the compound in question is included in the “Compendium of Pesticide Common Names”, which is accessible on the internet [A. Wood; Compendium of Pesticide Common Names, Copyright © 1995-2004]; for example, the compound “acetoprole” is described under the internet address http://www.alanwood.net/pesticides/acetoprole.html.
Most of the active ingredients described above are referred to hereinabove by a so-called “common name”, the relevant “ISO common name” or another “common name” being used in individual cases. If the designation is not a “common name”, the nature of the designation used instead is given in round brackets for the particular compound; in that case, the IUPAC name, the IUPAC/Chemical Abstracts name, a “chemical name”, a “traditional name”, a “compound name” or a “development code” is used or, if neither one of those designations nor a “common name” is used, an “alternative name” is employed. “CAS Reg. No” means the Chemical Abstracts Registry Number.
The active ingredient mixture of the compounds of formula I selected from the compounds defined in the Tables A-1 to A-126 and Table P and Table E with active ingredients described above comprises a compound selected from one compound defined in the Tables A-1 to A-126 and Table P and Table E and an active ingredient as described above preferably in a mixing ratio of from 100:1 to 1:6000, especially from 50:1 to 1:50, more especially in a ratio of from 20:1 to 1:20, even more especially from 10:1 to 1:10, very especially from 5:1 and 1:5, special preference being given to a ratio of from 2:1 to 1:2, and a ratio of from 4:1 to 2:1 being likewise preferred, above all in a ratio of 1:1, or 5:1, or 5:2, or 5:3, or 5:4, or 4:1, or 4:2, or 4:3, or 3:1, or 3:2, or 2:1, or 1:5, or 2:5, or 3:5, or 4:5, or 1:4, or 2:4, or 3:4, or 1:3, or 2:3, or 1:2, or 1:600, or 1:300, or 1:150, or 1:35, or 2:35, or 4:35, or 1:75, or 2:75, or 4:75, or 1:6000, or 1:3000, or 1:1500, or 1:350, or 2:350, or 4:350, or 1:750, or 2:750, or 4:750. Those mixing ratios are by weight.
The mixtures as described above can be used in a method for controlling pests, which comprises applying a composition comprising a mixture as described above to the pests or their environment, with the exception of a method for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body.
The mixtures comprising a compound of formula I selected from the compounds defined in the Tables A-1 to A-126 and Table P and Table E and one or more active ingredients as described above can be applied, for example, in a single “ready-mix” form, in a combined spray mixture composed from separate formulations of the single active ingredient components, such as a “tank-mix”, and in a combined use of the single active ingredients when applied in a sequential manner, i.e. one after the other with a reasonably short period, such as a few hours or days. The order of applying the compounds of formula I and the active ingredients as described above is not essential for working the present invention.
The compositions according to the invention can also comprise further solid or liquid auxiliaries, such as stabilizers, for example unepoxidized or epoxidized vegetable oils (for example epoxidized coconut oil, rapeseed oil or soya oil), antifoams, for example silicone oil, preservatives, viscosity regulators, binders and/or tackifiers, fertilizers or other active ingredients for achieving specific effects, for example bactericides, fungicides, nematocides, plant activators, molluscicides or herbicides.
The compositions according to the invention are prepared in a manner known per se, in the absence of auxiliaries for example by grinding, screening and/or compressing a solid active ingredient and in the presence of at least one auxiliary for example by intimately mixing and/or grinding the active ingredient with the auxiliary (auxiliaries). These processes for the preparation of the compositions and the use of the compounds I for the preparation of these compositions are also a subject of the invention.
The application methods for the compositions, that is the methods of controlling pests of the abovementioned type, such as spraying, atomizing, dusting, brushing on, dressing, scattering or pouring—which are to be selected to suit the intended aims of the prevailing circumstances—and the use of the compositions for controlling pests of the abovementioned type are other subjects of the invention. Typical rates of concentration are between 0.1 and 1000 ppm, preferably between 0.1 and 500 ppm, of active ingredient. The rate of application per hectare is generally 1 to 2000 g of active ingredient per hectare, in particular 10 to 1000 g/ha, preferably 10 to 600 g/ha.
A preferred method of application in the field of crop protection is application to the foliage of the plants (foliar application), it being possible to select frequency and rate of application to match the danger of infestation with the pest in question. Alternatively, the active ingredient can reach the plants via the root system (systemic action), by drenching the locus of the plants with a liquid composition or by incorporating the active ingredient in solid form into the locus of the plants, for example into the soil, for example in the form of granules (soil application). In the case of paddy rice crops, such granules can be metered into the flooded paddy-field.
