WO2008009405A2 - Novel pyridazine derivatives - Google Patents

Novel pyridazine derivatives Download PDF

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Publication number
WO2008009405A2
WO2008009405A2 PCT/EP2007/006303 EP2007006303W WO2008009405A2 WO 2008009405 A2 WO2008009405 A2 WO 2008009405A2 EP 2007006303 W EP2007006303 W EP 2007006303W WO 2008009405 A2 WO2008009405 A2 WO 2008009405A2
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WO
WIPO (PCT)
Prior art keywords
formula
compound
pyridin
methyl
chloro
Prior art date
Application number
PCT/EP2007/006303
Other languages
French (fr)
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WO2008009405A3 (en
Inventor
Stephan Trah
Clemens Lamberth
Sebastian Volker Wendeborn
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Syngenta Participations Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GB0614154A external-priority patent/GB0614154D0/en
Priority claimed from GB0625313A external-priority patent/GB0625313D0/en
Application filed by Syngenta Participations Ag filed Critical Syngenta Participations Ag
Priority to CA002658254A priority Critical patent/CA2658254A1/en
Priority to MX2009000614A priority patent/MX2009000614A/en
Priority to US12/374,052 priority patent/US20100029668A1/en
Priority to EP07786105A priority patent/EP2049521A2/en
Priority to JP2009519851A priority patent/JP2009543821A/en
Priority to BRPI0714872-0A priority patent/BRPI0714872A2/en
Publication of WO2008009405A2 publication Critical patent/WO2008009405A2/en
Publication of WO2008009405A3 publication Critical patent/WO2008009405A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/58—1,2-Diazines; Hydrogenated 1,2-diazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to novel pyridazine derivatives as active ingredients which have microbiocidal activity, in particular fungicidal activity.
  • the invention also relates to preparation of these active ingredients, to novel heterocyclic derivatives used as intermediates in the preparation of these active ingredients, to preparation of these novel intermediates, to agrochemical compositions which comprise at least one of the novel active ingredients, to preparation of these compositions and to use of the active ingredients or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops or non-living materials by phytopathogenic microorganisms, preferably fungi.
  • the present invention provides a compound of formula I:
  • R 1 is hydrogen, C ⁇ C 6 alkyl, Ci-C 6 haloalkyl or C 3 -C 6 cycloalkyl;
  • R 2 is an optionally substituted heteroaryl
  • R 3 is an optionally substituted heteroaryl
  • R 4 is hydrogen, halogen, d-C 6 alkyl, CVC ⁇ haloalkyl, C r C 6 alkoxy, CVC ⁇ haloalkoxy, hydroxy or cyano; or an agrochemically usable salt form thereof.
  • Heteroaryl stands for aromatic ring systems comprising mono-, bi- or tricyclic systems wherein at least one oxygen, nitrogen or sulfur atom is present as a ring member.
  • Examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl,
  • heteroaryl groups may be optionally substituted. This means that they may carry one or more identical or different substituents. Normally not more than three substituents are present at the same time.
  • substituents of heteroaryl groups are: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, haloalkenyl, cycloalkenyl, alkynyl, haloalkynyl, alkyloxy, haloalkyloxy, cycloalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, alkenylthio, alkynylthio, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynyl,
  • Typical examples for optionally substituted heteroaryl include 3,5-difluoropyridin-2-yl, 3,5- dichloropyridin-2-yl, 3-chloro-5-fluoropyridine-2-yl, 5-chloro-3-fluoropyridin-2-yl, 3-fluoro-5- trifluoromethylpyridin-2-yl, 3-chloro-5-trifluoromethylpyridin-2-yl, 3-trifluoromethylpyridin-2-yl, 3-fluoropyridin-2-yl, 3-chloropyridin-2-yl, 5-fluoro-3-trifluoromethylpyridin-2-yl, 5-chloro-3- trifluoromethylpyridin-2-yl, 2,4-difluoropyridin-3-yl, 2,4-dichloropyridin-3-yl, 2,4,6- trifluoropyridin-3-yl, 2,4,6-trichloropyridin-3-yl, 3,5-di
  • halogen is fluorine, chlorine, bromine or iodine.
  • alkyl, alkenyl or alkynyl radicals may be straight-chained or branched.
  • Alkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the isomers thereof, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl.
  • a haloalkyl group may contain one or more identical or different halogen atoms and, for example, may stand for CH 2 CI, CHCI 2 , CCI 3 , CH 2 F, CHF 2 , CF 3 , CF 3 CH 2 , CH 3 CF 2 , CF 3 CF 2 or CCI 3 CCI 2 .
  • Cycloalkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • Alkenyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, ethenyl, allyl, 1-propenyl, buten-2-yl, buten-3-yl, penten-1-yl, penten-3-yl, hexen-1-yl or 4-methyl-3-pentenyl.
  • Alkynyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2- yl, 1-methyl-2-butynyl, hexyn-1-yl or 1-ethyl-2-butynyl.
  • the presence of one or more possible asymmetric carbon atoms in a compound of formula I means that the compounds may occur in optically isomeric, that means enantiomeric or diastereomeric forms.
  • optically isomeric that means enantiomeric or diastereomeric forms.
  • geometric isomerism that means cis-trans or (E)-(Z) isomerism may also occur.
  • atropisomers may occur as a result of restricted rotation about a single bond.
  • Formula I is intended to include all those possible isomeric forms and mixtures thereof.
  • the present invention intends to include all those possible isomeric forms and mixtures thereof for a compound of formula I.
  • R 1 is d-Cealkyl, d-Cehaloalkyl or C 3 -C 6 cycloalkyl.
  • R 2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyrid
  • R 3 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyrid
  • R 4 is halogen, d-C 6 alkyl, CrC ⁇ haloalkyl, d-Cealkoxy, C 1 -
  • Preferred subgroups of compounds of formula I according to the invention are those wherein R 1 is CrC ⁇ alkyl or d-C ⁇ haloalkyl;
  • R 2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl or quinolyl;
  • R 3 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl; and
  • R 4 is halogen, d-C 6 alkyl, d-C 6 alkoxy or hydroxy.
  • R 1 is d-Caalkyl or d-C 3 haloalkyl
  • R 2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl or quinolyl;
  • R 3 is an optionally substituted thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; and R 4 is chloro, fluoro, C r C 4 alkyl, C 1 -C 4 BIkOXy or hydroxy.
  • R 2 is an optionally substituted furyl, thienyl, pyridyl or pyrimidinyl or quinolyl;
  • R 3 is an optionally substituted thienyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl;
  • R 4 is chloro, fluoro, d-Csalkyl, CVCsalkoxy or hydroxy.
  • R 1 is methyl
  • R 2 is 2-chloro-pyridin-4yl, 6-chloro-pyridin-3-yl, 6-methyl-pyridin-3-yl or 5-methylsulfanyl- pyridin-2-yl;
  • R 3 is 3,5-dichloropyridin-2-yl
  • R 4 is chloro, methyl or methoxy.
  • Preferred individual compounds are: 3-chloro-5-(6-chloro-pyridin-3-yl)-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-pyridazine;
  • the compounds of formula 1.2 wherein R 1 , R 2 , R 3 and R 5 are as defined for compound of formula I and R 5 is C r C 6 alkyl or CrC 6 haloalkyl, can be obtained by reaction of a compound of formula 1.1 , wherein R 1 , R 2 and R 3 are as defined for compound of formula I and Hal is halogen, preferably fluorine, chlorine or bromine, with an alcohol R OH, wherein RR 55 iiss CCrrCCeeaallkkyyll oorr C di--CC 6 ⁇ hhaalloo;alkyl, and base or with a sodium alkoxide NaOR 5 , wherein R 5 is Ci-C 6 alkyl or C r C 6 haloalkyl.
  • the compounds of formula 1.3 wherein R 1 , R 2 , R 3 and R 6 are as defined for compound of formula I and R 6 is d-C ⁇ alkyl, can be obtained by reaction of a compound of formula 1.1 , wherein R 1 , R 2 and R 3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a Grignard reagent R 6 MgHaI, wherein R 6 is CVCealkyl and Hal is halogen, preferably chlorine or bromine, in the presence of a transition metal catalyst.
  • the compounds of formula 1.4 wherein R 1 , R 2 and R 3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula 1.1 , wherein R 1 , R 2 and R 3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a inorganic fluoride, e.g. potassium fluoride.
  • a compound of formula 1.1 wherein R 1 , R 2 and R 3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a inorganic fluoride, e.g. potassium fluoride.
  • the compounds of formula 1.1 wherein R 1 , R 2 and R 3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, can be obtained by reaction of a compound of formula 1.5, wherein R 1 , R 2 and R 3 are as defined for compound of formula I, with a phosphorus oxyhalide, e.g. phosphorus oxychloride or phosphorus oxybromide, or thionyl halide, e.g.thionyl chloride or thionyl bromide.
