Patent Application
20110015065
The present invention relates to the use of substituted sulfonic acid amide compounds and the N-oxides and the salts thereof for combating phytopathogenic harmful fungi, and to compositions and seeds comprising at least one such compound. The invention also relates to novel substituted sulfonic acid amide compounds and processes for preparing these compounds.
Substituted sulfonic acid amides with a 5-membered heteroarylmethyl bonded to the amide group have been generally mentioned earlier, inter alia the following compounds: 2-methyl-N-(5-methyl-furan-2-ylmethyl)-4-(2-methyl-thiazol-4-yl)-benzenesulfonamide (Chemical Abstracts Registry Number, hereinafter CAS-RN: 951606-62-5), N-(5-methyl-furan-2-ylmethyl)-4-(2-methyl-oxazol-4-yl)-benzenesulfonamide (CAS-RN: 933194-38-8), 5-{3-methoxy-4-[(5-methyl-furan-2-ylmethyl)-sulfamoyl]-phenyl}-isoxazole-3-carboxylic acid ethyl ester (CAS-RN: 932536-62-4), 4-(2-cyclopropyl-oxazol-5-yl)-N-(5-methyl-furan-2-ylmethyl)-benzenesulfonamide (CAS-RN: 932467-34-0), 5-(5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-sulfonic acid (5-methyl-furan-2-ylmethyl)-amide (CAS-RN: 932465-72-0), 5-(3-trifluoromethyl-isoxazol-5-yl)-thiophene-2-sulfonic acid (5-methyl-furan-2-ylmethyl)-amide (CAS-RN: 894895-13-7), 5-(3-methyl-isoxazol-5-yl)-thiophene-2-sulfonic acid (5-methyl-furan-2-ylmethyl)-amide (CAS-RN: 932357-49-8), 4-(3,4-dimethyl-isoxazol-5-yl)-2-methoxy-N-(5-methyl-furan-2-ylmethyl)benzenesulfonamide (CAS-RN: 894914-26-2), 2-methoxy-N-(5-methyl-furan-ylmethyl)-4-(3-methyl-isoxazol-5-yl)-benzenesulfonamide (CAS-RN: 894905-06-7) and 4-(2,6-dicyano-phenoxy)-cyclohexa-1,5-dienesulfonic acid (5-chloro-benzo[b]thiophen-2-ylmethyl)-amide (CAS-RN: 690626-95-0). No indication is as to which these compounds are fungicidal or of any other agrochemical use.
We have now found that certain sulfonic acid amides have good fungicidal activity against phytopathogenic harmful fungi.
WO 05/033081 describes sulfonic acid pyridin-4-ylmethylamide compounds and their use for combating phytopathogenic harmful fungi. The publication WO 06/097489 describes various pyridin-4-ylmethylamides of phenyl sulfonic acid and their use as fungicides.
The international non-published application PCT/EP2008/065958 as well as WO 08/062,011 and WO 06/097488 describe sulfonic acid amide compounds and their use as agrochemicals, inter alia as fungicides.
The compounds according to the present invention differ from those described in WO 05/033081, PCT/EP2008/065958, WO 08/062,011 and WO 06/097488, respectively by bearing a 5-membered heteroarylmethyl instead of a 6-membered heteroarylmethyl such as pyridin-4-ylmethyl.
A. K. Saha et al. describe in Bioorg. Med. Chem. Lett. 10, 2735-2739 (2000) certain N-substituted sulfonic acid (imidazol-4-ylmethyl) biarylamides, wherein the amide substituent is 2,4-dimethyl-pent-3-yl, hexyl, cyclohexyl, cyclohexylmethyl or 4-fluorphenylethyl. These compounds are supposed to be useful pharmaceuticals with antifungal activity and indeed the tables given contain activity data for human pathogenic yeasts and fungi. There is absolutely no mention of agricultural use or the fungicidal properties against phytopathogenic fungi of these (imidazol-4-ylmethyl) biarylamides in Bioorg. Med. Chem. Lett. 10, 2735-2739 (2000).
Besides, A. K. Saha et al. describe in J. Comb. Chem. 3, 181-188 (2001) a process for preparing 4-methaneamine imidazoles. Inter alia, the preparation of N-substituted sulfonic acid (imidazol-4-ylmethyl) biarylamides and of N-substituted sulfonic acid (imidazol-4-ylmethyl) biphenylamine amides of formula
wherein the amide substituent R1 is alkyl, cyclohexyl, cyclohexylmethyl, or phenylalkyl, A is —N— or a direct bond, and R2 may be optionally substituted phenyl, is mentioned, for which there is no use or characterizing data therein. The compounds according to the present invention differ from those N-substituted sulfonic acid (imidazol-4-ylmethyl)phenyl amides described above by Saha et al. by lacking the amide substituent R1.
However, with respect to their fungicidal activity, the action of the compounds disclosed is not always completely satisfactory. Based on this, it was an object of the present invention to provide compounds having improved action and/or a broadened activity spectrum against harmful fungi.
This object is achieved by substituted sulfonic acid compounds of formula Ia as defined herein and by the N-oxides and their salts, in particular the agriculturally acceptable salts.
Accordingly, the present invention relates to the use of compounds of formula I
wherein:
Most compounds of formula I are novel. Therefore, according to a second aspect, the invention provides compounds of formula I which are represented by formula Ia
wherein:
The present invention furthermore relates to processes for preparing the substituted sulfonic acid amide compounds of formula Ia.
The present invention furthermore relates to intermediates such as compounds of formulae II, III, IV and V.a to V.h.
The present invention furthermore relates to an agrochemical composition which comprises a solid or liquid carrier and at least one compound of formula I or an N-oxide or an agriculturally acceptable salt thereof.
The compounds of the present invention are useful for combating harmful fungi. Therefore the present invention furthermore relates to a method for combating harmful fungi, which process comprises treating the fungi or the materials, plants, the soil or seeds to be protected against fungal attack, with an effective amount of at least one compound of formula I or of an N-oxide or an agriculturally acceptable salt thereof.
Furthermore, the present invention relates to seed comprising a compound of formula I, or an N-oxide or an agriculturally acceptable salt thereof, in an amount of from 0.1 g to 10 kg per 100 kg of seed.
Depending on the substitution pattern, the compounds of formula I and their N-oxides may have one or more centers of chirality, in which case they are present as pure enantiomers or pure diastereomers or as enantiomer or diastereomer mixtures. Both, the pure enantiomers or diastereomers and their mixtures are subject matter of the present invention.
The compounds of formula I can be present in different crystal modifications whose biological activity may differ. They also form part of the subject matter of the present invention.
Agriculturally useful salts of the compounds I encompass especially the salts of those cations or the acid addition salts of those acids whose cations and anions, respectively, have no adverse effect on the fungicidal action of the compounds I. Suitable cations are thus in particular the ions of the alkali metals, preferably sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, of the transition metals, preferably manganese, copper, zinc and iron, and also the ammonium ion which, if desired, may carry one to four C1-C4-alkyl substituents and/or one phenyl or benzyl substituent, preferably diisopropylammonium, tetramethylammonium, tetrabutylammonium, trimethylbenzylammonium, furthermore phosphonium ions, sulfonium ions, preferably tri(C1-C4-alkyl)sulfonium, and sulfoxonium ions, preferably tri(C1-C4-alkyl)sulfoxonium.
Anions of useful acid addition salts are primarily chloride, bromide, fluoride, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C1-C4-alkanoic acids, preferably formate, acetate, propionate and butyrate. They can be formed by reacting a compound of formula I with an acid of the corresponding anion, preferably of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or nitric acid.
The compounds of formula I can be present in atropisomers arising from restricted rotation about a single bond of asymmetric groups. They also form part of the subject matter of the present invention.
In respect of the variables, the embodiments of the intermediates correspond to the embodiments of the compounds of formula I.
The term “compounds I” refers to compounds of formula I. Likewise, the term “compounds Ia” refers to compounds of formula Ia.
In the definitions of the variables given above, collective terms are used which are generally representative for the substituents in question. The term “Cn-Cm” indicates the number of carbon atoms possible in each case in the substituent or substituent moiety in question.
The term “halogen” refers to fluorine, chlorine, bromine and iodine.
The term “C1-C4-alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl. Likewise, the term “C1-C6-alkyl” refers to a straight-chained or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
The term “C1-C4-haloalkyl” refers to a straight-chained or branched alkyl group having 1 to 4 carbon atoms (as defined above), wherein some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl and pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2,2-difluoropropyl, 2,3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2,3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3,3,3-trifluoropropyl, 3,3,3-trichloropropyl, CH2—C2F5, CF2—C2F5, CF(CF3)2, 1-(fluoromethyl)-2-fluoroethyl, 1-(chloromethyl)-2-chloroethyl, 1-(bromomethyl)-2-bromoethyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl. Likewise, the term “C1-C6-haloalkyl” refers to a straight-chained or branched alkyl group having 1 to 6 carbon atoms.
The term “C1-C4-alkoxy” refers to a straight-chain or branched alkyl group having 1 to 4 carbon atoms (as defined above) which is bonded via an oxygen, at any position in the alkyl group, for example methoxy, ethoxy, n-propoxy, 1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy. Likewise, the term “C1-C4-alkoxy” refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
The term “C1-C4-haloalkoxy” refers to a C1-C4-alkoxy group as defined above, wherein some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example, OCH2F, OCHF2, OCF3, OCH2Cl, OCHCl2, OCCl3, chlorofluoromethoxy, dichlorofluoromethoxy, chlorodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluoroethoxy, 2,2,2-trichloroethoxy, OC2F5, 2-fluoropropoxy, 3-fluoropropoxy, 2,2-difluoropropoxy, 2,3-difluoro
propoxy, 2-chloropropoxy, 3-chloropropoxy, 2,3-dichloropropoxy, 2-bromo
propoxy, 3-bromopropoxy, 3,3,3-trifluoropropoxy, 3,3,3-trichloropropoxy, OCH2—C2F5, OCF2—C2F5, 1-(CH2F)-2-fluoroethoxy, 1-(CH2Cl)-2-chloroethoxy, 1-(CH2Br)-2-bromo
ethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy. Likewise, the term “C1-C6-haloalkoxy” refers to a C1-C6-alkoxy group as defined above, wherein some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above.
The term “C1-C4-alkoxy-C1-C4-alkyl” refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C1-C4-alkoxy group (as defined above). Likewise, the term “C1-C6-alkoxy-C1-C4-alkyl” refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C1-C6-alkoxy group (as defined above).
The term “C1-C4-haloalkoxy-C1-C4-alkyl” refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C1-C4-haloalkoxy group (as defined above). Likewise, the term “C1-C6-haloalkoxy-C1-C4-alkyl” refers to alkyl having 1 to 4 carbon atoms (as defined above), wherein one hydrogen atom of the alkyl radical is replaced by a C1-C6-alkoxy group (as defined above).
The term “C1-C4-alkoxy-C1-C4-alkoxy” refers to an C1-C4-alkoxy-C1-C4-alkyl group (as defined above), which is bonded via an oxygen atom to the remainder of the molecule.
The term “C1-C4-alkylthio” as used herein refers to straight-chain or branched alkyl groups having 1 to 4 carbon atoms (as defined above) bonded via a sulfur atom, at any position in the alkyl group, for example methylthio, ethylthio, propylthio, isopropylthio, and n butylthio. Likewise, the term “C1-C6-alkylthio” as used herein refers to straight-chain or branched alkyl groups having 1 to 6 carbon atoms (as defined above) bonded via a sulfur atom. Accordingly, the terms “C1-C4-haloalkylthio” and “C1-C6-haloalkylthio” as used herein refer to straight-chain or branched haloalkyl groups having 1 to 4 or 1 to 6 carbon atoms (as defined above) bonded through a sulfur atom, at any position in the haloalkyl group.
The terms “C1-C4-alkylsulfinyl” or “C1-C6-alkylsulfinyl” refer to straight-chain or branched alkyl groups having 1 to 4 or 1 to 6 carbon atoms (as defined above) bonded through a —S(═O)— moiety, at any position in the alkyl group, for example methylsulfinyl and ethylsulfinyl, and the like. Accordingly, the terms “C1-C4-haloalkylsulfinyl” and “C1-C6-haloalkylsulfinyl”, respectively, refer to straight-chain or branched haloalkyl groups having 1 to 4 and 1 to 6 carbon atoms (as defined above), respectively, bonded through a —S(═O)— moiety, at any position in the haloalkyl group.
The terms “C1-C4-alkylsulfonyl” and “C1-C6-alkylsulfonyl”, respectively, refer to straight-chain or branched alkyl groups having 1 to 4 and 1 to 6 carbon atoms (as defined above), respectively, bonded through a —S(═O)2— moiety, at any position in the alkyl group, for example methylsulfonyl. Accordingly, the terms “C1-C4-haloalkylsulfonyl” and “C1-C6-haloalkylsulfonyl”, respectively, refer to straight-chain or branched haloalkyl groups having 1 to 4 and 1 to 6 carbon atoms (as defined above), respectively, bonded through a —S(═O)2— moiety, at any position in the haloalkyl group.
The term “C1-C4-alkylamino” refers to an amino radical carrying one C1-C4-alkyl group (as defined above) as substituent, for example methylamino, ethylamino, propylamino, 1-methylethylamino, butylamino, 1-methylpropylamino, 2-methylpropylamino, 1,1-dimethylethylamino and the like. Likewise, the term “C1-C6-alkylamino” refers to an amino radical carrying one C1-C6-alkyl group (as defined above) as substituent.
The term “di(C1-C4-alkyl)amino” refers to an amino radical carrying two identical or different C1-C4-alkyl groups (as defined above) as substituents, for example dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, N-ethyl-N-methylamino, N-(n-propyl)-N-methylamino, N-(isopropyl)-N methylamino, N-(n-butyl)-N-methylamino, N-(n-pentyl)-N-methylamino, N-(2-butyl)-N methylamino, N-(isobutyl)-N-methylamino, and the like. Likewise, the term “di(C1-C6-alkyl)amino” refers to an amino radical carrying two identical or different C1-C6-alkyl groups (as defined above) as substituents.
The term “(C1-C4-alkoxy)carbonyl” refers to a C1-C4-alkoxy radical (as defined above) which is attached via a carbonyl group.
The term “di(C1-C4-alkyl)aminocarbonyl” refers to a di(C1-C4)alkylamino radical as defined above which is attached via a carbonyl group.
The term “phenoxy” and refers to a phenyl radical which is attached via an oxygen atom. Likewise, the term “phenoxy-C1-C4-alkyl” and refers to a phenoxy radical which is attached via a C1-C4-alkyl group (as defined above).
The term “C2-C4-alkenyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 4 carbon atoms and a double bond in any position, such as ethenyl, 1-propenyl, 2-propenyl (allyl), 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl. Likewise, the term “C2-C6-alkenyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and a double bond in any position.
The term “C2-C4-alkynyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 4 carbon atoms and containing at least one triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl. Likewise, the term “C2-C6-alkynyl” refers to a straight-chain or branched unsaturated hydrocarbon radical having 2 to 6 carbon atoms and at least one triple bond.
The term “C3-C8-cycloalkyl” refers to monocyclic saturated hydrocarbon radicals having 3 to 8 carbon ring members, such as cyclopropyl (C3C5), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term “C1-C4-alkyl-C3-C8-cycloalkyl” refers to a cycloalkyl radical having 3 to 8 carbon atoms (as defined above), wherein one hydrogen atom of the cycloalkyl radical is replaced by a C1-C4-alkyl group (as defined above).
The term “5-, 6- or 7-membered carbocycle” is to be understood as meaning both saturated or partially unsaturated carbocycles having 5, 6 or 7 ring members as well as phenyl. Examples for non-aromatic rings include cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, and the like.
The term “5-, 6-, or 7-membered heterocycle” wherein the ring member atoms of the heterocycle include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, is to be understood as meaning both saturated and partially unsaturated as well as aromatic heterocycles having 5, 6 or 7 ring atoms. Examples include:
The term “C1-C4-alkanediyl” refers to a divalent, branched, or straight-chain saturated hydrocarbon radical having 1 to 4 carbon atoms, derived from a C1-C4-alkyl group (as defined above) that has two points of attachment.
As used herein, the term “C3-C8-cycloalkylene” refers to a divalent radical derived from a C3-C8-cycloalkyl group (as defined above) that has two points of attachment. Likewise, the term “C3-C8-cycloalkenylene” refers to a divalent radical derived from a C3-C8-cycloalkenyl group (as defined above) that has two points of attachment. Accordingly, the term “heterocyclylene” refers to a heterocyclyl group (as defined above) that has two points of attachment.
Furthermore, the term “5- or 6-membered heteroarenediyl” refers to a divalent radical derived from an aromatic heteroaryl (as defined above) having two points of attachment. Examples of heteroarenediyl radicals are, for example, divalent radicals derived from pyridine, pyrimidine, pyridazine, 1,2,3-triazine, 1,2,4-triazine, 1,2,3,4-tetrazine, furan, thiophene, pyrrole, thiazole, thiadiazole, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, isothiazole, oxadiazole and the like. The aforementioned groups can be C-attached or N-attached where such is possible. For example, a group derived from pyrrole, imidiazole or pyrazole can be N-attached or C-attached.
The term “phenylene” refers to 1,2-phenylene (o-phenylene), 1,3-phenylene (m-phenylene) and 1,4-phenylene (p-phenylene).
