Patent Grant
8614217
The present application is a 35 U.S.C. §371 national phase conversion of PCT/EP2009/058427 filed Jul. 3, 2009, which claims priority of European Application No. 08356101.9 filed Jul. 4, 2008. The PCT International Application was published in the English language.
The present invention relates to hydroximoyl-tetrazole derivatives, their process of preparation, their use as fungicide active agents, particularly in the form of fungicide compositions and methods for the control of phytopathogenic fungi, notably of plants, using these compounds or compositions.
In European patent application no 1426371, there are disclosed certain tetrazoyloxime derivatives of the following chemical structure:
wherein A represents a tetrazolyl group, Het represents either a particular pyridinyl group or a particular thiazolyl group.
In Japanese patent application no 2004-131392, there are disclosed certain tetrazoyloxime derivatives of the following chemical structure:
wherein Q can be selected in a list of 15 various heterocycle groups.
In Japanese patent application no 2004-131416, there are disclosed certain tetrazoyloxime derivatives of the following chemical structure:
wherein Q can be selected among a pyridinyl group or a thiazolyl group.
The compounds disclosed in these three documents do not prove to provide a comparable utility than the compounds according to the invention.
It is always of high-interest in agriculture to use novel pesticide compounds in order to avoid or to control the development of resistant strains to the active ingredients. It is also of high-interest to use novel compounds being more active than those already known, with the aim of decreasing the amounts of active compound to be used, whilst at the same time maintaining effectiveness at least equivalent to the already known compounds. We have now found a new family of compounds which possess the above mentioned effects or advantages.
Accordingly, the present invention provides a tetrazoyloxime derivative of formula (I)
wherein
Any of the compounds according to the invention can exist as one or more stereoisomers depending on the number of stereogenic units (as defined by the IUPAC rules) in the compound. The invention thus relates equally to all the stereoisomers, and to the mixtures of all the possible stereoisomers, in all proportions. The stereoisomers can be separated according to the methods which are known per se by the man ordinary skilled in the art.
Notably, the stereostructure of the oxime moiety present in the heterocyclyloxime derivative of formula (I) includes (E) or (Z) isomer, and these stereoisomers form part of the present invention.
According to the invention, the following generic terms are generally used with the following meanings:
Preferred compounds of formula (I) according to the invention are those wherein X represents a hydrogen atom, a halogen atom, substituted or non-substituted C1-C8-alkyl, a substituted or non-substituted C1-C8-alkoxy, a cyano group, a methanesulfonyl group, a nitro group, a trifluoromethyl group or an aryl group.
Among the halogen atoms represented for X, a chlorine atom or a fluorine atom is particularly preferred. The substituted or non-substituted C1-C8-alkyl group represented for X is preferably an alkyl group having 1 to 4 carbon atoms and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. Among these alkyl groups, a methyl group or a tert-butyl group is particularly preferred.
The alkoxy group for X is preferably a substituted or non-substituted C1-C8-alkoxy group having 1 to 3 carbon atoms and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. Among these alkoxy groups, a methoxy group or an ethoxy group is particularly preferred.
Even more preferred compounds of formula (I) according to the invention are those wherein X represents a hydrogen atom.
Other preferred compounds of formula (I) according to the invention are those wherein Y represents a substituted or non-substituted C1-C8-alkyl group. Among these alkyl groups, an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, an n-propyl group or an isopropyl group is preferable. Among these alkyl groups, a methyl group is particularly preferred.
Other preferred compounds of formula (I) according to the invention are those wherein Q represents a substituted or non-substituted C3-C8-cycloalkyl-C1-C8-alkyl, substituted or non-substituted C3-C8-cycloalkenyl, substituted or non-substituted C2-C8-alkynyl, substituted or non-substituted C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, substituted or non-substituted C1-C8-halogenoalkoxyalkyl having 1 to 5 halogen atoms, substituted or non-substituted phenoxyalkyl, substituted or non-substituted C2-C8-alkenyloxy, substituted or non-substituted C2-C8-halogenoalkenyloxy having 1 to 5 halogen atoms, substituted or non-substituted C3-C8-alkynyloxy, substituted or non-substituted C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, substituted benzyloxy, substituted or non-substituted phenoxy, substituted aryl, substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S; substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl-[C1-C8]-alkyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S; saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl-[C1-C8]-halogenoalkyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S and having 1 to 5 halogen atoms; substituted or non-substituted C5-C12-fused bicycloalkyl, substituted or non-substituted C5-C12-fused bicycloalkenyl.
More preferred compounds of formula (I) according to the invention are those wherein Q represents a substituted or non-substituted C3-C8-cycloalkyl-C1-C8-alkyl, substituted or non-substituted C3-C8-cycloalkenyl, substituted or non-substituted C2-C8-alkynyl, substituted or non-substituted C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, substituted or non-substituted phenoxyalkyl, substituted or non-substituted C2-C8-alkenyloxy, substituted or non-substituted C3-C8-alkynyloxy, substituted or non-substituted C3-C8-halogenoalkynyloxy having 1 to 5 halogen atoms, substituted benzyloxy, substituted or non-substituted phenoxy, substituted aryl, substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S; substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl-[C1-C8]-alkyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S.
