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WO2012175513A1 - Thienylpyri(mi)dinylpyrazole - Google Patents

Thienylpyri(mi)dinylpyrazole Download PDF

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Publication number
WO2012175513A1
WO2012175513A1 PCT/EP2012/061741 EP2012061741W WO2012175513A1 WO 2012175513 A1 WO2012175513 A1 WO 2012175513A1 EP 2012061741 W EP2012061741 W EP 2012061741W WO 2012175513 A1 WO2012175513 A1 WO 2012175513A1
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butyl
amino
iso
alkyl
methyl
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PCT/EP2012/061741
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French (fr)
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Alexander Sudau
Julia Neumann
Jürgen BENTING
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Bayer Intellectual Property Gmbh
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    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to novel Thienylpyri(mi)dinylpyrazole and their agrochemically active salts, to their use and to methods and compositions for controlling phytopathogenic harmful fungi in and/or on plants or in and/or on seed of plants and for reducing mycotoxins in plants and parts of the plants, to processes for preparing such compounds and compositions and treated seed and also to their use for controlling phytopathogenic harmful fungi in agriculture, horticulture, forestry, in animal husbandry, in the protection of materials, in the domestic and hygiene field and for the reduction of mycotoxins in plants and parts of the plants.
  • Thienylpyri(mi)dinylpyrazole solve at least in some aspects the problems mentioned above and are suitable for use as crop protection agents, in particular as fungicides.
  • Some Arylazoles are already known as pharmaceutically active compounds (see for example WO 1998/52937, EP-A 1 553 096, WO 2004/29043, WO 1998/52940, WO 2000/31063, WO 1995/31451, WO 2002/57265 and WO 2000/39116), but not their surprising fungicidal activity.
  • the invention provides compounds of the formula (I),
  • R 1 represents Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, C3-C8- allenyl, Cs-Cs-trialkylsilyl, C4-C8-cycloalkenyl, Ci-C6-alkoxy-Ci-C6-alkyl, acyloxy-Ci-C6-alkyl, heteroaryl-Ci-Ce-alkyl, aryl-Ci-Ce-alkyl, Ci-C 6 -alkylthio-Ci-C 6 -alkyl, Ci-C 4 -alkyl-C(0)-Ci-C 6 - alkyl, C3-C 6 -cycloalkyl-C(0)-Ci-C 4 -alkyl, heterocyclyl-C(0)-Ci-C 4 -alkyl, Ci-C 4
  • R 2 represents H, cyano, halogen or represents Ci-C6-alkyl, C3-C6-cycloalkyl, heterocyclyl, C 2 -C8-alkenyl, C 2 -C8-alkinyl, Ci-Cs-alkoxy, C2-C8-alkynyloxy, Ci-Cs-alkylthio, Cs-Cs-trialkylsilyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, amino, dimethylamino or methoxy,
  • R 4 and R 5 represents independently of each other H, F, CI, Br, I, cyano, nitro, OH, SH, or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, C6-Ci 4 -aryl, C 1 -C4- alkoxy, 0-(C 6 -Ci 4 -aryl), S-(Ci-C 4 -alkyl), S(0)-(Ci-C 6 -alkyl), C(0)-(Ci-C 6 -alkyl), C(0)-(Ci-C 6 -alkyl), C 3 -C 8 - trialkylsilyl, heteroaryl, heterocyclyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R 16 or form together with the carbon atoms, which they are attached to, an optionally mono- or multi identical
  • R 6 represents Ci-C6-alkyl, H, halogen or represents Ci-C6-alkyl, Cs-Cs-cycloalkyl, C 2 -C8-alkenyl, C 2 -C8-alkinyl, C(0)-Ci-C6-alkyl, Ci-Cs- alkoxy, Ci-Cs-alkylthio, Ci-Cs-halogenalkoxy, Ci-C6-alkylsulphenyl, Ci-C6-alkylthio, C3-C8- trialkylsilyl, C6-Cio-aryl, heteroaryl, heterocyclyl, C6-Cio-aryloxy, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R 16
  • R 7 represents H, halogen, cyano, nitro, Ci-C6-alkyl, C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, C5-Cio-aryl, heteroaryl, heterocyclyl, or R 6 and R 7 together can form a 5- to 7-membered ring which can optionally be substituted with one or more substituents selected from: Ci-C i-alkyl, Ci-C i-halogenoalkyl, Ci-C i-alkoxy, C1-C4- halogenoalkoxy, halogen, hydroxyl, amino, cyano or nitro, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR 19 ,
  • R 8 represents H, halogen, cyano, Ci-C6-alkyl, C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, Ce- Cio-aryl, heteroaryl, heterocyclyl,
  • R 9 and R 10 represent H, C(S)R 14 , C(0)R 14 , SO2R 14 , C(0)OR 14 , OR 14 oder C(0)NR 14 R 15 or represents Ci-C6-alkyl , C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, C3-C8-cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, Ci-C6-alkyl, 0-C(0)R 17 , 0-P(0)(OR 17 ) 2 , 0-B(OR 17 ) 2 or 0-(Ci-C 4 -alkyl),
  • R 11 and R 20 represent H, C(S)R 12 , C(0)R 12 , SO2R 12 , C(0)OR 12 , OR 12 or C(0)NR 12 R 13 or represents Ci-C6-alkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, C3-C8-cycloalkyl, C6-Ci 4 -aryl, heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, Ci-C6-alkyl, 0-C(0)R 17 , O- P(0)(OR 17 ) 2 , 0-B(OR 17 ) 2 or 0-(Ci-C 4 -alkyl),
  • R 12 and R 13 represent H
  • Ci-C6-alkyl C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, C3-C8-cycloalkyl, Ce-Cw- aryl, heterocyclyl oder heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, Ci-C6-alkyl or Ci-C i-alkoxy, R 14 and R 15 represent H
  • Ci-C6-alkyl C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, Cs-Cs-cycloalkyl, Ce-Cw- aryl, benzyl, phenethyl, phenoxymethyl, heterocyclyl oder heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert- butyl, n-pentyl, cyclopropyl, or methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, methylsulfanyl, nitro,
  • R 16 represents OH, F, CI, Br, I, cyano, NH-C(0)R 17 , NR 17 R 18 , C(0)R 17 , C(0)OR 17 , C(0)NR 17 R 18 , or represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Cs-cycloalkyl, Ci-C4-alkoxy, C1-C4- alkylthio, 0-(C 3 -C 8 -cycloalkyl), S-(C 3 -C 8 -cycloalkyl), C 6 -Ci 4 -aryl, 0-(C 6 -Ci 4 -aryl), S-(C 6 -Ci 4 - aryl), heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, Ci
  • R 17 and R 18 represents Ci-C6-alkyl, C3-C6-cycloalkyl, C 2 -C6-alkenyl, C 2 -C6-alkinyl, benzyl, aryl each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano or represents H,
  • R 19 represents H, Ci-Ce-alkyl, C 3 -C 6 -cycloalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C(S)R 14 , C(0)R 14 , and also agrochemically active salts thereof.
  • the invention also provides the use of the compounds of the formula (I) as fungicides.
  • Thienylpyri(mi)dinylpyrazole of the formula (I) according to the invention and also their agrochemically active salts are highly suitable for controlling phytopathogenic harmful fungi and for the reduction of mycotoxins.
  • the compounds according to the invention mentioned above have in particular strong fungicidal activity and can be used both in crop protection, in the domestic and hygiene field, in the protection of materials and for the reduction of mycotoxins in plants and parts of the plants.
  • the compounds of the formula (I) can be present both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, and also optical isomers, such as R and S isomers or atropisomers, and, if appropriate, also of tautomers.
  • stereoisomers such as E and Z, threo and erythro, and also optical isomers, such as R and S isomers or atropisomers, and, if appropriate, also of tautomers.
  • optical isomers such as R and S isomers or atropisomers
  • CH 2 CH CH 2 , -CH 2 C ⁇ CH , -C ⁇ CH or R 6 and R 7 together can form a 5- to 7-membered ring which can optionally be substituted with one or more substituents selected from: methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, F, CI, Br, hydroxyl, amino, cyano or nitro, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR 19 ,
  • R 9 and R 10 represent H, C(S)R 14 , C(0)R 14 , SO2R 14 , C(0)OR 14 , OR 14 oder C(0)NR 14 R 15 , R 11 and R 20 represent H, C(S)R 12 , C(0)R 12 , SO2R 12 , C(0)OR 12 , OR 12 oder C(0)NR 12 R 13 or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 0-C(0)Me, 0-C(0)Et, 0-P(0)(OMe) 2 , 0-B(OMe) 2 , 0-B(OEt) 2 oder , methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, tert-butoxy substituted methyl, ethyl, n-propyl, iso-propyl,
  • R 12 and R 13 represent H
  • X 1 represents CH
  • R 1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, allyl, 3-methylbut-2-en-l-yl, prop-2-yn-l-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-2-yl, tetrahydrofuran-3-yl, oxetan-3-yl, thietan-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4- yl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-fluoroethyl, 2-
  • R 2 represents H, Methyl, Ethyl, n-propyl, methoxy, ethoxy, methylsulfanyl, methoxymethyl, difluoromethyl, 2-hydroxypropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 2-cyanoethyl,
  • R 3 represents H, amino, formamido, acetylamino, n-propionylamino, isobutyrylamino, (2- methylbutanoyl)amino, (3-methylbutanoyl)amino, (3,3-dimethylbutanoyl)amino,
  • R 7 represents H, F, CI, Methyl
  • R 8 represents H, CI
  • R 1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, cyclopropyl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-cyanoethyl, 1 -cyanopropan-2-yl, 2-methoxyethyl, 2- ethoxyethyl, cyclopropylmethyl,
  • R 2 represents H, methyl
  • R 3 represents H, acetylamino, n-propionylamino, isobutyrylamino, (2-methylbutanoyl)amino, (3- methylbutanoyl)amino, (methoxyacetyl)amino, (lactoylamino), (2-hydroxy-2- methylpropanoyl)amino, (phenyl acetyl) amino , ( cy c 1 opr opy lac etyl) amino ,
  • R 1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, cyclopropyl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-cyanoethyl, 1 -cyanopropan-2-yl, 2-methoxyethyl, 2- ethoxyethyl, cyclopropylmethyl where the other substituents have one or more of the meanings mentioned above, and to the agrochemically active salts thereof.
  • R 3 represents H, acetylamino, n-propionylamino, isobutyrylamino, (2-methylbutanoyl)amino, (3- methylbutanoyl)amino, (methoxyacetyl)amino, (lactoylamino), (2-hydroxy-2- methylp ro p an o yl) amin o , (phenyl ac etyl) amin o , ( cyc l op ro py l ac ety l) amino , (cyclopropylcarbonyl)amino, [(2-methylcyclopropyl)carbonyl] amino, (cyclobutylcarbonyl)amino, methacryloylamino, (3-methylbut-2-enoyl)amino, (benzoylamino), (3 -thienylcarbonyl)amino, (2-thienylcarbon
  • R 4 represents H
  • R 5 represents H, F
  • R 6 represents H, F, CI, Methyl
  • R 7 represents H
  • R 8 represents H
  • the compounds of the formula (I) have acidic or basic properties and can form salts, if appropriate also inner salts, or adducts with inorganic or organic acids or with bases or with metal ions. If the compounds of the formula (I) carry amino, alkylamino or other groups which induce basic properties, these compounds can be reacted with acids to give salts, or they are directly obtained as salts in the synthesis. If the compounds of the formula (I) carries hydroxyl, carboxyl or other groups which induce acidic properties, these compounds can be reacted with bases to give salts.
  • Suitable bases are, for example, hydroxides, carbonates, bicarbonates of the alkali metals and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary and tertiary amines having (Ci-C i)-alkyl groups, mono-, di- and trialkanolamines of (Ci-C i)-alkanols, choline and also chlorocholine.
  • the salts obtainable in this manner also have fungicidal properties.
  • inorganic acids are hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulphuric acid, phosphoric acid and nitric acid, and acidic salts, such as NaHS04 and KHSO4.
  • Suitable organic acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two phospho
  • Suitable metal ions are in particular the ions of the elements of the second main group, in particular calcium and magnesium, of the third and fourth main group, in particular aluminium, tin and lead, and also of the first to eighth transition group, in particular chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period.
  • the metals can be present in various valencies that they can assume.
  • Optionally substituted groups may be mono- or polysubstituted, where in the case of polysubstitution the substituents may be identical or different.
  • substituents halogen: fluorine, chlorine, bromine and iodine
  • 5-membered heteroaryl which contains one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom
  • 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom as ring members, for example (but not limited thereto) 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-imidazolyl, 4-imidazolyl, l,
  • 5-membered heteroaryl which is attached via nitrogen and contains one to four nitrogen atoms, or benzo-fused 5-membered heteroaryl which is attached via nitrogen and contains one to three nitrogen atoms: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms and one to three nitrogen atoms, respectively, as ring members and in which two adjacent carbon ring members or a nitrogen and an adjacent carbon ring member may be bridged by a buta-l,3-dien-l,4-diyl group in which one or two carbon atoms may be replaced by nitrogen atoms, where these rings are attached to the skeleton via one of the nitrogen ring members, for example (but not limited thereto) 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-l -yl, 1 -imidazolyl, 1,2,3-triazol-l -yl, 1,3,4-triazol- 1-yl;
  • 6-membered heteroaryl which contains one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain one to three or one to four nitrogen atoms as ring members, for example (but not limited thereto) 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4- pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, l,3,5-triazin-2-yl, l,2,4-triazin-3- yl and l,2,4,5-tetrazin-3-yl; benzo-fused 5-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulphur atom: for example (but not limited thereto) lH-indol-l -yl, lH-indol- 2-yl, lH-ind
  • the present invention furthermore relates to a process for preparing thienylpyri(mi)dinylpyrazole of the formula [I] according to the invention.
  • the Thienylpyri(mi)dinylpyrazole according to the invention of the formula [I] can be prepared in different ways. Below, the possible processes are firstly shown schematically and then described in detail. Unless otherwise indicated, the residues stated have the meanings given below the schemes.
  • the Thienylpyri(mi)dinylpyrazole according to the invention of the formula [I] can be produced by process A according to the following scheme.
  • Met 2 e.g. -B(OR*) 2
  • B(OR*) 2 e.g. -B(OiPr) 2 , -B(OH) 2 , -B(pinacolato)
  • Z l e.g. CI, Br, I, -OTos, -OMs, -OH
  • Z 2 e.g. CI, Br
  • a 7 R 15 , -OR 15
  • R a e.g. -NH-C(S)R 15 , -NH-C(0)R 15 , -NH C(0)OR 15 , -NH-C(0)NR 15 R 16 ,
  • PG e.g. tetrahydro-2H-pyran-2-yl, 2-(trimethylsilyl)ethoxy]methyl
  • Z 4 e.g. CH 3 , OAlkyl
  • Met 3 e.g. Sn(n-Bu) 3
  • a compound with the general formula [VII] is halogenated and a compound of the formula [V] is obtained. This is converted to a compound of the type [IV] by reaction with substrates of the type [VIII], whereby mixtures of pyrazole regioisomers can be formed. These can be separated into the individual regioisomers by common processes e.g. chromatographic processes.
  • a compound with the general formula [VII] is converted into a compound of the type [VI] by reaction with substrates of the type [VIII], whereby mixtures of pyrazole regioisomers can be formed.
  • Compounds of the formula [VI] can be halogenated whereas compounds of the type [IV] are obtained.
  • the compounds of the general formula [IV] can be reacted with substrates of the formula [IX-a] in a C-C coupling, whereby compounds of the formula [I] are obtained (Scheme 1).
  • the pyrazole compounds of the general formula [IV] can be converted into compounds of the type [III] by reaction with a boronic acid ester. These can be converted into compounds of the formula [I] by reaction with a substrate of the formula [X-a] in a C-C coupling reaction (Scheme 1).
  • compounds of the type [IV] can be converted into compounds of the formula [II] by reaction with a substrate of the formula [IX-b] in a C-C coupling reaction and subsequent deprotection. These compounds are likewise converted into the compounds of the type [I-a] by reaction with substrates of the formula [XI].
  • structures of the general formula [VI] can be obtained from alkynes of the general formula [XVI] by reaction with hydrazines.
  • the Intermediates of the general formula [XVI] can be formed by transition metal catalysed coupling of Acyl halides of the general formula [XIV] or by reaction of compounds of the general formula [XV] in the presence of carbon monoxide (scheme 2).
  • a compound with the general formula [XVII] can be reacted with a substrate of the formula [XVIII] in a C-C coupling reaction, whereby a compound with the formula [XIX] is formed. Next this compound is deprotected, whereby a compound of the general formula [XX] is obtained.
  • the pyrazole of the formula [XX] obtained is now reacted with substrates of the type [VIII], whereby the thienylpyri(mi)dinylpyrazole according to the invention of the formula [I-b] are obtained (Scheme 3).
  • a compound with the general formula [XXI] can be converted to a Weinreb amide with the formula [XXII]. This compounds is reacted with an acetylene in the presence of a strong base followed by treatment with hydrazine, whereby a pyrazole of the general formula [Vll-a] is obtained (Scheme 4).
  • the compounds of the formula [VIII] required for the reaction are commercially available or can be produced by literature methods (R. C. Larock, Comprehensive Organic Transformations, 2nd Edition, 1999, Wiley- VCH, p. 690 ff. and p. 1929 ff. and literature cited therein)
  • One method for the production of suitable compounds of the formula [VIII] (wherein R 1 in the case of an alkylation reaction e.g. stands for a substituted or unsubstituted alkyl or cycloalkyl residue), is for example the reaction of alcohols with methanesulphonyl chloride and triethylamine (Org. Lett.
  • dichloromethane chloroform, carbon tetrachloride
  • halogenated aromatic hydrocarbons e.g. chlorobenzene, dichlorobenzene
  • nitriles e.g. acetonitrile
  • carboxylic acid esters e.g. ethyl acetate
  • amides e.g. ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide
  • the preferred solvents are dimethylformamide and acetonitrile.
  • bases which can be used for this reaction are for example lithium hexamethyldisilazide (LiHMDS), potassium carbonate, caesium carbonate and sodium hydride.
  • LiHMDS lithium hexamethyldisilazide
  • the preferred base is sodium hydride.
  • at least 1 equivalent of base is used.
  • an acylation reaction with substrates of the formula [VIII] (wherein in R 1 a carbonyl group is directly bound to Z 1 )
  • a base e.g. pyridine, diisopropylethylamine, triethylamine or commercially available polymeric acid scavengers
  • the starting material is a salt, at least two equivalents of the acid scavenger are needed.
  • pyridine is used as the solvent, analogously to the literature described, the addition of a further base can in some cases be omitted (EP-A-1 000 062).
  • the reaction is normally effected at temperatures of 0°C - 100°C and preferably at 20°C - 30°C, but it can also be effected at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
  • the compounds [VI] or [IV] are separated from the reaction mixture by one of the usual separation techniques.
  • the compounds of the formula [VI] and [IV], wherein R 1 does not stand for hydrogen can be obtained as pure regioisomers or as a mixture of both possible regioisomers (wherein the group R 1 can occupy both positions on the N atom of the pyrazole).
  • these can be purified by physical methods (such as for example crystallization or chromatography methods) or can optionally also be used in the next step without prior purification.
  • halogenated pyrazoles of the formula [V] are either commercially available or can be produced by literature methods.
  • One method for the production of suitable halogenated pyrazoles is for example the bromination of corresponding pyrazoles [VII] (e.g. described in EP-A 1382 603) by reaction with N-bromosuccinimide in acetic acid.
  • Step (V3) One possibility for the synthesis of compounds of the formula [III] is shown in Scheme 1.
  • Compounds of the formula [III] can be produced by described methods e.g. via reaction of the halopyrazoles [IV] with boronic acid esters such as for example bispinacolatodiboron (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane) in the presence of a catalyst such as for example l, -bis(diphenyl-phosphino)ferrocene-palladium(II) dichloride in the presence of a base and a suitable solvent (see US 2009/0018156, WO 2007/024843 or EP-A 1 382 603).
  • boronic acid esters such as for example bispinacolatodiboron (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane
  • a catalyst such as for example l, -bis(
  • solvent all common solvents inert under the reaction conditions, such as for example sulphoxides (e.g. dimethyl sulphoxide), cyclic ethers (e.g. dioxan) and amides (e.g. N,N- dimethylformamide) can be used and the reaction can be effected in mixtures of two or more of these solvents.
  • the preferred solvents are dimethyl sulphoxide and dioxan.
  • the reaction will normally be effected at temperatures of 80°C - 120°C, and the preferred reaction temperature is about 85°C - 90°C.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between one hour and 16 hours.
  • compounds of the formula [III] can be produced by metallation of the halogenated pyrazoles [IV] with bases such as for example n-butyllithium and reaction with boronic acid esters such as for example trimethyl borate and subsequent reaction of the pyrazole-boronic acid obtained with pinacol (see e.g. J. Het. Chem. 2004, 41, 931-940 or EP-A 1 382 603 and WO 2007/16392).
  • Compounds of the formula [I] can also be produced for example by coupling of the halopyrazoles [IV] with metallated heterocycles of the formula [IX-a] (wherein Met 1 stands for a tin-compound such as for example Sn(n-Bu)s) in the presence of a catalyst, if necessary an inorganic or organic halide salt, if necessary a ligand and a suitable solvent at suitable temperatures by known literature procedures (see Synthesis 1992, 803-815).
  • compounds of the formula [IX-al] can also be prepared by other known literature methods.
  • One method for the production of suitable heterocycles [IX-al] is the metallation of the halopyridine [XXIII] with a base (such as for example n-butyllithium) in a solvent (such as for example diethyl ether or tetrahydrofuran) and subsequent reaction with a boronic acid ester (such as for example B(i-PrO)3 or B(OMe)3) and pinacol by known literature methods (Synthesis 2004, 4, 469-483 and literature described therein) (Scheme 6).
  • a base such as for example n-butyllithium
  • solvent such as for example diethyl ether or tetrahydrofuran
  • a boronic acid ester such as for example B(i-PrO)3 or B(OMe)3
  • compounds of the type [IX-b] can be synthetised according to literature described methods (WO 2011/042389) by reaction of the respective haloheterocycle precursor (replacement of Met 2 by CI, Br, I in [IX-b]) with bispinacolatodiboron in the presence of a catalyst.
  • haloheterocycles of the formula [XXIV] are commercially available or can be produced by literature procedures.
  • One method for the production of suitable haloheterocycles [IX- al] is the reaction of haloheterocycles of the formula [XXIV] with hexaalkylditin compounds (such as for example 1 , 1 , 1 ,2,2,2-hexabutylditin) in the presence of a catalyst (such as for example bis(triphenylphosphine)palladium(II) acetate), if necessary a fluoride ion source (such as for example tetrabutylammonium fluoride) and a solvent (such as for example tetrahydrofuran or diethyl ether) by methods described in the literature (WO 2003/095455 or WO 2007/104538) (Scheme 7).
  • Scheme 7 Scheme 7
  • ALK C r C 5 Alkyl [, ⁇ ]
  • compounds of the formula [IX-a2] can also be prepared by other known literature methods.
  • One method for the production of suitable haloheterocycles [IX-a2] is the metallation of the halopyridine [XXIV] using a metallation reagent (an alkyllithium compound such as for example n-butyllithium or a Grignard reagent such as for example isopropylmagnesium chloride) in a solvent (such as for example diethyl ether or tetrahydrofuran) and subsequent reaction with a trialkyltin halogen compound (such as for example BusSnCl) by known literature methods (WO 2008/008747 or Tetrahedron 1994, 275-284 and literature described therein) (Scheme 8).
  • a metallation reagent an alkyllithium compound such as for example n-butyllithium or a Grignard reagent such as for example isopropylmagnesium chloride
  • a solvent such
  • ALK C r C 5 Alkyl
  • solvents inert under the reaction conditions such as for example cyclic and acyclic ethers (diethyl ether, dimethoxymethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxan, diisopropyl ether, tert-butyl methyl ether), aromatic hydrocarbons (e.g. benzene, toluene, xylene), amides (e.g. dimethylformamide, dimethyl-acetamide, N-methylpyrrolidone) and sulphoxides (e.g. dimethyl sulphoxide) can be used or the reaction can be performed in mixtures of two or more of these solvents.
  • the preferred solvent is dimethylformamide.
  • Halide salts for the reaction of compounds of the formula [IX-a] which are preferably used in the process according to the invention are for example copper halides (e.g. CuBr or Cul), caesium halides (CsF) and tetraalkylammonium halides (TBAF).
  • copper halides e.g. CuBr or Cul
  • CsF caesium halides
  • TBAF tetraalkylammonium halides
  • the halide salts are preferably used in the process according to the invention in a proportion of 1 to 400 mol.%, based on the organic tin compound. However, mixtures of the halide salts can also be used in proportions of 1-400 mol.%. The addition of a mixture of copper iodide and caesium fluoride in proportions of 1- 200 mol.% is particularly preferable.
  • catalysts for the reaction of compounds of the formula [IX-a] with halogenated pyrazoles of the formula [IV] the same catalysts can be used as are described below for the production of the compounds of the formula [I], by reaction of the compounds of the formula [III] and [X-a] described for step V5.
  • the quantity of catalyst, based on the heteroaromatics [IX-a] bearing the leaving group Met 1 is preferably 0.001 to 0.5 mol.%> and particularly preferably 0.01 to 0.2 mol.%>.
  • the catalyst can contain phosphorus-containing or arsenic-containing ligands or phosphorus- containing or arsenic-containing ligands can be added separately to the reaction mixture.
  • phosphorus-containing ligands preferably tri-n-alkylphosphanes, triarylphosphanes, dialkylaryl- phosphanes, alkyldiarylphosphanes and/or heteroarylphosphanes, such as tripyridylphosphane and trifurylphosphane, wherein the three substituents on the phosphorus can be the same or different, can be chiral or achiral and wherein one or more substituents can link the phosphorus groups of several phosphanes, wherein one part of this linkage can also be a metal atom, are suitable.
  • phosphanes such as triphenylphosphane, tri-tert-butylphosphane and tricyclohexyl-phosphane.
  • arsenic-containing ligands for example tri-n-alkylarsanes and triarylarsanes, wherein the three substituents on the arsenic can be the same or different, are suitable.
  • the total concentration of ligands, based on the heteroaromatics [IX-a] bearing the leaving group Met 1 is preferably up to 1 mol.%, particularly preferably 0.01 to 0.5 mol.%.
  • the educts, the solvent, the base, the halide salt, the catalyst and if necessary the ligand are thoroughly mixed and reacted preferably at a temperature of 0°C- 200°C, particularly preferably at 60-150°C.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
  • the reaction can also be run such that the various reactants are metered in a controlled manner in the course of the reaction, whereby different metering variants are possible.
  • the processes according to the invention are in general performed under normal pressure. However it is also possible to operate under increased or reduced pressure.
  • the reaction is in general performed using a blanket gas such as for example argon or nitrogen.
  • the molar reactant ratio of the halopyrazole [IV] to the organotin compound [IX-a2] is preferably 0.9 to 2.
  • the catalyst arising as a solid is removed by filtration, the crude product freed from the solvent or solvents and then purified by methods known to those skilled in the art and appropriate for the particular product, e.g. by recrystallization, distillation, sublimation, zone melting, melt crystallization or chromatography.
  • compounds of the formula [II] can be produced by coupling of the pyrazoleboronic acids [III] with heterocycles of the formula [X-b].
  • Compounds of the formula [X-a] (wherein X 1 stands for C-H) are commercially available or can be produced by literature procedures (Scheme 9).
  • One method for the production of suitable haloheterocycles [X-al] is the reaction of the pyridine N-oxides with halogenating agents (e.g. PC1 3 , POCI3, SOCb or methanesulphonyl chloride) (see Bioorg. Med. Chem. Lett. 2007, 17, 7, 1934-1937).
  • the pyridine N-oxides [XXV] are known or can be produced by oxidation of the corresponding pyridines (e.g. with H2O2, H2O2 + methyltrioxorhenium, m-chloroperoxybenzoic acid, dimethyl- dioxirane or H2O2 + manganese tetrakis(2,6-dichlorophenyl)porphyrin) by procedures described in the literature (ARKIVOC 2001 (i) 242-268 and references contained therein).
  • aminoheterocycles [XXVII] (wherein X 1 stands for C-H) are known or can be produced by removal of the N-BOC protective group from compounds of the formula [X-b-1] by procedures described in the literature (Aust. J. Chem. 1982, 35, 10, 2025-2034 and references contained therein).
  • Compounds of the formula [X-b] (wherein X 1 stands for C-H) are commercially available or can be produced by literature methods (Scheme 12).
  • One method for the production of suitable N-Boc- haloheterocycles [X-b-1] is the reaction of suitable acids (e.g.
  • the carboxylic acids [XXIX] are known or can be produced from commercially available precursors by procedures described in the literature (see e.g. EP-A 1 650 194), for example from the commercially available pyridine-2-carboxylic acid by reaction with thionyl chloride in dimethylformamide.
  • compounds of the general formula [L] can also be produced by oxidation of commercially available 4-halo-2-methyl-pyridine derivatives by known literature procedures (Aust. J. Chem. 1982, 35, 2025-2034).
  • solvents inert under the reaction conditions such as for example alcohols (e.g. methanol, ethanol, 1-propanol, 2- propanol, ethylene glycol, 1-butanol, 2-butanol, tert-butanol), cyclic and acyclic ethers (diethyl ether, dimethoxymethane, di ethylene glycol dimethyl ether, tetrahydrofuran, dioxan, diisopropyl ether, tert-butyl methyl ether), aromatic hydrocarbons (e.g.
  • alcohols e.g. methanol, ethanol, 1-propanol, 2- propanol, ethylene glycol, 1-butanol, 2-butanol, tert-butanol
  • cyclic and acyclic ethers diethyl ether, dimethoxymethane, di ethylene glycol dimethyl ether, tetrahydrofuran, dioxan, diiso
  • benzene, toluene, xylene hydrocarbons (e.g. hexane, iso-hexane, heptane, cyclohexane), ketones (e.g. acetone, ethyl methyl ketone, iso-butyl methyl ketone), nitriles (e.g. acetonitrile, propionitrile, butyronitrile) and amides (e.g. dimethyl-formamide, dimethylacetamide, N-methylpyrrolidone) and water can be used or the reaction can be effected in mixtures of two or more of these solvents.
  • the preferred solvent is dioxan.
  • Bases which are preferably used in the process according to the invention are alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkali and alkaline earth metal acetates, alkali and alkaline earth metal alcoholates, and primary, secondary and tertiary amines.
  • Preferred bases are alkali metal carbonates such as for example caesium carbonate, sodium carbonate and potassium carbonate.
  • the base is preferably used in a proportion of 100 to 1000 mol.%, based on the aromatic boronic acid.
  • the preferred proportion is 600 to 800 mol.%.
  • catalysts for example palladium metal, palladium compounds and/or nickel compounds can be used.
  • the catalysts can also be applied onto a solid carrier, such as activated charcoal or aluminium oxide.
  • catalysts are tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)-palladium dichloride and bis-(diphenylphosphino)ferrocenepalladium dichloride.
  • the palladium compound can also be generated in situ, such as for example palladium(II) acetate from palladium(II) chloride and sodium acetate.
  • the quantity of catalyst, based on the heteroaromatics [X-a] and [X-b] bearing the leaving group Z 2 , is preferably 0.001 to 0.5 mol.% and particularly preferably 0.01 to 0.2 mol.%.
  • the catalyst can contain phosphorus-containing ligands or phosphorus-containing ligands can be added separately to the reaction mixture.
  • phosphorus-containing ligands are tri-n-alkylphosphanes, triarylphosphanes, dialkylarylphosphanes, alkyldiarylphosphanes and/or heteroarylphosphanes, such as tripyridylphosphane and trifurylphosphane, wherein the three substituents on the phosphorus can be the same or different and wherein one or more substituents can link the phosphorus groups of several phosphanes, wherein one part of this linkage can also be a metal atom.
  • Particularly preferable are phosphanes such as triphenylphosphane, tri-tert- butylphosphane and tricyclohexylphosphane.
  • the total concentration of phosphorus-containing ligands, based on the heteroaromatics [X-a] and [X-b] bearing the leaving group Z 2 is preferably up to 1 mol.%, particularly preferably 0.01 to 0.5 mol.%.
  • the educts, the solvent, the base, the catalyst and if appropriate the ligand are thoroughly mixed and reacted preferably at a temperature of 0°C - 200°C, particularly preferably at 100-170°C.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
  • the reaction can also be run such that the various reactants are metered in a controlled way in the course of the reaction, different metering variants being possible.
  • the molar reactant ratio of the heteroaromatic [X-a] and [X-b] to the organoboron compound [III] is preferably 0.9 to 1.5.
  • the processes according to the invention are generally performed under normal pressure. It is however also possible to operate under increased or reduced pressure.
  • the reaction is generally performed with the use of a blanket gas such as for example argon or nitrogen.
  • the catalyst arising as a solid is removed by filtration, the crude product freed from the solvent or solvents and then purified by methods known to those skilled in the art and appropriate for the particular product, e.g. by recrystallization, distillation, sublimation, zone melting, melt crystallization or chromatography.
  • a compound with the general formula [I-a] can be synthesized, analogously to procedures described in the literature (see e.g. WO 2004/052880 and e.g. T.W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 1999, John Wiley & Sons, Inc.), by a coupling reaction of a compound with the corresponding general formula [II] with a substrate of the general formula [XI] (with Z 3 e.g.
  • solvent all usual solvents inert under the reaction conditions, such as for example cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydro-carbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene) and nitriles (e.g. acetonitrile) can be used or the reaction can be effected in mixtures of two or more of these solvents.
  • the preferred solvents are tetrahydrofuran and dichloromethane.
  • At least one equivalent of an acid scavenger / a base e.g. Hiinig base, triethylamine or commercially available polymeric acid scavengers
  • a base e.g. Hiinig base, triethylamine or commercially available polymeric acid scavengers
  • the starting material is a salt, at least two equivalents of the acid scavenger are needed.
  • the reaction is normally effected at temperatures of 0°C - 100°C and preferably at 20°C - 30°C, but it can also be effected at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
  • Suitable coupling reagents are for example peptide coupling reagents (for example, N-(3-dimethyl- aminopropyl)-N'-ethyl-carbodiimide mixed with 4-dimethylamino-pyridine, N-(3-dimethylamino- propyl)-N'-ethyl-carbodiimide mixed with 1-hydroxy-benzotriazole, bromo-tripyrrolidino- phosphonium hexafluorophosphate, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc.).
  • peptide coupling reagents for example, N-(3-dimethyl- aminopropyl)-N'-ethyl-carbodiimide mixed with 4-dimethylamino-pyridine, N-(3-dimethylamino- propyl)-N'-
  • a base such as for example triethylamine or Hiinig base can be used in the reaction.
  • solvent all usual solvents inert under the reaction conditions, such as for example alcohols (e.g. methanol, ethanol, propanol), cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile) and amides (e.g.
  • alcohols e.g. methanol, ethanol, propanol
  • cyclic and acyclic ethers e.g. diethyl ether, tetrahydrofuran, dioxan
  • aromatic hydrocarbons e.g. benzene
  • N,N- dimethylformamide, ⁇ , ⁇ -dimethylacetamide can be used or the reaction can be performed in mixtures of two or more of these solvents.
  • the preferred solvent is dichloromethane.
  • the reaction is normally performed at temperatures of 0°C - 100°C and preferably at 0°C - 30°C, but it can also be performed at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
  • the compounds [I-a] are separated from the reaction mixture by one of the usual separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography.
  • Step (V7) One possibility for the synthesis of compounds of the formula [XIII] is shown in Scheme 2.
  • the reaction temperature can be varied from room temperature to the boiling point of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a couple of minutes and 48 hours.
  • compounds of the general formula [XIII] can be obtained according to known literature methods (J. Org. Chem. 2001, 66, 24, 8000-8009) by reacting an ester compound of general formula [XII] (where Z 3 stands for OAlkyl) with a methylketone of the general formula CH3COR 2 in the presence of a base (e.g. sodium hydride, lithium diisopropylamide or potassium tert. butanolate) and a solvent.