  • a phosphorus oxyhalide e.g. phosphorus oxychloride or phosphorus oxybromide
  • thionyl halide e.g.thionyl chloride or thionyl bromide.
  • the compounds of formula 1.5 wherein R 1 , R 2 and R 3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula II, wherein R 1 , R 2 and R 3 are as defined for compound of formula I, with a hydrazine derivative, e.g. hydrazine hydrate.
  • the compounds of formula II, wherein R 1 , R 2 and R 3 are as defined for compound of formula I 1 can be obtained by oxidation with oxygen, air or 3-chloroperbenzoic acid of a compound of formula III, wherein R 1 , R 2 and R 3 are as defined for compound of formula I.
  • the compounds of formula III, wherein R 1 , R 2 and R 3 are as defined for compound of formula I can be obtained by reaction of a compound of formula IV, wherein R 1 , R 2 and R 3 are as defined for compound of formula I, with a base, e.g. pyridine, triethylamine, diisopropylethylamine, 1 ,5-diazabicyclo[4.3.0]non-5-ene or 1 ,8-diazabicyclo[5.4.0]undec-7- ene.
  • a base e.g. pyridine, triethylamine, diisopropylethylamine, 1 ,5-diazabicyclo[4.3.0]non-5-ene or 1 ,8-diazabicyclo[5.4.0]undec-7- ene.
  • the compounds of formula IV wherein R 1 , R 2 and R 3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula V, wherein R 1 and R 2 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a compound of formula Vl, wherein R 3 is as defined for compound of formula I, and a base, e.g. pyridine, triethylamine, diisopropylethylamine, 1 ,5-diazabicyclo[4.3.0]non-5-ene or 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
  • a base e.g. pyridine, triethylamine, diisopropylethylamine, 1 ,5-diazabicyclo[4.3.0]non-5-ene or 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
  • novel compounds of formula I have, for practical purposes, a very advantageous spectrum of activities for protecting plants against diseases that are caused by fungi as well as by bacteria and viruses.
  • the compounds of formula I can be used in the agricultural sector and related fields of use as active ingredients for controlling plant pests or on non-living materials for control of spoilage microorganisms or organisms potentially harmfull to man.
  • the novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and are used for protecting numerous cultivated plants.
  • the compounds of formula I can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later e.g. from phytopathogenic microorganisms.
  • compositions comprising a compound of formula I before planting: seed, for example, can be dressed before being sown.
  • the active ingredients according to the invention can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation.
  • the composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing. The invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
  • the compounds according to present invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
  • the invention could be used to protect non-living materials from fungal attack, e.g. lumber, wall boards and paint.
  • the compounds of formula I are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Botrytis spp., Alternaria spp.) and Basidiomycetes (e.g. Rhizoctonia spp., Hemileia spp., Puccinia spp., Phakopsora spp., Ustilago spp., Tilletia spp.). Additionally, they are also effective against Ascomycetes (e.g.
  • Venturia spp. Blumeria spp., Podosphaera leucotricha, Monilinia spp., Fusarium spp., Uncinula spp., Mycosphaerella spp., Pyrenophora spp., Rhynchosporium secalis, Magnaporthe spp., Colletotrichum spp., Gaeumannomyces graminis, Tapesia spp.,
  • Ramularia spp. Microdochium nivale, Sclerotinia spp.
  • Oomycetes e.g. Phytophthora spp., Pythium spp., Plasmopara spp., Pseudoperonospora cubensis.
  • Outstanding activity has been observed against powdery mildews (e.g. Uncinula necator), rusts (e.g. Puccinia spp.) and leaf spots (e.g. Septoria tritici).
  • the novel compounds of formula I are effective against phytopathogenic bacteria and viruses (e.g. against Xanthomonas spp, Pseudomonas spp, Erwinia amylovora as well as against the tobacco mosaic virus).
  • target crops to be protected typically comprise the following species of plants: cereal (wheat, barley, rye, oat, rice, maize, sorghum and related species); beet (sugar beet and fodder beet); pomes, drupes and soft fruit (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and blackberries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); citrus fruit (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocado, cinnamomum, camphor) or plants such as tobacco
  • the target crops in accordance with the invention include conventional as well as genetically enhanced or engineered varieties such as, for example, insect resistant (e.g. Bt. and VIP varieties) as well as disease resistant, herbicide tolerant (e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®) and nematode tolerant varieties.
  • suitable genetically enhanced or engineered crop varieties include the Stoneville 5599BR cotton and Stoneville 4892BR cotton varieties.
  • the compounds of formula I are used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation.
  • compositions are conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g. in polymeric substances.
  • the methods of application such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances.
  • the compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
  • Suitable carriers and adjuvants can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO 97/33890.
  • the compounds of formula I are normally used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds.
  • further compounds can be e.g. fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
  • the compounds of formula I are normally used in the form of fungicidal compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula I, in free form or in agrochemically usable salt form, and at least one of the above-mentioned adjuvants.
  • the compounds of formula I can be mixed with other fungicides, resulting in some cases in unexpected synergistic activities.
  • Mixing components which are particularly preferred are: Azoles, such as azaconazole, BAY 14120, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, metconazole, myclobutanil, pefurazoate, penconazole, prothioconazole, pyrifenox, prochloraz, propiconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole;
  • Pyrimidinyl carbinoles such as ancymidol, fenarimol, nuarimol;
  • 2-amino-pyrimidines such as bupirimate, dimethirimol, ethirimol
  • Morpholines such as dodemorph, fenpropidine, fenpropimorph, spiroxamine, tridemorph;
  • Anilinopyrimidines such as cyprodinil, mepanipyrim, pyrimethanil;
  • Pyrroles such as fenpiclonil, fludioxonil
  • Phenylamides such as benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace, oxadixyl;
  • Benzimidazoles such as benomyl, carbendazim, debacarb, fuberidazole, thiaben- dazole;
  • Dicarboximides such as chlozolinate, dichlozoline, iprodione, myclozoline, procymi- done, vinclozoline;
  • Carboxamides such as boscalid, carboxin, fenfuram, flutolanil, mepronil, oxycarboxin, penthiopyrad, thifluzamide; guanidines, such as guazatine, dodine, iminoctadine; Strobilurines, such as azoxystrobin, dimoxystrobin, enestroburin, fluoxastrobin, kresoxim-methyl, metominostrobin, trifloxystrobin, orysastrobin, picoxystrobin, pyraclostrobin;
  • Dithiocarbamates such as ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb, ziram; N-halomethylthiotetrahydrophthalimides, such as captafol, captan, dichlofluanid, fluoromides, folpet, tolyfluanid;
  • Copper-compounds such as Bordeaux mixture, copper hydroxide, copper oxychloride, copper sulfate, cuprous oxide, mancopper, oxine-copper;
  • Nitrophenol-derivatives such as dinocap, nitrothal-isopropyl; Organo-phosphor-derivatives, such as edifenphos, iprobenphos, isoprothiolane, phosdiphen, pyrazophos, tolclofos-methyl; Pyridazine-derivatives which are known and may be prepared by methods as described in WO 05/121104, WO 06/001175 and WO 07/066601 , such as 3-chloro-5-(4- chloro-phenyl)-6-methyl-4-(2,4,6-trifIuoro-phenyl)-pyridazine (formula P.1), 3-chloro-6- methyl-5-p-tolyl-4-(2,4,6-trifluoro-phenyl)-pyridazine (formula P.2) and 3-chloro-4-(3-chloro-5- methoxy-pyridin-2-yl)-5
  • Triazolopyrimidine derivatives which are known and may be prepared by methods as described in WO98/46607, such as 5-chloro-7-(4-methyl-piperidin-1-yl)-6-(2,4,6-trifluoro- phenyl)- [1 ,2,4]triazoio[1 ,5-a]pyrimidine (formula T.1 );
  • Carboxamide derivatives which are known and may be prepared by methods as described in WO04/035589 and in WO06/37632, such as 3-difluoromethyl-1-methyl-1 H- pyrazole-4-carboxylic acid (9-isopropyp-1 ,2,3,4-tetrahaydro-1 ,4-methano-naphthalen-5-yl)- amide (formula U.1 );
  • Benzamide derivatives which are known and may be prepared by methods as described in WO 2004/016088, such as N- ⁇ -2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl ⁇ - 2-trifluoromethylbenzamide, which is also known under the name fluopyram (formula V.1 );
  • Another aspect of invention is related to the use of a compound of formula I 1 of a composition comprising at least one compound of formula I or of a fungicidal mixture comprising at least one compound of formula I in admixture with other fungicides, as described above, for controlling or preventing infestation of plants, harvested food crops or non-living materials by phytopathogenic microorganisms, preferably fungal organisms.
