专利汇可以提供Use of 4-aza indole derivatives for the reduction of mycotoxin contamination专利检索,专利查询,专利分析的服务。并且The present invention relates to a method of the reduction of mycotoxin contamination of plants and/or plant material and/or plant propagation material comprising applying to the plant or plant propagation material a effective amount of a compound of formula (I)
or a salt of N-oxide thereof. In addition, the present invention also relates to a composition comprising a compound of formula (I) and their use in methods for the reduction of mycotoxin contamination in plants.,下面是Use of 4-aza indole derivatives for the reduction of mycotoxin contamination专利的具体信息内容。
The present invention relates to the novel use of 4-aza-indoles, compositions comprising these compounds and their use in methods for the reduction of mycotoxin contamination in plants.
Certain 4-aza-indoles and their use in the prevention and treatment of human and animal disease, although not that caused by fungi, are described in
Numerous fungi are serious pests of economically important agricultural crops. Further, crop contamination by fungal toxins is a major problem for agriculture throughout the world.
Mycotoxins, such as aflatoxins, ochratoxins, patulin, fumonisins, zearalenones, and trichothecenes, are toxic fungal metabolites, often found in agricultural products that are characterized by their ability to cause health problems for humans and vertebrates. They are produced for example by different Fusarium and Aspergillus, Penicillium und Alternaria species.
Aflatoxins are toxins produced by Aspergillus species that grow on several crops, in particular on maize or corn before and after harvest of the crop as well as during storage. The biosynthesis of aflatoxins involves a complex polyketide pathway starting with acetate and malonate. One important intermediate is sterigmatocystin and O-methylsterigmatocystin which are direct precursors of aflatoxins. Important producers of aflatoxins are Aspergillus flavus, most strains of Aspergillus parasiticus, Aspergillus nomius, Aspergillus bombycis, Aspergillus pseudotamarii, Aspergillus ochraceoroseus, Aspergillus rambelli, Emericella astellata, Emericella venezuelensis, Bipolaris spp., Chaetomium spp., Farrowia spp., and Monocillium spp., in particular Aspergillus flavus and Aspergillus parasiticus (
Ochratoxins are mycotoxins produced by some Aspergillus species and Penicilium species, like A. ochraceus, A. carbonarius or P. viridicatum, Examples for Ochratoxins are ochratoxin A, B, and C. Ochratoxin A is the most prevalent and relevant fungal toxin of this group.
Fumonisins are toxins produced by Fusarium species that grow on several crops, mainly corn, before and after harvest of the crop as well as during storage. The diseases, Fusarium kernel, ear and stalk rot of corn, is caused by Fusarium verticillioides, F. subglutinans, F. moniliforme, and F. proliferatum. The main mycotoxins of these species are the fumonisins, of which more than ten chemical forms have been isolated. Examples for fumonisins are FB1, FB2 and FB3. In addition the above mentioned Fusarium species of corn can also produce the mycotoxins moniliformin and beauvericin. In particular Fusarium verticillioides is mentioned as an important pathogen of corn, this Fusarium species produces as the main mycotoxin fumonisins of the B-type.
Trichothecenes are those mycotoxins of primary concern which can be found in Fusarium diseases of small grain cereals like wheat, barley, rye, triticale, rice, sorghum and oat. They are sesquiterpene epoxide mycotoxins produced by species of Fusarium, Trichothecium, and Myrothecium and act as potent inhibitors of eukaryotic protein synthesis.
Some of these trichothecene producing Fusarium species also infect corn or maize.
Examples of trichothecene mycotoxins include T-2 toxin, HT-2 toxin, isotrichodermol, DAS, 3-deacetylcalonectrin, 3,15-dideacetylcalonectrin, scirpentriol, neosolaniol; 15-acetyldeoxynivalenol, 3-acetyldeoxynivalenol, nivalenol, 4-acetylnivalenol (fusarenone-X), 4,15-diacetylnivalenol, 4,7,15-acetylnivalenol, and deoxynivalenol (hereinafter "DON") and their various acetylated derivatives. The most common trichothecene in Fusarium head blight is DON produced for example by Fusarium graminearum and F. culmorum.
Another mycotoxin mainly produced by F. culmorum, F. graminearum and F. cerealis is zearalenone, a phenolic resorcyclic acid lactone that is primarily an estrogenic fungal metabolite.
Fusarium species that produce mycotoxins, such as fumonisins and trichothecenes, include F. acuminatum, F. crookwellense, F., verticillioides, F. culmorum, F. avenaceum, F. equiseti, F. moniliforme, F, graminearum (Gibberella zeae), F. lateritium, F. poae, F. sambucinum (G. pulicaris), F. proliferatum, F. subglutinans, F. sporotrichioides and other Fusarium species.
In contrast the species Microdochium nivale also a member of the so-called Fusarium complex is known to not produce any mycotoxins.
Both acute and chronic mycotoxicoses in farm animals and in humans have been associated with consumption of wheat, rye, barley, oats, rice and maize contaminated with Fusarium species that produce trichothecene mycotoxins. Experiments with chemically pure trichothecenes at low dosage levels have reproduced many of the features observed in moldy grain toxicoses in animals, including anemia and immunosuppression, haemorrage, emesis and feed refusal. Historical and epidemiological data from human populations indicate an association between certain disease epidemics and consumption of grain infected with Fusarium species that produce trichothecenes. In particular, outbreaks of a fatal disease known as alimentary toxic aleukia, which has occurred in Russia since the nineteenth century, have been associated with consumption of over-wintered grains contaminated with Fusarium species that produce the trichothecene T-2 toxin. In Japan, outbreaks of a similar disease called akakabi-byo or red mold disease have been associated with grain infected with Fusarium species that produce the trichothecene, DON. Trichothecenes were detected in the toxic grain samples responsible for recent human disease outbreaks in India and Japan. There exists, therefore, a need for agricultural methods for preventing, and crops having reduced levels of, mycotoxin contamination.
Further, mycotoxin-producing Fusarium species are destructive pathogens and attack a wide range of plant species. The acute phytotoxicity of mycotoxins and their occurrence in plant tissues also suggests that these mycotoxins play a role in the pathogenesis of Fusarium on plants. This implies that mycotoxins play a role in disease and, therefore, reducing their toxicity to the plant may also prevent or reduce disease in the plant. Further, reduction in disease levels may have the additional benefit of reducing mycotoxin contamination on the plant and particularly in grain where the plant is a cereal plant.
There is a need, therefore, to decrease the contamination by mycotoxins of plants and plant material before and/or after harvest and/or during storage.
