CA2309973A1 - Thiazole-derivatives having microbicidal and plant immunizing activities - Google Patents
Thiazole-derivatives having microbicidal and plant immunizing activities Download PDFInfo
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- CA2309973A1 CA2309973A1 CA002309973A CA2309973A CA2309973A1 CA 2309973 A1 CA2309973 A1 CA 2309973A1 CA 002309973 A CA002309973 A CA 002309973A CA 2309973 A CA2309973 A CA 2309973A CA 2309973 A1 CA2309973 A1 CA 2309973A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
- C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/06—1,2,3-Thiadiazoles; Hydrogenated 1,2,3-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Environmental Sciences (AREA)
- Plant Pathology (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dentistry (AREA)
- General Health & Medical Sciences (AREA)
- Agronomy & Crop Science (AREA)
- Zoology (AREA)
- Pest Control & Pesticides (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Compounds of formula (I) and process for protecting and immunizing plants against attack by phytopathogenic microorganisms by applying compounds of formula (I) wherein a) X is CR4 and Y is N; or b) X is N and Y is CR5; or c) X
and Y are N; and wherein Z is a C1-group to which 1-3 halogen atoms or 1-3 unsubstituted or substituted hetero atoms selected from the group O, S and N
are bonded; Z is CN, CO-A, CS-A or CH(OR10)2; A is hydrogen, halogen, OR6, SR7, N(R8)R9, ON(R11)R12 or N(R13)OR14; and wherein R1-R14 have the meanings given in the description.
and Y are N; and wherein Z is a C1-group to which 1-3 halogen atoms or 1-3 unsubstituted or substituted hetero atoms selected from the group O, S and N
are bonded; Z is CN, CO-A, CS-A or CH(OR10)2; A is hydrogen, halogen, OR6, SR7, N(R8)R9, ON(R11)R12 or N(R13)OR14; and wherein R1-R14 have the meanings given in the description.
Description
WO 99/32464 PCT/EI°98/08335 Thiazole isothiazole and thiadiazole-derivatives having microbicidaf and plant immunizin4 activities.
The invention relates to a method for protecting and immunizing plants against attack by phytopathogenic microorganisms by applying to the plants, to parts of the plants and/or to the locus of the plants a compound of formula I
R, R2 ~Z
\Y R
wherein a) X is CR4 and Y is N; or b) X is N and Y is CRS; or c) X and Y are N; and wherein Z is a C,-group to which 1-3 halogen atoms or 1-3 unsubstituted or substituted hetero atoms selected from the group O, S and N are bonded;
R, and Rz are independently H, OH, SH, CN, COOH, N02, NH2, halogen, C,-Csalkyl, haloC,-Csalkyl, alkoxyC,-Csalkyl, aminoC,-Csalkyf, alkoxaminoC,-Csalkyl, C,-Csalkoxy, halo-C,-Csalkoxy, C,-Csalkanoyloxy, aroyloxy, C,-Csalkoxycarbonyi, aryloxycarbonyl, benzyloxycarbonyl, C,-Csalkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C,-Csalkylaminocarbonyl, C,-Csdialkylaminocarbonyl, C,.Csalkylthio, haloC,-Csalkylthio, C,-Csalkylsulfinyl, haloC,-Csalkylsulfinyl, C,-Csalkylsulfonyl, haloC,-Csalkylsulfonyl, arylsulfinyl, arylsulfonyl, C2-Csalkenyl, haloC2-Csalkenyl, CZ-Csalkinyl, carboxyC,-Csalkyl, alkoxycarbonylC,-Csalkyl, haloalkoxycarbonylC,-Csalkyl, C3-Cscycloalkyl, alkanoylC,-Csalkyl, alkylcarbonyloxyC,-Csalkyl, phenylcarbonyloxyC,-Csalkyl, C,-Csalkylamino, C,-Csdialkylamino, C2-Csalkenylamino, C,-Csalkanoylamino, C,-Csalkoxycarbonylamino, benzylamino, benzoylamino, benzyioxyarbonylamino, phenyl, phenoxy, benzyl or phenethyl, wherein all the aromatic groups are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, hydroxy, C,-C4alkyl, halo-C,-C2alkyl, C,-C2alkoxy, halo-C,-C2alkoxy and nitro; or optionally substituted heterocyclyl; or tri(C,-Csalkyl)silyl or tri(C,-Csalkyl)silyloxy;
The invention relates to a method for protecting and immunizing plants against attack by phytopathogenic microorganisms by applying to the plants, to parts of the plants and/or to the locus of the plants a compound of formula I
R, R2 ~Z
\Y R
wherein a) X is CR4 and Y is N; or b) X is N and Y is CRS; or c) X and Y are N; and wherein Z is a C,-group to which 1-3 halogen atoms or 1-3 unsubstituted or substituted hetero atoms selected from the group O, S and N are bonded;
R, and Rz are independently H, OH, SH, CN, COOH, N02, NH2, halogen, C,-Csalkyl, haloC,-Csalkyl, alkoxyC,-Csalkyl, aminoC,-Csalkyf, alkoxaminoC,-Csalkyl, C,-Csalkoxy, halo-C,-Csalkoxy, C,-Csalkanoyloxy, aroyloxy, C,-Csalkoxycarbonyi, aryloxycarbonyl, benzyloxycarbonyl, C,-Csalkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C,-Csalkylaminocarbonyl, C,-Csdialkylaminocarbonyl, C,.Csalkylthio, haloC,-Csalkylthio, C,-Csalkylsulfinyl, haloC,-Csalkylsulfinyl, C,-Csalkylsulfonyl, haloC,-Csalkylsulfonyl, arylsulfinyl, arylsulfonyl, C2-Csalkenyl, haloC2-Csalkenyl, CZ-Csalkinyl, carboxyC,-Csalkyl, alkoxycarbonylC,-Csalkyl, haloalkoxycarbonylC,-Csalkyl, C3-Cscycloalkyl, alkanoylC,-Csalkyl, alkylcarbonyloxyC,-Csalkyl, phenylcarbonyloxyC,-Csalkyl, C,-Csalkylamino, C,-Csdialkylamino, C2-Csalkenylamino, C,-Csalkanoylamino, C,-Csalkoxycarbonylamino, benzylamino, benzoylamino, benzyioxyarbonylamino, phenyl, phenoxy, benzyl or phenethyl, wherein all the aromatic groups are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, hydroxy, C,-C4alkyl, halo-C,-C2alkyl, C,-C2alkoxy, halo-C,-C2alkoxy and nitro; or optionally substituted heterocyclyl; or tri(C,-Csalkyl)silyl or tri(C,-Csalkyl)silyloxy;
with the proviso that R, and R2 are not simultaneously a group selected from OH, SH, N02, NH2, C,-Csalkylamino, C,-Cgdialkylamino and C2-Cealkenylamino; or R, and R2 together are =O or =S; or R, and R2 together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 8 membered isocyclic or heterocyclic ring; or R2 and Z together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 7 membered lactone, lactame, thiolactone or thiolactame, which ring may have 1 to 2 additional hetero atoms selected from the group O, S and N;
R3, R, and RS are independently H, OH, SH, CN, N02, NH2, halogen, C,-Ceaikyl, haloC,-Csalkyl, hydroxyC,-Cealkyl, alkoxyC,-Csalkyl, aminoC,-Ceaikyl, alkoxaminoC,-Csalkyl, C,-Csalkoxy, C,-Cgalkylthio, haloC,-Cealkylthio, C,-Cealkylsulfinyl, haloC,-Cealkylsulfinyl, C,-Csalkylsulfonyl, haloC,-Ceaikylsulfonyl, halo-C,-Cealkoxy, CZ-Cealkenyl, haloC2-Csalkenyl, C2-Csalkinyl, carboxyC,-Cgalkyl, C,-Cgalkanoyl, C,-Csalkoxycarbonyl, alkoxycarbonylC,-CBalkyl, haloalkoxycarbonylC,-Cealkyl, C3-CBcycloalkyl, alkanoylC,-Csalkyl, alkylcarbonyloxyC,-Csalkyl, phenylcarbonyloxyC,-Cealkyl, C,-CBalkylamino, C,-Cgdialkylamino, C2-CBalkenylamino, C,-Cealkanoylamino, C,-CBalkoxycarbonylamino, benzylamino, benzoylamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C,-C,alkyl, halo-C,-CZalkyl, C,-C2alkoxy, halo-C,-C2alkoxy and vitro; or optionally substituted heterocyclyl.
The invention relates also to new compounds of formula i, to the preparation of those compounds, to new intermediates and to agrochemical compositions comprising at least one of those compounds as active ingredient.
Thiazole and thiadiazole derivatives having plant-fungicidal activities are known from EP-A-395,174, US 5,135,927, WO 96/17840, and WO 96/29871.
EP-A-757,987 and WO 97/20465 discloses thiazole and thiadiazole derivatives exhibiting plant immunizing activities. These compounds have no or very weak direct activity against fungi and bacteria, but protect the plants from phytopathogenic microorganisms by activation and stimulation of the plant's own defence system (immunisation).
That mode of action has also become known by the name 'Systemic Activated Resistance' ('SAR"). Such compounds and methods are ecologically advantageous and are complementary to current methods in crop protection. It is therefore desirable to provide more compounds and methods for protecting plants by immunizing them against attack by phytopathogenic microorganisms.
Surprisingly it has now been found that compounds of formula I can be used for protecting and immunizing plants against attack by microorganisms, such as phytopathogenic fungi, bacteria and viruses and for improving the qualities of the plants.
The formula I embraces all stereoisomeric forms and mixtures thereof, such as enantiomeric and diastereomeric pure forms and mixtures thereof.
The compounds of formula I and, where appropriate, their tautomers can be in the form of salts. Compounds of formula I that have at least one basic centre can form acid addition salts. Furthermore, compounds of formula I having at least one acid group can form salts with bases. Preference is given to agrochemicaily advantageous salts.
Z is a C,-group which means that no additional carbon atoms are directly attached to this group. Examples for the group Z are trihalomethyl, dihalomethyl or halomethyi as chloromethyl; formyl or an acetal or thioacetal thereof; a carboxylic acid or derivatives thereof, as nitrite, esters, anhydrides, thioesters, amides, amidines, imidic-,hydrazonic- and hydroxamic-acids or derivatives thereof; or heterocyclyl, as 2-imidazolyl, 2-pyrimidinyl and 2-thiazolyl.
Compounds of formula I wherein R, and R2 are simultaneously a group selected from OH, SH, N02, NH2, C,-Cealkylamino, C,-Cediaikylamino and C2-Cgalkenylamino are not stable in general and are thus not part of this invention.
Unless defined otherwise, the general terms used hereinbefore and hereinafter have the meanings given below:
Hydrocarbon radicals may be saturated or unsaturated, open-chained or cyclic, or mixed open-chained and cyclic, for example cyclopropylmethyl or benzyl.
Alkyl groups are straight-chained or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, sec-amyl, tert-amyl, 1-hexyl or 3-hexyl.
Unsaturated hydrocarbon radicals are alkenyl, alkynyl or alkenynyl groups having not more than three multiple bonds, for example butadienyl, hexatrienyl or 2-penten-4-ynyl.
R3, R, and RS are independently H, OH, SH, CN, N02, NH2, halogen, C,-Ceaikyl, haloC,-Csalkyl, hydroxyC,-Cealkyl, alkoxyC,-Csalkyl, aminoC,-Ceaikyl, alkoxaminoC,-Csalkyl, C,-Csalkoxy, C,-Cgalkylthio, haloC,-Cealkylthio, C,-Cealkylsulfinyl, haloC,-Cealkylsulfinyl, C,-Csalkylsulfonyl, haloC,-Ceaikylsulfonyl, halo-C,-Cealkoxy, CZ-Cealkenyl, haloC2-Csalkenyl, C2-Csalkinyl, carboxyC,-Cgalkyl, C,-Cgalkanoyl, C,-Csalkoxycarbonyl, alkoxycarbonylC,-CBalkyl, haloalkoxycarbonylC,-Cealkyl, C3-CBcycloalkyl, alkanoylC,-Csalkyl, alkylcarbonyloxyC,-Csalkyl, phenylcarbonyloxyC,-Cealkyl, C,-CBalkylamino, C,-Cgdialkylamino, C2-CBalkenylamino, C,-Cealkanoylamino, C,-CBalkoxycarbonylamino, benzylamino, benzoylamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C,-C,alkyl, halo-C,-CZalkyl, C,-C2alkoxy, halo-C,-C2alkoxy and vitro; or optionally substituted heterocyclyl.
The invention relates also to new compounds of formula i, to the preparation of those compounds, to new intermediates and to agrochemical compositions comprising at least one of those compounds as active ingredient.
Thiazole and thiadiazole derivatives having plant-fungicidal activities are known from EP-A-395,174, US 5,135,927, WO 96/17840, and WO 96/29871.
EP-A-757,987 and WO 97/20465 discloses thiazole and thiadiazole derivatives exhibiting plant immunizing activities. These compounds have no or very weak direct activity against fungi and bacteria, but protect the plants from phytopathogenic microorganisms by activation and stimulation of the plant's own defence system (immunisation).
That mode of action has also become known by the name 'Systemic Activated Resistance' ('SAR"). Such compounds and methods are ecologically advantageous and are complementary to current methods in crop protection. It is therefore desirable to provide more compounds and methods for protecting plants by immunizing them against attack by phytopathogenic microorganisms.
Surprisingly it has now been found that compounds of formula I can be used for protecting and immunizing plants against attack by microorganisms, such as phytopathogenic fungi, bacteria and viruses and for improving the qualities of the plants.
The formula I embraces all stereoisomeric forms and mixtures thereof, such as enantiomeric and diastereomeric pure forms and mixtures thereof.
The compounds of formula I and, where appropriate, their tautomers can be in the form of salts. Compounds of formula I that have at least one basic centre can form acid addition salts. Furthermore, compounds of formula I having at least one acid group can form salts with bases. Preference is given to agrochemicaily advantageous salts.
Z is a C,-group which means that no additional carbon atoms are directly attached to this group. Examples for the group Z are trihalomethyl, dihalomethyl or halomethyi as chloromethyl; formyl or an acetal or thioacetal thereof; a carboxylic acid or derivatives thereof, as nitrite, esters, anhydrides, thioesters, amides, amidines, imidic-,hydrazonic- and hydroxamic-acids or derivatives thereof; or heterocyclyl, as 2-imidazolyl, 2-pyrimidinyl and 2-thiazolyl.
Compounds of formula I wherein R, and R2 are simultaneously a group selected from OH, SH, N02, NH2, C,-Cealkylamino, C,-Cediaikylamino and C2-Cgalkenylamino are not stable in general and are thus not part of this invention.
Unless defined otherwise, the general terms used hereinbefore and hereinafter have the meanings given below:
Hydrocarbon radicals may be saturated or unsaturated, open-chained or cyclic, or mixed open-chained and cyclic, for example cyclopropylmethyl or benzyl.
Alkyl groups are straight-chained or branched and are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, sec-amyl, tert-amyl, 1-hexyl or 3-hexyl.
Unsaturated hydrocarbon radicals are alkenyl, alkynyl or alkenynyl groups having not more than three multiple bonds, for example butadienyl, hexatrienyl or 2-penten-4-ynyl.
Alkenyl is straight-chained or branched aikenyl, for example allyl, methallyl, 1-methylvinyl or but-2-en-1-yl. Preference is given to alkenyl radicals having a chain length of 2 to 4 carbon atoms.
Alkynyl may be straight-chained or branched, for example propargyl, but-1-yn-i-yl or but-1-yn-3-yl. Propargyl is preferred.
Cyclic unsaturated hydrocarbon radicals may be aromatic, for example phenyl and naphthyi, or non-aromatic, for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctadienyl, or partially aromatic, for example tetrahydronaphthyl and indanyl.
Halogen, or halo, is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Haloalkyl may contain identical or different halogen atoms, for example fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro-methyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 3,3,3-trifluoro-propyl.
Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy.
Haloalkoxy is, for example, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy and 2,2-difluoroethoxy.
Cycloalkyl is cyciopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alkanoyl is either straight-chained or branched. Examples are formyl, acetyl, propionyl, butyryl, pivaloyl and octanoyl.
A heterocyclyl radical is to be understood as being a 3 to 7-membered, aromatic or non-aromatic ring having hetero atoms N, O andlor S. Furthermore, an unsubstituted or substitu-ted benzo group may be fused onto such a heterocyclyl radical bonded to the rest of the molecule. Examples of heterocyclyl groups are pyridyl, pyrimidinyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, triazolyl, thienyl, furanyl, pyrrolyl, morpholinyl, oxazolyl and the correspon-ding partially or completely hydrogenated rings. Examples of heterocyclyl groups to which a benzo group is fused are quinolyl, isoquinofyl, benzoxazolyl, quinoxaiinyl, benzothiazolyl, benzimidazolyl, indolyl and indolinyl.
Aryl is phenyl, naphthyl, phenanthryl or fluorenyl, in particular phenyl.
The hydrocarbyi groups, as alkyl, alkenyl, alkynyl, and the haloalkyl, haloalkenyl, haloalkoxy and alkanoyl groups mentioned hereinabove and hereinbelow can be substituted by aryl, hetaryl, aryloxy, hetaryloxy, arylsulfenyl, arylsulfinyl, arylsulfonyl, heterarylsulfenyl, hetarylsulfinyl or heterarylsulfonyl, each of which is unsubstituted or additionally substituted.
All the aryl, hetaryi and heterocyclyl groups mentioned hereinabove and hereinbelow can be mono- or polysubstituted, for example by halogen, C,-C,,alkyl, C2-C4alkenyl, C2-C4alkynyl, C,-C4alkoxy, C,-C,alkylthio, C,-C~haloalkyl, C2-Cehaloalkenyi, C2-C4-haloalkynyl, C,-C,haloalkoxy, halogen, cyano, cyano-C,-CZalkyl, cyano-C,-CZalkoxy, OH, N02, SCN, thiocyanomethyl, Si(CH3)3, NH2, NH(C,-C,alkyl), N(C,-C,alkyl)2, C,-Cealkoxymethyl, C,-C,,haloalkylcarbonyl, C,-C4haloalkyloxycarbonyl, C,-C4alkylcarbonyl, C,-C4-alkoxycarbonyl, aminocarbonyl, C,-Cealkylaminocarbonyl, bis(C,-C,alkylamino)carbonyl, arylaminocarbonyl, arylaminothiocarbonyl, C,-C,aikoximinomethyl, -CSNHZ, -SH, C,-C4alkylthiomethyl, C2-C4alkenyloxy, C2-C4alkynyloxy, CZ-C,haloalkenyloxy, C,-C4alkylsulfinylmethyl, C,-C,alkyisulfonylmethyl, phenylsulfinylmethyl, phenylsulfonylmethyl, trifluoromethyfsulfonyl, C3-Cgcycloalkyl, C,-C4haloalkylcarbonyloxy, C,-C,alkylcarbonyloxy, C,-C,alkoxycarbonyloxy, haloalkoxycarb~onyloxy, aminocarbonyfoxy, C,-C4alkylaminocarbonyloxy, bis(C,-C,alkylamino)carbonyloxy, arylaminocarbonyloxy, arylaminothiocarbonyloxy.
Amongst the compounds and methods of their use the following groups are preferred:
(1 ) Compounds of formula R~ R2 S
LA .
R 4 _"C~
N R
The compounds of the formula R ~ OMe CO-NH-CHZ CHZ ~ ~ OMe CI -~~
N CI T
wherein -6- ' a) R, is OCO-CH3 and T is Br, b) R, is OH and T is Br, c) R, is OH and T is H, are known from WO 96/17840 as fungicides, but no indication is given therein to plant immunizing properties of these compounds ; these compounds are thus part of the invention only as far as the method for immunizing plants is concerned.
(2) Compounds of formula R~ R2 .S Z
_ LB.
Rs (3) Compounds of formula R~ R2 ,S
'Z LC.
~R
(4) Compounds of formula I, wherein Z is CN, CO-A, CS-A or CH{OR,o)2,;
A is hydrogen, halogen, ORs, SR,, N(Re)Ra, ON(R")R,2 or N(R,3)OR,4;
Rs to R" are independently hydrogen, an unsubstituted or substituted, open-chained, saturated or unsaturated hydrocarbon radical containing up to 8 carbon atoms, an unsubstituted or substituted, cyclic, saturated or unsaturated hydrocarbon radical containing up to 10 carbon atoms, unsubstituted or substituted benzyl or phenethyl, an unsubstituted or substituted acyl group containing up to 8 carbon atoms, an unsubstituted or substituted benzoyl group, or an unsubstituted or substituted heterocyclyl radical; or _7_ R8 and R9, or R" and R,2, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered, unsubstituted or substituted heterocycle having 1 to 3 hetero atoms selected from O, S and/or N;
R,o are identical or different and are C,-CBalkyl that is unsubstituted or substituted by phenyl, C,-C2alkoxy, phenoxy or by benzyloxy; or two substituents OR,o, together with the carbon atom to which they are bonded, form a cyclic acetal group that is unsubstituted or substituted by C,-C3alkyi, phenyl, benzyl, hydroxy or by C,-C3hydroxyalkyl.