  • a further aspect of invention is related to a method of controlling or preventing an infestation of crop plants or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula I as active ingredient to the plants, to parts of the plants or to the locus thereof, or to any part of the non-living materials.
  • Controlling or preventing means reducing the infestation of crop plants or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
  • a preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, which comprises the application of a compound of formula I, or an agrochemical composition which contains at least one of said compounds, is foliar application.
  • the frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen.
  • the compounds of formula I can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field.
  • the compounds of formula I may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.
  • a formulation that is, a composition containing the compound of formula I] and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula I, is prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
  • extenders for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
  • the agrochemical formulations will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
  • Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably from 10g to 1 kg a.i./ha, most preferably from 2Og to
  • Example 1 This example illustrates the preparation of 3-chloro-4-(3,5-dichloro-pyridin-2-yl)- 6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No. I. u.008)
  • reaction mixture is poured into water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated under reduced pressure.
  • the remainder is purified on silica gel, using a mixture of heptane / ethyl acetate 9 : 1 as eluent to obtain 1-(5-methylsulfanyl-pyridin-2-yl)propan-1-one as a yellow solid (m.p. 52 - 53 0 C).
  • Bromine (3.4 g) is added to the mixture of 1-(5-methylsulfanyl-pyridin-2-yl)propan-1-one (3.8 g), 0.05 ml of hydrobromic acid (33 % solution) and 40 ml of acetic acid at room temperature under a nitrogen atmosphere. Subsequently, the mixture is stirred for 1 h at 90 0 C. After cooling, te/f-butyl methyl ether is added, the obtained solid is filtered, washed with terf-butyl methyl ether and dried in vacuo to give a yellow solid.
  • reaction mixture is poured into water, acidified with 2 N hydrochloric acid and then extracted with ethyl acetate.
  • the combined organic layer is washed with a saturated aqueous sodium hydrogencarbonate solution and with brine, dried over sodium sulfate and evaporated under reduced pressure.
  • the remainder is purified by chromatography on silica gel, using a mixture of heptane / ethyl acetate 2 : 1 as eluent to obtain 3-(3,5-dichloro-pyridin-2-yl)-5-hydroxy-5-methyl-4-(5- methylsulfanyl-pyridin-2-yl)-5H-furan-2-one (Compound No. II. u.002) as a yellow foam.
  • Example 2 This example illustrates the preparation of 4-(3,5-dichloro-pyridin-2-yl)-3- methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No.l.u.009) and 4- (3-chloro-5-methoxy-pyridin-2-yl)-3-methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)- pyridazine
  • Example 3 This example illustrates the preparation of 4-(3,5-dichloro-pyridin-2-yl)-3,6- dimethyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No. I. u.010)
  • Methylmagnesium bromide (3 M in diethyl ether, 1.0 ml) is added slowly to a solution of 3- chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No.l.u.008, 0.3 g) and iron(lll) acetylacetonate (0.03 g) in 15 ml of tetrahydrofuran and 2 ml of 1-methyl-2-pyrrolidinone (NMP).
  • NMP 1-methyl-2-pyrrolidinone
  • R 1 , R 3 and R 4 are as defined in Table 1.
  • R 1 , R 3 and R 4 are as defined in Table 1.
  • R 1 , R 3 and R 4 are as defined in Table 1.
  • R 1 and R 3 are as defined in Table 2.
  • R 1 and R 3 are as defined in Table 2.
  • R 1 and R 3 are as defined in Table 2.
  • Table 3 shows selected melting point and selected NMR data, all with CDCI 3 as the solvent (unless otherwise stated, no attempt is made to list all characterising data in all cases) for compounds of Tables 1 and 2.
  • Table 3 Melting point and selected NMR data for compounds of Tables 1 and 2
  • Botrytis cinerea I tomato / preventive (Action against Botrvtis on tomato) 4 weeks old tomato plants cv. Roter Gnom are treated with the formulated test compound in a spray chamber. Two days after application tomato plants are inoculated by spraying a spore suspension on the test plants. After an incubation period of 3 days at 20 0 C and 95% r. h. in a greenhouse the disease incidence is assessed.
  • Compounds of formula I according to the invention in particular compounds l.u.008 and I. u.009, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.
  • Puccinia recondita /wheat / preventive Action against brown rust on wheat
  • 1 week old wheat plants cv. Arina are treated with the formulated test compound in a spray chamber.
  • wheat plants are inoculated by spraying a spore suspension (1 x 105 uredospores/ml) on the test plants.
  • a spore suspension (1 x 105 uredospores/ml) on the test plants.
  • the disease incidence is assessed 11 days after inoculation.
  • Ma ⁇ naporthe grisea (Pyricularia orvzae) I rice / preventive (Action against rice blast) 3 weeks old rice plants cv. Koshihikari are treated with the formulated test compound in a spray chamber. Two days after application rice plants are inoculated by spraying a spore suspension (1 x 10 5 conidia/ml) on the test plants. After an incubation period of 6 days at 25 0 C and 95% r. h. the disease incidence is assessed.
  • Uncinula necator/ grape / preventive (Action against powdery mildew on grape) 5 weeks old grape seedlings cv. Gutedel are treated with the formulated test compound in a spray chamber.
  • grape plants are inoculated by shaking plants infected with grape powdery mildew above the test plants.

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Abstract

The present invention relates to novel pyridazine derivatives of formula (I) as active ingredients which have microbiocidal activity, in particular fungicidal activity: wherein R1 is hydrogen, C1-C6alkyl, C1-C6haloalkyl or C3-C6cycloalkyl; R2 is an optionally substituted hereroaryl; R3 is an optionally substituted heteroaryl; and R4 is hydrogen, halogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, hydroxy or cyano; or an agrochemically usable salt form thereof.

Description

Novel pyridazine derivatives
The present invention relates to novel pyridazine derivatives as active ingredients which have microbiocidal activity, in particular fungicidal activity. The invention also relates to preparation of these active ingredients, to novel heterocyclic derivatives used as intermediates in the preparation of these active ingredients, to preparation of these novel intermediates, to agrochemical compositions which comprise at least one of the novel active ingredients, to preparation of these compositions and to use of the active ingredients or compositions in agriculture or horticulture for controlling or preventing infestation of plants, harvested food crops or non-living materials by phytopathogenic microorganisms, preferably fungi.
The present invention provides a compound of formula I:
Figure imgf000002_0001
wherein R1 is hydrogen, CτC6alkyl, Ci-C6haloalkyl or C3-C6cycloalkyl;
R2 is an optionally substituted heteroaryl;
R3 is an optionally substituted heteroaryl; and
R4is hydrogen, halogen, d-C6alkyl, CVCβhaloalkyl, CrC6alkoxy, CVCβhaloalkoxy, hydroxy or cyano; or an agrochemically usable salt form thereof.
Heteroaryl stands for aromatic ring systems comprising mono-, bi- or tricyclic systems wherein at least one oxygen, nitrogen or sulfur atom is present as a ring member. Examples are furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl and naphthyridinyl. Each heteroaryl can be linked by a carbon atom or by a nitrogen atom to the pyridazine.
The above heteroaryl groups may be optionally substituted. This means that they may carry one or more identical or different substituents. Normally not more than three substituents are present at the same time. Examples of substituents of heteroaryl groups are: halogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, haloalkenyl, cycloalkenyl, alkynyl, haloalkynyl, alkyloxy, haloalkyloxy, cycloalkoxy, alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkenyloxy, alkylthio, haloalkylthio, cycloalkylthio, alkenylthio, alkynylthio, alkylcarbonyl, haloalkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkoxyalkyl, cyano, nitro, hydroxy, mercapto, amino, alkylamino, dialkylamino. Typical examples for optionally substituted heteroaryl include 3,5-difluoropyridin-2-yl, 3,5- dichloropyridin-2-yl, 3-chloro-5-fluoropyridine-2-yl, 5-chloro-3-fluoropyridin-2-yl, 3-fluoro-5- trifluoromethylpyridin-2-yl, 3-chloro-5-trifluoromethylpyridin-2-yl, 3-trifluoromethylpyridin-2-yl, 3-fluoropyridin-2-yl, 3-chloropyridin-2-yl, 5-fluoro-3-trifluoromethylpyridin-2-yl, 5-chloro-3- trifluoromethylpyridin-2-yl, 2,4-difluoropyridin-3-yl, 2,4-dichloropyridin-3-yl, 2,4,6- trifluoropyridin-3-yl, 2,4,6-trichloropyridin-3-yl, 3,5-difluoropyridin-4-yl, 3,5-dichloropyridin-4- yl, 3-chloro-5-fluoropyridin-4-yl, 5-chloropyrimidin-4-yl, 5-fluoropyrimidin-4-yl, 5- trifluoromethylpyrimidin-4-yl, 4-chloropyridazin-3-yl, 4-fluoropyridazin-3-yl, 4- trifluoromethylpyridazin-3-yl, 3-chloropyrazin-2-yl, 3-fluoropyrazin-2-yl, 3- trifluoromethylpyrazin-2-yl, 3-fluorothiophen-2-yl, 3-chlorothiophen-2-yl, 3- trifluoromethylthiophen-2-yl, 2-fluorothiophen-3-yl, 2-chlorothiophen-3-yl, 2- trifluoromethylthiophen-3-yl, 2,5-difluorothiophen-3-yl, 2,5-dichlorothiophen-3-yl, 2-chloro-4- trifluoromethylthiazol-5-yl, 5-chlorofuran-2-yl, 5-bromofuran-5-yl, 5-chlorothiophen-2-yl, 5- bromothiophen-2-yl, 2-chloropyridin-4yl 6-chloropyridin-2-yl, 6-methylpyridin-2-yl, 6- chloropyridin-3-yl, 6-methylpyridin-3-yl, 5,6-dichloropyridin-3-yl, 2-chloropyridin-4-yl, 2- methylpyridin-4-yl, 2,6-dichloropyridin-4-yl, 2-methylpyrimidin-4-yl or 5-methylsulfanyl-pyridin- 2-yl.
