WO1998026664A1 - Fungicidal quinazolinones - Google Patents

Fungicidal quinazolinones Download PDF

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Publication number
WO1998026664A1
WO1998026664A1 PCT/US1997/022779 US9722779W WO9826664A1 WO 1998026664 A1 WO1998026664 A1 WO 1998026664A1 US 9722779 W US9722779 W US 9722779W WO 9826664 A1 WO9826664 A1 WO 9826664A1
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Prior art keywords
alkyl
optionally substituted
independently
formula
direct bond
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Application number
PCT/US1997/022779
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French (fr)
Inventor
Russell Frank Bellina
James Francis Bereznak
Joel Robert Christensen
Zen-Yu Chang
Maged Mohamed Fawzi
Eric Allen Marshall
William Karl Moberg
Morris Padgett Rorer
Charlene Gross Sternberg
Michael Paul Walker
William Thomas Zimmerman
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E.I. Du Pont De Nemours And Company
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Publication date
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to AU53803/98A priority Critical patent/AU5380398A/en
Priority to JP52783198A priority patent/JP2002513394A/en
Priority to EP97950927A priority patent/EP0946095A1/en
Priority to BR9714222-0A priority patent/BR9714222A/en
Publication of WO1998026664A1 publication Critical patent/WO1998026664A1/en

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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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/02—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom
    • A01N47/06—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having no bond to a nitrogen atom containing —O—CO—O— groups; Thio analogues thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • 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
    • 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
    • A01N43/84—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 six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/12—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, neither directly attached to a ring nor the nitrogen atom being a member of a heterocyclic ring
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/18—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof containing a —O—CO—N< group, or a thio analogue thereof, directly attached to a heterocyclic or cycloaliphatic ring
    • 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
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/10—Carbamic acid derivatives, i.e. containing the group —O—CO—N<; Thio analogues thereof
    • A01N47/22—O-Aryl or S-Aryl esters thereof

Definitions

  • This invention relates to certain fungicidal quinazolinones, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides.
  • This invention is directed to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of a compound of Formula I including all geometric and stereoisomers, N-oxides, agriculturally suitable salts thereof, and agricultural compositions containing them:
  • R 3 is Cl, Br, I, C r C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C r C 8 haloalkyl, C3-C 8 haloalkenyl, C 3 -C haloalkynyl, C C 8 alkoxy,
  • R13; R 4 is hydrogen, Cl, Br, I, C r C 4 alkyl, C r C 4 haloalkyl, C r C 4 alkoxy or
  • R 14 is B(OH) 2 ; OH; SH; cyano; CF 3 SO 3 ; C r C 4 haloalkylthio; C r C 4 haloalkylsulfinyl; -C4 haloalkylsulfonyl; thiocyanato; C 3 -C 8 trialkylsilyloxy, Rl 5 OCHR 16 O; (R 15 O) 2 CHO; R 15 SS; R l 5SCH(R !
  • each W is independently defined as -O-, -S(O) n -, -NR 5 -, -CH 2 O-, -CH 2 S(O) n -,
  • each R 9 is independently methyl, ethyl, methoxy, methylthio, halogen,
  • alkyl used in compound words such as “alkylthio” or “haloalkyl” includes straight-chain or branched alkyl, such as, methyl, ethyl, «-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers.
  • alkyl used alone includes straight-chain or branched alkyl, such as, methyl, ethyl, w-propyl, /-propyl, or the different butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl isomers.
  • Alkenyl includes straight-chain or branched alkenes such as vinyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl isomers.
  • Alkenyl also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl isomers.
  • Alkynyl can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
  • Alkoxy includes, for example, methoxy, ethoxy, propyloxy, 1-methylethoxy and the different butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, and decyloxy isomers.
  • Alkoxyalkyl denotes alkoxy substitution on alkyl. Examples of “alkoxyalkyl” include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • Alkenyloxy includes straight-chain or branched alkenyloxy moieties.
  • alkynyloxy includes straight-chain or branched alkynyloxy moieties. Examples of “alkynyloxy” include HC ⁇ CCH 2 O, CH 3 C----CCH 2 O and CH 3 C ⁇ CCH 2 CH 2 O.
  • Alkoxyalkenyl denotes alkoxy substitution of alkenyl.
  • alkynyloxyalkyl examples include CH ⁇ CCH 2 OCH 2 and CH 3 C ⁇ CCH 2 OCH 2 CH 2 .
  • Alkylthio includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, hexylthio, heptylthio and octylthio isomers.
  • Alkylthioalkyl denotes alkylthio substitution on alkyl.
  • alkylthioalkyl examples include CH 3 SCH 2 , CH 3 SCH 2 CH 2 , CH 3 CH 2 SCH 2 , CH 3 CH 2 CH 2 CH 2 SCH 2 and CH 3 CH 2 SCH 2 CH 2 .
  • alkenylthioalkyl denotes alkenyl substitution on sulfur which in turn is substituted on alkyl.
  • Alkynylthioalkyl denotes alkynyl substitution on sulfur which in turn is substituted on alkyl.
  • alkynylthioalkyl include CIfeCCH 2 SCH 2 and CH 3 C ⁇ CCH 2 SCH 2 CH 2 .
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptasulfonyl and octasulfonyl isomers.
  • Alkylsulfonylalkyl denotes alkylsulfonyl substitution on alkyl. Examples of “alkylsulfonylalkyl” include
  • alkenylthio is defined analogously to the above examples.
  • Cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepyl and cyclooctyl.
  • Cycloalkylalkyl denotes cycloalkyl substituted on alkyl. Examples of “cycloalkylalkyl” include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
  • halogen either alone or in compound words such as “haloalkyl” includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl”, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of “haloalkyl” include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CC1 2 .
  • haloalkynyl examples include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • haloalkoxy examples include CF 3 O, CCl 3 CH 2 O, HCF 2 CH 2 CH 2 O and CF 3 CH 2 O.
  • haloalkylthio examples include CC1 3 S, CF 3 S, CC1 3 CH 2 S and C1CH 2 CH 2 CH 2 S.
  • haloalkylsulfinyl examples include CF 3 S(O), CCl 3 S(O), CF 3 CH 2 S(O) and CF 3 CF 2 S(O).
  • haloalkylsulfonyl examples include CF 3 S(O) 2 , CCl 3 S(O) 2 , CF 3 CH 2 S(O) 2 and CF 3 CF 2 S(O) 2 .
  • Trialkylsilylalkyl denotes trialkylsilyl substitution on alkyl.
  • Examples of “trialkylsilylalkyl” include (CH 3 ) 3 SiCH 2 , and (CH 3 ) 3 SiCH 2 CH 3 .
  • Trialkylsilylalkynyl denotes trialkylsilyl substitution on alkynyl.
  • Examples of “trialkylsilylalkynyl” include (CH 3 ) 3 SiC ⁇ C and (CH 3 CH 2 )SiCH 2 C ⁇ C.
  • C j -C; The total number of carbon atoms in a substituent group is indicated by the "C j -C;" prefix where i and j are numbers from 1 to 10.
  • Cj-C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
  • the R 8 , R 9 and R 10 groups may substitute either ring.
  • the R 8 , R 9 and/or R 10 groups are shown in the structures Y-l to Y-100, it is noted that they do not need to be present since they are optional substituents.
  • N-oxides of compounds of Formula I can be made by oxidizing the corresponding nitrogen compound with a strong oxidizing agent such as wet ⁇ -chloroperoxybenzoic acid.
  • Compounds of Formula I can exist as one or more stereoisomers.
  • the various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers.
  • one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers.
  • the compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
  • the salts of the compounds of Formula I useful for this invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids.
  • the salts useful for this invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group.
  • the present invention comprises the fungicidal use of compounds selected from Formula I, including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof.
  • Preferred compounds for use in the method and compositions of this invention for reasons of better activity and/or ease of synthesis are:
  • each W is -O-, -S- or - ⁇ R 5 -; each Rl is CJ-CI Q alkyl, C 4 -C 10 cycloalkylalkyl or RU; each R 2 is C j -Cio alkyl, C 4 -C 10 cycloalkylalkyl or Rl 1; and R 3 is R l4 .
  • each W is -O-, -S- or - ⁇ R 5 -
  • each Rl is CJ-CI Q alkyl, C 4 -C 10 cycloalkylalkyl or RU
  • each R 2 is C j -Cio alkyl, C 4 -C 10 cycloalkylalkyl or Rl 1
  • R 3 is R l4 .
  • each W is -CH 2 O-, -CH 2 S(O) n - or -CH 2 ⁇ R 5 -; each R l is C J-CJQ alkyl, C -C ⁇ 0 cycloalkylalkyl or R l ; and each R 2 is CJ-CJQ alkyl, C 4 -CJO cycloalkylalkyl or R 1 1 .