The term “two radicals Ra that are bound to adjacent ring member atoms of the Het group may form together with said ring member atoms a fused cycle” refers to a condensed bicyclic ring system, wherein the heteroaryl carries a fused-on 5-, 6- or 7-membered carbocyclic or heterocyclic ring.
The term “two radicals Rc that are bound to adjacent ring member atoms of the D group may form together with said ring member atoms a fused cycle” refers to a condensed bicyclic ring system, wherein the C3-C8-cycloalkyl, phenyl and 5- or 6-membered heteroaryl, respectively carry a fused-on 5-, 6- or 7-membered carbocyclic or heterocyclic ring.
As regards the fungicidal activity of the compounds I, preference is given to those compounds I and where applicable also to compounds of all sub-formulae provided herein, for example formula I.a or formulae I.A to I.K and to the intermediates such as compounds II, III, IV and V.a to V.h, wherein the substituents and variables (e.g. Het, A, Y, D, Ra, Rb, Rc, Rd, Re, R′, R″ and R′″) have independently of each other or more preferably in combination the following meanings:
In a first embodiment, Het carries one heteroatom as ring member atom. Preference is given to compounds I, in which Het is a furanyl radical that is selected from furan-2-yl and furan-3-yl, where the aforementioned furanyl radicals carry 1, 2 or 3 identical or different substituents Ra. Preference is given to compounds I, in which Het is a thienyl radical that is selected from thien-2-yl and thien-3-yl, where the aforementioned thienyl radicals. Preference is given to compounds I, in which Het is a pyrrolyl radical that is selected from pyrrol-2-yl and pyrrol-3-yl.
In a further embodiment, Het carries 2 heteroatoms as ring member atoms, preferably at least one of these heteroatoms is N. Preference is given to compounds I, in which Het is a pyrazolyl radical that is selected from pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl, where the aforementioned pyrazolyl radicals carry 1, 2 or 3 identical or different substituents Ra. Preference is given to compounds I, in which Het is an isoxazolyl radical that is selected from isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, where the aforementioned isoxazolyl radicals carry 1 or 2 identical or different substituents Ra. Preference is given to compounds I, in which Het is an isothiazolyl radical that is selected from isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl, where the aforementioned isothiazolyl radicals carry 1 or 2 identical or different substituents Ra. Preference is given to compounds I, in which Het is an imidazolyl radical that is selected from imidazol-2-yl, imidazol-4-yl and imidazol-5-yl, where the aforementioned imidazolyl radicals carry 1, 2 or 3 identical or different substituents Ra. Preference is given to compounds I, in which Het is an oxazolyl radical that is selected from oxazol-2-yl, oxazol-4-yl and oxazol-5-yl, where the aforementioned oxazolyl radicals carry 1 or 2 identical or different substituents Ra. Preference is given to compounds I, in which Het is a thiazolyl radical that is selected from thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, where the aforementioned thiazolyl radicals carry 1 or 2 identical or different substituents Ra.
In a further embodiment, Het carries 3 heteroatoms as ring member atoms, preferably at least two of these heteroatoms are N. Preference is given to compounds I, in which Het is a 1,2,3-triazolyl radical that is selected from 1,2,3-triazol-4-yl and 1,2,3-triazol-5-yl, where the aforementioned 1,2,3-triazolyl radicals carry 1 or 2 identical or different substituents Ra. Preference is given to compounds I, in which Het is a 1,2,4-triazolyl radical that is selected from 1,2,4-triazol-3-yl and 1,2,4-triazol-5-yl, where the aforementioned 1,2,4-triazolyl radicals carry 1 or 2 identical or different substituents Ra. Preference is given to compounds I, in which Het is an 1,2,4-oxadiazolyl radical that is selected from 1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl, where the aforementioned 1,2,4-oxadiazolyl radicals carry one substituent Ra. Preference is given to compounds I, in which Het is an 1,3,4-oxadiazolyl radical that is selected from 1,3,4-oxadiazol-2-yl and 1,3,4-oxadiazol-5-yl, where the aforementioned 1,3,4-oxadiazolyl radicals carry one substituent Ra. Preference is given to compounds I, in which Het is a 1,2,3-thiadiazolyl radical that is selected from 1,2,3-thiadiazol-4-yl and 1,2,3-thiadiazol-5-yl, where the aforementioned 1,2,3-thiadiazolyl radicals carry 1 substituent Ra. Preference is given to compounds I, in which Het is a 1,2,4-thiadiazolyl radical that is selected from 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl, where the aforementioned 1,2,4-thiadiazolyl radicals carry 1 substituent Ra. Preference is given to compounds I, in which Het is a 1,3,4-thiadiazolyl radical that is selected from 1,3,4-thiadiazol-2-yl and 1,3,4-thiadiazol-5-yl, where the aforementioned 1,3,4-thiadiazolyl radicals carry 1 substituent Ra.
More preferred embodiments relate to compounds I and to its intermediates, wherein Het is one of the following radicals Het-a to Het-qq:
One embodiment relates to compounds I, wherein n is 1, 2, 3 or 4, more preferably n is 1 or 2. Another embodiment relates to compounds I, wherein n is 1. A further embodiment relates to compounds I, wherein n is 2. A further embodiment relates to compounds I, wherein n is 3.
A further embodiment relates to compounds I, wherein two radicals Ra that are bound to adjacent ring member atoms of the Het group do not form together with said ring member atoms any fused cycle.
Preferably, Ra is halogen, CN, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkoxy-C1-C4-alkyl, C3-C8-cycloalkyl or C1-C4-alkyl-C3-C8-cycloalkyl.
A further preferred embodiment relates to compounds I, wherein Ra is halogen and preferably selected from fluorine and chlorine and in particular, Ra is chlorine.
A further preferred embodiment relates to compounds I, wherein Ra is CN.
A further embodiment relates to compounds I, wherein Ra is C1-C4-alkyl and preferably selected from methyl, ethyl, n-propyl and i-propyl.
A further preferred embodiment relates to compounds I, wherein Ra is C1-C4-haloalkyl and preferably Ra is C1-C4-haloalkyl and selected from fluormethyl, difluormethyl, trifluormethyl, chlormethyl, dichlormethyl and trichlormethyl, and in particular, Ra is trifluormethyl.
A further preferred embodiment relates to compounds I, wherein Ra is C1-C4-alkoxy and preferably selected from methoxy, ethoxy, n-propyloxy and i-propyloxy.
A further preferred embodiment relates to compounds I, wherein Ra is C1-C4-haloalkoxy and preferably halomethoxy, such as difluormethoxy, trifluormethoxy, dichlormethoxy and trichlormethoxy, and haloethoxy, such as 2,2-difluorethoxy, 2,2,2-trifluorethoxy, 2,2-dichlorethoxy and 2,2,2-trichlorethoxy, and halo-n-propoxy, halo-i-propoxy, halo-n-butoxy, halo-1-methyl-propoxy, halo-2-methyl-propoxy or halo-1,1-dimethylethoxy.
A further preferred embodiment relates to compounds I, wherein Ra is C3-C8-cycloalkyl and preferably selected from cyclopropyl, cyclopentyl and cyclohexyl, and in particular, Ra is cyclopropyl.
A further embodiment relates to compounds I, wherein 2 radicals Ra that are bound to adjacent ring member atoms of the Het group form together with said ring member atoms a fused cycle being a fused 5-, 6- or 7-membered saturated, partially unsaturated or aromatic carbocycle or heterocycle, wherein the ring member atoms of the fused heterocycle include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein the fused carbocycle or heterocycle is unsubstituted and carries 1, 2, 3 or 4 identical or different radicals selected from the group consisting of halogen, CN, C1-C4-aralkoxy, C1-C4-haloalkyl and C1-C4-haloalkoxy. In the abovementioned embodiment, the fused cycle is preferably phenyl. In the abovementioned embodiment, the fused cycle is preferably a saturated carbocycle and in particular cyclohexyl. In the abovementioned embodiment, the fused cycle is preferably a partially unsaturated carbocycle and in particular cyclohexenyl.
Preference is given to compounds I, wherein two radicals Ra that are bound to adjacent ring member atoms of the Het group form together with said ring member atoms a fused optionally substituted 6-membered heteroaryl. In the abovementioned embodiment, the fused heteroaryl is pyridyl. In the abovementioned embodiment, the fused heteroaryl is pyridazinyl. In the abovementioned embodiment, the fused heteroaryl is pyrimidinyl. In the abovementioned embodiment, the fused heteroaryl is pyrazinyl.
Preference is given to compounds I, wherein two radicals Ra that are bound to adjacent ring member atoms of the Het group form together with said ring member atoms a fused optionally substituted 5-membered heteroaryl. In the abovementioned embodiment, the fused heteroaryl is furanyl. In the abovementioned embodiment, the fused heteroaryl is thienyl. In the abovementioned embodiment, the fused heteroaryl is pyrrolyl. In the abovementioned embodiment, the fused heteroaryl is pyrazolyl. In the abovementioned embodiment, the fused heteroaryl is isoxazolyl. In the abovementioned embodiment, the fused heteroaryl is isothiazolyl. In the abovementioned embodiment, the fused heteroaryl is imidazolyl. In the abovementioned embodiment, the fused heteroaryl is oxazolyl. In the abovementioned embodiment, the fused heteroaryl is thiazolyl.
In one embodiment, the two radicals Ra that are bound to adjacent ring member atoms of the Het group form together with said ring member atoms a fused 5-, 6- or 7-membered saturated, partially unsaturated or aromatic carbocycle or heterocycle, wherein the ring member atoms of the fused heterocycle include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein the fused carbocycle or heterocycle is unsubstituted.
In a further embodiment, two radicals Ra that are bound to adjacent ring member atoms of the Het group form together with said ring member atoms a fused 5-, 6- or 7-membered saturated, partially unsaturated or aromatic carbocycle or heterocycle, wherein the ring member atoms of the fused heterocycle include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein the fused carbocycle or heterocycle is substituted by 1, 2, 3 or 4 identical or different radicals selected from the group consisting of halogen, CN, C1-C4-alkoxy, alkyl and C1-C4-haloalkoxy.
One embodiment relates to compounds I, wherein A is phenylene or heteroarenediyl, as defined above, which both are unsubstituted or carry 1, 2, 3 or 4 identical or different substituents Rb.
Preference is given to compounds I, wherein A is phenylene, which is unsubstituted or carries 1, 2, 3 or 4 identical or different substituents Rb, with 1,3-phenylene or 1,4-phenylene being more preferred. More preference is given to compounds I, wherein A is 1,4-phenylene, which is unsubstituted or carries 1, 2 or 3 identical or different substituents Rb, in particular A is 1,4-phenylene, which is unsubstituted.
A further embodiment relates to compounds I, wherein A is C3-C8-cycloalkylene and preferably selected from 1,2-cyclohexylene, 1,3-cyclohexylene and 1,4-cyclohexylene, and wherein the aforementioned radicals are unsubstituted or carry 1, 2, 3 or 4 identical or different substituents Rb.
A further embodiment relates to compounds I, wherein A is a saturated or partially unsaturated heterocyclylene, wherein preferably the heterocyclylene, carries 1 or 2 heteroatoms as ring member atoms, more preferably one of these heteroatoms is N, wherein the aforementioned radicals are unsubstituted or carry 1, 2, 3 or 4 identical or different substituents Rb.
Likewise, a further embodiment relates to compounds I, wherein A is heteroarenediyl, and selected from the group consisting of pyridindiyl, pyrimidindiyl, pyridazindiyl, pyrazindiyl, triazindiyl, furandiyl, thiendiyl, pyrroldiyl, pyrazoldiyl, isoxazoldiyl, isothiazoldiyl, imidazoldiyl, oxazoldiyl, thiazoldiyl, triazoldiyl, thiadiazoldiyl, oxadiazoldiyl and tetrazoldiyl, and wherein the 18 last-mentioned radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rb. If one point of attachment is located on a nitrogen atom of the heteroarenediyl radical, said nitrogen atom is attached either to the sulfur atom of the sulfonamide group or to Y, with the point of attachment to Y being more preferred. In the abovementioned embodiment, the heteroarenediyl A preferably carries one heteroatom as ring member atoms, particularly the heteroatom is S. In the abovementioned embodiment, the heteroarenediyl A preferably carries 2 heteroatoms as ring member atoms, more preferably one of these heteroatoms is N. In the abovementioned embodiment, the heteroarenediyl A preferably carries 3 heteroatoms as ring member atoms, more preferably one of these heteroatoms is N. In the abovementioned embodiment, A is pyridindiyl. In the abovementioned embodiment, A is pyrimidindiyl. In the abovementioned embodiment, A is pyridazindiyl. In the abovementioned embodiment, A is pyrazindiyl. In the abovementioned embodiment, A is furandiyl. In the abovementioned embodiment, A is thiendiyl. In the abovementioned embodiment, A is pyrroldiyl. In the abovementioned embodiment, A is pyrazoldiyl. In the abovementioned embodiment, A is isoxazoldiyl. In the abovementioned embodiment, A is isothiazoldiyl. In the abovementioned embodiment, A is imidazoldiyl. In the abovementioned embodiment, A is oxazoldiyl. In the abovementioned embodiment, A is thiazoldiyl. In the abovementioned embodiment, A is 1,2,4-triazoldiyl. In the abovementioned embodiment, A is 1,2,4-thiadiazoldiyl. In the abovementioned embodiment, A is 1,2,4-oxadiazoldiyl.
Amongst compounds I, in which A is a 6-membered heteroarenediyl, particular preference given to those, in which A is pyridindiyl or pyrimidinyl and more preferably selected from pyridin-2,5-diyl, pyridin-2,6-diyl, pyridin-2,4-diyl, pyridin-3,5-diyl, pyrimidin-2,5-diyl, pyrimidin-2,4-diyl and pyrimidin-4,6-diyl, wherein each of the aforementioned 9 radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rb.
Amongst compounds I, in which A is a 5-membered heteroarenediyl, particular preference given to those, in which A is thiendiyl, thiazoldiyl, oxazoldiyl, pyrazoldiyl or pyridindiyl and more preferably is selected from the group consisting of thiophen-2,5-diyl, thiophen-2,4-diyl, thiophen-3,5-diyl, thiazol-2,5-diyl, thiazol-2,4-diyl, oxazol-2,5-diyl, oxazol-2,4-diyl, pyrazol-3,5-diyl, pyrazol-1,3-diyl and pyrazol-1,4-diyl, wherein each of the aforementioned 15 radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rb.
Particularly preferred embodiments relate to compounds I, in which A is one of the following radicals A-1 to A-138:
In one embodiment, the group A of compounds I carries 1 or 2 radicals Rb. In another embodiment, the group A of compounds I is unsubstituted or carries 1 radical Rb. In a further embodiment, the group A is unsubstituted. In a further embodiment, the group A carries 1 radical Rb. In a further embodiment, the group A carries 2 radicals Rb.
In one embodiment, Rb is halogen and preferably selected from fluorine and chlorine, and in particular, Rb is chlorine.
In a further embodiment, Rb is C1-C4-alkyl and selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-methyl-propyl, 2-methyl-propyl and 1,1-dimethylethyl, and preferably selected from methyl, ethyl, n-propyl and i-propyl, and in particular, Rb is methyl.
In a further embodiment, Rb is C1-C4-haloalkyl and preferably, Rb is C1-haloalkyl and selected from fluormethyl, difluormethyl, trifluormethyl, chlormethyl, dichlormethyl and trichlormethyl, and in particular, Rb is trifluormethyl.
In a further embodiment, Rb is C1-C4-alkoxy and selected from methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, 1-methyl-propyloxy, 2-methyl-propyloxy and 1,1-dimethylethyloxy, and in particular from methoxy and ethoxy.
In a further embodiment, Rb is C1-C4-haloalkoxy and preferably halomethoxy, such as difluormethoxy, trifluormethoxy, dichlormethoxy and trichlormethoxy, and haloethoxy, such as 2,2-difluorethoxy, 2,2,2-trifluorethoxy, 2,2-dichlorethoxy and 2,2,2-trichlorethoxy, and halo-n-propoxy, halo-i-propoxy, halo-n-butoxy, halo-1-methyl-propoxy, halo-2-methyl-propoxy or halo-1,1-dimethylethoxy.
One embodiment relates to compounds I, wherein Y is a direct bond or —O—. Another embodiment relates to compounds I, wherein Y is a direct bond, which are represented by formula I.A:
A further embodiment relates to compounds I, wherein Y is —O—, which are represented by formula I.B:
A further embodiment relates to compounds I, wherein Y is —N()—, wherein
is hydrogen or C1-C4-alkyl. If
is present, in one embodiment,
is C1-C4-alkyl, and selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, 1-methyl-propyl, 2-methyl-propyl and 1,1-dimethylethyl, and preferably selected from methyl, ethyl, n-propyl and i-propyl, and in particular,
is methyl. Particularly preferred compounds I, wherein Y is —N(CH3)—, which are represented by formula I.C:
A further embodiment relates to compounds I, wherein Y is —NH—, which are represented by formula I.D:
A further embodiment relates to compounds I, wherein Y is —S—, which are represented by formula I.E:
A further embodiment relates to compounds I, wherein Y is —S(═O)—, which are represented by formula I.F:
A further embodiment relates to compounds I, wherein Y is —S(═O)2—, which are represented by formula I.G:
A further embodiment relates to compounds I, wherein Y is —CH2—, which are represented by formula I.H:
A further embodiment relates to compounds I, wherein Y is —O(CH2)—, which are represented by formula I.J:
A further embodiment relates to compounds I, wherein Y is —(CH2)O—, which are represented by formula I.K:
One embodiment relates to compounds I, wherein D is C3-C8-cycloalkyl and preferably selected from cyclopropyl, cyclopentyl and cyclohexyl, and in particular cyclohexyl, and wherein the aforementioned radicals are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different substituents Rc.