In the above definition halogen is fluorine, chlorine, bromine or iodine.
The alkyl, alkenyl or alkynyl radicals may be straight-chained or branched. Alkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the isomers thereof, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or tert-pentyl.
A haloalkyl group may contain one or more identical or different halogen atoms and, for example, may stand for CH2CI, CHCI2, CCI3, CH2F, CHF2, CF3, CF3CH2, CH3CF2, CF3CF2 or CCI3CCI2.
Cycloalkyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alkenyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, ethenyl, allyl, 1-propenyl, buten-2-yl, buten-3-yl, penten-1-yl, penten-3-yl, hexen-1-yl or 4-methyl-3-pentenyl.
Alkynyl on its own or as part of another substituent is, depending upon the number of carbon atoms mentioned, for example, ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-2- yl, 1-methyl-2-butynyl, hexyn-1-yl or 1-ethyl-2-butynyl.
The presence of one or more possible asymmetric carbon atoms in a compound of formula I means that the compounds may occur in optically isomeric, that means enantiomeric or diastereomeric forms. As a result of the presence of a possible aliphatic C=C double bond, geometric isomerism, that means cis-trans or (E)-(Z) isomerism may also occur. Also atropisomers may occur as a result of restricted rotation about a single bond. Formula I is intended to include all those possible isomeric forms and mixtures thereof. The present invention intends to include all those possible isomeric forms and mixtures thereof for a compound of formula I.
In a first embodiment, R1 is d-Cealkyl, d-Cehaloalkyl or C3-C6cycloalkyl.
In a second embodiment, R2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl.
In a third embodiment, R3 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl.
In a fourth embodiment, R4 is halogen, d-C6alkyl, CrCεhaloalkyl, d-Cealkoxy, C1-
C6haloalkoxy or hydroxy.
Preferred subgroups of compounds of formula I according to the invention are those wherein R1 is CrCβalkyl or d-Cβhaloalkyl;
R2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl or quinolyl;
R3 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl; and
R4 is halogen, d-C6alkyl, d-C6alkoxy or hydroxy.
Most preferred subgroups of compounds of formula I according to the invention are those wherein
R1 is d-Caalkyl or d-C3haloalkyl;
R2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl or quinolyl;
R3 is an optionally substituted thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; and R4 is chloro, fluoro, CrC4alkyl, C1-C4BIkOXy or hydroxy.
Especially preferred subgroups of compounds of formula I according to the invention are those wherein R1 is methyl or ethyl;
R2 is an optionally substituted furyl, thienyl, pyridyl or pyrimidinyl or quinolyl;
R3 is an optionally substituted thienyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; and
R4 is chloro, fluoro, d-Csalkyl, CVCsalkoxy or hydroxy.
Particularly preferred subgroups of compounds of formula I according to the invention are those wherein
R1 is methyl;
R2 is 2-chloro-pyridin-4yl, 6-chloro-pyridin-3-yl, 6-methyl-pyridin-3-yl or 5-methylsulfanyl- pyridin-2-yl;
R3 is 3,5-dichloropyridin-2-yl; and
R4 is chloro, methyl or methoxy.
Preferred individual compounds are: 3-chloro-5-(6-chloro-pyridin-3-yl)-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-pyridazine;
4-(6-chloro-pyridin-3-yl)-5-(3,5-dichloro-pyridin-2-yl)-6-methoxy-3-methyl-pyridazine;
3-chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(6-methyl-pyridin-3-yl)-pyridazine;
4-(3,5-dichloro-pyridin-2-yl)-3-methoxy-6-methyl-5-(6-methyl-pyridin-3-yl)-pyridazine;
3-chloro-5-(2-chloro-pyridin-4-yl)-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-pyridazine; 4-(2-chloro-pyridin-4-yl)-5-(3,5-dichloro-pyridin-2-yl)-6-methoxy-3-methyl-pyridazine;
3-chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine; and
4-(3,5-dichloro-pyridin-2-yl)-3-methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine.
Certain pyridazine derivatives with two phenyl groups in positions 4 and 5 have been proposed for controlling plant-destructive fungi, for example in WO 2005/121104 and WO 2006/001175. However, the action of those preparations is not satisfactory in all aspects of agricultural needs. Surprisingly, with the compounds of formula I1 new kinds of fungicides having a high level of biological actitivity have now been found.
Compounds of formula (1.1), (I.2), (I.3), (I.4) and (I.5), in which R1, R2, R3, R5and R6 have the meanings given above, are all examples of compounds of general formula (I) and can be made as shown in the following schemes.
The compounds of formula 1.2, wherein R1, R2, R3 and R5 are as defined for compound of formula I and R5 is CrC6alkyl or CrC6haloalkyl, can be obtained by reaction of a compound of formula 1.1 , wherein R1, R2 and R3 are as defined for compound of formula I and Hal is halogen, preferably fluorine, chlorine or bromine, with an alcohol R OH, wherein RR55 iiss CCrrCCeeaallkkyyll oorr C di--CC6βhhaalloo;alkyl, and base or with a sodium alkoxide NaOR5, wherein R5 is Ci-C6alkyl or CrC6haloalkyl.
Figure imgf000007_0001
The compounds of formula 1.3, wherein R1, R2, R3 and R6 are as defined for compound of formula I and R6 is d-Cβalkyl, can be obtained by reaction of a compound of formula 1.1 , wherein R1, R2 and R3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a Grignard reagent R6MgHaI, wherein R6 is CVCealkyl and Hal is halogen, preferably chlorine or bromine, in the presence of a transition metal catalyst.
Figure imgf000007_0002
The compounds of formula 1.4, wherein R1, R2 and R3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula 1.1 , wherein R1, R2 and R3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a inorganic fluoride, e.g. potassium fluoride.
Figure imgf000008_0001
The compounds of formula 1.1 , wherein R1, R2 and R3 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, can be obtained by reaction of a compound of formula 1.5, wherein R1, R2 and R3 are as defined for compound of formula I, with a phosphorus oxyhalide, e.g. phosphorus oxychloride or phosphorus oxybromide, or thionyl halide, e.g.thionyl chloride or thionyl bromide.
Figure imgf000008_0002
The compounds of formula 1.5, wherein R1, R2 and R3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula II, wherein R1, R2 and R3 are as defined for compound of formula I, with a hydrazine derivative, e.g. hydrazine hydrate.
Figure imgf000008_0003
The compounds of formula II, wherein R1, R2 and R3 are as defined for compound of formula I1 can be obtained by oxidation with oxygen, air or 3-chloroperbenzoic acid of a compound of formula III, wherein R1, R2 and R3 are as defined for compound of formula I.
Figure imgf000009_0001
The compounds of formula III, wherein R1, R2 and R3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula IV, wherein R1, R2 and R3 are as defined for compound of formula I, with a base, e.g. pyridine, triethylamine, diisopropylethylamine, 1 ,5-diazabicyclo[4.3.0]non-5-ene or 1 ,8-diazabicyclo[5.4.0]undec-7- ene.
(Ml)
Figure imgf000009_0002
The compounds of formula IV, wherein R1, R2 and R3 are as defined for compound of formula I, can be obtained by reaction of a compound of formula V, wherein R1 and R2 are as defined for compound of formula I and Hal is halogen, preferably chlorine or bromine, with a compound of formula Vl, wherein R3 is as defined for compound of formula I, and a base, e.g. pyridine, triethylamine, diisopropylethylamine, 1 ,5-diazabicyclo[4.3.0]non-5-ene or 1 ,8- diazabicyclo[5.4.0]undec-7-ene.