(5) Compounds of formula I, wherein Z is CO-A or CS-A;
A is OR6, SR,, N(R8)R9, ON(R")R,2 or N(R,3)OR,4;
R6 to R,4 are independently H, C,-CBalkyl, haloC,-Cgalkyl, C,-Csalkoxycarbonyl, C,-C4alkanoylC,-C4alkyl, C3-Cgcycloalkyl, C3-Cscycloalkylmethyl, phenyl, benzyl, phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, C,-C4alkyl, halo-C,-C2alkyl, C,-CZalkoxy, haio-C,-C2alkoxy and C,-C2alkylenedioxy.
(6) Compounds of formula I, wherein R3 is H, OH, C,-CBalkyl, C3-CBCycloalkyl, haloC,-Csalkyl, C,-Caalkoxy or haloC,-Csaikoxy.
Alkynyl may be straight-chained or branched, for example propargyl, but-1-yn-i-yl or but-1-yn-3-yl. Propargyl is preferred.
Cyclic unsaturated hydrocarbon radicals may be aromatic, for example phenyl and naphthyi, or non-aromatic, for example cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctadienyl, or partially aromatic, for example tetrahydronaphthyl and indanyl.
Halogen, or halo, is fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.
Haloalkyl may contain identical or different halogen atoms, for example fluoromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloro-methyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trichloroethyl, 3,3,3-trifluoro-propyl.
Alkoxy is, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy.
Haloalkoxy is, for example, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy, 2-fluoroethoxy, 2-chloroethoxy and 2,2-difluoroethoxy.
Cycloalkyl is cyciopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alkanoyl is either straight-chained or branched. Examples are formyl, acetyl, propionyl, butyryl, pivaloyl and octanoyl.
A heterocyclyl radical is to be understood as being a 3 to 7-membered, aromatic or non-aromatic ring having hetero atoms N, O andlor S. Furthermore, an unsubstituted or substitu-ted benzo group may be fused onto such a heterocyclyl radical bonded to the rest of the molecule. Examples of heterocyclyl groups are pyridyl, pyrimidinyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, triazolyl, thienyl, furanyl, pyrrolyl, morpholinyl, oxazolyl and the correspon-ding partially or completely hydrogenated rings. Examples of heterocyclyl groups to which a benzo group is fused are quinolyl, isoquinofyl, benzoxazolyl, quinoxaiinyl, benzothiazolyl, benzimidazolyl, indolyl and indolinyl.
Aryl is phenyl, naphthyl, phenanthryl or fluorenyl, in particular phenyl.
The hydrocarbyi groups, as alkyl, alkenyl, alkynyl, and the haloalkyl, haloalkenyl, haloalkoxy and alkanoyl groups mentioned hereinabove and hereinbelow can be substituted by aryl, hetaryl, aryloxy, hetaryloxy, arylsulfenyl, arylsulfinyl, arylsulfonyl, heterarylsulfenyl, hetarylsulfinyl or heterarylsulfonyl, each of which is unsubstituted or additionally substituted.
All the aryl, hetaryi and heterocyclyl groups mentioned hereinabove and hereinbelow can be mono- or polysubstituted, for example by halogen, C,-C,,alkyl, C2-C4alkenyl, C2-C4alkynyl, C,-C4alkoxy, C,-C,alkylthio, C,-C~haloalkyl, C2-Cehaloalkenyi, C2-C4-haloalkynyl, C,-C,haloalkoxy, halogen, cyano, cyano-C,-CZalkyl, cyano-C,-CZalkoxy, OH, N02, SCN, thiocyanomethyl, Si(CH3)3, NH2, NH(C,-C,alkyl), N(C,-C,alkyl)2, C,-Cealkoxymethyl, C,-C,,haloalkylcarbonyl, C,-C4haloalkyloxycarbonyl, C,-C4alkylcarbonyl, C,-C4-alkoxycarbonyl, aminocarbonyl, C,-Cealkylaminocarbonyl, bis(C,-C,alkylamino)carbonyl, arylaminocarbonyl, arylaminothiocarbonyl, C,-C,aikoximinomethyl, -CSNHZ, -SH, C,-C4alkylthiomethyl, C2-C4alkenyloxy, C2-C4alkynyloxy, CZ-C,haloalkenyloxy, C,-C4alkylsulfinylmethyl, C,-C,alkyisulfonylmethyl, phenylsulfinylmethyl, phenylsulfonylmethyl, trifluoromethyfsulfonyl, C3-Cgcycloalkyl, C,-C4haloalkylcarbonyloxy, C,-C,alkylcarbonyloxy, C,-C,alkoxycarbonyloxy, haloalkoxycarb~onyloxy, aminocarbonyfoxy, C,-C4alkylaminocarbonyloxy, bis(C,-C,alkylamino)carbonyloxy, arylaminocarbonyloxy, arylaminothiocarbonyloxy.
Amongst the compounds and methods of their use the following groups are preferred:
(1 ) Compounds of formula R~ R2 S
LA .
R 4 _"C~
N R
The compounds of the formula R ~ OMe CO-NH-CHZ CHZ ~ ~ OMe CI -~~
N CI T
wherein -6- ' a) R, is OCO-CH3 and T is Br, b) R, is OH and T is Br, c) R, is OH and T is H, are known from WO 96/17840 as fungicides, but no indication is given therein to plant immunizing properties of these compounds ; these compounds are thus part of the invention only as far as the method for immunizing plants is concerned.
(2) Compounds of formula R~ R2 .S Z
_ LB.
Rs (3) Compounds of formula R~ R2 ,S
'Z LC.
~R
(4) Compounds of formula I, wherein Z is CN, CO-A, CS-A or CH{OR,o)2,;
A is hydrogen, halogen, ORs, SR,, N(Re)Ra, ON(R")R,2 or N(R,3)OR,4;
Rs to R" are independently hydrogen, an unsubstituted or substituted, open-chained, saturated or unsaturated hydrocarbon radical containing up to 8 carbon atoms, an unsubstituted or substituted, cyclic, saturated or unsaturated hydrocarbon radical containing up to 10 carbon atoms, unsubstituted or substituted benzyl or phenethyl, an unsubstituted or substituted acyl group containing up to 8 carbon atoms, an unsubstituted or substituted benzoyl group, or an unsubstituted or substituted heterocyclyl radical; or _7_ R8 and R9, or R" and R,2, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered, unsubstituted or substituted heterocycle having 1 to 3 hetero atoms selected from O, S and/or N;
R,o are identical or different and are C,-CBalkyl that is unsubstituted or substituted by phenyl, C,-C2alkoxy, phenoxy or by benzyloxy; or two substituents OR,o, together with the carbon atom to which they are bonded, form a cyclic acetal group that is unsubstituted or substituted by C,-C3alkyi, phenyl, benzyl, hydroxy or by C,-C3hydroxyalkyl.
(5) Compounds of formula I, wherein Z is CO-A or CS-A;
A is OR6, SR,, N(R8)R9, ON(R")R,2 or N(R,3)OR,4;
R6 to R,4 are independently H, C,-CBalkyl, haloC,-Cgalkyl, C,-Csalkoxycarbonyl, C,-C4alkanoylC,-C4alkyl, C3-Cgcycloalkyl, C3-Cscycloalkylmethyl, phenyl, benzyl, phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, C,-C4alkyl, halo-C,-C2alkyl, C,-CZalkoxy, haio-C,-C2alkoxy and C,-C2alkylenedioxy.
(6) Compounds of formula I, wherein R3 is H, OH, C,-CBalkyl, C3-CBCycloalkyl, haloC,-Csalkyl, C,-Caalkoxy or haloC,-Csaikoxy.
(7) Compounds of formula I, wherein R, is H, OH, NH2, halogen, COOH, C,-C,afkyl, haloC,-C4alkyl, C,-C,alkoxy, C,-C,alkanoyloxy, aroylyloxy, C,-C,alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, C,-C,alkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C,-C,alkylaminocarbonyl, C,-C,dialkylaminocarbonyl, alkanoylC,-C4alkyl, alkylcarbonyloxyC,-C,alkyl, C2-C4alkenyl, haloC2-C,alkenyl, C,-C,,alkylamino, C,-C4dialkylamino, C,-C,alkanoylamino, C,-C,alkoxycarbonylamino, benzylamino, benzoylamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C,-C,alkyl, halo-C,-CZalkyl, C,-CZalkoxy, halo-C,-Czalkoxy and vitro;
~RZ is H, OH, C,-C,,alkyl, C,-Cdalkoxy or phenyl; or R, and RZ together are a group selected from -g_ R,a R,~ R,e N_R ,s or R2+Z together are a group selected from R" R,a R" R,a H H
O O n Rn O O R ,e HO \O
O O
O O
wherein R", R,e and R,s are independently H or C,-C4alkyl;
R3 is H, halogen, C,-Csalkyl, haloC,-Cealkyl, C3-Ca-cycloalkyl, C,-C, alkoxycarbonyl, phenyl which is unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C4alkyl, halo-C,-C2alkyl, C,-CZalkoxy, halo-C,-C2alkoxy, amino, C,-C,alkylamino, C,-C,dialkylamino, benzylamino, C,-C,alkanoylamino, benzoylamino, C,-C4alkoxycarbonylamino, formyl, or a 4-7-membered cyclic or C,-C4alkyl open-chained acetal or thioacetal thereof;
R4 is H, OH, halogen, amino, C,-CBalkyl, C,-C<alkylamino, C,-C4alkenylylamino, C,-C4dialkylamino, benzylamino, C,-C4alkanoylamino, benzoylamino, C,-C4alkoxycarbonylamino.
~RZ is H, OH, C,-C,,alkyl, C,-Cdalkoxy or phenyl; or R, and RZ together are a group selected from -g_ R,a R,~ R,e N_R ,s or R2+Z together are a group selected from R" R,a R" R,a H H
O O n Rn O O R ,e HO \O
O O
O O
wherein R", R,e and R,s are independently H or C,-C4alkyl;
R3 is H, halogen, C,-Csalkyl, haloC,-Cealkyl, C3-Ca-cycloalkyl, C,-C, alkoxycarbonyl, phenyl which is unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C4alkyl, halo-C,-C2alkyl, C,-CZalkoxy, halo-C,-C2alkoxy, amino, C,-C,alkylamino, C,-C,dialkylamino, benzylamino, C,-C,alkanoylamino, benzoylamino, C,-C4alkoxycarbonylamino, formyl, or a 4-7-membered cyclic or C,-C4alkyl open-chained acetal or thioacetal thereof;
R4 is H, OH, halogen, amino, C,-CBalkyl, C,-C<alkylamino, C,-C4alkenylylamino, C,-C4dialkylamino, benzylamino, C,-C4alkanoylamino, benzoylamino, C,-C4alkoxycarbonylamino.
(8) Amongst group (7) those, wherein R3 is H, OH, halogen, C,-Cealkyl, haloC,-Cgalkyl, C3-Ca-cycloalkyl, C,-Caalkoxy, alkoxycarbonylC,-CBalkyl, phenyl, benzyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C,alkyl, halo-C,-C2alkyl, C,-C2alkoxy and halo-C,-C2alkoxy; or formyl, or a 4-7-membered cyclic or C,-C4alkyl open-chained acetal or thioacetal thereof;
R4 is H, OH, halogen, amino, C,-Cgalkyl, C,-C4alkylamino, C,-C4alkenylylamino, C,-C,dialkylamino, benzylamino, C,-C,alkanoylamino, benzoylamino, or C,-C4alkoxycarbonylamino.
-g-(g) Amongst group (6) those, wherein Z is CO-A or CS-A;
A is hydrogen, halogen, ORs, SRS, N(Re)R9, ON(R")R,2 or N(R,3)OR,4;
R6 to R9 and R" to R,4 are independently hydrogen, an unsubstituted or substituted, open-chained, saturated or unsaturated hydrocarbon radical containing up to 8 carbon atoms, an unsubstituted or substituted, cyclic, saturated or unsaturated hydrocarbon radical containing up to 10 carbon atoms, unsubstituted or substituted benzyl or phenethyl, an unsubstituted or substituted acyl group containing up to 8 carbon atoms, an unsubstituted or substituted benzoyl group, or an unsubstituted or substituted heterocyclyl radical; or R8 and R9, or R" and R,2, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered, unsubstituted or substituted heterocycle having 1 to 3 hetero atoms selected from O, S and/or N;
R,o are identical or different and are C,-Cgalkyl that is unsubstituted or substituted by phenyl, C,-C2alkoxy, phenoxy or by benzyloxy; or two substituents OR,o, together with the carbon atom to which they are bonded, form a cyclic acetal group that is unsubstituted or substituted by C,-C3alkyl, phenyl, benzyl, hydroxy or by C,-C3hydroxyalkyl.
(10) Amongst group (9) those, wherein A is OR6, SR,, or N(RB)R9;
R6, R,, R8 R9 are independently H, C,-Csalkyl, haloC,-CBalkyl, C,-C4alkoxycarbonyl, alkoxycarbonylC,-CBalkyl, C,-C,alkanoylC,-C,alkyl, C3-CBcycloalkyl, C3-Cscycioalkylmethyl, phenyl, benzyl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected~from halogen, C,-Cealkyl, halo-C,-CZalkyl, C,-C2alkoxy, halo-C,-C2alkoxy.
(11 ) Amongst group (g) those, wherein Z is CO-A;
A is OR6 or N(RB)R9;
R, is H, OH, halogen, C,-C<alkyl, haloC,-C4alkyl, C,-C,alkoxy, halo-C,-C,,alkoxy, amino, C,-C4alkylamino, C,-C4dialkylamino, benzylamino; phenyl, benzyl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 2 substituents independently selected from halogen, halo-C,-C2alkyl, C,-C2alkoxy, halo-C,-C2alkoxy;
WO 99/32464 PC'T/EP98/08335 R2 is H, OH, halogen, C,-C4alkyl, haloC,-Csaikyl, or phenyl, R3 is H, OH, C,-Csalkyl, C3-Cscycloalkyl, haloC,-Csalkyl, C,-Csalkoxy or haloC,-Csalkoxy, R4 is H or CI, Rs, Re and R9 are independently H, C,-Csalkyl, haloC,-Csalkyl, C,-Csaikoxy, haloC,-Csalkoxy, C,-C4alkoxycarbonyl, C,-C4alkanoylC,-Caalkyl, C3-Cscycloalkyl, C3-Cscycfoalkylmethyl, phenyl, benryl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C<alkyl, halo-C,-C2alkyl, C,-Czalkoxy, halo-C,-CZalkoxy.
(12) Amongst group (11 ) those, wherein R, is H, OH, halogen, C,-C,alkyl;
RZ is H.
R3 is H, cyclopropyl or CF3, R4 is CI.
(13) Amongst group (9) those, wherein R3 is H, halogen, C,-C,alkyl, haloC,-Caalkyl, C3-Cs-cycloalkyl, C,-C, alkoxycarbonyl, formyl, or a 4-7-membered cyclic or C,-C,alkyl open-chained acetal or thioacetal thereof.
(14) Compounds of formula R~ R2 S
Z LA
R 4.-'~~ I
N R
Z IS CO-A;
A is hydrogen, ORs, SRS, N(R8)R9;
R, is H, OH, halogen or C,-C4alkyl, RZ is H;
R3 is H, OH, C,-Csalkyl, C3-Cscycloalkyl, haloC,-Csalkyl, C,-Csalkoxy, haloC,-Csalkoxy, formyl, or a 4-7-membered cyclic or C,-Cealkyl open-chained acetal or thioacetal thereof;
R4 is CI;
Rs, R,, Re and R9 are independently H, C,-Csalkyl, haloC,-Csalkyl, C,-Csalkoxy, haloC,-Csalkoxy, C,-C4alkoxycarbonyl, C,-C,,alkanoylC,-C,alkyl, C3-Cscycloalkyl, C3-Cgcycloalkylmethyl, phenyl, benryl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C,alkyl, halo-C,-C2alkyl, C,-CZalkoxy, halo-C,-C2alkoxy.
(15) Amongst group (14) those, wherein A is ORs or SRS;
R, and R2 are H;
R3 is C,-Cgalkyl, C3-Cgcycloalkyl, CF3 or formyl;
R, is CI;
R6 and R, are independently H, C,-CBalkyl, phenyl, benzyl, or phenethyl, the phenyl rings of which are unsubstituted or substituted with 1 to 2 substituents independently selected from halogen, C,-Coalkyl, halo-C,-CZalkyl, C,-CZalkoxy and halo-C,-C2alkoxy.
Also preferred are the compounds of the tables.
The compounds of formula I may be prepared as outlined in the following reaction schemes.
Abbreviations:
position to which the rest of the molecule is attached S
Het: X' Y R
Hal: halogen L: leaving group, preferably chlorine, bromine, mesylate or tosylate.
R: a group which is inert under the reaction conditions -12- _ Scheme 1 Het-COOK Het-CH3 Het-H
halogenation Lithiation Lithiation reduction e.g.N-halosuccinimid e.9.butyllithium e.g.butyllithium e.g. LiAIH4 alomethyl~ation ~e g.HCI/CHZO
Het-CH20H Het-CHZ-Li Het-Li hatogenation L-CH2-COOR
e.g.SOCl2 OHC-COOK
"Amdt- ' ert" C02 carbonylation Het-CH2-Hal Het-CH2 COOR ~ duction Het-CH(OH)-COOR
e.g. CO/cat: cobalt-carbonyl e.g. H~/cat Of particular importance is the reaction step ~S CH2CI ~S CH2 COOH
X I
X ~ ~ ---,~ ~ Y
Y
Ra R3 11.1 1.1 wherein X, Y and R3 are as defined for formula I, which comprises reaction of a compound of formula 11.1 with carbon monoxide under pressure of 2-20 bars, preferably 5-10 bars, in presence of a catalyst, for example cobalt carbonyl and optionally a phase transfer catalyst.
Scheme 2 H H R 1-L/base H R ~ R2-L/base R 2 R , Het~z ----~ ---- ~
Het Het' \z z WO 99/32464 PCT/EP98/Ot3335 _ ~3 _ _ Scheme 3 NXS_ H X RNH2 H NHR
Het z e.g.N-Bromo ~ ~
Het"z Het"z succinimide Scheme 4 O R
H ~-R
OH ~ H O- \
,~OH R R ~O
Het - ~ -~ Het' O O
H NHR 'R~
OH R R HN ' R
Het'~ H O
O Het O
Scheme 5 ~ . Base O
2.
RO~O~R
O
O
. iH ~, gee O~'R Oxidation ~ ~/ R
Het Het ,~ Het 2. O O O
R2~O~R
O
Nu Het~H ~. Base p O~R HO
Nu - R
O Het "'~' Het O (nucleophil) O
'~ R
O
_~4_ _ The functional groups of the compounds of formula I can be converted by known methods.
For example, carboxylic acid derivatives can be converted as follows:
Scheme 6 RZ R~ A RZ R, NH3 R2 R, Het'' 'CO I
Het C
CO-A Het CONHZ
thionating agent reduction _H20 e.g. Lawesson reagent e~9~ scat e.g. SOCIz R2 R~ RZ R~
~ ~ Het ~CN
Het'~C~A Het'' CHO
acetalisation with alcohol or glycol R 2~ ~
Het CH(ORto)2 - _ Of importance are the syntheses of schemes 7 and 8 Scheme 7 t-Bu-0NO
CI COOR NH2 CS-NHZ S COOR CuCl2 H2N \\ I ---O R3 N Rs CI----~ I CI-~ I
N Rs N R3 ROH
reduction 1. reduction, e.g. LiAIH4 e.g.H~/Pd/C 2~ Halogenation; e.g.SOCl2 3. Carbonylation, e.g CO/Co2(CO)8 S COOR or S CH2COOR
H~\ ~ Cyanation/alcohoiysis H~ I
N Ra N R3 RO--~ I RO--~ I
N
WO 99/32464 ' PCT/EP98/08335 _~s_ _ Scheme 8 S COOR S COOR o~~tion S COOR
CI---<~ ~ ~ogenation ~ CI ---~ CI
N e.g. bromination ~N ~ Ha!