Even more preferred compounds of formula (I) according to the invention are those wherein Q represents a substituted or non-substituted C3-C8-cycloalkyl-C1-C8-alkyl, substituted or non-substituted C2-C8-alkynyl, substituted or non-substituted C1-C8-halogenoalkoxy having 1 to 5 halogen atoms, substituted or non-substituted phenoxyalkyl, substituted or non-substituted C2-C8-alkenyloxy, substituted or non-substituted C3-C8-alkynyloxy, substituted aryl, substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S; substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl-[C1-C8]-alkyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S
Even more particularly preferred compounds of formula (I) according to the invention are those wherein Q represents a substituted or non-substituted C8-C8-cycloalkyl-C1-C8-alkyl, substituted or non-substituted C4-C8-alkynyl, substituted or non-substituted C4-C8-halogenoalkoxy having 1 to 5 halogen atoms, substituted or non-substituted phenoxy-[C1-C3]-alkyl, substituted or non-substituted C4-C8-alkenyloxy, substituted or non-substituted C4-C8-alkynyloxy, substituted aryl, substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S; substituted or non-substituted, saturated or unsaturated 4-, 5-, 6- or 7-membered heterocyclyl-[C1-C8]-alkyl comprising up to 4 heteroatoms selected in the list consisting of N, O, S.
The above mentioned preferences with regard to the substituents of the compounds of formula (I) according to the invention can be combined in various manners. These combinations of preferred features thus provide sub-classes of compounds according to the invention. Examples of such sub-classes of preferred compounds according to the invention can combine:
In these combinations of preferred features of the substituents of the compounds according to the invention, the said preferred features can also be selected among the more preferred features of each of X, A1, A2, Y, Het1, Het2 and Q; so as to form most preferred subclasses of compounds according to the invention.
The present invention also relates to a process for the preparation of compounds of formula (I). Thus, according to a further aspect of the present invention, there is a provided process P1 for the preparation of compounds of formula (I), as herein-defined, as illustrated by the following reaction scheme:
wherein A, X, Z, Q and Het are as herein-defined and LG represents a leaving group. Suitable leaving groups can be selected in the list consisting of a halogen atom or other customary nucleofugal groups such as triflate, mesylate or tosylate.
For the compounds of formula (I) according to the invention, there is provided a second process P2 to yield to a compound of formula (I), according to known methods. In such a case there is provided a process P2 according to the invention and such a process P2 can be illustrated by the following reaction scheme:
For the compounds of formula (Ia), carrying out process P2 would previously require a deprotection step in order to yield the amino group. Amino-protecting groups and related methods of cleavage thereof are known and can be found in T. W. Greene and P. G. M. Wuts, Protective Group in Organic Chemistry, 3rd ed., John Wiley & Sons.
According to the invention, processes P1 and P2 can be performed if appropriate in the presence of a solvent and if appropriate in the presence of a base.
According to the invention, processes P1 and P2 can be performed if appropriate in the presence of a catalyst. Suitable catalyst can be selected in the list consisting of 4-dimethyl-aminopyridine, 1-hydroxy-benzotriazole or dimethylformamide.
In case LG′ represents a hydroxy group, process P2 according to the present invention can be performed in the presence of condensing agent. Suitable condensing agent can be selected in the list consisting of acid halide former, such as phosgene, phosphorous tri-bro-mide, phosphorous trichloride, phosphorous pentachloride, phosphorous trichloride oxide or thionyl chloride; anhydride former, such as ethyl chloroformate, methyl chloroformate, isopropyl chloroformate, isobutyl chloroformate or methanesulfonyl chloride; carbodiimides, such as N,N′-dicyclohexylcarbodiimide (DCC) or other customary condensing agents, such as phosphorous pentoxide, polyphosphoric acid, N,N′-carbonyl-diimidazole, 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine/tetrachloromethane, 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate or bromo-tripyrrolidino-phosphonium-hexafluorophosphate.
Suitable solvents for carrying out processes P1 and P2 according to the invention are customary inert organic solvents. Preference is given to using optionally halogenated aliphatic, alicyclic or aromatic hydrocarbons, such as petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene or decalin; chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichlorethane or trichlorethane; ethers, such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, methyl tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane or anisole; nitriles, such as acetonitrile, propionitrile, n- or iso-butyronitrile or benzonitrile; amides, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylformanilide, N-methylpyrrolidone or hexamethylphosphoric triamide; esters, such as methyl acetate or ethyl acetate, sulphoxides, such as dimethyl sulphoxide, or sulphones, such as sulpholane.