Another embodiment relates to compounds I, wherein D is phenyl, which is unsubstituted or carries 1, 2, 3, 4 or 5 identical or different substituents Rc.
A further embodiment relates to compounds I, in which D is a 6-membered heteroaryl, wherein the ring member atoms of the heteroaryl include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein the 6-membered heteroaryl is unsubstituted or carries 1, 2, 3 or 4 identical or different groups Rc.
If D is a 6-membered heteroaryl, in one embodiment, D carries at least one nitrogen as ring member atom. Preference is given to compounds I, in which D is a pyridyl radical that is selected from pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, and wherein the aforementioned pyridyl radicals are unsubstituted or carry 1, 2, 3 or 4 identical or different substituents R. Preference is also given to compounds I, in which D is a pyridazinyl radical that is selected from pyridazin-3-yl and pyridazin-4-yl, and wherein the aforementioned pyridazinyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc. Preference is given to compounds I, in which D is a pyrimidinyl radical that is selected from pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl and pyrimidin-6-yl, and wherein the aforementioned pyrimidinyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc. Preference is given to compounds I, in which D is a pyrazinyl radical that is selected from pyrazin-2-yl and pyrazin-3-yl, and wherein the aforementioned pyrazinyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc.
Another embodiment relates to compounds I in which D is a 5-membered heteroaryl, wherein the ring member atoms of the heteroaryl include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein the 5-membered heteroaryl is unsubstituted or carries 1, 2, 3 or 4 identical or different groups Rc.
If D is a 5-membered heteroaryl, in one embodiment, D carries at least one nitrogen as ring member atom.
If D is a 5-membered heteroaryl, in one embodiment, D carries one heteroatom as ring member atom. Preference is given to compounds I, in which D is a furanyl radical that is selected from furan-2-yl and furan-3-yl, and wherein the aforementioned furanyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc. Preference is given to compounds I, in which D is a thienyl radical that is selected from thien-2-yl and thien-3-yl, and wherein the aforementioned thienyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc. Preference is given to compounds I, in which D is a pyrrolyl radical that is selected from pyrrol-2-yl and pyrrol-3-yl, and wherein the aforementioned pyrrolyl radicals are unsubstituted or carry 1, 2, 3 or 4 identical or different substituents Rc.
If D is a 5-membered heteroaryl, in another embodiment, D carries 2 heteroatoms as ring member atoms. In the aforementioned embodiment, more preferably Het carries at least one nitrogen as ring member atom. Preference is given to compounds I, in which D is a pyrazolyl radical that is selected from pyrazol-3-yl, pyrazol-4-yl and pyrazol-5-yl, and wherein the aforementioned pyrazolyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc. Preference is given to compounds I, in which D is an isoxazolyl radical that is selected from isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, and wherein the aforementioned isoxazolyl radicals are unsubstituted or carry 1 or 2 identical or different substituents Rc. Preference is given to compounds I, in which D is an isothiazolyl radical that is selected from isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl, and wherein the aforementioned isothiazolyl radicals are unsubstituted or carry 1 or 2 identical or different substituents Rc. Preference is given to compounds I, in which D is an imidazolyl radical that is selected from imidazol-2-yl, imidazol-4-yl and imidazol-5-yl, and wherein the aforementioned imidazolyl radicals are unsubstituted or carry 1, 2 or 3 identical or different substituents Rc. Preference is given to compounds I, in which D is an oxazolyl radical that is selected from oxazol-2-yl, oxazol-4-yl and oxazol-5-yl, and wherein the aforementioned oxazolyl radicals are unsubstituted or carry 1 or 2 identical or different substituents Rc. Preference is given to compounds I, in which D is a thiazolyl radical that is selected from thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, and wherein the aforementioned thiazolyl radicals are unsubstituted or carry 1 or 2 identical or different substituents Rc.
If D is a 5-membered heteroaryl, in another embodiment, D carries 3 heteroatoms as ring member atoms. In the aforementioned embodiment, more preferably Het carries at least 2 nitrogens as ring member atoms. Preference is given to compounds I, in which D is a 1,2,3-triazolyl radical that is selected from 1,2,3-triazol-4-yl and 1,2,3-triazol-5-yl, and wherein the aforementioned 1,2,3-triazolyl radicals are unsubstituted or carry 1 or 2 identical or different substituents R. Preference is given to compounds I, in which D is a 1,2,4-triazolyl radical that is selected from 1,2,4-triazol-3-yl and 1,2,4-triazol-5-yl, and wherein the aforementioned 1,2,4-triazolyl radicals are unsubstituted or carry 1 or 2 identical or different substituents Rc. Preference is given to compounds I, in which D is an 1,2,4-oxadiazolyl radical that is selected from 1,2,4-oxadiazol-3-yl and 1,2,4-oxadiazol-5-yl, and wherein the aforementioned 1,2,4-oxadiazolyl radicals are unsubstituted or carry one substituent Rc. Preference is given to compounds I, in which D is an 1,3,4-oxadiazolyl radical that is selected from 1,3,4-oxadiazol-2-yl and 1,3,4-oxadiazol-5-yl, and wherein the aforementioned 1,3,4-oxadiazolyl radicals are unsubstituted or carry one substituent Rc. Preference is given to compounds I, in which D is a 1,2,3-thiadiazolyl radical that is selected from 1,2,3-thiadiazol-4-yl and 1,2,3-thiadiazol-5-yl, and wherein the aforementioned 1,2,3-thiadiazolyl radicals are unsubstituted or carry one substituent Rc. Preference is given to compounds I, in which D is a 1,2,4-thiadiazolyl radical that is selected from 1,2,4-thiadiazol-3-yl and 1,2,4-thiadiazol-5-yl, and wherein the aforementioned 1,2,4-thiadiazolyl radicals are unsubstituted or carry one substituent Rc. Preference is given to compounds I, in which D is a 1,3,4-thiadiazolyl radical that is selected from 1,3,4-thiadiazol-2-yl and 1,3,4-thiadiazol-5-yl, and wherein the aforementioned 1,3,4-thiadiazolyl radicals are unsubstituted or carry one substituent Rc.
Particularly preferred embodiments relate to compounds I, in which D is one of the following radicals D-1 to D-50:
One embodiment relates to compounds I, wherein D carries 1, 2 or 3 radicals Rc. Another embodiment relates to compounds I, wherein D carries 1 or 2 radicals Rc. A further embodiment relates to compounds I, wherein D carries one radical Rc. A further embodiment relates to compounds I, wherein D carries 2 radicals Rc. A further embodiment relates to compounds I, wherein D carries 3 radicals Rc. A further embodiment relates to compounds I, wherein D is unsubstituted.
In a further embodiment, two radicals Rc that are bound to adjacent ring member atoms of the D group do not form together with said ring member atoms any fused cycle.
In one embodiment, Rc is halogen and preferably selected from fluorine and chlorine and in particular, Rc is chlorine. In another embodiment, Rc is CN.
In a further embodiment, Rc is C1-C4-alkyl and preferably selected from methyl, ethyl, n-propyl and i-propyl, and in particular, Rc is methyl.
In a further embodiment, Rc is C1-C4-haloalkyl and more preferably, Rc is C1-haloalkyl and selected from fluormethyl, difluormethyl, trifluormethyl, chlormethyl, dichlormethyl and trichlormethyl, and in particular, Rc is trifluormethyl.
In a further embodiment, Rc is C1-C4-alkoxy and preferably selected from methoxy and ethoxy.
In a further embodiment, Rc is C1-C4-haloalkoxy and preferably halomethoxy, such as difluormethoxy, trifluormethoxy, dichlormethoxy and trichlormethoxy, and haloethoxy, such as 2,2-difluorethoxy, 2,2,2-trifluorethoxy, 2,2-dichlorethoxy and 2,2,2-trichlorethoxy, and halo-n-propoxy, halo-i-propoxy, halo-n-butoxy, halo-1-methyl-propoxy, halo-2-methyl-propoxy or halo-1,1-dimethylethoxy.
In a further embodiment, Rc is C3-C8-cycloalkyl and preferably selected from cyclopropyl, cyclopentyl and cyclohexyl, and in particular, Rc is cyclopropyl.
In a further embodiment, Rc is phenyl.
In a further embodiment, Rc is phenoxy.
In a further embodiment, Rc is a 6-membered heteroaryl, wherein the ring member atoms of the heteroaryl include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein Rc is unsubstituted or carries 1, 2, 3 or 4 identical or different groups Rd.
Another preferred embodiment relates to compounds I, wherein Rc is a 5-membered heteroaryl, wherein the ring member atoms of the heteroaryl include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein Rc is unsubstituted or carries 1, 2, 3 or 4 identical or different groups Rd.
Preference is given to compounds I, wherein two radicals Rc that are bound to adjacent ring member atoms of the Het group form together with said ring member atoms a fused optionally substituted 6-membered heteroaryl, wherein the fused 6-membered heteroaryl is unsubstituted and carries 1, 2, 3 or 4 identical or different Rc radicals. In the abovementioned embodiment, the fused heteroaryl is pyridyl. In the abovementioned embodiment, the fused heteroaryl is pyridazinyl. In the abovementioned embodiment, the fused heteroaryl is pyrimidinyl. In the abovementioned embodiment, the fused heteroaryl is pyrazinyl.
Preference is given to compounds I, wherein two radicals Rc that are bound to adjacent ring member atoms of the D group form together with said ring member atoms a fused optionally substituted 5-membered heteroaryl, wherein the fused 5-membered heteroaryl is unsubstituted and carries 1, 2, 3 or 4 identical or different Rc radicals. In the abovementioned embodiment, the fused heteroaryl is furanyl. In the abovementioned embodiment, the fused heteroaryl is thienyl. In the abovementioned embodiment, the fused heteroaryl is pyrrolyl. In the abovementioned embodiment, the fused heteroaryl is pyrazolyl. In the abovementioned embodiment, the fused heteroaryl is isoxazolyl. In the abovementioned embodiment, the fused heteroaryl is isothiazolyl. In the abovementioned embodiment, the fused heteroaryl is imidazolyl. In the abovementioned embodiment, the fused heteroaryl is oxazolyl. In the abovementioned embodiment, the fused heteroaryl is thiazolyl.
In a further embodiment, two radicals Rc that are bound to adjacent ring member atoms of the D group form together with said ring member atoms a fused 5-, 6- or 7-membered saturated, partially unsaturated or aromatic carbocycle or heterocycle, wherein the ring member atoms of the fused heterocycle include besides carbon atoms 1, 2, 3 or 4 heteroatoms selected from the group of N, O and S, and wherein the fused carbocycle or heterocycle is substituted by 1, 2, 3 or 4 Re radicals, and preferably, by 1, 2 or 3 Re radicals, more preferably by 1 or 2 Re radicals, and in particular by 1 radical Re. In the abovementioned embodiment, Re is preferably halogen and preferably selected from fluorine and chlorine and in particular, chlorine. In the abovementioned embodiment, Re is preferably CN. In the abovementioned embodiment, Re is preferably C1-C4-alkyl and in particular, Re is methyl. In the abovementioned embodiment, Re is preferably C1-C4-alkoxy and preferably selected methoxy and ethoxy. In the abovementioned embodiment, Re is preferably C1-C4-haloalkyl and more preferably, Re is C1-haloalkyl and selected from fluormethyl, difluormethyl, trifluormethyl, chlormethyl, dichlormethyl and trichlormethyl, and in particular Re is trifluormethyl.
If Rc is C(═O)R′, in one embodiment, R′ is selected from NH2, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy-C1-C4-alkoxy, C1-C4-haloalkoxy, C1-C4-alkylamino and di(C1-C4-alkyl)amino. If Rc is C(═O)R′, R′ is preferably NH2. If Rc is C(═O)R′, R′ is preferably C1-C4-alkyl and in particular, R′ is methyl. If Rc is C(═O)R′, R′ is preferably C1-C4-alkoxy and selected from methoxy, ethoxy, n-propyloxy, propyloxy, n-butyloxy, 1-methyl-propyloxy, 2-methyl-propyloxy and 1,1-dimethylethyloxy and in particular, from methoxy and ethoxy.
If Rc is C(═NOR″)R′″, in one embodiment, R′″ is C1-C4-alkyl, C1-C4-haloalkyl, C2-C4-alkenyl, C2-C4-alkynyl or C1-C4-alkoxy-C1-C4-alkyl.
If Rc is C(═NOR″)R′″, R″ is preferably C1-C4-alkyl and in particular, R″ is methyl. If Rc is C(═NOR″)R′″, R″ is preferably C2-C4-alkenyl and selected from vinyl, prop-1-en-3-yl, but-1-en-3-yl, but-1-en-4-yl and but-2-en-1-yl. If Rc is C(═NOR″)R′″, R″ is preferably C2-C4-alkynyl and selected from prop-1-in-3-yl, but-1-in-3-yl, but-1-in-4-yl and but-2-in-1-yl. If Rc is C(═NOR″)R′″, R″ is preferably C1-C4-alkoxy-C1-C4-alkyl and selected from methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl.
If Rc is C(═NOR″)R′″, in an embodiment, R′″ is C1-C4-alkyl and preferably selected from methyl, ethyl, n-propyl, i-propyl, and in particular, R′″ is methyl. If Rc is C(═NOR″)R′″, in another embodiment, R′″ is hydrogen.
If Rc is present, one embodiment relates to compounds I, wherein Rc carries 1, 2, 3 or 4 radicals Rd, preferably 1, 2 or 3 radicals Rd, and more preferably 1 or 2 radicals Rd. In a particularly preferred embodiment, Rc carries 1 radical Rd. In another particularly preferred embodiment, Rc carries 2 radicals Rd. In a further particularly preferred embodiment the group Rc carries 3 radicals Rd.
In one embodiment, Rd is halogen and preferably selected from fluorine and chlorine and in particular, Rc is chlorine. In another embodiment, Rd is CN.
In a further embodiment, Rd is C1-C4-alkyl and preferably selected from methyl, ethyl, n-propyl and i-propyl and in particular, Rd is methyl.
In a further embodiment, Rd is C1-C4-haloalkyl and more preferably, Rc is C1-haloalkyl and selected from fluormethyl, difluormethyl, trifluormethyl, chlormethyl, dichlormethyl and trichlormethyl, and in particular, Rd is trifluormethyl.
In a further embodiment, Rd is C1-C4-alkoxy and preferably selected from methoxy and ethoxy.
In a further embodiment, Rd is C1-C4-haloalkoxy and preferably halomethoxy, such as difluormethoxy, trifluormethoxy, dichlormethoxy and trichlormethoxy, and haloethoxy, such as 2,2-difluorethoxy, 2,2,2-trifluorethoxy, 2,2-dichlorethoxy and 2,2,2-trichlorethoxy, and halo-n-propoxy, halo-i-propoxy, halo-n-butoxy, halo-1-methyl-propoxy, halo-2-methyl-propoxy or halo-1,1-dimethylethoxy.
A skilled person will readily understand that the preferences given in connection with compounds I apply for formula Ia and formulae I.A to I.K as defined above.
The compounds I can be prepared by various routes in analogy-to prior art processes known per se for preparing sulfonamide compounds and, advantageously, by the synthesis shown in the following schemes and in the experimental part of this application.
Compounds III can be reacted with a heteroarylmethylamine compound II to obtain a compound I according to the present invention as shown below, wherein Het, A, Y and D are as defined above, and L is a leaving group such as hydroxy, phenoxy or halogen, preferably fluorine, chlorine or bromine:
The reaction of the sulfonyl compound III with compound II can be performed in accordance with standard methods of organic chemistry, see for example, Lieb. Ann. Chem. P. 641, 1990, or WO 05/033081.
This reaction is usually carried out in an inert organic solvent. Suitable solvents are aliphatic hydrocarbons, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as dichloromethane (DCM), chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, methyl tert.-butyl ether (MTBE), dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert.-butyl methyl ketone, and also dimethyl sulfoxide (DMSO), dimethylform
amide (DMF), dimethyl acetamide, N-methyl-2-pyrrolidone (NMP), N-methyl-2-pyrrolidone (NEP) and acetic acid ethyl ester, preferably THF, MTBE, DCM, chloroform, acetonitrile, toluene or DMF. It is also possible to use mixtures of the solvents mentioned.
The reaction is carried out in the presence of a base. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4 dimethylaminopyridine, and also bicyclic amines. Particular preference is given to potassium carbonate, triethylamine and pyridine. The bases are generally employed in equimolar amounts, in excess or, if appropriate, as solvent. The amount of base is typically 0.5 to 5 molar equivalents relative to 1 mole of compounds II.
Generally, the reaction is carried out at temperatures of from −30° C. to 120° C., preferably from −10 C to 100° C.
The amount of compound III is typically 0.3 to 3 molar equivalents relative to 1 mole of compounds II. The starting materials, i.e. compounds II and compounds III, are generally reacted in equimolar amounts; a small excess of either compound II or compound III may be advantageous.