  • Preferred 2a Compounds of Preferred 2 above wherein: R 3 is halogen, C r C 8 alkyl, C 3 -C 8 cycloalkyl or R 14 ; and
  • R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C C 4 haloalkylsulfonyl. Preferred 3.
  • each W is a direct bond
  • each R 1 is C C j o alkyl, C -C 10 cycloalkylalkyl or R U
  • Preferred 3a Compounds of Preferred 3 above wherein:
  • R 3 is halogen, C r C 8 alkyl, C 3 -C 8 cycloalkyl or R ]4 ; and R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C C 4 haloalkylsulfonyl.
  • R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C C 4 haloalkylsulfonyl.
  • W is a direct bond
  • R l is C r C w alkyl, C 4 -C 10 cycloalkylalkyl or RU;
  • R 2 is OH or halogen;
  • R 3 is halogen, C ⁇ -C 8 alkyl, C 3 -C 8 cycloalkyl or R 14 ; and R 14 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C j -C haloalkylsulfonyl.
  • R 14 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C j -C haloalkylsulfonyl.
  • R 1 and or R 2 is substituted C Cjo alkyl (preferably C r C 4 alkyl substituted with OH);
  • R 3 is halogen, C r C 8 alkyl, C 3 -C 8 cycloalkyl or R ⁇ 4 ;
  • R 4 is hydrogen, Cl, Br or I;
  • R l4 is OH, SH, cyano, CF 3 SO 3 , C r C 4 haloalkylthio, C r C 4 haloalkylsulfinyl or C j -C 4 haloalkylsulfonyl.
  • Most preferred are compounds selected from the group 2-chloro-6-iodo-3- «-propyl-4(3H)-quinazolinone;
  • W is a direct bond
  • the compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-30.
  • the definitions of W, Q, X, Y, R R 20 , m, n and p in the compounds of Formulae 1-16 below are as defined above in the Summary of the Invention.
  • Compounds of Formulae Ia-Iae are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Iae are as defined above for Formula I.
  • the synthesis of compounds of Formula I is described below. First, the synthesis of the quinazolinone ring system is described. In this first section, the groups Rl, WR 2 , R 3 , R 4 and/or (R ]9 ) p are incorporated into the substrates which are used in the syntheses described therein. Alternatively, the quinazolinone ring system can be prepared using a precursor to these groups, and then the R 1 , WR 2 , R 3 , R 4 and/or (R 19 ) p groups can be introduced afterwards. This alternate strategy is outlined in the second section of this synthetic summary.
  • the reaction may be run by treating the compounds 1 with excess amine in hydrocarbon, ethereal, alcoholic or polar aprotic solvents at temperatures ranging from ambient to 150 °C for 0.1 to 72 hours. Workup usually involves removal of reaction solvent in vacuo and, if necessary, purification by silica gel chromatography.
  • esters of Formula 2 are treated with thiophosgene at temperatures from about -20 to 100 °C for 1 -48 hours in an inert solvent. Often this reaction is performed in a bi-phasic mixture in the presence of an aqueous base (e.g., sodium bicarbonate).
  • an aqueous base e.g., sodium bicarbonate.
  • the resulting isothiocyanate may be isolated by extraction into a water-immiscible solvent such as methylene chloride, followed by drying of the organic extracts and evaporation under reduced pressure.
  • the isothiocyanate can be combined in situ with compounds of formula R 2 OH, R 2 SH or R 2 NHR 5 and stirred at about -20 to 100 °C for 0.1-24 hours.
  • the desired product of Formula 1 can be isolated from the reaction mixture by extraction and purified by silica gel chromatography or recrystallization.
  • the reaction may be carried out in a variety of solvents in the presence of homo/heterogeneous bases at temperatures from ambient to 150 °C for 0.1 to 24 hours.
  • suitable reaction solvents include hexanes, benzene, dioxane, tetrahydrofuran (THF), lower alkanols, NN-dimethylforamide (DMF) and halocarbon solvents.
  • Suitable bases include potassium carbonate, sodium hydroxide, triethylamine and pyridine.
  • Workup is achieved by removing reaction solvent in vacuo and partitioning the crude residue between dilute aqueous acid and a water-immiscible solvent. The water-immiscible phase is then separated, dried over sodium sulfate ( ⁇ a 2 SO 4 , anhydrous), concentrated, and purified by crystallization or silica gel chromatography to deliver pure I.
  • An anthranilic acid of Formula 3 is condensed with an isothiocyanate of Formula Rl-NCS to form the 2-thioquinazolinone of Formula 5.
  • the condensation is preferably performed in the presence of a base such as triethylamine.
  • S-Methylation of this compound affords the 2-(methylthio)-4(3H)-quinazolinone of Formula Ic.
  • Formula Ic is treated with a mixture of a base, for example sodium hydride, in R 2 O ⁇ solvent.
  • a base for example sodium hydride
  • the reaction mixture is stirred at a temperature from about 0 °C to 120 °C for 1 to
  • the desired 2-R 2 O quinazolinone can be isolated from the reaction mixture by extraction into a water-immiscible solvent, and purified by chromatography or recrystallization. Synthetic procedures for the preparation of related 4(3H)-quinazolinones are described in U.S. 3,755,582 and incorporated herein by reference.
  • the isothiocyanates of Formula R!-NCS can be prepared from the corresponding amine by treatment with thiophosgene as known in the art. For example, seeJ. Heterocycl. Chem., (1990), 27, 407.
  • the reaction is run using either aqueous NaOH or KOH at base concentrations ranging from 0.1 - 3 N.
  • the reaction may optionally be conducted in the presence of a co-solvent (e.g., ethanol) at temperatures ranging from ambient to reflux for 0.1 to 24 hours.
  • a co-solvent e.g., ethanol
  • Workup/purification is achieved by acidifying the crude reaction mixture and isolating the product 5a via suction filtration.
  • Compounds of Formula 5b are prepared by reacting the anthranilic acids 3 with suitable acyl isothiocyanates in an aprotic solvent such as acetone (Scheme 6).
  • the reaction is optionally conducted in the presence of a soluble base such as triethylamine at reflux temperatures for 0.1-24 hours.
  • a soluble base such as triethylamine
  • the precipitated product 5b is isolated by suction filtration and utilized without further purification. Analogous procedures are known in the art (Indian J. Chem., (1968), 6, 621 and Ann. Chim. (Rome), (1967), 57, 595).
  • OTs 2-R 2 S quinazolinone of Formula Id.
  • Bases such as sodium hydroxide and sodium hydride are suitable.
  • the 2-thiopyrimidinedione is dissolved or dispersed in an inert solvent such as N,N-dimethylformamide and treated with a base at a temperature from about -20 to 60 °C.
  • the reaction mixture may then be heated to just above ambient temperature to the reflux temperature of the solvent for 0.1 to 24 hours to effect deprotonation.
  • the reaction mixture is cooled and treated with R 2 -L and stirred for 0.1-24 hours at a temperature from about 20 °C to the reflux temperature of the solvent.
  • the quinazolinone of Formula Id can be isolated by extraction into a water-immiscible solvent, and purified by chromatography or recrystallization.
  • the reaction may be conducted either neat or in an inert solvent at temperatures ranging from 100 to 250 °C for 1-24 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the crude residue purified by silica gel chromatography to afford Ie. For similar procedures, seeHe v. Chim. Ada, (1968), 69, 1017.
  • the amides 7 are accessed from isatoic anhydrides of Formula 8 via treatment with amines of structure R ! N ⁇ 2 (Scheme 10).
  • Methods for the preparation of isatoic anhydrides are well-known in the literature, as is their conversion to aminobenzamides (see
  • Oxalates of Formula 6 are also well known and are either available commercially, or can be prepared using methods familiar to the skilled practitioner.
  • Fused bicyclic quinazolinones of Formula Ig compounds of Formula I wherein Q is O and W is S(O) or S(O) 2 , can be prepared by oxidation of the corresponding -SR 2 compound of Formula If using well-known procedures for oxidation of sulfur (Scheme 11). For example, see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York,
  • Fused bicyclic quinazolinones of Formula Ih compounds of Formula I wherein Q is O and W is NR 5 , can be prepared by the method illustrated in Scheme 12. This method is described in detail in U.S. 3,867,384 and incorporated herein by reference.
  • 2-methylthio quinazolinone of Formula 9 (Z SMe) with an excess of an amine of Formula HNR 5 R 2 at about 150 to 175 °C.
  • Phosgene, phosphorous trichloride, phosphorous oxybromide, phosphorous tribromide and diethylamino sulfur trifluoride (DAST), may also be used to access compounds of Formula 9, wherein Z is halogen from 2-thio-quinazolinones of Formula 5.
  • Amines of Formula HNR 5 R 2 are commercially available or can be prepared by well-known methods (March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), p 1153).
  • compounds of Formula lb and Id can be prepared by displacement of the 2-chlorine in the appropriate fused quinazolinone, rather than by displacement of the 2-SCH 3 group (Scheme 4) or S-alkylation of the thiocarbonyl (Scheme 8).