  • a base e.g. sodium hydride, lithium diisopropylamide or potassium tert. butanolate
  • Typical solvents include alcohols (e.g. ethanol) or ethers (e.g. THF).
  • compounds of the general formula [XIII] can be obtained according to known literature methods ⁇ Bioorg. Med. Chem. Lett. 2004 , 14, 2, 343-346) by reacting an methylketone general formula [XII] (where Z 3 stands for CH3) with an carboxylic acid ester of the general formula R 2 COOAlkyl in the presence of a base (e.g. sodium hydride, lithium diisopropylamide or potassium tert. butanolate) and a solvent.
  • a base e.g. sodium hydride, lithium diisopropylamide or potassium tert. butanolate
  • Typical solvents include alcohols (e.g. ethanol) or ethers (e.g. THF).
  • compounds [XII] are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
  • Compounds of the general formula [VII] may be obtained, according to known literature methods (Tetrahedron 1995, 51, 41, 11251-11256; J. Med. Chem. 2003, 46, 25, 5416-5427; WO 2008/108602 Al or J. Med. Chem. 1998, 41, 13, 2390-2410), by reacting a compound of general formula [XIII] with hydrazine or a hydrated form thereof.
  • Inert solvent such as cyclic or acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxane), alcohols (e.g. methanol or ethanol) can be used.
  • the reaction can be carried out in mixtures of two or more of these solvents.
  • a base e.g. triethylamine may be used if desired.
  • the reaction temperature can be varied from 10°C to 50°C but room temperature is preferred.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a couple of minutes and 48 hours.
  • the reaction can be performed in a microwave apparatus (e.g. CEM Explorer) at elevated temperature, which may shorten the reaction time.
  • compounds [VII] are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
  • Compounds of the general formula [VI] may be obtained, according to known literature methods (J. Med. Chem. 1998, 41, 13, 2390-2410), by reacting a compound of general formula [XIII] with hydrazine a hydrazine of general formula R 1 -NH-NH2 or a hydrated form thereof.
  • Inert solvent such as cyclic or acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxane), alcohols (e.g. methanol or ethanol) can be used.
  • the reaction can be carried out in mixtures of two or more of these solvents.
  • a base e.g. triethylamine may be used if desired.
  • the reaction temperature can be varied from 10 °C to 50 °C but room temperature is preferred.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a couple of minutes and 48 hours.
  • the reaction can be performed in a microwave apparatus (e.g. CEM Explorer) at elevated temperature, which may shorten the reaction time.
  • compounds [VII] are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
  • the alkynone [XVI] can be prepared by treating acid chloride [XIV] with an alkyne for example by transition-metal catalysis e.g. as described in Tetrahedron Lett. 2006, 47, 5527-5530 or in Synthesis 2003, 18, 2815-2826.
  • Transition-metal catalysis e.g. as described in Tetrahedron Lett. 2006, 47, 5527-5530 or in Synthesis 2003, 18, 2815-2826.
  • Compounds of the general formula [XIV] are commercially available or can be synthetised according to known synthesis methods (e.g. in J. Heterocycl. Chem. 1966, 3, 184-186 or J. Med. Chem. 2001, 44, 863-872).
  • the alkynone [XVI] can be prepared by carbonylative C-C coupling using thiophene halides [XV] with an alkyne employing carbon monoxide as described e.g. in Synlett 2008, 6, 886- 888 or J. Org. Chem. 2005, 70, 6097-6100.
  • Compounds of formula [VI] can be prepared by treating the alkynone of formula [XVI] with a hydrazine derivative under conditions used in state of the art methodology (e.g. in Eur. J. Org. Chem. 2008, 4157-4168 or Tetrahedron Lett. 2008, 49, 3805-3809).
  • Compounds of the formula [XIX] can be produced for example by coupling of the pyrazoles of the formula [XVII] (wherein Met stands for a borate ester or boronic acid such as for example B(OiPr)3 or B(OH)2) with compounds of the formula [XVIII] (wherein Z 4 represents a leaving group such as for example CI, Br, I, mesylate or inflate) in the presence of a catalyst, a base, if necessary a ligand and a suitable solvent at suitable temperatures by known literature procedures ⁇ Top. Curr. Chem. 2002, 219, 11 ; Organomet. Chem. 1999, 28, 147 and literature cited therein, Org. Lett.
  • the processes according to the invention are in general performed under normal pressure. However it is also possible to operate under increased or reduced pressure.
  • the reaction is in general performed using a blanket gas such as for example argon or nitrogen.
  • the molar reactant ratio of the pyrazole [XVII] to the compound of the formula [XVIII] is preferably 0.9 to 2.
  • the catalyst arising as a solid is removed by filtration, the crude product freed from the solvent or solvents and then purified by methods known to those skilled in the art and appropriate for the particular product, e.g. by recrystallization, distillation, sublimation, zone melting, melt crystallization or chromatography.
  • 2-(Trimethylsilyl-ethoxy)methyl and tetrahydropyran-2-yl protective groups can for example be removed in an acidic medium (e.g. with methanolic HCl or trifluoroacetic acid) by known literature procedures (WO 03/099822 and J. Org. Chem. 2008, 73, 4309-4312 and literature contained therein).
  • Benzylic protective groups can be removed hydrogenolytically with a hydrogen source (e.g. hydrogen, ammonium formate, formic acid or cyclohexene) in the presence of a catalyst (e.g. palladium on activated charcoal or palladium hydroxide on activated charcoal) by known literature procedures (EP-A 1 228 067).
  • a hydrogen source e.g. hydrogen, ammonium formate, formic acid or cyclohexene
  • a catalyst e.g. palladium on activated charcoal or palladium hydroxide on activated charcoal
  • solvent all usual solvents inert under the reaction conditions, such as for example alcohols (e.g. methanol, ethanol, propanol), cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile), carboxylate ester (e.g.
  • alcohols e.g. methanol, ethanol, propanol
  • cyclic and acyclic ethers e.g. diethyl ether, tetrahydrofuran, dioxan
  • aromatic hydrocarbons e.g. benzen
  • amides e.g. N,N-dimethylformamide, ⁇ , ⁇ -dimethylacetamide
  • dimethyl sulphoxide 1,3- dimethyl-2-imidazolinone
  • water and acetic acid can be used or the reaction can be performed in mixtures of two or more of these solvents.
  • the reaction is normally performed at temperatures of 0°C - 150°C and preferably at room temperature, but it can also be performed at the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between half an hour and 72 hours.
  • the compounds [XX] are separated from the reaction mixture by one of the usual separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or if desired can also be used in the next step without prior purification. It is moreover possible to isolate the compound of the general formula [XX] as a salt, e.g. as a salt of hydrochloric acid or trifluoroacetic acid.
  • a compound of the formula [XXI] is converted into a compound of the formula [XXII] by conversion of the acid into the amide of ⁇ , ⁇ -dimethyl-hydroxylamine by using amide formation methods, which are described in the literature (US 6,562,811 A, US 2003/158185 Al or J. Med. Chem. 2001 , vol. 44, 6, 863-872).
  • a further subject of the invention relates to an agent for the control of undesired microorganisms and for the reduction of mycotoxins in plants and plant parts, comprising at least one thienylpyri(mi)dinylpyrazole according to the present invention.
  • the invention relates to a method for the control of undesired microorganisms and for the reduction of mycotoxins in plants and plant parts, characterized in that the thienylpyri(mi)dinylpyrazoles according to the invention are applied onto the microorganisms and/or in their habitat.
  • the substances according to the invention have potent microbicidal activity and can be employed for controlling unwanted microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.
  • the present invention furthermore relates to a crop protection composition for controlling unwanted microorganisms, in particular unwanted fungi, which comprises the active compounds according to the invention.
  • unwanted microorganisms in particular unwanted fungi
  • these are preferably fungicidal compositions which comprise agriculturally suitable auxiliaries, solvents, carriers, surfactants or extenders.
  • the invention relates to a method for controlling unwanted microorganisms, characterized in that the active compounds according to the invention are applied to the phytopathogenic fungi and/or their habitat.
  • a carrier is a natural or synthetic organic or inorganic substance with which the active compounds are mixed or bonded for better applicability, in particular for application to plants or plant parts or seed.
  • the carrier which may be solid or liquid, is generally inert and should be suitable for use in agriculture.
  • Suitable solid or liquid carriers are: for example ammonium salts and ground natural minerals, such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and ground synthetic minerals, such as finely divided silica, alumina and natural or synthetic silicates, resins, waxes, solid fertilizers, water, alcohols, especially butanol, organic solvents, mineral and vegetable oils and derivatives of these. Mixtures of such carriers may also be used.
  • ground natural minerals such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth
  • ground synthetic minerals such as finely divided silica, alumina and natural or synthetic silicates, resins, waxes, solid fertilizers, water, alcohols, especially butanol, organic solvents, mineral and vegetable oils and derivatives of these. Mixtures of such carriers may also be used.
  • Suitable solid carriers for granules are: for example crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite, dolomite, and synthetic granules of inorganic and organic meals, and also granules of organic material such as sawdust, coconut shells, maize cobs and tobacco stalks.
  • Suitable liquefied gaseous extenders or carriers are liquids which are gaseous at ambient temperature and under atmospheric pressure, for example aerosol propellants, such as halogenated hydrocarbons, and also butane, propane, nitrogen and carbon dioxide.
  • aerosol propellants such as halogenated hydrocarbons, and also butane, propane, nitrogen and carbon dioxide.
  • Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, or else natural phospholipids such as cephalins and lecithins and synthetic phospholipids can be used in the formulations.
  • Other possible additives are mineral and vegetable oils. If the extender used is water, it is also possible to employ, for example, organic solvents as auxiliary solvents.
  • suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or dichloromethane, aliphatic hydrocarbons such as cyclohexane or paraffins, for example mineral oil fractions, mineral and vegetable oils, alcohols such as butanol or glycol and their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide and dimethyl sulphoxide, and also water.
  • aromatics such as xylene, toluene or alkylnaphthalenes
  • chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or dichloromethane
  • aliphatic hydrocarbons
  • compositions according to the invention may comprise additional further components, such as, for example, surfactants.
  • surfactants are emulsifiers and/or foam formers, dispersants or wetting agents having ionic or nonionic properties, or mixtures of these surfactants.
  • salts of polyacrylic acid salts of lignosulphonic acid, salts of phenolsulphonic acid or naphthalenesulphonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulphosuccinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyethoxylated alcohols or phenols, fatty esters of polyols, and derivatives of the compounds containing sulphates, sulphonates and phosphates, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates, arylsulphonates, protein hydrolyzates, lignosulphite waste liquors and methylcellulose.
  • the presence of a surfactant is required if one of the active compounds and/or one of the inert carriers is insoluble in water and when the application takes place in water.
  • the proportion of surfactants is between 5 and 40 per cent by weight of the composition according to the invention.
  • compositions and formulations according to the invention generally comprise between 0.05 and 99% by weight, 0.01 and 98% by weight, preferably between 0.1 and 95% by weight, particularly preferably between 0.5 and 90% of active compound, very particularly preferably between 10 and 70% by weight.
  • the active compounds or compositions according to the invention can be used as such or, depending on their respective physical and/or chemical properties, in the form of their formulations or the use forms prepared therefrom, such as aerosols, capsule suspensions, cold-fogging concentrates, warm-fogging concentrates, encapsulated granules, fine granules, flowable concentrates for the treatment of seed, ready-to-use solutions, dustable powders, emulsifiable concentrates, oil-in-water emulsions, water-in-oil emulsions, macrogranules, microgranules, oil-dispersible powders, oil-miscible flowable concentrates, oil-miscible liquids, foams, pastes, pesticide coated seed, suspension concentrates, suspoemulsion concentrates, soluble concentrates, suspensions, wettable powders, soluble powders, dusts and granules, water-soluble granules or tablets, water-soluble powders for the treatment of
  • the formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one customary extender, solvent or diluent, emulsifier, dispersant, and/or binder or fixative, wetting agent, water repellent, if appropriate desiccants and UV stabilizers and, if appropriate, dyes and pigments, defoamers, preservatives, secondary thickeners, adhesives, gibberellins and also further processing auxiliaries.
  • compositions according to the invention include not only formulations which are already ready for use and can be applied with a suitable apparatus to the plant or the seed, but also commercial concentrates which have to be diluted with water prior to use.
  • the active compounds according to the invention can be present as such or in their (commercial) formulations and in the use forms prepared from these formulations as a mixture with other (known) active compounds, such as insecticides, attractants, sterilants, bactericides, acaricides, ne- maticides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.
  • active compounds such as insecticides, attractants, sterilants, bactericides, acaricides, ne- maticides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.
  • the treatment according to the invention of the plants and plant parts with the active compounds or compositions is carried out directly or by action on their surroundings, habitat or storage space using customary treatment methods, for example by dipping, spraying, atomizing, irrigating, evaporating, dusting, fogging, broadcasting, foaming, painting, spreading-on, watering (drenching), drip irrigating and, in the case of propagation material, in particular in the case of seeds, furthermore as a powder for dry seed treatment, a solution for seed treatment, a water-soluble powder for slurry treatment, by incrusting, by coating with one or more coats, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method or to inject the active compound preparation or the active compound itself into the soil.
  • the invention furthermore includes a method for treating seed.
  • the invention furthermore relates to seed which has been treated in accordance with one of the methods described in the previous paragraph.
  • the seeds according to the invention are used in methods for the protection of seed from undesirable microorganisms. In these methods, seed treated with at least one active compound according to the invention is employed.
  • the active compounds or compositions according to the invention are also suitable for treating seed.
  • a large part of the damage to crop plants caused by harmful organisms is triggered by the infection of the seed during storage or after sowing both during and after germination of the plant. This phase is particularly critical since the roots and shoots of the growing plant are particularly sensitive, and even small damage may result in the death of the plant. Accordingly, there is great interest in protecting the seed and the germinating plant by using appropriate compositions.
  • the control of phytopathogenic fungi by treating the seed of plants has been known for a long time and is the subject of continuous improvements. However, the treatment of seed entails a series of problems which cannot always be solved in a satisfactory manner.
  • the present invention therefore also relates to a method for the protection of seed and germinating plants, from attack by phytopathogenic fungi, by treating the seed with a composition according to the invention.
  • the invention also relates to the use of the compositions according to the invention for treating seed for protecting the seed and the germinating plant against phytopathogenic fungi.
  • the invention relates to seed treated with a composition according to the invention for protection against phytopathogenic fungi.
  • One of the advantages of the present invention is that the particular systemic properties of the active compounds and compositions according to the invention mean that treatment of the seed with these active compounds and compositions not only protects the seed itself, but also the resulting plants after emergence, from phytopathogenic fungi. In this manner, the immediate treatment of the crop at the time of sowing or shortly thereafter can be dispensed with.
  • the active compounds or compositions according to the invention can be used in particular also for transgenic seed where the plant growing from this seed is capable of expressing a protein which acts against pests.
  • the active compounds or compositions according to the invention By treating such seed with the active compounds or compositions according to the invention, even by the expression of the, for example, insecticidal protein, certain pests may be controlled.
  • a further synergistic effect may be observed here, which additionally increases the effectiveness of the protection against attack by pests.
  • compositions according to the invention are suitable for protecting seed of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture and viticulture.
  • this takes the form of seed of cereals (such as wheat, barley, rye, triticale, sorghum/millet and oats), maize, cotton, soya beans, rice, potatoes, sunflower, bean, coffee, beet (for example sugar beet and fodder beet), peanut, oilseed rape, poppy, olive, coconut, cacao, sugar cane, tobacco, vegetables (such as tomato, cucumbers, onions and lettuce), turf and ornamentals (see also hereinbelow).
  • the treatment of the seed of cereals (such as wheat, barley, rye, triticale and oats), maize and rice is of particular importance.
  • transgenic seed As also described further below, the treatment of transgenic seed with the active compounds or compositions according to the invention is of particular importance.
  • the heterologous gene in transgenic seed can originate, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium.
  • this heterologous gene is from Bacillus sp., the gene product having activity against the European corn borer and/or the Western corn rootworm.
  • the heterologous gene originates from Bacillus thuringiensis.
  • the composition according to the invention is applied to the seed either alone or in a suitable formulation.
  • the seed is treated in a state in which it is stable enough to avoid damage during treatment.
  • the seed may be treated at any point in time between harvest and sowing.
  • the seed usually used has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits.
  • seed which has been harvested, cleaned and dried has been treated, for example, with water and then dried again.
  • the amount of the composition according to the invention applied to the seed and/or the amount of further additives is chosen in such a way that the germination of the seed is not adversely affected, or that the resulting plant is not damaged. This must be borne in mind in particular in the case of active compounds which can have phytotoxic effects at certain application rates.
  • compositions according to the invention can be applied directly, i.e. without containing any other components and undiluted. In general, it is preferred to apply the compositions to the seed in the form of a suitable formulation. Suitable formulations and methods for treating seed are known to the person skilled in the art and are described, for example, in the following documents: US 4,272,417 A, US 4,245,432 A, US 4,808,430 A, US 5,876,739 A, US 2003/0176428 Al , WO 2002/080675 Al, WO 2002/028186 A2.
  • the active compounds which can be used in accordance with the invention can be converted into the customary seed-dressing formulations, such as solutions, emulsions, suspensions, powders, foams, slurries or other coating compositions for seed, and also ULV formulations.
  • formulations are prepared in a known manner, by mixing the active compounds with customary additives such as, for example, customary extenders and also solvents or diluents, colorants, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins and also water.
  • customary additives such as, for example, customary extenders and also solvents or diluents, colorants, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins and also water.
  • Colorants which may be present in the seed-dressing formulations which can be used in accordance with the invention are all colorants which are customary for such purposes.
  • pigments which are sparingly soluble in water, but also dyes, which are soluble in water, may be used. Examples which may be mentioned are the colorants known by the names Rhodamin B, C.I. Pigment Red 112 and C.I. Solvent Red 1.
  • Suitable wetting agents which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which promote wetting and which are conventionally used for the formulation of agrochemical active compounds. Preference is given to using alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.
  • Suitable dispersants and/or emulsifiers which may be present in the seed-dressing formulations which can be used in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the formulation of agrochemical active compounds. Preference is given to using nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants.
  • Suitable nonionic dispersants which may be mentioned are, in particular, ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and their phosphated or sulphated derivatives.
  • Suitable anionic dispersants are, in particular, lignosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.
  • Secondary thickeners which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica are preferred.
  • Adhesives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all customary binders which can be employed in seed-dressing products.
  • Polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose may be mentioned as being preferred.
  • the gibberellins are known (cf. R. Wegler "Chemie der convinced für Schweizer- und Schadlingsbekampfungsstoff" [Chemistry of crop protection agents and pesticides], vol. 2, Springer Verlag, 1970, p. 401 -412).
  • the seed-dressing formulations which can be used in accordance with the invention can be employed for the treatment of a wide range of seed, including the seed of transgenic plants, either directly or after previously having been diluted with water.
  • additional synergistic effects may also occur in cooperation with the substances formed by expression.
  • All mixers which can conventionally be employed for the seed-dressing operation are suitable for treating seed with the seed-dressing formulations which can be used in accordance with the invention or with the preparations prepared therefrom by addition of water. Specifically, a procedure is followed during the seed-dressing operation in which the seed is placed into a mixer, the specific desired amount of seed-dressing formulations, either as such or after previously having been diluted with water, is added, and everything is mixed until the formulation is distributed uniformly on the seed. If appropriate, this is followed by a drying process.
  • the active compounds or compositions according to the invention have a potent microbicidal activity and can be employed for controlling undesirable microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.
  • Fungicides can be employed in crop protection for controlling Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes.
  • Bactericides can be employed in crop protection for controlling Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
  • the fungicidal compositions according to the invention can be used for the curative or protective control of phytopathogenic fungi. Accordingly, the invention also relates to curative and protective methods for controlling phytopathogenic fungi using the active compounds or compositions according to the invention, which are applied to the seed, the plant or plant parts, the fruit or the soil in which the plants grow.
  • compositions according to the invention for controlling phytopathogenic fungi in crop protection comprise an effective, but non-phytotoxic amount of the active compounds according to the invention.
  • Effective, but non-phytotoxic amount means an amount of the composition according to the invention which is sufficient to control the fungal disease of the plant in a satisfactory manner or to eradicate the fungal disease completely, and which, at the same time, does not cause any significant symptoms of phytotoxicity.
  • this application rate may vary within a relatively wide range. It depends on a plurality of factors, for example on the fungus to be controlled, the plant, the climatic conditions and the ingredients of the compositions according to the invention.
  • plants are understood here all plants and plant populations such as desired and undesired wild plants or crop plants (including naturally occurring crop plants).
  • Crop plants can be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant varieties which can or cannot be protected by varietal property rights.
  • Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes.
  • Parts of plants also include harvested plants and vegetative and generative propagation material, for example seedlings, tubers, rhizomes, cuttings and seeds.
  • the active compounds according to the invention are suitable for the protection of plants and plant organs, for increasing the harvest yields, for improving the quality of the harvested crop, while being well tolerated by plants, having favourable toxicity to warm-blooded species and being environmentally friendly. They may be preferably employed as crop protection agents. They are active against normally sensitive and resistant species and also against all or some stages of development.
  • plants which can be treated according to the invention cotton, flax, grapevine, fruit, vegetables, such as Rosaceae sp. (for example pome fruits such as apples and pears, but also stone fruits such as apricots, cherries, almonds and peaches, and soft fruits such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp.
  • Rubiaceae sp. for example coffee
  • Theaceae sp. Sterculiceae sp.
  • Rutaceae sp. for example lemons, oranges and grapefruit
  • Solanaceae sp. for example tomatoes
  • Liliaceae sp. for example lettuce
  • Umbelliferae sp. for example lettuce
  • Alliaceae sp. for example leeks, onions
  • peas for example peas
  • maj or crop plants such as Gramineae sp. (for example maize, turf, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Poaceae sp. (for example sugar cane), Asteraceae sp. (for example sunflower), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflower, Brussels sprouts, pak choi, kohlrabi, small radishes, and also oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example beans, peanuts), Papilionaceae sp. (for example soya beans), Solanaceae sp.
  • Gramineae sp. for example maize, turf, cereals such as wheat, rye, rice, barley, oats, millet and triticale
  • Poaceae sp. for example sugar cane
  • plants of the plant cultivars which are in each case commercially available or in use are treated according to the invention.
  • Plant cultivars are to be understood as meaning plants having new properties ("traits") and which have been obtained by conventional breeding, by mutagenesis or by recombinant DNA techniques. They can be cultivars, varieties, bio- or genotypes.
  • the method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds.
  • GMOs genetically modified organisms
  • Genetically modified plants are plants in which a heterologous gene has been stably integrated into the genome.
  • the expression "heterologous gene” essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example antisense technology, cosuppression technology or RNAi technology [RNA interference]).
  • a heterologous gene that is located in the genome is also called a transgene.
  • a transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
  • the treatment according to the invention may also result in superadditive ("synergistic") effects.
  • superadditive the following effects which exceed the effects which were actually to be expected: reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf colour, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products.
  • the active compounds according to the invention may also have a strengthening effect on plants. Accordingly, they are suitable for mobilizing the defence system of the plant against attack by unwanted phytopathogenic fungi and/or microorganisms and/or viruses. This may, if appropriate, be one of the reasons for the enhanced activity of the combinations according to the invention, for example against fungi.
  • Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, also those substances or combinations of substances which are capable of stimulating the defence system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi, the treated plants display a substantial degree of resistance to these unwanted phytopathogenic fungi.
  • the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment.
  • the period within which protection is brought about generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
  • Plants and plant varieties which are preferably treated according to the invention include all plants which have genetic material which imparts particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means). Plants and plant varieties which are also preferably treated according to the invention are resistant against one or more biotic stress factors, i.e. said plants have a better defence against animal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids.
  • Plants and plant varieties which may also be treated according to the invention are those plants which are resistant to one or more abiotic stress factors.
  • Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, waterlogging, increased soil salinity, increased exposure to minerals, exposure to ozone, exposure to strong light, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients or shade avoidance.
  • Plants and plant varieties which may also be treated according to the invention are those plants characterized by enhanced yield characteristics. Enhanced yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation.
  • Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including early flowering, flowering control for hybrid seed production, seedling vigour, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance.
  • Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
  • Plants that may be treated according to the invention are hybrid plants that already express the characteristics of heterosis, or hybrid effect, which results in generally higher yield, vigour, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male-sterile plants and sold to growers. Male-sterile plants can sometimes (e.g. in corn) be produced by detasseling (i.e. the mechanical removal of the male reproductive organs or male flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome.
  • detasseling i.e. the mechanical removal of the male reproductive organs or male flowers
  • male fertility in hybrid plants which contain the genetic determinants responsible for male sterility
  • This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male sterility.
  • Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described for Brassica species. However, genetic determinants for male sterility can also be located in the nuclear genome. Male-sterile plants can also be obtained by plant biotechnology methods such as genetic engineering.
  • a particularly useful means of obtaining male-sterile plants is described in WO 89/10396 in which, for example, a ribonuclease such as a barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
  • Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof.
  • glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS).
  • EPSPS 5-enolpyruvylshikimate-3-phosphate synthase
  • EPSPS 5-enolpyruvylshikimate-3-phosphate synthase
  • EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium, the CP4 gene of the bacterium Agrobacterium sp., the genes encoding a petunia EPSPS, a tomato EPSPS, or an Eleusine EPSPS. It can also be a mutated EPSPS.
  • Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyltransferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally occurring mutations of the abovementioned genes. Other herbicide-resistant plants are for example plants which have been made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate.
  • Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition.
  • One such efficient detoxifying enzyme is, for example, an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species for example). Plants expressing an exogenous phosphinothricin acetyltransferase have been described.
  • hydroxyphenylpyruvatedioxygenase HPPD
  • Hydroxyphenylpyruvatedioxygenases are enzymes that catalyse the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate.
  • Plants tolerant to HPPD inhibitors can be transformed with a gene encoding a naturally occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme.
  • Tolerance to HPPD inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD inhibitor.
  • Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme.
  • ALS inhibitors include, for example, sulphonylurea, imidazolinone, triazolopyrimidines, pyrimidinyl oxy(thio)benzoates, and/or sulphonylaminocarbonyltriazolinone herbicides.
  • Different mutations in the ALS enzyme also known as acetohydroxy acid synthase, AHAS
  • AHAS acetohydroxy acid synthase
  • plants tolerant to imidazolinone and/or sulphonylurea can be obtained by induced mutagenesis, by selection in cell cultures in the presence of the herbicide or by mutation breeding.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
  • insect-resistant transgenic plant includes any plant containing at least one transgene comprising a coding sequence encoding: 1) an insecticidal crystal protein from Bacillus thuringiensis or an insecticidal portion thereof, such as the insecticidal crystal proteins listed online at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/, or insecticidal portions thereof, for example proteins of the Cry protein classes Cryl Ab, Cryl Ac, CrylF, Cry2Ab, Cry3Ae or Cry3Bb or insecticidal portions thereof; or
  • a crystal protein from Bacillus thuringiensis or a portion thereof which is insecticidal in the presence of a second other crystal protein from Bacillus thuringiensis or a portion thereof, such as the binary toxin made up of the Cy34 and Cy35 crystal proteins; or
  • a hybrid insecticidal protein comprising parts of two different insecticidal crystal proteins from Bacillus thuringiensis, such as a hybrid of the proteins of 1) above or a hybrid of the proteins of 2) above, for example the Cryl A.1 05 protein produced by maize event MON98034 (WO 2007/027777); or
  • VIP vegetative insecticidal proteins
  • a secreted protein from Bacillus thuringiensis or Bacillus cereus which is insecticidal in the presence of a second secreted protein from Bacillus thuringiensis or B. cereus, such as the binary toxin made up of the VTPl A and VIP2A proteins; 7) a hybrid insecticidal protein comprising parts from different secreted proteins from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins in 1) above or a hybrid of the proteins in 2) above; or
  • 8) a protein of any one of points 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation (while still encoding an insecticidal protein), such as the VIP3Aa protein in cotton event COT 102.
  • insect-resistant transgenic plants also include any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8.
  • an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected or to delay insect resistance development to the plants, by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
  • Plants or plant varieties which may also be treated according to the invention are tolerant to abiotic stress factors. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance.
  • Particularly useful stress-tolerant plants include the following: a. plants which contain a transgene capable of reducing the expression and/or the activity of the poly(ADP-ribose)polymerase (PARP) gene in the plant cells or plants; b. plants which contain a stress tolerance-enhancing transgene capable of reducing the expression and/or the activity of the PARG-encoding genes of the plants or plant cells; c.
  • PARP poly(ADP-ribose)polymerase
  • plants which contain a stress tolerance-enhancing transgene coding for a plant-functional enzyme of the nicotinamide adenine dinucleotide salvage biosynthesis pathway including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide adenyltransferase, nicotinami de adenine dinuc le otide synthetas e or nicotinamide phosphoribosyltransferase.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention show altered quantity, quality and/or storage stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as, for example:
  • Transgenic plants which synthesize a modified starch which is altered with respect to its chemophysical traits, in particular the amylose content or the amylose/amylopectin ratio, the degree of branching, the average chain length, the distribution of the side chains, the viscosity behaviour, the gel resistance, the grain size and/or grain morphology of the starch in comparison to the synthesized starch in wild-type plant cells or plants, such that this modified starch is better suited for certain applications.
  • chemophysical traits in particular the amylose content or the amylose/amylopectin ratio, the degree of branching, the average chain length, the distribution of the side chains, the viscosity behaviour, the gel resistance, the grain size and/or grain morphology of the starch in comparison to the synthesized starch in wild-type plant cells or plants, such that this modified starch is better suited for certain applications.
  • Transgenic plants which synthesize non-starch carbohydrate polymers or which synthesize non-starch carbohydrate polymers with altered properties in comparison to wild-type plants without genetic modification.
  • Examples are plants which produce polyfructose, especially of the inulin and levan type, plants which produce alpha- 1,4-glucans, plants which produce alpha- 1,6- branched alpha- 1,4-glucans, and plants producing alternan.
  • Plants or plant varieties obtained by plant biotechnology methods such as genetic engineering which may also be treated according to the invention are plants, such as cotton plants, with altered fibre characteristics.
  • Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered fibre characteristics and include: a) plants, such as cotton plants, which contain an altered form of cellulose synthase genes; b) plants, such as cotton plants, which contain an altered form of rsw2 or rsw3 homologous nucleic acids; c) plants, such as cotton plants, with an increased expression of sucrose phosphate synthase; d) plants, such as cotton plants, with an increased expression of sucrose synthase; e) plants, such as cotton plants, wherein the timing of the plasmodesmatal gating at the basis of the fibre cell is altered, for example through downregulation of fibre-selective ⁇ -1,3- glucanase; f) plants,
  • Plants or plant cultivars which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics.
  • Such plants can be obtained by genetic transformation or by selection of plants containing a mutation imparting such altered oil characteristics and include: a) plants, such as oilseed rape plants, which produce oil having a high oleic acid content; b) plants, such as oilseed rape plants, which produce oil having a low linolenic acid content; c) plants, such as oilseed rape plants, which produce oil having a low level of saturated fatty acids.
  • transgenic plants which may be treated according to the invention are plants which comprise one or more genes which encode one or more toxins and are the transgenic plants available under the following trade names: YIELD GARD® (for example maize, cotton, soya beans), KnockOut® (for example maize), BiteGard® (for example maize), BT-Xtra® (for example maize), StarLink® (for example maize), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example maize), Protecta® and NewLeaf® (potato).
  • YIELD GARD® for example maize, cotton, soya beans
  • KnockOut® for example maize
  • BiteGard® for example maize
  • BT-Xtra® for example maize
  • StarLink® for example maize
  • Bollgard® cotton
  • Nucotn® cotton
  • Nucotn 33B® cotton
  • NatureGard® for example maize
  • herbicide-tolerant plants examples include maize varieties, cotton varieties and soya bean varieties which are available under the following trade names: Roundup Ready® (tolerance to glyphosate, for example maize, cotton, soya beans), Liberty Link® (tolerance to phosphinothricin, for example oilseed rape), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulphonylurea, for example maize).
  • Herbicide-resistant plants plants bred in a conventional manner for herbicide tolerance
  • Clearfield® for example maize.
  • transgenic plants which may be treated according to the invention are plants containing transformation events, or a combination of transformation events, and that are listed for example in the databases for various national or regional regulatory agencies (see for example http ://gmoinfo.jrc. ec. europa. eu/).
  • the active compounds or compositions according to the invention can be employed for protecting industrial materials against attack and destruction by unwanted microorganisms, such as, for example, fungi and insects.
  • the compounds according to the invention can be used alone or in combinations with other active compounds as antifouling compositions.
  • Industrial materials in the present context are understood as meaning non-living materials which have been prepared for use in industry.
  • industrial materials which are intended to be protected by active compounds according to the invention from microbial change or destruction can be adhesives, sizes, paper, wallpaper, and board, textiles, carpets, leather, wood, paints and plastic articles, cooling lubricants and other materials which can be infected with, or destroyed by, microorganisms.
  • Parts of production plants and buildings, for example cooling-water circuits, cooling and heating systems and ventilation and air-conditioning units, which may be impaired by the proliferation of microorganisms may also be mentioned within the scope of the materials to be protected.
  • Industrial materials which may be mentioned within the scope of the present invention are preferably adhesives, sizes, paper and board, leather, wood, paints, cooling lubricants and heat- transfer liquids, particularly preferably wood.
  • the active compounds or compositions according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mould.
  • the compounds according to the invention can be employed for protecting objects which come into contact with saltwater or brackish water, in particular hulls, screens, nets, buildings, moorings and signalling systems, against fouling.
  • the method according to the invention for controlling unwanted fungi can also be employed for protecting storage goods.
  • storage goods are to be understood as meaning natural substances of vegetable or animal origin or processed products thereof of natural origin, for which long-term protection is desired.
  • Storage goods of vegetable origin such as, for example, plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting.
  • Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture.
  • Storage goods of animal origin are, for example, hides, leather, furs and hairs.
  • the active compounds according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decolouration or formation of mould.
  • pathogens of fungal diseases which can be treated according to the invention may be mentioned by way of example, but not by way of limitation: diseases caused by powdery mildew pathogens, such as, for example, Blumeria species, such as, for example, Blumeria graminis; Podosphaera species, such as, for example, Podosphaera leucotricha; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Uncinula species, such as, for example, Uncinula necator; diseases caused by rust disease pathogens, such as, for example, Gymnosporangium species, such as, for example, Gymnosporangium sabinae; Hemileia species, such as, for example, Hemileia vastatrix; Phakopsora species, such as, for example, Phakopsora pachyrhizi and Phakopsora meibomiae; Puccinia species, such as, for example
  • Phytophthora species such as, for example, Phytophthora infestans
  • Plasmopara species such as, for example, Plasmopara viticola
  • Pseudoperonospora species such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis
  • Pythium species such as, for example, Pythium ultimum
  • Cercospora species such as, for example, Cercospora beticola
  • Cladiosporium species such as, for example, Cladiosporium cucumerinum
  • Cochliobolus species such as, for example, Cochliobolus sativus (conidia form: Drechslera, syn: Helminthosporium) or Cochli
  • Urocystis species such as, for example, Urocystis occulta
  • Ustilago species such as, for example, Ustilago nuda, U. nuda tritici
  • Botrytis species such as, for example, Botrytis cinerea
  • Penicillium species such as, for example, Penicillium expansum and Penicillium purpurogenum
  • Sclerotinia species such as, for example, Sclerotinia sclerotiorum
  • Sclerotinia species such as, for example, Sclerotinia sclerotiorum
  • Verticilium species such as, for example, Verticilium alboatrum; seed- and soil-borne rot and wilt diseases, and also diseases of seedlings, caused, for example, by Alternaria species, such as, for example, Alternaria brassicicola; Aphanomyces species, such as, for example, Aphanomyces euteiches; Ascochyta species, such as, for example, Ascochyta lentis; Aspergillus species, such as, for example, Aspergillus flavus; Cladosporium species, such as, for example, Cladosporium herbarum; Cochliobolus species, such as, for example, Cochliobolus sativus (conidia form: Drechslera, Bipolaris Syn: Helminthosporium); Colletotrichum species, such as, for example, Colletotrichum coccodes; Fusarium species, such as, for example, Fusarium culmorum; Gibberella species,
  • Verticillium species such as, for example, Verticillium dahliae
  • cancerous diseases, galls and witches' broom caused, for example, by Nectria species, such as, for example, Nectria galligena
  • wilt diseases caused, for example, by Monilinia species, such as, for example, Monilinia laxa
  • deformations of leaves, flowers and fruits caused, for example, by Exobasidium species, such as, for example, Exobasidium vexans
  • Taphrina species such as, for example, Taphrina deformans
  • degenerative diseases of woody plants caused, for example, by Esca species such as, for example, Phaeomoniella chlamydospora, Phaeoacremonium aleophilum or Fomitiporia mediterranea
  • Ganoderma species such as, for example, Ganoderma boninense
  • diseases of flowers and seeds caused, for example, by Botrytis species,
  • Pseudomonas species such as, for example, Pseudomonas syringae pv. lachrymans
  • Erwinia species such as, for example, Erwinia amylovora.
  • phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotinia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola).
  • Microorganisms capable of degrading or changing the industrial materials are, for example, bacteria, fungi, yeasts, algae and slime organisms.
  • the active compounds according to the invention preferably act against fungi, in particular moulds, wood-discoloring and wood-destroying fungi (Basidiomycetes), and against slime organisms and algae.
  • Microorganisms of the following genera may be mentioned as examples: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger; Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor; Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Escherichia, such as Escherichia coli; Pseudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus.
  • Alternaria such as Alternaria tenuis
  • the active compounds according to the invention also have very good antimycotic activity. They have a very broad antimycotic activity spectrum, in particular against dermatophytes and yeasts, moulds and diphasic fungi (for example against Candida species, such as Candida albicans, Candida glabrata), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species such as Microsporon canis and audouinii.
  • Candida species such as Candida albicans, Candida glabrata
  • Epidermophyton floccosum Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus
  • Trichophyton species such as Trichophyton mentagrophytes
  • Microsporon species such as Microsporon canis and audouinii.
  • the list of these fungi by no means limits the
  • the active compounds according to the invention can be used both in medical and in non-medical applications.
  • the application rates can be varied within a relatively wide range, depending on the kind of application.
  • the application rate of the active compounds according to the invention is
  • the combination according to the invention can be used in order to protect plants within a certain time range after the treatment against pests and/or phytopathogenic fungi and/or microorganisms.
  • the time range, in which protection is effected spans in general 1 to 28 days, preferably 1 to 14 days, more preferably 1 to 10 days, even more preferably 1 to 7 days after the treatment of the plants with the combinations or up to 200 days after the treatment of plant propagation material.
  • combinations and compositions according to the invention may also be used to reduce the contents of mycotoxins in plants and the harvested plant material and therefore in foods and animal feed stuff made therefrom.
  • mycotoxins can be specified: Deoxynivalenole (DON), Nivalenole, 15-Ac-DON, 3-Ac-DON, T2- und HT2- Toxins, Fumonisines, Zearalenone Moniliformine, Fusarine, Diaceotoxyscirpenole (DAS), Beauvericine, Enniatine, Fusaroproliferine, Fusarenole, Ochratoxines, Patuline, Ergotalkaloides und Aflatoxines, which are caused for example by the following fungal diseases: Fusarium spec, like Fusarium acuminatum, F. avenaceum, F. crookwellense, F.
  • Sarcomastigophora (Rhizopoda) wie Entamoebidae z.B. Entamoeba histolytica, Hartmanellidae z.B. Acanthamoeba sp., Harmanella sp.
  • Apicomplexa (Sporozoa) wie Eimeridae z.B. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anserina, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E.
  • Theileria spec wie Adeleina z.B. Hepatozoon canis, H. spec.
  • the crude mixture is filtered through a cartridge with Celite and the volatile components removed under vacuum.
  • the crude product is purified by chromatography on silica gel (cyclohexane /ethyl acetate) and 26.2 mg of 4-[5-(5-methyl-3-thienyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl]pyridine (41%) are obtained as a colourless oil.
  • the intermediates produced in the general procedure VI 3 can also be used in the deprotection reaction without further purification.
  • the protected thienylpyrazole [XIX-1] (26.2mg, 0.08mmol) crude product is dissolved in 2 mL methanol and treated with 800 ⁇ of HC1 in dioxane (4 molar). The solution is stirred at room temperature for lhr and then concentrated. The solid obtained is washed with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After drying and evaporation of the solvent 25.6 mg of 4-[3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine (54%) are obtained as a white solid.
  • the combined organic phases are washed with water (70 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a yellow oil.
  • the crude product is purified by silica gel chromatography (eluent: dichloromethane/methyl tert-butyl ether) to yield 590 mg (59%) of 3-(2,5-dimethyl-3-thienyl)-l- isopropyl-lH-pyrazole as a yellowish oil and 300 mg (30%) of 5-(2,5-dimethyl-3-thienyl)-l - isopropyl-lH-pyrazole as a yellow oil.
  • Aqueous 5% sodium thiosulfate (150 mL) and saturated aqueous sodium carbonate solution (100 mL) are added and the mixture is stirred at room temperature for 1 h, then extracted with MTBE (3 x 120 mL). The combined organic phases are washed with water (70 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a light brown oil.
  • 1,4-Dioxane and aqueous 2M sodium carbonate solution are degassed by bubbling a flow of argon through the solutions for 10 min.
  • 2.06 g 4-iodo-l-isopropyl-3-(3-thienyl)-lH-pyrazole (6.15 mmol) are weighed into a 100 mL three-necked round bottom flask equipped with a reflux condenser and an internal thermometer.
  • reaction mixture is evaporated under vacuum and purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 1.69 g (72%) of the intermediate tert-butyl ⁇ 4-[l - isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl ⁇ carbamate as a white solid.
  • 1,4-Dioxane and aqueous 2M sodium carbonate solution are degassed by bubbling a flow of argon through the solutions for 10 min.
  • 167.0 mg 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (0.75 mmol) and 36.6 mg l, -bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.05 mmol) are weighed into a microwave vial (2-5 mL reaction volume).
  • cyclopropanecarbonyl chloride (1.94 mmol) is added dropwise to a solution of 183.4 mg 4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-amine (0.65 mmol) and 0.27 mL triethylamine (1.94 mmol) in dichloromethane (2.5 mL). The mixture is stirred at room temperature overnight and diluted with 2.5 mL dichloromethane.
  • the stated logP value is the value for the stated pure compound or, if a mixture is present, for the main isomer (1 -substituted 3-aryl-lH-pyrazole).
  • the mass detection was effected with the Micronass ZQ2000 mass detector from Waters.
  • Method C Note on the determination of the logP values and mass detection: The stated logP values were determined in accordance with EEC-Directive 79/83 1 Annex V.A8 by UPLC (Ultra Performance Liquid Chromatography) on a reverse phase column (CI 8). HP1100; 50*2.1 Zorbax Eclipse Plus C18 1.8 micron; eluent A: acetonitrile (0.09% formic acid); eluent B: water (0.1% formic acid); linear gradient from 10% A to 95% A in 3.25 min; oven temperature 40°C; flow rate: 0.8 mL/min.
  • the mass detection was effected with the LCT Premier or SQD mass detector from Waters.
  • Emulsifier 1 part by weight of Alkylarylpolyglycolether
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • Emulsifier 1 part by weight of Alkylarylpolyglycolether To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • the test is evaluated 7 days after the inoculation. 0% means an efficacy which corresponds to that of the untreated control, while an efficacy of 100% means that no disease is observed.
  • Emulsifier 1 part by weight of Alkylarylpolyglycolether To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • the test is evaluated 7-9 days after the inoculation. 0%> means an efficacy which corresponds to that of the untreated control while an efficacy of 100%) means that no disease is observed.
  • Emulsifier 1 part by weight of Alkylarylpolyglycolether
  • active compound 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
  • the test is evaluated 7 days after the inoculation. 0%> means an efficacy which corresponds to that of the untreated control while an efficacy of 100%) means that no disease is observed.
  • the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 500ppm of active ingredient: 1 (95%), 6(95%), 7(90%), 8(80%), 9(95%), 10(95%), 11(70%), 12(95%), 16(90%), 18(80%), 19(95%), 21 (70%), 22(95%), 30(90%), 27(80%), 28(95%), 26(90%), 23(80%), 24(80%), 25(70%), 31(90).

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Abstract

Thienylpyri(mi)dinylpyrazole of the formula (I) in which R1 to R8 and X1 have the meanings given in the description, and agrochemically active salts, to their use and to methods and compositions for controlling phytopathogenic harmful fungi in and/or on plants or in and/or on seed of plants and for reducing mycotoxins in plants and parts of the plants, to processes for preparing such compounds and compositions and treated seed and also to their use for controlling phytopathogenic harmful fungi in agriculture, horticulture, forestry, in animal husbandry, in the protection of materials, in the domestic and hygiene field and for the reduction of mycotoxins in plants and parts of the plants

Description

Thienylpyri(mi)dinylpyrazole
The invention relates to novel Thienylpyri(mi)dinylpyrazole and their agrochemically active salts, to their use and to methods and compositions for controlling phytopathogenic harmful fungi in and/or on plants or in and/or on seed of plants and for reducing mycotoxins in plants and parts of the plants, to processes for preparing such compounds and compositions and treated seed and also to their use for controlling phytopathogenic harmful fungi in agriculture, horticulture, forestry, in animal husbandry, in the protection of materials, in the domestic and hygiene field and for the reduction of mycotoxins in plants and parts of the plants.
It is already known that certain Arylpyrazoles can be employed as fungicidal crop protection agents (see WO 2009/076440, WO 2003/49542 and WO 2001/30154). However, the fungicidal activity of these compounds is, in particular at low application rates, not always sufficient.
Since the ecological and economic demands made on modern crop protection agents are increasing constantly, for example with respect to activity spectrum, toxicity, selectivity, application rate, formation of residues and favourable manufacture, and there can furthermore be problems, for example, with resistance, there is a constant need to develop novel crop protection agents, in particular fungicides which, at least in some areas, have advantages over the known fungicides.
Surprisingly, it has now been found that the present Thienylpyri(mi)dinylpyrazole solve at least in some aspects the problems mentioned above and are suitable for use as crop protection agents, in particular as fungicides. Some Arylazoles are already known as pharmaceutically active compounds (see for example WO 1998/52937, EP-A 1 553 096, WO 2004/29043, WO 1998/52940, WO 2000/31063, WO 1995/31451, WO 2002/57265 and WO 2000/39116), but not their surprising fungicidal activity.
The invention provides compounds of the formula (I),
Figure imgf000002_0001
(I) in which the symbols have the following meanings: X1 represents C-H or N,
R1 represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, C3-C8- allenyl, Cs-Cs-trialkylsilyl, C4-C8-cycloalkenyl, Ci-C6-alkoxy-Ci-C6-alkyl, acyloxy-Ci-C6-alkyl, heteroaryl-Ci-Ce-alkyl, aryl-Ci-Ce-alkyl, Ci-C6-alkylthio-Ci-C6-alkyl, Ci-C4-alkyl-C(0)-Ci-C6- alkyl, C3-C6-cycloalkyl-C(0)-Ci-C4-alkyl, heterocyclyl-C(0)-Ci-C4-alkyl, Ci-C4-alkyl-C(0)0- Ci-Ce-alkyl, C3-C6-cycloalkyl-C(0)0-Ci-C4-alkyl, heterocyclyl-C(0)0- Ci-C4-alkyl, heterocyclyl-Ci-C6-alkyl, C6-Cio-aryl, heterocyclyl, heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or represents H, C(0)NR17R18, C(0)R17, C(0)OR17, S(0)2R17 C(S)NR17R18, C(S)R17, S(0)2NR17R18,
R2 represents H, cyano, halogen or represents Ci-C6-alkyl, C3-C6-cycloalkyl, heterocyclyl, C2-C8-alkenyl, C2-C8-alkinyl, Ci-Cs-alkoxy, C2-C8-alkynyloxy, Ci-Cs-alkylthio, Cs-Cs-trialkylsilyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, amino, dimethylamino or methoxy,
R3 represents H, halogen, cyano, OR11, C(0)ORu, C(0)SRu, C(S)ORu, C(0)Ru, C(S)RU, SR11, NR9R10, C(0)NRuR20, C(S)NRUR20, N(R17)C(0)ORu, N=CH-NR17R18, NH-CH-NR17R18, N=CR17R18, N(Ci-C6-alkyl)-NHR17, N=C(H)OR17, N=C(OR17)R18, N=C(SR17)R18, C(=NR17)NR17R18, SO(=NR17)R18, S02NRuR2°, SO2R11 or represents Ci-C6-alkyl, Cs-Cs-cycloalkyl, C2-C6-alkenyl, C2-C8-alkynyl, C6-Ci4-aryl, C2-C9- heterocyclyl, C2-C9-heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16, excluded are compounds with R3 equals substituted NH -phenyl if X1 equals N,
R4 and R5 represents independently of each other H, F, CI, Br, I, cyano, nitro, OH, SH, or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C6-Ci4-aryl, C1-C4- alkoxy, 0-(C6-Ci4-aryl), S-(Ci-C4-alkyl), S(0)-(Ci-C6-alkyl), C(0)-(Ci-C6-alkyl), C3-C8- trialkylsilyl, heteroaryl, heterocyclyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or form together with the carbon atoms, which they are attached to, an optionally mono- or multi identical or different by halogen, oxygen, cyano or Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C6-haloalkyl, Ci-C4-haloalkoxy, C3-C6-cycloalkyl substituted cycle with 5 to 8 ring atoms, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R6 represents Ci-C6-alkyl, H, halogen or represents Ci-C6-alkyl, Cs-Cs-cycloalkyl, C2-C8-alkenyl, C2-C8-alkinyl, C(0)-Ci-C6-alkyl, Ci-Cs- alkoxy, Ci-Cs-alkylthio, Ci-Cs-halogenalkoxy, Ci-C6-alkylsulphenyl, Ci-C6-alkylthio, C3-C8- trialkylsilyl, C6-Cio-aryl, heteroaryl, heterocyclyl, C6-Cio-aryloxy, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16
R7 represents H, halogen, cyano, nitro, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C5-Cio-aryl, heteroaryl, heterocyclyl, or R6 and R7 together can form a 5- to 7-membered ring which can optionally be substituted with one or more substituents selected from: Ci-C i-alkyl, Ci-C i-halogenoalkyl, Ci-C i-alkoxy, C1-C4- halogenoalkoxy, halogen, hydroxyl, amino, cyano or nitro, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R8 represents H, halogen, cyano, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, Ce- Cio-aryl, heteroaryl, heterocyclyl,
R9 and R10represent H, C(S)R14, C(0)R14, SO2R14, C(0)OR14, OR14 oder C(0)NR14R15 or represents Ci-C6-alkyl , C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, Ci-C6-alkyl, 0-C(0)R17 , 0-P(0)(OR17)2, 0-B(OR17)2 or 0-(Ci-C4-alkyl),
R11 and R20 represent H, C(S)R12, C(0)R12, SO2R12, C(0)OR12, OR12 or C(0)NR12R13 or represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl, C6-Ci4-aryl, heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, Ci-C6-alkyl, 0-C(0)R17 , O- P(0)(OR17)2, 0-B(OR17)2 or 0-(Ci-C4-alkyl),
R12 and R13 represent H
or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl, Ce-Cw- aryl, heterocyclyl oder heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, Ci-C6-alkyl or Ci-C i-alkoxy, R14 and R15 represent H
or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Cs-cycloalkyl, Ce-Cw- aryl, benzyl, phenethyl, phenoxymethyl, heterocyclyl oder heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert- butyl, n-pentyl, cyclopropyl, or methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, methylsulfanyl, nitro, trifluormethyl, difluormethyl, C(0)R17, C(0)OR17, C(0)NR17R18, SO2R17, OC(0)R17,
R16 represents OH, F, CI, Br, I, cyano, NH-C(0)R17, NR17R18, C(0)R17, C(0)OR17, C(0)NR17R18,
Figure imgf000005_0001
or represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Cs-cycloalkyl, Ci-C4-alkoxy, C1-C4- alkylthio, 0-(C3-C8-cycloalkyl), S-(C3-C8-cycloalkyl), C6-Ci4-aryl, 0-(C6-Ci4-aryl), S-(C6-Ci4- aryl), heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, Ci-C6-alkyl or Ci-C4-alkoxy,
R17 and R18 represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, benzyl, aryl each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano or represents H,
R19 represents H, Ci-Ce-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C(S)R14, C(0)R14,
Figure imgf000005_0002
and also agrochemically active salts thereof.
The invention also provides the use of the compounds of the formula (I) as fungicides.
Thienylpyri(mi)dinylpyrazole of the formula (I) according to the invention and also their agrochemically active salts are highly suitable for controlling phytopathogenic harmful fungi and for the reduction of mycotoxins. The compounds according to the invention mentioned above have in particular strong fungicidal activity and can be used both in crop protection, in the domestic and hygiene field, in the protection of materials and for the reduction of mycotoxins in plants and parts of the plants.
The compounds of the formula (I) can be present both in pure form and as mixtures of various possible isomeric forms, in particular of stereoisomers, such as E and Z, threo and erythro, and also optical isomers, such as R and S isomers or atropisomers, and, if appropriate, also of tautomers. What is claimed are both the E and the Z isomers, and the threo and erythro, and also the optical isomers, mixtures of these isomers, and also the possible tautomeric forms.
Preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below: X1 represents C-H,
R1 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, -CH=CHCH3, -C≡CCH3, 3-methylbut-2-en-l-yl, but-2-en-l-yl, but-3-en-2-yl, prop-2-yn-l-yl, but-2-yn- 1 -yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1 -cyclopropylethyl, -CH=C=CH2, trimethylsilyl, tert- butyldimethylsilyl, cyclohexenyl 2-methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2- ethoxyethyl, tert-butoxy-methyl, cyanomethyl, 1 -cyanoethyl, 2-cyanoethyl, 1 -cyanopropan-2-yl, trifluormethyl, difluormethyl, 2-fluoroethyl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2- chloroethyl, (2,2-dichlorocyclopropyl)methyl, trifluoromethoxy, difluoromethoxy, 2- (trifluoromethoxy) ethyl, methylacetate, ethylacetate, pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, (l,3-thiazol-5-yl)methyl, (l,3-thiazol-4-yl)methyl, l,3-thiazol-3-yl)methyl,
(l,3-oxazol-5-yl)methyl, (l,3-oxa-4-yl)methyl, (l,3-oxa-3-yl)methyl, phenylmethyl, phenylethyl, methylthio, ethylthio, n-propylthio, iso-propylthio, tertbutylthio, n-butylthio, sec-butylthio, iso- butylthio, methylthioalkyl, phenyl, benzyl, naphthalenyl, oxiranyl, aziridinyl, 2- tetrahydrofuranyl, 3-tetrahydrofuranyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4-yl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl,
3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-iso- thiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5- oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
2- pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin- 3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl,
3- isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5- yl, 4-isothiazolin-5-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, l,3-dioxan-5-yl, 2-tetra- hydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydro-pyridazinyl, 4-hexahy- dropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2- piperazinyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, lH-pyrrol-l-yl, lH-pyrrol-2-yl, lH-pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5- yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol- 1-yl, pyrazol-3-yl, pyrazol-4-yl, imidazol-l -yl, imidazol-2-yl, imidazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, morpholine, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or represents H, C(0)NR17R18, C(0)R17, C(0)OR17, S(0)2R17 C(S)NR17R18, C(S)R17, S(0)2NR17R18, R2 represents H, cyano, Br, CI, F or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CH=CH2, -C≡CH, -C≡CCH3, -CH2C≡CH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, -0-CH2C≡CH, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, iso-propylsulfanyl, tertbutylsulfanyl, n-butylsulfanyl, sec- butylsulfanyl, iso-butylsulfanyl, trimethylsilyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, cyano, amino, dimethylamino or methoxy,
R3 represents H, F, CI, Br, cyano, OR11, C(0)ORu, C(0)Ru, NR9R10, C(0)NRuR20, N=C(OR17)R18, N=C(SR17)R18, SO(=NR17)R18, N(Ci-C6-alkyl)-NHR17 or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, -CH=CHCH3, -C≡CCH3, but-2-en-l-yl, but-3-en-2-yl, but-2-yn-l-yl, phenyl, benzyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16, R4, R5 represents independently of each other H, F, CI, Br, cyano, nitro, OH, SH or represents methyl, ethyl, cyclopropyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, phenyl, methoxy, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or form together with the carbon atoms, which they are attached to, an optionally mono- or multi identical or different by F, CI, Br, oxygen, cyano or alkyl, cycloalkyl, heterocyclyl, haloalkyl, alkoxy, aryl, hetaryl substituted cycle with 5 to 8 ring atoms, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R6 represents H, CI, F, Methyl, Ethyl, Cyano, difluoromethyl, trifluoromethyl, or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, methylthio, ethylthio, n- propylthio, iso-propylthio, tertbutylthio, n-butylthio, sec-butylthio, iso-butylthio, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16
R7 represents H, F, CI, Br, cyano, nitro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, -
CH2CH=CH2, -CH2C≡CH , -C≡CH or R6 and R7 together can form a 5- to 7-membered ring which can optionally be substituted with one or more substituents selected from: methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, F, CI, Br, hydroxyl, amino, cyano or nitro, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R8 represents H, F, CI, Br, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH2, -CH2CF CH2, - CH2C≡CH , -C≡CH,
R9 and R10represent H, C(S)R14, C(0)R14, SO2R14, C(0)OR14, OR14 oder C(0)NR14R15, R11 and R20 represent H, C(S)R12, C(0)R12, SO2R12, C(0)OR12, OR12 oder C(0)NR12R13 or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 0-C(0)Me, 0-C(0)Et, 0-P(0)(OMe)2, 0-B(OMe)2 , 0-B(OEt)2 oder , methoxy, ethoxy, n- propoxy, iso-propoxy, n-butoxy, tert-butoxy substituted methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, phenyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano,
R12 and R13 represent H
or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, phenyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl or methoxy, ethoxy, n-propoxy, iso- propoxy, n-butoxy, tert-butoxy, R14 and R15 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, - CH2CH=CH2, -CH2C≡CH, -C≡CH, phenyl, naphthalenyl, benzyl, phenethyl, phenoxymethyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, thienyl, thietanyl, oxetanyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, piperidinyl, indanyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, or methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, tert-butoxy, methylsulfanyl, nitro, trifluormethyl, difluormethyl, acetyl, methoxycarbonyl, ethoxycarbonyl represents hydrogen, represents OH, F, CI, Br, I, cyano, NH-C(0)R17, NR17R18, C(0)R17, C(0)OR17, C(0)NR17R18, S02R17 represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, phenyl, methoxy, ethoxy, tetrahydrofuranyl, 3 -tetrahydrofuranyl, 2-pyrrolidinyl, 3 -pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-iso- thiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5- oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl,
2- pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-
3- yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-Isoxazolin-4-yl, 4-Isoxazolin-4-yl, 2-Isoxazolin-5-yl, 3-Isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl,
2- isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5- yl, 4-isothiazolin-5-yl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl, 2-piperazinyl, furan-2-yl, furan-
3- yl, thiophen-2-yl, thiophen-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, lH-pyrrol-l-yl, lH-pyrrol-2-yl, lH-pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-l-yl, pyrazol-3-yl, pyrazol-4- yl, Imidazol-l-yl, Imidazol-2-yl, Imidazol-4-yl, Pyridin-2-yl, Pyridin-3-yl, pyridin-4-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, methoxy, und R18 represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, -CH2CH=CH2, -CH2C≡CH , -C≡CH, benzyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano represents H, represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=C]¾ -CH2CH=CH2, -CH2C≡CH , - C≡CH, C(S)R14, C(0)R14, SO2R14, C(0)OR14 and also agrochemically active salts thereof.
Particular preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below:
X1 represents CH,
R1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, allyl, 3-methylbut-2-en-l-yl, prop-2-yn-l-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-2-yl, tetrahydrofuran-3-yl, oxetan-3-yl, thietan-3-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4- yl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-fluoroethyl, 2-
(trifluoromethoxy) ethyl, cyanomethyl, 1 -cyanoethyl, 2-cyanoethyl, 1 -cyanopropan-2-yl, 2- methoxyethyl, 2-ethoxyethyl, 2-(methylsulfanyl)ethyl, cyclopropylmethyl, 1 -cyclopropylethyl, (2,2-dichlorocyclopropyl)methyl, 2-fluorobenzyl, l-(2-fluorophenyl)ethyl, 3-cyanobenzyl,
R2 represents H, Methyl, Ethyl, n-propyl, methoxy, ethoxy, methylsulfanyl, methoxymethyl, difluoromethyl, 2-hydroxypropan-2-yl, hydroxymethyl, 2-hydroxyethyl, 2-cyanoethyl,
R3 represents H, amino, formamido, acetylamino, n-propionylamino, isobutyrylamino, (2- methylbutanoyl)amino, (3-methylbutanoyl)amino, (3,3-dimethylbutanoyl)amino,
(methoxyacetyl)amino, [(2-methoxyethoxy)acetyl] amino, (3,3,3-trifluoropropanoyl)amino, (cyanoacetyl)amino, (lactoylamino), (2-hydroxy-2-methylpropanoyl)amino, [(methylsulfanyl)acetyl] amino, [2-(4-chlorophenoxy)propanoyl] amino, (phenylacetyl)amino, (3- phenylpropanoyl)amino, [3-(4-chlorophenyl)propanoyl]amino, [2-(4- fluorophenyl)propanoyl] amino, [2-(2-fluorophenyl)propanoyl]amino, (cyclopentylacetyl)amino, (cyclopropylacetyl)amino, (cyclopropylcarbonyl)amino, [(2-methylcyclopropyl)carbonyl] amino, [(l-chlorocyclopropyl)carbonyl] amino, (cyclobutylcarbonyl)amino, (2,3-dihydro-lH-inden-2- ylcarbonyl)amino, [(2-phenylcyclopropyl)carbonyl]amino, methacryloylamino, (3-methylbut-2- enoyl)amino, (4-methylpent-3-enoyl)amino, (benzoylamino), (4-fluorobenzoyl)amino, (3- thienylcarbonyl)amino, (2-thienylcarbonyl)amino, (tetrahydrofuran-2-ylcarbonyl)amino, (tetrahydrofuran-3-ylcarbonyl)amino, (tetrahydro-2H-pyran-4-ylcarbonyl)amino, (methoxycarbonyl)amino, (ethoxycarbonyl)amino, (isopropoxycarbonyl)amino, (tert- butoxycarbonyl)amino, diacetylamino, dipropionylamino, diisobutyrylamino, bis(methoxyacetyl)amino, bis(3 -methy lb utanoyl) amino, bis(cyclopropylcarbonyl)amino, bis(cyclopropylcarbonyl)amino, acetyl(isobutyryl)amino, butyryl(cyclopropylcarbonyl)amino, (cyclopropylcarbonyl)(propionyl)amino, (cyclopropylcarbonyl)(methoxyacetyl)amino, (cyclopropylcarbonyl)(3-methylbutanoyl)amino, (cyclopropylcarbonyl)(pentanoyl)amino, i s ob utyry l(pr o ionyl) amino , (cy c 1 opr opy lc arb onyl) (me thoxycarb onyl) amino , (cyclopropylcarbonyl)(ethoxycarbonyl)amino, [(E)-(dimethylamino)methylene]amino, methylcarbamoyl, (ethylcarbamoyl)amino,
R4, R5 represents H, F, CI or form together with the carbon atoms to which they are bound, an optionally mono- or multi identical or different by F, CI, Br, oxygen, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluormethyl, difluormethyl, trifluormethoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl substituted cycle, wherein they together stand for -(CH=CH-N(R19), -(CH=CH-CH=N)-, -(NH- CH=N)- or -(CH2-C(0)-N(R19), R6 H, CI, F, Methyl, Ethyl, Cyano, difluoromethyl, trifluoromethyl,
R7 represents H, F, CI, Methyl,
R8 represents H, CI
R19 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n- pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH2, -CH2CF CH2, -CH2C≡CH , - C≡CH, acetyl, n-propionyl, isobutyryl, 2-methylbutanoyl, 3-methylbutanoyl, 3,3- dimethylbutanoyl, cyclopropylcarbonyl and also agrochemically active salts thereof.
Very particular preference is given to compounds of the formula (I) in which one or more of the symbols have one of the meanings below: X1 represents CH,
R1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, cyclopropyl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-cyanoethyl, 1 -cyanopropan-2-yl, 2-methoxyethyl, 2- ethoxyethyl, cyclopropylmethyl,
R2 represents H, methyl, R3 represents H, acetylamino, n-propionylamino, isobutyrylamino, (2-methylbutanoyl)amino, (3- methylbutanoyl)amino, (methoxyacetyl)amino, (lactoylamino), (2-hydroxy-2- methylpropanoyl)amino, (phenyl acetyl) amino , ( cy c 1 opr opy lac etyl) amino ,
(cyclopropylcarbonyl)amino, [(2-methylcyclopropyl)carbonyl]amino, (cyclobutylcarbonyl)amino, methacryloylamino, (3-methylbut-2-enoyl)amino, (benzoylamino), (3-thienylcarbonyl)amino, (2-thienylcarbonyl)amino, R4 represents H, R5 represents H, F, R6 represents H, F, CI, methyl, R7 represents H, R8 represents H and also agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which X1 represents CH, where the other substituents have one or more of the meanings mentioned above and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, cyclopropyl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-cyanoethyl, 1 -cyanopropan-2-yl, 2-methoxyethyl, 2- ethoxyethyl, cyclopropylmethyl where the other substituents have one or more of the meanings mentioned above, and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which R2 represents H, Methyl where the other substituents have one or more of the meanings mentioned above, and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R3 represents H, acetylamino, n-propionylamino, isobutyrylamino, (2-methylbutanoyl)amino, (3- methylbutanoyl)amino, (methoxyacetyl)amino, (lactoylamino), (2-hydroxy-2- methylp ro p an o yl) amin o , (phenyl ac etyl) amin o , ( cyc l op ro py l ac ety l) amino , (cyclopropylcarbonyl)amino, [(2-methylcyclopropyl)carbonyl] amino, (cyclobutylcarbonyl)amino, methacryloylamino, (3-methylbut-2-enoyl)amino, (benzoylamino), (3 -thienylcarbonyl)amino, (2-thienylcarbonyl)amino
where the other substituents have one or more of the meanings mentioned above,
and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R4 represents H,
where the other substituents have one or more of the meanings mentioned above,
and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R5 represents H, F
where the other substituents have one or more of the meanings mentioned above,
and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R6 represents H, F, CI, Methyl
where the other substituents have one or more of the meanings mentioned above,
and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R7 represents H,
where the other substituents have one or more of the meanings mentioned above,
and to the agrochemically active salts thereof.
Very particular preference is furthermore given to compounds of the formula (I) in which
R8 represents H,
where the other substituents have one or more of the meanings mentioned above, and to the agrochemically active salts thereof.
The radical definitions given above can be combined with one another as desired. Moreover, individual definitions may not apply.
Depending on the nature of the substituents defined above, the compounds of the formula (I) have acidic or basic properties and can form salts, if appropriate also inner salts, or adducts with inorganic or organic acids or with bases or with metal ions. If the compounds of the formula (I) carry amino, alkylamino or other groups which induce basic properties, these compounds can be reacted with acids to give salts, or they are directly obtained as salts in the synthesis. If the compounds of the formula (I) carries hydroxyl, carboxyl or other groups which induce acidic properties, these compounds can be reacted with bases to give salts. Suitable bases are, for example, hydroxides, carbonates, bicarbonates of the alkali metals and alkaline earth metals, in particular those of sodium, potassium, magnesium and calcium, furthermore ammonia, primary, secondary and tertiary amines having (Ci-C i)-alkyl groups, mono-, di- and trialkanolamines of (Ci-C i)-alkanols, choline and also chlorocholine.
The salts obtainable in this manner also have fungicidal properties. Examples of inorganic acids are hydrohalic acids, such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide, sulphuric acid, phosphoric acid and nitric acid, and acidic salts, such as NaHS04 and KHSO4. Suitable organic acids are, for example, formic acid, carbonic acid and alkanoic acids, such as acetic acid, trifluoroacetic acid, trichloroacetic acid and propionic acid, and also glycolic acid, thiocyanic acid, lactic acid, succinic acid, citric acid, benzoic acid, cinnamic acid, oxalic acid, alkylsulphonic acids (sulphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylsulphonic acids or aryldisulphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two sulphonic acid groups), alkylphosphonic acids (phosphonic acids having straight-chain or branched alkyl radicals of 1 to 20 carbon atoms), arylphosphonic acids or aryldiphosphonic acids (aromatic radicals, such as phenyl and naphthyl, which carry one or two phosphonic acid radicals), where the alkyl and aryl radicals may carry further substituents, for example p-toluenesulphonic acid, salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, etc.
Suitable metal ions are in particular the ions of the elements of the second main group, in particular calcium and magnesium, of the third and fourth main group, in particular aluminium, tin and lead, and also of the first to eighth transition group, in particular chromium, manganese, iron, cobalt, nickel, copper, zinc and others. Particular preference is given to the metal ions of the elements of the fourth period. Here, the metals can be present in various valencies that they can assume.