The compounds of formula I of the invention and compositions thereof are also be suitable for the protection of plant propagation material, for example seeds, such as fruit, tubers or kernels, or nursery plants, against pests of the abovementioned type. The propagation material can be treated with the compound prior to planting, for example seed can be treated prior to sowing. Alternatively, the compound can be applied to seed kernels (coating), either by soaking the kernels in a liquid composition or by applying a layer of a solid composition. It is also possible to apply the compositions when the propagation material is planted to the site of application, for example into the seed furrow during drilling. These treatment methods for plant propagation material and the plant propagation material thus treated are further subjects of the invention. Typical treatment rates would depend on the plant and pest/fungi to be controlled and are generally between 1 to 200 grams per 100 kg of seeds, preferably between 5 to 150 grams per 100 kg of seeds, such as between 10 to 100 grams per 100 kg of seeds.
The term seed embraces seeds and plant propagules of all kinds including but not limited to true seeds, seed pieces, suckers, corns, bulbs, fruit, tubers, grains, rhizomes, cuttings, cut shoots and the like and means in a preferred embodiment true seeds.
The present invention also comprises seeds coated or treated with or containing a compound of formula I. The term “coated or treated with and/or containing” generally signifies that the active ingredient is for the most part on the surface of the seed at the time of application, although a greater or lesser part of the ingredient may penetrate into the seed material, depending on the method of application. When the said seed product is (re)planted, it may absorb the active ingredient. In an embodiment, the present invention makes available a plant propagation material adhered thereto with a compound of formula I. Further, it is hereby made available, a composition comprising a plant propagation material treated with a compound of formula I.
Seed treatment comprises all suitable seed treatment techniques known in the art, such as seed dressing, seed coating, seed dusting, seed soaking and seed pelleting. The seed treatment application of the compound formula I can be carried out by any known methods, such as spraying or by dusting the seeds before sowing or during the sowing/planting of the seeds.
In each aspect and embodiment of the invention, “consisting essentially” and inflections thereof are a preferred embodiment of “comprising” and its inflections, and “consisting of” and inflections thereof are a preferred embodiment of “consisting essentially of” and its inflections.
The disclosure in the present application makes available each and every combination of embodiments disclosed herein.
It should be noted that the disclosure herein in respect of a compound of formula I applies equally in respect of a compound of each of formulae I*, I′a, I-1, and I-1′a, and vice a versa.
The compounds of the invention can be distinguished from other similar compounds by virtue of greater efficacy at low application rates and/or different pest control, which can be verified by the person skilled in the art using the experimental procedures, using lower concentrations if necessary, for example 10 ppm, 5 ppm, 2 ppm, 1 ppm or 0.2 ppm; or lower application rates, such as 300, 200 or 100, mg of Al per m2. The greater efficacy can be observed by an increased safety profile (against non-target organisms above and below ground (such as fish, birds and bees), improved physico-chemical properties, or increased biodegradability).
The Examples which follow serve to illustrate the invention. Certain compounds of the invention can be distinguished from known compounds by virtue of greater efficacy at low application rates, which can be verified by the person skilled in the art using the experimental procedures outlined in the Examples, using lower application rates if necessary, for example 50 ppm, 24 ppm, 12.5 ppm, 6 ppm, 3 ppm, 1.5 ppm, 0.8 ppm or 0.2 ppm.
24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10,000 ppm DMSO stock solutions by pipetting. After drying, the plates were infested with L2 larvae (6-8 per well). The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 6 days after infestation. Control of Chilo suppressalis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.
The following compounds resulted in at least 80% control in at least one of the three categories (mortality, anti-feedant effect, or growth inhibition) at an application rate of 200 ppm: E3, E4, E7, E8, P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P13, P14, P16, P18, P19, P20, P21, P22, P24, P26, P27, P29, P30, P31, P32, P33, P34, P35, P37, P39.
Maize sprouts placed onto an agar layer in 24-well microtiter plates were treated with aqueous test solutions prepared from 10,000 ppm DMSO stock solutions by spraying. After drying, the plates were infested with L2 larvae (6 to 10 per well). The samples were assessed for mortality and growth inhibition in comparison to untreated samples 4 days after infestation.
The following compounds gave an effect of at least 80% control in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: E3, E4, E5, E6, E7, E8, E9, E10, E12, E13, E39, P1, P2, P3, P4, P5, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P19, P20, P21, P23, P24, P26, P27, P28, P29, P30, P31, P34, P35, P36, P37.
Test compounds prepared from 10′000 ppm DMSO stock solutions were applied by pipette into 24-well microtiter plates and mixed with sucrose solution. The plates were closed with a stretched Parafilm. A plastic stencil with 24 holes was placed onto the plate and infested pea seedlings were placed directly on the Parafilm. The infested plate was closed with a gel blotting paper and another plastic stencil and then turned upside down. The samples were assessed for mortality 5 days after infestation.
The following compounds resulted in at least 80% mortality at a test rate of 12 ppm: E3, E7, E12, P2, P16, P20, P21, P26, P31, P32.