  • 2-chlorine in the appropriate fused quinazolinone
  • 2-SCH 3 group Scheme 4
  • S-alkylation of the thiocarbonyl Scheme 8
  • WR 2 , R 3 , R 4 and/or (R !9 ) p substituents may be more conveniently introduced after cyclization to form the quinazolinone system.
  • R 5 H precursor of Formula Ii as illustrated in Scheme 13.
  • DMSO/oxalyl chloride/Et 3 N Tetrahedron, (1990), 46, 1295.
  • the oxidations may be conducted in halocarbon solvents at temperatures ranging from -78 °C to 100 °C and the desired product isolated by filtration from the reaction mixture.
  • the precursors of Formula II may be synthesized from compounds of Formula 10 through contact with aqueous base (Scheme 15) as demonstrated in the art (Tetrahedron, (1990), 46, 1295).
  • the reaction may be conducted using aqueous K 2 CO 3 , NaCO 3 , or NaOH at temperatures of ambient to 50 °C for 0.5-72 hours.
  • the product II can be isolated by extraction of the aqueous reaction mixture with a water-immiscible solvent, followed by drying and concentration of the organic phase in vacuo.
  • Acid halides of Formula 11 can be prepared from the corresponding -acetoxy acids by treatment with oxalyl chloride as described in Tetrahedron, (1990), 46, 1295.
  • the requisite ⁇ -acetoxy acids are well known and accessible via methods known in the art (e.g., Ber., (1904), 37, 3971 ; J. Org. Chem., (1990), 55, (1928); Tetrahedron Asymmetrie, (1990), 9, 87).
  • the reaction may be run in solvents such as DMF, THF, benzene, acetonitrile, or neat at temperatures ranging from ambient to 150 °C.
  • Bases such as potassium carbonate (K 2 CO 3 ), sodium hydroxide (NaOH), or sodium hydride (NaH) may be employed to facilitate the reaction.
  • Workup is achieved by concentrating the crude reaction mixture in vacuo and partitioning the residue between a water-immiscible solvent and water. Drying and concentration of the water-immiscible phase delivers Io, which may be further purified by recrystallization or column chromatography.
  • Halides of Formula In can be prepared from aminobenzamides 7 in a manner analogous to that described inJ. Med. Chem., (1979), 22, 95. Reaction of acid halides 12 with the aminobenzamides 7 in acetic acid (HOAc) at temperatures ranging from ambient to reflux for 0.1-24 hours affords the halides In after cooling, concentrating in vacuo, and optional purification via column chromatography and/or recrystallization (Scheme 18).
  • HOAc acetic acid
  • the acid halides 12 are either commercially available or preparable using established methods.
  • Aminobenzamides 7 may be accessed as described previously in this document.
  • carbenoid species such as 13 and subsequent reaction with Ip to deliver compounds of Formula Ir can be accomplished by the analogous application of known methods (e.g. J. Het. Chem., (1990), 27, 807). Likewise, established methods can be applied in preparing the acylated/thioacylated materials Ir and Is (see, for example,J Med. Chem., (1985), 28, $16).
  • Salts of compounds of Formula I can be formed by treating the free base of the corresponding compound with strong acids such as hydrochloric or sulfuric acid. Salts can also be prepared by alkylation of a tertiary amine group in the molecule to form, for example, the trialkylammonium salt. N-Oxides of compounds of Formula I can be made by oxidizing the corresponding reduced nitrogen compound with a strong oxidizing agent such as et ⁇ -chloroperoxybenzoic acid. Synthesis of RU Groups
  • R l 1 group can be prepared by incorporation of the R l 1 group after the synthesis of the quinazolinone ring system.
  • the aziridines of Formula Iw can be prepared from the alkenes of Formula 14 by condensation with a nitrene as illustrated in Scheme 23 and described in Abramovitch, R. J. Chem. Soc, Chem. Commun., (1972), 1160.
  • the NH aziridine compound of Formula Ix can be prepared from the corresponding epoxide by contact with sodium azide and triphenylphosphine as illustrated below in Scheme 24 and described by Ittah, Y. in J. Org. Chem. , ( 1978), 43, 4271.
  • the episulfide of Formula Iy can also be prepared from the epoxide using triphenylphosphine sulfide using techniques taught by Chan, T. inJ Am. Chem. Soc, (1972), 94, 2880.
  • oxetanes of Formula Iz may be achieved by ring expansion of the corresponding epoxide using dimethyloxosulfonium methylide as illustrated in Scheme 25 and described by J. Okuma inJ Org. Chem., (1983), 48, 5133. In some cases, a mixture of regioisomers will be obtained. Additional methods for preparing oxetanes, as well as other 4-membered ring heterocycles, from an alkene precursor are well-known in the art. For example, see: Buchi, G., J. Am. Chem. Soc, (1954), 76, 4327; and Pifferi, G., J Heterocyclic Chem., (1967), 4, 619.
  • dioxolane compounds can be prepared from the glycol using known methods.
  • a method exemplifying the preparation of the dimethyl - dioxolane is illustrated in Scheme 26 and described by A. Hampton inJ Am. Chem. Soc, (1961), 83, 3640.
  • Scheme 26 A method exemplifying the preparation of the dimethyl - dioxolane is illustrated in Scheme 26 and described by A. Hampton inJ Am. Chem. Soc, (1961), 83, 3640.
  • the glycol of Formula 15 can be prepared from the alkene of Formula 14 using vicinal bis-hydroxylation reagents such as osmium tetroxide (see Wade, P., Tetrahedron Lett., (1989), 5969).
  • 5-membered ring compounds can be prepared from the alkene of Formula 14 using a 1,3-dipole cyclization.
  • reaction of 14 with bromonitrile oxide produces the dihydroisoxazole of Formula lab as illustrated in Scheme 27 (see Wade, P., in J. Org. Chem., (1990), 55, 3045).
  • 1,3-dipoles are known to react with alkenes and alkynes of Formulae 14 and 16, respectively, in cycloaddition reactions. Dipoles and methods for generating them are described in 1,3-Dipolar Cycloaddition Reactions, A. Padwa, Ed., Wiley Interscience, NY, 1984, Vols. 1 and 2; and Comprehensive Heterocyclic Chemistry, Katritzky, A., Ed., Pergamon, NY, 1984, Vol. 5, p 143). Examples of known 1,3 dipoles are nitrile ylides, nitrile imines, nitrile sulfides, diazoalkanes, azides, azomethine ylides and nitrones.
  • Compounds of Formula I wherein R 11 comprises a 6-membered ring heterocycle can be prepared from the alkene of Formula 14 by [4+2] cycloaddition with a suitable heterodiene. For example, conditions similar to those described by Krespan, C, inJ Am.
  • alkynes can also engage in reactions with heterodiene systems to afford unsaturated ring compounds such as those of
  • heterodienes known to undergo cycloaddition reactions are thiophene, furan, ⁇ , ⁇ -unsaturated aldehydes and ketones, ⁇ , ⁇ -unsaturated thiocarbonyl compounds, ⁇ , ⁇ -unsaturated imines, vinyl nitroso species, azoalkenes, acyldiimides, acyl sulfenes, ⁇ -quinones, and thioamide-N-methylium salts.
  • the regiochemical course of the [4+2] condensation depends on the structure of the alkene or alkyne and the heterodiene. Both regioisomers are often obtained in which case the desired regioisomer can be isolated by chromatography or recrystallization.
  • Iaf Acids of Formula 3 are optimally reacted with isocyanates of Formula 17 at temperatures from ambient to about 150 °C in the presence of an inert solvent and base, followed by solvent distillation and heating of the subsequent residue to 200-250 °C for about 0.5 to 1 hour.
  • Suitable solvents for this transformation include acetonitrile, DMF, or dioxane.
  • Suitable bases include triethylamine or pyridine.
  • Phosphonates of Formula Iah are accessible by reacting halides of Formula lag with phosphites of Formula 18 (Scheme 32).
  • Step B Preparation of methyl 5-iodo-2-isothiocyanatobenzoate
  • 2-amino-5-iodobenzoate hydrochloride 20.0 g, 0.063 mol
  • Toluene 720 mL
  • water 180 mL
  • sodium bicarbonate 49 g, 0.583 mol
  • thiophosgene 13.2 mL, 0.172 mol
  • the biphasic mixture was stirred at room temperature for 24 h, diluted with water (400 mL), and the phases separated.
  • the organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 21.43 g of the title compound, ]
  • H NMR 300 MHz, CDC1 3
  • Step D Preparation of 6-iodo-2-propoxy-4(3H)-quinazolinone Methyl 5-iodo-2-[(propoxythioxomethyl)amino]benzoate (1.0 g, 2.64 mmol) was combined with ammonia-saturated 1-propanol (20 mL) in a lightly-capped nalgene® vessel and stirred at room temperature for 24 hours.