Suitable bases for carrying out processes P1 and P2 according to the invention are inorganic and organic bases which are customary for such reactions. Preference is given to using alkaline earth metal, alkali metal hydride, alkali metal hydroxides or alkali metal alkoxides, such as sodium hydroxide, sodium hydride, calcium hydroxide, potassium hydroxide, potassium tert-butoxide or other ammonium hydroxide, alkali metal carbonates, such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, alkali metal or alkaline earth metal acetates, such as sodium acetate, potassium acetate, calcium acetate, and also tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine, tributylamine, N,N-dimethylaniline, pyridine, N-methylpiperidine, N,N-dimethyl-aminopyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
When carrying out processes P1 and P2 according to the invention, the reaction temperature can independently be varied within a relatively wide range.
Generally, process P1 according to the invention is carried out at temperatures between −20° C. and 160° C.
Processes P1 and P2 according to the invention are generally independently carried out under atmospheric pressure. However, it is also possible to operate under elevated or reduced pressure.
When carrying out process P1 according to the invention, generally 1 mol or an excess of derivative of formula Het-CH2-LG and from 1 to 3 mol of base are employed per mole of hydroximoyl tetrazole of formula (II). It is also possible to employ the reaction components in other ratios.
Work-up is carried out by customary methods. Generally, the reaction mixture is treated with water and the organic phase is separated off and, after drying, concentrated under reduced pressure. If appropriate, the remaining residue can be freed by customary methods, such as chromatography or recrystallization, from any impurities that can still be present.
Compounds according to the invention can be prepared according to the above described processes. It will nevertheless be understood that, on the basis of his general knowledge and of available publications, the skilled worker will be able to adapt these processes according to the specifics of each of the compounds according to the invention that is desired to be synthesised.
When A represents a substituent of formula A1, as herein-described, the compounds of formula (II), useful as a starting material, can be prepared, for example, by reacting hydroxylamine with the corresponding ketones of formula (V)
that can be prepared, for example, according to the method described by R. Raap (Can. J. Chem. 1971, 49, 2139) by addition of a tetrazolyl lithium species to esters of formula
or any of their suitable synthetic equivalents like, for example:
When A represents a substituent of formula A2, as herein-described, the compounds of general formula (II) useful as a starting material, can be prepared, for example, from oximes of formula
and 5-substituted tetrazole according to the method described by J. Plenkiewicz et al. (Bull. Soc. Chim. Belg. 1987, 96, 675).
The present invention also relates to a novel process for the preparation of compounds of formula (I). Thus, according to a further aspect of the present invention, there is a provided process P3 for the preparation of compounds of formula (I), as herein-defined, as illustrated by the following reaction scheme:
Suitable leaving groups can be selected in the list consisting of a halogen atom or other customary nucleofugal groups such as alcoolate, hydroxide, carboxylate or cyanide.
The first step of process P3 according to the invention, namely, the conversion of compound of formula (V) into a compound of formula (Ia) is carried out at temperatures between 110° C. and 180° C.
When carrying out the first step of process P3 according to the invention, namely, the conversion of compound of formula (V) into a compound of formula (Ia), the reaction is performed under microwave irradiation.
In a further aspect, the present invention relates to compounds of formula (VI) or one of its salts useful as intermediate compounds or materials for the process of preparation P3 according to the invention. The present invention thus provides compounds of formula (VI)
or one of its salts wherein Het′ represents a pyridyl group of formula (Het′1) or a thiazolyl group of formula (Het′2):
In a further aspect, the present invention also relates to a fungicide composition comprising an effective and non-phytotoxic amount of an active compound of formula (I).
The expression “effective and non-phytotoxic amount” means an amount of composition according to the invention which is sufficient to control or destroy the fungi present or liable to appear on the crops and which does not entail any appreciable symptom of phytotoxicity for the said crops. Such an amount can vary within a wide range depending on the fungus to be controlled, the type of crop, the climatic conditions and the compounds included in the fungicide composition according to the invention. This amount can be determined by systematic field trials, which are within the capabilities of a person skilled in the art.
Thus, according to the invention, there is provided a fungicide composition comprising, as an active ingredient, an effective amount of a compound of formula (I) as herein defined 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 can be a solid or a liquid. Examples of suitable supports include clays, natural or synthetic silicates, silica, resins, waxes, solid fertilizers, water, alcohols, in particular butanol organic solvents, mineral and plant oils and derivatives thereof. Mixtures of such supports can also be used.
The composition according to the invention can also comprise additional components. In particular, the composition can 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 can 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 above compounds containing sulphate, sulphonate and phosphate functions. The presence of at least one surfactant is generally essential if the active compound and/or the inert support are water-insoluble and if the vector agent for the application is water. Preferably, surfactant content can be comprised from 5% to 40% by weight of the composition.
Optionally, additional components can 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 can contain from 0.05 to 99% by weight of active compound, preferably 10 to 70% by weight.