Optionally substituted groups may be mono- or polysubstituted, where in the case of polysubstitution the substituents may be identical or different. In the definitions of the symbols given in the formulae above, collective terms were used which are generally representative for the following substituents: halogen: fluorine, chlorine, bromine and iodine; aryl: an unsubstituted or optionally substituted 6- to 14-membered partially or fully unsaturated mono-, bi- or tricyclic ring system having up to 3 ring members selected from the groups C(=0), (C=S), where at least one of the rings of the ring system is fully unsaturated, such as, for example (but not limited thereto) benzene, naphthalene, tetrahydronaphthalene, anthracene, indane, phenanthrene, azulene; alkyl: saturated, straight-chain or branched hydrocarbon radicals having 1 to 8 carbon atoms, for example (but not limited thereto) Ci-C6-alkyl, such as methyl, ethyl, propyl, 1 -methylethyl, butyl, 1- methylpropyl, 2-methylpropyl, 1 , 1 -dimethylethyl, pentyl, 1 -methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1 , 1 -dimethylpropyl, 1 ,2-dimethylpropyl, 1 -methylpentyl, 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 1 , 1 -dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2- trimethylpropyl, 1 ,2,2-trimethylpropyl, 1 - ethyl- 1 -methylpropyl and 1-ethy 1-2 -methylpropyl; alkenyl: unsaturated, straight-chain or branched hydrocarbon radicals having 2 to 8 carbon atoms and a double bond in any position, for example (but not limited thereto) C2-C6-alkenyl, such as ethenyl, 1- propenyl, 2-propenyl, 1 -methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1 -prop enyl, 2-methyl- 1-propenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1-butenyl, 2-methyl- 1-butenyl, 3 -methyl- 1 -butenyl, 1 -methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl, 1 , 1 -dimethyl-2- propenyl, 1,2-dimethyl-l-propenyl, 1 ,2-dimethyl-2-propenyl, 1- ethyl- 1 -prop enyl, l-ethyl-2-propenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1-pentenyl, 2-methyl- 1-pentenyl, 3- methyl- 1-pentenyl, 4-methyl- 1-pentenyl, 1 -methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2- pentenyl, 4-methyl-2-pentenyl, l-methyl-3-pentenyl, 2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4- methyl-3-pentenyl, l-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4- pentenyl, l,l-dimethyl-2-butenyl, l,l-dimethyl-3-butenyl, 1 ,2-dimethyl- 1-butenyl, l,2-dimethyl-2- butenyl, l,2-dimethyl-3-butenyl, 1,3-dimethyl-l -butenyl, l,3-dimethyl-2-butenyl, l,3-dimethyl-3- butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-l -butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3- butenyl, 3, 3 -dimethyl- 1-butenyl, 3,3-dimethyl-2-butenyl, 1- ethyl- 1 -butenyl, l-ethyl-2-butenyl, 1-ethyl- 3-butenyl, 2-ethyl- 1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, l,l,2-trimethyl-2-propenyl, 1-ethyl- l-methyl-2-propenyl, l-ethyl-2-methyl-l -propenyl and l-ethyl-2-methyl-2-propenyl; alkynyl: straight-chain or branched hydrocarbon groups having 2 to 8 carbon atoms and a triple bond in any position, for example (but not limited thereto) C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2- propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 -methyl-2-propynyl, 1 -pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, l-methyl-2-butynyl, l-methyl-3-butynyl, 2-methyl-3-butynyl, 3 -methyl- 1-butynyl, 1,1- dimethyl-2-propynyl, l-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1- methyl-2-pentynyl, l-methyl-3-pentynyl, 1 -methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4- pentynyl, 3 -methyl- 1 -pentynyl, 3 -methy 1-4 -pentynyl, 4-methyl-l -pentynyl, 4-methyl-2-pentynyl, 1,1- dimethyl-2-butynyl, l,l-dimethyl-3-butynyl, l,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 3,3- dimethyl- 1-butynyl, l-ethyl-2-butynyl, l-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1 -ethyl- l-methyl-2- propynyl; alkoxy: saturated, straight-chain or branched alkoxy radicals having 1 to 8 carbon atoms, for example (but not limited thereto) Ci-C6-alkoxy, such as methoxy, ethoxy, propoxy, 1 -methylethoxy, butoxy, 1- methylpropoxy, 2-methylpropoxy, 1 , 1 -dimethylethoxy, pentoxy, 1 -methylbutoxy, 2-methylbutoxy, 3- methylbutoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, hexoxy, 1,1-dimethylpropoxy, 1 ,2-dimethyl- propoxy, 1 -methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy, 1 , 1 -dimethylbutoxy, 1 ,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy, 1 ,2,2-trimethylpropoxy, 1 -ethyl- 1 -methylpropoxy and l-ethyl-2-methylpropoxy; alkylthio: saturated, straight-chain or branched alkylthio radicals having 1 to 8 carbon atoms, for example (but not limited thereto) Ci-C6-alkylthio, such as methylthio, ethylthio, propylthio, 1- methylethylthio, butylthio, 1 -methylpropylthio, 2-methylpropylthio, 1 , 1 -dimethylethylthio, pentylthio, 1 -methylbutylthio, 2-methylbutylthio, 3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, 1 , 1 -dimethylpropylthio, 1 ,2-dimethylpropylthio, 1-methylpentylthio, 2-methylpentylthio, 3- methylpentylthio, 4-methylpentylthio, 1 , 1 -dimethylbutylthio, 1 ,2-dimethylbutylthio, 1,3- dimethylbutylthio, 2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio, 1- ethylbutylthio, 2-ethylbutylthio, 1 , 1 ,2-trimethylpropylthio, 1 ,2,2-trimethylpropylthio, 1 -ethyl- 1- methylpropylthio and l-ethyl-2-methylpropylthio; alkoxycarbonyl: an alkoxy group having 1 to 6 carbon atoms (as mentioned above) which is attached to the skeleton via a carbonyl group (-CO-); alkylsulphinyl: saturated, straight-chain or branched alkylsulphinyl radicals having 1 to 8 carbon atoms, for example (but not limited thereto) Ci-C6-alkylsulphinyl, such as methylsulphinyl, ethylsulphinyl, propylsulphinyl, 1 -methylethylsulphinyl, butylsulphinyl, 1 -methylpropylsulphinyl, 2- methylpropylsulphinyl, 1 , 1 -dimethylethylsulphinyl, pentylsulphinyl, 1 -methylbutylsulphinyl, 2- methylbutylsulphinyl, 3 -methylbutylsulphinyl, 2,2-dimethylpropylsulphinyl, 1 -ethylpropylsulphinyl, hexylsulphinyl, 1 , 1 -dimethylpropylsulphinyl, 1 ,2-dimethylpropylsulphinyl, 1 -methylpentylsulphinyl, 2- methylpentyl sulphinyl, 3 -methylpentylsulphinyl, 4-methylpentylsulphinyl, 1 , 1 -dimethylbutylsulphinyl, 1 ,2-dimethylbutylsulphinyl, 1 ,3 -dimethylbutylsulphinyl, 2,2-dimethylbutylsulphinyl, 2,3-dimethyl- butylsulphinyl, 3,3-dimethylbutylsulphinyl, 1-ethylbutylsulphinyl, 2-ethylbutylsulphinyl, 1,1,2- trimethylpropylsulphinyl, 1 ,2,2-trimethylpropylsulphinyl, 1 -ethyl- 1 -methylpropylsulphinyl and 1 -ethyl- 2-methylpropylsulphinyl; alkylsulphonyl: saturated, straight-chain or branched alkylsulphonyl radicals having 1 to 8 carbon atoms, for example (but not limited thereto) Ci-C6-alkylsulphonyl, such as methylsulphonyl, ethylsulphonyl, propylsulphonyl, 1 -methylethylsulphonyl, butylsulphonyl, 1 -methylpropylsulphonyl, 2- methylpropylsulphonyl, 1 , 1 -dimethylethylsulphonyl, pentylsulphonyl, 1 -methylbutylsulphonyl, 2- methylbutylsulphonyl, 3-methylbutylsulphonyl, 2,2-dimethylpropylsulphonyl, 1 -ethylpropylsulphonyl, hexylsulphonyl, 1 , 1 -dimethylpropylsulphonyl, 1 ,2-dimethylpropylsulphonyl, 1 -methylpentylsulphonyl, 2-methylpentylsulphonyl, 3 -methylpentylsulphonyl, 4-methylpentylsulphonyl, 1 , 1 -dimethyl- butylsulphonyl, 1 ,2-dimethylbutylsulphonyl, 1 ,3-dimethylbutylsulphonyl, 2,2-dimethylbutylsulphonyl, 2,3-dimethylbutylsulphonyl, 3,3-dimethylbutylsulphonyl, 1 -ethylbutylsulphonyl, 2-ethylbutylsulphonyl, 1 , 1 ,2-trimethylpropylsulphonyl, 1 ,2,2-trimethylpropylsulphonyl, 1 -ethyl- 1 -methylpropylsulphonyl and l -ethyl-2-methylpropylsulphonyl; cycloalkyl: monocyclic, saturated hydrocarbon groups having 3 to 10 carbon ring members, for example (but not limited thereto) cyclopropyl, cyclopentyl and cyclohexyl; aloalkyl: straight-chain or branched alkyl groups having 1 to 8 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) Ci-C3-haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1 -chloroethyl, 1 -bromoethyl, 1 -fluoro- ethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-di- fluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and l , l , l -trifluoroprop-2- yi; haloalkoxy: straight-chain or branched alkoxy groups having 1 to 8 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) Ci-C3-haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichloro fluoromethoxy, chlorodifluoromethoxy, 1 - chloroethoxy, 1 -bromoethoxy, 1 -fluoroethoxy, 2-fluoroethoxy, 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, pentafluoroethoxy and l , l , l -trifluoroprop-2-oxy; haloalkylthio: straight-chain or branched alkylthio groups having 1 to 8 carbon atoms (as mentioned above), where in these groups some or all of the hydrogen atoms may be replaced by halogen atoms as mentioned above, for example (but not limited thereto) Ci-C3-haloalkylthio, such as chloromethylthio, bromomethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio, dichloro fluoromethylthio, chlorodifluoromethylthio, 1 - chloroethylthio, 1 -bromoethylthio, 1 -fluoroethylthio, 2-fluoroethylthio, 2,2-difluoroethylthio, 2,2,2- trifluoroethylthio, 2-chloro-2-fluoroethylthio, 2-chloro-2,2-difluoroethylthio, 2,2-dichloro-2- fluoroethylthio, 2,2,2-trichloroethylthio, pentafluoroethylthio and 1 , 1 , 1 -trifluoroprop-2-ylthio; heteroaryl: a 5 or 6-membered completely unsaturated monocyclic ring system which contains one to four heteroatoms from the group consisting of oxygen, nitrogen and sulphur; if the ring contains a plurality of oxygen atoms, these are not directly adjacent;
5-membered heteroaryl which contains one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms or one to three nitrogen atoms and one sulphur or oxygen atom as ring members, for example (but not limited thereto) 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 3- pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-imidazolyl, 4-imidazolyl, l,2,4-oxadiazol-3-yl, l,2,4-oxadiazol-5-yl, l,2,4-thiadiazol-3-yl, l,2,4-thiadiazol-5-yl, l,2,4-triazol-3-yl, l,3,4-oxadiazol-2-yl, l,3,4-thiadiazol-2-yl and l,3,4-triazol-2-yl;
5- membered heteroaryl which is attached via nitrogen and contains one to four nitrogen atoms, or benzo-fused 5-membered heteroaryl which is attached via nitrogen and contains one to three nitrogen atoms: 5-membered heteroaryl groups which, in addition to carbon atoms, may contain one to four nitrogen atoms and one to three nitrogen atoms, respectively, as ring members and in which two adjacent carbon ring members or a nitrogen and an adjacent carbon ring member may be bridged by a buta-l,3-dien-l,4-diyl group in which one or two carbon atoms may be replaced by nitrogen atoms, where these rings are attached to the skeleton via one of the nitrogen ring members, for example (but not limited thereto) 1-pyrrolyl, 1-pyrazolyl, 1,2,4-triazol-l -yl, 1 -imidazolyl, 1,2,3-triazol-l -yl, 1,3,4-triazol- 1-yl;
6- membered heteroaryl which contains one to four nitrogen atoms: 6-membered heteroaryl groups which, in addition to carbon atoms, may contain one to three or one to four nitrogen atoms as ring members, for example (but not limited thereto) 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4- pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, l,3,5-triazin-2-yl, l,2,4-triazin-3- yl and l,2,4,5-tetrazin-3-yl; benzo-fused 5-membered heteroaryl which contains one to three nitrogen atoms or one nitrogen atom and one oxygen or sulphur atom: for example (but not limited thereto) lH-indol-l -yl, lH-indol- 2-yl, lH-indol-3-yl, lH-indol-4-yl, lH-indol-5-yl, lH-indol-6-yl, lH-indol-7-yl, IH-benzimidazol-l-yl, lH-benzimidazol-2-yl, lH-benzimidazol-4-yl, benzimidazol-5-yl, lH-indazol-l-yl, lH-indazol-3-yl, lH-indazol-4-yl, lH-indazol-5-yl, lH-indazol-6-yl, lH-indazol-7-yl, 2H-indazol-2-yl, 1 -benzofuran-2- yl, l-benzofuran-3-yl, l-benzofuran-4-yl, l-benzofuran-5-yl, l-benzofuran-6-yl, l-benzofuran-7-yl, 1- benzothiophen-2-yl, l-benzothiophen-3-yl, l-benzothiophen-4-yl, l-benzothiophen-5-yl, 1- benzothiophen-6-yl, 1 -benzothiophen-7-yl, l,3-benzothiazol-2-yl and l,3-benzoxazol-2-yl, benzo-fused 6-membered heteroaryl which contains one to three nitrogen atoms: for example (but not limited thereto) quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7- yl, quinolin-8-yl, isoquinolin-l-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl, and isoquinolin-8-yl; heterocyclyl: a three- to fifteen-member ed saturated or partially unsaturated heterocycle which contains one to four heteroatoms from the group consisting of oxygen, nitrogen and sulphur: mono-, bi- or tricyclic heterocycles which contain, in addition to carbon ring members, one to three nitrogen atoms and/or one oxygen or sulphur atom or one or two oxygen and/or sulphur atoms; if the ring contains a plurality of oxygen atoms, these are not directly adjacent; such as, for example (but not limited thereto), oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4- isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4- oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4- imidazolidinyl, l,2,4-oxadiazolidin-3-yl, l,2,4-oxadiazolidin-5-yl, l,2,4-thiadiazolidin-3-yl, 1,2,4- thiadiazolidin-5-yl, l,2,4-triazolidin-3-yl, l,3,4-oxadiazolidin-2-yl, l,3,4-thiadiazolidin-2-yl, 1,3,4- triazolidin-2-yl, 2,3-dihydrofur-2-yl, 2,3-dihydrofur-3-yl, 2,4-dihydrofur-2-yl, 2,4-dihydrofur-3-yl, 2,3- dihydrothien-2-yl, 2,3-dihydrothien-3-yl, 2,4-dihydrothien-2-yl, 2,4-dihydrothien-3-yl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4- isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-iso- thiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2,3-di- hydropyrazol-l-yl, 2,3-dihydropyrazol-2-yl, 2,3-dihydropyrazol-3-yl, 2,3-dihydropyrazol-4-yl, 2,3- dihydropyrazol-5-yl, 3,4-dihydropyrazol-l-yl, 3,4-dihydropyrazol-3-yl, 3,4-dihydropyrazol-4-yl, 3,4- dihydropyrazol-5-yl, 4,5-dihydroopyrazol-l-yl, 4,5-dihydropyrazol-3-yl, 4,5-dihydropyrazol-4-yl, 4,5- dihydropyrazol-5-yl, 2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-3-yl, 2,3-dihydrooxazol-4-yl, 2,3-di- hydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 3,4- dihydrooxazol-5-yl, 3,4-dihydrooxazol-2-yl, 3,4-dihydrooxazol-3-yl, 3,4-dihydrooxazol-4-yl, 2- piperidinyl, 3-piperidinyl, 4-piperidinyl, l,3-dioxan-5-yl, 2-tetrahydropyranyl, 4-tetrahydropyranyl, 2- tetrahydrothienyl, 3-hexahydropyridazinyl, 4-hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4- hexahydropyrimidinyl, 5-hexahydropyrimidinyl, 2-piperazinyl, l,3,5-hexahydrotriazin-2-yl and 1,2,4- hexahydrotriazin-3-yl; Not included are combinations which contradict natural laws and which the person skilled in the art would therefore have excluded based on his expert knowledge. Excluded are, for example, ring structures having three or more adjacent oxygen atoms.
The present invention furthermore relates to a process for preparing thienylpyri(mi)dinylpyrazole of the formula [I] according to the invention.
Explanation of the Processes and Intermediates
The Thienylpyri(mi)dinylpyrazole according to the invention of the formula [I] can be prepared in different ways. Below, the possible processes are firstly shown schematically and then described in detail. Unless otherwise indicated, the residues stated have the meanings given below the schemes. The Thienylpyri(mi)dinylpyrazole according to the invention of the formula [I] can be produced by process A according to the following scheme.
Scheme
Figure imgf000021_0001
Met'= e.g. -Sn(Bu)3, -B(OR*)2
Met2= e.g. -B(OR*)2
B(OR*)2= e.g. -B(OiPr)2, -B(OH)2, -B(pinacolato)
Zl= e.g. CI, Br, I, -OTos, -OMs, -OH
Z2= e.g. CI, Br
Z = e.g. CI, -OH
A7 = R15, -OR15
R a= e.g. -NH-C(S)R15, -NH-C(0)R15, -NH C(0)OR15, -NH-C(0)NR15R16,
PG = e.g. tetrahydro-2H-pyran-2-yl, 2-(trimethylsilyl)ethoxy]methyl
In addition, the intermediates of the formula [VI] and [VII] can be prepared by process B (Scheme 2)
Scheme 2
Figure imgf000022_0001
[XV]
Z4= e.g. CH3, OAlkyl
Z5= e.g. NMe2, OH, OAlkyl Z6= e.g. CI, Br, I
In addition, the thienylpyri(mi)dinylpyrazole according to the invention of the formula [I-b] can also be prepared by process C (Scheme 3)
Figure imgf000023_0001
Met3 = e.g. Sn(n-Bu)3
In addition, the intermediates of the formula [VII] can be produced by process D (Scheme 4)
Figure imgf000023_0002
[XXI] [XXII] [Vll-a]
Compounds of the formula [III]
Figure imgf000024_0001
[III]
wherein the symbols R1 , R2 , R4 , R5 , R6 , R7, R8and X1 have the aforesaid general, preferred, particularly preferred, quite particularly preferred, most preferred or especially preferred meanings, and salts thereof, are novel.
For example the compounds of the type [III] listed in the following table are novel:
Figure imgf000024_0003
wherein
X1 stands for = C-H and
R4, R5 for H
Compounds of the formula [IV]
Figure imgf000024_0002
[IV]
wherein the symbols R1 , R2 , R6 , R7 and R8 have the aforesaid general, preferred, particularly preferred and very particularly preferred meanings, and salts thereof, are novel. For example the compounds of the type [IV] listed in the following table are novel:
Figure imgf000025_0001
1 In the determination of the logP values, the methods described below were used.
2 The mass stated is the peak of the isotope pattern of the [M+H]+ ion with the highest intensity; if the [M-H]" ion was detected, the mass value is marked with a 2.
The production of the compounds with the general formula [I] by process A can be effected as follows:
A compound with the general formula [VII] is halogenated and a compound of the formula [V] is obtained. This is converted to a compound of the type [IV] by reaction with substrates of the type [VIII], whereby mixtures of pyrazole regioisomers can be formed. These can be separated into the individual regioisomers by common processes e.g. chromatographic processes. Alternatively, a compound with the general formula [VII] is converted into a compound of the type [VI] by reaction with substrates of the type [VIII], whereby mixtures of pyrazole regioisomers can be formed. Compounds of the formula [VI] can be halogenated whereas compounds of the type [IV] are obtained. The compounds of the general formula [IV] can be reacted with substrates of the formula [IX-a] in a C-C coupling, whereby compounds of the formula [I] are obtained (Scheme 1).
Alternatively, the pyrazole compounds of the general formula [IV] can be converted into compounds of the type [III] by reaction with a boronic acid ester. These can be converted into compounds of the formula [I] by reaction with a substrate of the formula [X-a] in a C-C coupling reaction (Scheme 1).
Alternatively, compounds of the type [IV] can be converted into compounds of the formula [II] by reaction with a substrate of the formula [IX-b] in a C-C coupling reaction and subsequent deprotection. These compounds are likewise converted into the compounds of the type [I-a] by reaction with substrates of the formula [XI].
Furthermore, compounds of the type [III] can be converted into compounds of the formula [II] by reaction with a substrate of the formula [X-b] in a C-C coupling reaction and subsequent deprotection (Scheme 1).
The synthesis of the intermediates with the general formula [VI] by process B can be effected as follows:
Compounds of the general formula [XII] and converted into structures of the formula [XIII] by known methods. The 1,3-diketo compounds or enamides of the structure [XIII] can be converted with hydrazine into structures of the formula [VII]. Alternatively, structures of the formula [XIII] can be converted into compounds of the formula [VI], whereas mixture of the pyrazole isomers can be obtained, depending on the nature of R^scheme 2).
Furthermore, structures of the general formula [VI] can be obtained from alkynes of the general formula [XVI] by reaction with hydrazines. The Intermediates of the general formula [XVI] can be formed by transition metal catalysed coupling of Acyl halides of the general formula [XIV] or by reaction of compounds of the general formula [XV] in the presence of carbon monoxide (scheme 2).
The production of the compounds with the general formula [I-b] by process C can be effected as follows:
A compound with the general formula [XVII] can be reacted with a substrate of the formula [XVIII] in a C-C coupling reaction, whereby a compound with the formula [XIX] is formed. Next this compound is deprotected, whereby a compound of the general formula [XX] is obtained. The pyrazole of the formula [XX] obtained is now reacted with substrates of the type [VIII], whereby the thienylpyri(mi)dinylpyrazole according to the invention of the formula [I-b] are obtained (Scheme 3).
The synthesis of the intermediates with the general formula [VII] by process D can be effected as follows:
A compound with the general formula [XXI] can be converted to a Weinreb amide with the formula [XXII]. This compounds is reacted with an acetylene in the presence of a strong base followed by treatment with hydrazine, whereby a pyrazole of the general formula [Vll-a] is obtained (Scheme 4).
Step (VI) One possibility for the synthesis of compounds of the formula [VI] is shown in Scheme 1.
Compounds of the formula [VI], wherein R1 does not stand for hydrogen, can be synthesized analogously to procedures described in the literature (Bioorg. Med. Chem. Lett. 2000, 10, 1351-1356 or J. Am. Chem. Soc. 2007, 129, 26, 8064-8065), by reaction of compounds of the type [VII] with a substrate of the general formula [VIII] (wherein Z1 represents a leaving group, such as for example CI, Br, I, -OTos, -OMs or the like), if necessary in the presence of a solvent and an acid scavenger/base.
Compounds of the formula [VI], wherein R1 does not stand for hydrogen, can moreover be synthesized analogously to procedures described in the literature (Mitsunobu, O. Synthesis 1981, 1- 28), e.g. by reaction of compounds of the type [VII] with a substrate of the general formula [VIII] (wherein Z1 stands for -OH) in the presence of a phosphane (e.g. triphenylphosphane) and an azodicarboxylate (e.g. diethyl azodicarboxylate) and a solvent (e.g. THF).
Likewise, these synthesis methods can also be used for the conversion of the halogenated pyrazoles of the formula [V] into compounds of the formula [IV].
Compounds of the type [VII], can be produced e.g. by known literature methods {Tetrahedron, 2003, 59, 555-560) from commercial acetophenones by reaction with dimethylformamide dimethyl acetal and hydrazine.
The compounds of the formula [VIII] required for the reaction are commercially available or can be produced by literature methods (R. C. Larock, Comprehensive Organic Transformations, 2nd Edition, 1999, Wiley- VCH, p. 690 ff. and p. 1929 ff. and literature cited therein) One method for the production of suitable compounds of the formula [VIII] (wherein R1 in the case of an alkylation reaction e.g. stands for a substituted or unsubstituted alkyl or cycloalkyl residue), is for example the reaction of alcohols with methanesulphonyl chloride and triethylamine (Org. Lett. 2008, 10, 4425-4428) or by Appel reaction with triphenylphosphine and CC (e.g. described in Tetrahedron 2008, 64, 7247-7251). The production of suitable compounds of the formula [VIII] (wherein in R1 in the case of an acylation reaction a carbonyl group is directly bound to Z1), is effected by known literature methods (e.g. Jerry March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, p. 437 ff. and the literature cited therein).
Depending on the chemical structure of the substrates of the general formula [VIII], certain preferred combinations in the selection of a suitable solvent and a suitable base can be found. In the case of an alkylation reaction with substrates of the formula [VIII] (wherein R1 in the case of an alkylation reaction e.g. stands for a substituted or unsubstituted alkyl or cycloalkyl residue) all usual solvents inert under the reaction conditions, such as for example cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile), carboxylic acid esters (e.g. ethyl acetate), amides (e.g. Ν,Ν-dimethylformamide, N,N-dimethylacetamide), dimethyl sulphoxide or l,3-dimethyl-2-imidazolinone, can be used or the reaction can be effected in mixtures of two or more of these solvents. The preferred solvents are dimethylformamide and acetonitrile. In the case of an alkylation reaction with substrates of the formula [VIII] (wherein R1 in the case of an alkylation reaction e.g. stands for a substituted or unsubstituted alkyl or cycloalkyl residue) bases which can be used for this reaction are for example lithium hexamethyldisilazide (LiHMDS), potassium carbonate, caesium carbonate and sodium hydride. The preferred base is sodium hydride. As a rule at least 1 equivalent of base is used. In the case of an acylation reaction with substrates of the formula [VIII] (wherein in R1 a carbonyl group is directly bound to Z1) all usual solvents inert under the reaction conditions, such as for example cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile) and aromatic heterocyclic amine (pyridine) can be used or the reaction can be effected in mixtures of two or more of these solvents. The preferred solvents are tetrahydrofuran and dichloromethane.
In the case of an acylation reaction with substrates of the formula [VIII] (wherein in R1 a carbonyl group is directly bound to Z1) e.g. one equivalent of an acid scavenger / a base (e.g. pyridine, diisopropylethylamine, triethylamine or commercially available polymeric acid scavengers) relative to the starting materials of the general formula [V] or [VII] can be used. If the starting material is a salt, at least two equivalents of the acid scavenger are needed. If pyridine is used as the solvent, analogously to the literature described, the addition of a further base can in some cases be omitted (EP-A-1 000 062). The reaction is normally effected at temperatures of 0°C - 100°C and preferably at 20°C - 30°C, but it can also be effected at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours. After completion of the reaction, the compounds [VI] or [IV] are separated from the reaction mixture by one of the usual separation techniques. Depending on the nature of the substrate of the formula [VIII] used and the reaction conditions, the compounds of the formula [VI] and [IV], wherein R1 does not stand for hydrogen, can be obtained as pure regioisomers or as a mixture of both possible regioisomers (wherein the group R1 can occupy both positions on the N atom of the pyrazole). In the event that mixtures of regioisomers are obtained, these can be purified by physical methods (such as for example crystallization or chromatography methods) or can optionally also be used in the next step without prior purification.
Step (V2)
One possibility for the synthesis of compounds of the formula [V] is shown in Scheme 1. The halogenated pyrazoles of the formula [V] are either commercially available or can be produced by literature methods. One method for the production of suitable halogenated pyrazoles is for example the bromination of corresponding pyrazoles [VII] (e.g. described in EP-A 1382 603) by reaction with N-bromosuccinimide in acetic acid.
Step (V3) One possibility for the synthesis of compounds of the formula [III] is shown in Scheme 1.
Compounds of the formula [III] can be produced by described methods e.g. via reaction of the halopyrazoles [IV] with boronic acid esters such as for example bispinacolatodiboron (4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane) in the presence of a catalyst such as for example l, -bis(diphenyl-phosphino)ferrocene-palladium(II) dichloride in the presence of a base and a suitable solvent (see US 2009/0018156, WO 2007/024843 or EP-A 1 382 603).
As the solvent, all common solvents inert under the reaction conditions, such as for example sulphoxides (e.g. dimethyl sulphoxide), cyclic ethers (e.g. dioxan) and amides (e.g. N,N- dimethylformamide) can be used and the reaction can be effected in mixtures of two or more of these solvents. The preferred solvents are dimethyl sulphoxide and dioxan. The reaction will normally be effected at temperatures of 80°C - 120°C, and the preferred reaction temperature is about 85°C - 90°C. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between one hour and 16 hours.
Other synthetic methods described in the literature can likewise be used for the production of the compounds of the formula [III]. For example compounds of the formula [III] can be produced by metallation of the halogenated pyrazoles [IV] with bases such as for example n-butyllithium and reaction with boronic acid esters such as for example trimethyl borate and subsequent reaction of the pyrazole-boronic acid obtained with pinacol (see e.g. J. Het. Chem. 2004, 41, 931-940 or EP-A 1 382 603 and WO 2007/16392).
Step (V4)
A possibility for the synthesis of compounds of the formula [I] is shown in Scheme 1. Compounds of the formula [I] can be produced for example by coupling of the halogenated pyrazoles [IV] with metallated heterocycles of the formula [IX-a] (wherein Met1 stands for a borate ester or boronic acid such as for example B(OiPr)3 , B(OH)2) in the presence of a catalyst, a base, if necessary a ligand and a suitable solvent at suitable temperatures by known literature procedures {Top. Curr. Chem. 2002, 219, 11 ; Organomet. Chem. 1999, 28, 147 and literature cited therein, 2005, 7, 21, 4753-4756). (Scheme 1)
In analogy, the synthesis of the pyrazoles [II] from the compounds of the type [IV] described in Scheme 1 can be effected with this process.
Compounds of the formula [I] can also be produced for example by coupling of the halopyrazoles [IV] with metallated heterocycles of the formula [IX-a] (wherein Met1 stands for a tin-compound such as for example Sn(n-Bu)s) in the presence of a catalyst, if necessary an inorganic or organic halide salt, if necessary a ligand and a suitable solvent at suitable temperatures by known literature procedures (see Synthesis 1992, 803-815).
Compounds of the formula [IX-al] (wherein X1 stands for C-H) are commercially available or can be produced by literature procedures. One method for the production of suitable haloheterocycles [IX-al] is the reaction of haloheterocycles of the formula [XXIII] with bispinacolatodiboron in the presence of a catalyst (such as for example Pd(OAc)2 or PdCl2(dppf)), if necessary a ligand (such as for example l,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolium chloride), a base (such as for example potassium acetate or sodium acetate) and a solvent (such as for example tetrahydrofuran or dimethyl sulphoxide) by methods described in the literature (Bioorg. Med. Chem. Lett. 2006, 16, 5, 1277-1281 and WO 2011/042389) (Scheme 5). Scheme 5
Figure imgf000031_0001
[XXIII] [IX-a1]
Alternatively, compounds of the formula [IX-al] (wherein X stands for C-H) can also be prepared by other known literature methods. One method for the production of suitable heterocycles [IX-al] is the metallation of the halopyridine [XXIII] with a base (such as for example n-butyllithium) in a solvent (such as for example diethyl ether or tetrahydrofuran) and subsequent reaction with a boronic acid ester (such as for example B(i-PrO)3 or B(OMe)3) and pinacol by known literature methods (Synthesis 2004, 4, 469-483 and literature described therein) (Scheme 6).
Scheme 6
Figure imgf000031_0002
[XXIII] [IX-a1]
In analogy, compounds of the type [IX-b] can be synthetised according to literature described methods (WO 2011/042389) by reaction of the respective haloheterocycle precursor (replacement of Met2 by CI, Br, I in [IX-b]) with bispinacolatodiboron in the presence of a catalyst.
Compounds of the formula [IX-a2] (wherein X1 stands for N) are commercially available or can be produced by literature procedures. One method for the production of suitable haloheterocycles [IX- al] is the reaction of haloheterocycles of the formula [XXIV] with hexaalkylditin compounds (such as for example 1 , 1 , 1 ,2,2,2-hexabutylditin) in the presence of a catalyst (such as for example bis(triphenylphosphine)palladium(II) acetate), if necessary a fluoride ion source (such as for example tetrabutylammonium fluoride) and a solvent (such as for example tetrahydrofuran or diethyl ether) by methods described in the literature (WO 2003/095455 or WO 2007/104538) (Scheme 7). Scheme 7
Figure imgf000032_0001
Hal = Br,CI,l
[XXIV] ALK = CrC5 Alkyl [,χ^]
Alternatively, compounds of the formula [IX-a2] (wherein X1 stands for N) can also be prepared by other known literature methods. One method for the production of suitable haloheterocycles [IX-a2] is the metallation of the halopyridine [XXIV] using a metallation reagent (an alkyllithium compound such as for example n-butyllithium or a Grignard reagent such as for example isopropylmagnesium chloride) in a solvent (such as for example diethyl ether or tetrahydrofuran) and subsequent reaction with a trialkyltin halogen compound (such as for example BusSnCl) by known literature methods (WO 2008/008747 or Tetrahedron 1994, 275-284 and literature described therein) (Scheme 8).
Scheme 8
Figure imgf000032_0002
ALK = CrC5 Alkyl
[XXIV] [IX-a2]
Compounds of the formula [XXIII] and [XXIV] are commercially available or can be prepared for example by acylation of corresponding amine (in the case R3 = -NH2) by known literature methods (e.g. J. Org. Chem. 2004, 69, 543-548). Another method for the preparation of the compounds of the type [XXIII] and [XXIV] consists in the halogenation of the corresponding hydroxyheterocycles analogously to the halogenation methods stated for the synthesis of the compounds [X-al] and [XXVII].
In the coupling of the halopyrazoles [IV] with metallated heterocycles of the formula [IX-a] (wherein Met stands for a borate ester or boronic acid such as for example B(OiPr)3 or B(OH)2), the selection of solvent, base, temperature, catalysts and added ligands if necessary can vary depending on the borate ester substrate used and comprises the possible variations described under step (V5) for the C-C coupling of compound of the formula [III] with substrates of the formula [X- a].
In the coupling of the halopyrazoles [IV] with metallated heterocycles of the formula [IX-a] (wherein Met1 stands for an alkyltin bearing group such as for example Sn(Bu)3), the selection of a catalyst, if necessary an inorganic or organic halide salt, if necessary a ligand and a suitable solvent at suitable temperatures can vary depending on the alkyltin substrate used.
As the solvent for the reaction of compounds of the formula [IX-a], all usual solvents inert under the reaction conditions, such as for example cyclic and acyclic ethers (diethyl ether, dimethoxymethane, diethylene glycol dimethyl ether, tetrahydrofuran, dioxan, diisopropyl ether, tert-butyl methyl ether), aromatic hydrocarbons (e.g. benzene, toluene, xylene), amides (e.g. dimethylformamide, dimethyl-acetamide, N-methylpyrrolidone) and sulphoxides (e.g. dimethyl sulphoxide) can be used or the reaction can be performed in mixtures of two or more of these solvents. The preferred solvent is dimethylformamide.
Halide salts for the reaction of compounds of the formula [IX-a] which are preferably used in the process according to the invention are for example copper halides (e.g. CuBr or Cul), caesium halides (CsF) and tetraalkylammonium halides (TBAF).
The halide salts are preferably used in the process according to the invention in a proportion of 1 to 400 mol.%, based on the organic tin compound. However, mixtures of the halide salts can also be used in proportions of 1-400 mol.%. The addition of a mixture of copper iodide and caesium fluoride in proportions of 1- 200 mol.% is particularly preferable. As catalysts for the reaction of compounds of the formula [IX-a] with halogenated pyrazoles of the formula [IV] the same catalysts can be used as are described below for the production of the compounds of the formula [I], by reaction of the compounds of the formula [III] and [X-a] described for step V5.
The quantity of catalyst, based on the heteroaromatics [IX-a] bearing the leaving group Met1, is preferably 0.001 to 0.5 mol.%> and particularly preferably 0.01 to 0.2 mol.%>.
The catalyst can contain phosphorus-containing or arsenic-containing ligands or phosphorus- containing or arsenic-containing ligands can be added separately to the reaction mixture. As phosphorus-containing ligands, preferably tri-n-alkylphosphanes, triarylphosphanes, dialkylaryl- phosphanes, alkyldiarylphosphanes and/or heteroarylphosphanes, such as tripyridylphosphane and trifurylphosphane, wherein the three substituents on the phosphorus can be the same or different, can be chiral or achiral and wherein one or more substituents can link the phosphorus groups of several phosphanes, wherein one part of this linkage can also be a metal atom, are suitable. Particularly preferable are phosphanes such as triphenylphosphane, tri-tert-butylphosphane and tricyclohexyl-phosphane. As arsenic-containing ligands, for example tri-n-alkylarsanes and triarylarsanes, wherein the three substituents on the arsenic can be the same or different, are suitable.
The total concentration of ligands, based on the heteroaromatics [IX-a] bearing the leaving group Met1, is preferably up to 1 mol.%, particularly preferably 0.01 to 0.5 mol.%.
To effect the process according to the invention, advantageously the educts, the solvent, the base, the halide salt, the catalyst and if necessary the ligand are thoroughly mixed and reacted preferably at a temperature of 0°C- 200°C, particularly preferably at 60-150°C. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours. Other than as a one-pot reaction, the reaction can also be run such that the various reactants are metered in a controlled manner in the course of the reaction, whereby different metering variants are possible.
The processes according to the invention are in general performed under normal pressure. However it is also possible to operate under increased or reduced pressure. The reaction is in general performed using a blanket gas such as for example argon or nitrogen.
The molar reactant ratio of the halopyrazole [IV] to the organotin compound [IX-a2] is preferably 0.9 to 2.
After completion of the reaction, the catalyst arising as a solid is removed by filtration, the crude product freed from the solvent or solvents and then purified by methods known to those skilled in the art and appropriate for the particular product, e.g. by recrystallization, distillation, sublimation, zone melting, melt crystallization or chromatography.
