Patent Application
20240108006
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.
There have now been found novel pesticidally active compounds.
The present invention accordingly relates, in a first aspect, to a compound of the formula I
wherein:
wherein, R′4a, R′4b and R′4c, independently of each other and independently of Y1 to Y4, are selected from hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy and C1-C3haloalkoxy;
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-Cncycloalkylcarbonyl” as used herein refers to a 3-n membered cycloalkyl group attached to a carbonyl (C═O) group, which carbonyl group is connected to the rest of the molecule. Similarly, the terms “C1-Cnalkylcarbony”, “C1-Cnalkoxycarbonyl”, “phenyloxycarbonyl” and “benzyloxycarbonyl” as used herein refers to an alkyl, alkoxy, phenyloxy and benzyloxy group attached to a carbonyl (C═O) group, which carbonyl group is connected to the rest of the molecule.
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 “C3-C6cycloalkylC1-C4haloalkoxy” as used herein refers to a 3 to 6 membered cycloalkyl group connected to a 1 to 4 membered haloalkoxy, which haloalkoxy group is connected to the rest of the molecule.
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 “trimethylsilaneC1-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 “C1-C4alkylsulfonylamino” as used herein refers to C1-Cnalkylsulfonyl moiety linked through an amino (or NH) group; examples are methylsulfonyl amino (MeS(O)2NH—).
The term “aminosulfonyl” as used herein refers to an amino moiety linked through a sulfonyl group, i.e. NH2S(O)2—.
The term “C1-C4alkylaminosulfonyl” as used herein refers to a C1-Cnalkylamino moiety linked through a sulfonyl group; examples are, i.e. MeNHS(O)2—, EtNHS(O)2.
The term “di(C1-C4alkyl)aminosulfonyl” as used herein refers to a di(C1-C4alkyl)amino moiety linked through a sulfonyl group; examples are, i.e. Me2NS(O)2—, Et(Me)NS(O)2.
The term “C3-C6cycloalkylaminosulfonyl” as used herein refers to a C3-C6cycloalkylamino moiety linked through a sulfonyl group; examples are, i.e. cyclopropylNHS(O)2—.
The term “—O—C1-C2haloalkanediyl-O—” as used herein refers to a straight-chain saturated halogenated divalent group attached via each of the oxygen atoms and having 1 or 2 carbon atoms between the oxygen atoms. When referring to the T ring, the —O—C1-C2haloalkanediyl-O— group is connected to adjacent ring members of the T ring (i.e. phenyl, pyridine, pyrimidine, pyrazine, pyridazine or a five or nine membered heteroaromatic ring) via the oxygen atoms of the —O—C1-C2haloalkanediyl-O—group and the oxygen atoms are linked by 1 to 2 carbon atoms substituted with one or more halogen atoms. Examples include —OCF2O— and —OCF2CF2O—. Together with the two adjacent ring members of the T ring to which it is attached, the —O—C1-C2haloalkanediyl-O— group thus forms a 5- or 6-membered ring.
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.
Halogen or “halo” is generally fluorine, chlorine, bromine, or iodine. This also applies, correspondingly, to halogen in combination with other meanings, such as haloalkyl.
The term “heteroaryl” as used herein refers to a 5- or 6-membered aromatic monocyclic ring having 1 to 3 heteroatoms independently selected from N, O and S. Examples are heteroaryls J-1 to J-41 shown in Scheme A below. Preferred heteroaryl is pyridyl, pyrimidinyl and pyrazolyl.
Examples of nine membered heteroaromatic rings for T are heteroaromatics made up of two rings, having 1 to 3 carbon atoms replaced independently by nitrogen, sulfur, or oxygen (the heteroatoms can be in one ring or distributed amongst the two). Examples are purinyl, thieno[2,3-d]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, quinolinyl, cinnolinyl, quinoxalinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl and benzothiazolyl.
The term “nine or ten membered bicyclic heterocyclic ring” as used herein in context of the ring formed by T and R1b with the N atom refers to a partially or fully saturated ring; having in addition to the N atom, optionally 1 or 2 more heteroatoms selected from N and O. An example of a 9-membered heterocyclic ring formed by R1b and T together is indolinyl.
The term “spiroheterocyclic ring” as used herein refers to an 8- to 12-membered spiro ring, preferably a ten membered spiro ring, having 3 to 4 heteroatoms selected from N and O, which ring is partially or fully saturated. If substituted, the substituent can be on a carbon atom or a heteroatom. An example of spiroheterocyclic ring is oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl.
The pyridine, pyrimidine, pyrazine and pyridazine groups (unsubstituted or substituted) for R4 and R4a are each connected via a carbon atom on the respective ring to the rest of the compound.
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 Qa and Y1, and the arrow used, for example, in scheme A, represent the point of connection or 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 T, X, R1a, R1b, R3, and Q 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 T, X, R1a, R1b, R3, and Q 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,
In an embodiment of each aspect of the invention, R1a is
In an embodiment of each aspect of the invention, R1b is
In an embodiment of each aspect of the invention, R1a and R1b together is
In an embodiment of each aspect of the invention, T is
In an embodiment of each aspect of the invention, R1b and T together with the nitrogen atom form
In an embodiment of each aspect of the invention, R2 is, independent of each other, selected from
When R2 is a divalent group, T carries only one such divalent group as R2 and said divalent group is connected to T via two adjacent ring members of T. Examples of divalent groups include —O—C1-C2haloalkanediyl-O—, —CH2—C(CH3)2—O—, —CH2—C(CH3)2—S—, —CH2—C(CH3)2—SO2. Examples of —O—C1-C2haloalkanediyl-O— include —O—CF2—CF2—O—, —O—CFH—CF2—O—, —O—CFH—CFH—O—, —OCH2—CHF—O—, —OCH2—CF2—O—, —O—CF2—O—, and —O—CFH—O—; preferably —O—CF2CF2—O—, and —O—CF2—O—. In an embodiment, T is phenyl, pyridine, pyrimidine, pyrazine, pyridazine or a five or nine membered heteroaromatic ring, substituted via two adjacent ring members of the phenyl, pyridine, pyrimidine, pyrazine, pyridazine or five or nine membered heteroaromatic ring, with a divalent groups selected from —O—C1-C2haloalkanediyl-O—, —CH2—C(CH3)2—O—, —CH2—C(CH3)2—S—, —CH2—C(CH3)2—SO2, preferably selected from —O—CF2CF2—O—, and —O—CF2—O—.
In an embodiment of each aspect of the invention, R3 is
In an embodiment of each aspect of the invention, Q is
In an embodiment of each aspect of the invention, R4 is
In an embodiment of each aspect of the invention, R4a is
In an embodiment of each aspect of the invention, when Y1 is selected as R4a, R′4a and R′4c, independently of each other, are
In an embodiment of each aspect of the invention, when Y2 is selected as R4a,
In an embodiment of each aspect of the invention, when Y3 is selected as R4a, R′4a and R′4b, independently of each other, are
In an embodiment of each aspect of the invention, when Y4 is selected as R4a,
In an embodiment of each aspect of the invention, R5 is
In an embodiment of each aspect of the invention, R5a is
In an embodiment of each aspect of the invention, R5b is
In an embodiment of each aspect of the invention, Re is
In an embodiment of each aspect of the invention, R7 is
In an embodiment of each aspect of the invention, R8 is
In an embodiment of each aspect of the invention, Rx is independently selected from
In an embodiment of each aspect of the invention, RY is independently selected from
In an embodiment of each aspect of the invention, RZ is independently selected from
The present invention, accordingly, makes available a compound of formula I having the substituents T, X, R1a, R1b, R3 and Q as defined above in all combinations/each permutation.
Accordingly, made available, for example, is a compound of formula I with X as oxygen; T being an embodiment B (i.e. T is phenyl, pyridine, pyrimidine, pyrazine, pyridazine or a heteroaromatic ring selected from J-13, J-16, J-22, J-25, J-26, J-27, J-28, J-31, J-36, J-37, J-38, J-39, J-40, J-41, thieno[2,3-d]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, and indazolyl, each of which, independent of each other, is substituted with one to three substituents independently selected from R2), where R2 is of embodiment A (i.e. R2, independently of the ring and the number of substituents, is selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, CN, C3-C4cycloalkyl, C3-C6cycloalkylcarbonyl, phenyl, heteroaryl selected from J-1 and J-41, each of C3-C4cycloalkyl, phenyl or heteroaryl, independent of each other, being substituted with one to three substituents Rx, OR6, piperidin-2-one-1-yl, pyridin-2-one-1-yl, azetidin-1-yl optionally substituted with Rx, pyrrolidin-1-yl, C3-C6cycloalkylC1-C4alkyl substituted with one or two substituents Rz, C3-C6cycloalkylC1-C3alkoxy optionally substituted with Rx, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C1-C4alkylsulfanyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfonyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfinyl optionally substituted by one to three substituents Rx, C(O)NR7R8, C1-C4alkylsulfonylamino, aminosulfonyl, C1-C4alkylaminosulfonyl, di(C1-C4alkyl)aminosulfonyl, C3-C6cycloalkylaminosulfonyl, —O—C1-C2haloalkanediyl-O—, and 10 membered optionally substituted spiroheterocyclic ring); R1a being embodiment D (i.e. R1a is hydrogen, C1-C6alkyl, C1-C6cyanoalkyl, C1-C3alkoxy-C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6haloalkenyl, C2-C6alkynyl, C2-C6haloalkynyl, C3-C4cycloalkylC1-C2alkyl-, benzyloxycarbonyl, or benzyl); R1b being embodiment I (i.e. R1b is hydrogen, methyl, propargyl, or cyclopropyl-methyl); R3 being embodiment B (i.e. R3 is methyl or trifluoromethyl); and Q is embodiment F (i.e. Q is Qa-1, or Qb-1), where R4 is embodiment K (i.e. R4 is pyrimidin-2-yl, pyridin-2-yl, 5-bromopyrimidin-2-yl, 5-bromopyridin-2-yl, 5-cyanopyrimidin-2-yl, or 5-cyanopyridin-2-yl); R4a is embodiment G (i.e. R4a is 1,2,3-triazol-2-yl (or Y2), pyrimidin-2-yl, or 5-cyanopyridin-2-yl); R6 is of embodiment E (i.e. R6 is phenyl, J-1, J-17, or cyclopropylmethyl, each of which, independent of each other, is optionally substituted with one to three substituents independently selected from F, Cl, Br, and cyclopropyl); R7 is of embodiment D (i.e. R7 is hydrogen); R8 is of embodiment D (i.e. R8 is cyclopentyl); Rx is of embodiment B (i.e. Rx is independently selected from F, Cl, Br, OCF2H, CF3, cyclopropyl, OCH3 and CN); and Rz is of embodiment B (i.e. Rz is independently selected from oxo, F, Cl, Br, OCF2H, OCH3 and CN).
In an embodiment, the compound of formula I is formula Iaa and Iab (with asterisk indicating a stereogenic centre), wherein T, R1a, R1b, R3 are as defined in the first aspect and Q1 corresponds to Q as defined in the first aspect, each with the corresponding embodiments as described above. The preferred stereochemistry of compounds of formula Iaa and Iab is that depicted in formula I′a above.