Accordingly, a further aspect of the present invention relates to a process for preparing compounds Ia as defined before, which comprises reacting an aminomethylheteroaryl compound II
wherein Het, Ra and n have one of the meanings given above, under basic conditions with a sulfonic acid derivative III
wherein A, Y and D have one of the meanings given above and L is hydroxy, phenoxy, fluoro, chloro or bromo.
Alternatively, a sulfonamide compound III.a, wherein A, Y and D are as defined above, is reacted with a halomethylheteroaryl compound IV, wherein Het, Ra and n are as defined above and Hal is a halogen atom, preferably chlorine, to obtain directly a compound I according to the present invention:
The reaction can be carried out in an inert organic solvent using aequeous ammonia or by introduction of gaseous ammonia. Suitable solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert.-butanol; ethers such as diethyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, anisole and tetrahydrofuran; nitriles, such as acetonitrile and propionitrile; ketones such as acetone, methylethyl-ketone, diethyl-ketone and tert.-butylmethyl-ketone; and also dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone and acetic acid ethyl ester, preferably methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethyl formamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and acetic acid ethyl ester. It is also possible to use mixtures of the solvents mentioned.
The reaction is carried out in the presence of a base where appropriate using a catalyst such as dimethylamino-pyridine. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal and alkaline earth metal alcoholates such as sodium methanolate,
The compounds I can be prepared by various routes in analogy-to prior art processes known per se for preparing sulfonamide compounds and, advantageously, by the synthesis shown in the following schemes and in the experimental part of this application.
Compounds II, wherein Ra and n are as defined above, can be reacted with compounds III, wherein A, Y and D are as defined above and L is a leaving group such as hydroxy, phenoxy or halogen, preferably fluorine, chlorine or bromine, to obtain compounds I as shown below:
The reaction of compounds III with compounds II can be performed in accordance with standard methods of organic chemistry, see e.g. Lieb. Ann. Chem. P. 641, 1990, or WO 05/033081.
This reaction is usually carried out in an inert organic solvent. Suitable solvents are aliphatic hydrocarbons, aromatic hydrocarbons, such as toluene, o-, m- and p-xylene, halogenated hydrocarbons, such as dichloromethane (DCM), chloroform and chlorobenzene, ethers, such as diethyl ether, diisopropyl ether, methyl tert.-butyl ether (MTBE), dioxane, anisole and tetrahydrofuran (THF), nitriles, such as acetonitrile and propionitrile, ketones, such as acetone, methyl ethyl ketone, diethyl ketone and tert.-butyl methyl ketone, and also dimethyl sulfoxide (DMSO), dimethylform
amide (DMF), dimethyl acetamide, N-methyl-2-pyrrolidone (NMP), N-methyl-2-pyrrolidone (NEP) and acetic acid ethyl ester, preferably THF, MTBE, DCM, chloroform, acetonitrile, toluene or DMF, and the mixtures thereof.
The reaction is carried out in the presence of a base. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4 dimethylaminopyridine, and also bicyclic amines. Particular preference is given to potassium carbonate, triethylamine and pyridine. The bases are generally employed in catalytic amounts; however, they can also be used in equimolar amounts, in excess or, if appropriate, as solvent. The amount of base is typically 0.5 to 5 molar equivalents relative to 1 mole of compounds II.
Generally, the reaction is carried out at temperatures of from −30° C. to 120° C., preferably from −10 C to 100° C.
The amount of compound III is typically 0.3 to 3 molar equivalents relative to 1 mole potassium methanolate, potassium tert.-butanolate and dimethoxy-magnesium, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4 dimethylaminopyridine, and also bicyclic amines. Particular preference is given to potassium carbonate, sodium carbonate, potassium t-butanolate, potassium methanlolate, potassium ethanolate, sodium hydride, triethylamine and pyridine. The bases are generally employed in equimolar amounts, in excess or, if appropriate, as solvent. The excess of base is typically 0.5 to 5 molar equivalents relative to 1 mole of compounds II.
Accordingly, a further aspect of the present invention relates to a process for preparing sulfonamide compounds Ia as defined before, which comprises reacting a haloheteroarylmethyl compound of formula IV
wherein Het, Ra and n have one of the meanings given above and Hal is fluoro, chloro or bromo, under basic conditions with a sulfonamide of formula III.a
wherein A, Y and D have one of the meanings given above.
Aminomethylheteroaryl compounds II are known from the literature or are commercially available or they can be prepared for example by reduction of the corresponding oxime V.a, nitrile V.b, or amide V.c or azide V.d as described below, wherein Het, n and Ra are as defined above. Appropriate methods therefor are known to those skilled in the art (cf. U.S. Pat. No. 4,920,128; WO 05/16892; Indian J. Chem., Sect. B 14B(10), 766-9, 1976; J. Med Chem. 49(24), 6987-7001, 2006; WO 06/23844; Bioorg. Med. Chem. Lett. 14(10), 2543-2546, 2004; J. Chem. Soc., Perkin Trans. 1 (7), 765-776, 1999; Synth. Commun. 22(13), 1939-48, 1992; Synthesis (12), 1100-4, 1985; Bioorg. Med. Chem. Lett. 17(20), 5518-5522; 2007; WO 2005123704; J. Med Chem. 49(3), 955-970; 2006; J. Agric. Food Chem. 52(7), 1918-1922, 2004; U.S. Pat. No. 6,403,803; or Synthesis (4), 360-5, 1990).
Methods suitable for the reduction of an oxime compound V.a to the corresponding compound II have been described in the literature e.g. in March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” (John Wiley & Sons, New York, 4th edition, 1992, pp. 1218-1219).
Methods suitable for the reduction of a nitrile compound V.b to the corresponding compound II have been described in the literature, e.g. in March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” (John Wiley & Sons, New York, 4th edition, 1992, pp. 918-919).
Methods suitable for the reduction of an amide compound V.c to the corresponding compound II have been described in the literature, e.g. in March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” (John Wiley & Sons, New York, 4th edition, 1992, pp. 1212-1213).
The oxime compound V.a can be prepared for example from either the respective aldehyde compound (X=CHO; compound V.e) or the methyl derivative (X=CH3; compound V.f), in analogy to Houben-Weyl, vol. 10/4, Thieme, Stuttgart, 1968; vol. 11/2, 1957; vol E5, 1985; J. Prakt. Chem-Chem. Ztg. 336(8), pp. 695-697, 1994; Tetrahedron Lett. 42(39), pp. 6815-6818, 2001; or Heterocycles, 29(9), pp. 1741-1760, 1989. The aldehyde compound V.e can be synthesized from a heteroaryl compound in analogy to J. Org. Chem. 51(4), pp. 536-537, 1986, or from a halo derivative (X=halogen, compound V.g) as shown in Eur. J. Org. Chem., 2003, (8), pp. 1576-1588; Tetrahedron Lett. 1999, 40 (19), pp. 3719-3722; Tetrahedron, 1999, 55 (41), pp. 12149-12156.
The nitrile compound V.b is either commercially available or can be prepared in analogy to the route described in Heterocycles, 41(4), 675 (1995), Chem. Pharm. Bull., 21, 1927 (1973) or J. Chem. Soc., 426 (1942), e.g. from the corresponding haloheteroaryl compound V.f by reaction with CuCN, NaCN or KCN. The compounds V.g are either commercially available or can be synthesized according to standard methods.
The amide compound V.c can be prepared, for example, from the corresponding carboxylic acid chloride by reaction with ammonia.
A further method to build up heteroarylmethylamine compounds II is shown below. A halomethylheteroaryl compound IV is reacted with ammonia to obtain a compound II, wherein Het Ra and n are as defined above, and Hal is halogen, preferably chlorine:
According to this process, compound IV is either commercially available or can be prepared in analogy known procedures (March, J. “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” (Wiley & Sons, New York, 3rd edition, 1985, p. 1151)).
In one alternative, this reaction can be carried out in aequeous ammonia. In another alternative, this reaction can be carried out in condensed ammonia.
In a third alternative, the reaction can be carried out in an inert organic solvent using aequeous ammonia or by introduction of gaseous ammonia. Suitable solvents are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert.-butanol; ethers such as diethyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, anisole and tetrahydrofuran; nitriles, such as acetonitrile and propionitrile; and also dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide and N-methyl-2-pyrrolidone, preferably methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, acetonitrile, dimethyl formamide, dimethyl sulfoxide and N-methyl-2-pyrrolidone. It is also possible to use mixtures of the solvents mentioned.
This reaction is usually carried out at temperatures of from −60° C. to 120° C., preferably from −10° C. to 50° C., in the presence of a base or with an excess of ammonia. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide, alkali metal and alkaline earth metal oxides, such as lithium oxide, sodium oxide, calcium oxide and magnesium oxide, alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal bicarbonates, such as sodium bicarbonate, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4 dimethylaminopyridine, and also bicyclic amines. The bases are generally employed in equimolar amounts, in excess or, if appropriate, as solvent. The amount of base is typically 0.5 to 5 molar equivalents relative to 1 mole of compounds IV, preferably 0.5 to molar 2 equivalents relative to 1 mole of compound IV.
Generally, the starting materials are reacted with one another in equimolar amounts. In terms of yield it may be advantageous to employ an excess of ammonia, based on compound IV.
A further method to build up compounds II using a protection group is shown below. A compound IV is reacted with protected amines VI, wherein VI carries at least one protection group, to obtain after deprotection a compound II, wherein Het, Ra and n are as defined above, and Z is hydrogen or a protection group:
Protection of amino groups against reaction during one or more synthesis steps is a procedure well known and described in the art. Examples of suitable protection groups are those which are customarily used in organic synthesis, preferably t-butyloxycarbonyl, benzyloxycarbonyl, allyloxy-carbonyl, diformyl or phthaloyl. Further details on suitable protection groups and their cleavage may be found in Greene T. W. and Wits P. G. “Protective groups in organic synthesis” (John Wiley & Sons, New York, 1999, pages 494 et sqq.).
The first reaction introducing a protection group depicted in scheme 5 is generally carried out in an inert organic solvent. Suitable solvents, in general, are alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol and tert.-butanol; ethers such as diethyl ether, diisopropyl ether, tert.-butyl methyl ether, dioxane, anisole and tetrahydrofuran; nitriles, such as acetonitrile and propionitrile; ketones such as acetone, methylethyl-ketone, diethyl-ketone and tert.-butylmethyl-ketone; and also dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone and acetic acid ethyl ester, preferably methanol, ethanol, isopropanol, dioxane, tetrahydrofuran, acetonitrile, acetone, dimethyl formamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone and acetic acid ethyl ester. It is also possible to use mixtures of the solvents mentioned.
This reaction is usually carried out at temperatures of from −20° C. to 100° C., preferably from 0° C. to 60° C., in the presence of a base where appropriate using a catalyst such as dimethylamino-pyridine. Suitable bases are, in general, inorganic compounds, such as alkali metal and alkaline earth metal hydrides, such as lithium hydride, sodium hydride, potassium hydride and calcium hydride, alkali metal and alkaline earth metal carbonates, such as sodium carbonate, lithium carbonate, potassium carbonate and calcium carbonate, and also alkali metal and alkaline earth metal alcoholates such as sodium methanolate, potassium methanolate, potassium tert.-butanolate and dimethoxy-magnesium, moreover organic bases, for example tertiary amines, such as trimethylamine, triethylamine, diisopropylethylamine and N-methylpiperidine, pyridine, substituted pyridines, such as collidine, lutidine and 4 dimethylaminopyridine, and also bicyclic amines. Particular preference is given to sodium hydride, sodium carbonate, potassium methanolate, potassium tert.-butanolate, potassium ethanolate, triethylamine and pyridine. The bases are generally employed in equimolar amounts, in excess or, if appropriate, as solvent. The amount of base is typically 0.1 to 5 molar equivalents relative to 1 mole of compounds IV, preferably 1 to 2 molar equivalents.
The cleavage of the protection groups depicted in the second reaction may be found in Greene T. W. and Wits P. G. “Protective groups in organic synthesis” (John Wiley & Sons, New York, 1999, pages 494 et sqq.).
A further method to build up compounds II is shown in below, wherein Het, Ra and n are as defined above and Boc is tert-butyloxycarbonyl.
According to the process depicted above, the hydrogenation of the nitrile V.b in the presence of a catalyst, such as Raney nickel or palladium-on-carbon and t-butyl dicarbonate gives the N-protected compound V.h. On treating with hydrogen bromide/glacial acetic acid or with trifluoroacetic acid containing water, the compound V.h can be deprotected to yield a compound II.
Compounds II, wherein Ra is alkoxy, haloalkoxy, alkylthio or haloalkylthio, can be prepared in analogy to standard processes from a compound V.h, wherein Ra is halogen, especially chlorine, for example in analogy to methods described in Journal of Heterocyclic Chemistry (2005), 42(7), 1369-1379, Tetrahedron Letters, 47(26), 4415-4418, 2006 or Chemical & Pharmaceutical Bulletin 31(12), 4533-8, 1983. This synthesis route is shown below, wherein Het, Ra and n are as defined above, and X′ is a cation:
A compound V.h is reacted with a compound VII to give a compound VIII. Depending on the Ra* group to be introduced, the compounds VII are inorganic alkoxides, haloalkoxides, thiolates or halothiolates. The reaction is effected advantageously in an inert solvent. The cation X′ in formula VII is of little importance; for practical reasons, ammonium salts, tetraalkylammonium salts such as tetramethylammonium or tetraethylammonium salts, or alkali metal salts or alkaline earth metal salts are typically preferred. Suitable solvents comprise ethers such as dioxane, diethyl ether, methyl tert-butyl ether and preferably tetrahydrofuran, halogenated hydrocarbons such as dichloromethane or dichloroethane, aromatic hydrocarbons such as toluene, and mixtures thereof. Deprotection of the amino group in compound VIII to give the desired compound II can be accomplished as described above for deprotection of compound V.h.
Compounds II, wherein Ra is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl or alkyl-cycloalkyl, can advantageously be prepared by reacting compounds II, wherein Ra is halogen, with organometallic compounds Ra-Mt wherein Ra is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl or alkyl-cycloalkyl and Mt is lithium, magnesium or zinc. The reaction is effected preferably in the presence of catalytic or, in particular, at least equimolar amounts of transition metal salts and/or compounds, in particular in the presence of Cu salts such as Cu(I) halides and especially Cu(I) iodide, or Pd-catalyzed. The reaction is effected generally in an inert organic solvent, for example one of the aforementioned ethers, in particular tetrahydrofuran, an aliphatic or cycloaliphatic hydrocarbon such as hexane, cyclohexane and the like, an aromatic hydrocarbon such as toluene, or in a mixture of these solvents. The temperatures required for this purpose are in the range of from −100 to +100° C. and especially in the range from −80° C. to +40° C.
Sulfonic acid compounds III are known from prior art or can be obtained according to procedures known in the art.
A suitable method to build up sulfonic acid compounds III.a, wherein D, A and Y are defined as above, and Hal is halogen and L is chlorine, is shown below:
An alternative method to build up compounds III.a is shown below:
A suitable method to build up sulfonic acid derivatives III, wherein A is phenylene and the moiety D-Y is located in para position with respect to the sulfonyl group (also referred herein as “para”-III), is shown below, wherein Y, D and L are as defined above:
Sulfonation of the compound X with pyridine-SO3 or dioxane-SO3 complex affords mainly sulfonic acid derivative “para”-III, wherein L is OH (for sulfonation procedure cf. Mizuno, A. et. al., Tetrahedron Lett. 2000, 41, 6605.).
Sulfonation of the compound X with oleum under heating affords mainly sulfonic acid compound “para”-III, wherein L is OH, as well (cf. U.S. Pat. No. 4,874,894).
Sulfonation of compound X with chlorosulfonic acid affords mainly optionally substituted benzenesulfonic acid (“para”-III), wherein L is Cl (cf. WO 03/055857, WO 03/016313 or WO 02/64593).
Compounds of formula X are known from prior art or can be obtained according to procedures known in the art.
A suitable method to build compounds X, wherein Y is —O—, is shown below, wherein D and A are as defined above and Hal means halogen:
Reaction of a halogen substituted cyclic compound XI with a compound XII in the presence of a copper (I) salt and of a basic substance affords ether derivatives of compounds X. This reaction may be accelerated by addition of heavy metal salts such as Cu (I) compounds.
A suitable method to build up compounds X, wherein Y is —S— or —N, is shown below:
Compounds I or their respective intermediates, wherein Y is —N()— and
means hydrogen, can be converted to compounds, wherein
is C1-C4-alkyl, by conventional processes such as alkylation. Examples of suitable alkylating agents include alkyl halides, such as alkyl chloride, alkyl bromide or alkyl iodide, examples being methyl chloride, methyl bromide or methyl iodide, or dialkyl sulfates such as dimethyl sulfate or diethyl sulfate. The reaction with the alkylating agent is carried out advantageously in the presence of a solvent. Solvents used for these reactions are—depending on temperature range—aliphatic, cycloaliphatic or aromatic hydrocarbons such as hexane, cyclohexane, toluene, xylene, chlorinated aliphatic and aromatic hydrocarbons such as dichloromethane, chlorobenzene, open-chain dialkyl ethers such as diethyl ether, di-n-propyl ether, methyl tert-butyl ether, cyclic ethers such as tetrahydrofuran, 1,4-dioxane, glycol ethers such as dimethyl glycol ether, or mixtures of these solvents.