Step CV5)
One possibility for the synthesis of compounds of the formula [I] and for the synthesis of compounds of the formula [III] is shown in Scheme 1. Compounds of the formula [I] can be produced for example by coupling of the pyrazoleboronic acids [III] with heterocycles of the formula [X-a] (wherein Z2 represents a leaving group such as for example CI or Br) in the presence of a catalyst, a base and a suitable solvent at suitable temperatures by known literature procedures {Top. Curr. Chem. 2002, 219, 11 ; Organomet. Chem. 1999, 28, 147 and literature cited therein). In a similar manner, compounds of the formula [II] can be produced by coupling of the pyrazoleboronic acids [III] with heterocycles of the formula [X-b]. Compounds of the formula [X-a] (wherein X1 stands for C-H) are commercially available or can be produced by literature procedures (Scheme 9). One method for the production of suitable haloheterocycles [X-al] is the reaction of the pyridine N-oxides with halogenating agents (e.g. PC13, POCI3, SOCb or methanesulphonyl chloride) (see Bioorg. Med. Chem. Lett. 2007, 17, 7, 1934-1937).
Scheme 9
Figure imgf000035_0001
H, alkyl, Aryl
[XXV] [X-a1]
The pyridine N-oxides [XXV] are known or can be produced by oxidation of the corresponding pyridines (e.g. with H2O2, H2O2 + methyltrioxorhenium, m-chloroperoxybenzoic acid, dimethyl- dioxirane or H2O2 + manganese tetrakis(2,6-dichlorophenyl)porphyrin) by procedures described in the literature (ARKIVOC 2001 (i) 242-268 and references contained therein).
A further method for the production of suitable haloheterocycles [X-al] is the reaction of the 4- hydroxypyridine compounds [XXVI] with halogenating agents (e.g. PCI3, POCI3) by known literature procedures (Pol. J. Chem. 1981, 55, 4, 925 - 929) (Scheme 10). Scheme 10
Figure imgf000035_0002
The hydroxypyridines [XXVI] are known.
Alternatively, compounds of the formula [X-a] (wherein X1 stands for C-H) are commercially available or can be produced by literature methods (Scheme 11). One method for the production of suitable haloheterocycles [X-a-2] is the reaction of aminoheterocycles of the formula [XXVII] with acid chlorides in the presence of a base and a solvent (Synth. Commun. 1997, 27, 5, 861-870). Scheme 11
Figure imgf000036_0001
[XXVII] [X-a-2]
The aminoheterocycles [XXVII] (wherein X1 stands for C-H) are known or can be produced by removal of the N-BOC protective group from compounds of the formula [X-b-1] by procedures described in the literature (Aust. J. Chem. 1982, 35, 10, 2025-2034 and references contained therein).
The aminoheterocycles [XXVII] (wherein X1 stands for N) are known or can be produced by halogenation of the hydroxy compounds (Z2= -OH) by procedures described in the literature (e.g. after J. Med. Chem. 2006, 49, 14, 4409-4424). Compounds of the formula [X-b] (wherein X1 stands for C-H) are commercially available or can be produced by literature methods (Scheme 12). One method for the production of suitable N-Boc- haloheterocycles [X-b-1] is the reaction of suitable acids (e.g. 4-bromo-picolinic acid) [XXIX] with diphenylphosphoryl azide and tert-butanol (Aust. J. Chem. 1982, 35, 2025-2034, J. Med. Chem. 1992, 35, 15, 2761-2768 or US 5,112,837 A). Scheme 12
Figure imgf000036_0002
[XXIX] [X-b-1]
The carboxylic acids [XXIX] are known or can be produced from commercially available precursors by procedures described in the literature (see e.g. EP-A 1 650 194), for example from the commercially available pyridine-2-carboxylic acid by reaction with thionyl chloride in dimethylformamide. Alternatively, compounds of the general formula [L] can also be produced by oxidation of commercially available 4-halo-2-methyl-pyridine derivatives by known literature procedures (Aust. J. Chem. 1982, 35, 2025-2034).
Compounds of the formula [X-b] (wherein X1 stands for N) are commercially available or can be produced by literature methods (Scheme 13). One method for the production of suitable N-Boc- haloheterocycles [X-b-2] is the chlorination of the hydroxy compounds (e.g. (4-hydroxy-pyrimidin- 2-yl)carbamate) with phosphorus oxychloride {Chem. Pharm. Bull. 2003, 51, 8, 975-977).
Scheme 13
Figure imgf000037_0001
[XXX] [X-b-2] The hydroxy compounds [XXX] are known or can be produced from commercially available precursors by procedures described in the literature {Chem. Pharm. Bull. 2003, 51, 8, 975-977).
As the solvent for the synthesis of compounds of the formula [I] and [II] all usual solvents inert under the reaction conditions, such as for example alcohols (e.g. methanol, ethanol, 1-propanol, 2- propanol, ethylene glycol, 1-butanol, 2-butanol, tert-butanol), cyclic and acyclic ethers (diethyl ether, dimethoxymethane, di ethylene glycol dimethyl ether, tetrahydrofuran, dioxan, diisopropyl ether, tert-butyl methyl ether), aromatic hydrocarbons (e.g. benzene, toluene, xylene), hydrocarbons (e.g. hexane, iso-hexane, heptane, cyclohexane), ketones (e.g. acetone, ethyl methyl ketone, iso-butyl methyl ketone), nitriles (e.g. acetonitrile, propionitrile, butyronitrile) and amides (e.g. dimethyl-formamide, dimethylacetamide, N-methylpyrrolidone) and water can be used or the reaction can be effected in mixtures of two or more of these solvents. The preferred solvent is dioxan.
Bases which are preferably used in the process according to the invention are alkali and alkaline earth metal hydroxides, alkali and alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkali and alkaline earth metal acetates, alkali and alkaline earth metal alcoholates, and primary, secondary and tertiary amines. Preferred bases are alkali metal carbonates such as for example caesium carbonate, sodium carbonate and potassium carbonate.
In the process according to the invention, the base is preferably used in a proportion of 100 to 1000 mol.%, based on the aromatic boronic acid. The preferred proportion is 600 to 800 mol.%.
As catalysts, for example palladium metal, palladium compounds and/or nickel compounds can be used. The catalysts can also be applied onto a solid carrier, such as activated charcoal or aluminium oxide. Palladium catalysts wherein the palladium is present in the oxidation state (0) or (II), such as tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)palladium dichloride, bis(diphenyl- phosphino)ferrocenepalladium dichloride, palladium ketonates, palladium acetylacetonates (such as for example palladium bisacetylacetonate), nitrilepalladium halides (such as for example bis- (benzonitrile)palladium dichloride, bis(acetonitrile)-palladium dichloride), palladium halides (PdCb, Na2PdCl4, Na2PdCle), allylpalladium halides, palladium biscarboxylates (such as for example palladium-II acetate) and tetrachloropalladic acid are preferred. Particularly preferred catalysts are tetrakis(triphenylphosphine)-palladium, bis(triphenylphosphine)-palladium dichloride and bis-(diphenylphosphino)ferrocenepalladium dichloride. The palladium compound can also be generated in situ, such as for example palladium(II) acetate from palladium(II) chloride and sodium acetate.
The quantity of catalyst, based on the heteroaromatics [X-a] and [X-b] bearing the leaving group Z2, is preferably 0.001 to 0.5 mol.% and particularly preferably 0.01 to 0.2 mol.%. The catalyst can contain phosphorus-containing ligands or phosphorus-containing ligands can be added separately to the reaction mixture. Preferably suitable as phosphorus-containing ligands are tri-n-alkylphosphanes, triarylphosphanes, dialkylarylphosphanes, alkyldiarylphosphanes and/or heteroarylphosphanes, such as tripyridylphosphane and trifurylphosphane, wherein the three substituents on the phosphorus can be the same or different and wherein one or more substituents can link the phosphorus groups of several phosphanes, wherein one part of this linkage can also be a metal atom. Particularly preferable are phosphanes such as triphenylphosphane, tri-tert- butylphosphane and tricyclohexylphosphane.
The total concentration of phosphorus-containing ligands, based on the heteroaromatics [X-a] and [X-b] bearing the leaving group Z2 is preferably up to 1 mol.%, particularly preferably 0.01 to 0.5 mol.%.
To effect the process according to the invention, expediently the educts, the solvent, the base, the catalyst and if appropriate the ligand are thoroughly mixed and reacted preferably at a temperature of 0°C - 200°C, particularly preferably at 100-170°C. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours. Other than as a one-pot reaction, the reaction can also be run such that the various reactants are metered in a controlled way in the course of the reaction, different metering variants being possible.
The molar reactant ratio of the heteroaromatic [X-a] and [X-b] to the organoboron compound [III] is preferably 0.9 to 1.5. The processes according to the invention are generally performed under normal pressure. It is however also possible to operate under increased or reduced pressure. The reaction is generally performed with the use of a blanket gas such as for example argon or nitrogen. After completion of the reaction, the catalyst arising as a solid is removed by filtration, the crude product freed from the solvent or solvents and then purified by methods known to those skilled in the art and appropriate for the particular product, e.g. by recrystallization, distillation, sublimation, zone melting, melt crystallization or chromatography.
Step (V6)
One possibility for the synthesis of compounds of the formula [I-a] is shown in Scheme 1.
A compound with the general formula [I-a] can be synthesized, analogously to procedures described in the literature (see e.g. WO 2004/052880 and e.g. T.W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis, 1999, John Wiley & Sons, Inc.), by a coupling reaction of a compound with the corresponding general formula [II] with a substrate of the general formula [XI] (with Z3 e.g. = CI, Br, F or -OH) if necessary in the presence of an acid scavenger/base wherein the definitions of the residues R1, R2, R3a, R4, R5 and X1 in the above schemes correspond to the aforesaid definitions.
Acid halides [XI] (Z3 = CI) or the corresponding carboxylic acids [XI] (Z3 = OH) are commercially available or preparable by processes described in the literature. In addition, a substrate with the general formula [XI], with Z3 = CI, can be prepared from the corresponding acid (Z3 = OH) by chlorination using known literature processes (R. C. Larock, Comprehensive Organic Transformations, 2nd Edition, 1999, Wiley- VCH, page 1929 ff. and literature cited therein).
As the solvent, all usual solvents inert under the reaction conditions, such as for example cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydro-carbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene) and nitriles (e.g. acetonitrile) can be used or the reaction can be effected in mixtures of two or more of these solvents. The preferred solvents are tetrahydrofuran and dichloromethane.
At least one equivalent of an acid scavenger / a base (e.g. Hiinig base, triethylamine or commercially available polymeric acid scavengers) relative to the starting material of the general formula [II] is used. If the starting material is a salt, at least two equivalents of the acid scavenger are needed.
The reaction is normally effected at temperatures of 0°C - 100°C and preferably at 20°C - 30°C, but it can also be effected at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
To effect the process (V6) according to the invention for the production of the compounds of the formula [I-a] in general 0.2 to 2 mol, preferably 0.5 to 0.9 mol, of amino derivative of the formula [II] is used per mol of the carboxylic acid halide of the formula [XI]. The workup is effected by evaporation of the volatile components under vacuum and treatment of the crude material with ammoniacal methanol solution (7 molar). After completion of the reaction, the compounds [I-a] are separated from the reaction mixture by one of the usual separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography.
Alternatively, a compound of the formula [I-a] can also by synthesized from the corresponding compound of the formula [II] with a substrate of the formula [XI] with Z3 = -OH in the presence of a coupling reagent analogously to procedures described in the literature (e.g. Tetrahedron 2005, 61, 10827-10852, and references cited therein).
Suitable coupling reagents are for example peptide coupling reagents (for example, N-(3-dimethyl- aminopropyl)-N'-ethyl-carbodiimide mixed with 4-dimethylamino-pyridine, N-(3-dimethylamino- propyl)-N'-ethyl-carbodiimide mixed with 1-hydroxy-benzotriazole, bromo-tripyrrolidino- phosphonium hexafluorophosphate, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, etc.).
If necessary, a base, such as for example triethylamine or Hiinig base can be used in the reaction.
As the solvent, all usual solvents inert under the reaction conditions, such as for example alcohols (e.g. methanol, ethanol, propanol), cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile) and amides (e.g. N,N- dimethylformamide, Ν,Ν-dimethylacetamide) can be used or the reaction can be performed in mixtures of two or more of these solvents. The preferred solvent is dichloromethane. The reaction is normally performed at temperatures of 0°C - 100°C and preferably at 0°C - 30°C, but it can also be performed at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between a few minutes and 48 hours.
After completion of the reaction, the compounds [I-a] are separated from the reaction mixture by one of the usual separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography.
Compounds of the general formula [I-a] in which R3a stands for -NR12R12 (symmetrically or unsymmetrically bisacylated aminopyridines) can be produced directly by the aforesaid method from compounds of the general formula [I-a], in which R3a stands for -NHR12 (monoacylated aminopyridines), by reaction with acid halides of the formula [XI] (Z3= e.g. CI, F).
Step (V7) One possibility for the synthesis of compounds of the formula [XIII] is shown in Scheme 2.
Compounds of the general formula [XIII] (where Z4 stands for NMe2, OAlkyl) may be obtained, according to known literature methods (US2002/19404 Al ; Bioorg. Med. Chem. 2009, 17, 5, 2091-2100; J. Het. Chem. 2007, 44, 2, 355-361) by reacting a compound of general formula [XII] (where Z3 stands for Methyl) with a formylating agent such as an alkyl formiate (e.g. methyl formiate), a trialkyl orthoformiate (e.g. trimethyl orthoformiate) or an acetal of N,N- dialkylformamide. A solvent is used optionally. Typical solvents include alcohols (e.g. ethanol), esters (e.g. ethyl acetate), ethers (e.g. THF) and also more polar solvents such as DMF or NMP. The reaction temperature can be varied from room temperature to the boiling point of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a couple of minutes and 48 hours.
Alternatively, compounds of the general formula [XIII] (where Z4 stands for OH) can be obtained according to known literature methods (J. Org. Chem. 2001, 66, 24, 8000-8009) by reacting an ester compound of general formula [XII] (where Z3 stands for OAlkyl) with a methylketone of the general formula CH3COR2 in the presence of a base (e.g. sodium hydride, lithium diisopropylamide or potassium tert. butanolate) and a solvent. Typical solvents include alcohols (e.g. ethanol) or ethers (e.g. THF).
Alternatively, compounds of the general formula [XIII] (where Z4 stands for OH) can be obtained according to known literature methods {Bioorg. Med. Chem. Lett. 2004 , 14, 2, 343-346) by reacting an methylketone general formula [XII] (where Z3 stands for CH3) with an carboxylic acid ester of the general formula R2COOAlkyl in the presence of a base (e.g. sodium hydride, lithium diisopropylamide or potassium tert. butanolate) and a solvent. Typical solvents include alcohols (e.g. ethanol) or ethers (e.g. THF).
After the reaction has ended, compounds [XII] are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography, or they can, if appropriate, also be used for the next step without prior purification.
Compounds of the general formula [XII] are commercially available or can be synthetised according to known synthesis methods (e.g. in Monatshefte Chem. 1989, 120, 53-63 or J. Am. Chem. Soc. 1947, 69, 3096-3098).
Step (V8)
One possibility for the synthesis of compounds of the formula [VII] is shown in Scheme 2.
Compounds of the general formula [VII] may be obtained, according to known literature methods (Tetrahedron 1995, 51, 41, 11251-11256; J. Med. Chem. 2003, 46, 25, 5416-5427; WO 2008/108602 Al or J. Med. Chem. 1998, 41, 13, 2390-2410), by reacting a compound of general formula [XIII] with hydrazine or a hydrated form thereof. Inert solvent such as cyclic or acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxane), alcohols (e.g. methanol or ethanol) can be used. The reaction can be carried out in mixtures of two or more of these solvents. A base e.g. triethylamine may be used if desired. The reaction temperature can be varied from 10°C to 50°C but room temperature is preferred. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a couple of minutes and 48 hours. The reaction can be performed in a microwave apparatus (e.g. CEM Explorer) at elevated temperature, which may shorten the reaction time. After the reaction has ended, compounds [VII] are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
Step (V9)
One possibility for the synthesis of compounds of the formula [VI] is shown in Scheme 2.
Compounds of the general formula [VI] may be obtained, according to known literature methods (J. Med. Chem. 1998, 41, 13, 2390-2410), by reacting a compound of general formula [XIII] with hydrazine a hydrazine of general formula R1-NH-NH2 or a hydrated form thereof. Inert solvent such as cyclic or acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxane), alcohols (e.g. methanol or ethanol) can be used. The reaction can be carried out in mixtures of two or more of these solvents. A base e.g. triethylamine may be used if desired. The reaction temperature can be varied from 10 °C to 50 °C but room temperature is preferred. The reaction time varies depending on the scale of the reaction and the reaction temperature, but is generally between a couple of minutes and 48 hours. The reaction can be performed in a microwave apparatus (e.g. CEM Explorer) at elevated temperature, which may shorten the reaction time. After the reaction has ended, compounds [VII] are removed from the reaction mixture using one of the customary separation techniques. If required, the compounds are purified by recrystallisation, distillation or chromatography.
Step (VI 0) One possibility for the synthesis of compounds of the formula [XVI] is shown in Scheme 2.
The alkynone [XVI] can be prepared by treating acid chloride [XIV] with an alkyne for example by transition-metal catalysis e.g. as described in Tetrahedron Lett. 2006, 47, 5527-5530 or in Synthesis 2003, 18, 2815-2826. Compounds of the general formula [XIV] are commercially available or can be synthetised according to known synthesis methods (e.g. in J. Heterocycl. Chem. 1966, 3, 184-186 or J. Med. Chem. 2001, 44, 863-872).
One possibility for the synthesis of compounds of the formula [XVI] is shown in Scheme 2. Alternatively, the alkynone [XVI] can be prepared by carbonylative C-C coupling using thiophene halides [XV] with an alkyne employing carbon monoxide as described e.g. in Synlett 2008, 6, 886- 888 or J. Org. Chem. 2005, 70, 6097-6100.
Compounds of the general formula [XV] are commercially available or can be synthetised according to known synthesis methods (e. g. in EP 1424333 Al or Acta Chemica Scandinavica B, 1976, 30, 439-449).
Step (VI 2)
One possibility for the synthesis of compounds of the formula [VI] is shown in Scheme 2.
Compounds of formula [VI] can be prepared by treating the alkynone of formula [XVI] with a hydrazine derivative under conditions used in state of the art methodology (e.g. in Eur. J. Org. Chem. 2008, 4157-4168 or Tetrahedron Lett. 2008, 49, 3805-3809).
Step (VI 3)
One possibility for the synthesis of compounds of the formula [XIX] is shown in Scheme 3.
Compounds of the formula [XIX] can be produced for example by coupling of the pyrazoles of the formula [XVII] (wherein Met stands for a borate ester or boronic acid such as for example B(OiPr)3 or B(OH)2) with compounds of the formula [XVIII] (wherein Z4 represents a leaving group such as for example CI, Br, I, mesylate or inflate) in the presence of a catalyst, a base, if necessary a ligand and a suitable solvent at suitable temperatures by known literature procedures {Top. Curr. Chem. 2002, 219, 11 ; Organomet. Chem. 1999, 28, 147 and literature cited therein, Org. Lett. 2005, 7, 21, 4753-4756). Compounds of the formula [XIX] can be moreover produced for example by coupling of the pyrazoles of the formula [XVII] (wherein Met3 stands for an alkyltin-bearing group such as for example -Sn(Bu)3) with compounds of the formula [XVIII] (wherein Z4 represents a leaving group such as for example CI, Br, I, mesylate or inflate) in the presence of a catalyst, if necessary an inorganic or organic halide salt, if necessary a ligand and a suitable solvent at suitable temperatures by known literature procedures (see Synthesis 1992, 803-815).
Compounds of the formula [XVIII] such as for example 3-bromothiophene are known and commercially available. Compounds of the formula [XVII] such as 4-[l-(tetrahydro-2H-pyran-2- yl)-5-(tributylstannyl)-lH-pyrazol-4-yl]pyridine can be prepared according to literature described synthesis methods (WO 2011/042389).
In the coupling of the pyrazoles [XVII] with compounds of the formula [XVIII] the selection of solvent, base, temperature, catalysts, halide salts and added ligand if necessary can vary depending on the pyrazole [XVII] used and comprises the possible variations described under (V4).
The processes according to the invention are in general performed under normal pressure. However it is also possible to operate under increased or reduced pressure.
The reaction is in general performed using a blanket gas such as for example argon or nitrogen.
The molar reactant ratio of the pyrazole [XVII] to the compound of the formula [XVIII] is preferably 0.9 to 2.
After completion of the reaction, the catalyst arising as a solid is removed by filtration, the crude product freed from the solvent or solvents and then purified by methods known to those skilled in the art and appropriate for the particular product, e.g. by recrystallization, distillation, sublimation, zone melting, melt crystallization or chromatography.
Step (VI 4)
One possibility for the synthesis of compounds of the formula [XX] is shown in Scheme 3. A compound of the formula [XIX] is converted into a compound of the formula [XX] by suitable methods for the removal of protective groups, which are described in the literature ( "Protective Groups in Organic Synthesis "; Third Edition; Theodora W. Greene, Peter G. M. Wuts; 1999, Wiley- VCH, p. 494-653, and literature cited there).
2-(Trimethylsilyl-ethoxy)methyl and tetrahydropyran-2-yl protective groups can for example be removed in an acidic medium (e.g. with methanolic HCl or trifluoroacetic acid) by known literature procedures (WO 03/099822 and J. Org. Chem. 2008, 73, 4309-4312 and literature contained therein). Benzylic protective groups can be removed hydrogenolytically with a hydrogen source (e.g. hydrogen, ammonium formate, formic acid or cyclohexene) in the presence of a catalyst (e.g. palladium on activated charcoal or palladium hydroxide on activated charcoal) by known literature procedures (EP-A 1 228 067). As the solvent, all usual solvents inert under the reaction conditions, such as for example alcohols (e.g. methanol, ethanol, propanol), cyclic and acyclic ethers (e.g. diethyl ether, tetrahydrofuran, dioxan), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), halogenated aromatic hydrocarbons (e.g. chlorobenzene, dichlorobenzene), nitriles (e.g. acetonitrile), carboxylate ester (e.g. ethyl acetate), amides (e.g. N,N-dimethylformamide, Ν,Ν-dimethylacetamide), dimethyl sulphoxide, 1,3- dimethyl-2-imidazolinone, water and acetic acid can be used or the reaction can be performed in mixtures of two or more of these solvents.
The reaction is normally performed at temperatures of 0°C - 150°C and preferably at room temperature, but it can also be performed at the reflux temperature of the reaction mixture. The reaction time varies depending on the scale of the reaction and the reaction temperature, but generally lies between half an hour and 72 hours.
After completion of the reaction, the compounds [XX] are separated from the reaction mixture by one of the usual separation techniques. If necessary, the compounds are purified by recrystallization, distillation or chromatography or if desired can also be used in the next step without prior purification. It is moreover possible to isolate the compound of the general formula [XX] as a salt, e.g. as a salt of hydrochloric acid or trifluoroacetic acid.
Step (VI 5)
One possibility for the synthesis of compounds of the formula [XXII] is shown in Scheme 4.
A compound of the formula [XXI] is converted into a compound of the formula [XXII] by conversion of the acid into the amide of Ν,Ο-dimethyl-hydroxylamine by using amide formation methods, which are described in the literature (US 6,562,811 A, US 2003/158185 Al or J. Med. Chem. 2001 , vol. 44, 6, 863-872).
Step (VI 6)
One possibility for the synthesis of compounds of the formula [Vll-a] is shown in Scheme 4. A compound of the formula [XXII] is converted into a compound of the formula [Vll-a] by conversion of the weinreb amide into an intermediary acyl alkyne according to known literature methods (J. Org. Chem. 2000, vol. 65, 17, 5114-5119) followed by treatment with hydrazine and cyclisation to the pyrazole according to literature methods (US 6,310,049 A).
A furth er s ubj e ct o f th e inv enti o n re l at e s t o th e n o nm e di c in a l u s e o f th e thienylpyri(mi)dinylpyrazole according to the invention or mixtures thereof for the control of undesired microorganisms and for the reduction of mycotoxins in plants and plant parts.
A further subject of the invention relates to an agent for the control of undesired microorganisms and for the reduction of mycotoxins in plants and plant parts, comprising at least one thienylpyri(mi)dinylpyrazole according to the present invention.
In addition, the invention relates to a method for the control of undesired microorganisms and for the reduction of mycotoxins in plants and plant parts, characterized in that the thienylpyri(mi)dinylpyrazoles according to the invention are applied onto the microorganisms and/or in their habitat.
The substances according to the invention have potent microbicidal activity and can be employed for controlling unwanted microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.
The present invention furthermore relates to a crop protection composition for controlling unwanted microorganisms, in particular unwanted fungi, which comprises the active compounds according to the invention. These are preferably fungicidal compositions which comprise agriculturally suitable auxiliaries, solvents, carriers, surfactants or extenders. Moreover, the invention relates to a method for controlling unwanted microorganisms, characterized in that the active compounds according to the invention are applied to the phytopathogenic fungi and/or their habitat.
According to the invention, a carrier is a natural or synthetic organic or inorganic substance with which the active compounds are mixed or bonded for better applicability, in particular for application to plants or plant parts or seed. The carrier, which may be solid or liquid, is generally inert and should be suitable for use in agriculture.
Suitable solid or liquid carriers are: for example ammonium salts and ground natural minerals, such as kaolins, clays, talc, chalk, quartz, attapulgite, montmorillonite or diatomaceous earth, and ground synthetic minerals, such as finely divided silica, alumina and natural or synthetic silicates, resins, waxes, solid fertilizers, water, alcohols, especially butanol, organic solvents, mineral and vegetable oils and derivatives of these. Mixtures of such carriers may also be used. Suitable solid carriers for granules are: for example crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite, dolomite, and synthetic granules of inorganic and organic meals, and also granules of organic material such as sawdust, coconut shells, maize cobs and tobacco stalks.
Suitable liquefied gaseous extenders or carriers are liquids which are gaseous at ambient temperature and under atmospheric pressure, for example aerosol propellants, such as halogenated hydrocarbons, and also butane, propane, nitrogen and carbon dioxide.
Tackifiers such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, or else natural phospholipids such as cephalins and lecithins and synthetic phospholipids can be used in the formulations. Other possible additives are mineral and vegetable oils. If the extender used is water, it is also possible to employ, for example, organic solvents as auxiliary solvents. Essentially, suitable liquid solvents are: aromatics such as xylene, toluene or alkylnaphthalenes, chlorinated aromatics and chlorinated aliphatic hydrocarbons such as chlorobenzenes, chloroethylenes or dichloromethane, aliphatic hydrocarbons such as cyclohexane or paraffins, for example mineral oil fractions, mineral and vegetable oils, alcohols such as butanol or glycol and their ethers and esters, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, strongly polar solvents such as dimethylformamide and dimethyl sulphoxide, and also water.
The compositions according to the invention may comprise additional further components, such as, for example, surfactants. Suitable surfactants are emulsifiers and/or foam formers, dispersants or wetting agents having ionic or nonionic properties, or mixtures of these surfactants. Examples of these are salts of polyacrylic acid, salts of lignosulphonic acid, salts of phenolsulphonic acid or naphthalenesulphonic acid, polycondensates of ethylene oxide with fatty alcohols or with fatty acids or with fatty amines, substituted phenols (preferably alkylphenols or arylphenols), salts of sulphosuccinic esters, taurine derivatives (preferably alkyl taurates), phosphoric esters of polyethoxylated alcohols or phenols, fatty esters of polyols, and derivatives of the compounds containing sulphates, sulphonates and phosphates, for example alkylaryl polyglycol ethers, alkylsulphonates, alkyl sulphates, arylsulphonates, protein hydrolyzates, lignosulphite waste liquors and methylcellulose. The presence of a surfactant is required if one of the active compounds and/or one of the inert carriers is insoluble in water and when the application takes place in water. The proportion of surfactants is between 5 and 40 per cent by weight of the composition according to the invention.
It is possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic colorants such as alizarin colorants, azo colorants and metal phthalocyanine colorants, and trace nutrients such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc. If appropriate, other additional components may also be present, for example protective colloids, binders, adhesives, thickeners, thixotropic substances, penetrants, stabilizers, sequestering agents, complex formers. In general, the active compounds can be combined with any solid or liquid additive customarily used for formulation purposes. The compositions and formulations according to the invention generally comprise between 0.05 and 99% by weight, 0.01 and 98% by weight, preferably between 0.1 and 95% by weight, particularly preferably between 0.5 and 90% of active compound, very particularly preferably between 10 and 70% by weight.
The active compounds or compositions according to the invention can be used as such or, depending on their respective physical and/or chemical properties, in the form of their formulations or the use forms prepared therefrom, such as aerosols, capsule suspensions, cold-fogging concentrates, warm-fogging concentrates, encapsulated granules, fine granules, flowable concentrates for the treatment of seed, ready-to-use solutions, dustable powders, emulsifiable concentrates, oil-in-water emulsions, water-in-oil emulsions, macrogranules, microgranules, oil-dispersible powders, oil-miscible flowable concentrates, oil-miscible liquids, foams, pastes, pesticide coated seed, suspension concentrates, suspoemulsion concentrates, soluble concentrates, suspensions, wettable powders, soluble powders, dusts and granules, water-soluble granules or tablets, water-soluble powders for the treatment of seed, wettable powders, natural products and synthetic substances impregnated with active compound, and also microencapsulations in polymeric substances and in coating materials for seed, and also ULV cold- fogging and warm- fogging formulations.
The formulations mentioned can be prepared in a manner known per se, for example by mixing the active compounds with at least one customary extender, solvent or diluent, emulsifier, dispersant, and/or binder or fixative, wetting agent, water repellent, if appropriate desiccants and UV stabilizers and, if appropriate, dyes and pigments, defoamers, preservatives, secondary thickeners, adhesives, gibberellins and also further processing auxiliaries.
The compositions according to the invention include not only formulations which are already ready for use and can be applied with a suitable apparatus to the plant or the seed, but also commercial concentrates which have to be diluted with water prior to use.
The active compounds according to the invention can be present as such or in their (commercial) formulations and in the use forms prepared from these formulations as a mixture with other (known) active compounds, such as insecticides, attractants, sterilants, bactericides, acaricides, ne- maticides, fungicides, growth regulators, herbicides, fertilizers, safeners and/or semiochemicals.
The treatment according to the invention of the plants and plant parts with the active compounds or compositions is carried out directly or by action on their surroundings, habitat or storage space using customary treatment methods, for example by dipping, spraying, atomizing, irrigating, evaporating, dusting, fogging, broadcasting, foaming, painting, spreading-on, watering (drenching), drip irrigating and, in the case of propagation material, in particular in the case of seeds, furthermore as a powder for dry seed treatment, a solution for seed treatment, a water-soluble powder for slurry treatment, by incrusting, by coating with one or more coats, etc. It is furthermore possible to apply the active compounds by the ultra-low volume method or to inject the active compound preparation or the active compound itself into the soil.
The invention furthermore includes a method for treating seed. The invention furthermore relates to seed which has been treated in accordance with one of the methods described in the previous paragraph. The seeds according to the invention are used in methods for the protection of seed from undesirable microorganisms. In these methods, seed treated with at least one active compound according to the invention is employed.
The active compounds or compositions according to the invention are also suitable for treating seed. A large part of the damage to crop plants caused by harmful organisms is triggered by the infection of the seed during storage or after sowing both during and after germination of the plant. This phase is particularly critical since the roots and shoots of the growing plant are particularly sensitive, and even small damage may result in the death of the plant. Accordingly, there is great interest in protecting the seed and the germinating plant by using appropriate compositions. The control of phytopathogenic fungi by treating the seed of plants has been known for a long time and is the subject of continuous improvements. However, the treatment of seed entails a series of problems which cannot always be solved in a satisfactory manner. Thus, it is desirable to develop methods for protecting the seed and the germinating plant which dispense with, or at least reduce considerably, the additional application of crop protection agents after sowing or after emergence of the plants. It is furthermore desirable to optimize the amount of active compound employed in such a way as to provide optimum protection for the seed and the germinating plant from attack by phytopathogenic fungi, but without damaging the plant itself by the active compound employed. In particular, methods for the treatment of seed should also take into consideration the intrinsic fungicidal properties of transgenic plants in order to achieve optimum protection of the seed and the germinating plant with a minimum of crop protection agents being employed.
The present invention therefore also relates to a method for the protection of seed and germinating plants, from attack by phytopathogenic fungi, by treating the seed with a composition according to the invention. The invention also relates to the use of the compositions according to the invention for treating seed for protecting the seed and the germinating plant against phytopathogenic fungi. Furthermore, the invention relates to seed treated with a composition according to the invention for protection against phytopathogenic fungi.
The control of phytopathogenic fungi which damage plants post-emergence is carried out primarily by treating the soil and the above-ground parts of plants with crop protection agents. Owing to the concerns regarding a possible impact of the crop protection agents on the environment and the health of humans and animals, there are efforts to reduce the amount of active compounds applied.
One of the advantages of the present invention is that the particular systemic properties of the active compounds and compositions according to the invention mean that treatment of the seed with these active compounds and compositions not only protects the seed itself, but also the resulting plants after emergence, from phytopathogenic fungi. In this manner, the immediate treatment of the crop at the time of sowing or shortly thereafter can be dispensed with.
It is also considered to be advantageous that the active compounds or compositions according to the invention can be used in particular also for transgenic seed where the plant growing from this seed is capable of expressing a protein which acts against pests. By treating such seed with the active compounds or compositions according to the invention, even by the expression of the, for example, insecticidal protein, certain pests may be controlled. Surprisingly, a further synergistic effect may be observed here, which additionally increases the effectiveness of the protection against attack by pests.
The compositions according to the invention are suitable for protecting seed of any plant variety which is employed in agriculture, in the greenhouse, in forests or in horticulture and viticulture. In particular, this takes the form of seed of cereals (such as wheat, barley, rye, triticale, sorghum/millet and oats), maize, cotton, soya beans, rice, potatoes, sunflower, bean, coffee, beet (for example sugar beet and fodder beet), peanut, oilseed rape, poppy, olive, coconut, cacao, sugar cane, tobacco, vegetables (such as tomato, cucumbers, onions and lettuce), turf and ornamentals (see also hereinbelow). The treatment of the seed of cereals (such as wheat, barley, rye, triticale and oats), maize and rice is of particular importance.
As also described further below, the treatment of transgenic seed with the active compounds or compositions according to the invention is of particular importance. This refers to the seed of plants containing at least one heterologous gene which allows the expression of a polypeptide or protein having insecticidal properties. The heterologous gene in transgenic seed can originate, for example, from microorganisms of the species Bacillus, Rhizobium, Pseudomonas, Serratia, Trichoderma, Clavibacter, Glomus or Gliocladium. Preferably, this heterologous gene is from Bacillus sp., the gene product having activity against the European corn borer and/or the Western corn rootworm. Particularly preferably, the heterologous gene originates from Bacillus thuringiensis. Within the context of the present invention, the composition according to the invention is applied to the seed either alone or in a suitable formulation. Preferably, the seed is treated in a state in which it is stable enough to avoid damage during treatment. In general, the seed may be treated at any point in time between harvest and sowing. The seed usually used has been separated from the plant and freed from cobs, shells, stalks, coats, hairs or the flesh of the fruits. Thus, it is possible to use, for example, seed which has been harvested, cleaned and dried to a moisture content of less than 15% by weight. Alternatively, it is also possible to use seed which, after drying, has been treated, for example, with water and then dried again.
When treating the seed, care must generally be taken that the amount of the composition according to the invention applied to the seed and/or the amount of further additives is chosen in such a way that the germination of the seed is not adversely affected, or that the resulting plant is not damaged. This must be borne in mind in particular in the case of active compounds which can have phytotoxic effects at certain application rates.
The compositions according to the invention can be applied directly, i.e. without containing any other components and undiluted. In general, it is preferred to apply the compositions to the seed in the form of a suitable formulation. Suitable formulations and methods for treating seed are known to the person skilled in the art and are described, for example, in the following documents: US 4,272,417 A, US 4,245,432 A, US 4,808,430 A, US 5,876,739 A, US 2003/0176428 Al , WO 2002/080675 Al, WO 2002/028186 A2. The active compounds which can be used in accordance with the invention can be converted into the customary seed-dressing formulations, such as solutions, emulsions, suspensions, powders, foams, slurries or other coating compositions for seed, and also ULV formulations.