  • Step B Preparation of S-[3,4-dihvdro-4-oxo-3-propyl-2-rpropylthio)-6-quinazolinyl] dimethylcarbamothioate O-[3,4-dihydro-4-oxo-3-propyl-2-(propylthio)-6-quinazolinyl]dimethylcarbamo-thioate
  • Step C Preparation of 6-[(difluoromethyl)thio]-3-propyl-2-(propylthio -4(3H)- quinazolinone
  • Step B Preparation of 6.6'-dithiobis[3-propyl-2-(propylthio)-4(3H)-quinazolinone]
  • 6-Iodo-3 «-propyl-2-thio-4(3H)-quinazolinedione (5 g, 0.014 moles, prepared from propyl isothiocyanate in a manner similar to that described in Example 4, Step A using 2-amino-5-iodo benzoic acid in place of 2-amino-5-hydroxybenzoic acid) was slurried in n-propyl acetate and treated with phosgene (2.1 mL, 0.029 mol). The slurry was heated at reflux for 1 hour. The excess phosgene was removed by co-distillation with r ⁇ -propyl acetate at atmospheric pressure. The pot residue was then evaporated to dryness under vacuum.
  • phosgene 2.1 mL, 0.029 mol
  • R 3 6-C1
  • R 4 H
  • R 1 CH 2 CH 2 CH 3)
  • R 3 6-C1
  • R 4 H
  • Compounds of Formula I used in this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant.
  • the formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature.
  • Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels.
  • Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible (“wettable”) or water-soluble.
  • Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or “overcoated”). Encapsulation can control or delay release of the active ingredient.
  • Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation.
  • the formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight.
  • Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsi ⁇ ers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
  • Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers.
  • Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate.
  • Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
  • Solutions can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wetmilling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 141-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714.
  • Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
  • Compound 25 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
  • Granule Compound 25 10.0% attapulgite granules (low volatile matter
  • Example C Extruded Pellet Compound 25 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%.
  • Example D Emulsifiable Concentrate
  • Compound 25 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
  • the compounds of Formula I are useful as plant disease control agents.
  • the present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound.
  • the compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops.
  • pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Septoria tritici, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides, Cercospora beticola, Botrytis cinerea, Monilinia fructicola, Pyricularia oryzae, Podosphaera leucotricha, Venturia inaequalis, Erysiphe graminis, Uncinula necatur, Puccinia recondita, Puccinia graminis, Hemileia vastatrix, Puccinia striiformis, Puccinia arachidis, Rhizoctonia solani, Sphaerotheca fuligine
  • Compounds of Formula I can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection.
  • insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene
  • insecticides such as abamectin, acep
  • Preferred for better control of plant diseases caused by fungal plant pathogens e.g., lower use rate or broader spectrum of plant pathogens controlled
  • resistance management are mixtures of a compound of this invention with a fungicide selected from the group: flusilazole, epoxiconazole, fenpropimorph, fenpropidin, azoxystrobin, kresoxim methyl, benomyl, mancozeb and cymoxanil.
  • Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing.
  • the compounds can also be applied to the seed to protect the seed and seedling.
  • Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
  • BIOLOGICAL EXAMPLES OF THE INVENTION Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in the following tests. Spraying these 200 ppm test suspensions to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha.
  • TEST A The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
  • TEST B The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
  • TEST C The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made.
  • test suspension was sprayed to the point of run-off on rice seedlings.
  • seedlings were inoculated with a spore suspension of Pyricularia oryzae (the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made.
  • test suspension was sprayed to the point of run-off on tomato seedlings.
  • seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
  • Phytophthora infestans the causal agent of potato and tomato late blight
  • TEST E The test suspension was sprayed to the point of run-off on grape seedlings. The following day the seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made. TEST F The test suspension was sprayed to the point of run-off on cucumber seedlings.
  • Plasmopara viticola the causal agent of grape downy mildew
  • Results for Tests A-F are given in Table A.
  • a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls).
  • a dash (-) indicates no test results.
  • ND indicates disease control not determined due to phytotoxicity.
  • Test A 48 98 0 0 0 28 0 Cmpd No. Test B Test C Test D Test E Test F

Abstract

A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of a compound of Formula (I), N-oxides, agriculturally suitable salts thereof, and agricultural compositions containing them, wherein Q is independently defined as O or S; and W, R?1-R4, R19¿, and p are as defined in the disclosure. Also disclosed are compositions containing the compounds of Formula (I).

Description

TITLE FUNGICIDAL QUINAZOLINONES BACKGROUND OF THE INVENTION This invention relates to certain fungicidal quinazolinones, their N-oxides, agriculturally suitable salts and compositions, and methods of their use as fungicides.
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
Khim. Prir. Soedin., (1982), 18, p 112 describes the synthesis and alkylation of 2-mercapto-4-quinazolinones and their fungicidal activity. U.S. 3,755,582, U.S. 3,867,384, WO 94/26722 and U. S. Patent Application Number 08/333,179 disclose certain 4(3H)-quinazolinone fungicides.
SUMMARY OF THE INVENTION This invention is directed to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of a compound of Formula I including all geometric and stereoisomers, N-oxides, agriculturally suitable salts thereof, and agricultural compositions containing them:
Figure imgf000003_0001
wherein
R3 is Cl, Br, I, CrC8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, CrC8 haloalkyl, C3-C8 haloalkenyl, C3-C haloalkynyl, C C8 alkoxy,
CrC8 haloalkoxy, C3-C8 alkenyloxy, C3-C8 alkynyloxy, CrC8 alkylthio,
CrC8 alkylsulfonyl, C2-C8 alkoxyalkyl, C3-C8 trialkylsilyl, ΝR6R7,
C5-C8 trialkylsilylalkynyl, R14 or phenyl optionally substituted with at least one
R13; R4 is hydrogen, Cl, Br, I, CrC4 alkyl, CrC4 haloalkyl, CrC4 alkoxy or
CrC haloalkoxy; or when R3 and R4 are on adjacent atoms they can be taken together as -OC(R16)2O-; R14 is B(OH)2; OH; SH; cyano; CF3SO3; CrC4 haloalkylthio; CrC4 haloalkylsulfinyl; -C4 haloalkylsulfonyl; thiocyanato; C3-C8 trialkylsilyloxy, Rl5OCHR16O; (R15O)2CHO; R15SS; Rl5SCH(R!6)S; SF5; Rl7C(=Y); R18C(=Y)X; Rl7χC(=Y); (Rl )XC(=Y)X; O(Y=)P(ORl8)2; isothiocyanato; pyridinyl, furanyl, thienyl, benzofuranyl, benzo jthiophenyl, aryloxy, arylthio or quinolinyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; C2-alkenyl or C2-alkynyl each substituted with CN, CO2R6 or phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; each R15 is
Figure imgf000004_0001
each W is independently defined as -O-, -S(O)n-, -NR5-, -CH2O-, -CH2S(O)n-,