CH 3 with NBS v e.g. Mn02 or CHO
N-methylmorpholine-N-oxide acetalis~n Ci S reduction CH -OH
I O CI-~ I O
N O~E e.g.:l.iAIH4 N jE
O
chlorination CI ,S I CHzCI ca~i~ S CH2COOH
e.g. SOCI2 or --~N O\E CI~ I O
Ph3P/CCI4 O/ e.g.CO/Co2(CO)8 N ~E
O
CI~S I CO-A hydrolysis CI--~S I CO-A
N ~ N CHO
O-E
E: optionally substituted C2-CSmethylene Of particular importance is the reaction step g CH2CI g CHZ COOH
~ 4--C
N
ILA.1 LA.1 which comprises reaction of a compound of formula ILA.1 with carbon monoxide under pressure of 2-20 bars, preferably 5-10 bars, in presence of a catalyst, for example cobalt carbonyl and optionally a phase transfer catalyst.
WO 99/32464 PCT/EP98/pg335 -17- _ Particulartly preferred is this reaction with compounds wherein R3 is C,-Csalkyl, CF3 or an acetal group, and R4 is CI.
Suitable bases, leaving groups, solvents and catalysts are known to the skilled person.
The thiazoles, isothiazoles and thiadiazoles can be synthesized by known methods or in analogy thereto according to the following references:
111 1.3-Thiazoles Ahluwalia V. K. et al, Heterocycles, 32, (1991 ), 907.
Fukatsu H. et al, Heterocycles, 29, (1989) 1517.
Byers J. R.et al, Org. Synthesis II, (1943) 31.
1.2 1.2-Isothiazoles R. G. Micetich, Can J. Chem.; (1970), 48, 2006.
Adams A., Slack, J. Chem. Soc. (1959) 3061.
Buttimore D. et al, J. Chem. Soc. (1963) 2032.
Wooldrige K.R.H. Adv. Het. Chem. (1972), 14, 1.
1.3 1.2.3-Thiadiazoles Hurd C. D., Mori E. J., J. Am. Chem. Soc., (1995), 5359.
Ramsky S. !. et al., Acta Pharm. Suecica 10, (1973), 285.
Scheitauer S., Mayer R. Chem. Ber. 100, (1967), 1413.
R. Raap, Can. J. Chem. (1968), 46. 2255.
The compounds of the invention can be used in the agricultural sector and related fields preventively and/or curatively. Besides their microbicidal properties, the compounds exhibit plant immunizing properties, i.e. plants can be protected by activation and stimulation of the plant's own defense system (immunization) which is known as "Systemic Activated Resistance" ("SAR").
Accordingly, with the compounds and methods of the invention, it is possible to control plant diseases on the one hand by strengthening the plant by activating its own defence system and on the other hand by additionally controlling the pathogens directly. The compounds offer a long lasting protection against a variety of pathogenes in different crops.
The compounds I can also be used as dressings in the treatment of seed (fruit, tubers, grains) and plant cuttings to provide protection against fungus infections as well as against phytopathogenic fungi which occur in the soil.
The compounds I are effective, for example, against phytopathogenic fungi belonging to the following classes: Fungi imperfecti (e.g. Botrytis, Pyricularia, Helminthosporium, Fusarium, Septoria, Cercospora and Altemaria) and Basidiomycetes (e.g. Rhizoctonia, Hemileia, Puccinia). Moreover, they are effective against the classes of the Ascomycetes (e.g.
Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula) and Oomycetes (e.g.
Phyto-phthora, Pythium, Plasmopara).
Target crops to be protected within the scope of the present invention comprise e.g. the following species of plants: cereals (wheat, barley, rye, oats, rice, maize, sorghum and related species); beet (sugar beet and fodder beet); pomes, stone fruit and soft fruit (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and black-berries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (marrows, cucumber, melons); fibre plants (cotton, flax, hemp, jute);
citrus fruit (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocados, cinnamon, camphor); and plants such as tobacco, nuts, coffee, aubergines, sugar cane, tea, pepper, vines, hops, bananas and natural rubber plants, as well as ornamentals.
The compounds I are generally used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession, with further compounds.
These further compounds can be, for example, fertilisers or micronutrient donors or other preparations that influence plant growth. They can also be selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or other application-promoting adjuvants customarily employed in formulation technology.
Suitable solvents, carriers and adjuvants are known to the skilled person.
A preferred method of applying a compound of formula !, or an agrochemical composition comprising at least one of those compounds, is application to the leaves (foliar application).
The frequency and rate of application depend upon the risk of infestation by the correspon-ding pathogen. The compounds I can, however, also penetrate the plant through the roots via the soil (systemic action) if the locus of the plant is impregnated with a liquid formulation or if the substances are introduced in solid form into the soil, e.g. in the form of granules (soil application). In paddy rice crops, such granules can be applied in metered amounts to the flooded rice field. In order to treat seed, the compounds I can, however, also be applied to the seeds (coating), either by impregnating the grains or tubers with a liquid formulation of the active ingredient, or by coating them with a solid formulation.
Advantageous rates of application are normally from 5 g to 2 kg of active ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 kg a.i./ha, especially from 20 g to 600 g a.i./ha.
When the compounds are used as seed dressings, dosages of from 10 mg to 1 g of active ingredient per kg of seed are advantageously employed.
The agrochemical compositions generally comprise 0.1 to 99 % by weight, preferably 0.1 to 95 % by weight, of a compound of formula 1, 99.9 to 1 % by weight, preferably 99.8 to 5 by weight, of a solid or liquid adjuvant and 0 to 25 % by weight, preferably 0.1 to 25 % by weight, of a surfactant.
Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ dilute formulations.
The compositions may also comprise further auxiliaries, such as stabilisers, antifoams, viscosity regulators, binders or tackifiers, as well as fertilisers or other active ingredients for obtaining special effects.
The compounds of formula I can be mixed with other fungicides, producing in some cases unexpected synergistic effects.
Especially preferred mixing partners are azoles, as azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, metconazole, myclobutanil, pefurazoate, penconazole, pyrifenox, prochloraz, propiconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole;
pyrimidinyl carbinoies, as ancymidol, fenarimol, nuarimol;
2-amino-pyrimidines, as bupirimate, dimethirimol, ethirimol;
morpholines, as dodemorph, fenpropidin, fenpropimorph, spiroxamin, tridemorph;
anilinopyrimidines, as cyprodinil, mepanipyrim, pyrimethanil;
pyrroles, as fenpiclonil, fludioxonil;
phenylamides, as benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace, oxadixyi;
benzimidazoles, as benomyl, carbendazim, debacarb, fuberidazole, thiabendazole;
dicarboximides, as chlozolinate, dichlozoline, iprodione, myclozoline, procymidone, vinclozolin;
carboxamides, as carboxin, fenfuram, flutolanil, mepronil, oxycarboxin, thifluzamide;
guanidines, as guazatine, dodine, iminoctadine;
strobilurines, as azoxystrobin, kresoxim-methyl, SSF-126 (metominostrobin or fenominostrobin; SSF-129 (a-methoximino-N-methyl-2-[(2,5-dimethylphenoxy)methyl}-benzeneacetamide), trifloxystrobin (2-[a-([(a-methyl-3-trifluormethyl-benzyl)imino}-oxy}-o-tolyl] -glyoxylsaure-methylester-O-methyloxim);
dithiocarbamates, as ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb, ziram;
N-halomethylthiodicarboximides, as captafol, captan, dichlofluanid, fluoromide, folpet, tolyfluanid;
copper compounds, as Bordeaux-mixture, copper hydroxide, copper oxychloride, copper sulfate, cuprous oxide, mancopper, oxine-copper;
nitrophenol-derivatives, as dinocap, nitrothal-isopropyl;
organo-P-derivatives, as edifenphos, iprobenphos, isoprothiolane, phosdiphen, pyrazophos, tolclofos-methyl;
other compounds, as acibenzolar-S-methyl, anilazine, blasticidin-S, chinomethionat, chloroneb, chtorothalonil, cymoxanil, dichlone, diclomezine, dicloran, diethofencarb, dimethomorph, dithianon, etridiazole, famoxadone, fentin, ferimzone,fluazinam, flusulfamide, fenhexamid, fosetyl-aluminium, hymexazol, kasugamycin, methasulfocarb, pencycuron, phthalide, polyoxins, probenazole, propamocarb, pyroquilon, quinoxyfen, quintozene, sulfur, triazoxide, tricyclazole, triforine, validamycin.
Examples A. Preparation Examples Abbreviations: Me = methyl; Et = ethyl; Pr = n-propyl; i-Pr = isopropyl; Bu =
n-butyl; i-Bu =
isobutyl; sec-Bu = sec-butyl; t-butyl = tert-butyl, Ph = phenyl; Ac = acetyl, THF =
tetrahydrofuran; TPP = triphenylphosphine; Val = valine; m.p. = melting point 1. Compound No.l.1 lEl CI~S ~ S CI NaAIH2(OCH2CHZOCH3)z CI-.(S ~ OH
OOH S~ C ~I
N F N F N F
F F F F C F F
A g S O
S
CI~ ~ OOH ~ C02 / Coz(CO)e CI~ ~ SCI
~~N F N F
F F F F
E D
A mixture of thiazols A (synthesized according to EP 0279239) (25.5 g, 0.11 Mol) and thionyl chloride (26.2 g, 0.22 Mol) in 25m1 of toluene, is held at reflux for 1.5 hours. After, evaporation of the toluene under reduced pressure, 24 g of the acid chloride B
(b.p 90-92°, 45mbar) is distilled through a Vigreux column.
To the acid chloride B (97.5 g, 0.39 Mol) in 11 dry tetrahydrofuran at -70°C under nitrogen atmosphere, NaAIH2(OCH2CH20CH3)2 (commercial solution 3.5M in toluene, 0.429Mo1), diluted in 300m1 of toluene, is added dropwise. After 45min of stirring at -70°C, the cooling bath is removed and the reaction is quenched with 370 ml of 3.5N HCI is added.
The organic phase extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure and flash-chromatographed to afford 67.5g of the alcohol C as an oil.
A mixture of alcohol C (60 g, 0.276 Mol) and thionyl chloride (98.5 g, 0828 Mol) in 400 ml of dichloromethane containing 0.1 ml of dimethyl formamide is stirred at reflux for 8 hours:
Another portion of thionyl chloride (16.4 g, 0.138 Mol) is then added and the reaction heated for additional 16 hours. After the reaction is cooled down to room temperature, the solvent is removed under reduced pressure (60°C, 200 mbar) and the resulting crude yellow oil is distilled through a 5 cm Vigreux column (92-95°C, 20 mbar) to give 53.5 g of compound D as an colorless oil.
A mixture of compound D (125 g, 1.059 Mol), benzyitriethylammonium chloride (4.8 g, 0.042 Mol), cobalt carbonyl (7.2 g, 0.042 Mol), sodium carbonate (101 g, 2.4 Mol), 1.5 I of water and 1.361 of dichloromethane is stirred under carbon monoxide pressure (10 bars) for 24 hours at room temperature. The biphasic mixture is then filtered over celite, extracted two times with dichloromethane. The water phase is acidified with105 ml of concentrated HCI
and extracted with ethyl acetate. The organic layer is then washed with brine, dried over sodium sulfate, treated with active charcoal at 60°C, filtered over celite and concentrated in vacuo to give 114 g of the acid E which is used without further purification.
2. Compound No 2 5 (J) lby Amdt-Eistert-reaction) CI S OH 1. (COCI)2 S CH
---_-~. CI C-NzTMS PhCH 20H S
N HZ _~ CI--( ~ COOCHZPh 2. Me3SICH N
z 2 80 C N
G
H
To compound G (2.0 g, 10.44 mmol) dissolved in 20 ml of dichloromethane at 0°C, is added oxalyl chloride (0.9 ml, 10.5 mmol}. After the development of carbon dioxide stopped, 0.1 ml of dimethylformamide is added and the yellow suspension is stirred at room temperature for 3 hours. The resulting yellow solution is then concentrated under reduced pressure, dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml acetonitrile, cooled down to 0°C, and successively treated with triethylamine (1.8 ml), trimethylsilyldiazomethane (commercial 2N solution in hexane) (6.05 ml, 13.05 mmol). After 12 hours of stirring at 0°C, the solvents are evaporated under reduced pressure, and the intermediate diazoketone G is rearanged in a mixture of 13 ml of benzylalcohol and 13 ml of trimethylpyridine at 180°C for 8 min. The dark mixture is cooled down to room tempature, diluted with ethyl acetate, washed 3 times with citric acid (10% aqueous solution). The ethyl acetate layer is dried over magnesium sulfate, filtered, evaporated under reduced pressure, and flash-chromatographed to give the compound J as an oil.
3. Compound No.1 2 S ~ COOCH3 c.--.y 2-Chloro-4-trifluoromethyl-5-acetic acid (10 g, 40.71 mmol) in f 00 ml of methanol is heat-refluxed in presence of concentrated sulfuric acid (4 g, 40.71 mol) for l2hours. After cooling at room temperature, the methanol is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and successively washed with a saturated solution of sodium bicarbonate (3 times) and brine. After drying over magnesium sulfate, the ethyl acetate layer is filtered, evaporated under reduced pressure and flash-chromatographed on silica-gel to give 10.368 of the the title compound as a pate red oil.
4. Compound No.1 21 S NCO-NH-CH(COOMe)-CH(CH3)z C!--~\ I
N CFa The acid chloride of comp. 1.2 (78.5 g, 0.2973 Mol) and L-Valine methyl ester hydrochloride are suspended in 600 ml of toluene, and heated at 110°C
for 25 minutes. The resulting clear solution is cooled down to room temperature, extracted successively with water, a saturated solution of sodium bicarbonate, brine. The organic layer is then dried over sodium sulfate and the solvent removed under reduced pressure to give a crude oil which is chromatographed on silica-gel to afford 1028 of the title compound (mp:51-53°C).
5. Compound No 1 76 Br S ~COOCH3 c!---~\ 1 A mixture of compound 1.2 (9 g, 34.7 mmol) and N-Bromosuccinimide (15.49 g, 87 mmol) in 200 ml of carbon tetrachloride, irradiated w'tth a 150W quartz lamp is heated at reflux temperature. After 1.5 hours of stirring, the mixture is cooled down to room temperature and filtered over celite. After removal of the solvent under reduced pressure, the filtrate is suspended in hexane at 60°C and the solid filtered over celite. The hexane evaporated under reduced pressure to give a red oil, which after distillation (150°C, 0.13mbars) gives 10g of the title compound as a pale red oil.
6. Compound No. 1 97 NH-CH2 Ph ~ COOCH3 cl--~\ I
N CFs A mixture of compound 1.76 (1 g, 2.9 mmol) and (0.63 g, 5.9 mmol) of benzylamin is stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture is removed under reduced pressure, and chromatographed on silica to give 0.8 g of the title compound as an oil.
7. Compound No 1 82 \ COOCH3 CI--<\ ( Compound 1.2 (1 g, 3.8 mmol) is added to a suspension of sodium hydride (55%
in mineral oil) (0.17g, 4,2mmol) in tetrahydrofuran at -50°C, and the resulting red solution stirred for 1 hour at -35°C. After this period, methyl iodide (0.7 g, 5 mmol) is rapidly added. After 2 hours of stirring, the reaction is quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, evaporated under reduced pressure and chromatographed on silica to give 0.72 g of the title compound as a pale yellow oil.
8. Compound No.1.92 ~COOCH3 cl--~~
Compound 1.2 (1 g, 3.8 mmol) is added to a suspension of sodium hydride (55%
in mineral oil) (0.17 g, 4,2 mmol) in dry tetrahydrofuran at -50°C, and the resulting red solution stirred for 1 hr at -35°C. Methyl chloroformiate ( 6 mmol) is then added, and after 2hours of stirring, the reaction is quenched with a saturated aqueous ammonium chloride solution, and heated up to room temperature. After extraction with ethyl acetate, the organic layer is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The reaction mixture is purified on silica to afford 0.79g of the title compound as a white solid.
R4 is H, OH, halogen, amino, C,-Cgalkyl, C,-C4alkylamino, C,-C4alkenylylamino, C,-C,dialkylamino, benzylamino, C,-C,alkanoylamino, benzoylamino, or C,-C4alkoxycarbonylamino.
-g-(g) Amongst group (6) those, wherein Z is CO-A or CS-A;
A is hydrogen, halogen, ORs, SRS, N(Re)R9, ON(R")R,2 or N(R,3)OR,4;
R6 to R9 and R" to R,4 are independently hydrogen, an unsubstituted or substituted, open-chained, saturated or unsaturated hydrocarbon radical containing up to 8 carbon atoms, an unsubstituted or substituted, cyclic, saturated or unsaturated hydrocarbon radical containing up to 10 carbon atoms, unsubstituted or substituted benzyl or phenethyl, an unsubstituted or substituted acyl group containing up to 8 carbon atoms, an unsubstituted or substituted benzoyl group, or an unsubstituted or substituted heterocyclyl radical; or R8 and R9, or R" and R,2, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered, unsubstituted or substituted heterocycle having 1 to 3 hetero atoms selected from O, S and/or N;
R,o are identical or different and are C,-Cgalkyl that is unsubstituted or substituted by phenyl, C,-C2alkoxy, phenoxy or by benzyloxy; or two substituents OR,o, together with the carbon atom to which they are bonded, form a cyclic acetal group that is unsubstituted or substituted by C,-C3alkyl, phenyl, benzyl, hydroxy or by C,-C3hydroxyalkyl.
(10) Amongst group (9) those, wherein A is OR6, SR,, or N(RB)R9;
R6, R,, R8 R9 are independently H, C,-Csalkyl, haloC,-CBalkyl, C,-C4alkoxycarbonyl, alkoxycarbonylC,-CBalkyl, C,-C,alkanoylC,-C,alkyl, C3-CBcycloalkyl, C3-Cscycioalkylmethyl, phenyl, benzyl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected~from halogen, C,-Cealkyl, halo-C,-CZalkyl, C,-C2alkoxy, halo-C,-C2alkoxy.
(11 ) Amongst group (g) those, wherein Z is CO-A;
A is OR6 or N(RB)R9;
R, is H, OH, halogen, C,-C<alkyl, haloC,-C4alkyl, C,-C,alkoxy, halo-C,-C,,alkoxy, amino, C,-C4alkylamino, C,-C4dialkylamino, benzylamino; phenyl, benzyl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 2 substituents independently selected from halogen, halo-C,-C2alkyl, C,-C2alkoxy, halo-C,-C2alkoxy;
WO 99/32464 PC'T/EP98/08335 R2 is H, OH, halogen, C,-C4alkyl, haloC,-Csaikyl, or phenyl, R3 is H, OH, C,-Csalkyl, C3-Cscycloalkyl, haloC,-Csalkyl, C,-Csalkoxy or haloC,-Csalkoxy, R4 is H or CI, Rs, Re and R9 are independently H, C,-Csalkyl, haloC,-Csalkyl, C,-Csaikoxy, haloC,-Csalkoxy, C,-C4alkoxycarbonyl, C,-C4alkanoylC,-Caalkyl, C3-Cscycloalkyl, C3-Cscycfoalkylmethyl, phenyl, benryl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C<alkyl, halo-C,-C2alkyl, C,-Czalkoxy, halo-C,-CZalkoxy.
(12) Amongst group (11 ) those, wherein R, is H, OH, halogen, C,-C,alkyl;
RZ is H.
R3 is H, cyclopropyl or CF3, R4 is CI.
(13) Amongst group (9) those, wherein R3 is H, halogen, C,-C,alkyl, haloC,-Caalkyl, C3-Cs-cycloalkyl, C,-C, alkoxycarbonyl, formyl, or a 4-7-membered cyclic or C,-C,alkyl open-chained acetal or thioacetal thereof.
(14) Compounds of formula R~ R2 S
Z LA
R 4.-'~~ I
N R
Z IS CO-A;
A is hydrogen, ORs, SRS, N(R8)R9;
R, is H, OH, halogen or C,-C4alkyl, RZ is H;
R3 is H, OH, C,-Csalkyl, C3-Cscycloalkyl, haloC,-Csalkyl, C,-Csalkoxy, haloC,-Csalkoxy, formyl, or a 4-7-membered cyclic or C,-Cealkyl open-chained acetal or thioacetal thereof;
R4 is CI;
Rs, R,, Re and R9 are independently H, C,-Csalkyl, haloC,-Csalkyl, C,-Csalkoxy, haloC,-Csalkoxy, C,-C4alkoxycarbonyl, C,-C,,alkanoylC,-C,alkyl, C3-Cscycloalkyl, C3-Cgcycloalkylmethyl, phenyl, benryl, or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C,-C,alkyl, halo-C,-C2alkyl, C,-CZalkoxy, halo-C,-C2alkoxy.