The effect of fungicides on mycotoxin contamination in crops is discussed controversially as contradicting results are found. Disease development and mycotoxin production by the infecting fungi is influenced by a variety of factors not being limited to weather conditions, agricultural techniques, fungicide dose and application, growth stage of crops, colonization of crops by different fungi species, susceptibility of host crops and infection mode of fungi species. For example Microdochium nivale not producing any mycotoxin is able to reduce growth and DON accumulation of F. culmorum. It is also known that the different fungi use separate routes when infecting the plant. For example Fusarium species producing fumonisins are known to infect maize by wound inoculation. The wounds are mainly caused by insects like the European and Southwestern corn borer or the corn earworm, in particular by the European corn borer (Ostrinia nubialis). Therefore it is discussed that maize being transformed with genes coding for insecticidal proteins for example with those from Bacillus thuringiensis should show reduced level of mycotoxins, in particular fumonisins (
Therefore prohibiting fungal infection via controlling insects that promote infection by wounding is not sufficient for reducing effectively mycotoxin contamination of maize, especially for DON, Zearalenone and aflatoxins.
It has also to be mentioned that breeding for fungal resistance in crops in contrast to insecticidal resistance is much more difficult. There have been several classical and transgenic breeding approaches, but obviously a high level of resistance is difficult to obtain.
Therefore the problem to be solved by the present invention is to provide compounds which lead by their application on plants and/or plant material to a reduction in mycotoxins in all plant and plant material.
Accordingly, the present invention provides a method of reducing mycotoxin contamination in plants and/or any plant material and/or plant propagation material comprising applying to the plant or plant propagation material an effective amount of a compound of formula (I):
wherein:
(iii) optionally substituted aryl, heteroaryl, cyclyl or heterocyclyl, or
(iv) -C(O)R10, -C(O)NR10R11, -C(S)NR10R11, -C(NOR10)R11, -C(O)OR10, -OR10, -SR10, -S(O)R10, -S(O)NR10R11, -S(O)2NR10R11, -S(O)2R10, -NR10R11, -P(O)(OR10XOR11) or -OP(O)(OR10XOR11);
and/or
independently, (i) R1 and R2, (ii) R1 and R3 (iii) R2 and R3, (iv) R3 and R5, (v) R5 and R6, (vi) R5 and R18, (vii) R5 and R19, (viii) R14 and R15 and (ix) R18 and R19 form an optionally substituted aryl, heteroaryl, cyclyl or heterocyclyl group containing from 5 to 18 ring atoms;
or a salt of N-oxide thereof. Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
"Alkenyl" means a linear monovalent saturated hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least one double bond, e.g. ethenyl, propenyl and the like. Where appropriate, an alkenyl group can be of either the (E)- or (Z)-configuration. Preferably, linear alkenyl groups contain two to six carbon atoms and more preferably are selected from ethenyl, prop- 1-enyl, prop-2-enyl, prop-1,2-dienyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,2-dienyl and but-1,3-dienyl. Preferably, branched alkenyl groups contain three to six carbon atoms and more preferably are selected from 1-methylethenyl, 1-methylprop-l-enyl, 1-methylprop-2- enyl, 2-methylprop-l-enyl and 2-methylprop-2-enyl.
"Allenyl" means a linear monovalent saturated hydrocarbon radical of three to eight carbon atoms, or a branched monovalent hydrocarbon radical of three to eight carbon atoms containing at least two double bonds between three contiguous carbon atoms, e.g. propa-1,2 dienyl, penta-1,2 dienyl, penta-2,3 dienyl, hexa-1,2-dienyl and the like. Where appropriate, an alkenyl group can be of either the (R)- or (S)-configuration. Preferred is propa-1,2- dienyl.
"Alkynyl" means a linear monovalent saturated hydrocarbon radical of two to eight carbon atoms, or a branched monovalent hydrocarbon radical of four to eight carbon atoms, containing at least one triple bond, e.g. ethynyl, propynyl and the like. Preferably, linear alkynyl groups contain two to six carbon atoms and more preferably are selected from ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl and but-3-ynyl. Preferably, branched alkynyl groups contain four to six carbon atoms and more preferably are selected from 1-methylprop-2-ynyl, 3-methylbut-1-ynyl, 1-methylbut-2-ynyl, 1-methylbut-3-ynyl and 1 -methylbut-3-ynyl.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical or three to six carbon atoms, e.g.
methylene, ethylene, propylene, 2-methylpropylene and the like. Preferred alkylene groups are the divalent radicals of the alkyl groups defined above.
"Alkenylene" means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g. ethenylene, propenylene and the like. Preferred alkenylene groups are the divalent radicals of the alkenyl groups defined above.
"Cyclyl" means a monovalent cyclic hydrocarbon radical of three to eight ring carbons, preferably three to six ring carbons, e.g. cyclopropyl, cyclohexyl and the like.
Cyclyl groups may be fully saturated or mono- or di-unsaturated. Preferably, cyclyl groups contain three to six ring carbons, more preferably they are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Mono-unsaturated cyclyl groups are preferably selected from cyclobutenyl, cyclopentenyl and cyclohexenyl.
"Heterocyclyl" means a cyclyl radical containing one, two or three ring heteroatoms selected from N, O or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being carbon where one or two carbon atoms may optionally be replaced by a carbonyl group. Examples of such rings include, but are not limited to, oxirane, oxetane, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,4-dioxane, aziridine, azetidine, pyrrolidine, piperidine, oxazinane, morpholine, thiomorpholine, imidazolidine, pyrazolidine and piperazine. More preferably, the heterocyclyl group contains three to five ring atoms including one O and/or one N ring atom.
"Aryl" means a monovalent moncyclic or bicyclic aromatic hydrocarbon radical of six to ten ring carbons atoms. Suitable aryl groups include phenyl and naphthyl, in particular, phenyl.
"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of five to ten ring atoms, preferably five or six ring atoms, containing one, two, three or four ring heteroatoms selected, independently, from N, O or S, the remaining ring atoms being carbon. Examples of heteroaryl groups include, but are not limited to pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, thiophenyl, isoazolyl, and tetrazolyl groups.
"Alkoxy" means a radical -OR, where R is optionally substituted alkyl, alkenyl or alkynyl or an optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl group or an aralkyl or heteroaralkyl group. Preferably, alkoxy groups are selected from methoxy, ethoxy, 1 -methyl ethoxy, propoxy, 1-methylpropoxy and 2-methylpropoxy. More preferably alkoxy means methoxy or ethoxy.
"Halo" or "halogen" means fluoro, chloro, bromo or iodo, preferably chloro or fluoro.
"Haloalkyl" means alkyl as defined above substituted with one or more of the same or different halo atoms. Examples of haloalkyl groups include, but are not limited to fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-trifluoroethyl, 2-chloro-ethyl, 2-iodoethyl, 3-fluoropropyl, 3-chloropropyl, 2-trifluoro-l-chloroethyl and 1 -difluoro-2- difluoro-3-trifluoropropyl.
"Haloalkenyl" means alkenyl as defined above substituted with one or more of the same or different halo atoms. Examples of haloalkenyl groups include, but are not limited to 2-dibromoethenyl, 2-fluoro-2-bromoethenyl, 5-bromopent-3-enyl and 3 dichloroprop-2-enyl.
"Aralkyl" means a radical -RaRb where Ra is an alkylene or alkenylene group and Rb is an aryl group as defined above.