These formulations are prepared in a known manner, by mixing the active compounds with customary additives such as, for example, customary extenders and also solvents or diluents, colorants, wetting agents, dispersants, emulsifiers, antifoams, preservatives, secondary thickeners, adhesives, gibberellins and also water.
Colorants which may be present in the seed-dressing formulations which can be used in accordance with the invention are all colorants which are customary for such purposes. In this context, not only pigments, which are sparingly soluble in water, but also dyes, which are soluble in water, may be used. Examples which may be mentioned are the colorants known by the names Rhodamin B, C.I. Pigment Red 112 and C.I. Solvent Red 1.
Suitable wetting agents which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which promote wetting and which are conventionally used for the formulation of agrochemical active compounds. Preference is given to using alkylnaphthalenesulphonates, such as diisopropyl- or diisobutylnaphthalenesulphonates.
Suitable dispersants and/or emulsifiers which may be present in the seed-dressing formulations which can be used in accordance with the invention are all nonionic, anionic and cationic dispersants conventionally used for the formulation of agrochemical active compounds. Preference is given to using nonionic or anionic dispersants or mixtures of nonionic or anionic dispersants. Suitable nonionic dispersants which may be mentioned are, in particular, ethylene oxide/propylene oxide block polymers, alkylphenol polyglycol ethers and tristryrylphenol polyglycol ether, and their phosphated or sulphated derivatives. Suitable anionic dispersants are, in particular, lignosulphonates, polyacrylic acid salts and arylsulphonate/formaldehyde condensates.
Antifoams which may be present in the seed-dressing formulations which can be used in accordance with the invention are all foam-inhibiting substances conventionally used for the formulation of agrochemical active compounds. Silicone antifoams and magnesium stearate can preferably be used. Preservatives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Dichlorophene and benzyl alcohol hemiformal may be mentioned by way of example.
Secondary thickeners which may be present in the seed-dressing formulations which can be used in accordance with the invention are all substances which can be employed for such purposes in agrochemical compositions. Cellulose derivatives, acrylic acid derivatives, xanthan, modified clays and finely divided silica are preferred.
Adhesives which may be present in the seed-dressing formulations which can be used in accordance with the invention are all customary binders which can be employed in seed-dressing products. Polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol and tylose may be mentioned as being preferred.
Gibberellins which can be present in the seed-dressing formulations which can be used in accordance with the invention are preferably the gibberellins Al , A3 (= gibberellic acid), A4 and A7; gibberellic acid is especially preferably used. The gibberellins are known (cf. R. Wegler "Chemie der Pflanzenschutz- und Schadlingsbekampfungsmittel" [Chemistry of crop protection agents and pesticides], vol. 2, Springer Verlag, 1970, p. 401 -412).
The seed-dressing formulations which can be used in accordance with the invention can be employed for the treatment of a wide range of seed, including the seed of transgenic plants, either directly or after previously having been diluted with water. In this context, additional synergistic effects may also occur in cooperation with the substances formed by expression.
All mixers which can conventionally be employed for the seed-dressing operation are suitable for treating seed with the seed-dressing formulations which can be used in accordance with the invention or with the preparations prepared therefrom by addition of water. Specifically, a procedure is followed during the seed-dressing operation in which the seed is placed into a mixer, the specific desired amount of seed-dressing formulations, either as such or after previously having been diluted with water, is added, and everything is mixed until the formulation is distributed uniformly on the seed. If appropriate, this is followed by a drying process. The active compounds or compositions according to the invention have a potent microbicidal activity and can be employed for controlling undesirable microorganisms, such as fungi and bacteria, in crop protection and in the protection of materials.
Fungicides can be employed in crop protection for controlling Plasmodiophoromycetes, Oomycetes, Chytridiomycetes, Zygomycetes, Ascomycetes, Basidiomycetes and Deuteromycetes. Bactericides can be employed in crop protection for controlling Pseudomonadaceae, Rhizobiaceae, Enterobacteriaceae, Corynebacteriaceae and Streptomycetaceae.
The fungicidal compositions according to the invention can be used for the curative or protective control of phytopathogenic fungi. Accordingly, the invention also relates to curative and protective methods for controlling phytopathogenic fungi using the active compounds or compositions according to the invention, which are applied to the seed, the plant or plant parts, the fruit or the soil in which the plants grow.
The compositions according to the invention for controlling phytopathogenic fungi in crop protection comprise an effective, but non-phytotoxic amount of the active compounds according to the invention. "Effective, but non-phytotoxic amount" means an amount of the composition according to the invention which is sufficient to control the fungal disease of the plant in a satisfactory manner or to eradicate the fungal disease completely, and which, at the same time, does not cause any significant symptoms of phytotoxicity. In general, this application rate may vary within a relatively wide range. It depends on a plurality of factors, for example on the fungus to be controlled, the plant, the climatic conditions and the ingredients of the compositions according to the invention.
The fact that the active compounds are well tolerated by plants at the concentrations required for controlling plant diseases permits the treatment of above-ground parts of plants, of propagation stock and seeds, and of the soil. All plants and plant parts can be treated in accordance with the invention. By plants are understood here all plants and plant populations such as desired and undesired wild plants or crop plants (including naturally occurring crop plants). Crop plants can be plants which can be obtained by conventional breeding and optimization methods or by biotechnological and genetic engineering methods or combinations of these methods, including the transgenic plants and including the plant varieties which can or cannot be protected by varietal property rights. Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. Parts of plants also include harvested plants and vegetative and generative propagation material, for example seedlings, tubers, rhizomes, cuttings and seeds.
The active compounds according to the invention are suitable for the protection of plants and plant organs, for increasing the harvest yields, for improving the quality of the harvested crop, while being well tolerated by plants, having favourable toxicity to warm-blooded species and being environmentally friendly. They may be preferably employed as crop protection agents. They are active against normally sensitive and resistant species and also against all or some stages of development.
The following plants may be mentioned as plants which can be treated according to the invention: cotton, flax, grapevine, fruit, vegetables, such as Rosaceae sp. (for example pome fruits such as apples and pears, but also stone fruits such as apricots, cherries, almonds and peaches, and soft fruits such as strawberries), Ribesioidae sp., Juglandaceae sp., Betulaceae sp., Anacardiaceae sp., Fagaceae sp., Moraceae sp., Oleaceae sp., Actinidaceae sp., Lauraceae sp., Musaceae sp. (for example banana plants and banana plantations), Rubiaceae sp. (for example coffee), Theaceae sp., Sterculiceae sp., Rutaceae sp. (for example lemons, oranges and grapefruit); Solanaceae sp. (for example tomatoes), Liliaceae sp., Asteraceae sp. (for example lettuce), Umbelliferae sp., Cruciferae sp., Chenopodiaceae sp., Cucurbitaceae sp. (for example cucumber), Alliaceae sp. (for example leeks, onions), Papilionaceae sp. (for example peas); maj or crop plants such as Gramineae sp. (for example maize, turf, cereals such as wheat, rye, rice, barley, oats, millet and triticale), Poaceae sp. (for example sugar cane), Asteraceae sp. (for example sunflower), Brassicaceae sp. (for example white cabbage, red cabbage, broccoli, cauliflower, Brussels sprouts, pak choi, kohlrabi, small radishes, and also oilseed rape, mustard, horseradish and cress), Fabacae sp. (for example beans, peanuts), Papilionaceae sp. (for example soya beans), Solanaceae sp. (for example potatoes), Chenopodiaceae sp. (for example sugar beet, fodder beet, Swiss chard, beetroot); useful plants and ornamental plants in gardens and forests; and in each case genetically modified types of these plants. As already mentioned above, it is possible to treat all plants and their parts according to the invention. In a preferred embodiment, wild plant species and plant cultivars, or those obtained by conventional biological breeding methods, such as crossing or protoplast fusion, and also parts thereof, are treated. In a further preferred embodiment, transgenic plants and plant cultivars obtained by genetic engineering, if appropriate in combination with conventional methods (Genetically Modified Organisms), and parts thereof are treated. The term "parts" or "parts of plants" or "plant parts" has been explained above. Particularly preferably, plants of the plant cultivars which are in each case commercially available or in use are treated according to the invention. Plant cultivars are to be understood as meaning plants having new properties ("traits") and which have been obtained by conventional breeding, by mutagenesis or by recombinant DNA techniques. They can be cultivars, varieties, bio- or genotypes.
The method of treatment according to the invention can be used in the treatment of genetically modified organisms (GMOs), e.g. plants or seeds. Genetically modified plants (or transgenic plants) are plants in which a heterologous gene has been stably integrated into the genome. The expression "heterologous gene" essentially means a gene which is provided or assembled outside the plant and when introduced in the nuclear, chloroplastic or mitochondrial genome gives the transformed plant new or improved agronomic or other properties by expressing a protein or polypeptide of interest or by downregulating or silencing other gene(s) which are present in the plant (using for example antisense technology, cosuppression technology or RNAi technology [RNA interference]). A heterologous gene that is located in the genome is also called a transgene. A transgene that is defined by its particular location in the plant genome is called a transformation or transgenic event.
Depending on the plant species or plant varieties, their location and growth conditions (soils, climate, vegetation period, diet), the treatment according to the invention may also result in superadditive ("synergistic") effects. Possible are thus, for example, the following effects which exceed the effects which were actually to be expected: reduced application rates and/or a widening of the activity spectrum and/or an increase in the activity of the active compounds and compositions which can be used according to the invention, better plant growth, increased tolerance to high or low temperatures, increased tolerance to drought or to water or soil salt content, increased flowering performance, easier harvesting, accelerated maturation, higher harvest yields, bigger fruits, larger plant height, greener leaf colour, earlier flowering, higher quality and/or a higher nutritional value of the harvested products, higher sugar concentration within the fruits, better storage stability and/or processability of the harvested products.
At certain application rates, the active compounds according to the invention may also have a strengthening effect on plants. Accordingly, they are suitable for mobilizing the defence system of the plant against attack by unwanted phytopathogenic fungi and/or microorganisms and/or viruses. This may, if appropriate, be one of the reasons for the enhanced activity of the combinations according to the invention, for example against fungi. Plant-strengthening (resistance-inducing) substances are to be understood as meaning, in the present context, also those substances or combinations of substances which are capable of stimulating the defence system of plants in such a way that, when subsequently inoculated with unwanted phytopathogenic fungi, the treated plants display a substantial degree of resistance to these unwanted phytopathogenic fungi. Thus, the substances according to the invention can be employed for protecting plants against attack by the abovementioned pathogens within a certain period of time after the treatment. The period within which protection is brought about generally extends from 1 to 10 days, preferably 1 to 7 days, after the treatment of the plants with the active compounds.
Plants and plant varieties which are preferably treated according to the invention include all plants which have genetic material which imparts particularly advantageous, useful traits to these plants (whether obtained by breeding and/or biotechnological means). Plants and plant varieties which are also preferably treated according to the invention are resistant against one or more biotic stress factors, i.e. said plants have a better defence against animal and microbial pests, such as against nematodes, insects, mites, phytopathogenic fungi, bacteria, viruses and/or viroids.
Plants and plant varieties which may also be treated according to the invention are those plants which are resistant to one or more abiotic stress factors. Abiotic stress conditions may include, for example, drought, cold temperature exposure, heat exposure, osmotic stress, waterlogging, increased soil salinity, increased exposure to minerals, exposure to ozone, exposure to strong light, limited availability of nitrogen nutrients, limited availability of phosphorus nutrients or shade avoidance. Plants and plant varieties which may also be treated according to the invention are those plants characterized by enhanced yield characteristics. Enhanced yield in said plants can be the result of, for example, improved plant physiology, growth and development, such as water use efficiency, water retention efficiency, improved nitrogen use, enhanced carbon assimilation, improved photosynthesis, increased germination efficiency and accelerated maturation. Yield can furthermore be affected by improved plant architecture (under stress and non-stress conditions), including early flowering, flowering control for hybrid seed production, seedling vigour, plant size, internode number and distance, root growth, seed size, fruit size, pod size, pod or ear number, seed number per pod or ear, seed mass, enhanced seed filling, reduced seed dispersal, reduced pod dehiscence and lodging resistance. Further yield traits include seed composition, such as carbohydrate content, protein content, oil content and composition, nutritional value, reduction in anti-nutritional compounds, improved processability and better storage stability.
Plants that may be treated according to the invention are hybrid plants that already express the characteristics of heterosis, or hybrid effect, which results in generally higher yield, vigour, health and resistance towards biotic and abiotic stress factors. Such plants are typically made by crossing an inbred male-sterile parent line (the female parent) with another inbred male-fertile parent line (the male parent). Hybrid seed is typically harvested from the male-sterile plants and sold to growers. Male-sterile plants can sometimes (e.g. in corn) be produced by detasseling (i.e. the mechanical removal of the male reproductive organs or male flowers) but, more typically, male sterility is the result of genetic determinants in the plant genome. In that case, and especially when seed is the desired product to be harvested from the hybrid plants, it is typically useful to ensure that male fertility in hybrid plants, which contain the genetic determinants responsible for male sterility, is fully restored. This can be accomplished by ensuring that the male parents have appropriate fertility restorer genes which are capable of restoring the male fertility in hybrid plants that contain the genetic determinants responsible for male sterility. Genetic determinants for male sterility may be located in the cytoplasm. Examples of cytoplasmic male sterility (CMS) were for instance described for Brassica species. However, genetic determinants for male sterility can also be located in the nuclear genome. Male-sterile plants can also be obtained by plant biotechnology methods such as genetic engineering. A particularly useful means of obtaining male-sterile plants is described in WO 89/10396 in which, for example, a ribonuclease such as a barnase is selectively expressed in the tapetum cells in the stamens. Fertility can then be restored by expression in the tapetum cells of a ribonuclease inhibitor such as barstar.
Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may be treated according to the invention are herbicide-tolerant plants, i.e. plants made tolerant to one or more given herbicides. Such plants can be obtained either by genetic transformation, or by selection of plants containing a mutation imparting such herbicide tolerance.
Herbicide-tolerant plants are for example glyphosate-tolerant plants, i.e. plants made tolerant to the herbicide glyphosate or salts thereof. For example, glyphosate-tolerant plants can be obtained by transforming the plant with a gene encoding the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS). Examples of such EPSPS genes are the AroA gene (mutant CT7) of the bacterium Salmonella typhimurium, the CP4 gene of the bacterium Agrobacterium sp., the genes encoding a petunia EPSPS, a tomato EPSPS, or an Eleusine EPSPS. It can also be a mutated EPSPS. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate oxidoreductase enzyme. Glyphosate-tolerant plants can also be obtained by expressing a gene that encodes a glyphosate acetyltransferase enzyme. Glyphosate-tolerant plants can also be obtained by selecting plants containing naturally occurring mutations of the abovementioned genes. Other herbicide-resistant plants are for example plants which have been made tolerant to herbicides inhibiting the enzyme glutamine synthase, such as bialaphos, phosphinothricin or glufosinate. Such plants can be obtained by expressing an enzyme detoxifying the herbicide or a mutant glutamine synthase enzyme that is resistant to inhibition. One such efficient detoxifying enzyme is, for example, an enzyme encoding a phosphinothricin acetyltransferase (such as the bar or pat protein from Streptomyces species for example). Plants expressing an exogenous phosphinothricin acetyltransferase have been described.
Further herbicide-tolerant plants are also plants that have been made tolerant to the herbicides inhibiting the enzyme hydroxyphenylpyruvatedioxygenase (HPPD). Hydroxyphenylpyruvatedioxygenases are enzymes that catalyse the reaction in which para-hydroxyphenylpyruvate (HPP) is transformed into homogentisate. Plants tolerant to HPPD inhibitors can be transformed with a gene encoding a naturally occurring resistant HPPD enzyme, or a gene encoding a mutated HPPD enzyme. Tolerance to HPPD inhibitors can also be obtained by transforming plants with genes encoding certain enzymes enabling the formation of homogentisate despite the inhibition of the native HPPD enzyme by the HPPD inhibitor. Tolerance of plants to HPPD inhibitors can also be improved by transforming plants with a gene encoding an enzyme prephenate dehydrogenase in addition to a gene encoding an HPPD-tolerant enzyme.
Further herbicide-resistant plants are plants that have been made tolerant to acetolactate synthase (ALS) inhibitors. Known ALS inhibitors include, for example, sulphonylurea, imidazolinone, triazolopyrimidines, pyrimidinyl oxy(thio)benzoates, and/or sulphonylaminocarbonyltriazolinone herbicides. Different mutations in the ALS enzyme (also known as acetohydroxy acid synthase, AHAS) are known to confer tolerance to different herbicides and groups of herbicides. The production of sulphonylurea-tolerant plants and imidazolinone-tolerant plants has been described in the international publication WO 1996/033270. Further sulphonylurea- and imidazolinone-tolerant plants have also been described, for example in WO 2007/024782.
Other plants tolerant to imidazolinone and/or sulphonylurea can be obtained by induced mutagenesis, by selection in cell cultures in the presence of the herbicide or by mutation breeding.
Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are insect-resistant transgenic plants, i.e. plants made resistant to attack by certain target insects. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such insect resistance.
In the present context, the term "insect-resistant transgenic plant" includes any plant containing at least one transgene comprising a coding sequence encoding: 1) an insecticidal crystal protein from Bacillus thuringiensis or an insecticidal portion thereof, such as the insecticidal crystal proteins listed online at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/, or insecticidal portions thereof, for example proteins of the Cry protein classes Cryl Ab, Cryl Ac, CrylF, Cry2Ab, Cry3Ae or Cry3Bb or insecticidal portions thereof; or
2) a crystal protein from Bacillus thuringiensis or a portion thereof which is insecticidal in the presence of a second other crystal protein from Bacillus thuringiensis or a portion thereof, such as the binary toxin made up of the Cy34 and Cy35 crystal proteins; or
3) a hybrid insecticidal protein comprising parts of two different insecticidal crystal proteins from Bacillus thuringiensis, such as a hybrid of the proteins of 1) above or a hybrid of the proteins of 2) above, for example the Cryl A.1 05 protein produced by maize event MON98034 (WO 2007/027777); or
4) a protein of any one of points 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation, such as the Cry3Bbl protein in maize events MON863 or MON88017, or the Cry3A protein in maize event MIR 604;
5) an insecticidal secreted protein from Bacillus thuringiensis or Bacillus cereus, or an insecticidal portion thereof, such as the vegetative insecticidal proteins (VIP) listed at: http://www.lifesci.sussex.ac.uk/Home/Neil_Crickmore/Bt/vip.html, e.g. proteins from the VIP3Aa protein class; or
6) a secreted protein from Bacillus thuringiensis or Bacillus cereus which is insecticidal in the presence of a second secreted protein from Bacillus thuringiensis or B. cereus, such as the binary toxin made up of the VTPl A and VIP2A proteins; 7) a hybrid insecticidal protein comprising parts from different secreted proteins from Bacillus thuringiensis or Bacillus cereus, such as a hybrid of the proteins in 1) above or a hybrid of the proteins in 2) above; or
8) a protein of any one of points 1) to 3) above wherein some, particularly 1 to 10, amino acids have been replaced by another amino acid to obtain a higher insecticidal activity to a target insect species, and/or to expand the range of target insect species affected, and/or because of changes induced in the encoding DNA during cloning or transformation (while still encoding an insecticidal protein), such as the VIP3Aa protein in cotton event COT 102.
Of course, insect-resistant transgenic plants, as used herein, also include any plant comprising a combination of genes encoding the proteins of any one of the above classes 1 to 8. In one embodiment, an insect-resistant plant contains more than one transgene encoding a protein of any one of the above classes 1 to 8, to expand the range of target insect species affected or to delay insect resistance development to the plants, by using different proteins insecticidal to the same target insect species but having a different mode of action, such as binding to different receptor binding sites in the insect.
Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are tolerant to abiotic stress factors. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such stress resistance. Particularly useful stress-tolerant plants include the following: a. plants which contain a transgene capable of reducing the expression and/or the activity of the poly(ADP-ribose)polymerase (PARP) gene in the plant cells or plants; b. plants which contain a stress tolerance-enhancing transgene capable of reducing the expression and/or the activity of the PARG-encoding genes of the plants or plant cells; c. plants which contain a stress tolerance-enhancing transgene coding for a plant-functional enzyme of the nicotinamide adenine dinucleotide salvage biosynthesis pathway, including nicotinamidase, nicotinate phosphoribosyltransferase, nicotinic acid mononucleotide adenyltransferase, nicotinami de adenine dinuc le otide synthetas e or nicotinamide phosphoribosyltransferase.
Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention show altered quantity, quality and/or storage stability of the harvested product and/or altered properties of specific ingredients of the harvested product such as, for example:
1) Transgenic plants which synthesize a modified starch which is altered with respect to its chemophysical traits, in particular the amylose content or the amylose/amylopectin ratio, the degree of branching, the average chain length, the distribution of the side chains, the viscosity behaviour, the gel resistance, the grain size and/or grain morphology of the starch in comparison to the synthesized starch in wild-type plant cells or plants, such that this modified starch is better suited for certain applications.
2) Transgenic plants which synthesize non-starch carbohydrate polymers or which synthesize non-starch carbohydrate polymers with altered properties in comparison to wild-type plants without genetic modification. Examples are plants which produce polyfructose, especially of the inulin and levan type, plants which produce alpha- 1,4-glucans, plants which produce alpha- 1,6- branched alpha- 1,4-glucans, and plants producing alternan.
3) Transgenic plants which produce hyaluronan. Plants or plant varieties (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as cotton plants, with altered fibre characteristics. Such plants can be obtained by genetic transformation, or by selection of plants containing a mutation imparting such altered fibre characteristics and include: a) plants, such as cotton plants, which contain an altered form of cellulose synthase genes; b) plants, such as cotton plants, which contain an altered form of rsw2 or rsw3 homologous nucleic acids; c) plants, such as cotton plants, with an increased expression of sucrose phosphate synthase; d) plants, such as cotton plants, with an increased expression of sucrose synthase; e) plants, such as cotton plants, wherein the timing of the plasmodesmatal gating at the basis of the fibre cell is altered, for example through downregulation of fibre-selective β-1,3- glucanase; f) plants, such as cotton plants, which have fibres with altered reactivity, for example through the expression of the N-acetylglucosaminetransferase gene including nodC and chitin synthase genes. Plants or plant cultivars (obtained by plant biotechnology methods such as genetic engineering) which may also be treated according to the invention are plants, such as oilseed rape or related Brassica plants, with altered oil profile characteristics. Such plants can be obtained by genetic transformation or by selection of plants containing a mutation imparting such altered oil characteristics and include: a) plants, such as oilseed rape plants, which produce oil having a high oleic acid content; b) plants, such as oilseed rape plants, which produce oil having a low linolenic acid content; c) plants, such as oilseed rape plants, which produce oil having a low level of saturated fatty acids.
Particularly useful transgenic plants which may be treated according to the invention are plants which comprise one or more genes which encode one or more toxins and are the transgenic plants available under the following trade names: YIELD GARD® (for example maize, cotton, soya beans), KnockOut® (for example maize), BiteGard® (for example maize), BT-Xtra® (for example maize), StarLink® (for example maize), Bollgard® (cotton), Nucotn® (cotton), Nucotn 33B® (cotton), NatureGard® (for example maize), Protecta® and NewLeaf® (potato). Examples of herbicide-tolerant plants which may be mentioned are maize varieties, cotton varieties and soya bean varieties which are available under the following trade names: Roundup Ready® (tolerance to glyphosate, for example maize, cotton, soya beans), Liberty Link® (tolerance to phosphinothricin, for example oilseed rape), IMI® (tolerance to imidazolinone) and SCS® (tolerance to sulphonylurea, for example maize). Herbicide-resistant plants (plants bred in a conventional manner for herbicide tolerance) which may be mentioned include the varieties sold under the name Clearfield® (for example maize).
Particularly useful transgenic plants which may be treated according to the invention are plants containing transformation events, or a combination of transformation events, and that are listed for example in the databases for various national or regional regulatory agencies (see for example http ://gmoinfo.jrc. ec. europa. eu/). Moreover, in the protection of materials, the active compounds or compositions according to the invention can be employed for protecting industrial materials against attack and destruction by unwanted microorganisms, such as, for example, fungi and insects.
Furthermore, the compounds according to the invention can be used alone or in combinations with other active compounds as antifouling compositions. Industrial materials in the present context are understood as meaning non-living materials which have been prepared for use in industry. For example, industrial materials which are intended to be protected by active compounds according to the invention from microbial change or destruction can be adhesives, sizes, paper, wallpaper, and board, textiles, carpets, leather, wood, paints and plastic articles, cooling lubricants and other materials which can be infected with, or destroyed by, microorganisms. Parts of production plants and buildings, for example cooling-water circuits, cooling and heating systems and ventilation and air-conditioning units, which may be impaired by the proliferation of microorganisms may also be mentioned within the scope of the materials to be protected. Industrial materials which may be mentioned within the scope of the present invention are preferably adhesives, sizes, paper and board, leather, wood, paints, cooling lubricants and heat- transfer liquids, particularly preferably wood. The active compounds or compositions according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decoloration or formation of mould. Moreover, the compounds according to the invention can be employed for protecting objects which come into contact with saltwater or brackish water, in particular hulls, screens, nets, buildings, moorings and signalling systems, against fouling. The method according to the invention for controlling unwanted fungi can also be employed for protecting storage goods. Here, storage goods are to be understood as meaning natural substances of vegetable or animal origin or processed products thereof of natural origin, for which long-term protection is desired. Storage goods of vegetable origin, such as, for example, plants or plant parts, such as stems, leaves, tubers, seeds, fruits, grains, can be protected freshly harvested or after processing by (pre)drying, moistening, comminuting, grinding, pressing or roasting. Storage goods also include timber, both unprocessed, such as construction timber, electricity poles and barriers, or in the form of finished products, such as furniture. Storage goods of animal origin are, for example, hides, leather, furs and hairs. The active compounds according to the invention may prevent disadvantageous effects, such as rotting, decay, discoloration, decolouration or formation of mould.
Some pathogens of fungal diseases which can be treated according to the invention may be mentioned by way of example, but not by way of limitation: diseases caused by powdery mildew pathogens, such as, for example, Blumeria species, such as, for example, Blumeria graminis; Podosphaera species, such as, for example, Podosphaera leucotricha; Sphaerotheca species, such as, for example, Sphaerotheca fuliginea; Uncinula species, such as, for example, Uncinula necator; diseases caused by rust disease pathogens, such as, for example, Gymnosporangium species, such as, for example, Gymnosporangium sabinae; Hemileia species, such as, for example, Hemileia vastatrix; Phakopsora species, such as, for example, Phakopsora pachyrhizi and Phakopsora meibomiae; Puccinia species, such as, for example, Puccinia recondita, Puccinia graminis, Puccinia striiformis or Puccinia triticina; Uromyces species, such as, for example, Uromyces appendiculatus; diseases caused by pathogens from the group of the Oomycetes, such as, for example, Albugo species, such as, for example, Albugo Candida; Bremia species, such as, for example, Bremia lactucae; Peronospora species, such as, for example, Peronospora pisi or P. brassicae; Phytophthora species, such as, for example, Phytophthora infestans; Plasmopara species, such as, for example, Plasmopara viticola; Pseudoperonospora species, such as, for example, Pseudoperonospora humuli or Pseudoperonospora cubensis; Pythium species, such as, for example, Pythium ultimum; leaf blotch diseases and leaf wilt diseases caused, for example, by Alternaria species, such as, for example, Alternaria solani; Cercospora species, such as, for example, Cercospora beticola; Cladiosporium species, such as, for example, Cladiosporium cucumerinum; Cochliobolus species, such as, for example, Cochliobolus sativus (conidia form: Drechslera, syn: Helminthosporium) or Cochliobolus miyabeanus; Colletotrichum species, such as, for example, Colletotrichum lindemuthanium; Cycloconium species, such as, for example, Cycloconium oleaginum; Diaporthe species, such as, for example, Diaporthe citri; Elsinoe species, such as, for example, Elsinoe fawcettii; Gloeosporium species, such as, for example, Gloeosporium laeticolor; Glomerella species, such as, for example, Glomerella cingulata; Guignardia species, such as, for example, Guignardia bidwelli; Leptosphaeria species, such as, for example, Leptosphaeria maculans or Leptosphaeria nodorum; Magnaporthe species, such as, for example, Magnaporthe grisea; Mycosphaerella species, such as, for example, Mycosphaerella graminicola, Mycosphaerella arachidicola or Mycosphaerella fijiensis; Phaeosphaeria species, such as, for example, Phaeosphaeria nodorum; Pyrenophora species, such as, for example, Pyrenophora teres or Pyrenophora tritici repentis; Ramularia species, such as, for example, Ramularia collo-cygni or Ramularia areola; Rhynchosporium species, such as, for example, Rhynchosporium secalis; Septoria species, such as, for example, Septoria apii or Septoria lycopersici; Typhula species, such as, for example, Typhula incarnata; Venturia species, such as, for example, Venturia inaequalis; root and stem diseases caused, for example, by Corticium species, such as, for example, Corticium graminearum; Fusarium species, such as, for example, Fusarium oxysporum; Gaeumannomyces species, such as, for example, Gaeumannomyces graminis; Plasmodiophora species, such as, for example, Plasmodiophora brassicae; Rhizoctonia species, such as, for example, Rhizoctonia solani; Sarocladium species, such as, for example, Sarocladium oryzae; Sclerotium species, such as, for example, Sclerotium oryzae; Tapesia species, such as, for example, Tapesia acuformis; Thielaviopsis species, such as, for example, Thielaviopsis basicola; ear and panicle diseases (including corn cobs) caused, for example, by Alternaria species, such as, for example, Alternaria spp.; Aspergillus species, such as, for example, Aspergillus flavus; Cladosporium species, such as, for example, Cladosporium cladosporioides; Claviceps species, such as, for example, Claviceps purpurea; Fusarium species, such as, for example, Fusarium culmorum; Gibberella species, such as, for example, Gibberella zeae; Monographella species, such as, for example, Monographella nivalis; diseases caused by smut fungi, such as, for example, Sphacelotheca species, such as, for example, Sphacelotheca reiliana; Tilletia species, such as, for example, Tilletia caries, T. controversa; Urocystis species, such as, for example, Urocystis occulta; Ustilago species, such as, for example, Ustilago nuda, U. nuda tritici; fruit rot caused, for example, by Aspergillus species, such as, for example, Aspergillus flavus; Botrytis species, such as, for example, Botrytis cinerea; Penicillium species, such as, for example, Penicillium expansum and Penicillium purpurogenum; Sclerotinia species, such as, for example, Sclerotinia sclerotiorum;
Verticilium species, such as, for example, Verticilium alboatrum; seed- and soil-borne rot and wilt diseases, and also diseases of seedlings, caused, for example, by Alternaria species, such as, for example, Alternaria brassicicola; Aphanomyces species, such as, for example, Aphanomyces euteiches; Ascochyta species, such as, for example, Ascochyta lentis; Aspergillus species, such as, for example, Aspergillus flavus; Cladosporium species, such as, for example, Cladosporium herbarum; Cochliobolus species, such as, for example, Cochliobolus sativus (conidia form: Drechslera, Bipolaris Syn: Helminthosporium); Colletotrichum species, such as, for example, Colletotrichum coccodes; Fusarium species, such as, for example, Fusarium culmorum; Gibberella species, such as, for example, Gibberella zeae; Macrophomina species, such as, for example, Macrophomina phaseolina; Micro dochium species, such as, for example, Microdochium nivale; Monographella species, such as, for example, Monographella nivalis; Penicillium species, such as, for example, Penicillium expansum; Phoma species, such as, for example, Phoma lingam; Phomopsis species, such as, for example, Phomopsis sojae; Phytophthora species, such as, for example, Phytophthora cactorum; Pyrenophora species, such as, for example, Pyrenophora graminea; Pyricularia species, such as, for example, Pyricularia oryzae; Pythium species, such as, for example, Pythium ultimum; Rhizoctonia species, such as, for example, Rhizoctonia solani; Rhizopus species, such as, for example, Rhizopus oryzae; Sclerotium species, such as, for example, Sclerotium rolfsii; Septoria species, such as, for example, Septoria nodorum; Typhula species, such as, for example, Typhula incarnata;
Verticillium species, such as, for example, Verticillium dahliae; cancerous diseases, galls and witches' broom caused, for example, by Nectria species, such as, for example, Nectria galligena; wilt diseases caused, for example, by Monilinia species, such as, for example, Monilinia laxa; deformations of leaves, flowers and fruits caused, for example, by Exobasidium species, such as, for example, Exobasidium vexans; Taphrina species, such as, for example, Taphrina deformans; degenerative diseases of woody plants caused, for example, by Esca species, such as, for example, Phaeomoniella chlamydospora, Phaeoacremonium aleophilum or Fomitiporia mediterranea; Ganoderma species, such as, for example, Ganoderma boninense; diseases of flowers and seeds caused, for example, by Botrytis species, such as, for example, Botrytis cinerea; diseases of plant tubers caused, for example, by Rhizoctonia species, such as, for example, Rhizoctonia solani; Helminthosporium species, such as, for example, Helminthosporium solani; diseases caused by bacterial pathogens, such as, for example, Xanthomonas species, such as, for example, Xanthomonas campestris pv. oryzae; Pseudomonas species, such as, for example, Pseudomonas syringae pv. lachrymans; Erwinia species, such as, for example, Erwinia amylovora.
Preference is given to controlling the following diseases of soya beans:
Fungal diseases on leaves, stems, pods and seeds caused, for example, by alternaria leaf spot (Alternaria spec, atrans tenuissima), anthracnose (Colletotrichum gloeosporoides dematium var. truncatum), brown spot (Septoria glycines), cercospora leaf spot and blight (Cercospora kikuchii), choanephora leaf blight (Choanephora infundibulifera trispora (Syn.)), dactuliophora leaf spot (Dactuliophora glycines), downy mildew (Peronospora manshurica), drechslera blight (Drechslera glycini), frogeye leaf spot (Cercospora sojina), leptosphaerulina leaf spot (Leptosphaerulina trifolii), phyllostica leaf spot (Phyllosticta sojaecola), pod and stem blight (Phomopsis sojae), powdery mildew (Microsphaera diffusa), pyrenochaeta leaf spot (Pyrenochaeta glycines), rhizoctonia aerial, foliage, and web blight (Rhizoctonia solani), rust (Phakopsora pachyrhizi, Phakopsora meibomiae), scab (Sphaceloma glycines), stemphylium leaf blight (Stemphylium botryosum), target spot (Corynespora cassiicola). Fungal diseases on roots and the stem base caused, for example, by black root rot (Calonectria crotalariae), charcoal rot (Macrophomina phaseolina), fusarium blight or wilt, root rot, and pod and collar rot (Fusarium oxysporum, Fusarium orthoceras, Fusarium semitectum, Fusarium equiseti), mycoleptodiscus root rot (Mycoleptodiscus terrestris), neocosmospora (Neocosmospora vasinfecta), pod and stem blight (Diaporthe phaseolorum), stem canker (Diaporthe phaseolorum var. caulivora), phytophthora rot (Phytophthora megasperma), brown stem rot (Phialophora gregata), pythium rot (Pythium aphanidermatum, Pythium irregulare, Pythium debaryanum, Pythium myriotylum, Pythium ultimum), rhizoctonia root rot, stem decay, and damping-off (Rhizoctonia solani), sclerotinia stem decay (Sclerotinia sclerotiorum), sclerotinia southern blight (Sclerotinia rolfsii), thielaviopsis root rot (Thielaviopsis basicola). Microorganisms capable of degrading or changing the industrial materials which may be mentioned are, for example, bacteria, fungi, yeasts, algae and slime organisms. The active compounds according to the invention preferably act against fungi, in particular moulds, wood-discoloring and wood-destroying fungi (Basidiomycetes), and against slime organisms and algae. Microorganisms of the following genera may be mentioned as examples: Alternaria, such as Alternaria tenuis; Aspergillus, such as Aspergillus niger; Chaetomium, such as Chaetomium globosum; Coniophora, such as Coniophora puetana; Lentinus, such as Lentinus tigrinus; Penicillium, such as Penicillium glaucum; Polyporus, such as Polyporus versicolor; Aureobasidium, such as Aureobasidium pullulans; Sclerophoma, such as Sclerophoma pityophila; Trichoderma, such as Trichoderma viride; Escherichia, such as Escherichia coli; Pseudomonas, such as Pseudomonas aeruginosa; Staphylococcus, such as Staphylococcus aureus.