Compounds I or the respective intermediates, wherein Y is —S(═O)— and —S(═O)2—, can be prepared by oxidation from respective thioethers as shown below, wherein Het, A and D are as defined above:
Suitable oxidizing agents are hydrogen peroxide, e.g. in acetic acid, 3-chloroperoxybenzoic acid e.g. in dichloromethane, chloroform, carbon tetrachloride or chlorobenzene.
Compounds I or the respective intermediates, wherein Y is —CH2O—, can be prepared by etherification of the respective hydroxy compounds such as compound XV with the halogen derivatives such as XIV according to scheme 13, wherein Het, A and D are as defined above:
Compounds of the formula I or the respective intermediates, wherein Y is —OCH2—, can be prepared by etherification of the respective hydroxy compounds such as XVII with the halogen derivatives such as XVI as shown below, wherein Het, A and D are as defined above:
The N-oxides may be prepared from the compounds I according to conventional oxidation methods, for example by treating compounds I with an organic peracid such as metachloroperbenzoic acid (cf. WO 03/64572 or J. Med. Chem. 38(11), 1892-903, 1995); or with inorganic oxidizing agents such as hydrogen peroxide (cf. J. Heterocycl. Chem. 18(7), 1305-8, 1981) or oxone (cf. J. Am. Chem. Soc. 123(25), 5962-5973, 2001). The oxidation may lead to pure mono-N-oxides, or to a mixture of different N-oxides, which can be separated by conventional methods such as chromatography.
If individual compounds I cannot be obtained by the routes described above, they can be prepared by derivatization of other compounds I.
If the synthesis yields mixtures of isomers, a separation is generally not necessarily required since in some cases the individual isomers can be interconverted during workup for use or during application (for example under the action of light, acids or bases). Such conversions may also take place after use, for example in the treatment of plants in the treated plant, or in the harmful fungus to be controlled.
The compounds I and the compositions according to the invention, respectively, are suitable as fungicides. They are distinguished by an outstanding effectiveness against a broad spectrum of phytopathogenic fungi, including soil-borne fungi, which derive especially from the classes of the Plasmodiophoromycetes, Peronosporomycetes (syn. Oomycetes), Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes (syn. Fungi imperfecti). Some are systemically effective and they can be used in crop protection as foliar fungicides, fungicides for seed dressing and soil fungicides. Moreover, they are suitable for controlling harmful fungi, which inter alia occur in wood or roots of plants.
The compounds I and the compositions according to the invention are particularly important in the control of a multitude of phytopathogenic fungi on various cultivated plants, such as cereals, e.g. wheat, rye, barley, triticale, oats or rice; beet, e.g. sugar beet or fodder beet; fruits, such as pomes, stone fruits or soft fruits, e.g. apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries, blackberries or gooseberries; leguminous plants, such as lentils, peas, alfalfa or soybeans; oil plants, such as rape, mustard, olives, sunflowers, coconut, cocoa beans, castor oil plants, oil palms, ground nuts or soybeans; cucurbits, such as squashes, cucumber or melons; fiber plants, such as cotton, flax, hemp or jute; citrus fruit, such as oranges, lemons, grapefruits or mandarins; vegetables, such as spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, cucurbits or paprika; lauraceous plants, such as avocados, cinnamon or camphor; energy and raw material plants, such as corn, soybean, rape, sugar cane or oil palm; corn; tobacco; nuts; coffee; tea; bananas; vines (table grapes and grape juice grape vines); hop; turf; natural rubber plants or ornamental and forestry plants, such as flowers, shrubs, broad-leaved trees or evergreens, e.g. conifers; and on the plant propagation material, such as seeds, and the crop material of these plants.
Preferably, compounds I and compositions thereof, respectively are used for controlling a multitude of fungi on field crops, such as potatoes sugar beets, tobacco, wheat, rye, barley, oats, rice, corn, cotton, soybeans, rape, legumes, sunflowers, coffee or sugar cane; fruits; vines; ornamentals; or vegetables, such as cucumbers, tomatoes, beans or squashes.
The term “plant propagation material” is to be understood to denote all the generative parts of the plant such as seeds and vegetative plant material such as cuttings and tubers (e.g. potatoes), which can be used for the multiplication of the plant. This includes seeds, roots, fruits, tubers, bulbs, rhizomes, shoots, sprouts and other parts of plants, including seedlings and young plants, which are to be transplanted after germination or after emergence from soil. These young plants may also be protected before transplantation by a total or partial treatment by immersion or pouring.
Preferably, treatment of plant propagation materials with compounds I and compositions thereof, respectively, is used for controlling a multitude of fungi on cereals, such as wheat, rye, barley and oats; rice, corn, cotton and soybeans.
The term “cultivated plants” is to be understood as including plants which have been modified by breeding, mutagenesis or genetic engineering including but not limiting to agricultural biotech products on the market or in development (cf. http://www.bio.org/speeches/pubs/er/agri_products.asp). Genetically modified plants are plants, which genetic material has been so modified by the use of recombinant DNA techniques that under natural circumstances cannot readily be obtained by cross breeding, mutations or natural recombination. Typically, one or more genes have been integrated into the genetic material of a genetically modified plant in order to improve certain properties of the plant. Such genetic modifications also include but are not limited to targeted post-transitional modification of protein(s), oligo- or polypeptides e.g. by glycosylation or polymer additions such as prenylated, acetylated or farnesylated moieties or PEG moieties.
Plants that have been modified by breeding, mutagenesis or genetic engineering, e.g. have been rendered tolerant to applications of specific classes of herbicides, such as hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors; acetolactate synthase (ALS) inhibitors, such as sulfonyl ureas (see e.g. U.S. Pat. No. 6,222,100, WO 01/82685, WO 00/26390, WO 97/41218, WO 98/02526, WO 98/02527, WO 04/106529, WO 05/20673, WO 03/14357, WO 03/13225, WO 03/14356, WO 04/16073) or imidazolinones (see e.g. U.S. Pat. No. 6,222,100, WO 01/82685, WO 00/026390, WO 97/41218, WO 98/002526, WO 98/02527, WO 04/106529, WO 05/20673, WO 03/014357, WO 03/13225, WO 03/14356, WO 04/16073); enolpyruvylshikimate-3-phosphate synthase (EPSPS) inhibitors, such as glyphosate (see e.g. WO 92/00377); glutamine synthetase (GS) inhibitors, such as glufosinate (see e.g. EP-A 242 236, EP-A 242 246) or oxynil herbicides (see e.g. U.S. Pat. No. 5,559,024) as a result of conventional methods of breeding or genetic engineering. Several cultivated plants have been rendered tolerant to herbicides by conventional methods of breeding (mutagenesis), e.g. Clearfield® summer rape (Canola, BASF SE, Germany) being tolerant to imidazolinones, e.g. imazamox. Genetic engineering methods have been used to render cultivated plants such as soybean, cotton, corn, beets and rape, tolerant to herbicides such as glyphosate and glufosinate, some of which are commercially available under the trade names RoundupReady® (glyphosate-tolerant, Monsanto, U.S.A.) and LibertyLink® (glufosinate-tolerant, Bayer CropScience, Germany).
Furthermore, plants are also covered that are by the use of recombinant DNA techniques capable to synthesize one or more insecticidal proteins, especially those known from the bacterial genus Bacillus, particularly from Bacillus thuringiensis, such as δ-endotoxins, e.g. CryIA(b), CryIA(c), CryIF, CryIF(a2), CryIIA(b), CryIIIA, CryIIIB(b1) or Cry9c; vegetative insecticidal proteins (VIP), e.g. VIP1, VIP2, VIP3 or VIP3A; insecticidal proteins of bacteria colonizing nematodes, e.g. Photorhabdus spp. or Xenorhabdus spp.; toxins produced by animals, such as scorpion toxins, arachnid toxins, wasp toxins, or other insect-specific neurotoxins; toxins produced by fungi, such Streptomycetes toxins, plant lectins, such as pea or barley lectins; agglutinins; proteinase inhibitors, such as trypsin inhibitors, serine protease inhibitors, patatin, cystatin or papain inhibitors; ribosome-inactivating proteins (RIP), such as ricin, maize-RIP, abrin, luffin, saporin or bryodin; steroid metabolism enzymes, such as 3-hydroxysteroid oxidase, ecdysteroid-IDP-glycosyl-transferase, cholesterol oxidases, ecdysone inhibitors or HMG-CoA-reductase; ion channel blockers, such as blockers of sodium or calcium channels; juvenile hormone esterase; diuretic hormone receptors (helicokinin receptors); stilben synthase, bibenzyl synthase, chitinases or glucanases. In the context of the present invention these insecticidal proteins or toxins are to be understood expressly also as pre-toxins, hybrid proteins, truncated or otherwise modified proteins. Hybrid proteins are characterized by a new combination of protein domains, (see, e.g. WO 02/015701). Further examples of such toxins or genetically modified plants capable of synthesizing such toxins are disclosed, e.g., in EP-A 374 753, WO 93/007278, WO 95/34656, EP-A 427 529, EP-A 451 878, WO 03/18810 and WO 03/52073. The methods for producing such genetically modified plants are generally known to the person skilled in the art and are described, e.g. in the publications mentioned above. These insecticidal proteins contained in the genetically modified plants impart to the plants producing these proteins tolerance to harmful pests from all taxonomic groups of athropods, especially to beetles (Coeloptera), two-winged insects (Diptera), and moths (Lepidoptera) and to nematodes (Nematoda). Genetically modified plants capable to synthesize one or more insecticidal proteins are, e.g., described in the publications mentioned above, and some of which are commercially available such as YieldGard® (corn cultivars producing the Cry1Ab toxin), YieldGard® Plus (corn cultivars producing Cry1Ab and Cry3Bb1 toxins), Starlink® (corn cultivars producing the Cry9c toxin), Herculex® RW (corn cultivars producing Cry34Ab1, Cry35Ab1 and the enzyme Phosphinothricin-N-Acetyltransferase [PAT]); NuCOTN® 33B (cotton cultivars producing the Cry1Ac toxin), Bollgard® I (cotton cultivars producing the Cry1Ac toxin), Bollgard® II (cotton cultivars producing Cry1Ac and Cry2Ab2 toxins); VIPCOT® (cotton cultivars producing a VIP-toxin); NewLeaf® (potato cultivars producing the Cry3A toxin); BtXtra®, NatureGard®, KnockOut®, BiteGard®, Protecta®, Bt11 (e.g. Agrisure® CB) and Bt176 from Syngenta Seeds SAS, France, (corn cultivars producing the Cry1Ab toxin and PAT enzyme), MIR604 from Syngenta Seeds SAS, France (corn cultivars producing a modified version of the Cry3A toxin, c.f. WO 03/018810), MON 863 from Monsanto Europe S.A., Belgium (corn cultivars producing the Cry3Bb1 toxin), IPC 531 from Monsanto Europe S.A., Belgium (cotton cultivars producing a modified version of the Cry1Ac toxin) and 1507 from Pioneer Overseas Corporation, Belgium (corn cultivars producing the Cry1F toxin and PAT enzyme).
Furthermore, plants are also covered that are by the use of recombinant DNA techniques capable to synthesize one or more proteins to increase the resistance or tolerance of those plants to bacterial, viral or fungal pathogens. Examples of such proteins are the so-called “pathogenesis-related proteins” (PR proteins, see, e.g. EP-A 392 225), plant disease resistance genes (e.g. potato cultivars, which express resistance genes acting against Phytophthora infestans derived from the mexican wild potato Solanum bulbocastanum) or T4-lysozym (e.g. potato cultivars capable of synthesizing these proteins with increased resistance against bacteria such as Erwinia amylvora). The methods for producing such genetically modified plants are generally known to the person skilled in the art and are described, e.g. in the publications mentioned above.
Furthermore, plants are also covered that are by the use of recombinant DNA techniques capable to synthesize one or more proteins to increase the productivity (e.g. bio mass production, grain yield, starch content, oil content or protein content), tolerance to drought, salinity or other growth-limiting environmental factors or tolerance to pests and fungal, bacterial or viral pathogens of those plants.
Furthermore, plants are also covered that contain by the use of recombinant DNA techniques a modified amount of substances of content or new substances of content, specifically to improve human or animal nutrition, e.g. oil crops that produce health-promoting long-chain omega-3 fatty acids or unsaturated omega-9 fatty acids (e.g. Nexera® rape, DOW Agro Sciences, Canada).
Furthermore, plants are also covered that contain by the use of recombinant DNA techniques a modified amount of substances of content or new substances of content, specifically to improve raw material production, e.g. potatoes that produce increased amounts of amylopectin (e.g. Amflora® potato, BASF SE, Germany).