(15) Amongst group (14) those, wherein A is ORs or SRS;
R, and R2 are H;
R3 is C,-Cgalkyl, C3-Cgcycloalkyl, CF3 or formyl;
R, is CI;
R6 and R, are independently H, C,-CBalkyl, phenyl, benzyl, or phenethyl, the phenyl rings of which are unsubstituted or substituted with 1 to 2 substituents independently selected from halogen, C,-Coalkyl, halo-C,-CZalkyl, C,-CZalkoxy and halo-C,-C2alkoxy.
Also preferred are the compounds of the tables.
The compounds of formula I may be prepared as outlined in the following reaction schemes.
Abbreviations:
position to which the rest of the molecule is attached S
Het: X' Y R
Hal: halogen L: leaving group, preferably chlorine, bromine, mesylate or tosylate.
R: a group which is inert under the reaction conditions -12- _ Scheme 1 Het-COOK Het-CH3 Het-H
halogenation Lithiation Lithiation reduction e.g.N-halosuccinimid e.9.butyllithium e.g.butyllithium e.g. LiAIH4 alomethyl~ation ~e g.HCI/CHZO
Het-CH20H Het-CHZ-Li Het-Li hatogenation L-CH2-COOR
e.g.SOCl2 OHC-COOK
"Amdt- ' ert" C02 carbonylation Het-CH2-Hal Het-CH2 COOR ~ duction Het-CH(OH)-COOR
e.g. CO/cat: cobalt-carbonyl e.g. H~/cat Of particular importance is the reaction step ~S CH2CI ~S CH2 COOH
X I
X ~ ~ ---,~ ~ Y
Y
Ra R3 11.1 1.1 wherein X, Y and R3 are as defined for formula I, which comprises reaction of a compound of formula 11.1 with carbon monoxide under pressure of 2-20 bars, preferably 5-10 bars, in presence of a catalyst, for example cobalt carbonyl and optionally a phase transfer catalyst.
Scheme 2 H H R 1-L/base H R ~ R2-L/base R 2 R , Het~z ----~ ---- ~
Het Het' \z z WO 99/32464 PCT/EP98/Ot3335 _ ~3 _ _ Scheme 3 NXS_ H X RNH2 H NHR
Het z e.g.N-Bromo ~ ~
Het"z Het"z succinimide Scheme 4 O R
H ~-R
OH ~ H O- \
,~OH R R ~O
Het - ~ -~ Het' O O
H NHR 'R~
OH R R HN ' R
Het'~ H O
O Het O
Scheme 5 ~ . Base O
2.
RO~O~R
O
O
. iH ~, gee O~'R Oxidation ~ ~/ R
Het Het ,~ Het 2. O O O
R2~O~R
O
Nu Het~H ~. Base p O~R HO
Nu - R
O Het "'~' Het O (nucleophil) O
'~ R
O
_~4_ _ The functional groups of the compounds of formula I can be converted by known methods.
For example, carboxylic acid derivatives can be converted as follows:
Scheme 6 RZ R~ A RZ R, NH3 R2 R, Het'' 'CO I
Het C
CO-A Het CONHZ
thionating agent reduction _H20 e.g. Lawesson reagent e~9~ scat e.g. SOCIz R2 R~ RZ R~
~ ~ Het ~CN
Het'~C~A Het'' CHO
acetalisation with alcohol or glycol R 2~ ~
Het CH(ORto)2 - _ Of importance are the syntheses of schemes 7 and 8 Scheme 7 t-Bu-0NO
CI COOR NH2 CS-NHZ S COOR CuCl2 H2N \\ I ---O R3 N Rs CI----~ I CI-~ I
N Rs N R3 ROH
reduction 1. reduction, e.g. LiAIH4 e.g.H~/Pd/C 2~ Halogenation; e.g.SOCl2 3. Carbonylation, e.g CO/Co2(CO)8 S COOR or S CH2COOR
H~\ ~ Cyanation/alcohoiysis H~ I
N Ra N R3 RO--~ I RO--~ I
N
WO 99/32464 ' PCT/EP98/08335 _~s_ _ Scheme 8 S COOR S COOR o~~tion S COOR
CI---<~ ~ ~ogenation ~ CI ---~ CI
N e.g. bromination ~N ~ Ha!
CH 3 with NBS v e.g. Mn02 or CHO
N-methylmorpholine-N-oxide acetalis~n Ci S reduction CH -OH
I O CI-~ I O
N O~E e.g.:l.iAIH4 N jE
O
chlorination CI ,S I CHzCI ca~i~ S CH2COOH
e.g. SOCI2 or --~N O\E CI~ I O
Ph3P/CCI4 O/ e.g.CO/Co2(CO)8 N ~E
O
CI~S I CO-A hydrolysis CI--~S I CO-A
N ~ N CHO
O-E
E: optionally substituted C2-CSmethylene Of particular importance is the reaction step g CH2CI g CHZ COOH
~ 4--C
N
ILA.1 LA.1 which comprises reaction of a compound of formula ILA.1 with carbon monoxide under pressure of 2-20 bars, preferably 5-10 bars, in presence of a catalyst, for example cobalt carbonyl and optionally a phase transfer catalyst.
WO 99/32464 PCT/EP98/pg335 -17- _ Particulartly preferred is this reaction with compounds wherein R3 is C,-Csalkyl, CF3 or an acetal group, and R4 is CI.
Suitable bases, leaving groups, solvents and catalysts are known to the skilled person.
The thiazoles, isothiazoles and thiadiazoles can be synthesized by known methods or in analogy thereto according to the following references:
111 1.3-Thiazoles Ahluwalia V. K. et al, Heterocycles, 32, (1991 ), 907.
Fukatsu H. et al, Heterocycles, 29, (1989) 1517.
Byers J. R.et al, Org. Synthesis II, (1943) 31.
1.2 1.2-Isothiazoles R. G. Micetich, Can J. Chem.; (1970), 48, 2006.
Adams A., Slack, J. Chem. Soc. (1959) 3061.
Buttimore D. et al, J. Chem. Soc. (1963) 2032.
Wooldrige K.R.H. Adv. Het. Chem. (1972), 14, 1.
1.3 1.2.3-Thiadiazoles Hurd C. D., Mori E. J., J. Am. Chem. Soc., (1995), 5359.
Ramsky S. !. et al., Acta Pharm. Suecica 10, (1973), 285.
Scheitauer S., Mayer R. Chem. Ber. 100, (1967), 1413.
R. Raap, Can. J. Chem. (1968), 46. 2255.
The compounds of the invention can be used in the agricultural sector and related fields preventively and/or curatively. Besides their microbicidal properties, the compounds exhibit plant immunizing properties, i.e. plants can be protected by activation and stimulation of the plant's own defense system (immunization) which is known as "Systemic Activated Resistance" ("SAR").
Accordingly, with the compounds and methods of the invention, it is possible to control plant diseases on the one hand by strengthening the plant by activating its own defence system and on the other hand by additionally controlling the pathogens directly. The compounds offer a long lasting protection against a variety of pathogenes in different crops.
The compounds I can also be used as dressings in the treatment of seed (fruit, tubers, grains) and plant cuttings to provide protection against fungus infections as well as against phytopathogenic fungi which occur in the soil.
The compounds I are effective, for example, against phytopathogenic fungi belonging to the following classes: Fungi imperfecti (e.g. Botrytis, Pyricularia, Helminthosporium, Fusarium, Septoria, Cercospora and Altemaria) and Basidiomycetes (e.g. Rhizoctonia, Hemileia, Puccinia). Moreover, they are effective against the classes of the Ascomycetes (e.g.
Venturia and Erysiphe, Podosphaera, Monilinia, Uncinula) and Oomycetes (e.g.
Phyto-phthora, Pythium, Plasmopara).
Target crops to be protected within the scope of the present invention comprise e.g. the following species of plants: cereals (wheat, barley, rye, oats, rice, maize, sorghum and related species); beet (sugar beet and fodder beet); pomes, stone fruit and soft fruit (apples, pears, plums, peaches, almonds, cherries, strawberries, raspberries and black-berries); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa beans, groundnuts); cucumber plants (marrows, cucumber, melons); fibre plants (cotton, flax, hemp, jute);
citrus fruit (oranges, lemons, grapefruit, mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika); lauraceae (avocados, cinnamon, camphor); and plants such as tobacco, nuts, coffee, aubergines, sugar cane, tea, pepper, vines, hops, bananas and natural rubber plants, as well as ornamentals.
The compounds I are generally used in the form of compositions and can be applied to the crop area or plant to be treated, simultaneously or in succession, with further compounds.
These further compounds can be, for example, fertilisers or micronutrient donors or other preparations that influence plant growth. They can also be selective herbicides as well as insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of these preparations, if desired together with further carriers, surfactants or other application-promoting adjuvants customarily employed in formulation technology.
Suitable solvents, carriers and adjuvants are known to the skilled person.
A preferred method of applying a compound of formula !, or an agrochemical composition comprising at least one of those compounds, is application to the leaves (foliar application).
The frequency and rate of application depend upon the risk of infestation by the correspon-ding pathogen. The compounds I can, however, also penetrate the plant through the roots via the soil (systemic action) if the locus of the plant is impregnated with a liquid formulation or if the substances are introduced in solid form into the soil, e.g. in the form of granules (soil application). In paddy rice crops, such granules can be applied in metered amounts to the flooded rice field. In order to treat seed, the compounds I can, however, also be applied to the seeds (coating), either by impregnating the grains or tubers with a liquid formulation of the active ingredient, or by coating them with a solid formulation.
Advantageous rates of application are normally from 5 g to 2 kg of active ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 kg a.i./ha, especially from 20 g to 600 g a.i./ha.
When the compounds are used as seed dressings, dosages of from 10 mg to 1 g of active ingredient per kg of seed are advantageously employed.
The agrochemical compositions generally comprise 0.1 to 99 % by weight, preferably 0.1 to 95 % by weight, of a compound of formula 1, 99.9 to 1 % by weight, preferably 99.8 to 5 by weight, of a solid or liquid adjuvant and 0 to 25 % by weight, preferably 0.1 to 25 % by weight, of a surfactant.
Whereas commercial products will preferably be formulated as concentrates, the end user will normally employ dilute formulations.
The compositions may also comprise further auxiliaries, such as stabilisers, antifoams, viscosity regulators, binders or tackifiers, as well as fertilisers or other active ingredients for obtaining special effects.
The compounds of formula I can be mixed with other fungicides, producing in some cases unexpected synergistic effects.
Especially preferred mixing partners are azoles, as azaconazole, bitertanol, bromuconazole, cyproconazole, difenoconazole, diniconazole, epoxiconazole, fenbuconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, metconazole, myclobutanil, pefurazoate, penconazole, pyrifenox, prochloraz, propiconazole, tebuconazole, tetraconazole, triadimefon, triadimenol, triflumizole, triticonazole;
pyrimidinyl carbinoies, as ancymidol, fenarimol, nuarimol;
2-amino-pyrimidines, as bupirimate, dimethirimol, ethirimol;
morpholines, as dodemorph, fenpropidin, fenpropimorph, spiroxamin, tridemorph;
anilinopyrimidines, as cyprodinil, mepanipyrim, pyrimethanil;
pyrroles, as fenpiclonil, fludioxonil;
phenylamides, as benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace, oxadixyi;
benzimidazoles, as benomyl, carbendazim, debacarb, fuberidazole, thiabendazole;
dicarboximides, as chlozolinate, dichlozoline, iprodione, myclozoline, procymidone, vinclozolin;
carboxamides, as carboxin, fenfuram, flutolanil, mepronil, oxycarboxin, thifluzamide;
guanidines, as guazatine, dodine, iminoctadine;
strobilurines, as azoxystrobin, kresoxim-methyl, SSF-126 (metominostrobin or fenominostrobin; SSF-129 (a-methoximino-N-methyl-2-[(2,5-dimethylphenoxy)methyl}-benzeneacetamide), trifloxystrobin (2-[a-([(a-methyl-3-trifluormethyl-benzyl)imino}-oxy}-o-tolyl] -glyoxylsaure-methylester-O-methyloxim);
dithiocarbamates, as ferbam, mancozeb, maneb, metiram, propineb, thiram, zineb, ziram;
N-halomethylthiodicarboximides, as captafol, captan, dichlofluanid, fluoromide, folpet, tolyfluanid;
copper compounds, as Bordeaux-mixture, copper hydroxide, copper oxychloride, copper sulfate, cuprous oxide, mancopper, oxine-copper;
nitrophenol-derivatives, as dinocap, nitrothal-isopropyl;
organo-P-derivatives, as edifenphos, iprobenphos, isoprothiolane, phosdiphen, pyrazophos, tolclofos-methyl;
other compounds, as acibenzolar-S-methyl, anilazine, blasticidin-S, chinomethionat, chloroneb, chtorothalonil, cymoxanil, dichlone, diclomezine, dicloran, diethofencarb, dimethomorph, dithianon, etridiazole, famoxadone, fentin, ferimzone,fluazinam, flusulfamide, fenhexamid, fosetyl-aluminium, hymexazol, kasugamycin, methasulfocarb, pencycuron, phthalide, polyoxins, probenazole, propamocarb, pyroquilon, quinoxyfen, quintozene, sulfur, triazoxide, tricyclazole, triforine, validamycin.
Examples A. Preparation Examples Abbreviations: Me = methyl; Et = ethyl; Pr = n-propyl; i-Pr = isopropyl; Bu =
n-butyl; i-Bu =
isobutyl; sec-Bu = sec-butyl; t-butyl = tert-butyl, Ph = phenyl; Ac = acetyl, THF =
tetrahydrofuran; TPP = triphenylphosphine; Val = valine; m.p. = melting point 1. Compound No.l.1 lEl CI~S ~ S CI NaAIH2(OCH2CHZOCH3)z CI-.(S ~ OH
OOH S~ C ~I
N F N F N F
F F F F C F F
A g S O
S
CI~ ~ OOH ~ C02 / Coz(CO)e CI~ ~ SCI
~~N F N F
F F F F
E D
A mixture of thiazols A (synthesized according to EP 0279239) (25.5 g, 0.11 Mol) and thionyl chloride (26.2 g, 0.22 Mol) in 25m1 of toluene, is held at reflux for 1.5 hours. After, evaporation of the toluene under reduced pressure, 24 g of the acid chloride B
(b.p 90-92°, 45mbar) is distilled through a Vigreux column.
To the acid chloride B (97.5 g, 0.39 Mol) in 11 dry tetrahydrofuran at -70°C under nitrogen atmosphere, NaAIH2(OCH2CH20CH3)2 (commercial solution 3.5M in toluene, 0.429Mo1), diluted in 300m1 of toluene, is added dropwise. After 45min of stirring at -70°C, the cooling bath is removed and the reaction is quenched with 370 ml of 3.5N HCI is added.
The organic phase extracted with ethyl acetate, dried over sodium sulfate, concentrated under reduced pressure and flash-chromatographed to afford 67.5g of the alcohol C as an oil.
A mixture of alcohol C (60 g, 0.276 Mol) and thionyl chloride (98.5 g, 0828 Mol) in 400 ml of dichloromethane containing 0.1 ml of dimethyl formamide is stirred at reflux for 8 hours:
Another portion of thionyl chloride (16.4 g, 0.138 Mol) is then added and the reaction heated for additional 16 hours. After the reaction is cooled down to room temperature, the solvent is removed under reduced pressure (60°C, 200 mbar) and the resulting crude yellow oil is distilled through a 5 cm Vigreux column (92-95°C, 20 mbar) to give 53.5 g of compound D as an colorless oil.
A mixture of compound D (125 g, 1.059 Mol), benzyitriethylammonium chloride (4.8 g, 0.042 Mol), cobalt carbonyl (7.2 g, 0.042 Mol), sodium carbonate (101 g, 2.4 Mol), 1.5 I of water and 1.361 of dichloromethane is stirred under carbon monoxide pressure (10 bars) for 24 hours at room temperature. The biphasic mixture is then filtered over celite, extracted two times with dichloromethane. The water phase is acidified with105 ml of concentrated HCI
and extracted with ethyl acetate. The organic layer is then washed with brine, dried over sodium sulfate, treated with active charcoal at 60°C, filtered over celite and concentrated in vacuo to give 114 g of the acid E which is used without further purification.
2. Compound No 2 5 (J) lby Amdt-Eistert-reaction) CI S OH 1. (COCI)2 S CH
---_-~. CI C-NzTMS PhCH 20H S
N HZ _~ CI--( ~ COOCHZPh 2. Me3SICH N
z 2 80 C N
G
H
To compound G (2.0 g, 10.44 mmol) dissolved in 20 ml of dichloromethane at 0°C, is added oxalyl chloride (0.9 ml, 10.5 mmol}. After the development of carbon dioxide stopped, 0.1 ml of dimethylformamide is added and the yellow suspension is stirred at room temperature for 3 hours. The resulting yellow solution is then concentrated under reduced pressure, dissolved in a mixture of 10 ml tetrahydrofuran and 10 ml acetonitrile, cooled down to 0°C, and successively treated with triethylamine (1.8 ml), trimethylsilyldiazomethane (commercial 2N solution in hexane) (6.05 ml, 13.05 mmol). After 12 hours of stirring at 0°C, the solvents are evaporated under reduced pressure, and the intermediate diazoketone G is rearanged in a mixture of 13 ml of benzylalcohol and 13 ml of trimethylpyridine at 180°C for 8 min. The dark mixture is cooled down to room tempature, diluted with ethyl acetate, washed 3 times with citric acid (10% aqueous solution). The ethyl acetate layer is dried over magnesium sulfate, filtered, evaporated under reduced pressure, and flash-chromatographed to give the compound J as an oil.
3. Compound No.1 2 S ~ COOCH3 c.--.y 2-Chloro-4-trifluoromethyl-5-acetic acid (10 g, 40.71 mmol) in f 00 ml of methanol is heat-refluxed in presence of concentrated sulfuric acid (4 g, 40.71 mol) for l2hours. After cooling at room temperature, the methanol is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, and successively washed with a saturated solution of sodium bicarbonate (3 times) and brine. After drying over magnesium sulfate, the ethyl acetate layer is filtered, evaporated under reduced pressure and flash-chromatographed on silica-gel to give 10.368 of the the title compound as a pate red oil.
4. Compound No.1 21 S NCO-NH-CH(COOMe)-CH(CH3)z C!--~\ I
N CFa The acid chloride of comp. 1.2 (78.5 g, 0.2973 Mol) and L-Valine methyl ester hydrochloride are suspended in 600 ml of toluene, and heated at 110°C
for 25 minutes. The resulting clear solution is cooled down to room temperature, extracted successively with water, a saturated solution of sodium bicarbonate, brine. The organic layer is then dried over sodium sulfate and the solvent removed under reduced pressure to give a crude oil which is chromatographed on silica-gel to afford 1028 of the title compound (mp:51-53°C).
5. Compound No 1 76 Br S ~COOCH3 c!---~\ 1 A mixture of compound 1.2 (9 g, 34.7 mmol) and N-Bromosuccinimide (15.49 g, 87 mmol) in 200 ml of carbon tetrachloride, irradiated w'tth a 150W quartz lamp is heated at reflux temperature. After 1.5 hours of stirring, the mixture is cooled down to room temperature and filtered over celite. After removal of the solvent under reduced pressure, the filtrate is suspended in hexane at 60°C and the solid filtered over celite. The hexane evaporated under reduced pressure to give a red oil, which after distillation (150°C, 0.13mbars) gives 10g of the title compound as a pale red oil.
6. Compound No. 1 97 NH-CH2 Ph ~ COOCH3 cl--~\ I
N CFs A mixture of compound 1.76 (1 g, 2.9 mmol) and (0.63 g, 5.9 mmol) of benzylamin is stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture is removed under reduced pressure, and chromatographed on silica to give 0.8 g of the title compound as an oil.
7. Compound No 1 82 \ COOCH3 CI--<\ ( Compound 1.2 (1 g, 3.8 mmol) is added to a suspension of sodium hydride (55%
in mineral oil) (0.17g, 4,2mmol) in tetrahydrofuran at -50°C, and the resulting red solution stirred for 1 hour at -35°C. After this period, methyl iodide (0.7 g, 5 mmol) is rapidly added. After 2 hours of stirring, the reaction is quenched with a saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, evaporated under reduced pressure and chromatographed on silica to give 0.72 g of the title compound as a pale yellow oil.