"Heteroaralkyl" means a radical -RaRb where Ra is an alkylene or alkenylene group and Rb is a heteroaryl group as defined above.
"Acyl" means -C(O)R, wherein R is hydrogen, optionally substituted alkyl, alkenyl or alkynyl or optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl.
"Acyloxy" means a radical -OC(O)R where R is hydrogen, optionally substituted alkyl, alkenyl or alkynyl or optionally substituted cyclyl, heterocyclyl, aryl or heteroaryl.
The groups defined above, in particular, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyl, aryl and heteroaryl groups, may be optionally substituted by one or more substituents independently selected from halogen, hydroxyl, cyano, alkyl (optionally substituted by
cyano), haloalkyl, alkenyl, haloalkenyl, alkynyl (optionally substituted by -C(O)OR), haloalkynyl, cyclyl (optionally substituted by cyano, halogen, hydroxyl or methyl), heterocyclyl, aryl (optionally substituted by halogen), heteroaryl, alkoxy (optionally substituted by alkoxy or acyl), -C(O)R, -C(O)OR, -SR, -S(O)R, -S(O)2R, -S(O)NRR', -OS(O)NRR', -P(O)(OR)(OR'), -0(P)(O)(OR)(OR'), -NRR', -NRC(O)OR', -C(O)NRR', -O-N=CRR' or trialkylsilyl, wherein R and R' are, independently, hydrogen or alkyl, alkoxy, haloalkyl, alkenyl, haloalkenyl, alkynyl, cyclyl, heterocyclyl, aryl or heteroaryl. In particular, R and R' are, independently, hydrogen or alkyl (in particular, methyl or ethyl). Preferred optional substituents are alkoxy (in particular, methoxy or ethoxy), hydroxyl, cyano, halogen (in particular, fluoro, chloro or bromo), heterocyclyl (in particular, oxirane or tetrahydrofuran), heteroaryl (in particular, pyridyl), -C(O)OR (wherein R is hydrogen or alkyl (in particular, methyl or ethyl)) and trialkylsilyl (in particular, trimethylsilyl).
The compounds of formula (I) may exist in different geometric or optical isomeric forms or in different tautomeric forms. One or more centres of chirality may be present, in which case compounds of the formula (I) may be present as pure enantiomers, mixtures of enantiomers, pure diastereomers or mixtures of diastereomers. There may be double bonds present in the molecule, such as C=C or C=N bonds, in which case compounds of formula (I) may exist as single isomers of mixtures of isomers. Centres of tautomerisation may be present. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.
Suitable salts of the compounds of formula (I) include acid addition salts such as those with an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic or phthalic acid, or a sulphonic acid such as methane, benzene or toluene sulphonic acid. Other examples of organic carboxylic acids include haloacids such as trifiuoroacetic acid.
N-oxides are oxidised forms of tertiary amines or oxidised forms of nitrogen containing heteroaromatic compounds. They are described in many books for example in "
In particularly preferred embodiments of the invention, the preferred groups for X1 and X2 and R1 to R25, in any combination thereof, are as set out below.
Preferably, X1 is CH.
Preferably, X2 is CR5. More preferably, X2 is CH.
Preferably, R1 is hydrogen, halogen, cyano, optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, optionally substituted aryl or -C(O)R10, wherein the optional substituents in all cases are as defined above and, more preferably, are selected from hydroxyl, alkoxy, halogen or trialkylsilyl. More preferably, R1 is hydrogen, halogen, cyano or optionally substituted C1-6 alkyl or C2-6 alkynyl (in particular, the C2-6 alkynyl is 2- trimethylsilyl-ethynyl). Even more preferably, R1 is hydrogen, chloro, bromo, cyano or methyl. Most preferably, R1 is hydrogen, chloro or methyl.
Preferably, R2 is hydrogen or C1-6 alkyl. More preferably, R2 is hydrogen or methyl. Most preferably, R2 is hydrogen.
Preferably, R3 is hydrogen, hydroxyl, -C(O)R12, -OR12, -C(O)OR12, -OC(O)R12, - S(O)2R12, optionally substituted C1-6 alkyl, C2-6 alkenyl, C3-6 allenyl, C2-6 alkynyl or optionally substituted saturated cyclyl, wherein the optional substitutents in all cases are as defined above and, more preferably, are selected from cyano, halogen, hydroxyl, C1-4 alkyl, C2-4 alkenyl, alkoxy (optionally substituted by alkoxy or acyl), cyclyl, heterocyclyl, aryl, heteroaryl, -NH2, trialkylsilyl, -C(O)R or -C(O)OR (wherein R is hydrogen, methyl or ethyl). More preferably, R3 is hydrogen, -OR12 or optionally substituted C1-6 alkyl, C2-4 alkenyl, C3-4 allenyl or C2-4 alkynyl. Most preferably, R3 is hydrogen, cyanomethyl, aminoethyl, aminopropyl, prop-2-enyl, prop-2-ynyl, propa-1,2-dienyl, methoxymethyl, 2-fluoromethyl, - OCH2C≡CH, -OCH2OCH3, -OCH2CN, -OCH(CH3)CN. Preferably, R4 is hydrogen, halogen, optionally substituted C2-6 alkynyl or optionally substituted aryl or heteroaryl, wherein the optional substituents are as defined above and, more preferably, are selected from hydroxyl, halogen (in particular, fluoro or chloro), haloalkyl, acyl or C1-4 alkyl (in particular, methyl). More preferably, R4 is optionally substituted phenyl or optionally substituted heteroaryl. Even more preferably, R4 is
optionally substituted phenyl. Even more preferably, R4 is phenyl, 3-methylphenyl, 3- trifluoromethylphenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5- difluorophenyl or 3 -methyl-4- fluorophenyl. Most preferably, R4 is phenyl or 4-fluorophenyl.
Preferably R5 is hydrogen, halogen, optionally substituted C1-6 alkyl, C2-6 alkenyl or
C2-6 alkynyl, or forms an optionally substituted aryl, heteraryl, cyclyl or hetercycyl ring with R6, wherein the optional substituents in all cases are as defined above and, more preferably, are selected from halogen, cyano, hydroxyl, haloalkyl or C1-4 alkyl. Preferably, the ring formed with R6 is a 5 or 6 membered heterocycle. More preferably, R5 is hydrogen or halogen. Most preferably, R5 is hydrogen.
Preferably R6 is hydrogen, chloro, -C(O)OR18, -NR18R19, -N=CR20 or forms an optionally substituted aryl, heteroaryl, cyclyl or heterocycyl ring with R5 as defined above. More preferably, R6 is hydrogen or -NR18R19. More preferably, R6 is -NHR19. More preferably, R6 is -NHC(O)R23.
Preferably R7 and R8 are, independently, hydrogen, hydroxyl, cyano, -NR21R22 or optionally substituted C1-6 alkyl, wherein the optional substituents are as defined above and, more preferably, are selected from halogen, cyano, hydroxyl or haloalkyl. More preferably, R7 and R8 are, independently hydrogen, hydroxyl or -NR21R22. Most preferably, R7 and R8 are both hydrogen.