Figure imgf000009_0003
Surprisingly, it has now been found that the novel compounds of formula I have, for practical purposes, a very advantageous spectrum of activities for protecting plants against diseases that are caused by fungi as well as by bacteria and viruses. The compounds of formula I can be used in the agricultural sector and related fields of use as active ingredients for controlling plant pests or on non-living materials for control of spoilage microorganisms or organisms potentially harmfull to man. The novel compounds are distinguished by excellent activity at low rates of application, by being well tolerated by plants and by being environmentally safe. They have very useful curative, preventive and systemic properties and are used for protecting numerous cultivated plants. The compounds of formula I can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit, blossoms, leaves, stems, tubers, roots) of different crops of useful plants, while at the same time protecting also those parts of the plants that grow later e.g. from phytopathogenic microorganisms.
It is also possible to use compounds of formula I as dressing agents for the treatment of plant propagation material, e.g., seed, such as fruits, tubers or grains, or plant cuttings (for example rice), for the protection against fungal infections as well as against phytopathogenic fungi occurring in the soil. The propagation material can be treated with a composition comprising a compound of formula I before planting: seed, for example, can be dressed before being sown. The active ingredients according to the invention can also be applied to grains (coating), either by impregnating the seeds in a liquid formulation or by coating them with a solid formulation. The composition can also be applied to the planting site when the propagation material is being planted, for example, to the seed furrow during sowing. The invention relates also to such methods of treating plant propagation material and to the plant propagation material so treated.
Furthermore the compounds according to present invention can be used for controlling fungi in related areas, for example in the protection of technical materials, including wood and wood related technical products, in food storage, in hygiene management.
In addition, the invention could be used to protect non-living materials from fungal attack, e.g. lumber, wall boards and paint.
The compounds of formula I are, for example, effective against the phytopathogenic fungi of the following classes: Fungi imperfecti (e.g. Botrytis spp., Alternaria spp.) and Basidiomycetes (e.g. Rhizoctonia spp., Hemileia spp., Puccinia spp., Phakopsora spp., Ustilago spp., Tilletia spp.). Additionally, they are also effective against Ascomycetes (e.g. Venturia spp., Blumeria spp., Podosphaera leucotricha, Monilinia spp., Fusarium spp., Uncinula spp., Mycosphaerella spp., Pyrenophora spp., Rhynchosporium secalis, Magnaporthe spp., Colletotrichum spp., Gaeumannomyces graminis, Tapesia spp.,
Ramularia spp., Microdochium nivale, Sclerotinia spp.) and Oomycetes (e.g. Phytophthora spp., Pythium spp., Plasmopara spp., Pseudoperonospora cubensis). Outstanding activity has been observed against powdery mildews (e.g. Uncinula necator), rusts (e.g. Puccinia spp.) and leaf spots (e.g. Septoria tritici). Furthermore, the novel compounds of formula I are effective against phytopathogenic bacteria and viruses (e.g. against Xanthomonas spp, Pseudomonas spp, Erwinia amylovora as well as against the tobacco mosaic virus).
Within the scope of present invention, target crops to be protected typically comprise the following species of plants: cereal (wheat, barley, rye, oat, rice, maize, sorghum and related species); beet (sugar beet and fodder beet); pomes, drupes and soft fruit (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and blackberries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); citrus fruit (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocado, cinnamomum, camphor) or plants such as tobacco, nuts, coffee, eggplants, sugar cane, tea, pepper, vines, hops, bananas and natural rubber plants, as well as turf and ornamentals.
The target crops in accordance with the invention include conventional as well as genetically enhanced or engineered varieties such as, for example, insect resistant (e.g. Bt. and VIP varieties) as well as disease resistant, herbicide tolerant (e.g. glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady® and LibertyLink®) and nematode tolerant varieties. By way of example, suitable genetically enhanced or engineered crop varieties include the Stoneville 5599BR cotton and Stoneville 4892BR cotton varieties. The compounds of formula I are used in unmodified form or, preferably, together with the adjuvants conventionally employed in the art of formulation. To this end they are conveniently formulated in known manner to emulsifiable concentrates, coatable pastes, directly sprayable or dilutable solutions or suspensions, dilute emulsions, wettable powders, soluble powders, dusts, granulates, and also encapsulations e.g. in polymeric substances. As with the type of the compositions, the methods of application, such as spraying, atomising, dusting, scattering, coating or pouring, are chosen in accordance with the intended objectives and the prevailing circumstances. The compositions may also contain further adjuvants such as stabilizers, antifoams, viscosity regulators, binders or tackifiers as well as fertilizers, micronutrient donors or other formulations for obtaining special effects.
Suitable carriers and adjuvants can be solid or liquid and are substances useful in formulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers. Such carriers are for example described in WO 97/33890.
The compounds of formula I are normally used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession with further compounds. These further compounds can be e.g. fertilizers or micronutrient donors or other preparations, which influence the growth of plants. They can also be selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or application promoting adjuvants customarily employed in the art of formulation.
The compounds of formula I are normally used in the form of fungicidal compositions for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound of formula I, in free form or in agrochemically usable salt form, and at least one of the above-mentioned adjuvants.
The compounds of formula I can be mixed with other fungicides, resulting in some cases in unexpected synergistic activities. Mixing components which are particularly preferred are: Azoles, such as azaconazole, BAY 14120, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, metconazole, myclobutanil, pefurazoate, penconazole, prothioconazole, pyrifenox, prochloraz, propiconazole, simeconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole;
Pyrimidinyl carbinoles, such as ancymidol, fenarimol, nuarimol;
2-amino-pyrimidines, such as bupirimate, dimethirimol, ethirimol;
Morpholines, such as dodemorph, fenpropidine, fenpropimorph, spiroxamine, tridemorph;
Anilinopyrimidines, such as cyprodinil, mepanipyrim, pyrimethanil;
Pyrroles, such as fenpiclonil, fludioxonil;
Phenylamides, such as benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace, oxadixyl;
Benzimidazoles, such as benomyl, carbendazim, debacarb, fuberidazole, thiaben- dazole;
Dicarboximides, such as chlozolinate, dichlozoline, iprodione, myclozoline, procymi- done, vinclozoline;
Carboxamides, such as boscalid, carboxin, fenfuram, flutolanil, mepronil, oxycarboxin, penthiopyrad, thifluzamide; guanidines, such as guazatine, dodine, iminoctadine; Strobilurines, such as azoxystrobin, dimoxystrobin, enestroburin, fluoxastrobin, kresoxim-methyl, metominostrobin, trifloxystrobin, orysastrobin, picoxystrobin, pyraclostrobin;
Dithiocarbamates, such as ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb, ziram; N-halomethylthiotetrahydrophthalimides, such as captafol, captan, dichlofluanid, fluoromides, folpet, tolyfluanid;
Copper-compounds, such as Bordeaux mixture, copper hydroxide, copper oxychloride, copper sulfate, cuprous oxide, mancopper, oxine-copper;
Nitrophenol-derivatives, such as dinocap, nitrothal-isopropyl; Organo-phosphor-derivatives, such as edifenphos, iprobenphos, isoprothiolane, phosdiphen, pyrazophos, tolclofos-methyl; Pyridazine-derivatives which are known and may be prepared by methods as described in WO 05/121104, WO 06/001175 and WO 07/066601 , such as 3-chloro-5-(4- chloro-phenyl)-6-methyl-4-(2,4,6-trifIuoro-phenyl)-pyridazine (formula P.1), 3-chloro-6- methyl-5-p-tolyl-4-(2,4,6-trifluoro-phenyl)-pyridazine (formula P.2) and 3-chloro-4-(3-chloro-5- methoxy-pyridin-2-yl)-5-(4-chloro-phenyl)-6-methyl-pyridazine (formula P.3);
Figure imgf000014_0001
Triazolopyrimidine derivatives which are known and may be prepared by methods as described in WO98/46607, such as 5-chloro-7-(4-methyl-piperidin-1-yl)-6-(2,4,6-trifluoro- phenyl)- [1 ,2,4]triazoio[1 ,5-a]pyrimidine (formula T.1 );
Figure imgf000014_0002
T.1
Carboxamide derivatives which are known and may be prepared by methods as described in WO04/035589 and in WO06/37632, such as 3-difluoromethyl-1-methyl-1 H- pyrazole-4-carboxylic acid (9-isopropyp-1 ,2,3,4-tetrahaydro-1 ,4-methano-naphthalen-5-yl)- amide (formula U.1 );
Figure imgf000015_0001
U.1
Benzamide derivatives which are known and may be prepared by methods as described in WO 2004/016088, such as N-{-2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl}- 2-trifluoromethylbenzamide, which is also known under the name fluopyram (formula V.1 );
Figure imgf000015_0002
V.1 and
Various others, such as acibenzolar-S-methyl, anilazine, benthiavalicarb, blasticidin-S, chinomethionate, chloroneb, chlorothalonil, cyflufenamid, cymoxanil, dichlone, diclocymet, diclomezine, dicloran, diethofencarb, dimethomorph, flumorph, dithianon, ethaboxam, etridiazole, famoxadone, fenamidone, fenoxanil, fentin, ferimzone, fluazinam, fluopicolide, flusulfamide, fenhexamid, fosetyl-aluminium, hymexazol, iprovalicarb, cyazofamid, kasugamycin, mandipropamid, methasulfocarb, metrafenone, nicobifen, pencycuron, phthalide, polyoxins, probenazole, propamocarb, proquinazid, pyroquilon, quinoxyfen, quintozene, sulfur, tiadinil, triazoxide, tricyclazole, triforine, validamycin, zoxamide and glyphosate.