-CH2NR5-, -C(=O)-, -C(=Y)O-, -OC(=Y)-, -OC(=Y)O-, -NHC(=Y)NH-, -NHC(=Y)O-, -OC(=Y)NH-, -C(=Y)NH-, -NHC(=Y)- or a direct bond; the directionality of the W linkage is defined such that the moiety depicted on the left side of the linkage is bonded to the quinazolinone heterocycle and the moiety on the right side is bonded to R2; each n is independently 0, 1 or 2; each Q is independently defined as O or S; each R1 is independently defined as C Cj alkyl; C3-C6 cycloalkyl; C3-CJQ alkenyl; C3-C10 alkynyl; CJ-CJO haloalkyl; C3-C10 haloalkenyl; C3-C10 haloalkynyl; C2-C10 alkoxyalkyl; C2-Cι0 alkyl thioalkyl; C -C10 alkyl sulfonylalkyl; C4-Cj0 cycloalkylalkyl; C4-C1Q alkenyloxyalkyl; C -C10 alkynyloxyalkyl; C4-C10 alkenyl thioalkyl; C4-C10 alkynylthioalkyl; C^-CJQ haloalkoxyalkyl; C -C10 alkoxyalkenyl; C4-C10 alkylthioalkenyl; C -Cι0 trialky 1 s i ly 1 alkyl ; -CIQ alkoxy; RU; Rl?C(=S); R18C(=S)X; Rl7XC(=Y); (Rl7)XC(=Y)X; pyridinyl, furanyl, thienyl, benzofuranyl, benzo[b]thiophenyl or quinolinyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or CrC10 alkyl substituted with NR6R7, nitro, cyano, OH, SH, OC(=O)R20, C(=O)SR6 or phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; each X is independently O, NR17 or S; each Y is independently O or S; each R2 is independently defined as C CjQ alkyl; C3-C7 cycloalkyl; C3-Cιo alkenyl; C3-C10 alkynyl; C Cl0 haloalkyl; C3-C10 haloalkenyl; C3-C10 haloalkynyl; C2-C10 alkoxyalkyl; C2-C10 alkylthioalkyl; C -C10 alkylsulfonylalkyl; C4-Cj0 cycloalkylalkyl; -CJQ alkenyloxyalkyl; C4-CIQ alkynyloxyalkyl; C4-C10 alkenylthioalkyl; C4-CIQ alkynylthioalkyl; CJ-CIQ haloalkoxyalkyl; C4-CJO alkoxyalkenyl; C4-C10 alkyl thioalkenyl; C4-C10 trialkylsilylalkyl; R1 1; phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or C Cjo a^yl substituted with one or more substituents selected from the group NR6R7, cyano, nitro, OH, SH, OC(=O)R20, CO2R6, O(Y=)P(OR18)2, (O=)P(OR1 )2 and phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or when a W is -NR5-, then the R2 attached to said W can additionally be selected from -OR7; -N=CR6R6; -NR6R7; and pyridinyl, furanyl and thienyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or when a W is -O-, then the R2 attached to said W can additionally be selected from -N=CR6R6 and -NR6R7; or when a W is -O-, -S(O)n-, -NR5- or -CH2O-, then the R2 attached to said W can additionally be
Figure imgf000005_0001
when a W is a direct bond and R1 is other than CF3; then the R2 attached to said W can additionally be selected from OH and halogen; or when a W is a direct bond, then the R2 attached to said W can additionally be selected from O(Y=)P(OR18)2, S(Y=)P(OR1 )2, O-S(O)R18, O-S(O)2R18, O-S(O)2ORl 8 and thiocyanato; each R5 is independently defined as hydrogen, Cj-C4 alkyl or C(=O)R12; each R6 is independently hydrogen; Cj-C alkyl; or phenyl optionally substituted with at least one R13; each R7 is independently hydrogen; C C8 alkyl; or phenyl optionally substituted with at least one R13; or each pair of R6 and R7, when attached to the same nitrogen atom, can independently be taken together as -CH2CH2CH2CH2-, -CH2(CH2)3CH2-, -CH2CH2OCH2CH2-, -CH2CH(CH3)CH2CH(CH3)CH2- or -CH2CH(CH3)OCH(CH3)CH2-; each R8 is independently Cj-Cg alkyl; C alkoxy; C1-C6 haloalkyl; halogen;
C2-C8 alkynyl; C C6 alkylthio; phenyl or phenoxy each optionally substituted with at least one R13; cyano; nitro; Cj-C6 haloalkoxy; Cj-C6 haloalkylthio;
C2-C6 alkenyl; C2-C6 haloalkenyl; acetyl; C(=O)SMe; or N(CrC2 alkyl)2; each R9 is independently methyl, ethyl, methoxy, methylthio, halogen,
C(=O)S(CrC3 alkyl), C(O)NR6R7 or trifluoromethyl; each R10 is independently halogen; each R11 is independently CJ-CJO alkyl substituted with an 8-, 9- or 10-membered fused carbobicyclic or fused heterobicyclic ring; or R1 1 is CJ-CIQ alkyl substituted with a 3-, 4-, 5- or 6-membered heteromonocyclic ring; wherein said heterobicyclic or heteromonocyclic rings contain 1 to 4 heteroatoms independently selected from the group nitrogen, oxygen and sulfur, provided that each heterobicyclic or heteromonocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs, wherein said heterobicyclic or heteromonocyclic ring is bonded to the alkyl group through a carbon atom of the ring, and wherein said carbobicyclic, heterobicyclic or heteromonocyclic ring is optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; each R12 is independently defined as hydrogen, CrC alkyl, Cj-C4 alkoxy or NR6R7; each R13 is independently halogen, CrC4 alkyl, CrC4 alkoxy, CrC4 haloalkyl, nitro or cyano; each R16 is independently hydrogen, halogen, CrC4 alkyl or Cj-Cg haloalkyl; each R17 is independently hydrogen, Cj-C4 alkyl or C Cg haloalkyl; each R18 is CrC6 alkyl, CrC6 haloalkyl or phenyl optionally substituted with R13; R19 is Cl, Br or I; each R20 is independently C alkyl or Cj-C4 haloalkyl; m is 1, 2 or 3; and p is 0, 1 or 2; provided that when W is -O-, -S(O)n- or -NR5-; R2 is other than and CrC10 alkyl
Figure imgf000006_0001
substituted with one or more substituents selected from the group cyano, nitro,
OH, SH, OC(=O)R20, O(Y=)P(OR18)2 or (O=)P(OR1 )2; and R* is other than R17C(=S), Rl8C(=S)X, Rl7XC(=Y), (R17)XC(=Y)X, and CrC10 alkyl substituted with OH, SH, OC(=O)R20 or C(=O)SR6; then R3 is R14; when Rl is R17OC(=O)O, R17OC(=O)S or R17OC(=O)NH; then W is other than -CH2O-, -CH2S(O)n-, -CH2NR5- and a direct bond; and when WR2 is NHCF3, then R1 is other than CrC6 alkyl and C3-C6 cycloalkyl. DETAILS OF THE INVENTION In the above recitations, the term "alkyl", used in compound words such as "alkylthio" or "haloalkyl" includes straight-chain or branched alkyl, such as, methyl, ethyl, «-propyl, /-propyl, or the different butyl, pentyl or hexyl isomers. The term "alkyl", used alone includes straight-chain or branched alkyl, such as, methyl, ethyl, w-propyl, /-propyl, or the different butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl isomers. "Alkenyl" includes straight-chain or branched alkenes such as vinyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl isomers. "Alkenyl" also includes polyenes such as 1 ,2-propadienyl and 2,4-hexadienyl. "Alkynyl" includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl isomers. "Alkynyl" can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl.
"Alkoxy" includes, for example, methoxy, ethoxy, propyloxy, 1-methylethoxy and the different butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, and decyloxy isomers. "Alkoxyalkyl" denotes alkoxy substitution on alkyl. Examples of "alkoxyalkyl" include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. "Alkenyloxy" includes straight-chain or branched alkenyloxy moieties. Examples of "alkenyloxy" include H2C=CHO, H2C=CHCH2O, (CH3)2C=CHCH2O, (CH3)CH=CHCH2O, (CH3)CH=C(CH3)CH2O and CH2=CHCH2CH2O. "Alkynyloxy" includes straight-chain or branched alkynyloxy moieties. Examples of "alkynyloxy" include HC≡CCH2O, CH3C----CCH2O and CH3C≡CCH2CH2O. "Alkoxyalkenyl" denotes alkoxy substitution of alkenyl. "Alkoxyalkenyl" includes straight-chain or branched alkoxyalkenyl moieties. Examples of "alkoxyalkenyl" include (CH3)2CHOCH2CH=CH and CH3OCH2CH=CH. "Alkenyloxyalkyl" denotes alkenyl substitution on oxygen which in turn is substituted on alkyl. Examples "alkenyloxyalkyl" include CH2=CHCH2OCH2 and CH3CH=CHCH2OCH2CH2. "Alkynyloxyalkyl" denotes alkynyl substitution on oxygen which in turn is substituted on alkyl. Examples of "alkynyloxyalkyl" include CH≡CCH2OCH2 and CH3C≡CCH2OCH2CH2. "Alkylthio" includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio, hexylthio, heptylthio and octylthio isomers. "Alkylthioalkyl" denotes alkylthio substitution on alkyl. Examples of "alkylthioalkyl" include CH3SCH2, CH3SCH2CH2, CH3CH2SCH2, CH3CH2CH2CH2SCH2 and CH3CH2SCH2CH2. "Alkenylthioalkyl" denotes alkenyl substitution on sulfur which in turn is substituted on alkyl. Examples of "alkenylthioalkyl" include CH2=CHCH SCH2 and CH3CH=CHCH2SCH2CH2. "Alkylthioalkenyl" denotes alkylthio substitution on alkenyl. Examples of "alkylthioalkenyl" include CH3SCH=CH and CH3CH2SCH=CH. "Alkynylthioalkyl" denotes alkynyl substitution on sulfur which in turn is substituted on alkyl. Examples of "alkynylthioalkyl" include CIfeCCH2SCH2 and CH3C≡CCH2SCH2CH2. Examples of "alkylsulfonyl" include CH3S(O)2, CH3CH2S(O)2, CH3CH2CH2S(O)2, (CH3)2CHS(O)2 and the different butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptasulfonyl and octasulfonyl isomers. "Alkylsulfonylalkyl" denotes alkylsulfonyl substitution on alkyl. Examples of "alkylsulfonylalkyl" include
CH3S(O)2CH2, CH3CH2CH2S(O)2CH2 and (CH3)2CHS(O)2CH2CH2. "Alkenylthio" is defined analogously to the above examples.
"Cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepyl and cyclooctyl. "Cycloalkylalkyl" denotes cycloalkyl substituted on alkyl. Examples of "cycloalkylalkyl" include cyclopropylmethyl, cyclopentylethyl, and other cycloalkyl moieties bonded to straight-chain or branched alkyl groups.