Preferably, R10, R11, R14, R15, R16 and R17 are, independently, hydrogen or optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, wherein the optional substituents are as defined above and, more preferably, are hydroxyl, halogen, cyano or alkoxy. More preferably R10, R11, R14, R15, R16 and R17 are, independently, hydrogen or optionally substituted C1-3 alkyl. Most preferably, R10, R11, R14, R15, R16 and R17 are, independently, hydrogen, methyl or ethyl.
Preferably R12 and R13 are, independently, optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl or optionally substituted C3-6 cyclyl, wherein the optional substituents in all cases are as defined above and, more preferably are hydroxyl, halogen, cyano, alkoxy, cyclyl (optionally substituted with hydroxyl or methyl), -C(O)OR, -OS(O)NRR' (wherein R and R' are, independently, hydrogen, alkyl, alkenyl or alkynyl). More preferably, R12 and
R13 are, independently, optionally substituted C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl. Most preferably, R12 and R13 are, independently, cyanomethyl, prop-2-enyl or prop-2-ynyl.
Preferably R18 is hydrogen, optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, -C(O)R23, -C(O)OR23, -S(O)2R23 or -C(O)NR23R24 or forms an optionally substituted heterocyclyl ring with R19, wherein the optional substituents in all cases are as defined above and, more preferably are selected from hydroxyl, cyano, halogen or alkoxy. More preferably, R18 is hydrogen, C1-4 substituted alkyl, C2-4 alkenyl, or C2-4 alkynyl. Preferably the C1-4 alkyl group is ethyl or iso-propyl. Preferably, the C2-4 alkenyl group is propen-2-enyl. Preferably, the C2-4 alkynyl group is prop-2ynyl or but-2-ynyl. Most preferably, R18 is hydrogen.
Preferably R19 is hydrogen, -C(S)R23, -C(O)R23, -C(O)OR23, -S(O)2R23 or -C(O)NR23R24 optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, optionally substituted aryl, heteroaryl, cyclyl or heterocyclyl or forms an optionally substituted heterocyclyl ring with R18, wherein the optional substituents in all case are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen, alkoxy, cyclyl or heterocyclyl. More preferably, R19 is hydrogen, -C(S)R23, -C(O)R23 or -C(O)OR23 or optionally substituted C1-4 alkyl. Preferably, the optionally substituted C1-4 alkyl is iso-butyl. Most preferably, R19 is hydrogen, -C(O)R23 or -C(O)OR23.
Preferably, R20 is -NR21R22.
Preferably, R21 and R22 are, independently, hydrogen, optionally substituted C1-4 alkyl or -C(O)OR25, wherein the optional substituents are as defined above and, more preferably, are selected from hydroxyl, cyano, halogen, alkoxy, acyl, cyclyl or heterocyclyl. More preferably, R21 and R22 are, independently, hydrogen or optionally substituted C1-4 alkyl. Most preferably, R21 and R22 are, independently, hydrogen, methyl or ethyl.
Preferably R23 and R24 are, independently, hydrogen, hydroxyl, optionally substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl or optionally substituted cyclyl or aryl, wherein the optional substituents in all cases are as defined above and, more preferably, are hydroxyl, halogen, cyano, C1-4 alkyl, alkoxy, haloalkenyl, cyclyl or -C(O)OR (wherein R is cyclyl). Preferably, the aryl group is optionally substituted phenyl. More preferably, the aryl group is 3-halophenyl or 4-halophenyl. More preferably, R23 and R24 are, independently, hydrogen, optionally substituted C1-6 alkyl or C2-6 alkenyl or an optionally substituted saturated or mono-unsaturated cyclyl group. Even more preferably, R23 and R24 are, independently, optionally substituted C1-6 alkyl or an optionally substituted C3-6 saturated cyclyl group. Preferably the optionally substituted C1-6 alkyl is methyl, ethyl or iso-propyl. Preferably, the C3-6 saturated cyclyl group is a cyclopropyl or cyclobutyl group, which may be substituted with one or more substituents being selected from cyano, halogen (preferably fluoro), C1-4 alkyl (preferably methyl) or haloalkenyl.
Preferably, R25 is C1-4 alkyl. More preferably, R25 is methyl, ethyl, propyl or 2- dimethylethyl.
In a particularly preferred embodiment, when R3 is hydrogen, R6 is other than hydrogen. More preferably, R3 is hydrogen and R6 is -NR18R19. More preferably, R3 is hydrogen and R6 is -NHR19. More preferably, R3 is hydrogen and R6 is -NHC(O)R23.
In an alternative preferred embodiment, R6 is hydrogen and R3 is other than hydrogen. More preferably, R6 is hydrogen and R3 is -OR12 or optionally substituted C1-6 alkyl, C2-4 alkenyl, C3-4 allenyl or C2-4 alkynyl. Most preferably, R6 is hydrogen and R3 is cyanomethyl, aminoethyl, aminopropyl, prop-2-enyl, prop-2-ynyl, propa-1,2-dienyl, methoxymethyl, 2-fluoromethyl, -OCH2 C≡CH, -OCH2OCH3, -OCH2CN, -OCH(CH3)CN.
In a particular embodiment, the method of the invention utilises a compound of formula (Ia)
wherein R1, R2, R3, R4, R7 and R8 are as defined above and, preferably:
and R4 is optionally substituted aryl (in particular, phenyl or naphthyl), the optional substituents being as defined above and, more preferably halogen or C1-4 alkyl.
More preferably, R1 is hydrogen, halo or optionally substituted C1-4 alkyl, wherein the optional substituent is preferably hydroxyl; R10 is methyl or ethyl; R2, R7 and R8 are, independently, hydrogen, methyl, ethyl or chloro; R3 is hydrogen, -OR12 or optionally substituted C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl; and R4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and C1-4 alkyl (in particular, methyl).
Even more preferably, R1 is hydrogen, chloro or methyl; R2, R7 and R8 are each hydrogen; R3 is hydrogen, cyanomethyl, prop-2-enyl or prop-2-ynyl; and R4 is phenyl, 2- fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl or 3-methyl- 4-fluorophenyl and most preferably is 4-fluorophenyl.
In a particular embodiment, the method of the invention utilises a compound of formula (Ib):
wherein R1, R2, R3, R4, R6, R7 and R8 are as defined above and, preferably:
More preferably, R1 is hydrogen, halo or optionally substituted C1-4 alkyl; R2 is hydrogen or methyl; R3 is hydrogen, optionally substituted C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl or -OR12; R4 is phenyl, which is optionally substituted by at least one substituent selected from halogen and C1-4 alkyl; R6 is halogen or -NR18R19 and R18 is hydrogen, prop-2- enyl or prop-2-ynyl and R19 is -C(O)R23 and R23 is hydrogen, methyl, ethyl, iso-propyl, 1- methylethyl, 1 -methylpropyl, 2-dimethylethyl, propyl, 1-methylethenyl, 2-methylprop-1- enyl, but-3-enyl, cyclopropyl, 1-methylcyclopropyl, 1-fluorocyclopropyl or cyclobutyl; R7 is hydrogen, chloro, fluoro or methyl; and R8 is hydrogen, chloro, methyl or 2-methoxy-1- ethylamino.