In an embodiment, Q1 is
Similarly, the present invention makes available a compound of formulae Iaa and Iab having the substituents T, R1a, R1b, R3 and Q1 as defined in all combinations/each permutation
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen or sulfur; as T phenyl, pyridine, or a five or nine membered heteroaromatic ring, each of which, independent of each other, can be substituted with one to three substituents independently selected from R2; where R2, independently of the ring and of the number of substituents, is selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, CN, C3-C4cycloalkyl, 03-C6cycloalkylcarbonyl, phenyl, heteroaryl selected from J-1 and J-41, each of C3-C4cycloalkyl, phenyl or heteroaryl, independent of each other, being substituted with one to three substituents RX, OR6, piperidin-2-one-1-yl, pyridin-2-one-1-yl, azetidin-1-yl optionally substituted with RX, pyrrolidin-1-yl, O3—C6cycloalkylC1-C4alkyl substituted with one or two substituents Rz, C3-C6cycloalkylC1-C3alkoxy optionally substituted with RX, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C1-C4alkylsulfanyl optionally substituted by one to three substituents RX, C1-C4alkylsulfonyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfinyl optionally substituted by one to three substituents Rx, C(O)NR7R8, C1-C4alkylsulfonylamino, aminosulfonyl, C1-C4alkylaminosulfonyl, di(C1-C4alkyl)aminosulfonyl, C3-C6cycloalkylaminosulfonyl, —O—C1-C2haloalkanediyl-O—, and 10 membered optionally substituted spiroheterocyclic ring; where RB is phenyl, benzyl, heteroaryl selected from J-1 to J-41, C3-C6cycloalkyl, or C3-C6cycloalkylC1-C3alkyl, each of which, independent of each other, is optionally substituted with one to three substituents independently selected from Rx; R7 and R8 independently of each other is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl, wherein the C1-C3alkyl or C3-C6cycloalkyl, independent of each other, is optionally substituted with one to three substituents independently selected from Rz; where RX is independently selected from halogen, C1-C3haloalkyl, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkoxy and CN; where Rz is independently selected from oxo, halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy and CN; as R1a and R1b, independent of each other, hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl, or as R1a and R1b together —CH2—O—CH2—; or T and R1b together is nine membered bicyclic partially saturated heterocyclic ring substituted with C1-C3haloalkyl; as R3 methyl or trifluoromethyl; and as Q selected from Qa-1 to Qa-16 and Qb-1 to Qb-13; where R4 is pyridine, or pyrimidine; wherein the pyridine or pyrimidine, independently of each other, is optionally substituted with one substituent selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C4cycloalkyl, halo, hydroxyl, CN, C1-C6haloalkoxy, C2-C6haloalkenyloxy, C2-C6haloalkynyloxy, C3-C4halocycloalkoxy, C3-C6cycloalkylC1-C4haloalkoxy, NH2C(O)—, NH2C(S)—, (OH)N═C(NH2)—, J-13 optionally substituted by 1 to 3 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy and C1-C3haloalkoxy, J-20 optionally substituted by 1 to 3 substituents independently selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy and C1-C3haloalkoxy and 1H-tetrazol-5-yl; and where R4a is pyridine, pyrimidine, pyrazine or pyridazine, wherein the pyridine, pyrimidine, pyrazine or pyridazine, independent of each other, is optionally substituted with one substituent selected from C1-C3haloalkyl, C3-C4cycloalkyl, halogen, cyano and C1-C3haloalkoxy. or is selected from Y1 to Y4; wherein, R′4a, R′4b and R′4c, independently of each other and independently of Y1 to Y4, are selected from hydrogen, halogen, CN, C1-C3alkyl, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkoxy and C1-C3haloalkoxy.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen or sulfur; as T phenyl, pyridine, or a five or nine membered heteroaromatic ring, each of which, independent of each other, can be substituted with one to three substituents independently selected from R2; where R2, independently of the ring and of the number of substituents, is selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, CN, C3-C4cycloalkyl, C3-C6cycloalkylcarbonyl, phenyl, heteroaryl selected from J-1 and J-41, each of C3-C4cycloalkyl, phenyl or heteroaryl, independent of each other, being substituted with one to three substituents Rx, ORB, piperidin-2-one-1-yl, pyridin-2-one-1-yl, azetidin-1-yl optionally substituted with Rx, pyrrolidin-1-yl, C3-C6cycloalkylC1-C4alkyl substituted with one or two substituents Rz, C3-C6cycloalkylC1-C3alkoxy optionally substituted with Rx, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C1-C4alkylsulfanyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfonyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfinyl optionally substituted by one to three substituents Rx, C(O)NR7R8, C1-C4alkylsulfonylamino, aminosulfonyl, C1-C4alkylaminosulfonyl, di(C1-C4alkyl)aminosulfonyl, C3-C6cycloalkylaminosulfonyl, —O—C1-C2haloalkanediyl-O—, and 10 membered optionally substituted spiroheterocyclic ring; where RB is phenyl, benzyl, heteroaryl selected from J-1 to J-41, C3-C6cycloalkyl, or C3-C6cycloalkylC1-C3alkyl, each of which, independent of each other, is optionally substituted with one to three substituents independently selected from Rx; R7 and R8 independently of each other is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl, wherein the C1-C3alkyl or C3-C6cycloalkyl, independent of each other, is optionally substituted with one to three substituents independently selected from Rz; where Rx is independently selected from halogen, C1-C3haloalkyl, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkoxy and CN; where Rz is independently selected from oxo, halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy and CN; as R1a and R1b, independent of each other, hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl, or as R1a and R1b together —CH2—O—CH2—; or T and R1b together is nine membered bicyclic partially saturated heterocyclic ring substituted with C1-C3haloalkyl; as R3 methyl or trifluoromethyl; and as Q selected from Qaa to Qag and Qba to Qbf.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen or sulfur; as T phenyl, pyridine, or a five or nine membered heteroaromatic ring, each of which, independent of each other, can be substituted with one to three substituents independently selected from R2; where R2, independently of the ring and of the number of substituents, is selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, CN, C3-C4cycloalkyl, C3-C6cycloalkylcarbonyl, phenyl, heteroaryl selected from J-1 and J-41, each of C3-C4cycloalkyl, phenyl or heteroaryl, independent of each other, being substituted with one to three substituents Rx, ORB, piperidin-2-one-1-yl, pyridin-2-one-1-yl, azetidin-1-yl optionally substituted with Rx, pyrrolidin-1-yl, C3-C6cycloalkylC1-C4alkyl substituted with one or two substituents Rz, C3-C6cycloalkylC1-C3alkoxy optionally substituted with Rx, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C1-C4alkylsulfanyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfonyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfinyl optionally substituted by one to three substituents Rx, C(O)NR7R8, C1-C4alkylsulfonylamino, aminosulfonyl, C1-C4alkylaminosulfonyl, di(C1-C4alkyl)aminosulfonyl, C3-C6cycloalkylaminosulfonyl, —O—C1-C2haloalkanediyl-O—, and 10 membered optionally substituted spiroheterocyclic ring; where RB is phenyl, benzyl, heteroaryl selected from J-1 to J-41, C3-C6cycloalkyl, or C3-C6cycloalkylC1-C3alkyl, each of which, independent of each other, is optionally substituted with one to three substituents independently selected from Rx; R7 and R8 independently of each other is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl, wherein the C1-C3alkyl or C3-C6cycloalkyl, independent of each other, is optionally substituted with one to three substituents independently selected from Rz; where Rx is independently selected from halogen, C1-C3haloalkyl, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkoxy and CN; where Rz is independently selected from oxo, halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy and CN; as R1a and R1b, independent of each other, hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl, or as R1a and R1b together —CH2—O—CH2—; or T and R1b together is nine membered bicyclic partially saturated heterocyclic ring substituted with C1-C3haloalkyl; as R3 methyl or trifluoromethyl; and as Q selected from Qaa, Qab, Qba and Qbb.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen or sulfur; as T phenyl, pyrid-2-yl (or J-1), J-2, J-3, J-4. J-5, J-6, J16, J-26, J-27, J-28, J41, thieno[2,3-d]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, or indazolyl each of which, independent of each other, is substituted with one to three substituents independently selected from R2; where R2, independently of the ring and of the number of substituents, is selected from halogen, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, CN, C3-C4cycloalkyl, heteroaryl selected from J-1 and J-41, each of C3-C4cycloalkyl, or heteroaryl, independent of each other, is substituted with one to three substituents Rx, ORB, C3-C6cycloalkylC1-C4alkyl substituted with one or two substituents Rz, C3-C6cycloalkylC1-C3alkoxy optionally substituted with Rx, C1-C5cyanoalkyl, C1-C5cyanoalkoxy, C1-C4alkylsulfanyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfonyl optionally substituted by one to three substituents Rx, C1-C4alkylsulfinyl optionally substituted by one to three substituents Rx, C(O)NR7R8, C1-C4alkylsulfonylamino, aminosulfonyl, C1-C4alkylaminosulfonyl, C3-C6cycloalkylaminosulfonyl, —O—C1-C2haloalkanediyl-O—, and 10 membered optionally substituted spiroheterocyclic ring; where RB is phenyl, benzyl, heteroaryl selected from J-1 to J-41, C3-C6cycloalkyl, or C3-C6cycloalkylC1-C3alkyl, each of which, independent of each other, is optionally substituted with one to three substituents independently selected from Rx; R7 and R8 independently of each other is hydrogen, C1-C3alkyl, or C3-C6cycloalkyl, wherein the C1-C3alkyl or C3-C6cycloalkyl, independent of each other, is optionally substituted with one to three substituents independently selected from Rz; where Rx is independently selected from halogen, C1-C3haloalkyl, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkoxy and CN; where Rz is independently selected from oxo, halogen, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy and CN; as R1a and R1b, independent of each other, hydrogen, methyl, ethyl, cyanomethyl, methoxymethyl, cyclopropyl-methyl, allyl, propargyl, benzyloxycarbonyl, or benzyl, or as R1a and R1b together —CH2—O—CH2—; or T and R1b together is nine membered bicyclic partially saturated heterocyclic ring substituted with C1-C3haloalkyl; as R3 methyl or trifluoromethyl; and as Q selected from Qaa, Qab, Qba and Qbb.
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen or sulfur; as T phenyl, or pyridine, each of which, independent of each other, is substituted with one to three substituents independently selected from R2, where R2, independently of the ring and of the number of substituents, is selected from trifluoromethyl, fluorine, iodine, bromine chlorine, ORB where R is J-1 substituted by 1 to 2 substituents independently selected from chloro and trifluoromethyl, difluoromethoxy, 1,1,2,2-tettrafluoroethoxy, and —O—CF2O—; as R1a and R1b, independent of each other, hydrogen or methyl; or T and R1b together is nine membered bicyclic partially saturated heterocyclic ring substituted with C1-C3haloalkyl; as R3 methyl; and as Q either Qaa or QabIn an embodiment of each aspect of the invention, the compound of formula I is represented by formula I′a and has as X oxygen or sulfur; as T phenyl, or pyridine, each of which, independent of each other, is substituted with one to three substituents independently selected from R2, where R2, independently of the ring and of the number of substituents, is selected from trifluoromethyl, fluorine, iodine, bromine chlorine, ORB where R is J-1 substituted by 1 to 2 substituents independently selected from chloro and trifluoromethyl, difluoromethoxy, 1,1,2,2-tettrafluoroethoxy, and —O—CF2O—; as R1a and R1b, independent of each other, hydrogen or methyl; or T and R1b together is indolinyl substituted with C1-C3haloalkyl; as R3 methyl; and as Q either Qaa or Qab
In an embodiment of each aspect of the invention, the compound of formula I has as X oxygen; as T phenyl, or pyridine, each of which, independent of each other, is substituted with one to three substituents independently selected from R2, where R2, independently of the ring and of the number of substituents, is selected from trifluoromethyl, fluorine, iodine, bromine chlorine, difluoromethoxy, and 1,1,2,2-tettrafluoroethoxy; as R1a and R1b are each hydrogen; as R3 methyl; and as Q either Qaa or Qab.