The compounds I and compositions thereof, respectively, are particularly suitable for controlling the following plant diseases:
Albugo spp. (white rust) on ornamentals, vegetables (e.g. A. candida) and sunflowers (e.g. A. tragopogonis); Alternaria spp. (Alternaria leaf spot) on vegetables, rape (A. brassicola or brassicae), sugar beets (A. tenuis), fruits, rice, soybeans, potatoes (e.g. A. solani or A. alternata), tomatoes (e.g. A. solani or A. alternata) and wheat; Aphanomyces spp. on sugar beets and vegetables; Ascochyta spp. on cereals and vegetables, e.g. A. tritici (anthracnose) on wheat and A. hordei on barley; Bipolaris and Drechslera spp. (teleomorph: Cochliobolus spp.), e.g. Southern leaf blight (D. maydis) or Northern leaf blight (B. zeicola) on corn, e.g. spot blotch (B. sorokiniana) on cereals and e.g. B. oryzae on rice and turfs; Blumeria (formerly Erysiphe) graminis (powdery mildew) on cereals (e.g. on wheat or barley); Botrytis cinerea (teleomorph: Botryotinia fuckeliana: grey mold) on fruits and berries (e.g. strawberries), vegetables (e.g. lettuce, carrots, celery and cabbages), rape, flowers, vines, forestry plants and wheat; Bremia lactucae (downy mildew) on lettuce; Ceratocystis (syn. Ophiostoma) spp. (rot or wilt) on broad-leaved trees and evergreens, e.g. C. ulmi (Dutch elm disease) on elms; Cercospora spp. (Cercospora leaf spots) on corn (e.g. Gray leaf spot: C. zeae-maydis), rice, sugar beets (e.g. C. beticola), sugar cane, vegetables, coffee, soybeans (e.g. C. sojina or C. kikuchii) and rice; Cladosporium spp. on tomatoes (e.g. C. fulvum: leaf mold) and cereals, e.g. C. herbarum (black ear) on wheat; Claviceps purpurea (ergot) on cereals; Cochliobolus (anamorph: Helminthosporium of Bipolaris) spp. (leaf spots) on corn (C. carbonum), cereals (e.g. C. sativus, anamorph: B. sorokiniana) and rice (e.g. C. miyabeanus, anamorph: H. oryzae); Colletotrichum (teleomorph: Glomerella) spp. (anthracnose) on cotton (e.g. C. gossypii), corn (e.g. C. graminicola: Anthracnose stalk rot), soft fruits, potatoes (e.g. C. coccodes: black dot), beans (e.g. C. lindemuthianum) and soybeans (e.g. C. truncatum or C. gloeosporioides); Corticium spp., e.g. C. sasakii (sheath blight) on rice; Corynespora cassiicola (leaf spots) on soybeans and or namentals; Cycloconium spp., e.g. C. oleaginum on olive trees; Cylindrocarpon spp. (e.g. fruit tree canker or young vine decline, teleomorph: Nectria or Neonectria spp.) on fruit trees, vines (e.g. C. liriodendri, teleomorph: Neonectria liriodendri: Black Foot Disease) and ornamentals; Dematophora (teleomorph: Rosellinia) necatrix (root and stem rot) on soybeans; Diaporthe spp., e.g. D. phaseolorum (damping off) on soybeans; Drechslera (syn. Helminthosporium, teleomorph: Pyrenophora) spp. on corn, cereals, such as barley (e.g. D. teres, net blotch) and wheat (e.g. D. tritici-repentis: tan spot), rice and turf; Esca (dieback, apoplexy) on vines, caused by Formitiporia (syn. Phellinus) punctata, F. mediterranea, Phaeomoniella chlamydospora (earlier Phaeoacremonium chlamydosporum), Phaeoacremonium aleophilum and/or Botryosphaeria obtusa; Elsinoe spp. on pome fruits (E. pyri), soft fruits (E. veneta: anthracnose) and vines (E. ampelina: anthracnose); Entyloma oryzae (leaf smut) on rice; Epicoccum spp. (black mold) on wheat; Erysiphe spp. (powdery mildew) on sugar beets (E. betae), vegetables (e.g. E. pisi), such as cucurbits (e.g. E. cichoracearum), cabbages, rape (e.g. E. cruciferarum); Eutypa lata (Eutypa canker or dieback, anamorph: Cytosporina lata, syn. Libertella blepharis) on fruit trees, vines and ornamental woods; Exserohilum (syn. Helminthosporium) spp. on corn (e.g. E. turcicum); Fusarium (teleomorph: Gibberella) spp. (wilt, root or stem rot) on various plants, such as F. graminearum or F. culmorum (root rot, scab or head blight) on cereals (e.g. wheat or barley), F. oxysporum on tomatoes, F. solani on soybeans and F. verticillioides on corn; Gaeumannomyces graminis (take-all) on cereals (e.g. wheat or barley) and corn; Gibberella spp. on cereals (e.g. G. zeae) and rice (e.g. G. fujikuroi: Bakanae disease); Glomerella cingulata on vines, pome fruits and other plants and G. gossypii on cotton; Grain-staining complex on rice; Guignardia bidwellii (black rot) on vines; Gymnosporangium spp. on rosaceous plants and junipers, e.g. G. sabinae (rust) on pears; Helminthosporium spp. (syn. Drechslera, teleomorph: Cochliobolus) on corn, cereals and rice; Hemileia spp., e.g. H. vastatrix (coffee leaf rust) on coffee; Isariopsis clavispora (syn. Cladosporium vitis) on vines; Macrophomina phaseolina (syn. phaseoli) (root and stem rot) on soybeans and cotton; Microdochium (syn. Fusarium) nivale (pink snow mold) on cereals (e.g. wheat or barley); Microsphaera diffusa (powdery mildew) on soybeans; Monilinia spp., e.g. M. laxa, M. fructicola and M. fructigena (bloom and twig blight, brown rot) on stone fruits and other rosaceous plants; Mycosphaerella spp. on cereals, bananas, soft fruits and ground nuts, such as e.g. M. graminicola (anamorph: Septoria tritici, Septoria blotch) on wheat or M. fijiensis (black Sigatoka disease) on bananas; Peronospora spp. (downy mildew) on cabbage (e.g. P. brassicae), rape (e.g. P. parasitica), onions (e.g. P. destructor), tobacco (P. tabacina) and soybeans (e.g. P. manshurica); Phakopsora pachyrhizi and P. meibomiae (soybean rust) on soybeans; Phialophora spp. e.g. on vines (e.g. P. tracheiphila and P. tetraspora) and soybeans (e.g. P. gregata: stem rot); Phoma lingam (root and stem rot) on rape and cabbage and P. betae (root rot, leaf spot and damping-off) on sugar beets; Phomopsis spp. on sunflowers, vines (e.g. P. viticola: can and leaf spot) and soybeans (e.g. stem rot: P. phaseoli, teleomorph: Diaporthe phaseolorum); Physoderma maydis (brown spots) on corn; Phytophthora spp. (wilt, root, leaf, fruit and stem root) on various plants, such as paprika and cucurbits (e.g. P. capsici), soybeans (e.g. P. megasperma, syn. P. sojae), potatoes and tomatoes (e.g. P. infestans: late blight) and broad-leaved trees (e.g. P. ramorum: sudden oak death); Plasmodiophora brassicae (club root) on cabbage, rape, radish and other plants; Plasmopara spp., e.g. P. viticola (grapevine downy mildew) on vines and P. halstedii on sunflowers; Podosphaera spp. (powdery mildew) on rosaceous plants, hop, pome and soft fruits, e.g. P. leucotricha on apples; Polymyxa spp., e.g. on cereals, such as barley and wheat (P. graminis) and sugar beets (P. betae) and thereby transmitted viral diseases; Pseudocercosporella herpotrichoides (eyespot, teleomorph: Tapesia yallundae) on cereals, e.g. wheat or barley; Pseudoperonospora (downy mildew) on various plants, e.g. P. cubensis on cucurbits or P. humili on hop; Pseudopezicula tracheiphila (red fire disease or, rotbrenner', anamorph: Phialophora) on vines; Puccinia spp. (rusts) on various plants, e.g. P. triticina (brown or leaf rust), P. striiformis (stripe or yellow rust), P. hordei (dwarf rust), P. graminis (stem or black rust) or P. rectindita (brown or leaf rust) on cereals, such as e.g. wheat, barley or rye, and asparagus (e.g. P. asparagi); Pyrenophora (anamorph: Drechslera) tritici-repentis (tan spot) on wheat or P. teres (net blotch) on barley; Pyricularia spp., e.g. P. oryzae (teleomorph: Magnaporthe grisea, rice blast) on rice and P. grisea on turf and cereals; Pythium spp. (damping-off) on turf, rice, corn, wheat, cotton, rape, sunflowers, soybeans, sugar beets, vegetables and various other plants (e.g. P. ultimum or P. aphanidermatum); Ramularia spp., e.g. R. collo-cygni (Ramularia leaf spots, Physiological leaf spots) on barley and R. beticola on sugar beets; Rhizoctonia spp. on cotton, rice, potatoes, turf, corn, rape, potatoes, sugar beets, vegetables and various other plants, e.g. R. solani (root and stem rot) on soybeans, R. solani (sheath blight) on rice or R. cerealis (Rhizoctonia spring blight) on wheat or barley; Rhizopus stolonifer (black mold, soft rot) on strawberries, carrots, cabbage, vines and tomatoes; Rhynchosporium secalis (scald) on barley, rye and triticale; Sarocladium oryzae and S. attenuatum (sheath rot) on rice; Sclerotinia spp. (stem rot or white mold) on vegetables and field crops, such as rape, sunflowers (e.g. S. sclerotiorum) and soybeans (e.g. S. rolfsii or S. sclerotiorum); Septoria spp. on various plants, e.g. S. glycines (brown spot) on soybeans, S. tritici (Septoria blotch) on wheat and S. (syn. Stagonospora) nodorum (Stagonospora blotch) on cereals; Uncinula (syn. Erysiphe) necator (powdery mildew, anamorph: Oidium tuckeri) on vines; Setospaeria spp. (leaf blight) on corn (e.g. S. turcicum, syn. Helminthosporium turcicum) and turf; Sphacelotheca spp. (smut) on corn, (e.g. S. reiliana: head smut), sorghum and sugar cane; Sphaerotheca fuliginea (powdery mildew) on cucurbits; Spongospora subterranea (powdery scab) on potatoes and thereby transmitted viral diseases; Stagonospora spp. on cereals, e.g. S. nodorum (Stagonospora blotch, teleomorph: Leptosphaeria [syn. Phaeosphaeria] nodorum) on wheat; Synchytrium endobioticum on potatoes (potato wart disease); Taphrina spp., e.g. T. deformans (leaf curl disease) on peaches and T. pruni (plum pocket) on plums; Thielaviopsis spp. (black root rot) on tobacco, pome fruits, vegetables, soybeans and cotton, e.g. T. basicola (syn. Chalara elegans); Tilletia spp. (common bunt or stinking smut) on cereals, such as e.g. T. tritici (syn. T. caries, wheat bunt) and T. controversa (dwarf bunt) on wheat; Typhula incarnata (grey snow mold) on barley or wheat; Urocystis spp., e.g. U. occulta (stem smut) on rye; Uromyces spp. (rust) on vegetables, such as beans (e.g. U. appendiculatus, syn. U. phaseoli) and sugar beets (e.g. U. betae); Ustilago spp. (loose smut) on cereals (e.g. U. nuda and U. avaenae), corn (e.g. U. maydis: corn smut) and sugar cane; Venturia spp. (scab) on apples (e.g. V. inaequalis) and pears; and Verticillium spp. (wilt) on various plants, such as fruits and ornamentals, vines, soft fruits, vegetables and field crops, e.g. V. dahliae on strawberries, rape, potatoes and tomatoes.
The compounds I and compositions thereof, respectively, are also suitable for controlling harmful fungi in the protection of materials (e.g. wood, paper, paint dispersions, fiber or fabrics) and in the protection of stored products. As to the protection of wood and construction materials, the particular attention is paid to the following harmful fungi: Ascomycetes such as Ophiostoma spp., Ceratocystis spp., Aureobasidium pullulans, Sclerophoma spp., Chaetomium spp., Humicola spp., Petriella spp., Trichurus spp.; Basidiomycetes such as Coniophora spp., Coriolus spp., Gloeophyllum spp., Lentinus spp., Pleurotus spp., Poria spp., Serpula spp. and Tyromyces spp., Deuteromycetes such as Aspergillus spp., Cladosporium spp., Penicillium spp., Trichorma spp., Alternaria spp., Paecilomyces spp. and Zygomycetes such as Mucor spp., and in addition in the protection of stored products the following yeast fungi are worthy of note: Candida spp. and Saccharomyces cerevisae.
The compounds I and compositions thereof, respectively, may be used for improving the health of a plant. The invention also relates to a method for improving plant health by treating a plant, its propagation material and/or the locus where the plant is growing or is to grow with an effective amount of compounds I and compositions thereof, respectively.
The term “plant health” is to be understood to denote a condition of the plant and/or its products which is determined by several indicators alone or in combination with each other such as yield (e.g. increased biomass and/or increased content of valuable ingredients), plant vigor (e.g. improved plant growth and/or greener leaves (“greening effect”)), quality (e.g. improved content or composition of certain ingredients) and tolerance to abiotic and/or biotic stress. The above identified indicators for the health condition of a plant may be interdependent or may result from each other.
The compounds of formula I can be present in different crystal modifications whose biological activity may differ. They are likewise subject matter of the present invention.
The compounds I are employed as such or in form of compositions by treating the fungi or the plants, plant propagation materials, such as seeds, soil, surfaces, materials or rooms to be protected from fungal attack with a fungicidally effective amount of the active substances. The application can be carried out both before and after the infection of the plants, plant propagation materials, such as seeds, soil, surfaces, materials or rooms by the fungi.
Plant propagation materials may be treated with compounds I as such or a composition comprising at least one compound I prophylactically either at or before planting or transplanting.
The invention also relates to agrochemical compositions comprising a solvent or solid carrier and at least one compound I and to the use for controlling harmful fungi.
An agrochemical composition comprises a fungicidally effective amount of a compound I. The term “effective amount” denotes an amount of the composition or of the compounds I, which is sufficient for controlling harmful fungi on cultivated plants or in the protection of materials and which does not result in a substantial damage to the treated plants. Such an amount can vary in a broad range and is dependent on various factors, such as the fungal species to be controlled, the treated cultivated plant or material, the climatic conditions and the specific compound I used.
The compounds I, their N-oxides and salts can be converted into customary types of agrochemical compositions, e.g. solutions, emulsions, suspensions, dusts, powders, pastes and granules. The composition type depends on the particular intended purpose; in each case, it should ensure a fine and uniform distribution of the compound according to the invention.
Examples for composition types are suspensions (SC, OD, FS), pastes, pastilles, wettable powders or dusts (WP, SP, SS, WS, DP, DS) or granules (GR, FG, GG, MG), which can be water-soluble or wettable, as well as gel formulations for the treatment of plant propagation materials such as seeds (GF).
Usually the composition types (e.g. SC, OD, FS, WG, SG, WP, SP, SS, WS, GF) are employed diluted. Composition types such as DP, DS, GR, FG, GG and MG are usually used undiluted.
The compositions are prepared in a known manner (cf. U.S. Pat. No. 3,060,084, EP-A 707 445 (for liquid concentrates), Browning: “Agglomeration”, Chemical Engineering, Dec. 4, 1967, 147-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, S. 8-57 and ff. WO 91/13546, U.S. Pat. No. 4,172,714, U.S. Pat. No. 4,144,050, U.S. Pat. No. 3,920,442, U.S. Pat. No. 5,180,587, U.S. Pat. No. 5,232,701, U.S. Pat. No. 5,208,030, GB 2,095,558, U.S. Pat. No. 3,299,566, Klingman: Weed Control as a Science (J. Wiley & Sons, New York, 1961), Hance et al.: Weed Control Handbook (8th Ed., Blackwell Scientific, Oxford, 1989) and Mollet, H. and Grubemann, A.: Formulation technology (Wiley VCH Verlag, Weinheim, 2001).
The agrochemical compositions may also comprise auxiliaries which are customary in agrochemical compositions. The auxiliaries used depend on the particular application form and active substance, respectively.
Examples for suitable auxiliaries are solvents, solid carriers, dispersants or emulsifiers (such as further solubilizers, protective colloids, surfactants and adhesion agents), organic and anorganic thickeners, bactericides, anti-freezing agents, anti-foaming agents, if appropriate colorants and tackifiers or binders (e.g. for seed treatment formulations).
Suitable solvents are water, organic solvents such as mineral oil fractions of medium to high boiling point, such as kerosene or diesel oil, furthermore coal tar oils and oils of vegetable or animal origin, aliphatic, cyclic and aromatic hydrocarbons, e.g. toluene, xylene, paraffin, tetrahydronaphthalene, alkylated naphthalenes or their derivatives, alcohols such as methanol, ethanol, propanol, butanol and cyclohexanol, glycols, ketones such as cyclohexanone and gamma-butyrolactone, fatty acid dimethylamides, fatty acids and fatty acid esters and strongly polar solvents, e.g. amines such as N-methylpyrrolidone.
Solid carriers are mineral earths such as silicates, silica gels, talc, kaolins, limestone, lime, chalk, bole, loess, clays, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic materials, fertilizers, such as, e.g., ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas, and products of vegetable origin, such as cereal meal, tree bark meal, wood meal and nutshell meal, cellulose powders and other solid carriers.
Suitable surfactants (adjuvants, wetters, tackifiers, dispersants or emulsifiers) are alkali metal, alkaline earth metal and ammonium salts of aromatic sulfonic acids, such as ligninsoulfonic acid (Borresperse® types, Borregard, Norway) phenolsulfonic acid, naphthalenesulfonic acid (Morwet® types, Akzo Nobel, U.S.A.), dibutylnaphthalenesulfonic acid (Nekal® types, BASF, Germany), and fatty acids, alkylsulfonates, alkylarylsulfonates, alkyl sulfates, laurylether sulfates, fatty alcohol sulfates, and sulfated hexa-, hepta- and octadecanolates, sulfated fatty alcohol glycol ethers, furthermore condensates of naphthalene or of naphthalenesulfonic acid with phenol and formaldehyde, polyoxy-ethylene octylphenyl ether, ethoxylated isooctylphenol, octylphenol, nonylphenol, alkylphenyl polyglycol ethers, tributylphenyl polyglycol ether, tristearylphenyl polyglycol ether, alkylaryl polyether alcohols, alcohol and fatty alcohol/ethylene oxide condensates, ethoxylated castor oil, polyoxyethylene alkyl ethers, ethoxylated polyoxypropylene, lauryl alcohol polyglycol ether acetal, sorbitol esters, lignin-sulfite waste liquors and proteins, denatured proteins, polysaccharides (e.g. methylcellulose), hydrophobically modified starches, polyvinyl alcohols (Mowiol® types, Clariant, Switzerland), polycarboxylates (Sokolan® types, BASF, Germany), polyalkoxylates, polyvinylamines (Lupasol® types, BASF, Germany), polyvinylpyrrolidone and the copolymers thereof.
Examples for thickeners (i.e. compounds that impart a modified flowability to compositions, i.e. high viscosity under static conditions and low viscosity during agitation) are polysaccharides and organic and anorganic clays such as Xanthan gum (Kelzan®, CP Kelco, U.S.A.), Rhodopol® 23 (Rhodia, France), Veegum® (R.T. Vanderbilt, U.S.A.) or Attaclay® (Engelhard Corp., NJ, USA).
Bactericides may be added for preservation and stabilization of the composition. Examples for suitable bactericides are those based on dichlorophene and benzylalcohol hemi formal (Proxel® from ICI or Acticide® RS from Thor Chemie and Kathon® MK from Rohm & Haas) and isothiazolinone derivatives such as alkylisothiazolinones and benzisothiazolinones (Acticide® MBS from Thor Chemie).
Examples for suitable anti-freezing agents are ethylene glycol, propylene glycol, urea and glycerin.
Examples for anti-foaming agents are silicone emulsions (such as e.g. Silikon® SRE, Wacker, Germany or Rhodorsil®, Rhodia, France), long chain alcohols, fatty acids, salts of fatty acids, fluoroorganic compounds and mixtures thereof.
Suitable colorants are pigments of low water solubility and water-soluble dyes. Examples to be mentioned and the designations rhodamin B, C. I. pigment red 112, C. I. solvent red 1, pigment blue 15:4, pigment blue 15:3, pigment blue 15:2, pigment blue 15:1, pigment blue 80, pigment yellow 1, pigment yellow 13, pigment red 112, pigment red 48:2, pigment red 48:1, pigment red 57:1, pigment red 53:1, pigment orange 43, pigment orange 34, pigment orange 5, pigment green 36, pigment green 7, pigment white 6, pigment brown 25, basic violet 10, basic violet 49, acid red 51, acid red 52, acid red 14, acid blue 9, acid yellow 23, basic red 10, basic red 108.
Examples for tackifiers or binders are polyvinylpyrrolidons, polyvinylacetates, polyvinyl alcohols and cellulose ethers (Tylose®, Shin-Etsu, Japan).
Powders, materials for spreading and dusts can be prepared by mixing or concomitantly grinding the compounds I and, if appropriate, further active substances, with at least one solid carrier.
Granules, e.g. coated granules, impregnated granules and homogeneous granules, can be prepared by binding the active substances to solid carriers. Examples of solid carriers are mineral earths such as silica gels, silicates, talc, kaolin, attaclay, limestone, lime, chalk, bole, loess, clay, dolomite, diatomaceous earth, calcium sulfate, magnesium sulfate, magnesium oxide, ground synthetic materials, fertilizers, such as, e.g., ammonium sulfate, ammonium phosphate, ammonium nitrate, ureas, and products of vegetable origin, such as cereal meal, tree bark meal, wood meal and nutshell meal, cellulose powders and other solid carriers.