Even more preferably, R1 is hydrogen, chloro or methyl; R2 hydrogen or methyl; R3 is hydrogen, cyanomethyl, prop-2-enyl or prop-2-ynyl; R4 is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-methylphenyl or 3-methyl-4-fluorophenyl and most preferably is 4-fluorophenyl; R6 is -NR18R19 and R18 is hydrogen and R19 is -C(O)R23 and R23 is methyl, ethyl, iso-propyl, cyclopropyl, cyclobutyl or 1-methylcyclopropyl; R7 hydrogen; and R8 is hydrogen, chloro or methyl.
In a particular embodiment, the method of the invention utilises a compound of formula (Ic)
wherein R1, R2, R3, R4, R6, R7 and R8 are as defined above and, preferably:
More preferably R1, R2, R7 and R8 are, independently, hydrogen, methyl, ethyl or chloro; R3 is hydrogen, haloalkyl, alkoxyalkyl, alkenyl or alkynyl; R4 is optionally substituted phenyl, the optional substituent being halogen; and R6 is hydrogen or -NR18R19 wherein R18 is hydrogen and R19 is 2-methoxy-1-methylethyl, -C(S)R23 or -C(O)R23 and R23 is C1-4 alkyl.
Even more preferably, R1, R2, R7 and R8 are, independently, hydrogen; R3 is hydrogen, 2-fluoroethyl, methoxymethyl, prop-1,2-diene or prop-2-ynyl; R4 is fluorophenyl (in particular, 4-fluorophenyl); and R6 is -NR18R19 wherein R18 is hydrogen and R19 is - C(O)R23 and R23 methyl, ethyl, 1-methylethyl, 1-dimethylethyl or 3-methylpropyl.
More particularly, compounds for use in the present invention are shown in Table 1 (compounds of formula (Ia)), Table 2 (compounds of formula (Ib)) and Table 3 (compounds of formula (Ic)) below:
As indicated above, it has now been found that the compounds of formula I are useful in reducing mycotoxin contamination when they are applied to a plant and/or any plant material and/or plant propagation material in an effective amount.
In a particular embodiment the fungi producing the mycotoxins are selected from the group of the following species: F. acuminatum, F. crookwellense, F., verticillioides, F. culmorum, F. avenaceum, F. equiseti, F. moniliforme, F. graminearum (Gibberella zeae), F. lateritium, F. poae, F. sambucinum (G. pulicaris), F. proliferatum, F. subglutinans and F. sporotrichioides, Aspergillus flavus, most strains of Aspergillus parasiticus and Aspergillus nomius, A. ochraceus, A. carbonarius or P. viridicatum.
In a very particular embodiment the fungi producing the mycotoxins are selected from the group of the following species: F., verticillioides, F. culmorum, F. moniliforme, F. graminearum (Gibberella zeae), F. proliferatum, Aspergillus flavus, most strains of Aspergillus parasiticus and Apergillus nomius, A. ochraceus, A. carbonarius.
In a very particular embodiment the fungi producing the mycotoxins are selected from the group of the following species: F. verticillioides, F. proliferatum, F. graminearum (Gibberella zeae), Aspergillus flavus, and Aspergillus parasiticus.
In a very particular embodiment the fungi producing the mycotoxins are selected from the group of the following species: F., verticillioides, F. proliferatum, F. graminearum.
In a very particular embodiment the fungi producing the mycotoxins are selected from the group of the following species: Aspergillus flavus, and Aspergillus parasiticus.
In a particular embodiment the mycotoxins are selected from the following group: aflatoxins B1, B2, G1 and G2, ochratoxin A, B, C as well as T-2 toxin, HT-2 toxin, isotrichodermol, DAS, 3-deacetylcalonectrin, 3,15-dideacetylcalonectrin, scirpentriol, neosolaniol; zearalenone, 15-acetyldeoxynivalenol, nivalenol, 4-acetylnivalenol (fusarenone-X), 4,15-diacetylnivalenol, 4,7,15-acetylnivalenol, and deoxynivalenol (hereinafter "DON") and their various acetylated derivatives as well as fumonisins of the B-type as FB1, FB2, FB3.
In a very particular embodiment the mycotoxins are selected from the following group: aflatoxins B1, B2, G1 and G2, zearalenone, deoxynivalenol (hereinafter "DON") and their various acetylated derivatives as well as fumonisins of the B-type as FB1, FB2, FB3.
In a very particular embodiment the mycotoxins are selected from the following group: aflatoxins B1, B2, G1 and G2.
In a very particular embodiment the mycotoxins are selected from the following group: aflatoxins B1.
In a very particular embodiment the mycotoxins are selected from the following group: zearalenone, deoxynivalenol (hereinafter "DON") and their various acetylated derivatives.
In a very particular embodiment the mycotoxins are selected from the following group: fumonisins of the B-type as FB1, FB2, FB3.
In a particular embodiment of the invention plant or plant material before and/or after harvest and/or during storage has at least 10 % less mycotoxin, more preferable at least 20 % less mycotoxins, more preferable at least 40 % less mycotoxins, more preferable at least 50 % less mycotoxins more preferable at least 80 % less mycotoxin contamination than plant or plant material before and/or after harvest and/or during storage which has not been treated.
In a particular embodiment of the invention plant or plant material before harvest has at least 10 % less aflatoxins, more preferable at least 20 % aflatoxin, more preferable at least 40 % aflatoxins, more preferable at least 50 % aflatoxins, more preferable at least 80 % aflatoxin contamination than plant or plant material before harvest which has not been treated.
In a particular embodiment of the invention plant or plant material after harvest has at least 10 % less fumonisins, more preferable at least 20 % fumonisins, more preferable at least 40 % fumonisins, more preferable at least 50 % fumonisins, more preferable at least 80 % fumonisin contamination than plant or plant material after harvest which has not been treated.
In a particular embodiment of the invention plant or plant material during storage has at least 10 % less DON, more preferable at least 20 % DON, more preferable at least 40 % DON, more preferable at least 50 % DON, more preferable at least 80 % DON contamination than plant or plant during storage which has not been treated.
According to the invention all plants and plant material can be treated. By plants is meant all plants and plant populations such as desirable and undesirable wild plants, cultivars (including naturally occurring cultivars) and plant varieties (whether or not protectable by plant variety or plant breeder's rights). Cultivars and plant varieties can be plants obtained by conventional propagation and breeding methods which can be assisted or supplemented by one or more biotechnological methods such as by use of double haploids, protoplast fusion, random and directed mutagenesis, molecular or genetic markers or by bioengineering and genetic engineering methods including transgenic plants.
By plant material is meant all above ground and below ground parts and organs of plants such as shoot, leaf, flower, blossom and root, whereby for example leaves, needles, stems, branches, blossoms, fruiting bodies, fruits and seed as well as roots, corms and rhizomes are listed.