8. Compound No.1.92 ~COOCH3 cl--~~
Compound 1.2 (1 g, 3.8 mmol) is added to a suspension of sodium hydride (55%
in mineral oil) (0.17 g, 4,2 mmol) in dry tetrahydrofuran at -50°C, and the resulting red solution stirred for 1 hr at -35°C. Methyl chloroformiate ( 6 mmol) is then added, and after 2hours of stirring, the reaction is quenched with a saturated aqueous ammonium chloride solution, and heated up to room temperature. After extraction with ethyl acetate, the organic layer is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The reaction mixture is purified on silica to afford 0.79g of the title compound as a white solid.
9. Compound No. 1.99 HsC CHs ~ COOCH3 cl--~~
To a suspension of sodium hydride (55% in mineral oil)(0.61 g, 25.4 mmol) at -50°C, is added compound 1.2 (3 g, 11.55 mmol). After 2.5 hours of stirring at -30°C, the red mixture is cooled down to -78°C, treated with methyiiodide (4.92 g, 34,65 mmol), and slowly heated up to -20C over a period of l.5hrs. After hydrolysis with a saturated aqueous ammonium chloride solution, the reaction mixture is extracted with ethyl acetate, dried over magnesium sulfate, and after evaporation of the solvent under reduced pressure, the resulting crude material is purified by flash-chromatography to give 2.06g of the title compound as an oil.
To a suspension of sodium hydride (55% in mineral oil)(0.61 g, 25.4 mmol) at -50°C, is added compound 1.2 (3 g, 11.55 mmol). After 2.5 hours of stirring at -30°C, the red mixture is cooled down to -78°C, treated with methyiiodide (4.92 g, 34,65 mmol), and slowly heated up to -20C over a period of l.5hrs. After hydrolysis with a saturated aqueous ammonium chloride solution, the reaction mixture is extracted with ethyl acetate, dried over magnesium sulfate, and after evaporation of the solvent under reduced pressure, the resulting crude material is purified by flash-chromatography to give 2.06g of the title compound as an oil.
10. Compound No.1.100 OH
~COOEt CI---~\
N CFs To a tetrahydrofuran solution kept at -78°C of lithium diisopropylamide, prepared at 0°C
from diisopropylamine (0.83 ml, 5.9 mmol) and n-butyl lithium (3.33 ml, 5.3 mmol), 2-chloro-4-trifluoromethyl-thiazole is slowly added (1 g, 5.33 mmol). After 2 hours of stirring, the green solution is transferred, via a canula to a flask containing a solution of ethylglyoxylate (50% toluene commercial solution) (15m1, 10.6mmol) in tetrahydrofuran kept at -78°C. After minutes, the mixture is treated with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate and concentrated in vacuo. The resulting crude residue is then purified by chromatography on silica-gel to give 0.28 g of the title compound as an oil.
~COOEt CI---~\
N CFs To a tetrahydrofuran solution kept at -78°C of lithium diisopropylamide, prepared at 0°C
from diisopropylamine (0.83 ml, 5.9 mmol) and n-butyl lithium (3.33 ml, 5.3 mmol), 2-chloro-4-trifluoromethyl-thiazole is slowly added (1 g, 5.33 mmol). After 2 hours of stirring, the green solution is transferred, via a canula to a flask containing a solution of ethylglyoxylate (50% toluene commercial solution) (15m1, 10.6mmol) in tetrahydrofuran kept at -78°C. After minutes, the mixture is treated with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate and concentrated in vacuo. The resulting crude residue is then purified by chromatography on silica-gel to give 0.28 g of the title compound as an oil.
11. Compound No.1.106 HO CHs ~COOEt CI--~\
2-chloro-4-trifluoromethyl-thiazole (0.5 g, 2,66 mmol) dissolved in tetrahydrofurane is treated at -78°C with lithium hexamethyldisilyamide (commercial solution, 1 M in tetrahydrofuran, 2,67m1), stirred for 1.5 hours, followed by the addition of ethylpyruvate (0.305 ml, 2.9 mmol). After the reaction is completed, it is quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure and chromatographed on silica-gel to afford 0.730 g of the title compound as a yellow oil.
2-chloro-4-trifluoromethyl-thiazole (0.5 g, 2,66 mmol) dissolved in tetrahydrofurane is treated at -78°C with lithium hexamethyldisilyamide (commercial solution, 1 M in tetrahydrofuran, 2,67m1), stirred for 1.5 hours, followed by the addition of ethylpyruvate (0.305 ml, 2.9 mmol). After the reaction is completed, it is quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure and chromatographed on silica-gel to afford 0.730 g of the title compound as a yellow oil.
12. Compound No. 1.113 COOEt Lr3 2-Chloro-4-trifluoromethyl-thiazole (2 g, 10.66 mmol) dissolved in tetrahydrofuran is treated at -78°C with lithium hexamethyldisilyamide {commercial solution, 1 M
in tetrahydrofuran, 2,67 ml), stirred for 1.5 hours, followed by the addition of ethylbromopyruvate {1.79 ml, 12.79 mmol). After the reaction is completed, it is quenched with a saturated aqueous ammonium chloride solution and heated up to room temperature. The reaction mixture is then extracted with ethyl acetate, the organic layer dried over magnesium sulfate, the solvent removed under reduced pressure, and the crude material chromatographed on silica-gel to afford 0.2548 of 2.088 of the title compound as oils.
in tetrahydrofuran, 2,67 ml), stirred for 1.5 hours, followed by the addition of ethylbromopyruvate {1.79 ml, 12.79 mmol). After the reaction is completed, it is quenched with a saturated aqueous ammonium chloride solution and heated up to room temperature. The reaction mixture is then extracted with ethyl acetate, the organic layer dried over magnesium sulfate, the solvent removed under reduced pressure, and the crude material chromatographed on silica-gel to afford 0.2548 of 2.088 of the title compound as oils.
13. Compounds Nos. 2.18 (Dl. 2.19 (R). 2.25 S) !Scheme 13) (a) A mixture of compound K (179 g, 0.871 Mol) NBS (159.8 g, 0.871 Mol) and Azoisobutyronitrile (AIBN) (14.6 g, 87 mmol) in 600 ml of CCI4 is heated at reflux for 16 hrs.
After cooling, the crude mixture is filtered, concentrated under reduced pressure and flash-chromatographed to afford 190 g of compound L contaminated with the starting material K.
(b) To a solution of compound L (189.4 g, 0.666 Mot) in 1.5 I of acetonitrile, is added 0.3 I of 4A molecular sieves followed by N-methylmorpholine-N-oxide {139.2 g, 0.99 Mol).
After 2.5 hrs. of stirring at room temperature, the mixture is filtered on silicagel, concentrated in vacuo and purified by flasf~-chromatography to give 92 g of aldehyde M.
(c) A solution of aldehyde L (91.25 g, 0.415 Mol), ethylene glycol (29 ml, 0.5 Mol) and p-totuenesulfonic acid (9.12 g, 41 mmol) is heated for 16 hrs. at reflux in 300 ml of benzene while water is destilled off. After cooling, the crude mixture is extracted with water and ether, the organic phase is then dried over MgS04, concentrated under reduced pressure and purified by flash-chromatography to give 65 g of the dioxolane N.
_28_ _ Scheme 13 COOEt COOEt g COOEt CI~\ I S
CI~
N (a) ~N Br (b) \N ~ CHO
K L M
COOEt CHZOH
CI~\
O
..__". N ~ ~ O
(~) N
p N O O
COOH
I
_'~' CI"-~\ ~ O -.~ N O
(e) N
p O p P
_~ CI S COOMe CI S COOMe '_"~\ ~
(9) N O (h) N CHO
pJ
R
(d) To a suspension of LiAIHa (1.78 g, 45.4 mmol) in 220 ml of dry THF at 0°C, is added dropwise compound N (10 g, 37.9 mmol) dissolved in 100 ml of THF. After 5 min of stirring the reaction is completed. The mixture is successively treated with 1.78 ml of water, 1.78 ml of NaOH (15% aqueous solution) and 5.34 ml of water. The suspension is then filtered over celite, extracted 3 times with ethylacetate and water. The combined organic phases are concentrated under reduced pressure and chromatographed on silica to afford 31 g of the alcohol O.
(e) To a solution of compound O ( 9.85 g, 44.46 mmol) in 180 ml of CC14 is added triphenlyphosphine (11.8 g, 44.46 mmol). The mixture is stirred at 85°C
for 24 hrs. After cooling, the crude solution is concentrated under reduced pressure and purified by chromatography on silica to afford 6.4 g of compound P.
(f) A mixture of compound P {7.43 g, 30.9 mmol), benzyltriethylammonium chloride (283 mg, 1.24 mmol), cobalt carbonyl (423 mg, 1.24 mmol), sodium carbonate (5.83 g, 69.4 mmol), 68 ml of water and 62 ml of dichloromethane is stirred under carbon monoxide pressure (10 bars) for 24 hours at room temperature. The biphasic mixture is then filtered over celite, extracted two times with dichloromethane. The water phase is acidified to pH 2 with concentrated HCI and extracted with ethyl acetate. The organic layer is then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 3.2 g of the acid D which is used without further purification.
(g) A solution of the acid Q in THF is carefully treated at room temperature with an ether solution diazomethane. The reaction is monitored by tlc. After completion of the reaction, the crude mixture is concentrated under reduced pressure and chromatographed to 2 g of the methylester R.
(h) Compound R (1.61 g, 6.47 mmol) is stirred for 40 min in 19 ml of THF, 19 ml of water and 9 ml of trifluoroacetic acid. After evaporation of the solvent, the crude mixture is diluted with ether and washed with NaHC03 (sat. aqueous solution). The ether phase is concentrated under reduced pressure to afford the aldehyde S which is an oil.
The aldehyde group may be converted by known methods into many different other groups.
Table 1.A
Table 1 R , R 2 ~ CO-A
CI~\
No. R, RZ A Phys. data m.p °C
1.1. H H OH 122-123°C
1.2. H H OMe oil 1.3. H H oil o-~co~Ec 1.4. H H Of Bu oil 1.5. H H OCH2CH=CH2 oil 1.6. H H ocHZ~ oil '~ /0 1.7. H H OCH2Ph oil 1.8. H H oil OCH= \ ~ OMe 1.9. H H oMe solid OCHz \ ~ OMe 1.10. H H o~ oil ocHz ~ ~ oMe OMe 1.11. H H M°O OMe oil ocH2 ~ ~ oMg 1.12. H H o\ oil ocH2 ~ 00/
No. R, R2 A Phys. data m.p °C
1.13. H H M°° solid ocH2 ~ ~ oMe 1.14. H H oil OCHZ \ ~ OCF~
1.15. H H solid OCHz \ / NOZ
1.16. H H oil OCHz \ ~ OCHzPh 1.17. H H oil OCHi ~ ~N
1.18. H H 90-91 ocHZ
N
1.19. H H cl oil oCH~ ~ ~-CI
N
1.20. H H OCH2C4Me oil 1.21. H H CoZMe 51-53 NH---1.22. H H NMe2 1.23. H H NHMe 1.24. H H NHEt 1.25. H H NHn-Bu 1.26. H H NHt-Bu 1.27. H H cl 127-8 NHCHz \ ~ CI
1.28. H H 142-3 NHCHz ~ ~ CI
No. R, R2 A phys. data m.p °C
1.29. H H ~I 122-3 NHCHz \ ~ CI
1.30. H H G solid NHCHz \
1.31. H H F 105-6 NHCHZ ~ ~ F
1.32. H H F 51-2 NHCHz F
1.33. H H F solid NHCH~ \
1.34. H H F 85-6 F
1.35. H H F solid NHCHs ~ ~ F
1.36: H H F 115-6 NHCHz \
1.37. H H 110-20 NHCHi ~ ~ F
1.38. H H F 123-4 NHCH2 ~ ~ Br No. R, R2 A Phys. data m.p °C
1.39. H H ~F~ 98 NHCHz 1.40. H H ~F~ 97-101 NHCHz 1.41. H H 102-4 NHCHZ ~ ~ CF3 1.42. H H ~F3 106-7 NHCHs \
CFA
1.43. H H 99-101 Me 1.44. H , H 120 NHCH2 ~ ~ Me 1.45. H H solid NHCHZ \ ~ NOz 1.46. H H NHCH2Ph 110-1 1.47. H H 126-30 NHCHz ~ ~ OMe 1.48. H H Mao 115 NHCH2 \
1.49. H H oMe 107-8 NHCHZ \
1.50. H H oMe 132-3 NHCHz \ ~ OMe WO 99/32464 PC'T/EP98/08335 _~_ _ No. R, R2 A Phys. data m.p °C
1.51. H H Meo 159-60 NHCHz ~ ~ OMe Me0 1.52. H H oMe 140-2 NHCHZ
OMe 1.53. H H o~ 130-1 NHCHs ~ ~ O
1.54. H H Br 1 gg-g NH
Br 1.55. H H Br solid NH ~ ~ Br Br 1.56. H Br 51 NH \ ~ OCF~
Br 1.57. H H ONHCOOCH2Ph oil 1.58. H H ONHCH(CH3)Z oii 1.59. H H ONHC(CH3)3 oii 1.60. H H ON=C(CH3)OEt oil 1.61. H H ONHCOOC(CH3)3 oil 1.62. H H ONHCOOEt oil 1.63. H H ONHS02Ph 114-20 1.64. H H NHOC(Ph)3 177 1.65. H H NHOCH2Ph 78-85 1.66. H H NHOMe 117-8 1.67. H H NHOCH2CH=CH2 73-4 No. R, R2 A Phys. data m.p C
1.68.H H NHOC(CH3)3 solid 1.69.H H NHOPh 1.70.H H F F solid NHOCHz \ / F
F F
1.71.H H SMe oil 1.72.H H SEt 1.73.H H SPh 1.74.H H SCH2Ph 1.75.Br H OH oil 1.76.Br H OMe oil 1.77.F H OH
1.78.F H OMe oil 1.79.CI H OMe 1.80.CI H OH
1.81.Me H OH oil 1.82.Me H OMe oil 1.83.Et H OMe oil 1.84.Et H OH oil 1.85.Pr H OH
1.86.Pr H OMe 1.87.nBu H OH
1.88.nBu H OMe 1.89.CH2CH=CH2 H OH oil 1.90.CH2Ph H OH 127-8C
1.91.CH2Ph H OMe oil 1.92.COOMe H OMe oil 1.93.CHZCOOH H OH 130-1 C
1.94.NH2 H OH 166-7C
1.95.NHZ.HCI H OMB 176-7C
1.96.NEt2 H OMe 56-8C
No. R, R2 A Phys. data .
m.P C
1.97. NHCH2Ph H OMe oil 1.98. Me Me OH 137-8C
1.99. Me Me OMe oil 1.100.OH H OEt oil 1.101.OH H OH
1. OAc H OEt oil i 02.
R' R _ _ A
1.103.a H OEt oil oco 1.104.OMe H OEt oil 1.105.OSi-t-BuMe2 H OEt oil 1.106.OH Me OEt oil 1.107.OH CF3 OMe oil 1.108.OH Ph OEt 77-9C
1.109.OH CHZBr OEt oil 1.110.s cF, OH OEt oil cl--~~
N CHI
1.111.s cF~ H OMe 151-2C
~
CI~~
I H
~
N CoOMe ~:
1.112.R1+R2 H OEt oil =O
1.113.R1+RZ H OEt oil U
1.114.rN OH OEt oil N~/N~C~
Table 1.B
Compounds of the formula R~
NiS ~ ~'CO-A
CI
wherein the R,, R2 and A have the meanings of the corresponding compounds of Table 1.A.
Table 1.C
Compounds of the formula R~
NiS ~ NCO-A
wherein R,, R2 and A have the meanings of the corresponding compounds of Table 1.A.
Phys. data of compounds) of Table 1.C:
No. R, R2 A Phys. data m.p. °C
1.C.1 H H OH oil _3g_ Table 2.A
R~ RZ
NCO-A
CI--~\
N R
No R, RZ R3 A Phys.data m.p.C
2.1. H H H OCH2Ph oil 2.2. H H H OH
2.3. H H Me OCHZPh oil 2.4. H H Me OH
2.5. H H Et OCHZPh oil 2.6. H H Et OMe oil 2.7. H H Et OH 191-3 2.8. H H n-Pr OMe oil 2.9. H H 2-Pr OMe oil 2.10. H H 2-Pr OH
2.11. H H cyclo-Pr OMe oil 2.12. H H t-Bu OMe oil 2.13. H H t-Bu OH
2.14. H H Ph OMe oil 2.15. H ?-I CH2Ph OMe oil 2.16. H H 2-thiophenyl OMe oil 2.17. H H COOMe OMe oil 2.18. H H ~~ ~ OH oil 2.19. H H ~ OMe oil ~
~
-39- _ No R, R2 R3 A Phys.data m.p.C
2.20. H H o OH
2.21. H H s OH
s 2.22. H H s- OH
2.23. H H /s OH
S
2.24. H H o OMe 2.25. H H CHO OMe oil 2.26. H H CH20H OMe solid 2.27. H H CH2CI OMe oil 2.28. H H CH2Br OMe 2.29. H H CH2F OMe 2.30. H H CH2NHC00- OMe t-Bu 2.31. H H CH2NEtz OMe 2.32. H H CH2NH2 OMe 2.33. H H CH2NHOH OMe 2.34. H H CH=CH2 OMe 2.35. H H CH=CHCOOMe OMe 2.36. H H CH=CHMe OMe 2.37. H H CH=CBrz OMe 2.38. H H CHOHMe OMe 2.39. H H CHOHEt OMe 2.40. H H CHOHCIMe OMe 2.41. H H CHOHFMe OMe 2.42. H H CHOHBrMe OMe WO 99/32464 PC'T/EP98/08335 No R, R2 R3 A Phys.data m.p.C
2.43. H H CH=CF2 OMe 2.44. H H COEt OMe 2.45. H H CHOHMe OMe 2.46. H H CHCIMe OMe 2.47. H H CHFMe OMe 2.48. H H CHBrMe OMe 2.49. H H 4-CI-Ph OMe 2.50. H H 3-Me0-Ph OMe 2.51. H H 2,4-Me2-Ph OMe 2.52. H H - H OMe 2.53. Br H COHMe2 OCH2Ph 2.54. Br H COHEt2 OH
2.55. F H Et OCHZPh 2.56. CI H Et OH
2.57. CI H n-Pr OCH2Ph 2.58. Me H 2-Pr OMe 2.59. Et H cyclo-Pr OH
2.60. Et H t-Bu OMe 2.61. Pr H t-Bu OMe 2.62. Pr H Ph OH
2.63. nBu H CHzPh OMe 2.64. nBu H 2-thiophen OMe 2.65. CH2CH=CH2 H COOMe OH
2.66. CH2Ph H ~~ ~ OMe 2.67. CHZPh H ~ OMe ~
2.68. COOMe H OMe ~ ~
No R, R2 R3 A Phys.data nl.~.C
2.69. CHZCOOH H s OMe s 2.70. NH2 H - OMe ~
r s-2.71. NH2.HC1 H /s\ OCH2Ph s 2.72. NEt2 H o OH
2.73. NHCH2Ph H CHO OCHZPh 2.74. Me H CH20H OH
2.75. Me H CHZCI OCHZPh 2.76. OH H CHZBr OMe 2.77. OH H CH2F OH
2.78. OAc H CHCI2 OMe 2.79. _ c~ H H OMe oco 2.80, OMe H Me OH
2.81. OSi-t-BuMez H Me OMe 2.82. OH H Et OMe 2.83. OH H Et OH
2.84. OH H Et OMe 2.85. OH H n-Pr OMe 2.86. s cF, CF3 2-Pr OMe ci--N
2.87. s cF, Ph 2-Pr OMe ci-.<\
~COOMe 2.88. R,+R2 CH2Br cyclo-Pr OMe =O
WO 99/32464 PCf/EP98/08335 No R, RZ R3 A Phys.data m.p.°C
2.89. R~+RZ ~ OH t-Bu OMe 2.90. H H cyclo-Pr OCHZPh oil Ta le 2.B
Compounds of the formula O-A
N
C~
wherein R,, R2, R3 and A have the meanings of the corresponding compounds of Table 2.A.
Table 2.C
Compounds of the formula i O-A
N
wherein R,, R2, R3 and A have the meanings of the corresponding compounds of Table 2.A.