Compositions according to the invention can be used in various forms 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. 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 compounds according to the invention can also be mixed with one or more insecticide, fungicide, bactericide, attractant, acaricide or pheromone active substance or other compounds with biological activity. The mixtures thus obtained have a broadened spectrum of activity. The mixtures with other fungicide compounds are particularly advantageous. The composition according to the invention comprising a mixture of a compound of formula (I) with a bactericide compound can also be particularly advantageous
According to another object of the present invention, there is provided a method for controlling the phytopathogenic fungi of plants, crops or seeds, characterized in that an agronomically effective and substantially non-phytotoxic quantity of a pesticide composition according to the invention is applied as seed treatment, foliar application, stem application, drench or drip application (chemigation) to the seed, the plant or to the fruit of the plant or to soil or to inert substrate (e.g. inorganic substrates like sand, rockwool, glasswool; expanded minerals like perlite, vermiculite, zeolite or expanded clay), Pumice, Pyroclastic materials or stuff, synthetic organic substrates (e.g. polyurethane) organic substrates (e.g. peat, composts, tree waste products like coir, wood fibre or chips, tree bark) or to a liquid substrate (e.g. floating hydroponic systems, Nutrient Film Technique, Aeroponics) wherein the plant is growing or wherein it is desired to grow.
The expression “are applied to the plants to be treated” is understood to mean, for the purposes of the present invention, that the pesticide composition which is the subject of the invention can be applied by means of various methods of treatment such as:
The method according to the invention can either be a curing, preventing or eradicating method.
In this method, a composition used can be prepared beforehand by mixing the two or more active compounds according to the invention.
According to an alternative of such a method, it is also possible to apply simultaneously, successively or separately compounds (A) and (B) so as to have the conjugated (A)/(B) effects, of distinct compositions each containing one of the two or three active ingredients (A) or (B).
The dose of active compound usually applied in the method of treatment according to the invention is generally and advantageously
The doses herein indicated are given as illustrative Examples of method according to the invention. A person skilled in the art will know how to adapt the application doses, notably according to the nature of the plant or crop to be treated.
Under specific conditions, for example according to the nature of the phytopathogenic fungus to be treated or controlled, a lower dose can offer adequate protection. Certain climatic conditions, resistance or other factors like the nature of the phytopathogenic fungi or the degree of infestation, for example, of the plants with these fungi, can require higher doses of combined active ingredients. The optimum dose usually depends on several factors, for example on the type of phytopathogenic fungus to be treated, on the type or level of development of the infested plant, on the density of vegetation or alternatively on the method of application.
Without it being limiting, the crop treated with the pesticide composition or combination according to the invention is, for example, grapevine, but this could be cereals, vegetables, lucerne, soybean, market garden crops, turf, wood, tree or horticultural plants.
The method of treatment according to the invention can also be useful to treat propagation material such as tubers or rhizomes, but also seeds, seedlings or seedlings pricking out and plants or plants pricking out.
This method of treatment can also be useful to treat roots. The method of treatment according to the invention can also be useful to treat the over-ground parts of the plant such as trunks, stems or stalks, leaves, flowers and fruit of the concerned plant.
Among the plants that can be protected by the method according to the invention, mention can be made of cotton; flax; vine; fruit or vegetable crops such as Rosaceae sp. (for instance pip fruit such as apples and pears, but also stone fruit such as apricots, almonds and peaches), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actimidaceae sp., Lauraceae sp., Musaceae sp. (for instance banana trees and plantins), Rubiaceae sp., Theaceae sp., Sterculiceae sp., Rutaceae sp. (for instance lemons oranges and grapefruit); Solanaceae sp. (for instance tomatoes), Liliaceae sp., Asteraceae sp. (for instance lettuces), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp., Papilionaceae sp. (for instance peas), Rosaceae sp. (for instance strawberries); major crops such as Graminae sp. (for instance maize, lawn or cereals such as wheat, rice, barley and triticale), Asteraceae sp. (for instance sunflower), Cruciferae sp. (for instance colza), Fabacae sp. (for instance peanuts), Papilionaceae sp. (for instance soybean), Solanaceae sp. (for instance potatoes), Chenopodiaceae sp. (for instance beetroots); horticultural and forest crops; 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 (WO 1992/005251, WO 1995/009910, WO 1998/27806, WO 2005/002324, WO 2006/021972 and U.S. Pat. No. 6,229,072). 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 WO 1989/10396 in which, for example, a ribonuclease such as barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar (e.g. WO 1991/002069).
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 (Comai et al., Science (1983), 221, 370-371), the CP4 gene of the bacterium Agrobacterium sp. (Barry et al., Curr. Topics Plant Physiol. (1992), 7, 139-145), the genes encoding a Petunia EPSPS (Shah et al., Science (1986), 233, 478-481), a Tomato EPSPS (Gasser et al., J. Biol. Chem. (1988), 263, 4280-4289), or an Eleusine EPSPS (WO 2001/66704). It can also be a mutated EPSPS as described in for example EP-A 0837944, WO 2000/066746, WO 2000/066747 or WO 2002/026995. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxido-reductase enzyme as described in U.S. Pat. No. 5,776,760 and U.S. Pat. No. 5,463,175. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyl transferase enzyme as described in for example WO 2002/036782, WO 2003/092360, WO 2005/012515 and WO 2007/024782. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally-occurring mutations of the above-mentioned genes, as described in for example WO 2001/024615 or WO 2003/013226.