In a particular embodiment the plant material to be treated are leaves, shoots, flowers, grains, seeds.
In a particular embodiment the plant material to be treated are leaves, shoots, flowers, grains, seeds.
By 'plant propagation material' is meant generative and vegetative parts of a plant including seeds of all kinds (fruit, tubers, bulbs, grains etc), runners, pods, fruiting bodies, roots, rhizomes, cuttings, corms, cut shoots and the like.
Plant propagation material may also include plants and young plants which are to be transplanted after germination or after emergence from the soil.
Among the plants that can be protected by the method according to the invention, mention may be made of major field crops like corn, soybean, cotton, Brassica oilseeds such as Brassica napus (e.g. canola), Brassica rapa, B. juncea (e.g. mustard) and Brassica carinata, rice, wheat, sugarbeet, sugarcane, oats, rye, barley, millet, triticale, flax, vine and various fruits and vegetables of various botanical taxa such as Rosaceae sp. (for instance pip fruit such as apples and pears, but also stone fruit such as apricots, cherries, almonds and peaches, berry fruits such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for instance banana trees and plantings), Rubiaceae sp. (for instance coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for instance lemons, oranges and grapefruit) ; Solanaceae sp. (for instance tomatoes, potatoes, peppers, eggplant), Liliaceae sp., Compositiae sp. (for instance lettuce, artichoke and chicory - including root chicory, endive or common chicory), Umbelliferae sp. (for instance carrot, parsley, celery and celeriac), Cucurbitaceae sp. (for instance cucumber - including pickling cucumber, squash, watermelon, gourds and melons), Alliaceae sp. (for instance onions and leek), Cruciferae sp. (for instance white cabbage, red cabbage, broccoli, cauliflower, brussel sprouts, pak choi, kohlrabi, radish, horseradish, cress, Chinese cabbage), Leguminosae sp. (for instance peanuts, peas and beans beans - such as climbing beans and broad beans), Chenopodiaceae sp. (for instance mangold, spinach beet, spinach, beetroots), Malvaceae (for instance okra), Asparagaceae (for instance asparagus); horticultural and forest crops; ornamental plants; as well as genetically modified homologues of these crops.
In a particular embodiment crops from the family of Poaceae which is comprised of wheat, oat, barley, rye, triticale, millet, corn, maize can be protected by the method of the invention.
The methods, compounds and compositions of the present invention are suitable for reducing mycotoxin contamination on a number of plants and their propagation material including, but not limited to the following target crops: vine, flaxcotton,cereals (wheat, barley, rye, oats, millet, triticale, maize (including field corn, pop corn and sweet corn), rice, sorghum and related crops); beet (sugar beet and fodder beet); sugar beet, sugar cane, leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, sunflowers), Brassica oilseeds such as Brassica napus (e.g. canola), Brassica rapa, B. juncea (e.g. mustard) and Brassica carinata; cucumber plants (marrows, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); vegetables (spinach, lettuce, asparagus, cabbages, carrots, eggplants, onions, pepper, tomatoes, potatoes, paprika, okra); plantation crops (bananas, fruit trees, rubber trees, tree nurseries), ornamentals (flowers, shrubs, broad-leaved trees and evergreens, such as conifers); as well as other plants such as vines, bushberries (such as blueberries), caneberries, cranberries, peppermint, rhubarb, spearmint, sugar cane and turf grasses including, but not limited to, cool-season turf grasses (for example, bluegrasses (Poa L.), such as Kentucky bluegrass (Poa pratensis L.), rough bluegrass (Poa trivialis L.), Canada bluegrass (Poa compressa L.) and annual bluegrass (Poa annua L.); bentgrasses (Agrostis L.), such as creeping bentgrass (Agrostis palustris Huds.), colonial bentgrass (Agrostis tenius Sibth.), velvet bentgrass (Agrostis canina L.) and redtop (Agrostis alba L.); fescues (Festuca L.), such as tall fescue (Festuca arundinacea Schreb.), meadow fescue (Festuca elatior L.) and fine fescues such as creeping red fescue (Festuca rubra L.), chewings fescue (Festuca rubra var. commutata Gaud.), sheep fescue (Festuca ovina L.) and hard fescue (Festuca longifolia); and ryegrasses (Lolium L.), such as perennial ryegrass (Lolium perenne L.) and annual (Italian) ryegrass (Lolium multiflorum Lam.)) and warm-season turf grasses (for example, Bermudagrasses (Cynodon L. C. Rich), including hybrid and common Bermudagrass; Zoysiagrasses (Zoysia Willd.), St. Augustinegrass (Stenotaphrum secundatum (Walt.) Kuntze); and centipedegrass (Eremochloa ophiuroides (Munro.) Hack.)); various fruits and vegetables of various botanical taxa such as Rosaceae sp. (for instance pip fruit such as apples and pears, but also stone fruit such as apricots, cherries, almonds and peaches, berry fruits such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for instance banana trees and plantings), Rubiaceae sp. (for instance coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for instance lemons, oranges and grapefruit) ; Solanaceae sp. (for instance tomatoes, potatoes, peppers, eggplant), Liliaceae sp., Compositiae sp. (for instance lettuce, artichoke and chicory - including root chicory, endive or common chicory), Umbelliferae sp. (for instance carrot, parsley, celery and celeriac), Cucurbitaceae sp. (for instance cucumber - including pickling cucumber, squash, watermelon, gourds and melons), Alliaceae sp. (for instance onions and leek), Cruciferae sp. (for instance white cabbage, red cabbage, broccoli, cauliflower, brussel sprouts, pak choi, kohlrabi, radish, horseradish, cress, Chinese cabbage), Leguminosae sp. (for instance peanuts, peas and beans beans - such as climbing beans and broad beans), Chenopodiaceae sp. (for instance mangold, spinach beet, spinach, beetroots), Malvaceae (for instance okra), Asparagaceae (for instance asparagus); horticultural and forest crops; ornamental plants; as well as genetically modified homologues of these crops.
The method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression "heterologous gene" essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example, antisense technology, co suppression technology or RNA interference - RNAi - technology). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
Depending on the plant species or plant cultivars, their location and growth conditions (soils, climate, vegetation period, diet), the treatment according to the invention may also result in superadditive ("synergistic") effects. Thus, for example, reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf color, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products are possible, which exceed the effects which were actually to be expected.
At certain application rates, the active compound combinations according to the invention may also have a strengthening effect in plants. Accordingly, they are also suitable for mobilizing the defense system of the plant against attack by unwanted phytopathogenic fungi and/ or microorganisms and/or viruses. This may, if appropriate, be one of the reasons of the enhanced activity of the combinations according to the invention, for example against fungi. Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, those substances or combinations of substances which are capable of stimulating the defense system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi and/ or microorganisms and/or viruses, the treated plants display a substantial degree of resistance to these unwanted phytopathogenic fungi and/ or microorganisms and/or viruses. In the present case, unwanted phytopathogenic fungi and/ or microorganisms and/or viruses are to be understood as meaning phytopathogenic fungi, bacteria and viruses. Thus, the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment. The period of time within which protection is effected generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
Plants and plant cultivars which are preferably to be treated according to the invention include all plants which have genetic material which impart particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means).