Phys. data of compounds of Table 2.C:
No. R, R2 R3 A Phys.data m.p.C
2.C.3 H H Me OCH2Ph oil 2.C.5 H H Et OCH2Ph oil 2.C.7 H H Et OH oil 2.C.20 H H .o OH solid Co--i R, R2 iS ~ ~C
R
~C
N
Table 3.A
R, R2 S Z
CI-~~
N R
No. R, R2+ Z R3 Phys. data m.p.°C
3.1. H CF3 159-61 °C
H
~O
O
3.2. H H CF3 OII
""~
R,+Rz+Z
I
3.3. H ,~ ~ CF3 solid H
/O-~Me 'O
~
I
IO
3.4. H M ,,~ CF3 solid r < 'o ~
3.5. H Me' Me CF3 ~O
'NH
~
I
IO
3.s. H cF3 Me ~
N
~ ~O
X
' IO
_~_ No. R, Rz+ Z R3 Phys. data m.p.C
3.7. H ~ Me CF3 o~Me NH
3.8. H Me Me CF3 H
N--~Me /
r ' 'O
~
( I ' O
3.9. H Me a CF3 N- \~
'NH
~
( ~ I
O
3.10. H M ,,,~ CF3 N
C 'NH
~
I
'O
3.11. H Me H
HO
O
3.12. H H H Me "~
R1+R2+Z
I
3.13. H Me Me Et H
~
~
O--'r Me ~ ~~O
I IO
3.14. H M ,"~ Et ~<'o ~
No. R, R2+ 2 R3 Phys. data m.p.C
3.15. H Me Et Me ' ~0 'NH
x I
IO
3.16. H H ,"~ n-Pr N
l C 'O
X
I
'O
3.17. H Me ,,~ 2-Pr H
~
~
/O-'( Me 'NH
x I
IO
3.18. H Me Me 2-Pr H
~ ~
N~Me /
'O
N
I
IO
3.19. H Me M8 cyclo-P r H
~ ~
N~Me /
f ' 'NH
C
' I
O
3.20. H Me t-Bu Me N ' ~,( 'NH
X
, ~O
Table 3.B
Compounds of the formula R~ R2 \Z
N~ I
CI
wherein R,, R2, R3 and Z have the meanings of the corresponding compounds of Table 3.A.
Table 3.C
Compounds of the formula S \Z
N~ i N R
wherein R,, R2, R3 and Z have the meanings of the corresponding compounds of Table 3.A.
-47- _ Ta le 4.A
R, R2 S
R e~\
N R
No. R, RZ R3 R4 Z Phys.data m.p.C
4.1. H H CF3 Ph COOMe oil 4.2. H H Me CF3 COOH
4.3. H H CF3 H COOH
4.4. H H CF3 H COOMe oil 4.5. H H Me H COOEt solid 4.6. R,+R2 Me H COOEt solid =O
4.7. R,+R2=O Me NHCOOEt COOEt solid 4.8. R,+RZ Me NHn-Bu COOEt solid =O
4.9. R,+R2 Me NHt-Bu COOEt solid =O
4.10.H H Me NHMe COOEt solid 4.11.H H Me NHCH2CH=CH2 COOH solid 4.12.H H Et NH-t-Bu COOEt solid 4.13.H H Ph p-PhS02NH2 COOEt solid 4.14.H H p-CIPh NHPh COOEt solid 4.15.H H OH OH COOH solid 4.16.R,+R2 Me NH-COOEt COSMe =O
4.17.R,+R2 Me NH-n-Bu COSMe =O
4.18.R,+R2 Me NH-t-Bu COSMe =O
4.19.H H CF3 CF3 COSMe 4.20.H H CF3 OMe COOMe 4.21.H H CF3 OEt COOMe 4.22.H H CF3 O-n-Pr COOMe 4.23.H H CF3 SMe COOMe 4.24.H H CF3 SEt COOMe _48- _ No. R, RZ R3 R4 Z Phys.data m.p.C
4.25.H H CF3 SPh COOMe 4.26.H H CF3 NMez COOMe 4.27.H H CF3 NEt2 COOMe 4.28.H H CF3 NHZ COOMe 4.29.H H CF3 SH COOMe 4.30.H H CF3 NH2 CSOMe 4.31.H H Me CI p solid ---~
r _ 4.32.H H CF3 Ph CSOMe 4.33.H H Me CF3 CSOH
4.34.H H CF3 H CSOH
4.35.H H CF3 H CSOMe 4.36.H H Me H CSOEt 4.37.R,+RZ Me H COOEt =S
4.38.R,+R2 Me NHCOOEt COOEt =S
4.39.R,+RZ Me NH-n-Bu CSOEt =S
4.40.R,+R2 Me NH-t-Bu CSOEt =S
4.41.H H Me NHMe CSOEt 4.42.H H Me NHCH2CH=CH2 CSOH
4.43.H H Et NHt-Bu CSOEt 4.44.H H Ph p-PhS02NH2 CSOEt 4.45.H H p-CIPh NHPh CSOEt 4.46.H H OH OH CSOH
4.47.R,+R2 Me NH-COOEt CSSMe =O
4.48.R,+RZ Me NHn-Bu CSSMe =O
4.49.R,+R2 Me NHt-Bu CSSMe =S
4.50.H H Et CF3 COSMe 4.51.H H Et OMe COOMe 4.52.H H n-Pr OEt COOMe 4.53.H H i-Pr n-Pr COOMe 4.54.H H OH SMe COOMe No. R, R2 R3 R, Z Phys.data m.p.C
4.55.H H OH SEt COOMe 4.56.H H CF3 SPh CONHMe 4.57.H H CF3 NMe2 CONHMe 4.58.H H CF3 NEt2 CONHMe 4.59.H H CF3 NH2 CSNHMe 4.60.H H CF3 SH CSNHMe 4.61.H H CF3 CSNHMe Table 4.B
Compounds of the formula " 4 wherein R,, R2, R3, R,, and Z have the meanings of the corresponding compounds of Table 4.A.
Ta le 4.C
Compounds of the formula R, R2 S \Z
N~ I
N R
wherein R,, RZ, R3 and Z have the meanings of the corresponding compounds of Table 4.A.
Formulation Examples for similar purposes of pesticidal use are descibed for example in WO
97/33890.
Biological Examples Example B.1: Immunization of Cucumis sativus L a,.giainst Collgtotrichum lag~enarium a) After a cultivation period of 2 weeks, cucumber plants are sprayed with a spray mixture prepared from a wettable powder formulation of the test compound (concentration:
200 ppm). After 72 hours, the plants are infected with a spore suspension (1.0 x 105 spores/ml) of the fungus and incubated for 30 hours at high humidity and a temperature of 23°C. Incubation is then continued at normal humidity and 22°C
to 23°C.
Evaluation of protective action is made 7 to 8 days after infection and is based on fungus infestation.
b) After a cultivation period of 2 weeks, cucumber plants are treated by soil application with a spray mixture prepared from a wettable powder formulation of the test compound (concentration: 20 ppm, based on the volume of the soil). After 72 hours, the plants are infected with a spore suspension (1.5 x 105 spores/ml) of the fungus and incubated for 30 hours at high humidity and a temperature of 23°C. Incubation is then continued at normal humidity and 22°C.
Evaluation of protective action is made 7 to 8 days after infection and is based on fungus infestation.
Compounds of the Tables exhibit good activity in tests (a) and (b) and reduce fungus infestation to 0 tc 20 %. On the other hand, Colletotrichum infestation is 90 % on untreated and infected control plants.
c) Comparison test: Direct action against Colletotrichum laqenarium The fom~ulated active ingredient is mixed in various concentrations (100, 10, 1, 0.1 ppm) with autoclaved and cooled nutrient medium containing 10 000 spores per ml and is poured into microtitre plates. Incubation is then carried out at 22°C in the dark. After 2 to 3 days, fungus growth is measured by spectrophotometry.
With compounds of the Tables, no inhibition of fungus growth is observed; on the other hand, when the fungicide "Benomyl" (commercial product) is used as comparison substance at 0.2 ppm, 50 % inhibition (ECM) of fungus growth occurs.
Example B.2: Action against Phytophthora infestans on tomato lants a) After a cultivation period of 3 weeks, tomato plants are sprayed with a spray mixture prepared from a wettable powder formulation of the test compound (0.02 %
active ingre-dient). After 72 hours, the treated plants are infected with a sporangia suspension of the fungus. Fungus infestation is evaluated after incubation of the infected plants for 5 days at 90-100 % relative humidity and 20°C.
Compounds of the Tables exhibit good activityin the tests and reduce fungus infestation to 0 to 20 %. On the other hand, Phytophthora infestation is 60 % on untreated and infected control plants.
Example B.3: Action against Pyricularia oryzae on rice~~lants 2-week-old rice plants are watered with a spray mixture prepared from a wettable powder formulation of the test compound (0.006 % active ingredient, based on the volume of the soil). The pots are then filled with water until the lowermost parts of the stems of the rice plants are standing in water. After 96 hours, the treated rice plants are infected with a conidia suspension of the fungus. Fungus infestation is evaluated after incubation of the infected plants for 5 days at 95-100 % relative humidity and approximately 24°C.
In comparison with untreated control plants (100 % infestation), fungus infestation on rice plants treated with a spray mixture comprising a compound of the Tables as active ingre-dient is only approximately 50 %.
Example B.4: Action against Cercospora nicotine on tobacco plants a) Foliar application Tobacco plants (13 weeks old) are sprayed with a formulated solution of the test compound (concentration: 0.02 % active ingredient). Four days after treatment, the plants are inocu-lated with a sporangia suspension of Cercospora nicotine (150 000 spores/ml), kept for days in the dark at 25°C and high humidity and then incubated further under a normal day/night sequence.
Evaluation of the symptoms in the tests is based on the leaf surface infested with fungus.
Infestation is approximately 60 % on the control plants; on plants treated with compounds of the Tables, infestation is 0 to 30 %.
Example B.S: Action against Eryrsiphe graminis on wheat Protective action: 18-day-old wheat plants are sprayed with a formulated solution of the test compound (0.02 % active ingredient). Immediately after the treatment the plants are incuba-ted under cylinders. 24 hours later, the plants are covered. After a further 3 days, the treated plants are cut off above the primary leaf. The primary leaves are arranged horizon-tally and are inoculated in a dusting bell with Erysiphe graminis spores (spore density:
0.2 mg/mZ). The test is carried out in a climatic chamber with 12 hours of light (18 KLux), at 20°C and 12 hours of darkness, at 18°C. Infestation is evaluated 9 and 13 days after inoculation.
Compounds of the Tables exhibit good activity in the tests and reduce fungus infestation to 0 to 20 %. On the other hand, Erysiphe infestation is 70 % on untreated and infected control plants.
After cooling, the crude mixture is filtered, concentrated under reduced pressure and flash-chromatographed to afford 190 g of compound L contaminated with the starting material K.
(b) To a solution of compound L (189.4 g, 0.666 Mot) in 1.5 I of acetonitrile, is added 0.3 I of 4A molecular sieves followed by N-methylmorpholine-N-oxide {139.2 g, 0.99 Mol).
After 2.5 hrs. of stirring at room temperature, the mixture is filtered on silicagel, concentrated in vacuo and purified by flasf~-chromatography to give 92 g of aldehyde M.
(c) A solution of aldehyde L (91.25 g, 0.415 Mol), ethylene glycol (29 ml, 0.5 Mol) and p-totuenesulfonic acid (9.12 g, 41 mmol) is heated for 16 hrs. at reflux in 300 ml of benzene while water is destilled off. After cooling, the crude mixture is extracted with water and ether, the organic phase is then dried over MgS04, concentrated under reduced pressure and purified by flash-chromatography to give 65 g of the dioxolane N.
_28_ _ Scheme 13 COOEt COOEt g COOEt CI~\ I S
CI~
N (a) ~N Br (b) \N ~ CHO
K L M
COOEt CHZOH
CI~\
O
..__". N ~ ~ O
(~) N
p N O O
COOH
I
_'~' CI"-~\ ~ O -.~ N O
(e) N
p O p P
_~ CI S COOMe CI S COOMe '_"~\ ~
(9) N O (h) N CHO
pJ
R
(d) To a suspension of LiAIHa (1.78 g, 45.4 mmol) in 220 ml of dry THF at 0°C, is added dropwise compound N (10 g, 37.9 mmol) dissolved in 100 ml of THF. After 5 min of stirring the reaction is completed. The mixture is successively treated with 1.78 ml of water, 1.78 ml of NaOH (15% aqueous solution) and 5.34 ml of water. The suspension is then filtered over celite, extracted 3 times with ethylacetate and water. The combined organic phases are concentrated under reduced pressure and chromatographed on silica to afford 31 g of the alcohol O.
(e) To a solution of compound O ( 9.85 g, 44.46 mmol) in 180 ml of CC14 is added triphenlyphosphine (11.8 g, 44.46 mmol). The mixture is stirred at 85°C
for 24 hrs. After cooling, the crude solution is concentrated under reduced pressure and purified by chromatography on silica to afford 6.4 g of compound P.
(f) A mixture of compound P {7.43 g, 30.9 mmol), benzyltriethylammonium chloride (283 mg, 1.24 mmol), cobalt carbonyl (423 mg, 1.24 mmol), sodium carbonate (5.83 g, 69.4 mmol), 68 ml of water and 62 ml of dichloromethane is stirred under carbon monoxide pressure (10 bars) for 24 hours at room temperature. The biphasic mixture is then filtered over celite, extracted two times with dichloromethane. The water phase is acidified to pH 2 with concentrated HCI and extracted with ethyl acetate. The organic layer is then washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 3.2 g of the acid D which is used without further purification.
(g) A solution of the acid Q in THF is carefully treated at room temperature with an ether solution diazomethane. The reaction is monitored by tlc. After completion of the reaction, the crude mixture is concentrated under reduced pressure and chromatographed to 2 g of the methylester R.
(h) Compound R (1.61 g, 6.47 mmol) is stirred for 40 min in 19 ml of THF, 19 ml of water and 9 ml of trifluoroacetic acid. After evaporation of the solvent, the crude mixture is diluted with ether and washed with NaHC03 (sat. aqueous solution). The ether phase is concentrated under reduced pressure to afford the aldehyde S which is an oil.
The aldehyde group may be converted by known methods into many different other groups.
Table 1.A
Table 1 R , R 2 ~ CO-A
CI~\
No. R, RZ A Phys. data m.p °C
1.1. H H OH 122-123°C
1.2. H H OMe oil 1.3. H H oil o-~co~Ec 1.4. H H Of Bu oil 1.5. H H OCH2CH=CH2 oil 1.6. H H ocHZ~ oil '~ /0 1.7. H H OCH2Ph oil 1.8. H H oil OCH= \ ~ OMe 1.9. H H oMe solid OCHz \ ~ OMe 1.10. H H o~ oil ocHz ~ ~ oMe OMe 1.11. H H M°O OMe oil ocH2 ~ ~ oMg 1.12. H H o\ oil ocH2 ~ 00/
No. R, R2 A Phys. data m.p °C
1.13. H H M°° solid ocH2 ~ ~ oMe 1.14. H H oil OCHZ \ ~ OCF~
1.15. H H solid OCHz \ / NOZ
1.16. H H oil OCHz \ ~ OCHzPh 1.17. H H oil OCHi ~ ~N
1.18. H H 90-91 ocHZ
N
1.19. H H cl oil oCH~ ~ ~-CI
N
1.20. H H OCH2C4Me oil 1.21. H H CoZMe 51-53 NH---1.22. H H NMe2 1.23. H H NHMe 1.24. H H NHEt 1.25. H H NHn-Bu 1.26. H H NHt-Bu 1.27. H H cl 127-8 NHCHz \ ~ CI
1.28. H H 142-3 NHCHz ~ ~ CI
No. R, R2 A phys. data m.p °C
1.29. H H ~I 122-3 NHCHz \ ~ CI
1.30. H H G solid NHCHz \
1.31. H H F 105-6 NHCHZ ~ ~ F
1.32. H H F 51-2 NHCHz F
1.33. H H F solid NHCH~ \
1.34. H H F 85-6 F
1.35. H H F solid NHCHs ~ ~ F
1.36: H H F 115-6 NHCHz \
1.37. H H 110-20 NHCHi ~ ~ F
1.38. H H F 123-4 NHCH2 ~ ~ Br No. R, R2 A Phys. data m.p °C
1.39. H H ~F~ 98 NHCHz 1.40. H H ~F~ 97-101 NHCHz 1.41. H H 102-4 NHCHZ ~ ~ CF3 1.42. H H ~F3 106-7 NHCHs \
CFA
1.43. H H 99-101 Me 1.44. H , H 120 NHCH2 ~ ~ Me 1.45. H H solid NHCHZ \ ~ NOz 1.46. H H NHCH2Ph 110-1 1.47. H H 126-30 NHCHz ~ ~ OMe 1.48. H H Mao 115 NHCH2 \
1.49. H H oMe 107-8 NHCHZ \
1.50. H H oMe 132-3 NHCHz \ ~ OMe WO 99/32464 PC'T/EP98/08335 _~_ _ No. R, R2 A Phys. data m.p °C
1.51. H H Meo 159-60 NHCHz ~ ~ OMe Me0 1.52. H H oMe 140-2 NHCHZ
OMe 1.53. H H o~ 130-1 NHCHs ~ ~ O
1.54. H H Br 1 gg-g NH
Br 1.55. H H Br solid NH ~ ~ Br Br 1.56. H Br 51 NH \ ~ OCF~
Br 1.57. H H ONHCOOCH2Ph oil 1.58. H H ONHCH(CH3)Z oii 1.59. H H ONHC(CH3)3 oii 1.60. H H ON=C(CH3)OEt oil 1.61. H H ONHCOOC(CH3)3 oil 1.62. H H ONHCOOEt oil 1.63. H H ONHS02Ph 114-20 1.64. H H NHOC(Ph)3 177 1.65. H H NHOCH2Ph 78-85 1.66. H H NHOMe 117-8 1.67. H H NHOCH2CH=CH2 73-4 No. R, R2 A Phys. data m.p C
1.68.H H NHOC(CH3)3 solid 1.69.H H NHOPh 1.70.H H F F solid NHOCHz \ / F
F F
1.71.H H SMe oil 1.72.H H SEt 1.73.H H SPh 1.74.H H SCH2Ph 1.75.Br H OH oil 1.76.Br H OMe oil 1.77.F H OH
1.78.F H OMe oil 1.79.CI H OMe 1.80.CI H OH
1.81.Me H OH oil 1.82.Me H OMe oil 1.83.Et H OMe oil 1.84.Et H OH oil 1.85.Pr H OH
1.86.Pr H OMe 1.87.nBu H OH
1.88.nBu H OMe 1.89.CH2CH=CH2 H OH oil 1.90.CH2Ph H OH 127-8C
1.91.CH2Ph H OMe oil 1.92.COOMe H OMe oil 1.93.CHZCOOH H OH 130-1 C
1.94.NH2 H OH 166-7C
1.95.NHZ.HCI H OMB 176-7C
1.96.NEt2 H OMe 56-8C
No. R, R2 A Phys. data .
m.P C
1.97. NHCH2Ph H OMe oil 1.98. Me Me OH 137-8C
1.99. Me Me OMe oil 1.100.OH H OEt oil 1.101.OH H OH
1. OAc H OEt oil i 02.
R' R _ _ A
1.103.a H OEt oil oco 1.104.OMe H OEt oil 1.105.OSi-t-BuMe2 H OEt oil 1.106.OH Me OEt oil 1.107.OH CF3 OMe oil 1.108.OH Ph OEt 77-9C
1.109.OH CHZBr OEt oil 1.110.s cF, OH OEt oil cl--~~
N CHI
1.111.s cF~ H OMe 151-2C
~
CI~~
I H
~
N CoOMe ~:
1.112.R1+R2 H OEt oil =O
1.113.R1+RZ H OEt oil U
1.114.rN OH OEt oil N~/N~C~
Table 1.B
Compounds of the formula R~
NiS ~ ~'CO-A
CI
wherein the R,, R2 and A have the meanings of the corresponding compounds of Table 1.A.
Table 1.C
Compounds of the formula R~
NiS ~ NCO-A
wherein R,, R2 and A have the meanings of the corresponding compounds of Table 1.A.