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 for example described in U.S. Pat. No. 5,561,236; U.S. Pat. No. 5,648,477; U.S. Pat. No. 5,646,024; U.S. Pat. No. 5,273,894; U.S. Pat. No. 5,637,489; U.S. Pat. No. 5,276,268; U.S. Pat. No. 5,739,082; U.S. Pat. No. 5,908,810 and U.S. Pat. No. 7,112,665.
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 as described in WO 1996/038567, WO 1999/024585 and WO 1999/024586. 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. Such plants and genes are described in WO 1999/034008 and WO 2002/36787. 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, as described in WO 2004/024928.
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, as described for example in Tranel and Wright, Weed Science (2002), 50, 700-712, but also, in U.S. Pat. No. 5,605,011, U.S. Pat. No. 5,378,824, U.S. Pat. No. 5,141,870, and U.S. Pat. No. 5,013,659. The production of sulfonylurea-tolerant plants and imidazolinone-tolerant plants is described in U.S. Pat. No. 5,605,011; U.S. Pat. No. 5,013,659; U.S. Pat. No. 5,141,870; U.S. Pat. No. 5,767,361; U.S. Pat. No. 5,731,180; U.S. Pat. No. 5,304,732; U.S. Pat. No. 4,761,373; U.S. Pat. No. 5,331,107; U.S. Pat. No. 5,928,937; and U.S. Pat. No. 5,378,824; and international publication WO 1996/033270. Other imidazolinone-tolerant plants are also described in for example WO 2004/040012, WO 2004/106529, WO 2005/020673, WO 2005/093093, WO 2006/007373, WO 2006/015376, WO 2006/024351, and WO 2006/060634. Further sulfonylurea- and imidazolinone-tolerant plants are also described in for example WO 2007/024782.
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 example for soybeans in U.S. Pat. No. 5,084,082, for rice in WO 1997/41218, for sugar beet in U.S. Pat. No. 5,773,702 and WO 1999/057965, for lettuce in U.S. Pat. No. 5,198,599, or for sunflower in WO 2001/065922.
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).
The composition according to the invention can also be used against fungal diseases liable to grow on or inside timber. The term “timber” means all types of species of wood and all types of working of this wood intended for construction, for example solid wood, high-density wood, laminated wood and plywood. The method for treating timber according to the invention mainly consists in contacting one or more compounds according to the invention or a composition according to the invention; this includes for example direct application, spraying, dipping, injection or any other suitable means.
Among the diseases of plants or crops that can be controlled by the method according to the invention, mention can be made of:
Powdery mildew diseases such as:
The compounds according to the invention can also be used for the preparation of composition useful to curatively or preventively treat human or animal fungal diseases such as, for example, mycoses, dermatoses, trichophyton diseases and candidiases or diseases caused by Aspergillus spp., for example Aspergillus fumigatus.
The various aspects of the invention will now be illustrated with reference to the following table 1 of compound examples and the following preparation or efficacy examples.
The following table 1 illustrates in a non limiting manner examples of compounds according to the invention.
In table 1 we use the following abbreviations for specified claimed elements “Het” of the generic structure (I) of the invention:
In the following list we specify the double bond geometry of the examples of table 1 as shown here:
Example (Double Bond Geometry) of the Examples of Table 1:
1 (E), 2 (E), 3 (U), 4 (U), 5 (U), 6 (U), 7 (U), 8 (U), 9 (U), 10 (U), 11 (U), 12 (U), 13 (U), 14 (U), (U), 16 (U), 17 (U), 18 (U), 19 (U), 20 (U), 21 (U), 22 (U), 23 (U), 24 (U), 25 (U), 26 (U), 27 (U), 28 (U), 29 (U), 30 (U), 31 (U), 32 (U), 33 (U), 34 (U), 35 (U), 36 (U), 37 (U), 38 (U), 39 (U), 40 (U), 41 (U), 42 (U), 43 (U), 44 (U), 45 (U), 46 (U), 47 (U), 48 (U), 49 (Z), 50 (Z), 51 (Z), 52 (Z), 53 (Z), 54 (Z), 55 (Z), 56 (Z), 57 (Z), 58 (Z), 59 (Z), 60 (Z), 61 (Z), 62 (Z), 63 (Z), 64 (Z), 65 (Z), 66 (Z), 67 (Z), 68 (Z), 69 (U), 70 (U), 71 (U), 72 (U), 73 (U), 74 (U), 75 (U), 76 (U), 77 (U), 78 (U), 79 (U), 80 (U), 81 (U), 82 (U), 83 (U), 84 (U), 85 (U), 86 (U), 87 (U), 88 (U), 89 (U), 90 (U), 91 (U), 92 (U), 93 (U), 94 (U), 95 (U), 96 (U), 97 (U), 98 (U), 99 (U), 100 (U), 101 (U), 102 (U), 103 (U), 104 (U), 105 (U), 106 (U), 107 (U), 108 (U), 109 (U), 110 (U), 111 (U), 112 (U), 113 (U), 114 (U), 115 (U), 116 (U), 117 (U), 118 (U), 119 (U), 120 (U), 121 (U), 122 (U), 123 (U), 124 (U), 125 (U), 126 (U), 127 (U), 128 (U), 129 (U), 130 (U), 131 (U), 132 (U), 133 (U), 134 (U), 135 (U), 136 (U), 137 (U), 138 (U), 139 (U), 140 (U), 141 (U), 142 (U), 143 (U), 144 (U), 145 (U), 146 (U), 147 (U), 148 (U), 149 (U), 150 (U), 151 (U), 152 (U), 153 (U), 154 (Z), 155 (Z), 156 (Z), 157 (Z), 158 (Z), 159 (Z), 160 (Z), 161 (Z), 162 (Z), 163 (Z), 164 (Z), 165 (Z), 166 (Z), 167 (Z), 168 (Z), 169 (Z), 170 (Z), 171 (Z), 172 (Z), 173 (Z), 174 (Z), 175 (Z), 176 (Z), 177 (Z), 178 (Z), 179 (Z), 180 (Z), 181 (Z), 182 (Z), 183 (Z), 184 (Z), 185 (Z), 186 (Z), 187 (Z), 188 (Z), 189 (Z), 190 (Z), 191 (Z), 192 (Z), 193 (Z), 194 (Z), 195 (Z), 196 (Z), 197 (Z), 198 (Z), 199 (Z), 200 (Z), 201 (Z), 202 (Z), 203 (Z), 204 (Z), 205 (Z), 206 (Z), 207 (Z), 208 (U), 209 (Z), 210 (U), 211 (Z), 212 (Z), 213 (Z), 214 (Z), 215 (Z), 216 (Z), 217 (Z), 218 (Z), 219 (U), 220 (U), 221 (U), 222 (U), 223 (U), 224 (U), 225 (U), 226 (U), 227 (U), 228 (U), 229 (U), 230 (U), 231 (Z), 232 (Z), 233 (Z), 234 (Z), 235 (Z), 236 (Z), 237 (Z), 238 (Z), 239 (Z), 240 (Z), 241 (Z), 242 (U), 243 (Z), 244 (Z), 245 (Z), 246 (U), 247 (Z), 248 (Z), 249 (Z), 250 (Z), 251 (Z), 252 (Z), 253 (Z), 254 (Z), 255 (Z), 256 (Z), 257 (Z), 258 (Z), 259 (Z), 260 (Z), 261 (Z), 262 (U), 263 (U), 264 (U), 265 (U), 266 (Z), 267 (Z), 268 (Z), 269 (Z), 270 (Z), 271 (Z), 272 (Z), 273 (Z), 274 (Z), 275 (Z), 276 (Z), 277 (Z), 278 (Z), 279 (Z), 280 (Z), 281 (Z), 282 (Z), 283 (Z), 284 (Z), 285 (Z), 286 (Z), 287 (Z), 288 (Z), 289 (U), 290 (U), 291 (U), 292 (U), 293 (U), 294 (U), 295 (U), 296 (Z), 297 (Z), 298 (Z), 299 (Z), 300 (Z), 301 (Z), 302 (U), 303 (U), 304 (U), 305 (U), 306 (Z), 307 (Z), 308 (Z), 309 (Z), 310 (Z), 311 (Z), 312 (Z), 313 (Z), 314 (Z), 315 (U), 316 (U), 317 (Z), 318 (Z), 319 (Z), 320 (Z), 321 (Z), 322 (Z), 323 (Z), 324 (Z), 325 (Z), 326 (Z), 327 (Z), 328 (Z), 329 (Z), 330 (Z), 331 (Z), 332 (Z), 333 (Z), 334 (Z), 335 (Z), 336 (Z), 337 (Z), 338 (Z), 339 (Z), 340 (Z), 341 (Z), 342 (Z), 343 (Z), 344 (Z), 345 (Z), 346 (Z), 347 (Z), 348 (Z), 349 (Z), 350 (Z), 351 (Z), 352 (Z), 353 (Z), 354 (Z), 355 (Z), 356 (Z), 357 (Z), 358 (Z), 359 (Z), 360 (Z), 361 (Z), 362 (Z), 363 (Z), 364 (Z), 365 (Z), 366 (Z), 367 (Z), 368 (Z), 369 (Z), 370 (Z), 371 (U), 372 (U), 373 (U), 374 (Z), 375 (Z), 376 (Z), 377 (Z), 378 (Z), 379 (E),
Solvent: 49 parts by weight of N,N-Dimethylformamide
Emulsifier: 1 part by weight of Alkylarylpolyglycolether
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of Phytophthora infestans. The plants remain for one day in an incubation cabinet at approximately 22° C. and a relative atmospheric humidity of 100%. Then the plants are placed in an incubation cabinet at approximately 20° C. and a relative atmospheric humidity of 96%.
The test is evaluated 7 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following examples of table 1 according to the invention showed efficacy of 70% or even higher at a concentration of 500 ppm of active ingredient:
Examples Number 1, 2, 3, 4, 5, 6, 7, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 74, 75, 76, 78, 80, 83, 84, 90, 91, 92, 93, 94, 96, 98, 99, 100, 102, 103, 104, 105, 106, 109, 110, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 129, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 146, 148, 149, 151, 160, 165, 175, 176, 197, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 375, 376 and 377.