In addition, the active compounds according to the invention also have very good antimycotic activity. They have a very broad antimycotic activity spectrum, in particular against dermatophytes and yeasts, moulds and diphasic fungi (for example against Candida species, such as Candida albicans, Candida glabrata), and Epidermophyton floccosum, Aspergillus species, such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species, such as Trichophyton mentagrophytes, Microsporon species such as Microsporon canis and audouinii. The list of these fungi by no means limits the mycotic spectrum covered, but is only for illustration.
Accordingly, the active compounds according to the invention can be used both in medical and in non-medical applications.
When using the active compounds according to the invention as fungicides, the application rates can be varied within a relatively wide range, depending on the kind of application. The application rate of the active compounds according to the invention is
• when treating plant parts, for example leaves: from 0.1 to 10 000 g/ha, preferably from 10 to 1000 g/ha, particularly preferably from 50 to 300 g/ha (when the application is carried out by watering or dripping, it is even possible to reduce the application rate, especially when inert substrates such as rock wool or perlite are used);
• when treating seed: from 2 to 200 g per 100 kg of seed, preferably from 3 to 150 g per 100 kg of seed, particularly preferably from 2.5 to 25 g per 100 kg of seed, very particularly preferably from 2.5 to 12.5 g per 100 kg of seed;
• when treating the soil: from 0.1 to 10 000 g/ha, preferably from 1 to 5000 g/ha.
The doses herein indicated are given as illustrative examples of the method according to the invention. A person skilled in the art will know how to adapt the application doses, notably according to the nature of the plant or crop to be treated.
The combination according to the invention can be used in order to protect plants within a certain time range after the treatment against pests and/or phytopathogenic fungi and/or microorganisms. The time range, in which protection is effected, spans in general 1 to 28 days, preferably 1 to 14 days, more preferably 1 to 10 days, even more preferably 1 to 7 days after the treatment of the plants with the combinations or up to 200 days after the treatment of plant propagation material. Furthermore combinations and compositions according to the invention may also be used to reduce the contents of mycotoxins in plants and the harvested plant material and therefore in foods and animal feed stuff made therefrom. Especially but not exclusively the following mycotoxins can be specified: Deoxynivalenole (DON), Nivalenole, 15-Ac-DON, 3-Ac-DON, T2- und HT2- Toxins, Fumonisines, Zearalenone Moniliformine, Fusarine, Diaceotoxyscirpenole (DAS), Beauvericine, Enniatine, Fusaroproliferine, Fusarenole, Ochratoxines, Patuline, Ergotalkaloides und Aflatoxines, which are caused for example by the following fungal diseases: Fusarium spec, like Fusarium acuminatum, F. avenaceum, F. crookwellense, F. culmorum, F. graminearum ( Gibberella zeae), F. equiseti, F. fujikoroi, F. musarum, F. oxysporum, F. proliferatum, F. poae, F. pseudograminearum, F. sambucinum, F. scirpi, F. semitectum, F. solani, F. sporotrichoides, F. langsethiae, F. subglutinans, F. tricinctum, F. verticillioides and others but also by Aspergillus spec., Penicillium spec, Claviceps purpurea, Stachybotrys spec, and others. Die erfindungsgemaBen Wirkstoffe eignen sich auch auf dem Veterinarsektor bei giinstiger Warmbliitertoxizitat zur Bekampfung von parasitischen Protozoen, die in der Tierhaltung und Tierzucht bei Nutz-, Zucht-, Zoo-, Labor-, Versuchs- und Hobbytieren vorkommen. Sie sind dabei gegen alle oder einzelne Entwicklungsstadien der Schadlinge wirksam.
Landwirtschaftliche Nutz- oder Zuchttiere sind z.B. Saugetiere wie Schafe, Ziegen, Pferde, Esel, Kamele, Biiffel, Kaninchen sowie insbesondere Rinder und Schweine oder Vogel wie Puten, Enten, Ganse und insbesondere Hiihner oder gegebenenfalls auch Insekten, wie z. B. Bienen.
Haustiere sind z.B. Saugetiere wie Hamster, Meerschweinchen, Ratten, Mause sowie insbeonsdere Hunde und Katzen oder auch Stubenvogel.
Eine bevorzugte Ausfuhrungsform ist die Anwendung bei Vogeln. Eine weitere bevorzugte Ausfuhrungsform ist die Anwendung bei Saugetieren.
Durch die Anwendung sollen Krankheiten, Todesfalle und Leistungsminderungen (z. B . bei Fleisch, Milch, Wolle, Hauten, Eiern, Honig usw.) verhindert oder vermindert werden, so dass durch den Einsatz der erfindungsgemaBen Wirkstoffe eine wirtschaftlichere und einfachere Tierhaltung moglich ist.
Die Anwendung der erfindungsgemaBen Wirkstoffe erfolgt im Veterinarsektor und bei der Tierhaltung in an sich bekannter Weise direkt oder in Form von geeigneten Zubereitungen enteral, parenteral, dermal, nasal. Die enterale Anwendung der Wirkstoffe geschieht z.B. oral in Form von Pulver, Zapfchen, Tabletten, Kapseln, Pasten, Tranken, Granulaten, Drenchen, Boli, medikiertem Futter oder Trinkwasser. Die dermale Anwendung geschieht z.B. in Form des Tauchens (Dippen), Spriihens (Sprayen), Badens, Waschens, AufgieBens (pour-on and spot-on) und des Einpuderns. Die parenterale Anwendung geschieht z.B. in Form der Injektion (intramuscular, subcutan, intravenos, intraperitoneal) oder durch Implantate. Die Anwendung kann sowohl prophylaktisch als auch therapeutisch erfolgen.
Zu den parasitischen Protozoen zahlen:
Mastigophora (Flagellata) wie z.B. Trypanosomatidae z.B. Trypanosoma b. brucei, T.b. gambiense, T.b. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, wie z.B. Trichomonadidae z.B. Giardia lamblia, G. canis.
Sarcomastigophora (Rhizopoda) wie Entamoebidae z.B. Entamoeba histolytica, Hartmanellidae z.B. Acanthamoeba sp., Harmanella sp.
Apicomplexa (Sporozoa) wie Eimeridae z.B. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anserina, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec, E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec, Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I. spec, I. suis, Cystisospora spec, Cryptosporidium spec, insbesondere C. parvum, wie Toxoplasmadidae z.B. Toxoplasma gondii, Hammondia heydornii, Neospora caninum, Besnoitia besnoitii, wie Sarcocystidae z.B. Sarcocystis bovicanis, S. bovihominis, S. ovicanis, S. ovifelis, S. neurona, S. spec, S. suihominis wie Leucozoidae z.B. Leucozytozoon simondi, wie Plasmodiidae z.B. Plasmodium berghei, P. falciparum, P. malariae, P. ovale, P. vivax,
P. spec, wie Piroplasmea z.B. Babesia argentina, B. bovis, B. canis, B. spec, Theileria parva,
Theileria spec, wie Adeleina z.B. Hepatozoon canis, H. spec.
The preparation of the active substances according to the invention of the formula [I] follows from the following examples. However, the invention is not restricted to these examples.
Production of intermediates of the formula [XIII] :
3-(Dimethylamino)-l-(3-thienyl)prop-2-en-l-one [XIII-1] 13.94 g l-(thiophen-3-yl)ethanone (110.5 mmol) and 21.9 mL N,N-dimethylformamide dimethyl acetal (165.7 mmol) are heated under reflux overnight. After cooling to room temperature, all volatile components are evaporated under vacuum. 19.27 g (96%) of 3-(dimethylamino)-l-(3- thienyl)prop-2-en-l -one are obtained as a light brown solid and used in the next step without further purification. logP (pH 2.7): 1.23
MS (ESI): 182.1 ([M+H]+)
'H-NMR (400 MHz, de-DMSO): δ = 8.17 (dd, 1H), 8.62 (d, 1H), 7.50 (m, 2H), 5.73 (d, 1H), 3.12 (s, 3H, br), 2.89 (s, 3H, br) ppm l-(5-Chloro-3-thienyl)-3-(dimethylamino)prop-2-en-l-one [XIII-2]
18.60 g l-(5-chloro-3-thienyl)ethanone (115.8 mmol) and 23.0 mL N,N-dimethylformamide dimethyl acetal (173.7 mmol) are heated under reflux for 5 h. After cooling to room temperature, all volatile components are evaporated under vacuum. 24.86 g (99%) of l-(5-chloro-3-thienyl)-3- (dimethylamino)prop-2-en-l-one are obtained as a brown solid and used in the next step without further purification. logP (pH 2.7): 1.82
MS (ESI): 216.0 ([M+H]+)
'H-NMR (400 MHz, de-DMSO): δ = 8.04 (d, 1H), 7.66 (d, 1H), 7.49 (d, 1H), 5.68 (d, 1H), 3.13 (s, 3H, br), 2.90 (s, 3H, br) ppm l-(2,5-Dichloro-3-thienyl)-3-(dimethylamino)prop-2-en-l-one [XIII-3]
15.70 g l-(2,5-dichloro-3-thienyl)ethanone (80.5 mmol) and 21.3 mL N,N-dimethylformamide dimethyl acetal (161.0 mmol) are heated under reflux overnight. After cooling to room
temperature, all volatile components are evaporated under vacuum. 20.22 g (100%) of 1 -(2,5- dichloro-3-thienyl)-3-(dimethylamino)prop-2-en-l-one are obtained as a brown solid and used in the next step without further purification. logP (pH 2.7): 2.27
MS (ESI): 250.0 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 7.63 (d, 1H), 7.34 (s, 1H), 5.48 (d, 1H), 3.14 (s, 3H, br), 2.88 (s, 3H, br) ppm
The following compound can be produced by the same process:
3-(Dimethylamino)-l-(2,5-dimethyl-3-thienyl)prop-2-en-l-one [XIII-4] logP (pH 2.7): 1.92
MS (ESI): 210.1 ([M+H]+) ¾-NMR (400 MHz, de-DMSO): δ = 7.54 (d, 1H), 7.00 (s, 1H), 5.44 (d, 1H), 3.09 (s, 3H, br), 2.84 (s, 3H, br), 2.54 (s, 3H), 2.35 (s, 3H) ppm
Production of intermediates of the formula [XIX] : 4-[5-(5-methyl-3-thienyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl]pyridine [XIX-1]
100 mg (0.19 mmol) of 4-[l-(tetrahydro-2H-pyran-2-yl)-5-(tributylstannyl)-lH-pyrazol-4- yl]pyridine and 68 mg (0.38 mmol) of 4-bromo-2-methylthiophene are stirred in 1 mL dimethylformamide. To this are added 33 mg of tetrakis(triphenylphosphine)-palladium(0) (0.02 mmol, 15 mol%) and 3 mg of copper(I) iodide (0.01 mmol, 10 mol.%) and the mixture is degassed for 5 mins with blanket gas. After this the mixture is heated at 45°C for 2h. Next, the crude mixture is filtered through a cartridge with Celite and the volatile components removed under vacuum. The crude product is purified by chromatography on silica gel (cyclohexane /ethyl acetate) and 26.2 mg of 4-[5-(5-methyl-3-thienyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl]pyridine (41%) are obtained as a colourless oil.
4-[5-(5-methyl-3-thienyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl]pyridine [XIX-1] logP (pH 2.7): 1.34
MS (ESI): 326.03 ([M+H]+)
Production of intermediates of the formula [XX] : 4-[3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine [XX-1]
The intermediates produced in the general procedure VI 3 can also be used in the deprotection reaction without further purification.
The protected thienylpyrazole [XIX-1] (26.2mg, 0.08mmol) crude product is dissolved in 2 mL methanol and treated with 800μΕ of HC1 in dioxane (4 molar). The solution is stirred at room temperature for lhr and then concentrated. The solid obtained is washed with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After drying and evaporation of the solvent 25.6 mg of 4-[3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine (54%) are obtained as a white solid.
4- [3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl] pyridine [XX-1 ] logP (pH 2.7): 0.67
MS (ESI): 242.04 ([M+H]+)
Production of intermediates of the formula [XXII] : N-methoxy-N,5-dimethylthiophene-3-carboxamide [XXII-1 ] At 0 °C, to a stirred solution of 5-methylthiophene-3-carboxylic acid (20 g, 140.8 mmol) in CH2CI2 (200 mL) was added oxalyl chloride (24.3 mL), DMF (4.0 mL) and the reaction mixture was stirred at rt for 4 h. The solvent was evaporated, co distilled with CH2CI2 and the residue was diluted with CH2CI2 (200 mL), then added DIPEA (73.5 mL, 422.4 mmol) at 0 °C, followed by Ν,Ο-dimethyl- hydroxylamine (20.5 g, 211.2 mmol) and stirred at rt for 16 h. The reaction mixture was diluted with CH2CI2 (200 mL) washed with IN HCl solution, followed by H2O, the separated organic layer was dried (Na2SO i) and concentrated. The residual compound was purified by column chromatography (Silica gel, 5-10% EtO Ac/Petrol ether) to afford N-methoxy-N,5- dimethylthiophene-3-carboxamide (12 g, 46.1%) as a liquid. MS (ESI): 185 ([M+H]+)
¾-NMR (400 MHz, CDCI3): δ = 7.80 (d, 1H), 7.20 (s, 1H, br), 3.65 (s, 3H), 3.33 (s, 3H), 2.47 (s, 3H) ppm.
Production of intermediates of the formula [VII] by process (V8): 3-(3-Thienyl)-lH-pyrazole [VII-1] 18.00 g 3-(dimethylamino)-l -(3-thienyl)prop-2-en-l -one (99.3 mmol) and 9.66 mL hydrazine hydrate (198.6 mmol) are dissolved in ethanol (100 mL) and heated under reflux for 15 h. After cooling to room temperature, all volatile components are evaporated under vacuum. The residue is dissolved in ethyl acetate and washed with half-saturated aqueous ammonium chloride solution and brine. The organic phase is dried over magnesium sulphate and concentrated to yield a yellow solid. The crude is triturated with hexanes/MTBE to give 13.76 g (92%) of 3-(3-thienyl)-lH- pyrazole as a slightly yellow solid. logP (pH 2.7): 1.39
MS (ESI): 151.1 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 12.90 (s, 1H, br), 7.81-7.37 (m, 4H, br), 6.58 (s, 1H, br) ppm 3-(5-Chloro-3-thienyl)-lH-pyrazole [VII-2]
23.00 g l-(5-chloro-3-thienyl)-3-(dimethylamino)prop-2-en-l-one (106.6 mmol) and 10.38 mL hydrazine hydrate (213.3 mmol) are dissolved in ethanol (100 mL) and heated under reflux for 15 h. After cooling to room temperature, all volatile components are evaporated under vacuum. The residue is dissolved in ethyl acetate and washed with half-saturated aqueous ammonium chloride solution and brine. The organic phase is dried over magnesium sulphate and concentrated to yield a brown solid. The crude is recrystallized from dichloromethane/hexanes to give 18.88 g (96%) of 3- (5-chloro-3-thienyl)-lH-pyrazole as an orange solid. logP (pH 2.7): 2.04
MS (ESI): 185.0 ([M+H]+)
'H-NMR (400 MHz, de-DMSO): δ = 13.00 (s, 1H, br), 7.75 (s, 1H, br), 7.64 (s, 1H, br), 7.47 (s, 1H, br), 6.60 (s, 1H, br) ppm
3-(2,5-Dichloro-3-thienyl)-lH-pyrazole [VII-3]
20.00 g l-(2,5-dichloro-3-thienyl)-3-(dimethylamino)prop-2-en-l-one (80.0 mmol) and 7.78 mL hydrazine hydrate (159.9 mmol) are dissolved in ethanol (75 mL) and heated under reflux for 15 h. After cooling to room temperature, all volatile components are evaporated under vacuum. The residue is dissolved in ethyl acetate and washed with half-saturated aqueous ammonium chloride solution and brine. The organic phase is dried over magnesium sulphate and concentrated to yield an off-white solid. The crude is triturated with hexanes to give 14.33 g (80%) of 3-(2,5-dichloro-3- thienyl)-lH-pyrazole as a white solid. logP (pH 2.7): 2.78 MS (ESI): 218.9 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 13.13 (s, 1H, br), 7.86 (s, 1H, br), 7.45 (s, 1H, br), 6.78 (s, 1H) ppm
3-(2,5-Dimethyl-3-thienyl)-lH-pyrazole [VII-4]
2.16 g 3-(dimethylamino)-l -(2,5-dimethyl-3-thienyl)prop-2-en-l-one (10.32 mmol) and 0.65 mL hydrazine hydrate (13.42 mmol) are dissolved in ethanol (10 mL) and heated under reflux for 15 h. After cooling to room temperature, all volatile components are evaporated under vacuum to yield 821 mg (44%>) of 3-(2,5-dimethyl-3-thienyl)-lH-pyrazole as a brown oil that is used in the next step without further purification. logP (pH 2.7): 2.07 MS (ESI): 179.1 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 12.80 (s, 1H, br), 7.68 (s, 1H, br), 6.98 (s, 1H), 6.42 (s, 1H), 2.50 (s, 3H), 2.38 (s, 3H) ppm
Production of intermediates of the formula [VII] by process (VI 6): 3-(5-methyl-3-thienyl)-lH-pyrazole [VII-;
A stirred solution of TMS acetylene (9.6 mL) in THF (90 mL) was cooled to -78 °C, added n-BuLi (1.4M in THF, 36.6 mL) and stirred at -78 °C to -50 °C for 1.5 h, then to the reaction mixture was added a solution of N-methoxy-N,5-dimethylthiophene-3-carboxamide (5 g, 27.0 mmol) in THF (134 mL) dropwise and stirred at -78 °C for lh. Thereafter, the solvent was evaporated and the reaction mixture was quenched with saturated NH4CI solution and concentrated. The residue was dissolved in EtOH, added NH2NH2xH20 (3.1 mL) at 0 °C and stirred at rt for 16 h. The residual compound was purified by column chromatography (Silica gel, 20% EtOAc/hexane) to afford 3-(5- methyl-3-thienyl)-lH-pyrazole (2 g, 45.1%) as a solid. MS (ESI): 165 ([M+H]+)
¾-NMR (400 MHz, CDCI3): δ = 7.58 (d, 1H), 7.28 (d, 1H), 7.08 (s, 1H), 6.44 (d, 1H), 2.49 (s, 3H) ppm.
Production of intermediates of the formula [V] : 4-bromo-3-(5-methyl-3-thienyl)-lH-pyrazole [V-l] A stirred solution of 3-(5-methyl-3-thienyl)-lH-pyrazole (50 mg, 0.3 mmol) in CCL (2 mL) was added NBS (106 mg, 0.6 mmol), stirred overnight at 70-75 °C and monitored by TLC. The reaction mixture was distilled and the residue was diluted with CHCI3 and H2O; layers separated, aqueous layer extracted twice with CHCI3 and washed with H2O. The separated CHCI3 layer was distilled and the residue was purified by column chromatography (Silica gel, 100-200 mesh) to afford 4- bromo-3-(5-methyl-3-thienyl)-lH-pyrazole (40 mg, 55.2%) as a liquid.
MS (ESI): 243,245 ([M+H]+)
¾-NMR (400 MHz, CDCI3): δ = 7.61 (d, 1H), 7.60 (s, 1H), 7.18 (s, 1H), 2.53 (s, 3H) ppm. Production of intermediates of the formula [VI] : l-Isopropyl-3-(3-thienyl)-lH-pyrazole [VI-1] To a solution of 3.75 g 3-(3-thienyl)-lH-pyrazole (25.0 mmol) in dry NN-dimethylformamide (50 mL) under argon is added sodium hydride (1.50 g, 60% suspension in mineral oil, 37.4 mmol) in portions. The mixture is stirred at room temperature for 15 min, then cooled to -10 °C under argon. Isopropyl iodide (3.74 mL, 37.4 mmol) is added dropwise at -10 °C, and the reaction mixture is stirred at room temperature overnight. The yellow suspension is poured into water (100 mL) and extracted with MTBE (3 x 70 mL). The combined organic phases are washed with water (70 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a yellow oil. The crude product is purified by silica gel chromatography (eluent: dichloromethane/methyl teri-butyl ether) to yield 3.28 g (68%) of l-isopropyl-3-(3-thienyl)-lH-pyrazole as a yellowish oil and 676 mg (14%) of l-isopropyl-5-(3-thienyl)-lH-pyrazole as a brown oil. Main isomer: l-isopropyl-3-(3-thienyl)-lH-pyrazole [VI-1]: logP (pH 2.7): 2.56
MS (ESI): 193.1 ([M+H]+)
'H-NMR (400 MHz, de-DMSO): δ = 7.75 (d, 1H), 7.70 (m, 1H), 7.55 (m, 1H), 7.46 (dd, 1H), 6.55 (d, 1H), 4.50 (m, 1H), 1.43 (d, 6H) ppm Minor isomer: l-isopropyl-5-(3-thienyl)-lH-pyrazole: logP (pH 2.7): 2.52
MS (ESI): 193.1 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 7.70 (m, 2H), 7.48 (d, 1H), 7.27 (dd, 1H), 6.32 (d, 1H), 4.62 (m, 1H), 1.38 (d, 6H) ppm 3-(5-Chloro-3-thienyl)-l-isopropyl-lH-pyrazole [VI-2]
To a solution of 7.58 g 3-(5-chloro-3-thienyl)-lH-pyrazole (41.1 mmol) in dry NN- dimethylformamide (100 mL) under argon is added sodium hydride (2.46 g, 60%> suspension in mineral oil, 61.6 mmol) in portions. The mixture is stirred at room temperature for 15 min, then cooled to -10 °C under argon. Isopropyl iodide (6.15 mL, 61.6 mmol) is added dropwise at -10 °C, and the reaction mixture is stirred at room temperature overnight. The brown reaction mixture is poured into water (400 mL) and extracted with MTBE (3 x 150 mL). The combined organic phases are washed with water (150 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a brown oil. The crude product is purified by silica gel chromatography (eluent: dichloromethane/methyl teri-butyl ether) to yield 5.14 g (55%>) of 3-(5-chloro-3-thienyl)-l- isopropyl- lH-pyrazole as a yellowish oil and 863 mg (9%>) of 5-(5-chloro-3-thienyl)-l -isopropyl- lH-pyrazole as a brown oil.
Main isomer: 3-(5-chloro-3-thienyl)-l-isopropyl-lH-pyrazole [VI-2] logP (pH 2.7): 3.51
MS (ESI): 227.0 ([M+H]+) 'H-NMR (400 MHz, de-DMSO): δ 7.77 (d, 1H), 7.60 (d, 1H), 7.44 (d, 1H), 6.57 (d, 1H), 4.50 (m, 1H), 1.42 (d, 6H) ppm
Minor isomer: 5-(5-chloro-3-thienyl)-l-isopropyl-lH-pyrazole logP (pH 2.7): 3.30 MS (ESI): 227.0 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 7.60 (d, 1H), 7.49 (d, 1H), 7.33 (d, 1H), 6.36 (d, 1H), 4.61 (m, 1H), 1.38 (d, 6H) ppm
3-(2,5-Dichloro-3-thienyl)-l-isopropyl-lH-pyrazole [VI-3]
To a solution of 2.51 g 3-(2,5-dichloro-3-thienyl)-lH-pyrazole (11.5 mmol) in dry N,N- dimethylformamide (25 mL) under argon is added sodium hydride (0.92 g, 60% suspension in mineral oil, 22.9 mmol) in portions. The mixture is stirred at room temperature for 15 min, then cooled to -10 °C under argon. Isopropyl iodide (2.29 mL, 22.9 mmol) is added dropwise at -10 °C, and the reaction mixture is stirred at room temperature overnight. The brown reaction mixture is poured into water (200 mL) and extracted with MTBE (3 x 70 mL). The combined organic phases are washed with water (80 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a brown oil. The crude product is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 2.39 g (80%>) of 3-(2,5-dichloro-3-thienyl)-l -isopropyl- lH-pyrazole as a yellowish oil and 134 mg (4%>) of 5-(2,5-dichloro-3-thienyl)-l -isopropyl-lH- pyrazoleas a yellow oil. Main isomer: 3-(2,5-dichloro-3-thienyl)-l-isopropyl-lH-pyrazole [VI-3] logP (pH 2.7): 4.85
MS (ESI): 261.1 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 7.88 (d, 1H), 7.41 (s, 1H), 6.74 (d, 1H), 4.54 (m, 1H), 1.44 (d, 6H) ppm Minor isomer: 5-(2,5-dichloro-3-thienyl)-l-isopropyl-lH-pyrazole logP (pH 2.7): 4.01
MS (ESI): 261.1 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 7.57 (d, 1H), 7.30 (s, 1H), 6.35 (d, 1H), 4.30 (m, 1H), 1.35 (d, 6H) ppm
3-(2,5-Dimethyl-3-thienyl)-l-isopropyl-lH-pyrazole [VI-4]
To a solution of 829 mg 3-(2,5-dimethyl-3-thienyl)-lH-pyrazole (4.6 mmol) in dry NN- dimethylformamide (10 mL) under argon is added sodium hydride (274 mg, 60% suspension in mineral oil, 6.8 mmol) in portions. The mixture is stirred at room temperature for 15 min, then cooled to -10 °C under argon. Isopropyl iodide (0.68 mL, 9.1 mmol) is added dropwise at -10 °C, and the reaction mixture is stirred at room temperature overnight. The yellow suspension is poured into water (50 mL) and extracted with MTBE (3 x 70 mL). The combined organic phases are washed with water (70 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a yellow oil. The crude product is purified by silica gel chromatography (eluent: dichloromethane/methyl tert-butyl ether) to yield 590 mg (59%) of 3-(2,5-dimethyl-3-thienyl)-l- isopropyl-lH-pyrazole as a yellowish oil and 300 mg (30%) of 5-(2,5-dimethyl-3-thienyl)-l - isopropyl-lH-pyrazole as a yellow oil.
Main isomer: 3-(2,5-dimethyl-3-thienyl)-l-isopropyl-lH-pyrazole [VI-4] logP (pH 2.7): 3.72
MS (ESI): 221.1 ([M+H]+)
'H-NMR (400 MHz, de-DMSO): δ = 7.75 (d, 1H), 6.96 (s, 1H), 6.39 (d, 1H), 4.49 (m, 1H), 2.51 (s, 3H), 2.37 (s, 3H), 1.43 (d, 6H) ppm
Minor isomer: 5-(2,5-dimethyl-3-thienyl)-l-isopropyl-lH-pyrazole logP (pH 2.7): 3.46
MS (ESI): 221.1 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 7.50 (d, 1H), 6.67 (s, 1H), 6.17 (d, 1H), 4.29 (m, 1H), 2.41 (s, 3H), 2.23 (s, 3H), 1.32 (d, 6H) ppm l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazole [VI-5] To a stirred solution of 3-(5-methyl-3-thienyl)-lH-pyrazole (100 mg, 0.61 mmol) in THF (3 mL), KOH (37.6 mg, 0.67 mmol) was added, followed by the addition of Isopropyl bromide (147.5 mg, 1.2 mmol), the temperature of the reaction was raised to 60-65 °C and stirred overnight. Solvent was evaporated and the residue was extracted with EtOAc, washed with H20 and concentrated. The residual compound was purified by column chromatography (Silica gel, 30% MDC/n-hexane) to yield l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazole as an oil.
'H-NMR (400 MHz, CDC13): δ = 7.38 (d, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 6.37 (d, 1H), 4.51 (m, 1H), 2.50 (s, 3H), 1.52 (d, 6H) ppm.
Production of intermediates of the formula [IV] by process (VI) : 4-Iodo-l-isopropyl-3-(3-thienyl)-lH-pyrazole [IV-1]
To a solution of 3.13 g l-isopropyl-3-(3-thienyl)-lH-pyrazole (16.3 mmol) in dry NN- dimethylformamide (50 mL) under argon is added N-iodosuccinimide (4.03 g, 17.9 mmol) at -10 °C. The reaction mixture is stirred at room temperature for 2 d. Aqueous 5% sodium thiosulfate (100 mL) and saturated aqueous sodium carbonate solution (70 mL) are added and the mixture is stirred at room temperature for 1 h, then extracted with MTBE (3 x 80 mL). The combined organic phases are washed with water (70 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a yellow oil. The crude product is purified by silica gel
chromatography (eluent: cyclohexane/ethyl acetate) to yield 4.78 g (90%) 4-iodo-l-isopropyl-3-(3- thienyl)-lH-pyrazole as a slightly yellow oil. logP (pH 2.7): 3.67
MS (ESI): 319.0 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 8.04 (s, 1H), 7.93 (dd, 1H), 7.61 (m, 1H), 7.54 (dd, 1H), 4.52 (m, 1H), 1.43 (d, 6H) ppm
3-(5-Chloro-3-thienyl)-4-iodo-l-isopropyl-lH-pyrazole [IV-2] To a solution of 5.00 g 3-(5-chloro-3-thienyl)-l-isopropyl-lH-pyrazole (20.5 mmol) in dry NN- dimethylformamide (50 mL) under argon is added N-iodosuccinimide (5.08 g, 22.6 mmol) at -10 °C. The reaction mixture is stirred at room temperature for 2 d. Aqueous 5% sodium thiosulfate (150 mL) and saturated aqueous sodium carbonate solution (100 mL) are added and the mixture is stirred at room temperature for 1 h, then extracted with MTBE (3 x 120 mL). The combined organic phases are washed with water (70 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a light brown oil. The crude product is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 7.43 g (100%) 3-(5-chloro-3- thienyl)-4-iodo-l-isopropyl-lH-pyrazole as a slightly yellow oil. logP (pH 2.7): 4.76 MS (ESI): 352.9 ([M+H]+) 'H-NMR (400 MHz, de-DMSO): δ = 8.05 (s, 1H), 7.84 (d, 1H), 7.46 (d, 1H), 4.51 (m, 1H), 1.43 (d, 6H) ppm
3- (2,5-Dichloro-3-thienyl)-4-iodo-l-isopropyl-lH-pyrazole [IV-3]
To a solution of 4.69 g 3-(2,5-dichloro-3-thienyl)-l-isopropyl-lH-pyrazole (17.9 mmol) in dry NN-dimethylformamide (50 mL) under argon is added N-iodosuccinimide (4.42 g, 19.7 mmol) at -10 °C. The reaction mixture is stirred at room temperature for 2 d. The reaction mixture is heated to 105 °C for 4 h, then cooled to room temperature. Another portion of N-iodosuccinimide ( 1.00 g, 4.4 mmol) is added and the reaction mixture is stirred at 105 °C overnight. After cooling to room temperature, aqueous 5% sodium thiosulfate (150 mL) and saturated aqueous sodium carbonate solution (100 mL) are added and the mixture is stirred at room temperature for 1 h, then extracted with MTBE (3 x 150 mL). The combined organic phases are washed with water (100 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a yellow oil. The crude product is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 6.78 g (97%) 3-(2,5-dichloro-3-thienyl)-4-iodo-l-isopropyl-lH-pyrazole as a slightly yellow oil. logP (pH 2.7): 5.03
MS (ESI): 386.9 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 8.10 (s, 1H), 7.25 (s, 1H), 4.54 (m, 1H), 1.42 (d, 6H) ppm
4- bromo-l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazole [IV-4] To a stirred solution of 4-bromo-3-(5-methyl-3-thienyl)-lH-pyrazole (40 mg, 0.16 mmol) in THF (2 mL) was added KOH (18 mg, 0.32 mmol), isopropyl bromide (29 mg, 0.24 mmol) and the temperature of the reaction mixture was raised to 55-60 °C, stirred overnight and monitored by TLC. The solvent was evaporated, added EtOAc, followed by ¾0, dried (Na2S04) and concentrated. The residual compound was purified by column chromatography (Silica gel) to afford 4-bromo-l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazole (10 mg, 22.2%) as a liquid (in a 88:12 mixture of regioisomers). logP (pH 2.7): 4.15
MS (ESI): 285,287 ([M+H]+)
¾-NMR (400 MHz, CD3CN): δ = 7.71 (s, 1H), 7.67 (d, 1H), 7.29 (s, 1H), 4.49 (m, 1H), 2.52 (s, 3H), 1.48 (d, 6H) ppm. 3-(2,5-Dimethyl-3-thienyl)-4-iodo-l-isopropyl-lH-pyrazole [IV-5]
To a solution of 580 mg 3-(2,5-dimethyl-3-thienyl)-l-isopropyl-lH-pyrazole (2.63 mmol) in dry NN-dimethylformamide (10 mL) under argon is added N-iodosuccinimide (651 mg, 2.90 mmol) at 0 °C. The reaction mixture is stirred at room temperature overnight. Another portion of N- iodosuccinimide (118 mg, 0.53 mmol) is added and the reaction mixture is stirred overnight at room temperature. Aqueous 5% sodium thiosulfate (100 mL) and saturated aqueous sodium carbonate solution (70 mL) are added and the mixture is stirred at room temperature for 20 min, then extracted with MTBE (3 x 80 mL). The combined organic phases are washed with water (100 mL) and brine, dried over magnesium sulphate and concentrated to give the crude product as a yellow oil. The crude product is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 890 mg (93%) 3-(2,5-dimethyl-3-thienyl)-4-iodo-l-isopropyl-lH-pyrazole as a slightly yellow oil. logP (pH 2.7): 4.43
MS (ESI): 347.0 ([M+H]+) 'H-NMR (400 MHz, de-DMSO): δ = 8.00 (s, 1H), 6.87 (s, 1H), 4.50 (m, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 1.42 (d, 6H) ppm
Production of intermediates of the formula [II] by process (V4) : 4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-amine [II-l]
1,4-Dioxane and aqueous 2M sodium carbonate solution are degassed by bubbling a flow of argon through the solutions for 10 min. 2.06 g 4-iodo-l-isopropyl-3-(3-thienyl)-lH-pyrazole (6.15 mmol) are weighed into a 100 mL three-necked round bottom flask equipped with a reflux condenser and an internal thermometer. 36.8 mL degassed 1,4-dioxane, 2.36 g tert-butyl [4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl]carbamate (7.38 mmol), 454 m g o f bis(tricyclohexylphosphine)palladium(II) dichloride (0.62 mmol) and 12.3 mL degassed 2M sodium carbonate solution are added quickly. The reaction mixture is degassed by a flow of argon again for 1 min, then heated to reflux under argon for 3 h. After cooling to room temperature, the mixture was concentrated to half of its original volume and filtered through a short pad of silica with ethyl acetate. The filtrate is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated. The residue is dissolved in tert-butanol (10 mL) and dichloromethane (10 mL) and treated with 1.34 g di-tert-butyl dicarbonate (6.15 mmol) at room temperature for 2 d. The reaction mixture is evaporated under vacuum and purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 1.69 g (72%) of the intermediate tert-butyl {4-[l - isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl}carbamate as a white solid.
1.49 g Tert-butyl {4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl}carbamate (3.87 mmol) is dissolved in 35 mL dichloromethane and cooled to 0 °C. Trifluoroacetic acid (1.19 mL, 15.46 mmol) is added at 0 °C and the mixture is stirred at room temperature overnight. Another portion of trifluoroacetic acid (1.50 mL, 19.47 mmol) is added and the reaction mixture is stirred overnight. Another portion of trifluoroacetic acid (0.50 mL, 6.49 mmol) is added and the reaction mixture is stirred for 2 h. Saturated aqueous sodium carbonate solution is added and the reaction mixture is extracted with dichloromethane. The combined organic layers are washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to yield 1.11 g 4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-amine (99%) as a white solid.