Phys. data of compounds) of Table 1.C:
No. R, R2 A Phys. data m.p. °C
1.C.1 H H OH oil _3g_ Table 2.A
R~ RZ
NCO-A
CI--~\
N R
No R, RZ R3 A Phys.data m.p.C
2.1. H H H OCH2Ph oil 2.2. H H H OH
2.3. H H Me OCHZPh oil 2.4. H H Me OH
2.5. H H Et OCHZPh oil 2.6. H H Et OMe oil 2.7. H H Et OH 191-3 2.8. H H n-Pr OMe oil 2.9. H H 2-Pr OMe oil 2.10. H H 2-Pr OH
2.11. H H cyclo-Pr OMe oil 2.12. H H t-Bu OMe oil 2.13. H H t-Bu OH
2.14. H H Ph OMe oil 2.15. H ?-I CH2Ph OMe oil 2.16. H H 2-thiophenyl OMe oil 2.17. H H COOMe OMe oil 2.18. H H ~~ ~ OH oil 2.19. H H ~ OMe oil ~
~
-39- _ No R, R2 R3 A Phys.data m.p.C
2.20. H H o OH
2.21. H H s OH
s 2.22. H H s- OH
2.23. H H /s OH
S
2.24. H H o OMe 2.25. H H CHO OMe oil 2.26. H H CH20H OMe solid 2.27. H H CH2CI OMe oil 2.28. H H CH2Br OMe 2.29. H H CH2F OMe 2.30. H H CH2NHC00- OMe t-Bu 2.31. H H CH2NEtz OMe 2.32. H H CH2NH2 OMe 2.33. H H CH2NHOH OMe 2.34. H H CH=CH2 OMe 2.35. H H CH=CHCOOMe OMe 2.36. H H CH=CHMe OMe 2.37. H H CH=CBrz OMe 2.38. H H CHOHMe OMe 2.39. H H CHOHEt OMe 2.40. H H CHOHCIMe OMe 2.41. H H CHOHFMe OMe 2.42. H H CHOHBrMe OMe WO 99/32464 PC'T/EP98/08335 No R, R2 R3 A Phys.data m.p.C
2.43. H H CH=CF2 OMe 2.44. H H COEt OMe 2.45. H H CHOHMe OMe 2.46. H H CHCIMe OMe 2.47. H H CHFMe OMe 2.48. H H CHBrMe OMe 2.49. H H 4-CI-Ph OMe 2.50. H H 3-Me0-Ph OMe 2.51. H H 2,4-Me2-Ph OMe 2.52. H H - H OMe 2.53. Br H COHMe2 OCH2Ph 2.54. Br H COHEt2 OH
2.55. F H Et OCHZPh 2.56. CI H Et OH
2.57. CI H n-Pr OCH2Ph 2.58. Me H 2-Pr OMe 2.59. Et H cyclo-Pr OH
2.60. Et H t-Bu OMe 2.61. Pr H t-Bu OMe 2.62. Pr H Ph OH
2.63. nBu H CHzPh OMe 2.64. nBu H 2-thiophen OMe 2.65. CH2CH=CH2 H COOMe OH
2.66. CH2Ph H ~~ ~ OMe 2.67. CHZPh H ~ OMe ~
2.68. COOMe H OMe ~ ~
No R, R2 R3 A Phys.data nl.~.C
2.69. CHZCOOH H s OMe s 2.70. NH2 H - OMe ~
r s-2.71. NH2.HC1 H /s\ OCH2Ph s 2.72. NEt2 H o OH
2.73. NHCH2Ph H CHO OCHZPh 2.74. Me H CH20H OH
2.75. Me H CHZCI OCHZPh 2.76. OH H CHZBr OMe 2.77. OH H CH2F OH
2.78. OAc H CHCI2 OMe 2.79. _ c~ H H OMe oco 2.80, OMe H Me OH
2.81. OSi-t-BuMez H Me OMe 2.82. OH H Et OMe 2.83. OH H Et OH
2.84. OH H Et OMe 2.85. OH H n-Pr OMe 2.86. s cF, CF3 2-Pr OMe ci--N
2.87. s cF, Ph 2-Pr OMe ci-.<\
~COOMe 2.88. R,+R2 CH2Br cyclo-Pr OMe =O
WO 99/32464 PCf/EP98/08335 No R, RZ R3 A Phys.data m.p.°C
2.89. R~+RZ ~ OH t-Bu OMe 2.90. H H cyclo-Pr OCHZPh oil Ta le 2.B
Compounds of the formula O-A
N
C~
wherein R,, R2, R3 and A have the meanings of the corresponding compounds of Table 2.A.
Table 2.C
Compounds of the formula i O-A
N
wherein R,, R2, R3 and A have the meanings of the corresponding compounds of Table 2.A.
Phys. data of compounds of Table 2.C:
No. R, R2 R3 A Phys.data m.p.C
2.C.3 H H Me OCH2Ph oil 2.C.5 H H Et OCH2Ph oil 2.C.7 H H Et OH oil 2.C.20 H H .o OH solid Co--i R, R2 iS ~ ~C
R
~C
N
Table 3.A
R, R2 S Z
CI-~~
N R
No. R, R2+ Z R3 Phys. data m.p.°C
3.1. H CF3 159-61 °C
H
~O
O
3.2. H H CF3 OII
""~
R,+Rz+Z
I
3.3. H ,~ ~ CF3 solid H
/O-~Me 'O
~
I
IO
3.4. H M ,,~ CF3 solid r < 'o ~
3.5. H Me' Me CF3 ~O
'NH
~
I
IO
3.s. H cF3 Me ~
N
~ ~O
X
' IO
_~_ No. R, Rz+ Z R3 Phys. data m.p.C
3.7. H ~ Me CF3 o~Me NH
3.8. H Me Me CF3 H
N--~Me /
r ' 'O
~
( I ' O
3.9. H Me a CF3 N- \~
'NH
~
( ~ I
O
3.10. H M ,,,~ CF3 N
C 'NH
~
I
'O
3.11. H Me H
HO
O
3.12. H H H Me "~
R1+R2+Z
I
3.13. H Me Me Et H
~
~
O--'r Me ~ ~~O
I IO
3.14. H M ,"~ Et ~<'o ~
No. R, R2+ 2 R3 Phys. data m.p.C
3.15. H Me Et Me ' ~0 'NH
x I
IO
3.16. H H ,"~ n-Pr N
l C 'O
X
I
'O
3.17. H Me ,,~ 2-Pr H
~
~
/O-'( Me 'NH
x I
IO
3.18. H Me Me 2-Pr H
~ ~
N~Me /
'O
N
I
IO
3.19. H Me M8 cyclo-P r H
~ ~
N~Me /
f ' 'NH
C
' I
O
3.20. H Me t-Bu Me N ' ~,( 'NH
X
, ~O
Table 3.B
Compounds of the formula R~ R2 \Z
N~ I
CI
wherein R,, R2, R3 and Z have the meanings of the corresponding compounds of Table 3.A.
Table 3.C
Compounds of the formula S \Z
N~ i N R
wherein R,, R2, R3 and Z have the meanings of the corresponding compounds of Table 3.A.
-47- _ Ta le 4.A
R, R2 S
R e~\
N R
No. R, RZ R3 R4 Z Phys.data m.p.C
4.1. H H CF3 Ph COOMe oil 4.2. H H Me CF3 COOH
4.3. H H CF3 H COOH
4.4. H H CF3 H COOMe oil 4.5. H H Me H COOEt solid 4.6. R,+R2 Me H COOEt solid =O
4.7. R,+R2=O Me NHCOOEt COOEt solid 4.8. R,+RZ Me NHn-Bu COOEt solid =O
4.9. R,+R2 Me NHt-Bu COOEt solid =O
4.10.H H Me NHMe COOEt solid 4.11.H H Me NHCH2CH=CH2 COOH solid 4.12.H H Et NH-t-Bu COOEt solid 4.13.H H Ph p-PhS02NH2 COOEt solid 4.14.H H p-CIPh NHPh COOEt solid 4.15.H H OH OH COOH solid 4.16.R,+R2 Me NH-COOEt COSMe =O
4.17.R,+R2 Me NH-n-Bu COSMe =O
4.18.R,+R2 Me NH-t-Bu COSMe =O
4.19.H H CF3 CF3 COSMe 4.20.H H CF3 OMe COOMe 4.21.H H CF3 OEt COOMe 4.22.H H CF3 O-n-Pr COOMe 4.23.H H CF3 SMe COOMe 4.24.H H CF3 SEt COOMe _48- _ No. R, RZ R3 R4 Z Phys.data m.p.C
4.25.H H CF3 SPh COOMe 4.26.H H CF3 NMez COOMe 4.27.H H CF3 NEt2 COOMe 4.28.H H CF3 NHZ COOMe 4.29.H H CF3 SH COOMe 4.30.H H CF3 NH2 CSOMe 4.31.H H Me CI p solid ---~
r _ 4.32.H H CF3 Ph CSOMe 4.33.H H Me CF3 CSOH
4.34.H H CF3 H CSOH
4.35.H H CF3 H CSOMe 4.36.H H Me H CSOEt 4.37.R,+RZ Me H COOEt =S
4.38.R,+R2 Me NHCOOEt COOEt =S
4.39.R,+RZ Me NH-n-Bu CSOEt =S
4.40.R,+R2 Me NH-t-Bu CSOEt =S
4.41.H H Me NHMe CSOEt 4.42.H H Me NHCH2CH=CH2 CSOH
4.43.H H Et NHt-Bu CSOEt 4.44.H H Ph p-PhS02NH2 CSOEt 4.45.H H p-CIPh NHPh CSOEt 4.46.H H OH OH CSOH
4.47.R,+R2 Me NH-COOEt CSSMe =O
4.48.R,+RZ Me NHn-Bu CSSMe =O
4.49.R,+R2 Me NHt-Bu CSSMe =S
4.50.H H Et CF3 COSMe 4.51.H H Et OMe COOMe 4.52.H H n-Pr OEt COOMe 4.53.H H i-Pr n-Pr COOMe 4.54.H H OH SMe COOMe No. R, R2 R3 R, Z Phys.data m.p.C
4.55.H H OH SEt COOMe 4.56.H H CF3 SPh CONHMe 4.57.H H CF3 NMe2 CONHMe 4.58.H H CF3 NEt2 CONHMe 4.59.H H CF3 NH2 CSNHMe 4.60.H H CF3 SH CSNHMe 4.61.H H CF3 CSNHMe Table 4.B
Compounds of the formula " 4 wherein R,, R2, R3, R,, and Z have the meanings of the corresponding compounds of Table 4.A.
Ta le 4.C
Compounds of the formula R, R2 S \Z
N~ I
N R
wherein R,, RZ, R3 and Z have the meanings of the corresponding compounds of Table 4.A.
Formulation Examples for similar purposes of pesticidal use are descibed for example in WO
97/33890.
Biological Examples Example B.1: Immunization of Cucumis sativus L a,.giainst Collgtotrichum lag~enarium a) After a cultivation period of 2 weeks, cucumber plants are sprayed with a spray mixture prepared from a wettable powder formulation of the test compound (concentration:
200 ppm). After 72 hours, the plants are infected with a spore suspension (1.0 x 105 spores/ml) of the fungus and incubated for 30 hours at high humidity and a temperature of 23°C. Incubation is then continued at normal humidity and 22°C
to 23°C.
Evaluation of protective action is made 7 to 8 days after infection and is based on fungus infestation.
b) After a cultivation period of 2 weeks, cucumber plants are treated by soil application with a spray mixture prepared from a wettable powder formulation of the test compound (concentration: 20 ppm, based on the volume of the soil). After 72 hours, the plants are infected with a spore suspension (1.5 x 105 spores/ml) of the fungus and incubated for 30 hours at high humidity and a temperature of 23°C. Incubation is then continued at normal humidity and 22°C.
Evaluation of protective action is made 7 to 8 days after infection and is based on fungus infestation.
Compounds of the Tables exhibit good activity in tests (a) and (b) and reduce fungus infestation to 0 tc 20 %. On the other hand, Colletotrichum infestation is 90 % on untreated and infected control plants.
c) Comparison test: Direct action against Colletotrichum laqenarium The fom~ulated active ingredient is mixed in various concentrations (100, 10, 1, 0.1 ppm) with autoclaved and cooled nutrient medium containing 10 000 spores per ml and is poured into microtitre plates. Incubation is then carried out at 22°C in the dark. After 2 to 3 days, fungus growth is measured by spectrophotometry.
With compounds of the Tables, no inhibition of fungus growth is observed; on the other hand, when the fungicide "Benomyl" (commercial product) is used as comparison substance at 0.2 ppm, 50 % inhibition (ECM) of fungus growth occurs.
Example B.2: Action against Phytophthora infestans on tomato lants a) After a cultivation period of 3 weeks, tomato plants are sprayed with a spray mixture prepared from a wettable powder formulation of the test compound (0.02 %
active ingre-dient). After 72 hours, the treated plants are infected with a sporangia suspension of the fungus. Fungus infestation is evaluated after incubation of the infected plants for 5 days at 90-100 % relative humidity and 20°C.
Compounds of the Tables exhibit good activityin the tests and reduce fungus infestation to 0 to 20 %. On the other hand, Phytophthora infestation is 60 % on untreated and infected control plants.
Example B.3: Action against Pyricularia oryzae on rice~~lants 2-week-old rice plants are watered with a spray mixture prepared from a wettable powder formulation of the test compound (0.006 % active ingredient, based on the volume of the soil). The pots are then filled with water until the lowermost parts of the stems of the rice plants are standing in water. After 96 hours, the treated rice plants are infected with a conidia suspension of the fungus. Fungus infestation is evaluated after incubation of the infected plants for 5 days at 95-100 % relative humidity and approximately 24°C.
In comparison with untreated control plants (100 % infestation), fungus infestation on rice plants treated with a spray mixture comprising a compound of the Tables as active ingre-dient is only approximately 50 %.
Example B.4: Action against Cercospora nicotine on tobacco plants a) Foliar application Tobacco plants (13 weeks old) are sprayed with a formulated solution of the test compound (concentration: 0.02 % active ingredient). Four days after treatment, the plants are inocu-lated with a sporangia suspension of Cercospora nicotine (150 000 spores/ml), kept for days in the dark at 25°C and high humidity and then incubated further under a normal day/night sequence.
Evaluation of the symptoms in the tests is based on the leaf surface infested with fungus.
Infestation is approximately 60 % on the control plants; on plants treated with compounds of the Tables, infestation is 0 to 30 %.
Example B.S: Action against Eryrsiphe graminis on wheat Protective action: 18-day-old wheat plants are sprayed with a formulated solution of the test compound (0.02 % active ingredient). Immediately after the treatment the plants are incuba-ted under cylinders. 24 hours later, the plants are covered. After a further 3 days, the treated plants are cut off above the primary leaf. The primary leaves are arranged horizon-tally and are inoculated in a dusting bell with Erysiphe graminis spores (spore density:
0.2 mg/mZ). The test is carried out in a climatic chamber with 12 hours of light (18 KLux), at 20°C and 12 hours of darkness, at 18°C. Infestation is evaluated 9 and 13 days after inoculation.
Compounds of the Tables exhibit good activity in the tests and reduce fungus infestation to 0 to 20 %. On the other hand, Erysiphe infestation is 70 % on untreated and infected control plants.
Claims (10)
1. A process for protecting and immunizing plants against attack by phytopathogenic microorganisms which comprises applying a compound of formula I as active ingredient to the plants, to parts of the plants and/or to the locus of the plants wherein a) X is CR, and Y is N;or b) X is N and Y is CR5; or c) X and Y are N; and wherein Z is a C1-group to which 1-3 halogen atoms or 1-3 unsubstituted or substituted hetero atoms selected from the group O, S and N are bonded;
R1 and R2 are independently H, OH, SH, CN, COOH, NO2, NH2, halogen, C1-C6alkyl, haloC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, halo-C1-C6alkoxy, C1-C6alkanoyloxy, aroyloxy, C1-C6alkoxycarbonyl, aryloxycarbonyl, benzyloxy-carbonyl, C1-C6alkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C1-C6alkylamino-carbonyl, C1-C6dialkylaminocarbonyl, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, arylsulfinyl, arylsulfonyl, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, alkoxycarbonylC1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxy-C2-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkylamino, C2-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoylamino, benzyloxyarbonylamino, phenyl, phenoxy, benzyl or phenethyl, wherein all the aromatic groups are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl; or tri(C1-C6alkyl)silyl or tri(C1-C6alkyl)silyloxy;
with the proviso that R1 and R2 are not simultaneously a group selected from OH, SH, NO2, NH2, C1-C6alkylamino, C1-C6dialkylamino and C2-C6alkenylamino; or R1 and R2 together are =O or =S; or R1 and R2 together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 8 membered isocyclic or heterocyclic ring; or R2 and Z together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 7 membered lactone, lactame, thiolactone or thiolactame, which ring may have 1 to 2 additional hetero atoms selected from the group O, S and N;
R3, R4 and R5 are independently H, OH, SH, CN, NO2, NH2, halogen, C1-C6alkyl, halo-C1-C6alkyl, hydroxyC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, halo-C1-C6alkoxy, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, C1-C6alkanoyl, C1-C6alkoxycarbonyl, alkoxycarbonyl-C1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6Cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxyC1-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkylamino, C2-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoylamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl.
R1 and R2 are independently H, OH, SH, CN, COOH, NO2, NH2, halogen, C1-C6alkyl, haloC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, halo-C1-C6alkoxy, C1-C6alkanoyloxy, aroyloxy, C1-C6alkoxycarbonyl, aryloxycarbonyl, benzyloxy-carbonyl, C1-C6alkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C1-C6alkylamino-carbonyl, C1-C6dialkylaminocarbonyl, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, arylsulfinyl, arylsulfonyl, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, alkoxycarbonylC1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxy-C2-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkylamino, C2-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoylamino, benzyloxyarbonylamino, phenyl, phenoxy, benzyl or phenethyl, wherein all the aromatic groups are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl; or tri(C1-C6alkyl)silyl or tri(C1-C6alkyl)silyloxy;
with the proviso that R1 and R2 are not simultaneously a group selected from OH, SH, NO2, NH2, C1-C6alkylamino, C1-C6dialkylamino and C2-C6alkenylamino; or R1 and R2 together are =O or =S; or R1 and R2 together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 8 membered isocyclic or heterocyclic ring; or R2 and Z together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 7 membered lactone, lactame, thiolactone or thiolactame, which ring may have 1 to 2 additional hetero atoms selected from the group O, S and N;
R3, R4 and R5 are independently H, OH, SH, CN, NO2, NH2, halogen, C1-C6alkyl, halo-C1-C6alkyl, hydroxyC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, halo-C1-C6alkoxy, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, C1-C6alkanoyl, C1-C6alkoxycarbonyl, alkoxycarbonyl-C1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6Cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxyC1-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkylamino, C2-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoylamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl.