In an embodiment of each aspect of the invention, the compound of formula I is represented by formula I′a and has as X oxygen; as T phenyl, or pyridine, each of which, independent of each other, is substituted with one to three substituents independently selected from R2, where R2, independently of the ring and of the number of substituents, is selected from trifluoromethyl, fluorine, iodine, bromine chlorine, difluoromethoxy, and 1,1,2,2-tettrafluoroethoxy; as R1a and R1b are each hydrogen; as R3 methyl; and as Q either Qaa or Qab
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.
In another aspect, an example of which is shown in Schemes 1 and 2, the present invention makes available a process for preparing a compound of the formula I,
comprising reacting an amine of formula II
with (i) a compound of formula III when R1a is hydrogen (i.e. this corresponds to a compound of the formula I-a)
or (ii) with a compound of formula IV,
where X, R3, R1a, R1b, T and Q are as defined above for a compound of the formula I.
In another aspect, an example of which is shown in Scheme 4, the present invention makes available a process for preparing a compound of the formula I,
comprising reacting an amine of formula VI
with a compound of formula VII,
where X, R3, R1a, R1b, T and Q are as defined above for a compound of the formula I.
Compounds of formula I can be made, for example, as shown in scheme 1.
Reaction of a compound of the formula II with a compound of formula III gives a compound of the formula I-a, where X, R3, R1b, T and Q are as defined above for a compound of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C. preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Compounds of the formula II and III are either known, or they can be prepared by methods known to a person skilled in the art.
Reaction of a compound of the formula II with a compound of formula IV gives a compound of the formula I, where X, R3, R1a, R1b, T and Q are as defined above for a compound of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Compounds of the formula II are either known, or they can be prepared by methods known to a person skilled in the art.
Compounds of formula IV can be made, for example, as shown in scheme 3. Treatment of a compound of the formula V, with an amine of the formula VI gives compounds of the formula IV, where X, R3, R1a and Q are as defined above for a compound of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
Reaction of a compound of the formula VII with a compound of formula VI gives a compound of the formula I, where X, R3, R1a, R1b, T and Q are as defined above for a compound of formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Compounds of the formula II are either known, or they can be prepared by methods known to a person skilled in the art.
Compounds of formula VII can be made, for example, as shown in scheme 5. Treatment of a compound of the formula V, with an amine of the formula II gives compounds of the formula VII, where R1b, X and T are as defined above for a compound of formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
Reaction of a compound of the formula VIII with a compound of formula VI gives a compound of the formula I-b, where X, R3, R1a, T and Q are as defined above for a compound of formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Compounds of the formula VIII and VI are either known, or they can be prepared by methods known to a person skilled in the art.
Compounds of formula VI can be made, for example, as shown in scheme 7, where R3, R1a and Q are as defined above for a compound of formula I. Treatment of a compound of the formula VI-a, wherein X2 is a leaving group, such as a halogen or sulfonate, for instance bromide, with an amine of the formula XIX gives compounds of the formula VI. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Alternatively, treatment of a compound of the formula VI-b with an amine of the formula XIX gives compounds of the formula VI. This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Such methods, and the range of conditions to perform them, for the alkylation of amines and for the reductive alkylation of amines are well known to a person skilled in the art. The amines of formula XIX are either known, or they can be prepared by methods known to a person skilled in the art.
Compounds of formula VI-a can be made, for example, as shown in scheme 8, where R3 and Q are as defined above for a compound of formula I. Treatment of a compound of the formula VI-c with a halogenating agent, such as chlorine or bromine or N-bromosuccinimide, for example, gives compound of the formula VI-a, wherein the leaving group X2 is a halogen, for instance chloride or bromide. This reaction is done with or without a solvent, preferably in a solvent, with or without an additive, such as a radical starter, such as, for example, benzoyl peroxide or azoisobutyronitrile. The reaction can be done with or without exposure to visible light, or to UV light, and it can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Alternatively, a compound of the formula VI-b can be treated with a reducing agent, followed by reaction with a sulfonyl chloride, for instance methanesulfonyl chloride, to give a compound of the formula VI-a, wherein the leaving group X2 is a sulfonate, for instance a mesylate. This reaction can be done in a solvent, or without a solvent, in the presence of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as an amine base, for instance trimethylamine, or without a base, and it can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. A suitable reducing agent could be, for example, hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Such methods for the halogenation, the reduction of carbonyl compounds and the sulfonylation of alcohols, and the range of conditions to perform them, are well known to a person skilled in the art. The compounds of formula VI-b and the compounds of formula VI-c are either known, or they can be prepared by methods known to a person skilled in the art.
As shown in scheme 9, compounds of the formula I-d, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-c by treatment with a compound of formula IX, wherein X2a and X2b are leaving groups, such as halogen or sulfonate, for example bromide or iodide, or tosylate or mesylate. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Such transformations are known to the person skilled in the art.
As shown in scheme 9, compounds of the formula I-e, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-c by treatment with a compound of formula X, wherein X2a and X2b are leaving groups, such as halogen or sulfonate, for example bromide or iodide, or tosylate or mesylate. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Such transformations are known to the person skilled in the art.
As shown in scheme 9, compounds of the formula I-f, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-c by treatment with formaldehyde. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance 1,2-dichloroethane, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of an acid, such as an inorganic acid, for instance hydrochloric acid, or an organic acid, such as, for example, acetic acid or trifluoroacetic acid. Such transformations are known to the person skilled in the art. For instance, such transformations are described in Synthetic Communications (1996), 26(17), 3217-3224.
As shown in scheme 9, compounds of the formula I-g, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-c by treatment with formaldehyde and hydrogen sulfide. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance chloroform, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of an acid, such as an inorganic acid, for instance hydrochloric acid, or an organic acid, such as, for example, p-toluenesulfonic acid. Such transformations are known to the person skilled in the art. For instance, such transformations are described in Journal of Heterocyclic Chemistry (1972), 9(2), 231-4.
As shown in scheme 9, compounds of the formula I-h, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-c by treatment with formaldehyde and an amine XI, wherein Ry has the same meaning as defined for compounds of the formula I. The amine can be used as such or in the form of a salt, such as, for instance, in the form of a hydrochloride. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance ethanol, or in water, or in a mixture of solvents, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. with or without the addition of an acid, such as an inorganic acid, for instance hydrochloric acid, or an organic acid, such as, for example, p-toluenesulfonic acid. Such transformations are known to the person skilled in the art. For instance, such transformations are described in Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya (2005), 48(3), 106-108.
As shown in scheme 10, compounds of the formula I-i, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-g by treatment with an oxidizing agent, such as hydrogen peroxide or a peracid, for instance m-chloroperbenzoic acid. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance dichloromethane, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a catalyst, such as a metal catalyst, for instance 12-tungstophosphoric acid. Such transformations are well known to the person skilled in the art.
As shown in scheme 10, compounds of the formula I-j, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-g by treatment with an oxidizing agent, such as hydrogen peroxide or a peracid, for instance m-chloroperbenzoic acid. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance dichloromethane, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a catalyst, such as a metal catalyst, for instance 12-tungstophosphoric acid. Such transformations are well known to the person skilled in the art.
Alternatively, compounds of the formula I-j, wherein T, X, R3 and Q are as defined for formula I, can be made from compounds of formula I-i by treatment with an oxidizing agent, such as hydrogen peroxide or a peracid, for instance m-chloroperbenzoic acid. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance dichloromethane, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the addition of a catalyst, such as a metal catalyst, for instance 12-tungstophosphoric acid. Such transformations are well known to the person skilled in the art.
Compounds of formula I-k can be made, for example, as shown in scheme 11. Reaction of a compound of the formula X with a compound of formula VIII gives a compound of the formula XVI, wherein T and R3 have the same meaning as given above for compounds of the formula I. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile or N,N-dimethylformamide, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
Subsequent treatment of compound XVI with the known compound XII gives a compound of the formula XIII, wherein T and R3 have the same meaning as given above for compounds of the formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance dichloromethane, in a temperature range of −100 to +300° C., preferably between ambient temperature and 100° C., or between ambient temperature and 50° C., without a base or in the presence of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
Further reaction of compound XIII with hydrazine XIV gives the compound of formula I-k, wherein T, R3 and R4 have the same meaning as given above for compounds of the formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance 1,4-dioxane, or acetic acid, or a mixture of 1,4-dioxane and acetic acid, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., or between ambient temperature and 80° C. Within this sequence of transformations, the intermediate compounds of formula XVI and of formula XIII can be used as crude products for the subsequent step, or they can be purified, for instance by chromatography, and used in purified form for the next transformation.
Compounds of formula I-m can be made, for example, as shown in scheme 12. Reaction of a compound of the formula XV (wherein X05 is a leaving group such as chlorine, bromine, iodine, arysulfonate, alkylsulfonate or trifluoromethanesulfonate) with an amine of the formula XIX gives compounds of the formula XVII, wherein R1a and R3 have the same meaning as given above for compounds of the formula I. This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Such methods, and the range of conditions to perform them, for the reductive alkylation of amines are well known to a person skilled in the art.
Subsequent reaction of the intermediate of the formula XVII with a compound of the formula VIII gives a compound of the formula XIII, wherein T, R1a and R3 have the same meaning as given above for compounds of the formula I. This reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine.
Subsequently, the intermediate of the formula XVIII is reacted with a compound of the formula XX to give the compound of formula I-m, wherein T, R1a, R3 and R4a have the same meaning as given above for compounds of the formula I, and M1 in R4a-M1 is a metal, such as for instance lithium, or —MgCl, or —ZnBr, or —B(OH)2; or R4a-M1 represents a boronate, such as a pinacol ester of a boronic acid, or a stannane such as R4a—Sn(n-Bu)3. Such transformations are known to a person skilled in the art as Suzuki-, Kumada-, Negishi- or Stille-coupling reactions, respectively. Such reactions are carried out in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., in the presence of a catalyst, such as a metal catalyst, for instance a palladium catalyst, and a ligand, such as for example a phosphine ligand, or an N-heterocyclic carbene (NHC) ligand, or a phosphite ligand. The reaction can be done in the presence or absence of an additional metal catalyst, such as, for example, a copper salt, for instance CuI. The reaction is done with or without a base, which can be an inorganic base, such as potassium carbonate, or sodium hydroxide, or cesium carbonate, or an organic base, such as an amine base, for instance triethyl amine. This reaction is done with or without a solvent, preferentially in a solvent. Where the reaction mixture is heated, the reaction can be conducted under microwave irradiation or with conventional heating, such as heating the reaction vessel in an oil bath.
By an alternative route, compound XV can be reacted with a compound of the formula XX to give intermediate XXI, wherein R3 and R4a have the same meaning as given above for compounds of the formula I. This reaction is done essentially under in the same range of conditions as described for the transformation of intermediate XVIII to the compound of formula I-m. Subsequently, the intermediate XXI is reacted with amine XIX to give intermediate XVIIa, wherein R1a, R3 and R4a have the same meaning as given above for compounds of the formula I. This reaction is done in the presence of a reducing agent, essentially under the same conditions as described above for the transformation of compound XV to intermediate XVII.