Plants and plant cultivars which are also preferably to be treated according to the invention are resistant against one or more biotic stresses, i.e. said plants show a better defense against animal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids.
Plants and plant cultivars which may also be treated according to the invention are those plants which are resistant to one or more abiotic stresses. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, flooding, increased soil salinity, increased mineral exposure, ozon exposure, high light exposure, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients, shade avoidance.
Plants and plant cultivars which may also be treated according to the invention, are those plants characterized by enhanced yield characteristics. Increased yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including but not limited to, early flowering, flowering control for hybrid seed production, seedling vigor, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
Plants that may be treated according to the invention are hybrid plants that already express the characteristic of heterosis or hybrid vigor which results in generally higher yield, vigor, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male sterile plants and sold to growers. Male sterile plants can sometimes (e.g. in corn) be produced by detasseling, i.e. the mechanical removal of the male reproductive organs (or males flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome. In that case, and especially when seed is the desired product to be harvested from the hybrid plants it is typically useful to ensure that male fertility in the hybrid plants is fully restored. This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male-sterility. Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described in Brassica species. However, genetic determinants for male sterility can also be located in the nuclear genome. Male sterile plants can also be obtained by plant biotechnology methods such as genetic engineering. A particularly useful means of obtaining male-sterile plants is described in
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof. Plants can be made tolerant to glyphosate through different means. For example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium, the CP4 gene of the bacterium Agrobacterium sp., the genes encoding a Petunia EPSPS, a Tomato EPSPS, or an Eleusine EPSPS (
Other herbicide resistant plants are for example plants that are made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. One such efficient detoxifying enzyme is an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species). Plants expressing an exogenous phosphinothricin acetyltransferase are described.
Further herbicide-tolerant plants are also plants that are made tolerant to the herbicides inhibiting the enzyme hydroxyphenylpyruvatedioxygenase (HPPD). Hydroxyphenylpyruvatedioxygenases are enzymes that catalyze the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants tolerant to HPPD-inhibitors can be transformed with a gene encoding a naturally-occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme. Tolerance to HPPD-inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD-inhibitor. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme.
Still further herbicide resistant plants are plants that are made tolerant to acetolactate synthase (ALS) inhibitors. Known ALS-inhibitors include, for example, sulfonylurea, imidazolinone, triazolopyrimidines, pyrimidinyloxy(thio)benzoates, and/or sulfonylaminocarbonyltriazolinone herbicides. Different mutations in the ALS enzyme (also known as acetohydroxyacid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides. The production of sulfonylurea-tolerant plants and imidazolinone-tolerant plants is described. Other imidazolinone-tolerant plants are also described. Further sulfonylurea- and imidazolinone-tolerant plants are also described.
Other plants tolerant to imidazolinone and/or sulfonylurea can be obtained by induced mutagenesis, selection in cell cultures in the presence of the herbicide or mutation breeding as described for soybeans, for rice, for sugar beet, for lettuce, or for sunflower.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
An "insect-resistant transgenic plant", as used herein, includes any plant containing at least one transgene comprising a coding sequence encoding:
Of course, an insect-resistant transgenic plant, as used herein, also includes any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8. In one embodiment, an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected when using different proteins directed at different target insect species, or to delay insect resistance development to the plants by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are tolerant to abiotic stresses. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress tolerance plants include:
Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage-stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as :
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as cotton plants, with altered fiber characteristics. Such plants can be obtained by genetic transformation, or by selection of plants contain a mutation imparting such altered fiber characteristics and include:
Plants or plant cultivars (that can be obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation or by selection of plants contain a mutation imparting such altered oil characteristics and include:
Particularly useful transgenic plants which may be treated according to the invention are plants which comprise one or more genes which encode one or more toxins, such as the following which are sold under the trade names YIELD GARD® (for example maize, cotton, soya beans),
KnockOut® (for example maize), BiteGard® (for example maize), Bt-Xtra® (for example maize), StarLink® (for example maize), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B®(cotton), NatureGard® (for example maize), Protecta® and NewLeaf® (potato). Examples of herbicide-tolerant plants which may be mentioned are maize varieties, cotton varieties and soya bean varieties which are sold under the trade names Roundup Ready® (tolerance to glyphosate, for example maize, cotton, soya bean), Liberty Link® (tolerance to phosphinotricin, for example oilseed rape), IMI® (tolerance to imidazolinones) and STS® (tolerance to sulphonylureas, for example maize). Herbicide-resistant plants (plants bred in a conventional manner for herbicide tolerance) which may be mentioned include the varieties sold under the name Clearfield® (for example maize).
Particularly useful transgenic plants which may be treated according to the invention are plants containing transformation events, or combination of transformation events, that are listed for example in the databases from various national or regional regulatory agencies (see for example http://gmoinfo.jrc.it/gmp browse.aspx and http://www.agbios.com/dbase.php).
When used in the methods of the invention, the compounds of formula I may be in unmodified form or, preferably, formulated together with carriers and adjuvants conventionally employed in the art of formulation.
The invention therefore also relates to a composition for the control of mycotoxin contamination comprising a compound of formula (I) as defined above and an agriculturally acceptable support, carrier or filler.
According to the invention, the term "support" denotes a natural or synthetic, organic or inorganic compound with which the active compound of formula (I) is combined or associated to make it easier to apply, notably to the parts of the plant. This support is thus generally inert and should be agriculturally acceptable. The support may be a solid or a liquid. Examples of suitable supports include clays, natural or synthetic silicates, silica, resins, waxes, solid fertilisers, water, alcohols, in particular butanol, organic solvents, mineral and plant oils and derivatives thereof. Mixtures of such supports may also be used.
The composition according to the invention may also comprise additional components. In particular, the composition may further comprise a surfactant. The surfactant can be an emulsifier, a dispersing agent or a wetting agent of ionic or non-ionic type or a mixture of such surfactants. Mention may be made, for example, of polyacrylic acid salts, lignosulphonic acid salts, phenolsulphonic or naphthalenesulphonic acid salts, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (in particular alkylphenols or arylphenols), salts of sulphosuccinic acid esters, taurine derivatives (in particular alkyl taurates), phosphoric esters of polyoxyethylated alcohols or phenols, fatty acid esters of polyols, and derivatives of the present compounds containing sulphate, sulphonate and phosphate functions. The presence of at least one surfactant is generally essential when the active compound and / or the inert support are water-insoluble and when the vector agent for the application is water. Preferably, surfactant content may be comprised from 5% to 40% by weight of the composition.
Colouring agents such as inorganic pigments, for example iron oxide, titanium oxide, ferrocyanblue, and organic pigments such as alizarin, azo and metallophthalocyanine dyes, and trace elements such as iron, manganese, boron, copper, cobalt, molybdenum and zinc salts can be used.