Examples for composition types are:
1. Composition Types for Dilution with Water
i) Water-Soluble Concentrates (SL, LS)
10 parts by weight of a compound I according to the invention are dissolved in 90 parts by weight of water or in a water-soluble solvent. As an alternative, wetting agents or other auxiliaries are added. The active substance dissolves upon dilution with water. In this way, a composition having a content of 10% by weight of active substance is obtained.
ii) Dispersible Concentrates (DC)
20 parts by weight of a compound I according to the invention are dissolved in 70 parts by weight of cyclohexanone with addition of 10 parts by weight of a dispersant, e.g. polyvinylpyrrolidone. Dilution with water gives a dispersion. The active substance content is 20% by weight.
iii) Emulsifiable Concentrates (EC)
15 parts by weight of a compound I according to the invention are dissolved in 75 parts by weight of xylene with addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). Dilution with water gives an emulsion. The composition has an active substance content of 15% by weight.
iv) Emulsions (EW, EO, ES)
25 parts by weight of a compound I according to the invention are dissolved in 35 parts by weight of xylene with addition of calcium dodecylbenzenesulfonate and castor oil ethoxylate (in each case 5 parts by weight). This mixture is introduced into 30 parts by weight of water by means of an emulsifying machine (Ultraturrax) and made into a homogeneous emulsion. Dilution with water gives an emulsion. The composition has an active substance content of 25% by weight.
v) Suspensions (SC, OD, FS)
In an agitated ball mill, 20 parts by weight of a compound I according to the invention are comminuted with addition of 10 parts by weight of dispersants and wetting agents and 70 parts by weight of water or an organic solvent to give a fine active substance suspension. Dilution with water gives a stable suspension of the active substance. The active substance content in the composition is 20% by weight.
vi) Water-Dispersible Granules and Water-Soluble Granules (WG, SG)
50 parts by weight of a compound I according to the invention are ground finely with addition of 50 parts by weight of dispersants and wetting agents and prepared as water-dispersible or water-soluble granules by means of technical appliances (e.g. extrusion, spray tower, fluidized bed). Dilution with water gives a stable dispersion or solution of the active substance. The composition has an active substance content of 50% by weight.
vii) Water-Dispersible Powders and Water-Soluble Powders (WP, SP, SS, WS)
75 parts by weight of a compound I according to the invention are ground in a rotor-stator mill with addition of 25 parts by weight of dispersants, wetting agents and silica gel. Dilution with water gives a stable dispersion or solution of the active substance. The active substance content of the composition is 75% by weight.
viii) Gel (GF)
In an agitated ball mill, 20 parts by weight of a compound I according to the invention are comminuted with addition of 10 parts by weight of dispersants, 1 part by weight of a gelling agent wetters and 70 parts by weight of water or of an organic solvent to give a fine suspension of the active substance. Dilution with water gives a stable suspension of the active substance, whereby a composition with 20% (w/w) of active substance is obtained.
ix) Dustable Powders (DP, DS)
5 parts by weight of a compound I according to the invention are ground finely and mixed intimately with 95 parts by weight of finely divided kaolin. This gives a dustable composition having an active substance content of 5% by weight.
x) Granules (GR, FG, GG, MG)
0.5 parts by weight of a compound I according to the invention is ground finely and associated with 99.5 parts by weight of carriers. Current methods are extrusion, spray-drying or the fluidized bed. This gives granules to be applied undiluted having an active substance content of 0.5% by weight.
xi) ULV Solutions (UL)
10 parts by weight of a compound I according to the invention are dissolved in 90 parts by weight of an organic solvent, e.g. xylene. This gives a composition to be applied undiluted having an active substance content of 10% by weight.
The agrochemical compositions generally comprise between 0.01 and 95%, preferably between 0.1 and 90%, most preferably between 0.5 and 90%, by weight of active substance. The active substances are employed in a purity of from 90% to 100%, preferably from 95% to 100% (according to NMR spectrum).
Water-soluble concentrates (LS), flowable concentrates (FS), powders for dry treatment (DS), water-dispersible powders for slurry treatment (WS), water-soluble powders (SS), emulsions (ES) emulsifiable concentrates (EC) and gels (GF) are usually employed for the purposes of treatment of plant propagation materials, particularly seeds. These compositions can be applied to plant propagation materials, particularly seeds, diluted or undiluted. The compositions in question give, after two-to-tenfold dilution, active substance concentrations of from 0.01 to 60% by weight, preferably from 0.1 to 40% by weight, in the ready-to-use preparations. Application can be carried out before or during sowing. Methods for applying or treating agrochemical compounds and compositions thereof, respectively, on to plant propagation material, especially seeds, are known in the art, and include dressing, coating, pelleting, dusting, soaking and in-furrow application methods of the propagation material. In a preferred embodiment, the compounds or the compositions thereof, respectively, are applied on to the plant propagation material by a method such that germination is not induced, e.g. by seed dressing, pelleting, coating and dusting.
In a preferred embodiment, a suspension-type (FS) composition is used for seed treatment. Typically, a FS composition may comprise 1-800 g/l of active substance, 1-200 g/l Surfactant, 0 to 200 g/l antifreezing agent, 0 to 400 g/l of binder, 0 to 200 g/l of a pigment and up to 1 liter of a solvent, preferably water.
The active substances can be used as such or in the form of their compositions, e.g. in the form of directly sprayable solutions, powders, suspensions, dispersions, emulsions, oil dispersions, pastes, dustable products, materials for spreading, or granules, by means of spraying, atomizing, dusting, spreading, brushing, immersing or pouring. The application forms depend entirely on the intended purposes; it is intended to ensure in each case the finest possible distribution of the active substances according to the invention.
Aqueous application forms can be prepared from emulsion concentrates, pastes or wettable powders (sprayable powders, oil dispersions) by adding water. To prepare emulsions, pastes or oil dispersions, the substances, as such or dissolved in an oil or solvent, can be homogenized in water by means of a wetter, tackifier, dispersant or emulsifier. Alternatively, it is possible to prepare concentrates composed of active substance, wetter, tackifier, dispersant or emulsifier and, if appropriate, solvent or oil, and such concentrates are suitable for dilution with water.
The active substance concentrations in the ready-to-use preparations can be varied within relatively wide ranges. In general, they are from 0.0001 to 10%, preferably from 0.001 to 1% by weight of active substance.
The active substances may also be used successfully in the ultra-low-volume process (ULV), it being possible to apply compositions comprising over 95% by weight of active substance, or even to apply the active substance without additives.
When employed in plant protection, the amounts of active substances applied are, depending on the kind of effect desired, from 0.001 to 2 kg per ha, preferably from 0.005 to 2 kg per ha, more preferably from 0.05 to 0.9 kg per ha, in particular from 0.1 to 0.75 kg per ha.
In treatment of plant propagation materials such as seeds, e.g. by dusting, coating or drenching seed, amounts of active substance of from 0.1 to 1000 g, preferably from 1 to 1000 g, more preferably from 1 to 100 g and most preferably from 5 to 100 g, per 100 kilogram of plant propagation material (preferably seed) are generally required.
When used in the protection of materials or stored products, the amount of active substance applied depends on the kind of application area and on the desired effect. Amounts customarily applied in the protection of materials are, e.g., 0.001 g to 2 kg, preferably 0.005 g to 1 kg, of active substance per cubic meter of treated material.
Various types of oils, wetters, adjuvants, herbicides, bactericides, other fungicides and/or pesticides may be added to the active substances or the compositions comprising them, if appropriate not until immediately prior to use (tank mix). These agents can be admixed with the compositions according to the invention in a weight ratio of 1:100 to 100:1, preferably 1:10 to 10:1.
Adjuvants which can be used are in particular organic modified polysiloxanes such as Break Thru S 240®; alcohol alkoxylates such as Atplus 245®, Atplus MBA 1303®, Plurafac LF 300® and Lutensol ON 30®; EO/PO block polymers, e.g. Pluronic RPE 2035® and Genapol B®; alcohol ethoxylates such as Lutensol XP 80®; and dioctyl sulfosuccinate sodium such as Leophen RA®.
The compositions according to the invention can, in the use form as fungicides, also be present together with other active substances, e.g. with herbicides, insecticides, growth regulators, fungicides or else with fertilizers, as pre-mix or, if appropriate, not until immediately prior to use (tank mix).
Mixing the compounds I or the compositions comprising them in the use form as fungicides with other fungicides results in many cases in an expansion of the fungicidal spectrum of activity being obtained or in a prevention of fungicide resistance development. Furthermore, in many cases, synergistic effects are obtained.
The following list of active substances, in conjunction with which the compounds according to the invention can be used, is intended to illustrate the possible combinations but does not limit them:
The present invention furthermore relates to agrochemical compositions comprising a mixture of at least one compound I (component 1) and at least one further active substance useful for plant protection, e.g. selected from the groups A) to I) (component 2), in particular one further fungicide, e.g. one or more fungicide from the groups A) to F), as described above, and if desired one suitable solvent or solid carrier. Those mixtures are of particular interest, since many of them at the same application rate show higher efficiencies against harmful fungi. Furthermore, combating harmful fungi with a mixture of compounds I and at least one fungicide from groups A) to F), as described above, is more efficient than combating those fungi with individual compounds I or individual fungicides from groups A) to F). By applying compounds I together with at least one active substance from groups A) to I) a synergistic effect can be obtained, i.e. more then simple addition of the individual effects is obtained (synergistic mixtures).
According to this invention, applying the compounds I together with at least one further active substance is to be understood to denote, that at least one compound of formula I and at least one further active substance occur simultaneously at the site of action (i.e. the harmful fungi to be controlled or their habitats such as infected plants, plant propagation materials, particularly seeds, surfaces, materials or the soil as well as plants, plant propagation materials, particularly seeds, soil, surfaces, materials or rooms to be protected from fungal attack) in a fungicidally effective amount. This can be obtained by applying the compounds I and at least one further active substance simultaneously, either jointly (e.g. as tank-mix) or separately, or in succession, wherein the time interval between the individual applications is selected to ensure that the active substance applied first still occurs at the site of action in a sufficient amount at the time of application of the further active substance(s). The order of application is not essential for working of the present invention.
In binary mixtures, i.e. compositions according to the invention comprising one compound I (component 1) and one further active substance (component 2), e.g. one active substance from groups A) to I), the weight ratio of component 1 and component 2 generally depends from the properties of the active substances used, usually it is in the range of from 1:100 to 100:1, regularly in the range of from 1:50 to 50:1, preferably in the range of from 1:20 to 20:1, more preferably in the range of from 1:10 to 10:1 and in particular in the range of from 1:3 to 3:1.
In ternary mixtures, i.e. compositions according to the invention comprising one compound I (component 1) and a first further active substance (component 2) and a second further active substance (component 3), e.g. two active substances from groups A) to I), the weight ratio of component 1 and component 2 depends from the properties of the active substances used, preferably it is in the range of from 1:50 to 50:1 and particularly in the range of from 1:10 to 10:1, and the weight ratio of component 1 and component 3 preferably is in the range of from 1:50 to 50:1 and particularly in the range of from 1:10 to 10:1.
The components can be used individually or already partially or completely mixed with one another to prepare the composition according to the invention. It is also possible for them to be packaged and used further as combination composition such as a kit of parts.
In one embodiment, the kits may include one or more, including all, components that may be used to prepare a subject agrochemical composition. E.g., kits may include one or more fungicide component(s) and/or an adjuvant component and/or a insecticide component and/or a growth regulator component and/or a herbicide. One or more of the components may already be combined together or pre-formulated. In those embodiments where more than two components are provided in a kit, the components may already be combined together and as such are packaged in a single container such as a vial, bottle, can, pouch, bag or canister. In other embodiments, two or more components of a kit may be packaged separately, i.e., not pre-formulated. As such, kits may include one or more separate containers such as vials, cans, bottles, pouches, bags or canisters, each container containing a separate component for an agrochemical composition. In both forms, a component of the kit may be applied separately from or together with the further components or as a component of a combination composition according to the invention for preparing the composition according to the invention.
The user applies the composition according to the invention usually from a predosage device, a knapsack sprayer, a spray tank or a spray plane. Here, the agrochemical composition is made up with water and/or buffer to the desired application concentration, it being possible, if appropriate, to add further auxiliaries, and the ready-to-use spray liquor or the agrochemical composition according to the invention is thus obtained. Usually, 50 to 500 liters of the ready-to-use spray liquor are applied per hectare of agricultural useful area, preferably 100 to 400 liters.
According to one embodiment, individual components of the composition according to the invention such as parts of a kit or parts of a binary or ternary mixture may be mixed by the user himself in a spray tank and further auxiliaries may be added, if appropriate (tank mix).
In a further embodiment, either individual components of the composition according to the invention or partially premixed components, e.g. components comprising compounds I and/or active substances from the groups A) to I), may be mixed by the user in a spray tank and further auxiliaries and additives may be added, if appropriate (tank mix).
In a further embodiment, either individual components of the composition according to the invention or partially premixed components, e.g. components comprising compounds I and/or active substances from the groups A) to I), can be applied jointly (e.g. after tankmix) or consecutively.
Preference is also given to mixtures comprising a compound I (component 1) and at least one active substance selected from the strobilurines of group A) (component 2) and particularly selected from azoxystrobin, dimoxystrobin, fluoxastrobin, kresoxim-methyl, orysastrobin, picoxystrobin, pyraclostrobin and trifloxystrobin.
Preference is also given to mixtures comprising a compound I (component 1) and at least one active substance selected from the carboxamides of group B) (component 2) and particularly selected from bixafen, boscalid, sedaxane, fenhexamid, metalaxyl, isopyrazam, mefenoxam, ofurace, dimethomorph, flumorph, fluopicolid (picobenzamid), zoxamide, carpropamid, mandipropamid and N-(3′,4′,5′-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide.
Preference is given to mixtures comprising a compound of formula I (component 1) and at least one active substance selected from the azoles of group C) (component 2) and particularly selected from cyproconazole, difenoconazole, epoxiconazole, fluquinconazole, flusilazole, flutriafol, metconazole, myclobutanil, penconazole, propiconazole, prothioconazole, triadimefon, triadimenol, tebuconazole, tetraconazole, triticonazole, prochloraz, cyazofamid, benomyl, carbendazim and ethaboxam.
Preference is also given to mixtures comprising a compound I (component 1) and at least one active substance selected from the heterocyclic compounds of group D) (component 2) and particularly selected from fluazinam, cyprodinil, fenarimol, mepanipyrim, pyrimethanil, triforine, fludioxonil, dodemorph, fenpropimorph, tridemorph, fenpropidin, iprodione, vinclozoliri, famoxadone, fenamidone, probenazole, proquinazid, acibenzolar-S-methyl, captafol, folpet, fenoxanil, quinoxyfen and 5-ethyl-6-octyl-[1,2,4]triazolo[1,5-a]pyrimidine-7-ylamine.
Preference is also given to mixtures comprising a compound I (component 1) and at least one active substance selected from the carbamates of group E) (component 2) and particularly selected from mancozeb, metiram, propineb, thiram, iprovalicarb, benthiavalicarb and propamocarb.
Preference is also given to mixtures comprising a compound I (component 1) and at least one active substance selected from the fungicides given in group F) (component 2) and particularly selected from dithianon, fentin salts, such as fentin acetate, fosetyl, fosetyl-aluminium, H3PO3 and salts thereof, chlorthalonil, dichlofluanid, thiophanatmethyl, copper acetate, copper hydroxide, copper oxychloride, copper sulfate, sulfur, cymoxanil, metrafenone and spiroxamine.
Accordingly, the present invention furthermore relates to compositions comprising one compound I (component 1) and one further active substance (component 2), which further active substance is selected from the column “Component 2” of the lines B-1 to B-346 of Table B.
A further embodiment relates to the compositions B-1 to B-346 listed in Table B, where a row of Table B corresponds in each case to a fungicidal composition comprising one of the in the present specification individualized compounds of formula I (component 1) and the respective further active substance from groups A) to I) (component 2) stated in the row in question. Preferably, the compositions described comprise the active substances in synergistically effective amounts.
The active substances referred to as component 2, their preparation and their activity against harmful fungi is known (cf.: http://www.alanwood.net/pesticides/); these substances are commercially available. The compounds described by IUPAC nomenclature, their preparation and their fungicidal activity are also known (cf. Can. J. Plant Sci. 48(6), 587-94, 1968; EP-A 141 317; EP-A 152 031; EP-A 226 917; EP-A 243 970; EP-A 256 503; EP-A 428 941; EP-A 532 022; EP-A 1 028 125; EP-A 1 035 122; EP-A 1 201 648; EP-A 1 122 244, JP 2002316902; DE 19650197; DE 10021412; DE 102005009458; U.S. Pat. No. 3,296,272; U.S. Pat. No. 3,325,503; WO 98/46608; WO 99/14187; WO 99/24413; WO 99/27783; WO 00/29404; WO 00/46148; WO 00/65913; WO 01/54501; WO 01/56358; WO 02/22583; WO 02/40431; WO 03/10149; WO 03/11853; WO 03/14103; WO 03/16286; WO 03/53145; WO 03/61388; WO 03/66609; WO 03/74491; WO 04/49804; WO 04/83193; WO 05/120234; WO 05/123689; WO 05/123690; WO 05/63721; WO 05/87772; WO 05/87773; WO 06/15866; WO 06/87325; WO 06/87343; WO 07/82098; WO 07/90624).