The term "halogen", either alone or in compound words such as "haloalkyl", includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as "haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of "haloalkyl" include F3C, C1CH2, CF3CH2 and CF3CC12. The terms "haloalkenyl", "haloalkynyl", "haloalkoxy" and the like, are defined analogously to the term "haloalkyl". Examples of "haloalkenyl" include (C1)2C=CHCH2 and CF3CH2CH=CHCH2. Examples of "haloalkynyl" include HC≡CCHCl, CF3C≡C, CC13C≡C and FCH2C≡CCH2. Examples of "haloalkoxy" include CF3O, CCl3CH2O, HCF2CH2CH2O and CF3CH2O. Examples of "haloalkylthio" include CC13S, CF3S, CC13CH2S and C1CH2CH2CH2S. Examples of "haloalkylsulfinyl" include CF3S(O), CCl3S(O), CF3CH2S(O) and CF3CF2S(O). Examples of "haloalkylsulfonyl" include CF3S(O)2, CCl3S(O)2, CF3CH2S(O)2 and CF3CF2S(O)2.
"Trialkylsilylalkyl" denotes trialkylsilyl substitution on alkyl. Examples of "trialkylsilylalkyl" include (CH3)3SiCH2, and (CH3)3SiCH2CH3. "Trialkylsilylalkynyl" denotes trialkylsilyl substitution on alkynyl. Examples of "trialkylsilylalkynyl" include (CH3)3SiC≡C and (CH3CH2)SiCH2C≡C.
The total number of carbon atoms in a substituent group is indicated by the "Cj-C;" prefix where i and j are numbers from 1 to 10. For example, Cj-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl.
When a group contains a substituent which can be hydrogen, for example R4 or R7, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
In the above recitations, when a compound of Formula I is comprised of one or more heterocyclic rings, all substituents are attached to these rings through any available carbon or nitrogen by replacement of a hydrogen on said carbon or nitrogen.
Exemplary values of a 8-, 9- or 10-membered fused carbobicyclic or fused heterobicyclic ring, and a 3-, 4-, 5- or 6-membered heteromonocyclic ring wherein said heterobicyclic or heteromonocyclic rings contain 1 to 4 heteroatoms independently selected from the group nitrogen, oxygen and sulfur, provided that each heterobicyclic or heteromonocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs, include the ring systems illustrated in Exhibit 1. As with the carbon atoms in the ring, the nitrogen atoms which require substitution to fill their valence are substituted with hydrogen or with R8, R9 or R10. In the bicyclic ring systems (e.g., Y-66 — Y-90), the R8, R9 and R10 groups may substitute either ring. Although the R8, R9 and/or R10 groups are shown in the structures Y-l to Y-100, it is noted that they do not need to be present since they are optional substituents.
Exhibit 1
Figure imgf000009_0001
Figure imgf000009_0002
Y-6 Y-7 Y-8 Y-9 Y-10
Figure imgf000009_0003
Y-l 2 Y-13 Y-14 -15
Figure imgf000009_0004
Y-20
Figure imgf000010_0001
Figure imgf000010_0002
Y-26 Y-27 Y-28 Y-29 Y-30
Figure imgf000010_0003
Y-31 Y-32 Y-33 Y-34 Y-35
Figure imgf000010_0004
Figure imgf000010_0005
Y-50
Figure imgf000011_0001
Y-56 Y-57 Y-58 Y-59 Y-60
Figure imgf000011_0002
Y-61 Y-62 Y-63 Y-64 Y-65
Figure imgf000011_0003
Y-66 Y-67 Y-68 Y-69
Figure imgf000011_0004
Y- 70 Y-71 Y-72 Y-73
Figure imgf000012_0001
Y-74 Y-75 Y-76 Y-77
Figure imgf000012_0002
Y-78 Y-79 Y-80 Y-81
Figure imgf000012_0003
Figure imgf000012_0006
Y-82 Y-83 Y-84 Y-85
Figure imgf000012_0004
Figure imgf000012_0005
Figure imgf000013_0001
Y-96 Y-97 Y-98 Y-99 Y-l 00
One skilled in the art will appreciate that not all nitrogen containing heterocycles can form N-oxides since the nitrogen requires an available lone pair for oxidation to the oxide; one skilled in the art will recognize those nitrogen containing heterocycles which can form N-oxides. One skilled in the art will also recognize that the N-oxides of compounds of Formula I can be made by oxidizing the corresponding nitrogen compound with a strong oxidizing agent such as wetα-chloroperoxybenzoic acid.
Compounds of Formula I can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
The salts of the compounds of Formula I useful for this invention include acid-addition salts with inorganic or organic acids such as hydrobromic, hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric, lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric, 4-toluenesulfonic or valeric acids. The salts useful for this invention also include those formed with organic bases (e.g., pyridine, ammonia, or triethylamine) or inorganic bases (e.g., hydrides, hydroxides, or carbonates of sodium, potassium, lithium, calcium, magnesium or barium) when the compound contains an acidic group. Accordingly, the present invention comprises the fungicidal use of compounds selected from Formula I, including all geometric and stereoisomers, N-oxides and agriculturally suitable salts thereof. Preferred compounds for use in the method and compositions of this invention for reasons of better activity and/or ease of synthesis are:
Preferred 1. Compounds of Formula I above, and N-oxides and agriculturally suitable salts thereof, wherein: each W is -O-, -S- or -ΝR5-; each Rl is CJ-CIQ alkyl, C4-C10 cycloalkylalkyl or RU; each R2 is Cj-Cio alkyl, C4-C10 cycloalkylalkyl or Rl 1; and R3 is Rl4. Preferred 2. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: each W is -CH2O-, -CH2S(O)n- or -CH2ΝR5-; each Rl is C J-CJQ alkyl, C -Cι0 cycloalkylalkyl or Rl ; and each R2 is CJ-CJQ alkyl, C4-CJO cycloalkylalkyl or R1 1. Preferred 2a. Compounds of Preferred 2 above wherein: R3 is halogen, CrC8 alkyl, C3-C8 cycloalkyl or R14; and
Rl4 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or C C4 haloalkylsulfonyl. Preferred 3. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: each W is a direct bond; each R1 is C Cjo alkyl, C -C10 cycloalkylalkyl or RU; and each R2 is CrCιo alkyl, C4-CJO cycloalkylalkyl,
Figure imgf000014_0001
alkylsulfonylalkyl, CrC10 alkyl substituted with ΝR6R7, cyano, nitro, OH, OC(=O)R20, CO2R6, Rl 1 or phenyl optionally substituted with R8, R9 or Rl°. Preferred 3a. Compounds of Preferred 3 above wherein:
R3 is halogen, CrC8 alkyl, C3-C8 cycloalkyl or R]4; and Rl4 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or C C4 haloalkylsulfonyl. Preferred 4. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein:
W is a direct bond;
Rl is CrCw alkyl, C4-C10 cycloalkylalkyl or RU; R2 is OH or halogen;
R3 is halogen, Cι-C8 alkyl, C3-C8 cycloalkyl or R14; and R14 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or Cj-C haloalkylsulfonyl. Preferred 5. Compounds of Formula I above, N-oxides and agriculturally suitable salts thereof, wherein: R1 and or R2 is substituted C Cjo alkyl (preferably CrC4 alkyl substituted with OH); R3 is halogen, CrC8 alkyl, C3-C8 cycloalkyl or Rϊ4; R4 is hydrogen, Cl, Br or I; and Rl4 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or Cj-C4 haloalkylsulfonyl. Most preferred are compounds selected from the group 2-chloro-6-iodo-3-«-propyl-4(3H)-quinazolinone;
3-(cyclopropylmethyl)-2-(ethoxymethyl)-6-iodo-4(3H)-quinazolinone; and 6-iodo-2-(3-oxetanyloxy)-3-propyl-4(3H)-quinazolinone.
Of note are compounds of Formula I where W is a direct bond and R2 is O(Y=)P(ORl8)2, S(Y=)P(OR18)2, O-S(O)Rl8, O-S(O)2Rl8, O-S(O)2ORl8 or thiocyanato and compounds of Formula I where R2 is CJ-CJQ alkyl substituted with O(Y=)P(ORl 8)2 or (O=)P(ORl8)2. Also of note are compounds of Formula I where R14 is O(Y=)P(ORl8)2; isothiocyanato; aryloxy or arylthio each optionally substituted with R8, optionally substituted with R9 and optionally substituted with Rl°; or C2-alkenyl or C2-alkynyl each substituted with CN, CO2R6 or phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10. Further of note are compounds of Formula I where W is a direct bond, Rl is other than Rl?NΗC(=O)NΗ, CF3 and CrC10 alkyl substituted with CO2H and either R3 or R4 is other than hydrogen where the R2 attached to said W is OH or halogen.