Another aspect of invention is related to the use of a compound of formula I1 of a composition comprising at least one compound of formula I or of a fungicidal mixture comprising at least one compound of formula I in admixture with other fungicides, as described above, for controlling or preventing infestation of plants, harvested food crops or non-living materials by phytopathogenic microorganisms, preferably fungal organisms.
A further aspect of invention is related to a method of controlling or preventing an infestation of crop plants or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, which comprises the application of a compound of formula I as active ingredient to the plants, to parts of the plants or to the locus thereof, or to any part of the non-living materials. Controlling or preventing means reducing the infestation of crop plants or of non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, especially fungal organisms, to such a level that an improvement is demonstrated.
A preferred method of controlling or preventing an infestation of crop plants by phytopathogenic microorganisms, especially fungal organisms, which comprises the application of a compound of formula I, or an agrochemical composition which contains at least one of said compounds, is foliar application. The frequency of application and the rate of application will depend on the risk of infestation by the corresponding pathogen. However, the compounds of formula I can also penetrate the plant through the roots via the soil (systemic action) by drenching the locus of the plant with a liquid formulation, or by applying the compounds in solid form to the soil, e.g. in granular form (soil application). In crops of water rice such granulates can be applied to the flooded rice field. The compounds of formula I may also be applied to seeds (coating) by impregnating the seeds or tubers either with a liquid formulation of the fungicide or coating them with a solid formulation.
A formulation [that is, a composition containing the compound of formula I] and, if desired, a solid or liquid adjuvant or monomers for encapsulating the compound of formula I, is prepared in a known manner, typically by intimately mixing and/or grinding the compound with extenders, for example solvents, solid carriers and, optionally, surface active compounds (surfactants).
The agrochemical formulations will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
Advantageous rates of application are normally from 5g to 2kg of active ingredient (a.i.) per hectare (ha), preferably from 10g to 1 kg a.i./ha, most preferably from 2Og to
60Og a.i./ha. When used as seed drenching agent, convenient dosages are from 10mg to 1g of active substance per kg of seeds.
Whereas it is preferred to formulate commercial products as concentrates, the end user will normally use dilute formulations.
The following non-limiting examples illustrate the above-described invention in more detail.
Example 1 : This example illustrates the preparation of 3-chloro-4-(3,5-dichloro-pyridin-2-yl)- 6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No. I. u.008)
a) Preparation of 2-bromo-5-methylsulfanyl-pyridine n-Butyllithium (1.6 M in hexane, 32 ml) is added dropwise to the solution of 2,5-dibromo- pyridine (10 g) in 100 ml of diethyl ether at -75 °C under a nitrogen atmosphere. After stirring for 1 h at -75 0C, dimethyl disulfide (5 g) is added and stirring is continued for 1 h. Subsequently 50 ml of 1 N hydrochloric acid are added at - 20 0C, the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. 2-bromo-5- methylsulfanyl-pyridine is obtained as a brown solid, which is used in the next step without further purification.
b) Preparation of 1-(5-methylsulfanyl-pyridin-2-yl)-propan-1-one n-Butyllithium (1.6 M in hexane, 30 ml) is added dropwise to the solution of 2-bromo-5- methylsulfanyl-pyridine (8.1 g) in 370 ml of toluene at -75 0C under a nitrogen atmosphere. After stirring for 2 h at -75 0C, propionitrile (2.8 g) is added and stirring is continued for 1 h. Subsequently, 60 ml of 1 N hydrochloric acid are slowly added at -10 0C and the reaction mixture is neutralised with 2 N NaOH. The reaction mixture is poured into water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder is purified on silica gel, using a mixture of heptane / ethyl acetate 9 : 1 as eluent to obtain 1-(5-methylsulfanyl-pyridin-2-yl)propan-1-one as a yellow solid (m.p. 52 - 53 0C).
c) Preparation of 2-bromo-1-(5-methylsulfanyl-pyridin-2-yl)-propan-1-one
Bromine (3.4 g) is added to the mixture of 1-(5-methylsulfanyl-pyridin-2-yl)propan-1-one (3.8 g), 0.05 ml of hydrobromic acid (33 % solution) and 40 ml of acetic acid at room temperature under a nitrogen atmosphere. Subsequently, the mixture is stirred for 1 h at 90 0C. After cooling, te/f-butyl methyl ether is added, the obtained solid is filtered, washed with terf-butyl methyl ether and dried in vacuo to give a yellow solid. The suspension of this hydrobromide salt in 100 ml of terf-butyl methyl ether is stirred for 15 min with 80 ml of satured aqueous sodium hydrogencarbonate solution. After extraction with te/f-butyl methyl ether, the combined organic phases are washed with brine, dried over sodium sulfate and evaporated under reduced presure. 2-Bromo-1-(5-methylsulfanyl-pyridin-2-yl)-propan-1-one is obtained as a brown oil.
d) Preparation of 3-(3,5-dichloro-pyridin-2-yl)-5-hydroxy-5-methyl-4-(5-methylsulfanyl- pyridin-2-yl)-5H-furan-2-one (Compound No. II. u.002)
A mixture of 2-bromo-1-(5-methylsulfanyl-pyridin-2-yl)-propan-1-one (2.3 g), (3,5- dichloro-pyridin-2-yl)-acetic acid (2.0 g), 1.0 ml of triethylamine and 60 ml of acetonitrile is stirred for 16 h at room temperature. Subsequently 1 ,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3.2 g) is added under cooling and stirring is continued for further 2 h. Then air is blown through the reaction mixture for 1 h. The reaction mixture is poured into water, acidified with 2 N hydrochloric acid and then extracted with ethyl acetate. The combined organic layer is washed with a saturated aqueous sodium hydrogencarbonate solution and with brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane / ethyl acetate 2 : 1 as eluent to obtain 3-(3,5-dichloro-pyridin-2-yl)-5-hydroxy-5-methyl-4-(5- methylsulfanyl-pyridin-2-yl)-5H-furan-2-one (Compound No. II. u.002) as a yellow foam. e) Preparation of 4-(3,5-dichloro-pyridin-2-yi)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)- 2H-pyridazin-3-one (Compound No. l.u.006)
A mixture of 3-(3,5-dichloro-pyridin-2-yl)-5-hydroxy-5-methyl-4-(5-methylsulfanyl-pyridin- 2-yl)-5H-furan-2-one (Compound No. ll.u.002, 2.1 g), hydrazine hydrate (0.3 g) and 30 ml of 1-butanol is heated for 5 h to 120 0C. Subsequently, the mixture is cooled to room temperature and evaporated under reduced pressure. The remainder is stirred with terf-butyl methyl ether. The hereby obtained solid is filtered and washed with tert-butyl methyl ether to obtain 4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-2H-pyridazin-3- one (Compound No. l.u.006) as a beige solid, m.p. 229 0C.
f) A mixture of 4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)- 2H-pyridazin-3-one (Compound No. l.u.006, 1.2 g) and 4 ml of phosphorus oxychloride are mixed and heated at 110 0C for 3 h. The reaction mixture is cooled to room temperature and evaporated under reduced pressure. The remainder is taken up with ethyl acetate and water and the phases are separated. The organic layer is washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, using a mixture of heptane / ethyl acetate 3 : 1 as eluent to obtain 3-chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)- pyridazine (Compound No. I. u.008) as a yellow solid, m.p. 163 0C.