The mixtures of active substances can be prepared as compositions comprising besides the active ingredients at least one inert ingredient by usual means, e.g. by the means given for the compositions of compounds I.
Concerning usual ingredients of such compositions reference is made to the explanations given for the compositions containing compounds I.
The mixtures of active substances according to the present invention are suitable as fungicides, as are the compounds of formula I. They are distinguished by an outstanding effectiveness against a broad spectrum of phytopathogenic fungi, especially from the classes of the Ascomycetes, Basidiomycetes, Deuteromycetes and Peronosporomycetes (syn. Oomycetes). In addition, it is referred to the explanations regarding the fungicidal activity of the compounds and the compositions containing compounds I, respectively.
With due modification of the starting compounds, the procedures shown in the synthesis examples below were used to obtain further compounds I. The resulting compounds, together with physical data, are listed in Table I below.
HPC/MS conditions were as follows: HPLC column: RP-18 column (Chromolith Speed ROD from Merck KgaA, Germany), 50 mm×4.6 mm; Eluent: acetonitrile+0.1% trifluoroacetic acid (TFA)/water+0.1% TFA (gradient from 5:95 to 95:5 in 5 min at 40° C., flow of 1.8 ml/min; MS: Quadrupol Elektrospray Ionisation, 80 V (positive mode).
At 25 to 30° C. 25 ml of a 1 molar solution of lithium aluminium hydride in diethylether was added dropwise to 4.5 g 2,5-dimethyl-2H-pyrazole-3-carboxylic acid methyl ester in 50 ml diethylether. A solid precipitated and the reaction mixture was stirred for about 2 to 3 days at about 20 to 25° C. After dilution of the reaction mixture with 50 ml of MTBE a little volume of water was added. After filtration the precipitated wet solid was thoroughly washed with ethyl acetate. The solvent was removed in vacuo from the combined filtrate and washing fluids to yield 3.7 g of the title compound.
1H-NMR (CDCl3, δ in ppm): 5.9 (s, 1H); 4.6 (s, 2H); 4.0 (s, broad, 1H); 3.75 (s, 3H); 2.2 (s, 3H).
1.3 g of oxalic acid chloride in 40 ml DCM were cooled to −70° C. and 1.6 g DMSO in 10 ml DCM were added dropwise. After 5 min of stirring at −70° C. 1 g of (2,5-dimethyl-2H-pyrazol-3-yl)-methanol (example 1.1) in 10 ml DCM and 6 g triethylamine were added and the reaction mixture was allowed to warm to about 20 to 25° C. After extraction with water the reaction mixture was dried. After removing the solvents in vacuo, the resulting residue was purified by column chromatography over silica with cyclohexane/ethylacetate mixtures yielding 0.6 g of the title compound as a yellowish oil.
1H-NMR (CDCl3, δ in ppm): 9.8 (s, 1H); 6.7 (s, 1H); 4.1 (s, 3H); 2.3 (s, 3H).
0.6 g of 2,5-dimethyl-2H-pyrazole-3-carbaldehyde (example 1.2), 0.4 g of hydroxylamine hydrochloride and 0.8 g of potassium carbonate in 10 ml methanol were stirred for about 12 to 16 h at about 20 to 25° C. After removing the solvents in vacuo, the residue was dissolved in ethyl acetate and the organic phase was extracted with water. The aqueous phase was re-extracted with ethylacetate and the combined organic phases were dried. The solvent were removed in vacuo to yield 0.7 g of the title compound as a colourless solid.
1H-NMR (CDCl3, δ in ppm): 9.9 (s, broad, 1H); 8.1 (s, 1H, major isomer); 7.5 (s, 1H, minor isomer); 6.95 (s, 1H, minor isomer); 6.25 (s, 1H, major isomer); 4.0 (s, 3H; major isomer); 3.95 (s, 3H, minor isomer); 2.3 (s, 3H, minor isomer); 2.25 (s, 3H, major isomer).
0.7 g of 2,5-dimethyl-2H-pyrazole-3-carbaldehyde oxime (example 1.3) and 0.1 g of 5% palladium on charcoal in 10 ml acetic acid were stirred for 12 to 16 h under a hydrogen atmosphere. After removal of the catalyst by filtration the solvent was removed in vacuo. After resuspending the residue in ethyl acetate and dilute sodium hydroxide solution the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried and the solvents were removed in vacuo. The crystalline residue was stirred with a mixture of n-hexane and isopropanol, filtered off and dried to yield 0.6 g of the title compound as a yellowish solid.
1H-NMR (CDCl3, δ in ppm): 8.0 (s, broad, 2H); 5.95 (s, 1H); 3.75 (s, 5H); 2.2 (s, 3H).
0.5 g of C-(2,5-dimethyl-2H-pyrazol-3-yl)-methylamine (example 1.4.), 0.5 g 4-(5-trifluoromethyl-pyridin-2-yloxy)-benzenesulfonyl chloride and 1 ml triethylamine in 5 ml acetonitrile were stirred at for one hour at 20 to 25° C. After removing the solvent in vacuo, the residue was purified by column chromatography over silica RP 18 with acetonitrile/water mixtures to yield 0.3 g of the title compound as a colourless solid (m.p.=129-150° C.).
1H-NMR (CDCl3, δ in ppm): 8.45 (s, 1H); 8.0 (d, 1H); 7.9 (d, 2H); 7.3 (d, 2H); 7.1 (d, 1H); 5.85 (s, 1H); 5.3 (t, 1H); 4.15 (d, 2H); 3.7 (s, 3H); 2.15 (s, 3H).
To 1 g of 5-ethyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml DCM 1 ml sulfurylchloride was added dropwise. After stirring for 1 hour at about 20 to 25° C. the solvent was removed in vacuo and the residue was dissolved in MTBE. The organic phase was extracted with sodium hydrogencarbonate solution and passed through a column filled with silica. The solvent Was removed in vacuo to yield 1.2 g of the title compound as an yellow oil.
1H-NMR (CDCl3, δ in ppm): 4.4 (q; 2H); 4.1 (s, 3H); 2.65 (q, 2H); 1.4 (t, 3H); 1.25 (t, 3H).
To 13 g of 2,5-dimethyl-2H-pyrazole-3-carboxylic acid methyl ester (example 2.1) in 100 ml diethylether 50 ml of a 1 molar solution of lithium aluminium hydride in diethylether was added dropwise at 15 to 20° C. After stirring for 1 hour at 20 to 25° C. the reaction mixture was hydrolyzed with a little volume of water whereupon a white solid precipitated. The precipitated wet solid was filtered off over celite and was thoroughly washed with MTBE. The solvent was removed in vacuo from the combined organic phases to yield 10.5 g of the title compound.
1H-NMR (CDCl3, δ in ppm): 4.7 (s, 2H); 3.8 (s, 3H); 3.2 (s, broad, 1H); 2.6 (q, 2H); 1.2 (t, 3H).
To 1 g of (4-chloro-5-ethyl-2-methyl-2H-pyrazol-3-yl)-methanol (example 2.2) in 10 ml DCM 1 ml thionylchloride was added dropwise. After stirring for 1 hour the reaction mixture was extracted with water and a sodium bicarbonate solution. The organic phase was dried and the solvent was removed in vacuo to yield 1.1 g of the title compound as a yellow oil which slowly crystallized.
1H-NMR (CDCl3, δ in ppm): 4.6 (s, 2H); 3.9 (s, 3H); 2.6 (q, 2H); 1.25 (t, 3H).
Ammonia was introduced in 5 g of 4-(5-methyl-pyridin-2-yloxy)-benzenesulfonyl chloride in 50 ml dioxane for 1 hour at about 20 to 25° C. After removing the solvent in vacuo, the residue was suspended in DCM. Insoluble material was filtered off and the solution was passed through a column with silica eluting with ethyl acetate. The solvent was removed in vacuo to yield an oil which slowly crystallized. The crystals were stirred with a mixture of diisopropylether and hexane, filtered off and dried to obtain 3.5 g of the title compound.
1H-NMR (CDCl3, δ in ppm): 8.45 (s, 1H); 8.0 (m, 3H); 7.3 (d, 2H); 7.1 (d, 1H); 5.1 (s, 2H).
30 mg of sodium hydride were added to a solution of 0.3 g of 4-(5-methyl-pyridin-2-yloxy)-benzenesulfonamide (example 2.4) in 5 ml NMP. After stirring for 30 min at about 20 to 25° C. 0.2 g of 4-chloro-5-chloromethyl-3-ethyl-1-methyl-1H-pyrazole (example 2.3) were added and the reaction mixture was stirred for 12 to 16 h at 20 to 25° C. After dilution with water the reaction mixture was extracted with MTBE. The solvent was removed in vacuo and the resulting residue was purified by chromatography over silica RP-18 with acetonitrile/water-mixtures to yield 0.13 g of the title compound as colourless crystals (m.p.=158-160° C.).
1H-NMR (CDCl3, δ in ppm): 8.45 (s, 1H); 8.0 (d, 1H); 7.9 (d, 2H); 7.3 (d, 2H); 7.1 (d, 1H); 5.1 (t, 1H); 4.2 (d, 2H); 3.8 (s, 3H); 2.5 (q, 2H); 1.2 (t, 3H)
To a solution of 2 g 2,4,5-trimethyl-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml diethylether 11 ml of 1 molar solution of lithium aluminium hydride in diethylether were added dropwise at 10° C. After stirring the reaction mixture for about 1 hour at 20 to 25° C. the reaction mixture was diluted with 50 ml MTBE and a small volume of water was added. The reaction mixture was passed through a layer of celite and the solvents were removed in vacuo to yield 1.2 g of the title compound as an oil which slowly crystallized.
1H-NMR (CDCl3, δ in ppm): 4.55 (s, 2H); 3.75 (s, 2H); 3.35 (s, broad, 1H); 2.1 (s, 3H); 1.9 (s, 3H).
To a solution of 0.07 g (2,4,5-trimethyl-2H-pyrazol-3-yl)-methanol (example 3.1) in 2 ml DCM 3 drops of thionylchloride were added. After stirring for 1 hour at 20 to 25° C. the reaction mixture was hydrolyzed with sodium hydrogencarbonate solution and dried. The solvent were removed in vacuo to yield 0.07 g of the title compound.
1H-NMR (CDCl3, δ in ppm): 4.55 (s, 2H); 3.8 (s, 3H); 2.1 (s, 3H); 2.0 (s, 3H).
Ammonia was introduced for 2 h in a solution of 0.25 g 5-chloromethyl-1,3,4-trimethyl-1H-pyrazole (example 3.2) in 5 ml dioxane at 20 to 25° C. 0.5 g sodium iodide were added and further ammonia was introduced for 2 h. After stirring the reaction mixture for 12 to 16 h at 20 to 25° C. the solvents were removed in vacuo and the resulting crude residue was directly used for the next reaction step without further purification.
To the crude product of example 3.3 dissolved in 5 ml acetonitrile 0.25 g of 4-(5-methyl-pyridin-2-yloxy)-benzenesulfonyl chloride and 0.5 ml triethylamine were added. After stirring for 3 hours at 20 to 25° C. the solvents were removed in vacuo. The residue was resuspended in DCM and the organic phase was extracted with water. After removal of solvents in vacuo the residue was purified by chromatography over silica eluting with cyclohexane/ethylacetate mixtures to yield 0.1 g of the title compound.
1H-NMR (CDCl3, δ in ppm): 8.45 (s, 1H); 8.0 (d, 1H); 7.8 (d, 2H); 7.3 (d, 2H); 7.1 (d, 1H); 5.95 (t, 1H); 4.1 (d, 2H); 3.65 (s, 3H); 2.05 (s, 3H); 1.8 (s, 3H).
§different physical properties resulting from cis-trans isomerism; m.p. = melting point; Rt = HPLC retention time.
The fungicidal action of the compounds of the formula I was demonstrated by the following experiments:
The active compounds were formulated separately as a stock solution in dimethyl sulfoxide (DMSO) at a concentration of 10 000 ppm.
The stock solution was pipetted into a microtiter plate (MTP) and diluted to the stated active compound concentration using a pea juice-based aqueous nutrient medium for fungi. An aqueous zoospore suspension of Phytophthora infestans was then added. The plates were placed in a water vapor-saturated chamber at temperatures of 18° C. Using an absorption photometer, the MTPs were measured at 405 nm on day 7 after the inoculation. The measured parameters were compared to the growth of the active compound-free control variant (=100%) and the fungus- and active compound-free blank value to determine the relative growth in % of the pathogens in the individual active compounds.
In this test, the sample which had been treated with 31 ppm of the active compound from examples I-2, I-4, I-6, I-10, I-11, I-12, I-13, I-24, I-25, I-26, I-27, I-28, I-29, I-30, I-31, I-32, I-33, I-34, I-35, I-37, I-38, I-39, I-40, I-41, I-42, I-43, I-44, I-45, I-46, I-47, I-48, I-49 and I-50, respectively, showed up to at most 15% growth of the pathogen.
The stock solution was pipetted into a microtiter plate (MTP) and diluted to the stated active compound concentration using a malt-based aqueous nutrient medium for fungi. An aqueous spore suspension of Botrytis cinerea was then added. The plates were placed in a water vapor-saturated chamber at temperatures of 18° C. Using an absorption photometer, the microtiter plates were measured at 405 nm on day 7 after the inoculation. The measured parameters were compared to the growth of the active compound-free control variant (=100%) and the fungus- and active compound-free blank value to determine the relative growth in % of the pathogens in the individual active compounds. In this test, the sample which had been treated with 125 ppm of the active compound from example I-8 showed up to at most 15% growth of the pathogen.
The active compounds were formulated separately or together as a stock solution comprising 25 mg of active compound which was made up to 10 ml using a mixture of acetone and/or dimethyl sulfoxide (DMSO) and the emulsifier Wettol EM 31 (wetting agent having emulsifying and dispersing action based on ethoxylated alkylphenols) in a volume ratio of solvent/emulsifier of 99 to 1. This solution was then made up to 100 ml using water. This stock solution was diluted with the solvent/emulsifier/water mixture described to the active compound concentration given below.
Leaves of pot-grown soybean seedlings were inoculated with spores of Phakopsora pachyrhizi. To ensure the success of the artificial inoculation, the plants were transferred to a humid chamber with a relative humidity of about 95% and 23 to 27° C. for 24 h. The next day the plants were sprayed to run-off with an aqueous suspension, containing the concentration of active ingredient or their mixture as described below. The plants were allowed to air-dry. Then the trial plants were cultivated for 14 days in a greenhouse chamber at 23-27° C. and a relative humidity between 60 and 80%. The extent of fungal attack on the leaves was visually assessed as % diseased leaf area.
In this test, the plants which had been treated with 250 ppm of the active compound from examples I-89, I-90, I-91, I-92, I-93, I-94, I-95, I-96, I-97, I-99, I-100, I-101, I-108 and I-112, respectively, showed an infection of less than or equal to 17% whereas the untreated plants were 80% infected.
Leaves of pot-grown soy bean seedlings were sprayed to run-off with an aqueous suspension, containing the concentration of active ingredient or their mixture as described below. The plants were allowed to air-dry. The trial plants were cultivated for one day in a greenhouse chamber at 23-27° C. and a relative humidity between 60 and 80%. Then the plants were inoculated with spores of Phakopsora pachyrhizi. To ensure the success the artificial inoculation, the plants were transferred to a humid chamber with a relative humidity of about 95% and 23 to 27° C. for 24 h. The trial plants were cultivated for fourteen days in a greenhouse chamber at 23-27° C. and a relative humidity between 60 and 80%. The extent of fungal attack on the leaves was visually assessed as % diseased leaf area.
In this test, the plants which had been treated with 250 ppm of the active compound from examples I-65, I-67, I-68, I-71 and I-110, respectively, showed an infection of less than or equal to 18% whereas the untreated plants were 80% infected.
Leaves of pot-grown wheat seedling were sprayed to run-off with an aqueous suspension of the active compound or their mixture, prepared as described. The plants were allowed to air-dry. Two days later the plants were inoculated with an aqueous spore suspension of Septoria tritici. Then the trial plants were immediately transferred to a humid chamber at 18-22° C. and a relative humidity close to 100%. After 3 days the plants were transferred to a chamber with 18-22° C. and a relative humidity close to 70%. After 4 weeks the extent of fungal attack on the leaves was visually assessed as % diseased leaf area.
In this test, the plants which had been treated with 250 ppm of the active compound from examples I-74, I-76 and I-80, respectively, showed an infection of less than or equal to 15% whereas the untreated plants were 80% infected.
The active compounds were formulated separately as a stock solution having a concentration of 10000 ppm in dimethyl sulfoxide.
The stock solutions were mixed according to the ratio, pipetted onto a micro titer plate (MTP) and diluted with water to the stated concentrations. A spore suspension of Pyricularia oryzae in a yeast bactopeptone glycerol solution was then added. The plates were placed in a water vapor-saturated chamber at a temperature of 18° C. Using an absorption photometer, the MTPs were measured at 405 nm 10 days after the inoculation.
The spray solutions were prepared as described for “Examples of the action against harmful fungi” (II. B).
The trial was conducted as described for Use example 3.
| Number | Date | Country | Kind |
|---|---|---|---|
| 08101695.8 | Feb 2008 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2009/051509 | 2/10/2009 | WO | 00 | 8/6/2010 |