Subsequently, the intermediate of the formula XVIIa is reacted with a compound of the formula VIII to give the compound of the formula I-m, wherein T, R1a, R3 and R4a have the same meaning as given above for compounds of the formula I. This reaction is done essentially under the same conditions as described above for the transformation of intermediate XVII to intermediate XVIII.
Within these different multistep sequences, the intermediate compounds of formulas XVII, XVIIa, XVIII and XXI can be used as crude products for the respective subsequent step, or they can be purified, for instance by chromatography, and used in purified form for the next transformation. Compounds of the formula XV are known, or they can be prepared by methods known to a person skilled in the art.
Compounds of the formula I-n
can be prepared by the reaction of an amine of the formula XVIIb
wherein R1a, R3, R4a, R5a and R5b are as described in formula I with a compound of the formula VIII
wherein T is as described in formula I.
The chemistry is described in more detail in Scheme 6.
Amines of formula XVIIc may be obtained by biocatalyzed deracemization of amines of formula XVIId, wherein R3, R4a, R5a, and R5b are as defined in formula I. 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.
Treatment of a compound of the formula XVIIc with an amine of the formula XXII gives compounds of the formula XVIIb. This reaction is done in the presence of a reducing agent, such as for example hydrogen, or a hydride, such as sodium borohydride, with or without a catalyst, such as a hydrogenation catalyst, for example palladium on carbon, with or without the presence of an acid, such as acetic acid, or a Lewis acid, such as zinc bromide, in a solvent or without a solvent, such as, for instance, methanol. The reaction can be conducted in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C. Such methods, and the range of conditions to perform them, for the alkylation of amines and for the reductive alkylation of amines are well known to a person skilled in the art.
In an alternative process, compounds of formula XVIIc can be obtained from compounds of the formula XVIId wherein R3, R4a, R5a, and R5b are as described in formula I, following the synthesis described in Scheme 14:
Amines of formula XVIIc may be obtained from intermediates of formula XXV, wherein R3, R4a, R5a, and R5b are as described in formula I and Z3 is NPhth or NBoc2. Such intermediates can be obtained from alcohols of formula XXIII by a Mitsunobu reaction, which involves treating alcohols of formula XXIII with 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. Compounds of formula XXV can then be transformed into amines of formula XVIIb by treatment with hydrazine if Z3=NPhth or with acid, for example trifluoroacetic acid, if Z3=NBoc2.
Alternatively, amines of formula XVIIc may be obtained by reduction of azides of formula XXIV, wherein R3, R4a, R5a, and R5b are as 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 XXIV may be obtained by treatment of alcohols of formula XXIII, wherein R3, R4a, 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 XXIII may be obtained by enantioselective reduction of ketones of formula XVa, wherein R3, R4a, R5a, and R5b are as described in formula I. 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 XVIIc may also be prepared as outlined in Scheme 15.
Amines of formula XVIIc can be prepared by deprotection of amines of formula XXXI, wherein R3, R4a, R5a, and R5b are as described in formula I, for instance using an acid such as trifluoroacetic acid or hydrochloric acid. Amines of formula XXXI can be obtained by condensation of diamines of formula XXX, wherein R5a, and R5b are as described in formula I, on diketones of formula XXIX, wherein R3, and R4a are 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 XXIX may be formed by oxidation of hydroxyketones of formula XXVIII wherein R3, and R4a are as described in formula I. This oxidation can involve for instance SO3-pyridine in presence of DMSO and a base for instance triethylamine 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 XXVIII may be synthesized by cross-benzoin condensation between aldehydes of formula XXVII, wherein R4a is as described in formula I, and aldehydes of formula XXVI, wherein R3 is as described in formula 1. Aldehydes of formula XXVI 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 isopropyldiethylamine in a suitable solvent such as DCM or THE 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 XVIIe may be obtained by biocatalyzed deracemization of amines of formula XVIIf, wherein R3, R5a, and R5b are as defined in formula I and X07 is a leaving group such as bromine, chlorine or iodine. 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.
Alternatively, resolution of amines of formula XVIIf to give amines of formula XVIIe may be achieved using a chiral auxiliary, as described in Scheme 17.
Amines of formula XVIIe can be prepared from intermediates of formula XXXIII, wherein R3, R5a, and R5b are as in compounds of the formula I, X07 is a leaving group such as bromine, chlorine or iodine, and X12* is a chiral auxiliary, by treatment with acids such as HCl or bases such as NaOH. Chiral auxiliaries of formula XXXII are for instance mandelic acid or (1R)-menthylchloroformate. Intermediates of formula XXXIII can be formed by coupling of a chiral auxiliary of formula XXXII, wherein Xo is a leaving group, such as chlorine, with amines of the formula XVIIf. The reaction can be conducted neat or in a solvent, preferably in a solvent, such as an organic solvent, for instance acetonitrile, in a temperature range of −100 to +300° C., preferably between ambient temperature and 200° C., with or without the presence of a catalyst, for instance a metal catalyst, such as a palladium complex, and with or without the addition of a base, such as an inorganic base, for instance potassium carbonate, or an organic base, such as, for example, triethylamine. Compounds of the formula XXXII are either known, or they can be prepared by methods known to a person skilled in the art. Examples of such deracemization processes are reported in the literature, for instance in J. Org. Chem. 2007, 72, 485-493.
Alternatively, amines of formula XVIIe can be formed as described in Scheme 18.
Alternatively, amines of formula XVIIe may be obtained from intermediates of formula XXVa, wherein R3, R5a, and R5b are as described in formula I, X07 is a leaving group such as a halogen or sulfonate, for instance bromide, and Z3 is NPhth or NBoc2. Such intermediates can be obtained from alcohols of formula XXIIIa, wherein R3, R5a, and R5b are as described in formula I and X07 is a leaving group, by a Mitsunobu reaction, which involves treating alcohols of formula XXIIIa with 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 XXVa can then be transformed into amines of formula XVIIe by treatment with hydrazine if Z3=NPhth or with an acid, such as TFA, if Z3=NBoc2.
Alternatively, amines of formula XVIIe may be obtained by reduction of azides of formula XXIVa, wherein R3, R5a, and R5b are as described in formula I and X07 is a leaving group such as a halogen or sulfonate, for instance bromide, 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 XXIVa may be obtained by treatment of alcohols of formula XXIIIa 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 XXIIIa may be obtained by enantioselective reduction of ketones of formula XVb, wherein R3, R5a, and R5b are as described in formula I and X07 is a leaving group such as a halogen or sulfonate, for instance bromide. 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.
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 (when A2 and A3 are each N) 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-A according to the following Tables A-1 to A-243 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 I-A.
Table A-1 provides 8 compounds A-1.001 to A-1.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z. For example, A-1.002 is
Table A-2 provides 8 compounds A-2.001 to A-2.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-3 provides 8 compounds A-3.001 to A-3.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-4 provides 8 compounds A-4.001 to A-4.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-5 provides 8 compounds A-5.001 to A-5.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-6 provides 8 compounds A-6.001 to A-6.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-7 provides 8 compounds A-7.001 to A-7.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-8 provides 8 compounds A-8.001 to A-8.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-9 provides 8 compounds A-9.001 to A-9.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-10 provides 8 compounds A-10.001 to A-10.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-11 provides 8 compounds A-11.001 to A-11.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-12 provides 8 compounds A-12.001 to A-12.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CHs and Q are as defined in table Z.
Table A-13 provides 8 compounds A-13.001 to A-13.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-14 provides 8 compounds A-14.001 to A-14.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-15 provides 8 compounds A-15.001 to A-15.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-16 provides 8 compounds A-16.001 to A-16.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-17 provides 8 compounds A-17.001 to A-17.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-18 provides 8 compounds A-18.001 to A-18.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-19 provides 8 compounds A-19.001 to A-19.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-20 provides 8 compounds A-20.001 to A-20.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-21 provides 8 compounds A-21.001 to A-21.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-22 provides 8 compounds A-22.001 to A-22.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-23 provides 8 compounds A-23.001 to A-23.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-24 provides 8 compounds A-24.001 to A-24.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-25 provides 8 compounds A-25.001 to A-25.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-26 provides 8 compounds A-26.001 to A-26.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-27 provides 8 compounds A-27.001 to A-27.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-28 provides 8 compounds A-28.001 to A-28.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is H, R1a is H, R3 is CHs and Q are as defined in table Z.
Table A-29 provides 8 compounds A-29.001 to A-29.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-30 provides 8 compounds A-30.001 to A-30.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-31 provides 8 compounds A-31.001 to A-31.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-32 provides 8 compounds A-32.001 to A-32.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-33 provides 8 compounds A-33.001 to A-33.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-34 provides 8 compounds A-34.001 to A-34.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-35 provides 8 compounds A-35.001 to A-35.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-36 provides 8 compounds A-36.001 to A-36.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-37 provides 8 compounds A-37.001 to A-37.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-38 provides 8 compounds A-38.001 to A-38.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-39 provides 8 compounds A-39.001 to A-39.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-40 provides 8 compounds A-40.001 to A-40.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-41 provides 8 compounds A-41.001 to A-41.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-42 provides 8 compounds A-42.001 to A-42.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-43 provides 8 compounds A-43.001 to A-43.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-44 provides 8 compounds A-44.001 to A-44.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is CHs, R3 is CHs and Q are as defined in table Z.
Table A-45 provides 8 compounds A-45.001 to A-45.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-46 provides 8 compounds A-46.001 to A-46.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-47 provides 8 compounds A-47.001 to A-47.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-48 provides 8 compounds A-48.001 to A-48.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-49 provides 8 compounds A-49.001 to A-49.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-50 provides 8 compounds A-50.001 to A-50.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-51 provides 8 compounds A-51.001 to A-51.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-52 provides 8 compounds A-52.001 to A-52.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-53 provides 8 compounds A-53.001 to A-53.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-54 provides 8 compounds A-54.001 to A-54.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-55 provides 8 compounds A-55.001 to A-55.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-56 provides 8 compounds A-56.001 to A-56.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-57 provides 8 compounds A-57.001 to A-57.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-58 provides 8 compounds A-58.001 to A-58.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-59 provides 8 compounds A-59.001 to A-59.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-61 provides 8 compounds A-61.001 to A-61.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CFs, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CHs and Q are as defined in table Z.
Table A-62 provides 8 compounds A-62.001 to A-62.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-63 provides 8 compounds A-63.001 to A-63.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-64 provides 8 compounds A-64.001 to A-64.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-65 provides 8 compounds A-65.001 to A-65.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-66 provides 8 compounds A-66.001 to A-66.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-67 provides 8 compounds A-67.001 to A-67.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-68 provides 8 compounds A-68.001 to A-68.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-69 provides 8 compounds A-69.001 to A-69.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-70 provides 8 compounds A-70.001 to A-70.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-71 provides 8 compounds A-71.001 to A-71.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-72 provides 8 compounds A-72.001 to A-72.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-73 provides 8 compounds A-73.001 to A-73.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-74 provides 8 compounds A-74.001 to A-74.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-75 provides 8 compounds A-75.001 to A-75.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-76 provides 8 compounds A-76.001 to A-76.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CFs, S2 is CFs, R1b is CHs, R1a is H, R3 is CHs and Q are as defined in table Z.