Of note are compounds of Formula I where Rl4 is OH; SH; cyano; CF3SO3, Cj- haloalkylthio; CrC haloalkylsulfinyl; C C4 haloalkylsulfonyl; thiocyanato; C3-C8 trialkylsilyloxy, Rl5OCHR16O; (Rl5O)2CHO; Ri5SS; Rl5SCH(Rl6)S; SF5; Ri7C(=Y); Rl8C(=Y)X; RΪ7XC(=Y); (Rl7)XC(=Y)X; or pyridinyl, furanyl, thienyl, benzofuranyl, benzo[b]thiophenyl or quinolinyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with Rl°; where when W is a direct bond, the R2 attached thereto is other than OH and halogen; where R2 is other than CJ-CJO alkyl substituted with O(Y=)P(OR18)2 or (O=)P(ORl8)2; and/or compounds where W is a direct bond, the R2 attached thereto is other than O(Y=)P(OR18)2, S(Y=)P(ORi )2, O-S(O)Rl8, O-S(O)2R'8, O-S(O)2OR18 and thiocyanato.
The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1-30. The definitions of W, Q, X, Y, R R20, m, n and p in the compounds of Formulae 1-16 below are as defined above in the Summary of the Invention. Compounds of Formulae Ia-Iae are various subsets of the compounds of Formula I, and all substituents for Formulae Ia-Iae are as defined above for Formula I.
The synthesis of compounds of Formula I is described below. First, the synthesis of the quinazolinone ring system is described. In this first section, the groups Rl, WR2, R3, R4 and/or (R]9)p are incorporated into the substrates which are used in the syntheses described therein. Alternatively, the quinazolinone ring system can be prepared using a precursor to these groups, and then the R1, WR2, R3, R4 and/or (R19)p groups can be introduced afterwards. This alternate strategy is outlined in the second section of this synthetic summary.
Synthesis of the Quinazolinone Ring System
Compounds of Formula la, wherein, Q = O and W = O, S or NR5, are preparable by reacting compounds of Formula 1 with the appropriate amines RJ-NH2 (Scheme 1).
Scheme 1
Figure imgf000016_0001
la W = 0, S, NR5 The reaction may be run by treating the compounds 1 with excess amine in hydrocarbon, ethereal, alcoholic or polar aprotic solvents at temperatures ranging from ambient to 150 °C for 0.1 to 72 hours. Workup usually involves removal of reaction solvent in vacuo and, if necessary, purification by silica gel chromatography.
Compounds of Formula 1 are accessible through reaction of the esters 2 with thiophosgene and subsequent treatment with the compounds of formula R2OH, R2SH or
R2NHR5 as illustrated in Scheme 2.
Scheme 2
Figure imgf000016_0002
1
W = 0, S orNR5
Procedures relating to the conversion of compounds 2 to compounds 1 are cited in the art (Pharmazie, (1990), 45, 550; J. Het. Chem., (1982), 19, 1117). Esters of Formula 2 are treated with thiophosgene at temperatures from about -20 to 100 °C for 1 -48 hours in an inert solvent. Often this reaction is performed in a bi-phasic mixture in the presence of an aqueous base (e.g., sodium bicarbonate). The resulting isothiocyanate may be isolated by extraction into a water-immiscible solvent such as methylene chloride, followed by drying of the organic extracts and evaporation under reduced pressure. Alternatively, the isothiocyanate can be combined in situ with compounds of formula R2OH, R2SH or R2NHR5 and stirred at about -20 to 100 °C for 0.1-24 hours. The desired product of Formula 1 can be isolated from the reaction mixture by extraction and purified by silica gel chromatography or recrystallization.
Compounds of Formula lb wherein Q is O and W is either O or a direct bond, are preparable through contact of anthranilic acids 3 with compound of Formula 4a or 4b, respectively (Scheme 3).
Scheme 3
Figure imgf000017_0001
4b lb W = direct bond
The reaction may be carried out in a variety of solvents in the presence of homo/heterogeneous bases at temperatures from ambient to 150 °C for 0.1 to 24 hours. Examples of suitable reaction solvents include hexanes, benzene, dioxane, tetrahydrofuran (THF), lower alkanols, NN-dimethylforamide (DMF) and halocarbon solvents. Suitable bases include potassium carbonate, sodium hydroxide, triethylamine and pyridine. Workup is achieved by removing reaction solvent in vacuo and partitioning the crude residue between dilute aqueous acid and a water-immiscible solvent. The water-immiscible phase is then separated, dried over sodium sulfate (Νa2SO4, anhydrous), concentrated, and purified by crystallization or silica gel chromatography to deliver pure I.
Compounds of Formula 4a and 4b are cited in the art and may be prepared by known means (e.g., J Am. Chem. Soc., (1983), 105, 6985, Org. Prep. Proc. Int., (1992), 24, 147 and J. Het. Chem., (1986), 23, 53). Likewise, anthranilic acids of Formula 3 are well-known and can be prepared by established methods. For example, see March, J., Advanced Organic Chemistry, 3rd edition, John Wiley, New York (1985), p 983 and Pharmazie, (1973), 28, p 433.
Compounds of Formula lb, compounds of Formula I wherein W and Q are each O, can also be made by the method illustrated in Scheme 4.
An anthranilic acid of Formula 3 is condensed with an isothiocyanate of Formula Rl-NCS to form the 2-thioquinazolinone of Formula 5. The condensation is preferably performed in the presence of a base such as triethylamine. S-Methylation of this compound affords the 2-(methylthio)-4(3H)-quinazolinone of Formula Ic.
For the introduction of the R2O group, the 2-(methylthio)-4(3H)-quinazolinone of
Formula Ic is treated with a mixture of a base, for example sodium hydride, in R2OΗ solvent. The reaction mixture is stirred at a temperature from about 0 °C to 120 °C for 1 to
120 hours. The desired 2-R2O quinazolinone can be isolated from the reaction mixture by extraction into a water-immiscible solvent, and purified by chromatography or recrystallization. Synthetic procedures for the preparation of related 4(3H)-quinazolinones are described in U.S. 3,755,582 and incorporated herein by reference.
Scheme 4
Figure imgf000018_0001
Ic
Figure imgf000018_0002
lb
The isothiocyanates of Formula R!-NCS can be prepared from the corresponding amine by treatment with thiophosgene as known in the art. For example, seeJ. Heterocycl. Chem., (1990), 27, 407. Compounds of Formula 5a, a subset of 5 where Q = O and R = H, can be prepared by reacting compounds of Formula 5b with aqueous base (Scheme 5).
Scheme 5
Figure imgf000019_0001
The reaction is run using either aqueous NaOH or KOH at base concentrations ranging from 0.1 - 3 N. The reaction may optionally be conducted in the presence of a co-solvent (e.g., ethanol) at temperatures ranging from ambient to reflux for 0.1 to 24 hours. Workup/purification is achieved by acidifying the crude reaction mixture and isolating the product 5a via suction filtration.
Compounds of Formula 5b are prepared by reacting the anthranilic acids 3 with suitable acyl isothiocyanates in an aprotic solvent such as acetone (Scheme 6).
Scheme 6
Figure imgf000019_0002
5b
The reaction is optionally conducted in the presence of a soluble base such as triethylamine at reflux temperatures for 0.1-24 hours. Upon cooling to ambient temperature, the precipitated product 5b is isolated by suction filtration and utilized without further purification. Analogous procedures are known in the art (Indian J. Chem., (1968), 6, 621 and Ann. Chim. (Rome), (1967), 57, 595).
Synthesis of disulfides of Formula 5c (Scheme 7) can be accomplished from the thiocyanato materials 3a by reaction with isothiocyanates under conditions similar to those described in Scheme 4. Scheme 7
Figure imgf000020_0001
5c
Quinazolinones of Formula Id, compounds of Formula I wherein W is S and Q is O, can be prepared by a modification of the synthesis illustrated in Scheme 4. As illustrated in
Scheme 8, the 2-thiopyrimidinedione of Formula 5 is alkylated with R2-L wherein L is a typical leaving group such as Br, I, CH3SO3 (abbreviated OMs), or (4-CH3-Ph)SO3
(abbreviated OTs) to afford the 2-R2S quinazolinone of Formula Id. One or more equivalents of a base can be used to accelerate the process. Bases such as sodium hydroxide and sodium hydride are suitable.
Scheme 8
Figure imgf000020_0002
5 L = Br, I, OMs, OTs Id Typically, the 2-thiopyrimidinedione is dissolved or dispersed in an inert solvent such as N,N-dimethylformamide and treated with a base at a temperature from about -20 to 60 °C.
The reaction mixture may then be heated to just above ambient temperature to the reflux temperature of the solvent for 0.1 to 24 hours to effect deprotonation. The reaction mixture is cooled and treated with R2-L and stirred for 0.1-24 hours at a temperature from about 20 °C to the reflux temperature of the solvent. The quinazolinone of Formula Id can be isolated by extraction into a water-immiscible solvent, and purified by chromatography or recrystallization.