4-[l-Isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-amine [II-l] logP (pH 2.7): 1.06
MS (ESI): 285.1 ([M+H]+) Ti-NMR (400 MHz, de-DMSO): δ = 8.02 (s, 1H), 7.83 (d, 1H), 7.54 (m, 1H), 7.46 (m, 1H), 7.17 (dd, 1H), 6.40 (d, 1H), 5.85 (s, 2H, br), 4.52 (m, 1H), 1.47 (d, 6H) ppm
The Intermediate Tert-butyl {4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl}carbamate can be isolated and is characterised as follows logP (pH 2.7): 2.93 MS (ESI): 385.2 ([M+H]+)
¾-NMR (400 MHz, de-DMSO): δ = 9.70 (s, 1H), 8.16 (s, 1H), 8.13 (dd, 1H), 7.81 (d, 1H), 7.55 (m, 1H), 7.47 (m, 1H), 7.14 (dd, 1H), 6.87 (dd, 1H), 4.56 (m, 1H), 1.48 (d, 6H), 1.45 (s, 9H) ppm
Production of compounds of the formula [I] by process (V4)
4-[3-(5-Chloro-3-thienyl)-l-isopropyl-lH-pyrazol-4-yl]pyridine [1-1] {example 143} 1,4-Dioxane and aqueous 2M sodium carbonate solution are degassed by bubbling a flow of argon through the solutions for 10 min. 123.0 mg 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (0.60 mmol) and 36.9 mg bis(tricyclohexylphosphine)-palladium(II) dichloride (0.05 mmol) are weighed into a microwave vial (2-5 mL reaction volume). 176.3 mg 3-(5-chloro-3-thienyl)-4-iodo- 1-isopropyl-lH-pyrazole (0.50 mmol) are dissolved in 3.3 mL of degassed 1,4-dioxane and transferred to the reaction vial. 1.1 niL degassed 2M sodium carbonate solution is added quickly. The reaction mixture is degassed by a flow of argon again for 20 s. The microwave vial is closed with a septum cap and the reaction mixture is irradiated in a microwave oven to a temperature of 140 °C for 20 min. After cooling to room temperature, the orange-brown reaction mixture is diluted with ethyl acetate (3.0 mL) and filtered through a short pad of silica with ethyl acetate (2 x 5 mL). The combined filtrates are evaporated under vacuum and purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 99.1 g (61%) 4-[3-(5-Chloro-3-thienyl)-l-isopropyl- lH-pyrazol-4-yl]pyridine as a colorless oil. logP (pH 2.7): 1.48 MS (ESI): 304.1 ([M+H]+)
1H-NMR (400 MHz, de-DMSO): δ = 8.51 (dd, 2H), 8.25 (s, 1H), 7.37 (d, 1H), 7.31 (dd, 2H), 7.12 (d, 1H), 4.54 (m, 1H), 1.48 (d, 6H) ppm
4-[3-(5-Chloro-3-thienyl)-l-isopropyl-lH-pyrazol-4-yl]-3-fluoropyridine [1-2] {example 31}
1,4-Dioxane and aqueous 2M sodium carbonate solution are degassed by bubbling a flow of argon through the solutions for 10 min. 167.0 mg 3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine (0.75 mmol) and 36.6 mg l, -bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.05 mmol) are weighed into a microwave vial (2-5 mL reaction volume). 186.0 mg 3-(5-chloro-3- thienyl)-4-iodo-l-isopropyl-lH-pyrazole (0.50 mmol) are dissolved in 3.0 mL of degassed 1,4-dioxane and transferred to the reaction vial. 1.0 mL degassed 2M sodium carbonate solution is added quickly. The reaction mixture is degassed by a flow of argon again for 1 min. The microwave vial is closed with a septum cap and the reaction mixture is irradiated in a microwave oven to a temperature of 140 °C for 12 min. After cooling to room temperature, the black reaction mixture is diluted with dioxane (5.0 mL) and filtered through a short pad of silica with ethyl acetate (3 x 5 mL). The combined filtrates are evaporated under vacuum and purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 143.4 g (87%) 4-[3-(5-chloro-3- thienyl)-l-isopropyl-lH-pyrazol-4-yl]-3-fluoropyridine as a yellow oil. logP (pH 2.7): 3.35
MS (ESI): 322.0 ([M+H]+)
1H-NMR (400 MHz, de-DMSO): δ = 8.60 (d, 1H), 8.39 (dd, 1H), 8.17 (d, 1H), 7.35 (dd, 1H), 7.28 (d, 1H), 7.12 (d, 1H), 4.59 (m, 1H), 1.48 (d, 6H) ppm Production of compounds of the formula [I-a] by process (V6):
N-{4-[l-Isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl}cyclopropanecarboxamide [I-a- 1] {example 25} and
N-(Cyclopropylcarbonyl)-N-{4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2- yljcyclopropanecarboxamide [I-a-2] {example 42}
0.18 mL cyclopropanecarbonyl chloride (1.94 mmol) is added dropwise to a solution of 183.4 mg 4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-amine (0.65 mmol) and 0.27 mL triethylamine (1.94 mmol) in dichloromethane (2.5 mL). The mixture is stirred at room temperature overnight and diluted with 2.5 mL dichloromethane. 2.0 mL of the reaction mixture are adsorbed on Kieselgur and purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 89.2 mg (31 %) N-(cyclopropylcarbonyl)-N- {4- [1 -isopropyl-3-(3 -thienyl)- 1 H-pyrazol-4-yl]pyridin- 2-yl}cyclopropanecarboxamide as a white solid.
N-(Cyclopropylcarbonyl)-N-{4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2- yljcyclopropanecarboxamide [I-a-2] {example 42} logP (pH 2.7): 3.31
MS (ESI): 421.2 ([M+H]+)
1H-NMR (400 MHz, de-DMSO): δ = 8.47 (dd, 1H), 8.36 (s, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.37 (dd, 1H), 7.33 (d, 1H), 7.17 (dd, 1H), 4.54 (m, 1H), 1.95 (m, 2H), 1.49 (d, 6H), 0.95 (m, 4H), 0.90 (m, 4H) ppm The remaining reaction solution is evaporated under vacuum and treated with a solution of ammonia in methanol (7N, 3.0 mL, 21.0 mmol) at room temperature overnight. After concentration of the reaction mixture, the residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate) to yield 102.9 mg (44%) N- {4-[l-isopropyl-3-(3-thienyl)-lH-pyrazol-4- yl]pyridin-2-yl}cyclopropanecarboxamide as a white solid. N-{4-[l-Isopropyl-3-(3-thienyl)-lH-pyrazol-4-yl]pyridin-2-yl}cyclopropanecarboxamide [I-a- 1] {example 25} logP (pH 2.7): 1.91
MS (ESI): 353.1 ([M+H]+)
1H-NMR (400 MHz, de-DMSO): δ = 10.75 (s, 1H), 8.19 (dd, 1H), 8.12 (s, 1H), 8.11 (m, 1H), 7.54 (m, 1H), 7.47 (m, 1H), 7.14 (dd, 1H), 6.91 (dd, 1H), 4.55 (m, 1H), 2.00 (m, 1H), 1.48 (d, 6H), 0.80 (m, 4H) ppm
Production of compounds of the formula [I-b] by process (VI):
4-[l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine [I-b-1] 21mg (0.08 mmol) of 4-[5-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine are dissolved in 0.3mL Ν,Ν-dimethylformamide. 5mg of sodium hydride (1.3eq) as a 60% suspension in oil are added to this and the mixture is stirred for 20 mins at 25°C. Next, 22mg of isopropyl iodide (0.12 mmol) are added and the reaction mixture is stirred overnight at 25°C. For the workup, acetic acid (concentrated) is slowly added (0.2 eq) and then all volatile components are removed under high vacuum. The residue is dissolved in water and extracted several times with ethyl acetate. Next, the organic phase is dried (Na2SO i) and concentrated. Purification is effected by silica gel chromatography with the eluent cyclohexane (A) / ethyl acetate (B) (0%> B up to 100%) B). 7mg of a (66:34) mixture of 4-[l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine [I-b-1] and the regioisomer 4-[l-isopropyl-5-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine are obtained as a colourless solid.
4-[l-isopropyl-3-(5-methyl-3-thienyl)-lH-pyrazol-4-yl]pyridine [I-b-1] {Example No 6} logP (pH 2.7): 1.38
MS (ESI): 284.1 ([M+H]+) 1H-NMR (400 MHz, de-DMSO): δ = 8.48 (dd, 2H), 8.22 (s, 1H), 7.31 (dd, 2H), 7.18 (d, 1H), 6.87 (d, 1H), 4.52 (m, 1H), 2.44 (s, 3H), 1.48 (d, 6H) ppm
The compounds of the formula [I] named in the following Tables I and II are also obtained by the aforesaid methods.
Figure imgf000084_0001
(I) Table 1
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
[c] The examples 1, 2, 3 and 4 are hydrochloride salts. Table 2 NMR and Mass spectroscopic / logP data of compounds of the type [I]
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
1 The stated logP value is the value for the stated pure compound or, if a mixture is present, for the main isomer (1 -substituted 3-aryl-lH-pyrazole).
2 The stated mass is the peak of the isotope pattern of the [M+H]+ ion with the highest intensity; if the [M-H]- ion was detected,
3 In the determination of the logP values, the methods described below were used.
Method A Note on the determination of the logP values and mass detection: The stated logP values were determined in accordance with EEC-Directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on a reverse phase column (CI 8). Agilent 1 100 LC system; 50*4.6 Zorbax Eclipse Plus C18 1.8 micron; eluent A: acetonitrile (0.1% formic acid); eluent B: water (0.09%> formic acid); linear gradient from 10%> acetonitrile to 95% acetonitrile in 4.25 mins, then 95% acetonitrile for a further 1.25 mins; oven temperature 55°C; flow rate: 2.0 mL/min. The mass detection was effected with an Agilend MSD system.
Method B Note on the determination of the logP values and mass detection: The stated logP values were determined in accordance with EEC-Directive 79/831 Annex V.A8 by HPLC (High Performance Liquid Chromatography) on a reverse phase column (C18). HP1100; 50*4.6 Zorbax Eclipse Plus C18 1.8 micron; eluent A: acetonitrile (0.1% formic acid); eluent B: water (0.08% formic acid); linear gradient from 5% acetonitrile to 95% acetonitrile in 1.70 min, then 95% acetonitrile for a further 1.00 min; oven temperature 55°C; flow rate: 2.0 mL/min. The mass detection was effected with the Micronass ZQ2000 mass detector from Waters. Method C Note on the determination of the logP values and mass detection: The stated logP values were determined in accordance with EEC-Directive 79/83 1 Annex V.A8 by UPLC (Ultra Performance Liquid Chromatography) on a reverse phase column (CI 8). HP1100; 50*2.1 Zorbax Eclipse Plus C18 1.8 micron; eluent A: acetonitrile (0.09% formic acid); eluent B: water (0.1% formic acid); linear gradient from 10% A to 95% A in 3.25 min; oven temperature 40°C; flow rate: 0.8 mL/min. The mass detection was effected with the LCT Premier or SQD mass detector from Waters.
Calibration was performed with unbranched alkan-2-ones (with 3 to 16 carbon atoms), whose logP values are known (determination of the logP values on the basis of the retention times by linear interpolation between two successive alkanones). The lambda-max values were determined on the basis of the UV spectra from 200 nm to 400 nm in the maxima of the chromatographic signals. Use Examples
Example A
Phytophthora test (tomato) / preventive
Solvent: 49 parts by weight of N, N - Dimethylformamide
Emulsifier: 1 part by weight of Alkylarylpolyglycolether
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of Phytophthora infestans. The plants remain for one day in an incubation cabinet at approximately 22°C and a relative atmospheric humidity of 100%. Then the plants are placed in an incubation cabinet at approximately 20°C and a relative atmospheric humidity of 96%. The test is evaluated 7 days after the inoculation. 0%> means an efficacy which corresponds to that of the untreated control, while an efficacy of 100%) means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 500ppm of active ingredient: 1(80%), 6 (70%), 9 (70%), 16 (95%), 19 (80%), 21(80%), 22 (90%), 27(90%), 28(80%), 26(90%), 23(95%), 24(90%), 25(80%), 31(70%).
Example B
Sphaerotheca test (cucumber) / preventive
Solvent: 49 parts by weight of N, N - Dimethylformamide
Emulsifier: 1 part by weight of Alkylarylpolyglycolether To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of Sphaerotheca fuliginea. Then the plants are placed in a greenhouse at approximately 23 °C and a relative atmospheric humidity of approximately 70 %.
The test is evaluated 7 days after the inoculation. 0% means an efficacy which corresponds to that of the untreated control, while an efficacy of 100% means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 500ppm of active ingredient: 10(90%), 12(93%), 16(80%), 19(90%), 22(70%), 29(70%), 26(93%), 23(95%), 24(95%), 25(93%), 31(85%).
Example C
Pyrenophora test (barley) / preventive
Solvent: 49 parts by weight of N, N - Dimethylformamide
Emulsifier: 1 part by weight of Alkylarylpolyglycolether To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of Pyrenophora teres. The plants remain for 48 hours in an incubation cabinet at 22°C and a relative atmospheric humidity of 100%. Then the plants are placed in a greenhouse at a temperature of approximately 20°C and a relative atmospheric humidity of approximately 80%>.
The test is evaluated 7-9 days after the inoculation. 0%> means an efficacy which corresponds to that of the untreated control while an efficacy of 100%) means that no disease is observed.
In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 500ppm of active ingredient: 6(100%), 8(95%), 9(100%), 10(100%), 1 1(100%), 12(95%), 16(100%), 19(100%), 21 (80%), 22(100%), 30(95%), 27(100%), 28(100%), 29(94%), 26(95%), 23(100%), 24(95%), 25(90%), 31(100%).
Example D
Alternaria test (tomato) / preventive
Solvent: 49 parts by weight of N, N - Dimethylformamide
Emulsifier: 1 part by weight of Alkylarylpolyglycolether
To produce a suitable preparation of active compound, 1 part by weight of active compound is mixed with the stated amounts of solvent and emulsifier, and the concentrate is diluted with water to the desired concentration.
To test for preventive activity, young plants are sprayed with the preparation of active compound at the stated rate of application. One day after this treatment, the plants are inoculated with an aqueous spore suspension of Alternaria solani. The plants remain for one day in an incubation cabinet at approximately 22°C and a relative atmospheric humidity of 100%. Then the plants are placed in an incubation cabinet at approximately 20°C and a relative atmospheric humidity of 96%.
The test is evaluated 7 days after the inoculation. 0%> means an efficacy which corresponds to that of the untreated control while an efficacy of 100%) means that no disease is observed. In this test the following compounds according to the invention showed efficacy of 70% or even higher at a concentration of 500ppm of active ingredient: 1 (95%), 6(95%), 7(90%), 8(80%), 9(95%), 10(95%), 11(70%), 12(95%), 16(90%), 18(80%), 19(95%), 21 (70%), 22(95%), 30(90%), 27(80%), 28(95%), 26(90%), 23(80%), 24(80%), 25(70%), 31(90).

Claims

Patent Claims
Thienylpyri(mi)dinylpyrazole derivatives of the formula (I)
Figure imgf000108_0001
in which
X1 represents C-H or N,
R1 represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Ci-C6-alkoxy, C3-C6-cycloalkyl, C3-C8-allenyl, Cs-Cs-trialkylsilyl, C4-C8-cycloalkenyl Ci-C6-alkoxy-Ci-C6-alkyl, acyloxy-Ci-C6-alkyl, heteroaryl-Ci-C6-alkyl, aryl-Ci-C6-alkyl, Ci-C6-alkylthio-Ci-C6- alkyl, Ci-C4-alkyl-C(0)-Ci-C6-alkyl, C3-C6-cycloalkyl-C(0)-Ci-C4-alkyl, heterocyclyl- C(0)-Ci-C4-alkyl, Ci-C4-alkyl-C(0)0-Ci-C6-alkyl, C3-C6-cycloalkyl-C(0)0-Ci-C4- alkyl, heterocyclyl-C(0)0- Ci-C4-alkyl, heterocyclyl-Ci-C6-alkyl, C6-Cio-aryl, heterocyclyl, heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or represents H, C(0)NR17R18, C(0)R17, C(0)OR17, S(0)2R17 C(S)NR17R18, C(S)R17, S(0)2NR17R18,
R2 represents H, cyano, halogen or represents Ci-C6-alkyl, C3-C6-cycloalkyl, heterocyclyl, C2-C8-alkenyl, C2-C8-alkinyl, Ci- Cs-alkoxy, C2-C8-alkynyloxy, Ci-Cs-alkylthio, Cs-Cs-trialkylsilyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of halogen, cyano, amino, dimethylamino or methoxy,
R3 represents H, halogen, cyano, OR11, C(0)ORu, C(0)SRu, C(S)ORu, C(0)Ru, C(S)RU, SR11, NR9R10, C(0)NRuR20, C(S)NRUR20, N(R17)C(0)ORu, N=CH-NR17R18, NH-CH-NR17R18, N=CR17R18, N(Ci-C6-alkyl)-NHR17, N=C(H)OR17, N=C(OR17)R18, N=C(SR17)R18, C(=NR17)NR17R18, SO(=NR17)R18, S02NRuR2°, S02Ru or represents Ci-C6-alkyl, Cs-Cs-cycloalkyl, C2-C6-alkenyl, C2-C8-alkynyl, C6-Ci4-aryl, C2-C9-heterocyclyl, C2-C9-heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16, excluded are compounds with R3 equals substituted NH -phenyl if X1 equals N,
R4 and R5 represents independently of each other H, F, CI, Br, I, cyano, nitro, OH, SH, or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C6-Ci4-aryl, Ci-C4-alkoxy, 0-(C6-Ci4-aryl), S-(Ci-C4-alkyl), S(0)-(Ci-C6-alkyl), C(0)-(Ci-C6- alkyl), Cs-Cs-trialkylsilyl, heteroaryl, heterocyclyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of
R16 or form together with the carbon atoms, which they are attached to, an optionally mono- or multi identical or different by halogen, oxygen, cyano or Ci-C4-alkyl, Ci- C i-alkoxy, Ci-C6-haloalkyl, Ci-C i-haloalkoxy, C3-C6-cycloalkyl substituted cycle with
5 to 8 ring atoms, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R6 represents Ci-C6-alkyl, H, halogen or represents Ci-C6-alkyl, Cs-Cs-cycloalkyl, C2-C8-alkenyl, C2-C8-alkinyl, C(0)-Ci-C6- alkyl, Ci-Cs-alkoxy, Ci-Cs-alkylthio, Ci-Cs-halogenalkoxy, Ci-C6-alkylsulphenyl, Ci-
C6-alkylthio, Cs-Cs-trialkylsilyl, C6-Cio-aryl, heteroaryl, heterocyclyl, C6-Cio-aryloxy, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16
R7 represents H, halogen, cyano, nitro, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2- C6-alkinyl, Cs-Cio-aryl, heteroaryl, heterocyclyl, or R6 and R7 together can form a 5- to 7-membered ring which can optionally be substituted with one or more substituents selected from: Ci-C i-alkyl, C1-C4- halogenoalkyl, Ci-C4-alkoxy, Ci-C4-halogenoalkoxy, halogen, hydroxyl, amino, cyano or nitro, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R8 represents H, halogen, cyano, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6- alkinyl, C6-Cio-aryl, heteroaryl, heterocyclyl,
R9 and R10represent H, C(S)R14, C(0)R14, SO2R14, C(0)OR14, OR14 oder C(0)NR14R15 or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8- cycloalkyl, heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, Ci-Ce-alkyl, 0-C(0)R17 , 0-P(0)(OR17)2, 0-B(OR17)2 or 0-(Ci-C4- alkyl),
R11 and R20represent H, C(S)R12, C(0)R12, S02R12, C(0)OR12, OR12 or C(0)NR12R13 or represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, Cs-Cs-cycloalkyl, C6-Ci4-aryl, heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, Ci-Ce-alkyl, 0-C(0)R17 , 0-P(0)(OR17)2, 0-B(OR17)2 or 0-(Ci-C4-alkyl),
R12 and R13 represent H
or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8- cycloalkyl, C6-Ci4-aryl, heterocyclyl oder heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, Ci-C6-alkyl or Ci-C i-alkoxy,
R14 and R15 represent H
or represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8- cycloalkyl, C6-Ci4-aryl, benzyl, phenethyl, phenoxymethyl, heterocyclyl oder heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, n-pentyl, cyclopropyl, or methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, methylsulfanyl, nitro, trifluormethyl, difluormethyl, C(0)R17, C(0)OR17,
C(0)NR17R18, SO2R17, OC(0)R17,
R16 represents OH, F, CI, Br, I, cyano, NH-C(0)R17, N R17R18, C(0)R17, C(0)OR17, C(0)NR17R18, SO2R17, OC(0)R17 or represents Ci-C6-alkyl, C2-C6-alkenyl, C2-C6-alkinyl, C3-C8-cycloalkyl, Ci-C4-alkoxy, Ci-C4-alkylthio, 0-(C3-C8-cycloalkyl), S-(C3-C8-cycloalkyl), C6-Ci4-aryl, 0-(C6-Ci4- aryl), S-(C6-Ci4-aryl), heterocyclyl or heteroaryl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, Ci-C6-alkyl or Ci-C4-alkoxy,
R17 and R18 represents Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, benzyl, aryl each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano or represents H,
R represents H, Ci-C6-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkinyl, C(S)R14, C(0)R14, SO2R14, C(0)OR14, and also agrochemically active salts thereof.
The thienylpyri(mi)dinylpyrazole of the formula (I) as claimed in claim 1, in which
X1 represents CH,
R1 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, -CH=CH¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, -CH=CHCH3, - C≡CCH3, 3-methylbut-2-en-l-yl, but-2-en-l-yl, but-3-en-2-yl, prop-2-yn-l-yl, but-2- yn-l-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, 1- cyclopropylethyl, -CH=C=CH2, trimethylsilyl, tert-butyldimethylsilyl, cyclohexenyl, 2- methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, tert-butoxy-methyl, cyanomethyl, 1 -cyanoethyl, 2-cyanoethyl, l-cyanopropan-2-yl, trifluormethyl, difluormethyl, 2-fluoroethyl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, (2,2-dichlorocyclopropyl)methyl, trifluoromethoxy, difluoromethoxy, 2- (trifluoromethoxy) ethyl, methylacetate, ethylacetate, pyridin-2-ylmethyl, pyridin-3- ylmethyl, pyridin-4-ylmethyl, (l,3-thiazol-5-yl)methyl, (l,3-thiazol-4-yl)methyl, 1,3- thiazol-3-yl)methyl, (l,3-oxazol-5-yl)methyl, (l,3-oxa-4-yl)methyl, (l,3-oxa-3- yl)methyl, phenylmethyl, phenylethyl, methylthio, ethylthio, n-propylthio, iso- propylthio, tertbutylthio, n-butylthio, sec-butylthio, iso-butylthio, methylthioalkyl, phenyl, benzyl, naphthalenyl, oxiranyl, aziridinyl, 2-tetrahydrofuranyl, 3-tetrahydro- furanyl, tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-3-yl, tetrahydro-2H-pyran-4- yl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3- isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3-isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4- oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thiazolidinyl, 5-thiazolidinyl, 2- imidazolidinyl, 4-imidazolidinyl, 2-pyrrolin-2-yl, 2-pyrrolin-3-yl, 3-pyrrolin-2-yl, 3- pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4-isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-isoxazolin-4-yl, 4-isoxazolin-4-yl, 2-isoxazolin-5-yl, 3-isoxazolin-5-yl, 4-isoxazolin- 5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4-isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2-isothiazolin-5-yl, 3-isothiazolin-5-yl, 4- isothiazolin-5-yl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, l,3-dioxan-5-yl, 2-tetra- - I l l - hydropyranyl, 4-tetrahydropyranyl, 2-tetrahydrothienyl, 3-hexahydro-pyridazinyl, 4- hexahydropyridazinyl, 2-hexahydropyrimidinyl, 4-hexahydropyrimidinyl, 5- hexahydropyrimidinyl, 2-piperazinyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3- yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, IH-pyrrol-l -yl, lH-pyrrol-2-yl, 1H- pyrrol-3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5- yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-l-yl, pyrazol-3-yl, pyrazol- 4-yl, imidazol-l-yl, imidazol-2-yl, imidazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4- yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, morpholine, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or represents H, C(0)NR17R18, C(0)R17, C(0)OR17, S(0)2R17 C(S)NR17R18, C(S)R17, S(0)2NR17R18,
R2 represents H, cyano, Br, CI, F or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -Ο¾0Η=Ο¾, -C≡CH, -
C≡CCH3, -CH2C≡CH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert- butoxy, -0-CH2C≡CH, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, iso- propylsulfanyl, tertbutylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl, iso-butylsulfanyl, trimethylsilyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, cyano, amino, dimethylamino or methoxy,
R3 represents H, F, CI, Br, cyano, OR11, C(0)ORu, C(0)Ru, NR9R10, C(0)NRuR20, N=C(OR17)R18, N=C(SR17)R18, SO(=NR17)R18, N(Ci-C6-alkyl)-NHR17 or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, -CH2CF CH2, -
CH2C≡CH , -C≡CH, -CH=CHCH3, -C≡CCH3, but-2-en-l-yl, but-3-en-2-yl, but-2-yn- 1-yl, phenyl, benzyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16,
R4, R5 represents independently of each other H, F, CI, Br, cyano, nitro, OH, SH or represents methyl, ethyl, cyclopropyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH, phenyl, methoxy, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16 or form together with the carbon atoms, which they are attached to, an optionally mono- or multi identical or different by F, CI, Br, oxygen, cyano or alkyl, cycloalkyl, heterocyclyl, haloalkyl, alkoxy, aryl, hetaryl substituted cycle with 5 to 8 ring atoms, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R6 represents H, CI, F, Methyl, Ethyl, Cyano, difluoromethyl, trifluoromethyl, or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH2, -CH2CF CH2, - CH2C≡CH , -C≡CH, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, methylthio, ethylthio, n-propylthio, iso-propylthio, tertbutylthio, n-butylthio, sec- butylthio, iso-butylthio, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of R16
R7 represents H, F, CI, Br, cyano, nitro, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH or R6 and R7 together can form a 5- to 7-membered ring which can optionally be substituted with one or more substituents selected from: methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy, F, CI, Br, hydroxyl, amino, cyano or nitro, whereas the cycle consists of carbon atoms but may also contain 1 to 4 heteroatoms selected from oxygen, sulphur or NR19,
R8 represents H, F, CI, Br, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH¾ -CH2CH=CH2, -CH2C≡CH , -C≡CH,
R9 and R10represent H, C(S)R14, C(0)R14, SO2R14, C(0)OR14, OR14 oder C(0)NR14R15, R11 and R20 represent H, C(S)R12, C(0)R12, SO2R12, C(0)OR12, OR12 oder C(0)NR12R13 or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 0-C(0)Me, 0-C(0)Et, 0-P(0)(OMe)2, 0-B(OMe)2 , 0-B(OEt)2 oder , methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH¾ -CH2CH=CH2, -CH2C≡CH
, -C≡CH, phenyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano, R12 and R13 represent H
or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, -CH2CH=CH2, - CH2C≡CH , -C≡CH, phenyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl or methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,
R14 and R15 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=C¾ -CH2CH=CH2, -CH2C≡CH, -C≡CH, phenyl, naphthalenyl, benzyl, phenethyl, phenoxymethyl, pyridinyl, pyrazinyl, pyrimidinyl, furanyl, thienyl, thietanyl, oxetanyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, pyrrolidinyl, piperidinyl, indanyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec- butyl, tert-butyl, n-pentyl, cyclopropyl, or methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, tert-butoxy, methylsulfanyl, nitro, trifluormethyl, difluormethyl, acetyl, methoxycarbonyl, ethoxycarbonyl or represents hydrogen,
R16 represents OH, F, CI, Br, I, cyano, NH-C(0)R17, NR17R18, C(0)R17, C(0)OR17,
Figure imgf000114_0001
or represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, -CH2CH=CH2, - CH2C≡CH , -C≡CH, phenyl, methoxy, ethoxy, tetrahydrofuranyl, 3 -tetrahydrofuranyl, 2-pyrrolidinyl, 3 -pyrrolidinyl, 3-isoxazolidinyl, 4-isoxazolidinyl, 5-isoxazolidinyl, 3- isothiazolidinyl, 4-isothiazolidinyl, 5-isothiazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, 5-pyrazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5-oxazolidinyl, 2-thiazolidinyl, 4-thia- zolidinyl, 5-thiazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 2-pyrrolin-2-yl, 2- pyrrolin-3-yl, 3-pyrrolin-2-yl, 3-pyrrolin-3-yl, 2-isoxazolin-3-yl, 3-isoxazolin-3-yl, 4- isoxazolin-3-yl, 2-isoxazolin-4-yl, 3-Isoxazolin-4-yl, 4-Isoxazolin-4-yl, 2-Isoxazolin-5- yl, 3-Isoxazolin-5-yl, 4-isoxazolin-5-yl, 2-isothiazolin-3-yl, 3-isothiazolin-3-yl, 4- isothiazolin-3-yl, 2-isothiazolin-4-yl, 3-isothiazolin-4-yl, 4-isothiazolin-4-yl, 2- isothiazolin-5-yl, 3-isothiazolin-5-yl, 4-isothiazolin-5-yl, 2-piperidinyl, 3 -piperidinyl, 4-piperidinyl,
2-piperazinyl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, lH-pyrrol-l-yl, lH-pyrrol-2-yl, lH-pyrrol- 3-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, pyrazol-l-yl, pyrazol-3-yl, pyrazol-4- yl, Imidazol-l-yl, Imidazol-2-yl, Imidazol-4-yl, Pyridin-2-yl, Pyridin-3-yl, pyridin-4- yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrazin-2-yl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, I, OH, carbonyl, cyano, methyl, ethyl, methoxy,
R17 und R18 represents methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH=CH2, - CH2CF CH2, -CH2C≡CH , -C≡CH, benzyl, each of which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of F, CI, Br, OH, cyano or represents H,
R19 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH2, - CH2CH=CH2, -CH2C≡CH , -C≡CH, C(S)R14, C(0)R14, SO2R14, C(0)OR14 and also agrochemically active salts thereof.
3. The thienylpyri(mi)dinylpyrazole of the formula (I) as claimed in claim 1 and 2, in which
X1 represents CH,
R1 represents H, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, allyl, 3-methylbut-2- en-l-yl, prop-2-yn-l-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro- 2H-pyran-2-yl, tetrahydrofuran-3-yl, oxetan-3-yl, thietan-3-yl, tetrahydro-2H-pyran-3- yl, tetrahydro-2H-pyran-4-yl, 2,2-difluoroethyl, l,3-difluoropropan-2-yl, 2-chloroethyl, 2-fluoroethyl, 2-(trifluoromethoxy)ethyl, cyanomethyl, 1 -cyanoethyl, 2-cyanoethyl, 1- cyanopropan-2-yl, 2-methoxyethyl, 2-ethoxyethyl, 2-(methylsulfanyl)ethyl, cyclopropylmethyl, 1 -cyclopropylethyl, (2,2-dichlorocyclopropyl)methyl, 2- fluorobenzyl, l-(2-fluorophenyl)ethyl, 3-cyanobenzyl, R2 represents H, Methyl, Ethyl, n-propyl, methoxy, ethoxy, methylsulfanyl, methoxymethyl, difluoromethyl, 2-hydroxypropan-2-yl, hydroxymethyl, 2- hydroxyethyl, 2-cyanoethyl,
R3 represents H, amino, formamido, acetylamino, n-propionylamino, isobutyrylamino, (2- methylbutanoyl)amino, (3 -methylbutanoyl)amino, (3 ,3 -dimethylbutanoyl)amino, (methoxyacetyl)amino, [(2-methoxyethoxy)acetyl]amino, (3,3,3- trifluoropropanoyl)amino, (cyanoacetyl)amino, (lactoylamino), (2-hydroxy-2- methylpropanoyl)amino, [(methylsulfanyl) acetyl] amino, [2-(4- chlorophenoxy)propanoyl] amino, (phenylacetyl)amino, (3-phenylpropanoyl)amino, [3- (4-chlorophenyl)propanoyl] amino, [2-(4-fluorophenyl)propanoyl] amino, [2-(2- fluorophenyl)propanoyl] amino, (cyclopentylacetyl)amino, (cyclopropylacetyl)amino, (cyclopropylcarbonyl)amino, [(2-methylcyclopropyl)carbonyl] amino, [(1 - chlorocyclopropyl)carbonyl] amino, (cyclobutylcarbonyl)amino, (2,3 -dihydro- 1 H- inden-2-ylcarbonyl)amino, [(2-phenylcyclopropyl)carbonyl]amino, methacryloylamino, (3-methylbut-2-enoyl)amino, (4-methylpent-3-enoyl)amino, (benzoylamino), (4-fluorobenzoyl)amino, (3-thienylcarbonyl)amino, (2- thienylcarbonyl)amino, (tetrahydrofuran-2-ylcarbonyl)amino, (tetrahydrofuran-3 - ylcarbonyl)amino, (tetrahydro-2H-pyran-4-ylcarbonyl)amino, (methoxycarbonyl)amino, (ethoxycarbonyl)amino, (isopropoxycarbonyl)amino, (tert- butoxycarbonyl)amino, diacetylamino, dipropionylamino, diisobutyrylamino, bis(methoxyacetyl)amino, bis(3-methylbutanoyl)amino, b is (cyclopropylcarbonyl) amino, b is (cyclopropylcarbonyl) amino, acetyl(isobutyryl)amino, butyryl(cyclopropylcarbonyl)amino, (cyclopropylcarbonyl)(propionyl)amino, (cyclopropylcarbonyl)(methoxyacetyl)amino, (cyclopropylcarbonyl)(3-methylbutanoyl)amino,
(cyclopropylcarbonyl)(pentanoyl)amino, isobutyryl(propionyl)amino, (cyclopropylcarbonyl)(methoxycarbonyl)amino,
(cyclopropylcarbonyl)(ethoxycarbonyl)amino, [(E)-(dimethylamino)methylene]amino, methylcarbamoyl, (ethylcarbamoyl)amino,
R4, R5 represents H, F, CI or form together with the carbon atoms to which they are bound, an optionally mono- or multi identical or different by F, CI, Br, oxygen, cyano, methyl, ethyl, n-propyl, isopropyl, methoxy, trifluormethyl, difluormethyl, trifluormethoxy, cyclopropyl, cyclopropylmethyl, cyclobutyl substituted cycle, wherein they together stand for -(CH=CH-N(R19), -(CH=CH- CH=N)-, -(NH-CH=N)- or -(CH2-C(0)-N(R19), H, CI, F, Methyl, Ethyl, Cyano, difluoromethyl, trifluoromethyl,
R7 represents H, F, CI, Methyl,
R8 represents H, CI
R 19 represents H, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH=CH2, -
CH2CH=CH2, -CH2C=CH , -C=CH, acetyl, n-propionyl, isobutyryl, 2-methylbutanoyl, 3-methylbutanoyl, 3,3-dimethylbutanoyl, cyclopropylcarbonyl and also agrochemically active salts thereof.
4. A composition for controlling phytopathogenic harmful and mycotoxin producing fungi, characterized in that it comprises at least one thienylpyri(mi)dinylpyrazole of the formula (I) as claimed in any of the claims 1 to 3, in addition to extenders and/or surfactants.
5. The use of thienylpyri(mi)dinylpyrazole of the formula (I) as claimed in any of the claims 1 to 3 for controlling unwanted microorganisms.
6. A method for controlling phytopathogenic harmful and mycotoxin producing fungi, characterized in that thienylpyri(mi)dinylpyrazole of the formula (I) as claimed in any of the claims 1 to 3 are applied to the microorganisms and/or their habitat.
7. A process for preparing compositions for controlling unwanted microorganisms, characterized in that thienylpyri(mi)dinylpyrazole of the formula (I) according to any of the claims 1 to 3 are mixed with extenders and/or surfactants.
8. Use of thienylpyri(mi)dinylpyrazole of the formula (I) according to any of the claims 1 to 3 for treating transgenic plants.
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