24-well microtiter plates with artificial diet were treated with aqueous test solutions prepared from 10′000 ppm DMSO stock solutions by pipetting. After drying, Plutella eggs were pipetted through a plastic stencil onto a gel blotting paper and the plate was closed with it. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 8 days after infestation.
The following compounds gave an effect of at least 80% control in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm: E3, E4, E5, E6, E7, E8, P1, P2, P3, P4, P5, P6, P7, P8, P9, P10, P11, P12, P13, P14, P15, P16, P17, P18, P19, P20, P21, P22, P23, P24, P25, P26, P27, P28, P29, P30, P31, P33, P34, P35, P36, P37, P39.
Cotton leaf discs were placed onto agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10,000 ppm DMSO stock solutions. After drying the leaf discs were infested with five L1 larvae. The samples were assessed for mortality, anti-feeding effect, and growth inhibition in comparison to untreated samples 3 days after infestation. Control of Spodoptera littoralis by a test sample is given when at least one of the categories mortality, anti-feedant effect, and growth inhibition is higher than the untreated sample.
The following compounds resulted in at least 80% control in at least one of the three categories (mortality, anti-feedant effect, or growth inhibition) at an application rate of 200 ppm: E3, E4, E5, E6, E7, E8, E9, E10, E12, E13, P1, P2, P3, P4, P5, P6, P7, P8, P10, P11, P12, P13, P14, P16, P17, P20, P21, P23, P24, P26, P27, P28, P29, P31, P32, P34, P35, P36, P37, P39.
Test compounds were applied by pipette from 10,000 ppm DMSO stock solutions into 24-well plates and mixed with agar. Lettuce seeds were placed onto the agar and the multi well plate was closed by another plate which contained also agar. After 7 days the compound was absorbed by the roots and the lettuce grew into the lid plate. The lettuce leaves were then cut off into the lid plate. Spodoptera eggs were pipetted through a plastic stencil onto a humid gel blotting paper and the lid plate was closed with it. The samples were assessed for mortality, anti-feedant effect and growth inhibition in comparison to untreated samples 6 days after infestation.
The following compounds gave an effect of at least 80% in at least one of the three categories (mortality, anti-feeding, or growth inhibition) at a test rate of 12.5 ppm: E3.
Test compounds prepared from 10′000 ppm DMSO stock solutions were applied by a liquid handling robot into 96-well microtiter plates and mixed with a sucrose solution. Parafilm was stretched over the 96-well microtiter plate and a plastic stencil with 96 holes was placed onto the plate. Aphids were sieved into the wells directly onto the Parafilm. The infested plates were closed with a gel blotting card and a second plastic stencil and then turned upside down. The samples were assessed for mortality 5 days after infestation.
For example the following compounds resulted in at least 80% mortality at an application rate of 50 ppm: E3.
96-well microtiter plates containing artificial diet were treated with aqueous test solutions, prepared from 10,000 ppm DMSO stock solutions, by a liquid handling robot. After drying, eggs (˜30 per well) were infested onto a netted lid which was suspended above the diet. The eggs hatch and L1 larvae move down to the diet. The samples were assessed for mortality 9 days after infestation.
For example the following compounds gave an effect of at least 80% mortality at an application rate of 500 ppm: E3.
Sunflower leaf discs were placed onto agar in a 24-well microtiter plate and sprayed with aqueous test solutions prepared from 10,000 ppm DMSO stock solutions. After drying, the leaf discs were infested with an aphid population of mixed ages. The samples were assessed for mortality 6 days after infestation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm: P7, P12, P14, P17, P18, P21, P25.
Activity of compounds P19 and P6 according to the preparatory examples and of compounds from WO 2020/201398, respectively from WO 2021/068179 against Plutella xylostella (Example B4) is summarized in Table B10.
Plutella xylostella
Plutella xylostella
Plutella xylostella
Plutella xylostella
Table B10 shows that compounds P19 and P6 according to the invention exert a substantially better insecticidal action on Plutella xylostella than the compounds from the state of the art. This enhanced effect was not to be expected on the basis of the structural similarity of these compounds.
Activity of compounds P21 and P10 according to the preparatory examples and of compounds from WO 2020/201398, respectively from WO 2020/070049 against Diabrotica balteata (Example B32) is summarized in Table B11.
Diabrotica
balteata
Diabrotica
balteata
Diabrotica
balteata
Diabrotica
balteata
Table B11 shows that compounds P21 and P10 according to the invention exert a substantially better insecticidal action on Diabrotica balteata than the compounds from the state of the art. This enhanced effect was not to be expected on the basis of the structural similarity of these compounds.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111025712 | Jun 2021 | IN | national |
| 202111032997 | Jul 2021 | IN | national |
| 21211839.2 | Dec 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/065034 | 6/2/2022 | WO |