Solvent: 24.5 parts by weight of acetone
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for protective activity, young plants are sprayed with the preparation of active compound at the stated rate of application. After the spray coating has dried on, the plants are inoculated with an aqueous spore suspension of Plasmopara viticola and then remain for 1 day in an incubation cabinet at approximately 20° C. and a relative atmospheric humidity of 100%. The plant is subsequently placed for 4 days in a greenhouse at approximately 21° C. and a relative atmospheric humidity of approximately 90%. The plants are then misted and placed for 1 day in an incubation cabinet.
The test is evaluated 6 days after the inoculation. 0% means an efficacy which corresponds to that of the control, while an efficacy of 100% means that no disease is observed.
In this test the following examples of table 1 according to the invention showed efficacy of 70% or even higher at a concentration of 10 ppm of active ingredient:
Examples Number 1, 2, 3, 4, 5, 6, 7, 17, 18, 19, 20, 23, 24, 27, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 70, 71, 76, 80, 82, 84, 114, 115, 116, 135, 160, 202, 205, 206, 207, 208, 209, 212, 213, 214, 216, 218, 220, 221, 223, 226, 230, 233, 234, 237, 238, 376 and 377.
Wells of 96-hole microtitre plates are filled with 100 of a solution of the test compound in methanol together with the emulsifier alkylaryl polyglycol ether. Thereafter, the solvent is evaporated in a hood. At the next step, into each well 2000 of liquid potato dextrose medium is given that has been amended with an appropriate concentration of spores or mycelium suspension of the test fungus. The resulting concentrations of the test compounds in the microtitre well are 50, 5, 0.5 and 0.05 ppm. The resulting concentration of the emulsifier in all wells is constantly 300 ppm.
With the aid of a photometer the extinction in all wells is measured at the wavelength of 620 nm.
The microtiter plates are then transferred for 3-5 days onto a shaker at 20° C. and 85% relative humidity.
At the end of the incubation time the growth of the test organisms is measured again photometrically at the wavelength of 620 nm. The difference between the two extinction values (taken before and after incubation) is proportional to the growth of the test organism.
Based on the Δ extinction data from the different test concentrations and that of the untreated test organism (control) a dose-response curve is calculated. The concentration that is necessary to give 50% growth inhibition is defined and reported as ED50-value (=Effective Dose that causes 50% growth inhibition) in ppm (=mg/l).
In this test the following examples of table 1 according to the invention showed an ED50-value lower than 1 ppm: Examples Number 1, 2, 3, 4, 5, 6, 7, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 69, 71, 73, 77, 78, 80, 81, 82, 83, 84, 86, 87, 89, 91, 92, 93, 97, 99, 101, 103, 106, 109, 110, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 129, 130, 131, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 145, 146, 148, 149, 150, 151, 160, 164, 165, 171, 175, 176, 197, 198, 199, 200, 201, 202, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 221, 224, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 375, 376 and 377.
The following examples illustrate in a non-limiting manner the preparation and efficacy of the compounds of formula (I) according to the invention.
To a solution of N-hydroxy-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (21.5 g, 0.106 mol) in acetonitrile (638 mL) was added cesium carbonate (72.4 g, 0.222 mol), potassium iodide (1.76 g, 0.011 mol) and then 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (35.23 g, 0.111 mol), the white slurry was stirred at room temperature for four hours at room temperature. Water (700 mL) was added, the precipitate was filtered off and washed with water until colourless, then dried in vacuo overnight to yield to of 2-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [40.0 g; 86% of theory; HPLC/MS: m/z=440 (M+H); log P(HCOOH)=3.04].
To a solution of 2-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (119 g, 0.271 mol) in tetrahydrofuran (2610 mL) was added hydrazine hydrate (66.26 mL, 1.354 mol), the reaction mixture was stirred at room temperature for six hours at room temperature. The precipitate which has formed was filtered off and washed with tetrahydrofuran, the filtrate was then concentrated in vacuo to produce an off-white solid which was further purified by trituration in dichloromethane yielding to 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine [83.0 g; 94% of theory; HPLC/MS m/z=310 (M+H); log P(HCOOH)=1.14].
To a solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine (251 mg, 0.81 mmol) in dichloromethane (10 mL) was added triethylamine (0.22 mL, 1.62 mmol), hex-5-ynoyl chloride (211 mg, 1.62 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to N-{6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}hex-5-ynamide [200 mg; 95% of purity; 58% of theory; HPLC/MS: m/z=404 (M+H); log P(HCOOH)=2.98].
A suspension of N-hydroxyphthalimide (35.0 g, 214 mmol), 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (74.8 g, 236 mmol), cesium carbonate (146.8 g, 450 mmol) and potassium iodide (1.78 g, 10.7 mmol) in acetonitrile (350 mL) was stirred at room temperature for 18 h. Water (300 mL) was added, the precipitate was filtered off and washed with water until colourless, then dried in vacuo overnight to yield 2-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione as a colourless solid [85.0 g; 94% of theory; HPLC/MS m/z=400 (M+H); log P(HCOOH)=2.44].