Table A-77 provides 8 compounds A-77.001 to A-77.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-78 provides 8 compounds A-78.001 to A-78.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-79 provides 8 compounds A-79.001 to A-79.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-80 provides 8 compounds A-80.001 to A-80.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-81 provides 8 compounds A-81.001 to A-81.008 of formula I-A wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-82 provides 8 compounds A-82.001 to A-82.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-83 provides 8 compounds A-83.001 to A-83.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-84 provides 8 compounds A-84.001 to A-84.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-85 provides 8 compounds A-85.001 to A-85.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-86 provides 8 compounds A-86.001 to A-86.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-87 provides 8 compounds A-87.001 to A-87.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-88 provides 8 compounds A-88.001 to A-88.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-89 provides 8 compounds A-89.001 to A-89.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-90 provides 8 compounds A-90.001 to A-90.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-91 provides 8 compounds A-91.001 to A-91.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-92 provides 8 compounds A-92.001 to A-92.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is H, R1a is CHs, R3 is CHs and Q are as defined in table Z.
Table A-93 provides 8 compounds A-93.001 to A-93.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-94 provides 8 compounds A-94.001 to A-94.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-95 provides 8 compounds A-95.001 to A-95.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-96 provides 8 compounds A-96.001 to A-96.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-97 provides 8 compounds A-97.001 to A-97.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-98 provides 8 compounds A-98.001 to A-98.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-99 provides 8 compounds A-99.001 to A-99.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-100 provides 8 compounds A-100.001 to A-100.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-101 provides 8 compounds A-101.001 to A-101.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-102 provides 8 compounds A-102.001 to A-102.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-103 provides 8 compounds A-103.001 to A-103.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-104 provides 8 compounds A-104.001 to A-104.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-105 provides 8 compounds A-105.001 to A-105.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-106 provides 8 compounds A-106.001 to A-106.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-107 provides 8 compounds A-107.001 to A-107.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-108 provides 8 compounds A-108.001 to A-108.008 of formula I-A wherein Ax is C—CF3, S1 is Cl, S2 is CFs, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CHs and Q are as defined in table Z.
Table A-109 provides 8 compounds A-109.001 to A-109.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-110 provides 8 compounds A-110.001 to A-110.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-111 provides 8 compounds A-111.001 to A-111.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-112 provides 8 compounds A-112.001 to A-112.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-113 provides 8 compounds A-113.001 to A-113.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-114 provides 8 compounds A-114.001 to A-114.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-115 provides 8 compounds A-115.001 to A-115.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-116 provides 8 compounds A-116.001 to A-116.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-117 provides 8 compounds A-117.001 to A-117.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-118 provides 8 compounds A-118.001 to A-118.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-119 provides 8 compounds A-119.001 to A-119.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-120 provides 8 compounds A-120.001 to A-120.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-121 provides 8 compounds A-121.001 to A-121.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-122 provides 8 compounds A-122.001 to A-122.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-123 provides 8 compounds A-123.001 to A-123.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-124 provides 8 compounds A-124.001 to A-124.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CHs and Q are as defined in table Z.
Table A-125 provides 8 compounds A-125.001 to A-125.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-126 provides 8 compounds A-126.001 to A-126.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-127 provides 8 compounds A-127.001 to A-127.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-128 provides 8 compounds A-128.001 to A-128.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-129 provides 8 compounds A-129.001 to A-129.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-130 provides 8 compounds A-130.001 to A-130.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-131 provides 8 compounds A-131.001 to A-131.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-132 provides 8 compounds A-132.001 to A-132.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-133 provides 8 compounds A-133.001 to A-133.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-134 provides 8 compounds A-134.001 to A-134.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-135 provides 8 compounds A-135.001 to A-135.008 of formula I-A wherein Ax is C—CF3, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-136 provides 8 compounds A-136.001 to A-136.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-137 provides 8 compounds A-137.001 to A-137.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-138 provides 8 compounds A-138.001 to A-138.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-139 provides 8 compounds A-139.001 to A-139.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-140 provides 8 compounds A-140.001 to A-140.008 of formula I-A wherein Ax is C—CF3, S1 is CFs, S2 is Cl, R1b is CHs, R1a is CHs, R3 is CHs and Q are as defined in table Z.
Table A-141 provides 8 compounds A-141.001 to A-141.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-142 provides 8 compounds A-142.001 to A-142.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-143 provides 8 compounds A-143.001 to A-143.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-144 provides 8 compounds A-144.001 to A-144.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-145 provides 8 compounds A-145.001 to A-145.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-146 provides 8 compounds A-146.001 to A-146.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-147 provides 8 compounds A-147.001 to A-147.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-148 provides 8 compounds A-148.001 to A-148.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-149 provides 8 compounds A-149.001 to A-149.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-150 provides 8 compounds A-150.001 to A-150.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-151 provides 8 compounds A-151.001 to A-151.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-152 provides 8 compounds A-152.001 to A-152.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-153 provides 8 compounds A-153.001 to A-153.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-154 provides 8 compounds A-154.001 to A-154.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-155 provides 8 compounds A-155.001 to A-155.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-156 provides 8 compounds A-156.001 to A-156.008 of formula I-A wherein Ax is C—CF3, S1 is CFs, S2 is CFs, R1b is H, R1a is CH2-cyclopropyl, R3 is CHs and Q are as defined in table Z.
Table A-157 provides 8 compounds A-157.001 to A-157.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-158 provides 8 compounds A-158.001 to A-158.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-159 provides 8 compounds A-159.001 to A-159.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-160 provides 8 compounds A-160.001 to A-160.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-161 provides 8 compounds A-161.001 to A-161.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-162 provides 8 compounds A-162.001 to A-162.008 of formula I-A wherein Ax is C—CF3, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-163 provides 8 compounds A-163.001 to A-163.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-164 provides 8 compounds A-164.001 to A-164.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-165 provides 8 compounds A-165.001 to A-165.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-166 provides 8 compounds A-166.001 to A-166.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-167 provides 8 compounds A-167.001 to A-167.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-168 provides 8 compounds A-168.001 to A-168.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-169 provides 8 compounds A-169.001 to A-169.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-170 provides 8 compounds A-170.001 to A-170.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-171 provides 8 compounds A-171.001 to A-171.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-172 provides 8 compounds A-172.001 to A-172.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is H, R1a is H, R3 is CHs and Q are as defined in table Z.
Table A-173 provides 8 compounds A-173.001 to A-173.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-174 provides 8 compounds A-174.001 to A-174.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-175 provides 8 compounds A-175.001 to A-175.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-176 provides 8 compounds A-176.001 to A-176.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-177 provides 8 compounds A-177.001 to A-177.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-178 provides 8 compounds A-178.001 to A-178.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-179 provides 8 compounds A-179.001 to A-179.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-180 provides 8 compounds A-180.001 to A-180.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-181 provides 8 compounds A-181.001 to A-181.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-182 provides 8 compounds A-182.001 to A-182.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-183 provides 8 compounds A-183.001 to A-183.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-184 provides 8 compounds A-184.001 to A-184.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-185 provides 8 compounds A-185.001 to A-185.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-186 provides 8 compounds A-186.001 to A-186.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-187 provides 8 compounds A-187.001 to A-187.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-188 provides 8 compounds A-188.001 to A-188.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CFs, R1b is CH2-cyclopropyl, R1a is CHs, R3 is CHs and Q are as defined in table Z.
Table A-189 provides 8 compounds A-189.001 to A-189.008 of formula I-A wherein Ax is N, S1 is Cl, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-190 provides 8 compounds A-190.001 to A-190.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-191 provides 8 compounds A-191.001 to A-191.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-192 provides 8 compounds A-192.001 to A-192.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-193 provides 8 compounds A-193.001 to A-193.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-194 provides 8 compounds A-194.001 to A-194.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-195 provides 8 compounds A-195.001 to A-195.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-196 provides 8 compounds A-196.001 to A-196.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-197 provides 8 compounds A-197.001 to A-197.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-198 provides 8 compounds A-198.001 to A-198.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-199 provides 8 compounds A-199.001 to A-199.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-200 provides 8 compounds A-200.001 to A-200.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-201 provides 8 compounds A-201.001 to A-201.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-202 provides 8 compounds A-202.001 to A-202.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-203 provides 8 compounds A-203.001 to A-203.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-204 provides 8 compounds A-204.001 to A-204.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is CHs, R1a is CH2-cyclopropyl, R3 is CHs and Q are as defined in table Z.
Table A-205 provides 8 compounds A-205.001 to A-205.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-206 provides 8 compounds A-206.001 to A-206.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-207 provides 8 compounds A-207.001 to A-207.008 of formula I-A wherein Ax is N, S1 is Br, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-208 provides 8 compounds A-208.001 to A-208.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-209 provides 8 compounds A-209.001 to A-209.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-210 provides 8 compounds A-210.001 to A-210.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-211 provides 8 compounds A-211.001 to A-211.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-212 provides 8 compounds A-212.001 to A-212.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-213 provides 8 compounds A-213.001 to A-213.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-214 provides 8 compounds A-214.001 to A-214.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-215 provides 8 compounds A-215.001 to A-215.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-216 provides 8 compounds A-216.001 to A-216.008 of formula I-A wherein Ax is N, S1 is Br, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-217 provides 8 compounds A-217.001 to A-217.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-218 provides 8 compounds A-218.001 to A-218.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-219 provides 8 compounds A-219.001 to A-219.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-220 provides 8 compounds A-220.001 to A-220.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is CHs, R1a is H, R3 is CHs and Q are as defined in table Z.
Table A-221 provides 8 compounds A-221.001 to A-221.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-222 provides 8 compounds A-222.001 to A-222.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-223 provides 8 compounds A-223.001 to A-223.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-224 provides 8 compounds A-224.001 to A-224.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-225 provides 8 compounds A-225.001 to A-225.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Cl, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-226 provides 8 compounds A-226.001 to A-226.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-227 provides 8 compounds A-227.001 to A-227.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is H, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-228 provides 8 compounds A-228.001 to A-228.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-229 provides 8 compounds A-229.001 to A-229.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-230 provides 8 compounds A-230.001 to A-230.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-231 provides 8 compounds A-231.001 to A-231.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-232 provides 8 compounds A-232.001 to A-232.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-233 provides 8 compounds A-233.001 to A-233.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-234 provides 8 compounds A-234.001 to A-234.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is Br, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-235 provides 8 compounds A-235.001 to A-235.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is H, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-236 provides 8 compounds A-236.001 to A-236.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CFs, R1b is H, R1a is CHs, R3 is CHs and Q are as defined in table Z. Table A-237 provides 8 compounds A-237.001 to A-237.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is H, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-238 provides 8 compounds A-238.001 to A-238.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is CH3, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-239 provides 8 compounds A-239.001 to A-239.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is CH3, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-240 provides 8 compounds A-240.001 to A-240.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is CH3, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
Table A-241 provides 8 compounds A-241.001 to A-241.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is H, R3 is CH3 and Q are as defined in table Z.
Table A-242 provides 8 compounds A-242.001 to A-242.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH3, R3 is CH3 and Q are as defined in table Z.
Table A-243 provides 8 compounds A-243.001 to A-243.008 of formula I-A wherein Ax is N, S1 is CF3, S2 is CF3, R1b is CH2-cyclopropyl, R1a is CH2-cyclopropyl, R3 is CH3 and Q are as defined in table Z.
The compounds of formula I-B according to the following Tables B-1 to B-81 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 I-B.