Optionally, other additional components may also be included, e.g. protective colloids, adhesives, thickeners, thixotropic agents, penetration agents, stabilisers, sequestering agents. More generally, the active compounds can be combined with any solid or liquid additive, which complies with the usual formulation techniques.
In general, the composition according to the invention may contain from 0.05 to 99% by weight of active compounds, preferably from 10 to 70% by weight.
The combination or composition according to the invention can be used as such, in form of their formulations or as the use forms prepared therefrom, such as aerosol dispenser, capsule suspension, cold fogging concentrate, dustable powder, emulsifiable concentrate, emulsion oil in water, emulsion water in oil, encapsulated granule, fine granule, flowable concentrate for seed treatment, gas (under pressure), gas generating product, granule, hot fogging concentrate, macrogranule, microgranule, oil dispersible powder, oil miscible flowable concentrate, oil miscible liquid, paste, plant rodlet, powder for dry seed treatment, seed coated with a pesticide, soluble concentrate, soluble powder, solution for seed treatment, suspension concentrate (flowable concentrate), ultra low volume (ULV) liquid, ultra low volume (ULV) suspension, water dispersible granules or tablets, water dispersible powder for slurry treatment, water soluble granules or tablets, water soluble powder for seed treatment and wettable powder.
The treatment of plants and plant parts with the active compound combination according to the invention is carried out directly or by action on their environment, habitat or storage area by means of the normal treatment methods, for example by watering (drenching), drip irrigation, spraying, atomizing, broadcasting, dusting, foaming, spreading-on, and as a powder for dry seed treatment, a solution for seed treatment, a water-soluble powder for seed treatment, a water-soluble powder for slurry treatment, or by encrusting.
These compositions include not only compositions which are ready to be applied to the plant or seed to be treated by means of a suitable device, such as a spraying or dusting device, but also concentrated commercial compositions which must be diluted before application to the crop.
The active compounds within the composition according to the invention can be employed for reducing mycotoxin contamination in crop protection or in the protection of materials.
Within the composition according to the invention, bactericide compounds can be employed in crop protection for example for controlling Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
The composition according to the invention can be used to curatively or preventively reduce the mycotoxin contamination of plants or crops. Thus, according to a further aspect of the invention, there is provided a method for curatively or preventively reduce the mycotoxin contamination of comprising the use of a composition comprising a compound according to formula (I) according to the invention by application to the seed, the plant or to the fruit of the plant or to the soil in which the plant is growing or in which it is desired to grow.
Suitably, the active ingredient may be applied to plant propagation material to be protected by impregnating the plant propagation material, in particular, seeds, either with a liquid formulation of the fungicide or coating it with a solid formulation. In special cases, other types of application are also possible, for example, the specific treatment of plant cuttings or twigs serving propagation.
The present invention will now be described by way of the following non-limiting examples.
Calibration was done with not branched alkan2-ones (with 3 to 16 carbon atoms) with known logP-values (measurement of logP values using retention times with linear interpolation between successive alkanones).. lambda-maX-values were determined using UV-spectra from 200 nm to 400 nm and the peak values of the chromatographic signals.
Compounds were tested in microtiter plates in 7 concentrations ranging from 0.07 µM to 50 µM in DON-inducing liquid media (1g (NH4)2HPO4, 0.2g MgSO4x7H2O, 3g KH2PO4, 10g Glycerin, 5g NaCl and 40g Sachharose per liter), supplemented with 10 % oat extract, containing 0.5% DMSO, inoculated with a concentrated spore suspension of Fusarium graminearum at a final concentration of 2000 spores/ml.
The plate was covered and incubated at high humidity at 28°C for 7 days.
At start and after 3 days OD measurement at OD620 multiple read per well (square: 3 x 3) was taken to calculate the pI50 growth inhibition.
After 7 days 100µl 84/16 acetonitrile/water was added to each well and a sample of the liquid medium was taken and diluted 1:100 in 10 % acetonitrile. The amounts of DON and Acetyl-DON of the samples were analysed per HPLC-MS/MS and results were used to calculate pI50 inhibition of DON/AcDON production in comparison to a control without compound.
HPLC-MS/MS was done with the following parameters:
Gradient:
Compounds example numbers 2, 3, 7, 8, 9, 11 and 13 showed an activity of > 80 % of inhibition of DON/AcDON at 50 µM. Example numbers 1, 5, and 12 showed an activity of < 50 % of inhibition of DON/AcDON at 50 µM. Growth inhibition of Fusarium graminearum of the examples with activity > 80 % varied from 79 to 99 % at 50 µM.
Compounds were tested in microtiter plates in 5 concentrations ranging from 0.08 µM to 50 µM in fumonisin-inducing liquid media (0.5g malt extract, 1g yeast extract, 1g bacto peptone, 20 g Fructose, 1g KH2PO4, 0.3g MgSO4x7H2O, 0.3g KCl, 0.05g ZnSO4x7H2O and 0.01g CuSO4x5H2O per liter) containing 0.5% DMSO, inoculated with a concentrated spore suspension of Fusarium proliferatum at a final concentration of 2000 spores/ml.
Plates were covered and incubated at high humidity at 20 °C for 5 days
At start and after 5 days OD measurement at OD620 multiple read per well (square: 3 x 3) was taken to calculate the pI50 of growth inhibition.
After 5 days samples of each culture medium were taken and diluted 1:1000 in 50 % acetonitrile. The amounts of fumonisin FB1 of the samples were analysed per HPLC-MS/MS and results were used to calculate the pI50 of inhibition of FB1 production in comparison to a control without compound.
HPLC-MS/MS was done with the following parameters:
Gradient:
Compounds example numbers 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 12 and 13 showed an activity of > 80 % of inhibition of fumonisin FB1 at 50 µM. Example numbers 4 and 14 showed an activity of < 50 % of inhibition of fumonisin FB1 at 50 µM. Growth inhibition of Fusarium proliferatum of the examples with activity > 80 % varied from 30 to 100 % at 50 µM.
Compounds were tested in microtiter plates (96 well black flat and transparent bottom) in 10 concentrations ranging from 0.005 µM to 100 µM in Aflatoxin-inducing liquid media (20g sucrose, yeast extract 4g, KH2PO4 1g, and MgSO4 7H2O 0.5g per liter), supplemented with 20mM of Cavasol (hydroxypropyl-beta-cyclodextrin) and containing 1% of DMSO. The assay is started by inoculating the medium with a concentrated spore suspension of Aspergillus parasiticus at a final concentration of 1000 spores/ml.
After 7 days of culture, OD measurement at OD620nm with multiple read per well (circle: 4 x 4) was taken with an Infinite 1000 (Tecan) to calculate the pI50 of growth inhibition. In the same time bottom fluorescence measurement at Em360nm and Ex426nm with multiple read per well (square: 3 x 3) was taken to calculate the pI50 of aflatoxins inhibition according to
Compounds example numbers 1, 2, and 3 showed inhibition of aflatoxin production and of Aspergillus parasiticus growth. The pI50 values are listed in the table below.
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