Example 2: This example illustrates the preparation of 4-(3,5-dichloro-pyridin-2-yl)-3- methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No.l.u.009) and 4- (3-chloro-5-methoxy-pyridin-2-yl)-3-methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)- pyridazine
A mixture of 3-chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)- pyridazine (Compound No.l.u.008, 0.3 g), sodium methoxide (30% solution in methanol, 0.15 g) and 7 ml of methanol is heated for 16 h to 60 0C. Subsequently the reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The combined organic layer is washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane / ethyl acetate 1 : 3 as eluent to obtain 4-(3,5-dichloro-pyridin-2-yl)-3-methoxy-6- methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No.l.u.009), m.p. 170 - 171 0C and 4-(3-chloro-5-methoxy-pyridin-2-yl)-3-methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2- yl)-pyridazine, m.p. 147-149 0C.
Example 3: This example illustrates the preparation of 4-(3,5-dichloro-pyridin-2-yl)-3,6- dimethyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No. I. u.010)
Methylmagnesium bromide (3 M in diethyl ether, 1.0 ml) is added slowly to a solution of 3- chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No.l.u.008, 0.3 g) and iron(lll) acetylacetonate (0.03 g) in 15 ml of tetrahydrofuran and 2 ml of 1-methyl-2-pyrrolidinone (NMP). This mixture is stirred for 3 h at room temperature, then quenched by addition of dilute hydrochloric acid and extracted with ethyl acetate. The combined organic layer is dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on silica gel, using a mixture of heptane / ethyl acetate 1 :2 as eluent to give 4-(3,5-dichloro-pyridin-2-yl)-3,6-dimethyl-5-(5- methylsulfanyl-pyridin-2-yl)-pyridazine (Compound No.l.u.010) as a brown oil.
Tables 1 and 2 below illustrate examples of individual compounds of formula I and formula according to the invention.
Table 1 : individual compounds of formula I according to the invention
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0002
where a) 252 compounds of formula (l.a):
Figure imgf000029_0001
wherein R1, R3 and R4 are as defined in Table 1. b) 252 compounds of formula (l.b):
Figure imgf000030_0001
wherein R1, R3 and R4 are as defined in Table 1. c) 252 compounds of formula (l.c):
Figure imgf000030_0002
wherein R1, R3 and R4 are as defined in Table 1.
d) 252 compounds of formula (l.d):
Figure imgf000030_0003
wherein R1, R3 and R4 are as defined in Table 1.
e) 252 compounds of formula (l.e):
Figure imgf000030_0004
wherein R1, R3 and R4 are as defined in Table 1. f) 252 compounds of formula (l.f):
Figure imgf000031_0001
wherein R1, R3 and R4 are as defined in Table 1. g) 252 compounds of formula (l.g):
Figure imgf000031_0002
wherein R1, R3 and R4 are as defined in Table 1. h) 252 compounds of formula (Lh):
Figure imgf000031_0003
wherein R >1 , R and R are as defined in Table 1. i) 252 compounds of formula (Li):
Figure imgf000031_0004
wherein R1, R3 and R4 are as defined in Table 1. j) 252 compounds of formula (IJ):
Figure imgf000032_0001
wherein R i1 , n R3 and R are as defined in Table 1. k) 252 compounds of formula (l.k):
Figure imgf000032_0002
wherein R1, R3 and R4 are as defined in Table 1.
I) 252 compounds of formula (I.I):
Figure imgf000032_0003
wherein R1, R3 and R4 are as defined in Table 1. m) 252 compounds of formula (l.m):
Figure imgf000032_0004
wherein R1, R3 and R4 are as defined in Table 1. n) 252 compounds of formula (l.n):
Figure imgf000033_0001
wherein R , R and R are as defined in Table 1. o) 252 compounds of formula (l.o):
Figure imgf000033_0002
wherein R1, R3 and R4 are as defined in Table 1. p) 252 compounds of formula (l.p):
Figure imgf000033_0003
wherein R1, R3 and R4 are as defined in Table 1. q) 252 compounds of formula (l.q):
Figure imgf000033_0004
wherein R1, R3 and R4 are as defined in Table 1. r) 252 compounds of formula (l.r):
Figure imgf000034_0001
wherein R1, R3 and R4 are as defined in Table 1. s) 252 compounds of formula (l.s):
Figure imgf000034_0002
wherein R1, R3 and R4 are as defined in Table 1. t) 252 compounds of formula (l.t):
Figure imgf000034_0003
wherein R1, R3 and R4 are as defined in Table 1. u) 252 compounds of formula (l.u):
Figure imgf000034_0004
wherein R1, R3 and R4 are as defined in Table 1. Table 2: individual com ounds of formula Il accordin to the invention
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0002
where a) 72 compounds of formula (ll.a):
Figure imgf000037_0001
wherein R and R are as defined in Table 2. b) 72 compounds of formula (II. b):
Figure imgf000038_0001
wherein R1 and R3 are as defined in Table 2. c) 72 compounds of formula (II. c):
Figure imgf000038_0002
wherein R1 and R3 are as defined in Table 2. d) 72 compounds of formula (II. d):
Figure imgf000038_0003
wherein R1 and R3 are as defined in Table 2. e) 72 compounds of formula (II. e):
Figure imgf000038_0004
wherein R1 and R3 are as defined in Table 2. f) 72 compounds of formula (II. f):
Figure imgf000039_0001
wherein R1 and R3 are as defined in Table 2. g) 72 compounds of formula (ll.g):
Figure imgf000039_0002
wherein R1 and R3 are as defined in Table 2. h) 72 compounds of formula (II. h):
Figure imgf000039_0003
wherein R1 and R3 are as defined in Table 2. i) 72 compounds of formula (II. i):
Figure imgf000040_0001
wherein R1 and R3 are as defined in Table 2. j) 72 compounds of formula (ll.j):
Figure imgf000040_0002
wherein R1 and R3 are as defined in Table 2. k) 72 compounds of formula (II. k):
Figure imgf000040_0003
wherein R1 and R3 are as defined in Table 2.
I) 72 compounds of formula (II. I):
Figure imgf000040_0004
wherein R1 and R3 are as defined in Table 2. m) 72 compounds of formula (II. m):
Figure imgf000041_0001
wherein R1 and R3 are as defined in Table 2. n) 72 compounds of formula (II. n):
Figure imgf000041_0002
wherein R1 and R3 are as defined in Table 2. o) 72 compounds of formula (II. o):
Figure imgf000041_0003
wherein R1 and R3 are as defined in Table 2. p) 72 compounds of formula (II. p):
Figure imgf000042_0001
wherein R1 and R3 are as defined in Table 2. q) 72 compounds of formula (II. q):
Figure imgf000042_0002
wherein R1 and R3 are as defined in Table 2. r) 72 compounds of formula (II. r):
Figure imgf000042_0003
wherein R )1 R are as defined in Table 2. s) 72 compounds of formula (II. s):
Figure imgf000042_0004
wherein R1 and R3 are as defined in Table 2. t) 72 compounds of formula (II. t):
Figure imgf000043_0001
wherein R1 and R3 are as defined in Table 2.
u) 72 compounds of formula (II. u):
Figure imgf000043_0002
wherein R1 and R3 are as defined in Table 2.
Throughout this description, temperatures are given in degrees Celsius; "NMR" means nuclear magnetic resonance spectrum; and "%" is percent by weight, unless corresponding concentrations are indicated in other units.
The following abbreviations are used throughout this description: m.p. = melting point br = broad s = singlet dd = doublet of doublets d = doublet dt = doublet of triplets t = triplet q = quartet m = multiplet ppm = parts per million
Table 3 shows selected melting point and selected NMR data, all with CDCI3 as the solvent (unless otherwise stated, no attempt is made to list all characterising data in all cases) for compounds of Tables 1 and 2. Table 3: Melting point and selected NMR data for compounds of Tables 1 and 2
Figure imgf000044_0001
The compounds according to the present invention can be prepared according to the above-mentioned reaction schemes, in which, unless otherwise stated, the definition of each variable is as defined above for a compound of formula (I).
Biological examples
Alternaria solani I tomato / preventive (Action against Alternaria on tomato)
4 weeks old tomato plants cv. Roter Gnom are treated with the formulated test compound in a spray chamber. Two days after application tomato plants are inoculated by spraying a spore suspension on the test plants. After an incubation period of 4 days at 22 °C / 18 0C and 95% r. h. in a greenhouse the disease incidence is assessed.
Compounds of formula I according to the invention, in particular compounds 1.1.008 and l.u.008, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.
Botrytis cinerea I tomato / preventive (Action against Botrvtis on tomato) 4 weeks old tomato plants cv. Roter Gnom are treated with the formulated test compound in a spray chamber. Two days after application tomato plants are inoculated by spraying a spore suspension on the test plants. After an incubation period of 3 days at 20 0C and 95% r. h. in a greenhouse the disease incidence is assessed. Compounds of formula I according to the invention, in particular compounds l.u.008 and I. u.009, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.