Table B-1 provides 8 compounds B-1.001 to B-1.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-2 provides 8 compounds B-2.001 to B-2.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, W is CH2, R3 is CHs and Q are as defined in table Z. For example, B-2.002 and B-2.003 are:
Table B-3 provides 8 compounds B-3.001 to B-3.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Cl, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-4 provides 8 compounds B-4.001 to B-4.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-5 provides 8 compounds B-5.001 to B-5.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-6 provides 8 compounds B-6.001 to B-6.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-7 provides 8 compounds B-7.001 to B-7.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-8 provides 8 compounds B-8.001 to B-8.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-9 provides 8 compounds B-9.001 to B-9.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Cl, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-10 provides 8 compounds B-10.001 to B-10.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-11 provides 8 compounds B-11.001 to B-11.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-12 provides 8 compounds B-12.001 to B-12.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Cl, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-13 provides 8 compounds B-13.001 to B-13.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-14 provides 8 compounds B-14.001 to B-14.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, W is CH2, R3 is CHs and Q are as defined in table Z.
Table B-15 provides 8 compounds B-15.001 to B-15.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-16 provides 8 compounds B-16.001 to B-16.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-17 provides 8 compounds B-17.001 to B-17.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-18 provides 8 compounds B-18.001 to B-18.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is Br, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-19 provides 8 compounds B-19.001 to B-19.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-20 provides 8 compounds B-20.001 to B-20.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-21 provides 8 compounds B-21.001 to B-21.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Cl, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-22 provides 8 compounds B-22.001 to B-22.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-23 provides 8 compounds B-23.001 to B-23.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-24 provides 8 compounds B-24.001 to B-24.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-25 provides 8 compounds B-25.001 to B-25.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-26 provides 8 compounds B-26.001 to B-26.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-27 provides 8 compounds B-27.001 to B-27.008 of formula I-B wherein Ax is C—O—CF2CF2H, S1 is CF3, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-28 provides 8 compounds B-28.001 to B-28.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is Cl, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-29 provides 8 compounds B-29.001 to B-29.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is Cl, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-30 provides 8 compounds B-30.001 to B-30.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is Cl, W is O, R3 is CHs and Q are as defined in table Z.
Table B-31 provides 8 compounds B-31.001 to B-31.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-32 provides 8 compounds B-32.001 to B-32.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-33 provides 8 compounds B-33.001 to B-33.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-34 provides 8 compounds B-34.001 to B-34.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-35 provides 8 compounds B-35.001 to B-35.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-36 provides 8 compounds B-36.001 to B-36.008 of formula I-B wherein Ax is C—CF3, S1 is Cl, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-37 provides 8 compounds B-37.001 to B-37.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is Cl, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-38 provides 8 compounds B-38.001 to B-38.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is Cl, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-39 provides 8 compounds B-39.001 to B-39.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is Cl, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-40 provides 8 compounds B-40.001 to B-40.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-41 provides 8 compounds B-41.001 to B-41.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-42 provides 8 compounds B-42.001 to B-42.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-43 provides 8 compounds B-43.001 to B-43.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-44 provides 8 compounds B-44.001 to B-44.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-45 provides 8 compounds B-45.001 to B-45.008 of formula I-B wherein Ax is C—CF3, S1 is Br, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-46 provides 8 compounds B-46.001 to B-46.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is Cl, W is a direct bond, R3 is CHs and Q are as defined in table Z.
Table B-47 provides 8 compounds B-47.001 to B-47.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is Cl, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-48 provides 8 compounds B-48.001 to B-48.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is Cl, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-49 provides 8 compounds B-49.001 to B-49.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-50 provides 8 compounds B-50.001 to B-50.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-51 provides 8 compounds B-51.001 to B-51.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-52 provides 8 compounds B-52.001 to B-52.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-53 provides 8 compounds B-53.001 to B-53.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-54 provides 8 compounds B-54.001 to B-54.008 of formula I-B wherein Ax is C—CF3, S1 is CF3, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-55 provides 8 compounds B-55.001 to B-55.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is C1, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-56 provides 8 compounds B-56.001 to B-56.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is C1, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-57 provides 8 compounds B-57.001 to B-57.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is C1, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-58 provides 8 compounds B-58.001 to B-58.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-59 provides 8 compounds B-59.001 to B-59.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-60 provides 8 compounds B-60.001 to B-60.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-61 provides 8 compounds B-61.001 to B-61.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-62 provides 8 compounds B-62.001 to B-62.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is CFs, W is CH2, R3 is CHs and Q are as defined in table Z.
Table B-63 provides 8 compounds B-63.001 to B-63.008 of formula I-B wherein Ax is N, S1 is Cl, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-64 provides 8 compounds B-64.001 to B-64.008 of formula I-B wherein Ax is N, S1 is Br, S2 is C1, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-65 provides 8 compounds B-65.001 to B-65.008 of formula I-B wherein Ax is N, S1 is Br, S2 is C1, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-66 provides 8 compounds B-66.001 to B-66.008 of formula I-B wherein Ax is N, S1 is Br, S2 is C1, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-67 provides 8 compounds B-67.001 to B-67.008 of formula I-B wherein Ax is N, S1 is Br, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-68 provides 8 compounds B-68.001 to B-68.008 of formula I-B wherein Ax is N, S1 is Br, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-69 provides 8 compounds B-69.001 to B-69.008 of formula I-B wherein Ax is N, S1 is Br, S2 is Br, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-70 provides 8 compounds B-70.001 to B-70.008 of formula I-B wherein Ax is N, S1 is Br, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-71 provides 8 compounds B-71.001 to B-71.008 of formula I-B wherein Ax is N, S1 is Br, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-72 provides 8 compounds B-72.001 to B-72.008 of formula I-B wherein Ax is N, S1 is Br, S2 is CF3, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-73 provides 8 compounds B-73.001 to B-73.008 of formula I-B wherein Ax is N, S1 is CF3, S2 is C1, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-74 provides 8 compounds B-74.001 to B-74.008 of formula I-B wherein Ax is N, S1 is CF3, S2 is C1, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-75 provides 8 compounds B-75.001 to B-75.008 of formula I-B wherein Ax is N, S1 is CF3, S2 is C1, W is O, R3 is CH3 and Q are as defined in table Z.
Table B-76 provides 8 compounds B-76.001 to B-76.008 of formula I-B wherein Ax is N, S1 is CF3, S2 is Br, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-77 provides 8 compounds B-77.001 to B-77.008 of formula I-B wherein Ax is N, S1 is CF3, S2 is Br, W is CH2, R3 is CH3 and Q are as defined in table Z.
Table B-78 provides 8 compounds B-78.001 to B-78.008 of formula I-B wherein Ax is N, S1 is CF3, S2 is Br, W is O, R3 is CHs and Q are as defined in table Z.
Table B-79 provides 8 compounds B-79.001 to B-79.008 of formula I-B wherein AX is N, S1 is CF3, S2 is CF3, W is a direct bond, R3 is CH3 and Q are as defined in table Z.
Table B-80 provides 8 compounds B-80.001 to B-80.008 of formula I-B wherein AX is N, S1 is CF3, S2 is CF3, W is CH2, R3 is CH3 and Q are as defined in table Z. Table B-81 provides 8 compounds B-81.001 to B-81.008 of formula I-B wherein AX is N, S1 is CF3, S2 is CF3, W is 0, R3 is CH3 and Q are as defined in table Z.
In Tables A-i to A-243 and Tables B-i to B-8i, S1 and S2 do not represent a sulphur atom.
The compounds of formula I according to the following Table X 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.
Also made available are certain intermediate compounds of formulae Ill, IV, VII, XIII, and XVI, some of which are novel.
For example,
In further aspect, the present invention accordingly makes available compounds of formulae III, IV, VII, XIII, and XVI, wherein in each case, as applicable, X is sulfur or oxygen, R1a, R1b, R3, Q and T 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 III, IV, VII, XIII, and XVI.
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 potatos) 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 Cry1Fa2 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 for 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 storerooms 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, camellids, 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, or to 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:
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-243, Tables B-1 to B-81, Table X and Table P, preferably in Table X and Table P”) 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 Table X and Table P”) 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-243, Tables B-1 to B-81, Table X and Table P, preferably from Table X and Table P”) 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-243, Tables B-1 to B-81, Table X and Table P, preferably from Table X and Table P, 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 Tables A-1 to A-243, Tables B-1 to B-81, Table X and Table P, preferably from Table X and Table P is suitable for controlling Mamestra (preferably in vegetables), Cydia pomonella (preferably in apples), Empoasca (preferably in vegetables, vineyards), Leptinotarsa (preferably in potatos) 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 l/ha, especially from 10 to 1000 l/ha.
Preferred formulations can have the following compositions (weight %):
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 required dilution, which can be used 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.
The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.
Throughout this description, temperatures are given in degrees Celsius (° C.). 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.
LC/MS apparatus and methods are:
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 41 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 500° C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 1000 l/h, Mass range: 110 to 800 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 40° C., PDA Wavelength range (nm): 200 to 400, Solvent Gradient: A=water+5% Acetonitrile+0.1% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.3 min; Flow (ml/min) 0.6.
Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions, Capillary: 3.00 kV, Cone range: 30 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 50 l/h, Desolvation Gas Flow: 650 l/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 1.2 min; Flow (ml/min) 0.85.
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 x 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.
Spectra were recorded on a 6410 Triple Quadruple Mass Spectrometer from Agilent Technologies; (Agilent 1200 Series HPLC) equipped with an electrospray source (Polarity: Positive and Negative Polarity Switch, Scan Type: MS2 Scan, Capillary (kV): 4.00, Fragmentor (V): 100.00, Gas Temperature (° C.): 350, Gas Flow (L/min): 11, Nebulizer Gas (psi): 45, Mass range: 110 to 1000 Da, DAD Wavelength range: 210 to 400 nm). Column: KINETEX EVO C18, Column length: 50 mm, Internal diameter of column: 4.6 mm, Particle Size: 2.6 p, Column oven temperature: 40° C., Optimized Chromatographic Parameter: Gradient conditions: Solvent A: Water with 0.1% formic acid:Acetonitrile: 95:5 v/v; Solvent B: Acetonitrile with 0.1% formic acid; gradient: 10-100% B in 2.5 min; Flow (ml/min) 1.8.
Spectra were recorded on a Mass Spectrometer from Waters Corporation (QDA Single quadrupole mass spectrometer)), equipped with an electrospray source (Polarity: positive and negative ions), Detector Gain 1, Temperature Sample: 500° C., Cone Voltage: 10V, ESI Capillary Positive Voltage 0.8-Negative Voltage 0.8, Sampling Frequency 5 Hz, Mass range: 100 to 850 Da Source Temperature: 120° C., Desolvation Temperature: 600° C., Cone Gas Flow: 150 l/h, Desolvation Gas Flow: 1000 l/h, and an UPC2 from Waters Corporation: Binary solvent manager, heated column compartment, Sample manager, Isocratic solvent manager, convergence manager, diode-array detector, DAD Wavelength range (nm): 200 to 500, backpressure 1800 psi. Column: Daicel SFC CHIRALPAK® IC, 3 μm, 0.3 cm×10 cm, Temp: 40° C., Runtime: 4.8 min; Flow (ml/min) 2.0; Solvents: A=CO2, B=Methanol+0.1% NH4OH (30% in H2O); Gradient: 15% B isocratic for 4.8 min, then 100% A.