2. A compound of formula I
wherein a) X is CR4 and Y is N; or b) X is N and Y is CR5; or c) X and Y are N; and wherein Z is a C1-group to which 1-3 halogen atoms or 2-3 unsubstituted or substituted hetero atoms selected from the group O, S and N are bonded;
R1 and R2 are independently H, OH, SH, CN, COOH, NO2, NH2, halogen, C1-C6alkyl, haloC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, halo-C1-C6alkoxy, C1-C6alkanoyloxy, aroyloxy, C1-C6alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, C1-C6alkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, arylsulfinyl, arylsulfonyl, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, alkoxycarbonylC1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxyC1-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkylamino, C1-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoylamino, benzyloxyarbonylamino, phenyl, phenoxy, benzyl or phenethyl, wherein all the aromatic groups are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl; or tri(C1-C6alkyl)sliyl or tri(C1-C6alkyl)silyloxy;
with the proviso that R1 and R2 are not simultaneously a group selected from OH, SH, NO2, NH2, C1-C6alkylamino, C1-C6dialkylamino and C2-C6alkenylamino; or R1 and R2 together are =O or =S; or R1 and R2 together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 8 membered isocyclic or heterocyclic ring; or R2 and Z together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 7 membered lactone, lactame, thiolactone or thiolactame, which ring may have 1 to 2 additional hetero atoms selected from the group O, S and N;
R3, R4 and R5 are independently H, OH, SH, CN, NO2, NH2, halogen, C1-C6alkyl, haloC1-C6alkyl, hydroxyC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, halo-C1-C6alkoxy, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, C1-C6alkanoyl, C1-C6alkoxycarbonyl, alkoxycarbonylC1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxyC1-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkyiamino, C2-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoyiamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl;
A) with the exception of the compounds of the formula wherein a) R1 is OCO-CH3 and T is Br, b) R1 is OH and T is Br, c) R1 is OH and T is H;
and B) with the exception of thiadiazole derivatives having the formula wherein R' is methyl or phenyl, A is CH2, CHCI, CHCH3, C(CH3)2, CH-C6H5, and B is CHO, CN, COOH, COOCH3, COOC2H5, COOC3H,(iso), COOC8H17(n), COOCH2CH=CH2, CONH2, CONHCH3, CONHC3H7(iso), CON(CH3)2, pyrrolidinoyl, morpholinoyl, 4-methoxicarbonyl-piperazinoyl, 4-oxo-piperidinoyl, CH(SCH3)(SOCH3), CONH-C6H4-OCH3(4) or CON(CH3)C6H5;
-56a-and C) with the exception of thiazolyl derivatives having the formula wherein R20 is hydrogen, CH3, C2H5, R21 is hydrogen, CH3, C2H5, R22 is hydrogen, C1-C3alkyl, n-C4H9, Cl or Br, R23 is hydrogen, CH3, C2H5, or R22 and R23 together with the ring to which they are attached form a condensed six-membered carbocyclic aromatic ring which may be monochlorinated, and G represents CH or N;
and D) with the exception of 7-(1,2,3-thiadiazolyl-5-acetamido)-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid.
wherein a) X is CR4 and Y is N; or b) X is N and Y is CR5; or c) X and Y are N; and wherein Z is a C1-group to which 1-3 halogen atoms or 2-3 unsubstituted or substituted hetero atoms selected from the group O, S and N are bonded;
R1 and R2 are independently H, OH, SH, CN, COOH, NO2, NH2, halogen, C1-C6alkyl, haloC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, halo-C1-C6alkoxy, C1-C6alkanoyloxy, aroyloxy, C1-C6alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, C1-C6alkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C1-C6alkylaminocarbonyl, C1-C6dialkylaminocarbonyl, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, arylsulfinyl, arylsulfonyl, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, alkoxycarbonylC1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxyC1-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkylamino, C1-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoylamino, benzyloxyarbonylamino, phenyl, phenoxy, benzyl or phenethyl, wherein all the aromatic groups are unsubstituted or substituted from 1 to 5 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl; or tri(C1-C6alkyl)sliyl or tri(C1-C6alkyl)silyloxy;
with the proviso that R1 and R2 are not simultaneously a group selected from OH, SH, NO2, NH2, C1-C6alkylamino, C1-C6dialkylamino and C2-C6alkenylamino; or R1 and R2 together are =O or =S; or R1 and R2 together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 8 membered isocyclic or heterocyclic ring; or R2 and Z together with the carbon atom to which they are bonded are an unsubstituted or substituted 3 to 7 membered lactone, lactame, thiolactone or thiolactame, which ring may have 1 to 2 additional hetero atoms selected from the group O, S and N;
R3, R4 and R5 are independently H, OH, SH, CN, NO2, NH2, halogen, C1-C6alkyl, haloC1-C6alkyl, hydroxyC1-C6alkyl, alkoxyC1-C6alkyl, aminoC1-C6alkyl, alkoxaminoC1-C6alkyl, C1-C6alkoxy, C1-C6alkylthio, haloC1-C6alkylthio, C1-C6alkylsulfinyl, haloC1-C6alkylsulfinyl, C1-C6alkylsulfonyl, haloC1-C6alkylsulfonyl, halo-C1-C6alkoxy, C2-C6alkenyl, haloC2-C6alkenyl, C2-C6alkinyl, carboxyC1-C6alkyl, C1-C6alkanoyl, C1-C6alkoxycarbonyl, alkoxycarbonylC1-C6alkyl, haloalkoxycarbonylC1-C6alkyl, C3-C6cycloalkyl, alkanoylC1-C6alkyl, alkylcarbonyloxyC1-C6alkyl, phenylcarbonyloxyC1-C6alkyl, C1-C6alkylamino, C1-C6dialkyiamino, C2-C6alkenylamino, C1-C6alkanoylamino, C1-C6alkoxycarbonylamino, benzylamino, benzoyiamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro; or optionally substituted heterocyclyl;
A) with the exception of the compounds of the formula wherein a) R1 is OCO-CH3 and T is Br, b) R1 is OH and T is Br, c) R1 is OH and T is H;
and B) with the exception of thiadiazole derivatives having the formula wherein R' is methyl or phenyl, A is CH2, CHCI, CHCH3, C(CH3)2, CH-C6H5, and B is CHO, CN, COOH, COOCH3, COOC2H5, COOC3H,(iso), COOC8H17(n), COOCH2CH=CH2, CONH2, CONHCH3, CONHC3H7(iso), CON(CH3)2, pyrrolidinoyl, morpholinoyl, 4-methoxicarbonyl-piperazinoyl, 4-oxo-piperidinoyl, CH(SCH3)(SOCH3), CONH-C6H4-OCH3(4) or CON(CH3)C6H5;
-56a-and C) with the exception of thiazolyl derivatives having the formula wherein R20 is hydrogen, CH3, C2H5, R21 is hydrogen, CH3, C2H5, R22 is hydrogen, C1-C3alkyl, n-C4H9, Cl or Br, R23 is hydrogen, CH3, C2H5, or R22 and R23 together with the ring to which they are attached form a condensed six-membered carbocyclic aromatic ring which may be monochlorinated, and G represents CH or N;
and D) with the exception of 7-(1,2,3-thiadiazolyl-5-acetamido)-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid.
3. A compound according to claim 2 of formula I.A
-56b-
-56b-
4. A compound according to claim 2 of formula I.B.
5. A compound according to claim 2 of formula I.C
6. A compound according to claim 2 wherein Z is CN, CO-A, CS-A or CH(OR10)2;
A is hydrogen, halogen, OR6, SR7, N(R8)R9, ON(R11)R12 or N(R13)OR14;
R6 to R14 are independently hydrogen, an unsubstituted or substituted, open-chained, saturated or unsaturated hydrocarbon radical containing up to 8 carbon atoms, an unsubstituted or substituted, cyclic, saturated or unsaturated hydrocarbon radical containing up to 10 carbon atoms, unsubstituted or substituted benzyl or phenethyl, an unsubstituted or substituted aryl group containing up to 8 carbon atoms, an unsubstituted or substituted benzoyl group, or an unsubstituted or substituted heterocyclyl radical; or R8 and R9, or R11 and R12, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered, unsubstituted or substituted heterocycle having 1 to 3 hetero atoms selected from O, S and/or N;
R10 are identical or different and are C1-C6alkyl that is unsubstituted or substituted by phenyl, C1-C2alkoxy, phenoxy or by benzyloxy; or two substituents OR10, together with the carbon atom to which they are bonded, form a cyclic acetal group that is unsubstituted or substituted by C1-C3alkyl, phenyl, benzyl, hydroxy or by C1-C3hydroxyalkyl.
A is hydrogen, halogen, OR6, SR7, N(R8)R9, ON(R11)R12 or N(R13)OR14;
R6 to R14 are independently hydrogen, an unsubstituted or substituted, open-chained, saturated or unsaturated hydrocarbon radical containing up to 8 carbon atoms, an unsubstituted or substituted, cyclic, saturated or unsaturated hydrocarbon radical containing up to 10 carbon atoms, unsubstituted or substituted benzyl or phenethyl, an unsubstituted or substituted aryl group containing up to 8 carbon atoms, an unsubstituted or substituted benzoyl group, or an unsubstituted or substituted heterocyclyl radical; or R8 and R9, or R11 and R12, together with the nitrogen atom to which they are bonded, form a 5- or 6-membered, unsubstituted or substituted heterocycle having 1 to 3 hetero atoms selected from O, S and/or N;
R10 are identical or different and are C1-C6alkyl that is unsubstituted or substituted by phenyl, C1-C2alkoxy, phenoxy or by benzyloxy; or two substituents OR10, together with the carbon atom to which they are bonded, form a cyclic acetal group that is unsubstituted or substituted by C1-C3alkyl, phenyl, benzyl, hydroxy or by C1-C3hydroxyalkyl.
7. A compound according to claim 2 wherein R, is H, OH, NH2, halogen, COOH, C1-C4alkyl, haloC1-C4alkyl, C1-C4alkoxy, C1-C4alkanoyloxy, aroylyloxy, C1-C4alkoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, C1-C4alkylcarbonyl, arylcarbonyl, benzylcarbonyl, aminocarbonyl, C1-C4alkylaminocarbonyl, C1-C4dialkylaminocarbonyl, alkanoylC1-C4alkyl, alkylcarbonyloxyC1-C4alkyl, C2-C4alkenyl, haloC2-C4alkenyl, C1-C4alkylamino, C1-C4dialkylamino, C1-C4alkanoylamino, C1-C4alkoxycarbonylamino, benzylamino, benzoylamino, phenyl, phenoxy, benzyl or phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, hydroxy, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy and nitro;
R2 is H, OH, C1-C1alkyl, C1-C4alkoxy or phenyl; or R1 and R2 together are a group selected from R2+Z together are a group selected from wherein R17, R18 and R19 are independently H or C1-C4alkyl;
R3 is H, halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6-cycloalkyl, C1-C4alkoxycarbonyl, phenyl which is unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy, amino, C1-C4alkylamino, C1-C4dialkylamino, benzylamino, C1-C4alkanoylamino, benzoylamino, C1-C4alkoxycarbonylamino, formyl, or a 4-7-membered cyclic or C1-C4alkyl open-chained acetal or thioacetal thereof;
R4 is H, OH, halogen, amino, C1-C6alkyl, C1-C4alkyiamino, C1-C4alkenylylamino, C1-C4dialkylamino, benzylamino, C1-C4alkanoylamino, benzoylamino, C1-C4alkoxycarbonylamino.
R2 is H, OH, C1-C1alkyl, C1-C4alkoxy or phenyl; or R1 and R2 together are a group selected from R2+Z together are a group selected from wherein R17, R18 and R19 are independently H or C1-C4alkyl;
R3 is H, halogen, C1-C6alkyl, haloC1-C6alkyl, C3-C6-cycloalkyl, C1-C4alkoxycarbonyl, phenyl which is unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy, amino, C1-C4alkylamino, C1-C4dialkylamino, benzylamino, C1-C4alkanoylamino, benzoylamino, C1-C4alkoxycarbonylamino, formyl, or a 4-7-membered cyclic or C1-C4alkyl open-chained acetal or thioacetal thereof;
R4 is H, OH, halogen, amino, C1-C6alkyl, C1-C4alkyiamino, C1-C4alkenylylamino, C1-C4dialkylamino, benzylamino, C1-C4alkanoylamino, benzoylamino, C1-C4alkoxycarbonylamino.
8. A compound according to claim 3 of formula I.A
wherein Z is CO-A;
A is hydrogen, OR6, SR7, N(R8)R9;
R, is H, OH, halogen or C1-C4alkyl, R2 is H;
R3 is H, OH, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy or haloC1-C6alkoxy, formyl, or a 4-7-membered cyclic or C1-C4alkyl open-chained acetal or thioacetal thereof;
R4 is Cl;
R6, R7, R8 and R9 are independently H, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C4alkoxycarbonyl, C1-C4alkanoylC1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkylmethyl, phenyl, benzyl, er phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy.
wherein Z is CO-A;
A is hydrogen, OR6, SR7, N(R8)R9;
R, is H, OH, halogen or C1-C4alkyl, R2 is H;
R3 is H, OH, C1-C6alkyl, C3-C6cycloalkyl, haloC1-C6alkyl, C1-C6alkoxy or haloC1-C6alkoxy, formyl, or a 4-7-membered cyclic or C1-C4alkyl open-chained acetal or thioacetal thereof;
R4 is Cl;
R6, R7, R8 and R9 are independently H, C1-C6alkyl, haloC1-C6alkyl, C1-C6alkoxy, haloC1-C6alkoxy, C1-C4alkoxycarbonyl, C1-C4alkanoylC1-C4alkyl, C3-C6cycloalkyl, C3-C6cycloalkylmethyl, phenyl, benzyl, er phenethyl, the phenyl rings of which are unsubstituted or substituted from 1 to 3 substituents independently selected from halogen, C1-C4alkyl, halo-C1-C2alkyl, C1-C2alkoxy, halo-C1-C2alkoxy.
9. A process for the preparation of a compound of formula I.1 wherein X, Y and R3 are as defined for formula I, which comprises reaction of a compound of formula II.1 with carbon monoxide under pressure of 2-20 bars in presence of a catalyst.
10. A composition for protecting and immunizing plants against attack by microorganisms, comprising a compound of formula I of claim 2 together with a suitable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9726989.8 | 1997-12-22 | ||
| GBGB9726989.8A GB9726989D0 (en) | 1997-12-22 | 1997-12-22 | Organic compounds |
| PCT/EP1998/008335 WO1999032464A1 (en) | 1997-12-22 | 1998-12-18 | Thiazole-, isothiazole- and thiadiazole-derivatives having microbicidal and plant immunizing activities |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2309973A1 true CA2309973A1 (en) | 1999-07-01 |
Family
ID=10823994
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002309973A Abandoned CA2309973A1 (en) | 1997-12-22 | 1998-12-18 | Thiazole-derivatives having microbicidal and plant immunizing activities |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1042306A1 (en) |
| JP (1) | JP2001526277A (en) |
| CN (1) | CN1282324A (en) |
| AR (1) | AR017438A1 (en) |
| AU (1) | AU2054699A (en) |
| BR (1) | BR9814394A (en) |
| CA (1) | CA2309973A1 (en) |
| GB (1) | GB9726989D0 (en) |
| GT (1) | GT199800193A (en) |
| HU (1) | HUP0100619A3 (en) |
| IL (1) | IL136589A0 (en) |
| PL (1) | PL341290A1 (en) |
| TR (1) | TR200001740T2 (en) |
| WO (1) | WO1999032464A1 (en) |
| ZA (1) | ZA9811706B (en) |
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| US6310052B1 (en) | 1996-06-04 | 2001-10-30 | Queen's University At Kingston | Nitrate esters and their use for neurological conditions |
| CA2408686A1 (en) * | 2000-05-15 | 2002-11-12 | Basf Aktiengesellschaft | 3-arylisothiazoles and their use as herbicides |
| DE10029077A1 (en) * | 2000-06-13 | 2001-12-20 | Bayer Ag | New heterocyclic-substituted thiazole derivatives, useful as total or selective herbicides, insecticides, acaricides, nematocides, ectoparasiticides or antifouling agents |
| BR0208956A (en) | 2001-04-16 | 2004-07-13 | Tanabe Seiyaku Co | High Conductance Calcium Activated K Channel Opener |
| AU2002314744A1 (en) | 2001-04-17 | 2002-10-28 | Sepracor, Inc. | Thiazole and other heterocyclic ligands and use thereof |
| GB0712653D0 (en) | 2007-06-28 | 2007-08-08 | Syngenta Ltd | Novel herbicides |
| GB0717082D0 (en) | 2007-09-03 | 2007-10-10 | Syngenta Ltd | Novel herbicides |
| MX2012006349A (en) * | 2009-12-07 | 2012-10-03 | Cardioxyl Pharmaceuticals Inc | N-acyloxysulfonamide and n-hydroxy-n-acylsulfonamide derivatives. |
| US9018411B2 (en) | 2009-12-07 | 2015-04-28 | Cardioxyl Pharmaceuticals, Inc. | Bis-acylated hydroxylamine derivatives |
| BR112012030208A2 (en) * | 2010-05-27 | 2015-09-29 | Bayer Intelectual Property Gmbh | heterocyclic alkanol derivatives as fungicides |
| JP5872548B2 (en) * | 2010-05-27 | 2016-03-01 | バイエル・インテレクチュアル・プロパティ・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツングＢａｙｅｒ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ ＧｍｂＨ | Heterocyclic alkanol derivatives as fungicides |
| EP2576528A1 (en) * | 2010-05-27 | 2013-04-10 | Bayer CropScience AG | Heterocyclic alkanol derivatives as fungicides |
| EP2508511A1 (en) * | 2011-04-07 | 2012-10-10 | Laboratoire Biodim | Inhibitors of viral replication, their process of preparation and their therapeutical uses |
| CN102417505B (en) * | 2011-08-29 | 2014-07-09 | 南开大学 | Tetrazole compounds containing methyl-1,2,3-thiadiazole as well as preparation methods and application thereof |
| CN108752287A (en) * | 2018-05-21 | 2018-11-06 | 南开大学 | The preparation method and purposes of heterocycle tertiary alcohol derivative |
| CN108912108B (en) * | 2018-06-27 | 2021-09-03 | 中国科学院上海有机化学研究所 | Trifluoromethyl compound, preparation method thereof and application thereof in pesticide |
| CN113214241A (en) * | 2021-04-29 | 2021-08-06 | 华东理工大学 | Compound for detecting sclerotinia sclerotiorum of cruciferous vegetables and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE1953861C2 (en) * | 1969-10-25 | 1982-12-23 | Fujisawa Pharmaceutical Co., Ltd., Osaka | 7-tetrazolylacetamido-3-thiomethyl-3-cephem-4-carboxylic acids |
| BE793037A (en) * | 1971-12-23 | 1973-06-20 | Fujisawa Pharmaceutical Co | PROCESS FOR THE PREPARATION OF 7-ACYLAMINO-3-SUBSTITUE-3-CEPHEM-4-CARBOXYLIC ACID DERIVATIVES AND NEW PRODUCTS THUS OBTAINED |
| EP0213079A3 (en) * | 1985-08-23 | 1987-08-05 | Ciba-Geigy Ag | Thienylalkyl esters from alpha-imidazolinon nicotine and benzoe acids |
| US5135927A (en) * | 1987-01-30 | 1992-08-04 | Ciba-Geigy Corporation | Microbicidal composition |
| CA2014880A1 (en) * | 1989-04-27 | 1990-10-27 | Indu Sawhney | Thiazole derivatives |
| JP3726306B2 (en) * | 1994-04-27 | 2005-12-14 | 日産化学工業株式会社 | Pyrazolecarboxylic acid derivatives and plant disease control agents |
| WO1996017840A1 (en) * | 1994-12-06 | 1996-06-13 | Agrevo Uk Limited | Heterocyclyl substituted hydroxyacetamide derivatives as fongicides |
| MY113237A (en) * | 1995-03-31 | 2001-12-31 | Nihon Nohyaku Co Ltd | An agricultural and horticultural disease controller and a method for controlling the diseases |
| DE19545638A1 (en) * | 1995-12-07 | 1997-06-12 | Bayer Ag | Use of 1,2,3-thiadiazolecarboxylic acid (thio) esters to control pests |
| CN1072657C (en) * | 1996-09-30 | 2001-10-10 | 日本农药株式会社 | 1,2,3-thiadiazole derivs. and salts thereof, disease agent for agricultural and horticultural use and method for use thereof |
-
1997
- 1997-12-22 GB GBGB9726989.8A patent/GB9726989D0/en not_active Ceased
-
1998
- 1998-12-02 GT GT199800193A patent/GT199800193A/en unknown
- 1998-12-18 BR BR9814394-8A patent/BR9814394A/en not_active Application Discontinuation
- 1998-12-18 IL IL13658998A patent/IL136589A0/en unknown
- 1998-12-18 CN CN98812467.XA patent/CN1282324A/en active Pending
- 1998-12-18 AR ARP980106522A patent/AR017438A1/en not_active Application Discontinuation
- 1998-12-18 TR TR2000/01740T patent/TR200001740T2/en unknown
- 1998-12-18 HU HU0100619A patent/HUP0100619A3/en unknown
- 1998-12-18 JP JP2000525401A patent/JP2001526277A/en active Pending
- 1998-12-18 PL PL98341290A patent/PL341290A1/en not_active Application Discontinuation
- 1998-12-18 WO PCT/EP1998/008335 patent/WO1999032464A1/en not_active Application Discontinuation
- 1998-12-18 EP EP98965285A patent/EP1042306A1/en not_active Withdrawn
- 1998-12-18 AU AU20546/99A patent/AU2054699A/en not_active Abandoned
- 1998-12-18 CA CA002309973A patent/CA2309973A1/en not_active Abandoned
- 1998-12-21 ZA ZA9811706A patent/ZA9811706B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GT199800193A (en) | 2000-05-25 |
| PL341290A1 (en) | 2001-04-09 |
| WO1999032464A1 (en) | 1999-07-01 |
| AR017438A1 (en) | 2001-09-05 |
| CN1282324A (en) | 2001-01-31 |
| IL136589A0 (en) | 2001-06-14 |
| ZA9811706B (en) | 1999-06-22 |
| HUP0100619A3 (en) | 2002-03-28 |
| HUP0100619A2 (en) | 2001-06-28 |
| EP1042306A1 (en) | 2000-10-11 |
| TR200001740T2 (en) | 2000-11-21 |
| BR9814394A (en) | 2000-10-10 |
| GB9726989D0 (en) | 1998-02-18 |
| JP2001526277A (en) | 2001-12-18 |
| AU2054699A (en) | 1999-07-12 |
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