To a solution of 2-(6-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (50 g, 125 mmol) in THF (350 mL) was added dropwise hydrazine hydrate (61 mL, 1.25 mol) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. Purification of the residue on silica gel afforded 6-[(aminooxy)methyl]pyridin-2-amine as a colourless oil [10.0 g; 57% of theory; HPLC/MS: m/z=140 (M+H); log P(HCOOH)<−0.23].
Under protective gas (argon), a reaction tube containing a solution of (1-methyl-1H-tetrazol-5-yl)(phenyl)methanone (188 mg; 1.0 mmol), 6-[(aminooxy)methyl]pyridin-2-amine (139 mg; 1.0 mmol) and p-toluenesulfonic acid monohydrate (190 mg; 1.0 mmol) in 2-propanol (2 mL) is sealed and heated in a microwave oven at 160° C. for 90 min. For workup, the mixture is allowed to cool down, diluted with dichloromethane (10 mL) and washed twice with 3 ml each time of sat. aq. sodium bicarbonate. The aqueous phase is extracted with dichloromethane and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Purification on silica gel affords 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-amine as a colourless oil [205 mg; 66% of theory; HPLC/MS: m/z=310 (M+H); log P(HCOOH)=1.13].
To a stirred solution of 6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)-methyl]pyridin-2-amine (150 mg, 0.485 mmol) in dichloromethane (5 mL), was added pyridine (0.078 mL), 4-chlorobutyl carbonochloridate (166 mg, 0.970 mmol). The reaction mixture was stirred for 5 hours at room temperature, concentrated in vacuo, and then purified by silica gel chromatography to yield to 4-chlorobutyl {6-[({[(Z)-(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate [200 mg; 90% of purity; 84% of to theory; HPLC/MS: m/z=344 (M+H); log P(HCOOH)=3.67].
A suspension of N-hydroxyphthalimide (50.0 g, 306 mmol), 4-(chloromethyl)-1,3-thiazol-2-amine (50.1 g, 337 mmol), cesium carbonate (210 g, 0.64 mol) and potassium iodide (2.54 g, 15.3 mmol) in acetonitrile (440 mL) was stirred at room temperature for 18 h. Water (300 mL) was added, the precipitate was filtered off and washed with water until colourless, then dried in vacuo overnight to afford 2-[(2-amino-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a colourless solid [36.0 g; 43% of theory; HPLC/MS: m/z=276 (M+H); log P(HCOOH)=0.74].
To a solution of 2-[(2-amino-1,3-thiazol-4-yl)methoxy]-1H-isoindole-1,3(2H)-dione (10 g, 36.3 mmol) in THF (100 mL) was added dropwise hydrazine hydrate (9.1 g, 181 mmol) at room temperature. After stirring overnight at room temperature, the reaction mixture was filtered and the filtrate was concentrated to dryness in vacuo. Purification of the residue on silica gel afforded 4-[(aminooxy)methyl]-2-bromo-1,3-thiazole as a colourless oil [5.2 g; 99% of theory; HPLC/MS: m/z=146 (M+H); log P(HCOOH)<−0.23].
| Number | Date | Country | Kind |
|---|---|---|---|
| 08356101 | Jul 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/058427 | 7/3/2009 | WO | 00 | 4/27/2011 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2010/000841 | 1/7/2010 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20070232554 | Or et al. | Oct 2007 | A1 |
| 20100286173 | Beier et al. | Nov 2010 | A1 |
| 20110105566 | Beier et al. | May 2011 | A1 |
| 20110190353 | Beier et al. | Aug 2011 | A1 |
| Number | Date | Country |
|---|---|---|
| 142637 | Jun 2004 | EP |
| 1426371 | Jun 2004 | EP |
| 1038874 | Sep 2007 | EP |
| 2004 131392 | Apr 2004 | JP |
| 2004 131416 | Apr 2004 | JP |
| WO 2008006875 | Jan 2008 | WO |
| WO 2010000842 | Jul 2009 | WO |
| Entry |
|---|
| Patani et al., Chem. Rev., 1996, vol. 96, pp. 3147-3176. |
| U.S. Appl. No. 13/002,643, corresponding to PCT/EP2009/058428, having an International filing date of Jul. 3, 2009, published as WO/2010/000842, by Christian Beier et al. entitled Fungicide Hydroximoyl-Tetrazole Derivatives. |
| International Search Report dated Sep. 2, 2009 in corresponding International Application No. PCT/EP2009/058427. |
| Or, Yat Sun et al.: Preparation of 3,6-bridged 9,12-oxolide erythromycin analogs as antibacterial agents, XP002542028, retrieved from STN, CAN: 147:427649, Database Accession No. 2007:1121499, CAPLUS, abstract & US 2007/0232554 A1 (Or, Yat Sun et al.) filed Oct. 4, 2007. |
| Number | Date | Country | |
|---|---|---|---|
| 20110201613 A1 | Aug 2011 | US |