Spectra were recorded on a Mass Spectrometer from Waters Corporation (QDA Single quadrupole mass spectrometer)), equipped with an electrospray source (Polarity: positive and negative ions), Detector Gain 1, Probe Temperature: 350° C., Cone Voltage: 10V, ESI Capillary Positive Voltage 0.8-Negative Voltage 0.8, Sampling Frequency 5 Hz, Mass range: 100 to 850 Da Source Temperature: 120° C., Desolvation Temperature: 600° C., Cone Gas Flow: 150 l/h, Desolvation Gas Flow: 1000 l/h, and an UPC2 from Waters Corporation: Binary solvent manager, heated column compartment, Sample manager, Isocratic solvent manager, convergence manager, diode-array detector, DAD Wavelength range (nm): 200 to 500, backpressure 1800 psi. Column: Waters Torus™ 1-AA column, 1.7 μm, 3 mm×100 mm, Temp: 40° C., Runtime: 4.8 min; Flow (ml/min) 2.0; Solvents: A=CO2, B=Methanol; Gradient: 5% B isocratic for 4.8 min.
To a 2-neck RBF, equipped with a nitrogen inlet and condenser, charged 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethylammonium; 2,2,2-trifluoroacetate (1.5 g, 4.93 mmol) in acetonitrile (20 mL/g) then added Triethylamine (12.32 mmol, 1.26 g) at room temperature. Further phenyl chloroformate (7.39 mmol, 1.21 g) was added slowly. The reaction was heated and stirred at 80° C. for 2 hours under nitrogen atmosphere. Reaction mixture was cooled to room temperature, quenched with water, extracted with ethyl acetate twice. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get brown gummy mass (1.96 g, crude). The crude was purified by silica gel column chromatography using 50% ethyl acetate in cyclohexane and concentrated under reduced pressure to give phenyl N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]carbamate (1-1, 1.15 g) as white solid.
LC-MS (method 1): retention time 0.93 min, m/z 311.50 [M+H]+
1H NMR (400 MHz, chloroform-d) δ ppm 8.84-8.92 (m, 2H) 7.99-8.12 (m, 1H) 7.30-7.41 (m, 3H) 7.10 (d, J=7.83 Hz, 1H) 6.96-7.21 (m, 2H) 6.33 (br d, J=8.56 Hz, 1H) 6.09-6.19 (m, 1H) 1.63-1.72 (m, 3H)
In a clean and dry 25 ml RBF, charged phenyl N-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]carbamate (0.2 g, 0.644 mmol) and 2,4-bis(trifluoromethyl)aniline (3.223 mmol, 0.761 g) in triethylamine (20 mL/g, 28.7 mmol) at room temperature. Then reaction mass was heated and stirred at 120° C. for 2 h. The reaction was cooled to room temperature, solid precipitate out, diluted with pentane and filtered through Buchner funnel to crude which was purified by using C18 column and acetonitrile and water as eluent. The desired compound was eluted at 25% MeCN:H2O, which was lyophilized to give 1-[2,4-bis(trifluoromethyl)phenyl]-3-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]urea (180 mg) as white solid.
LC-MS (method 1): retention time 1.03 min, m/z 446.4 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (d, 2H) 8.19-8.28 (m, 3H) 8.03-8.19 (m, 1H) 7.85-7.92 (m, 2H) 7.67 (t, 1H) 5.81 (t, 1H) 1.54 (d, 3H)
M.P.: 189-191° C.
Alternatively, 1-[2,4-bis(trifluoromethyl)phenyl]-3-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]-urea (P1) can be prepared according to the following procedure:
To a solution of triphosgene (0.026 g, 0.09 mmol) in ethyl acetate (2 mL) at 0° C. was added 2,4-bis(trifluoromethyl)aniline (0.05 g, 0.22 mmol) and triethyl amine (0.06 g, 0.55 mmol). The resulting suspension was stirred for 45 min at 0° C. and then a solution of 1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethylammonium; 2,2,2-trifluoroacetate (0.07 g, 0.22 mmol) and triethyl amine (0.05 g, 0.45 mmol) in ethyl acetate (1 mL) was added. The resulting mixture was gradually warmed to room temperature and stirred for 18 h at this temperature. The reaction mixture was the partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtrated and concentrated under reduced pressure. The residue was purified as described in example P1, step B, to afford 1-[2,4-bis(trifluoromethyl)phenyl]-3-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]urea as white solid.
1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (200 mg, 1.05 mmol) was dissolved in tetrahydrofuran (3.5 mL/mmol) under Nitrogen at RT, then 1-isocyanato-3,5-bis(trifluoromethyl)benzene (1 equiv., 1.05 mmol) was added slowly followed by N,N-diethylethanamine (1 equiv., 1.0515 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water/brine and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed twice with water. The organic layer was dried, filtered and evaporated, to get 1-[3,5-bis(trifluoromethyl)phenyl]-3-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl) ethyl]urea (250 mg, 53%) as off white solid.
LC-MS (method 1): retention time 0.99 min, m/z 446.15 [M+H]+
1H NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1H) 9.02 (d, 2H) 8.20 (s, 1H) 7.98 (s, 2H) 7.67 (t, 1H) 7.56 (s, 1H) 7.22 (d, 1H) 5.82 (s, 1H) 1.52 (d, 3H)
M.P.: 124-127° C.
1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethanamine (100 mg, 0.525 mmol) was dissolved in tetrahydrofuran (3.5 mL/mmol) under argon at RT, then 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene (1 equiv., 0.525 mmol) was added slowly, followed by N,N-diethylethanamine (1 equiv., 0.525 mmol) and stirred at RT for 15 h. The reaction mixture was diluted with water/brine. The aqueous layer was extracted twice with EtOAc. The combined organic layers were washed twice with water. The organic layer was dried, filtered and evaporated to get 1-[3,5-bis(trifluoromethyl)phenyl]-3-[1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]thiourea (177 mg, 72%) as off white solid.
LC-MS (method 1): retention time 1.02 min, m/z 460.16 [M−H]+
1H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (br s, 1H) 9.03 (d, 2H) 8.84-8.98 (m, 1H) 8.21 (d, 3H) 7.74 (s, 1H) 7.66 (t, 1H) 6.33 (br d, 1H) 1.62 (d, 3H)
Under argon atmosphere, to a solution of triphosgene (0.151 g, 0.509 mmol, 0.5 equiv.) in acetonitrile (5 mL) cooled at 0° C. was added 4-chloro-6-(trifluoromethyl)pyridin-3-amine (0.20 g, 1.017 mmol, 1.0 equiv.) in acetonitrile (5 mL) and triethylamine (0.358 mL, 2.54 mmol, 2.5 equiv.). The reaction was stirred at 0° C. for 45 minutes. Then, a solution of [(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]ammonium; 2,2,2-trifluoroacetate (0.309 g, 1.017 mmol, 1.0 equiv.) and triethylamine (0.358 mL, 2.54 mmol, 2.5 equiv.) in acetonitrile (5 mL) was added to the reaction mixture at 0° C. and the solution was stirred at room temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was precipitated in diisopropylether, the resulting off-white solid was filtered and washed three times with diisopropylether to afford the desired compound, 1-[4-chloro-6-(trifluoromethyl)-3-pyridyl]-3-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]urea, as an off white solid.
LC-MS (method 2): retention time 0.82 min, m/z 413 [M+H+].
1H NMR (400 MHz, chloroform-d) δ ppm 9.54 (s, 1H) 8.96 (d, J=4.72 Hz, 2H) 8.18 (s, 1H) 8.08 (brd, J=9.08 Hz, 1H) 7.42-7.49 (m, 3H) 6.30-6.38 (m, 1H) 1.15 (d, J=6.18 Hz, 3H).
19F NMR (377 MHz, chloroform-d) δ ppm −67.51 (s, 3F).
M.P.: 191-193° C.
Under argon atmosphere. to a solution of 2,4-dichloro-5-nitrophenol (5.0 g, 24 mmol, 1.0 equiv.) in N,N-dimethylformamide (50 mL) was added portion wise potassium carbonate (11.0 g, 82 mmol, 3.5 equiv.). The reaction mixture was heated to 70° C. and stirred overnight at this temperature. The solution was quenched with water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 1,5-dichloro-2-nitro-4-(1,1,2,2-tetrafluoroethoxy)benzene as an orange oil.
LC-MS (method 2): retention time 1.22 min.
1H NMR (400 MHz, Chloroform-d) δ ppm 7.98 (s, 1H) 7.75 (s, 1H) 5.88-6.19 (m, 1H)
19F NMR (377 MHz, Chloroform-d) δ ppm −88.09 (s, 1F) −136.49 (s, 1F)
Under argon atmosphere, to a solution of 1,5-dichloro-2-nitro-4-(1,1,2,2-tetrafluoroethoxy)benzene (1.53 g, 4.97 mmol, 1.0 equiv.) in methanol (20 mL) was added palladium (0.265 g, 0.249 mmol, 0.05 equiv.). The reaction mixture was let under hydrogen atmosphere (3bar) for 2 hours at room temperature. Then, the mixture was diluted with methanol, filtered under argon atmosphere through a pad of Hyflo. The filtrate was concentrated under reduced pressure and the crude was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)aniline, as a yellow oil.
LC-MS (method 2): retention time 1.06 min, m/z 278 [M+H+].
1H NMR (400 MHz, Chloroform-d) δ ppm 7.36 (s, 1H) 6.77-6.80 (m, 1H) 5.81-6.12 (m, 1H) 4.18 (br d, J=8.72 Hz, 2H).
19F NMR (377 MHz, chloroform-d) δ ppm −88.33 (s, 2F) −136.53 (s, 2F).
Under argon atmosphere, to a solution of triphosgene (0.133 g, 0.45 mmol, 0.5 equiv.) in acetonitrile (4 mL) cooled at 0° C. was added 2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)aniline (0.25 g, 0.899 mmol, 1.0 equiv.) in acetonitrile (2 mL) and triethylamine (0.313 mL, 2.25 mmol, 2.5 equiv.). The reaction was stirred at 0° C. for 45 minutes. Then, a solution [(1S)-2-methoxy-1-methyl-2-oxo-ethyl]ammonium; chloride (0.126 g, 0.90 mmol, 1.0 equiv.) and triethylamine (0.314 mL, 2.25 mmol, 2.5 equiv.) in acetonitrile (3 mL) was added to the reaction mixture at 0° C. and the solution was stirred at room temperature overnight. The reaction was quenched with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, methyl (2S)-2-[[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl] carbamoylamino]propanoate, as a white solid.
LC-MS (method 2): retention time 1.04 min, m/z 407 [M+H+].
1H NMR (400 MHz, Chloroform-d) δ ppm 8.38 (s, 1H) 7.42 (s, 1H) 6.96 (s, 1H) 5.82-6.11 (m, 1H) 5.74 (br d, J=7.63 Hz, 1H) 4.61 (quin, J=7.27 Hz, 1H) 3.83 (s, 3H) 1.49 (d, J=7.27 Hz, 3H).
19F NMR (377 MHz, Chloroform-d) δ ppm −88.32 (s, 2F) −136.56 (s, 2F).