Puccinia recondita /wheat / preventive (Action against brown rust on wheat) 1 week old wheat plants cv. Arina are treated with the formulated test compound in a spray chamber. One day after application wheat plants are inoculated by spraying a spore suspension (1 x 105 uredospores/ml) on the test plants. After an incubation period of 1 day at 20 0C and 95% r. h. plants are kept for 10 days 20 0C / 18 0C (day/night) and 60% r.h. in a greenhouse. The disease incidence is assessed 11 days after inoculation.
Compounds of formula I according to the invention, in particular compounds 1.1.008 and I. u.009, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.
Maαnaporthe grisea (Pyricularia orvzae) I rice / preventive (Action against rice blast) 3 weeks old rice plants cv. Koshihikari are treated with the formulated test compound in a spray chamber. Two days after application rice plants are inoculated by spraying a spore suspension (1 x 105 conidia/ml) on the test plants. After an incubation period of 6 days at 25 0C and 95% r. h. the disease incidence is assessed.
Compounds of formula I according to the invention, in particular compounds 1.1.008 and l.u.010, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %. Pyrenophora teres (Helminthosporium teres) I barley / preventive (Action against net blotch on barley)
1 -week-old barley plants cv. Regina are treated with the formulated test compound in a spray chamber. Two days after application barley plants are inoculated by spraying a spore suspension (2.6 x 104 conidia/ml) on the test plants. After an incubation period of 4 days at
20 0C and 95% r. h. the disease incidence is assessed.
Compounds of formula I according to the invention, in particular compounds l.u.008 and l.u.010, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.
Seotoria tritici / wheat / preventive (Action against Septoria leaf spot on wheat)
2 weeks old wheat plants cv. Riband are treated with the formulated test compound in a spray chamber. One day after application wheat plants are inoculated by spraying a spore suspension (106 conidia/ml) on the test plants. After an incubation period of 1 day at 22 0C /
21 0C and 95% r. h. plants are kept at 22 0C / 21 0C and 70% r.h. in a greenhouse. The disease incidence is assessed 16 - 18 days after inoculation.
Compounds of formula I according to the invention, in particular compound 1.1.008, at 200 ppm inhibits fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.
Uncinula necator/ grape / preventive (Action against powdery mildew on grape) 5 weeks old grape seedlings cv. Gutedel are treated with the formulated test compound in a spray chamber. One day after application grape plants are inoculated by shaking plants infected with grape powdery mildew above the test plants. After an incubation period of 7 days at 24 0C / 22 0C and 70% r. h. under a light regime of 14/10 h (light/dark) the disease incidence is assessed. Compounds of formula I according to the invention, in particular compounds 1.1.008 and l.u.008, at 200 ppm inhibit fungal infestation in this test to at least 80 %, while under the same conditions untreated control plants are infected by the phytopathogenic fungi to over 80 %.

Claims

What is claimed is:
1. A compound of formula
Figure imgf000048_0001
wherein
R1 is hydrogen, Ci-Cβalkyl, Ci-C6haloalkyl or C3-C6cycloalkyl; R2 is an optionally substituted heteroaryl; R3 is an optionally substituted heteroaryl; and
R4 is hydrogen, halogen, Ci-C6alkyl, Ci-C6haloalkyl, d-Cδalkoxy, d-Cehaloalkoxy, hydroxy or cyano; or an agrochemically usable salt form thereof.
2. The compound according to claim 1 wherein R1 is CrC6alkyl, d-Cβhaloalkyl or C3- C6cycloalkyl.
3. The compound according to either claims 1 or 2 wherein R2 is an optionally substituted fury!, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl.
4. The compound according to any one of claims 1 to 3 wherein R3 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, quinolinyl, isoquinolyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl.
5. The compound according to any one of claims 1 to 4 wherein R4 is halogen, d-C6alkyl, CrCehaloalkyl, C1-C6BIkOXy,
Figure imgf000049_0001
or hydroxy.
6. The compound according to any one of claims 1 to 5 wherein R1 is Ci-C6alkyl or CrCehaloalkyl;
R2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl or quinolyl; R3 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or tetrazinyl; and R4 is halogen, Ci-C6alkyl, CrCεalkoxy or hydroxy.
7. The compound according to any one of claims 1 to 6 wherein R1 is Ci-C3alkyl or CrCahaloalkyl;
R2 is an optionally substituted furyl, thienyl, pyrrolyl, imidazolyl, pyridyl or pyrimidinyl or quinolyl;
R3 is an optionally substituted thienyl, pyrrolyl, imidazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; and R4 is chloro, fluoro, C1-C4alkyl, C1-C4BIkOXy or hydroxy.
8. The compound according to any one of claims 1 to 7 wherein R1 is methyl or ethyl;
R2 is an optionally substituted furyl, thienyl, pyridyl or pyrimidinyl or quinolyl; R3 is an optionally substituted thienyl, thiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl; and R4 is chloro, fluoro, Ci-C3alkyl, C1-CSaIkOXy or hydroxy.
9. The compound according to any one of claims 1 to 8 wherein R1 is methyl;
R2 is 2-chloro-pyridin-4yl, 6-chloro-pyridin-3-yl, 6-methyl-pyridin-3-yl or 5-methylsulfanyl- pyridin-2-yl; R3 is 3,5-dichloropyridin-2-yl; and R4 is chloro, methyl or methoxy.
10. A compound selected from 3-chloro-5-(6-chloro-pyridin-3-yl)-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-pyridazine; 4-(6-chloro-pyridin-3-yl)-5-(3,5-dichloro-pyridin-2-yl)-6-methoxy-3-methyl-pyridazine;
3-chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(6-methyl-pyridin-3-yl)-pyridazine;
4-(3,5-dichloro-pyridin-2-yl)-3-methoxy-6-methyl-5-(6-methyl-pyridin-3-yl)-pyridazine;
3-chloro-5-(2-chloro-pyridin-4-yl)-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-pyridazine;
4-(2-chloro-pyridin-4-yl)-5-(3,5-dichloro-pyridin-2-yl)-6-methoxy-3-methyl-pyridazine; 3-chloro-4-(3,5-dichloro-pyridin-2-yl)-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine; and
4-(3,5-dichloro-pyridin-2-yl)-3-methoxy-6-methyl-5-(5-methylsulfanyl-pyridin-2-yl)-pyridazine.
11. A process for the preparation of a compound of formula 1.1 ,
Figure imgf000050_0001
wherein R1, R2 and R3 are as defined for compound of formula I and Hal is halogen, which comprises reacting a compound of formula 1.5,
Figure imgf000050_0002
wherein R1, R2 and R3 are as defined for compound of formula I, with a phosphorus oxyhalide or a thionyl halide.
12. A process for the preparation of a compound of formula 1.5,
Figure imgf000051_0001
wherein R1, R2 and R3 are as defined for compound of formula I, which comprises reacting a compound of formula II,
Figure imgf000051_0002
wherein R1, R2 and R3 are as defined for compound of formula I1 with a hydrazine derivative.
13. A process for the preparation of a compound of formula II,
Figure imgf000051_0003
wherein R1, R2 and R3 are as defined for formula I, which comprises oxidising a compound of formula III,
Figure imgf000051_0004
wherein R1, R2 and R3 are as defined for compound of formula I, with oxygen, air or 3- chloroperbenzoic acid.
14. A process for the preparation of a compound of formula III,
Figure imgf000052_0001
wherein R1, R2 and R3 are as defined for compound of formula I, which comprises reacting a compound of formula IV,
Figure imgf000052_0002
wherein R1, R2 and R3 are as defined for compound of formula I, with a base.
15. A fungicidal composition for controlling or protecting against phytopathogenic microorganisms, comprising as active ingredient at least one compound as defined in any one of claims 1 to 10, in free form or in agrochemically usable salt form, and at least one adjuvant.
16. The composition according to claim 15, which comprises at least one additional fungicidally active compound, preferably selected from the group consisting of azoles, pyrimidinyl carbinoles, 2-amino-pyrimidines, morpholines, anilinopyrimidines, pyrroles, phenylamides, benzimidazoles, dicarboximides, carboxamides, strobilurines, dithiocarbamates, N-halomethylthiotetrahydrophthalimides, copper-compounds, nitrophenols, organo-phosphor-derivatives, pyridazines, triazolopyrimidines, carboxamides or benzamides.
17. The use of a compound as defined in any one of claims 1 to 10 for controlling or preventing infestation of plants, harvested food crops or non-living materials by phytopathogenic microorganisms.
18. A method of controlling or preventing an infestation of crop plants, harvested food crops or non-living materials by phytopathogenic or spoilage microorganisms or organisms potentially harmful to man, which comprises the application of a compound as defined in any one of claims 1 to 10, as active ingredient to the plant, to parts of the plants or to the locus thereof, to seeds or to any part of the non-living materials.
19. The method according to claim 18, wherein the phytopathogenic microorganisms are fungal organisms.
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