To a solution of methyl (2S)-2-[[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]carbamoylamino]propanoate (0.100 g, 0.246 mmol, 1.0 equiv.) and 1,2-dibromoethane (0.064 mL, 0.737 mmol, 3.0 equiv.) in tetrahydrofuran (1.23 mL) was slowly added sodium hydride (60 mass %, 0.025 g, 0.614 mmol, 2.5 equiv.) at 0° C. The reaction was stirred at 0° C. for 20 minutes, then it was allowed to warm to room temperature. The reaction was quenched with water and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate/ethanol (3:1) in cyclohexane) to afford the desired compound, methyl (2S)-2-[3-[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-oxo-imidazolidin-1-yl]propanoate, as a beige solid.
LC-MS (method 2): retention time 1.05 min, m/z 433 [M+H+].
A solution of methyl (2S)-2-[3-[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-oxo-imidazolidin-1-yl]propanoate (0.102 g, 0.235 mmol, 1.0 equiv.) in ammonia (7M in methanol, 0.47 mL, 3.3 mmol, 14 equiv.) was heated in microwave at 50° C. overnight. The reaction was concentrated under reduced pressure to afford the desired compound, (2S)-2-[3-[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-oxo-imidazolidin-1-yl]propenamide, as an off-white solid.
LC-MS (method 2): retention time 0.91 min. m/z 418 [M+H+].
Under argon atmosphere, to a solution of (2S)-2-[3-[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-2-oxo-imidazolidin-1-yl]propenamide (preparation described in example 3 step B) (0.103 g, 0.246 mmol, 1.0 equiv.) in dichloromethane (2.46 mL) was added N,N-dimethylformamide dimethyl acetal (0.066 mL, 0.493 mmol, 2.0 equiv.). The reaction mixture was stirred at 50° C. for 30 minutes, then concentrated under reduced pressure. The residue was dissolved in dioxane (1 mL) and pyrimidin-2-ylhydrazine (0.054 g, 0.495 mmol, 2.0 equiv.) and acetic acid (0.618 mL, 10.8 mmol, 43.6 equiv.) were added to the solution. The reaction mixture was stirred at 80° C. for 1 hour. The reaction mixture was quenched with sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate, the combined organic layers were washed twice with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography (ethyl acetate in cyclohexane) to afford the desired compound, 1-[2,4-dichloro-5-(1,1,2,2-tetrafluoroethoxy)phenyl]-3-[(1S)-1-(2-pyrimidin-2-yl-1,2,4-triazol-3-yl)ethyl]imidazolidin-2-one, as a white solid.
LC-MS (method 1): retention time 0.98 min, m/z 520 [M+H+].
1H NMR (400 MHz, Chloroform-d) δ ppm 8.48-8.58 (m, 2H) 7.89-7.98 (m, 1H) 7.55-7.61 (m, 1H) 6.84-6.92 (m, 1H) 5.83-6.18 (m, 2H) 3.46-3.55 (m, 1H) 1.89-1.99 (m, 3H) 1.54-1.57 (m, 3H) 1.20-1.27 (m, 1H)
M.P.: 207-209° C.
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 substance are preferred (the abbreviation “TX” means “one compound selected from the compounds defined in Tables A-1 to A-243, Tables B-1 to B-81, Table X and Table P, preferably in Table X and Table P”):
Plant extracts including: pine oil (Retenol®)+TX, azadirachtin (Plasma Neem Oil®+TX, AzaGuard®+TX, MeemAzal®+TX, Molt-X®+TX, Botanical IGR (Neemazad®+TX, Neemix®)+TX, canola oil (Lilly Miller Vegol®)+TX, Chenopodium ambrosioides near ambrosioides (Requiem®)+TX, Chrysanthemum extract (Crisant®)+TX, extract of neem oil (Trilogy®)+TX, essentials oils of Labiatae (Botania®)+TX, extracts of clove rosemary peppermint and thyme oil (Garden insect Killer®)+TX, Glycinebetaine (Greenstim®)+TX, garlic+TX, lemongrass oil (GreenMatch®)+TX, neem oil+TX, Nepeta cataria (Catnip oil)+TX, Nepeta catarina+TX, nicotine+TX, oregano oil (MossBuster®)+TX, Pedaliaceae oil (Nematon®)+TX, pyrethrum+TX, Quillaja saponaria (NemaQ®)+TX, Reynoutria sachalinensis (Regalia®+TX, Sakalia®)+TX, rotenone (Eco Roten®)+TX, Rutaceae plant extract (Soleo®)+TX, soybean oil (Ortho Ecosense®)+TX, tea tree oil (Timorex Gold®)+TX, thymus oil+TX, AGNIQUE® MMF+TX, BugOil®+TX, mixture of rosemary sesame pepermint thyme and cinnamon extracts (EF 300®)+TX, mixture of clove rosemary and peppermint extract (EF 400®)+TX, mixture of clove peppermint garlic oil and mint (Soil Shot®)+TX, kaolin (Screen®)+TX, storage glucam of brown algae (Laminarin®); pheromones including: blackheaded fireworm pheromone (3M Sprayable Blackheaded Fireworm Pheromone®)+TX, Codling Moth Pheromone (Paramount dispenser-(CM)/Isomate C-Plus®)+TX, Grape Berry Moth Pheromone (3M MEC-GBM Sprayable Pheromone®)+TX, Leafroller pheromone (3M MEC-LR Sprayable Pheromone®)+TX, Muscamone (Snip7 Fly Bait®+TX, Starbar Premium Fly Bait®)+TX, Oriental Fruit Moth Pheromone (3M oriental fruit moth sprayable Pheromone®)+TX, Peachtree Borer Pheromone (Isomate-P®)+TX, Tomato Pinworm Pheromone (3M Sprayable Pheromone®)+TX, Entostat powder (extract from palm tree) (Exosex CM®)+TX, (E+TX,Z+TX,Z)-3+TX,8+TX, 11 Tetradecatrienyl acetate+TX, (Z+TX,Z+TX,E)-7+TX,11+TX,13-Hexadecatrienal+TX, (E+TX,Z)-7+TX, 9-Dodecadien-1-yl acetate+TX, 2-Methyl-1-butanol+TX, Calcium acetate+TX, Scenturion®+TX, Biolure®+TX, Check-Mate®+TX, Lavandulyl senecioate,
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-243, Tables B-1 to B-81, Table X and Table P with active ingredients described above comprises a compound selected from one compound defined in the Tables A-1 to A-243, Tables B-1 to B-81, Table X and Table P, preferably defined in Tables X and Table P, 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 to 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-243, Tables B-1 to B-81, Table X and Table P 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 1.
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, Iaa, and Iab.
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: P1, P4, P5, P6, P7, P9, P10, P13, P14, P15, P25, P30, P35, P43, P45, P46, P48, P50, P51, P55, P58, P70, P72, P76, P79, P103, P106, P107, P114, P116, P118, P127, P128, P129, P130, P131, P132, P133, P135, P136, P137, P138, P140, P170, P172, P173, P176, P177, P178, P181, P182, P192, P200, P202, P205, P210, P212, P214, P215, P217, P219, P220, P221, P223, P235, P236, P237, P238, P240, P241, P242, P243, P244, P245, P247, P248, P249, P250, P251, P253, P255, P256, P257, P258, P260, P261, P263, P264, P265, P270, P271, P272, P273, P274, P275, P276, P277, P278, P279, P280, P294, P295, P296, P297, P299, P300, P303, P311, P314, P316, P318, P322, P323, P328, P332, P339, P342, P343, P344, P348, P350, P351, P355, P360, P367, P370, P371, P373, P376, P378, P379, P380, P383, P385, P388, P390, P391, P393, P395, P396, P397.
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:
Soybean leaves on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10,000 ppm DMSO stock solutions. After drying the leaves were infested with N2 nymphs. The samples were assessed for mortality and growth inhibition in comparison to untreated samples 5 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:
Sunflower leaf discs were placed on agar in 24-well microtiter plates and sprayed with aqueous test solutions prepared from 10,000 DMSO stock solutions. After drying the leaf discs were infested with a Frankliniella population of mixed ages. The samples were assessed for mortality 7 days after infestation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm:
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:
Roots of pea seedlings infested with an aphid population of mixed ages were placed directly into aqueous test solutions prepared from 10,000 DMSO stock solutions. The samples were assessed for mortality 6 days after placing seedlings into test solutions.
The following compounds resulted in at least 80% mortality at a test rate of 24 ppm:
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 gave an effect of at least 80% control at an application rate of 12.5 ppm:
P1, P5, P6, P18, P30, P35, P46, P48, P55, P57, P58, P72, P79, P99, P103, P122, P127, P130, P132, P133, P135, P137, P138, P172, P176, P177, P178, P179, P181, P182, P202, P205, P210, P214, P215, P219, P221, P231, P235, P236, P238, P241, P244, P250, P257, P269, P272, P273, P274, P276, P277, P278, P280, P304, P315, P316, P328, P332, P348, P355, P360, P380, P390, P391, P397.
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% in at least one of the two categories (mortality or growth inhibition) at an application rate of 200 ppm:
P1, P4, P5, P6, P7, P9, P10, P11, P12, P13, P14, P25, P26, P33, P35, P43, P46, P48, P50, P51, P55, P57, P58, P70, P72, P76, P79, P103, P107, P114, P118, P127, P128, P129, P130, P132, P133, P135, P136, P137, P138, P140, P161, P170, P171, P172, P173, P175, P176, P177, P178, P182, P191, P200, P202, P203, P205, P209, P210, P211, P214, P215, P217, P219, P220, P221, P223, P228, P229, P231, P235, P236, P237, P238, P240, P241, P243, P244, P245, P247, P248, P249, P250, P251, P253, P254, P255, P256, P257, P258, P259, P260, P261, P263, P264, P265, P270, P271, P272, P273, P274, P275, P276, P277, P278, P279, P280, P288, P290, P299, P300, P304, P305, P314, P316, P351, P367, P368, P369, P376, P380, P388, P390, P395, P396, P397.
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:
P1, P3, P4, P5, P6, P7, P11, P13, P14, P15, P18, P26, P35, P43, P46, P48, P55, P57, P58, P70, P72, P76, P79, P95, P102, P103, P114, P118, P127, P129, P130, P131, P132, P133, P135, P137, P140, P172, P173, P176, P177, P178, P182, P191, P197, P202, P203, P205, P209, P214, P215, P219, P223, P236, P237, P238, P240, P241, P242, P243, P244, P246, P247, P248, P249, P250, P251, P253, P254, P255, P256, P257, P261, P262, P263, P264, P265, P269, P271, P272, P273, P276, P277, P278, P279, P280, P300, P314, P316, P332, P343, P348, P350, P351, P360, P367, P369, P370, P373, P380, P383, P387, P388, P390, P395, P396.
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 also contained 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:
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.
The following compounds resulted in at least 80% mortality at an application rate of 50 ppm:
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.
The following compounds gave an effect of at least 80% average mortality at an application rate of 500 ppm:
Bean leaf discs on agar in 24-well microtiter plates were sprayed with aqueous test solutions prepared from 10,000 ppm DMSO stock solutions. After drying the leaf discs were infested with a mite population of mixed ages. The samples were assessed for mortality on mixed population (mobile stages) 8 days after infestation.
The following compounds resulted in at least 80% mortality at an application rate of 200 ppm:
Abbreviations used in synthesis schemes and preparatory examples
| Number | Date | Country | Kind |
|---|---|---|---|
| 202111003249 | Jan 2021 | IN | national |
| 202111017068 | Apr 2021 | IN | national |
| 202111053250 | Nov 2021 | IN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/051111 | 1/19/2022 | WO |