Compounds of Formula Ie, where W is C(=O)O, can be prepared by contacting compounds of Formula 7 with oxalates of Structure 6 as shown in Scheme 9. Scheme 9
Figure imgf000021_0001
Ie
The reaction may be conducted either neat or in an inert solvent at temperatures ranging from 100 to 250 °C for 1-24 hours. Upon cooling, the reaction mixture is concentrated in vacuo and the crude residue purified by silica gel chromatography to afford Ie. For similar procedures, seeHe v. Chim. Ada, (1968), 69, 1017.
The amides 7 are accessed from isatoic anhydrides of Formula 8 via treatment with amines of structure R!NΗ2 (Scheme 10). Methods for the preparation of isatoic anhydrides are well-known in the literature, as is their conversion to aminobenzamides (see
Synthesis, (1980), 505 andJ. Org. Chem., (1953), 18, 1427).
Scheme 10
Figure imgf000021_0002
Oxalates of Formula 6 are also well known and are either available commercially, or can be prepared using methods familiar to the skilled practitioner.
Fused bicyclic quinazolinones of Formula Ig, compounds of Formula I wherein Q is O and W is S(O) or S(O)2, can be prepared by oxidation of the corresponding -SR2 compound of Formula If using well-known procedures for oxidation of sulfur (Scheme 11). For example, see March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York,
(1985), p 1089.
Scheme 11
oxidation
Figure imgf000021_0003
If
Figure imgf000021_0004
Fused bicyclic quinazolinones of Formula Ih, compounds of Formula I wherein Q is O and W is NR5, can be prepared by the method illustrated in Scheme 12. This method is described in detail in U.S. 3,867,384 and incorporated herein by reference.
Scheme 12
Figure imgf000022_0001
Z = SMe, Cl, Br or I 9 Ih One method of preparation of compounds of Formula Ih is by treatment of a
2-methylthio quinazolinone of Formula 9 (Z = SMe) with an excess of an amine of Formula HNR5R2 at about 150 to 175 °C. A second method is to contact a 2-chloro- quinazolinone of Formula 9 (Z = Cl) with one equivalent of HNR5R2 and one equivalent of an acid scavenger, for example triethylamine, or with two equivalents of HNR5R2, at a temperature between 60 and 120 °C optionally in the presence of a solvent.
The preparation of compounds of quinazolinones wherein Z is SMe is described above and in U.S. 3,755,582. Compounds of Formula 9, wherein Z is halogen, are preparable by established means and are herein cited as fungicides as well. Compounds of Formula 9, wherein Z is Cl, may prepared as described in U.S.3,867,384 from 2-thioquinazolinones via treatment with sulfuryl chloride or phosphorous oxychloride. Phosgene, phosphorous trichloride, phosphorous oxybromide, phosphorous tribromide and diethylamino sulfur trifluoride (DAST), may also be used to access compounds of Formula 9, wherein Z is halogen from 2-thio-quinazolinones of Formula 5. Amines of Formula HNR5R2 are commercially available or can be prepared by well-known methods (March, J. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), p 1153).
In addition to the methods described above, compounds of Formula lb and Id can be prepared by displacement of the 2-chlorine in the appropriate fused quinazolinone, rather than by displacement of the 2-SCH3 group (Scheme 4) or S-alkylation of the thiocarbonyl (Scheme 8). For some compounds of Formula I, one skilled in the art recognizes that certain Rl,
WR2, R3, R4 and/or (R!9)p substituents may be more conveniently introduced after cyclization to form the quinazolinone system. For example, quinazolinones of Formula Ij, a subset of Ih wherein R5 is C(=O)R12, can be prepared by acylation of the corresponding R5 = H precursor of Formula Ii as illustrated in Scheme 13.
Figure imgf000023_0001
Ik The quinazolinones of Formula Ii are treated with an acylating agent of Formula Rl2C(=O)Ll, where Ll is an appropriate leaving group such as chlorine, OC(=O)(Cι-C alkyl) or OC(=O)H. In a similar fashion, compounds of Formula Ik, a subset of Ih where R5 is -C(=O)NHR7, can be prepared by condensing quinazolinones of Formula Ii with isocyanates of Formula R7N=C=O using well-known procedures.
Compounds of Formula Im, wherein Q is O and W is C(=O), are prepared by reaction of compounds of Formula II with a suitable oxidant as illustrated in Scheme 14. Suitable oxidants for this transformation are manganese dioxide (WO 9429267) or
Scheme 14
[oxidize]
Figure imgf000023_0003
Figure imgf000023_0002
DMSO/oxalyl chloride/Et3N (Tetrahedron, (1990), 46, 1295). The oxidations may be conducted in halocarbon solvents at temperatures ranging from -78 °C to 100 °C and the desired product isolated by filtration from the reaction mixture.
The precursors of Formula II may be synthesized from compounds of Formula 10 through contact with aqueous base (Scheme 15) as demonstrated in the art (Tetrahedron, (1990), 46, 1295). The reaction may be conducted using aqueous K2CO3, NaCO3, or NaOH at temperatures of ambient to 50 °C for 0.5-72 hours. The product II can be isolated by extraction of the aqueous reaction mixture with a water-immiscible solvent, followed by drying and concentration of the organic phase in vacuo. Scheme 15
Figure imgf000024_0001
10 II
Compounds of Formula 10 are synthesized by contacting aminobenzamides 7 with acid halides of Formula 1 1, as shown in Scheme 16.
Scheme 16
Figure imgf000024_0002
Aminobenzamides 7 are synthesized as previously described in this document. Acid halides of Formula 11 can be prepared from the corresponding -acetoxy acids by treatment with oxalyl chloride as described in Tetrahedron, (1990), 46, 1295. The requisite α-acetoxy acids are well known and accessible via methods known in the art (e.g., Ber., (1904), 37, 3971 ; J. Org. Chem., (1990), 55, (1928); Tetrahedron Asymmetrie, (1990), 9, 87).
Compounds of Formula Io, wherein Q = O and W = CH2O, CH2S or CH2NR5, can be assembled by reacting halides of Formula In with the nucleophiles R OH, R2SH or R2NHR5
(Scheme 17).
Scheme 17
Figure imgf000024_0003
In Io halo = Cl, Br or l
W = CH20, CH2S or CH2NR5 The reaction may be run in solvents such as DMF, THF, benzene, acetonitrile, or neat at temperatures ranging from ambient to 150 °C. Bases such as potassium carbonate (K2CO3), sodium hydroxide (NaOH), or sodium hydride (NaH) may be employed to facilitate the reaction. Workup is achieved by concentrating the crude reaction mixture in vacuo and partitioning the residue between a water-immiscible solvent and water. Drying and concentration of the water-immiscible phase delivers Io, which may be further purified by recrystallization or column chromatography.
Halides of Formula In can be prepared from aminobenzamides 7 in a manner analogous to that described inJ. Med. Chem., (1979), 22, 95. Reaction of acid halides 12 with the aminobenzamides 7 in acetic acid (HOAc) at temperatures ranging from ambient to reflux for 0.1-24 hours affords the halides In after cooling, concentrating in vacuo, and optional purification via column chromatography and/or recrystallization (Scheme 18).
Scheme 18
Figure imgf000025_0001
The acid halides 12 are either commercially available or preparable using established methods. Aminobenzamides 7 may be accessed as described previously in this document. Quinazolinones of Formula Ip, a subset of I wherein Q = O and R3 = Rl4 = VH, can serve as suitable substrates for the alternative production of compounds such as Iq, Ir and Is (Scheme 19).
Scheme 19
Figure imgf000026_0001
The generation of carbenoid species such as 13 and subsequent reaction with Ip to deliver compounds of Formula Ir can be accomplished by the analogous application of known methods (e.g. J. Het. Chem., (1990), 27, 807). Likewise, established methods can be applied in preparing the acylated/thioacylated materials Ir and Is (see, for example,J Med. Chem., (1985), 28, $16).
The reagents of Formula Rl7XC(=Y)Ll where l is an appropriate leaving group such as chlorine, OC(=O)(CrC4 alkyl) or OC(=O)Η and Formula R17N=C=Y are readily available commercially or via known procedures.
Compounds of Formula Iu, compounds of Formula I wherein Q is S, can be prepared as illustrated in Scheme 20.
Scheme 20
Figure imgf000026_0002
It Iu
Treatment of the quinazolinone of Formula It with phosphorous pentasulfide or Lawesson's reagent [2,4-bis(4-methoxyphenyl)-l ,3-dithia-2,4-diphosphetane-2,4-disulfide] in an inert solvent such as dioxane at a temperature from 0 °C to the reflux temperature of the solvent for 0.1 to 72 hours affords the pyrimidinethione of Formula Iu. This procedure is described in U.S. 3,755,582 and incorporated herein by reference.
Salts of compounds of Formula I can be formed by treating the free base of the corresponding compound with strong acids such as hydrochloric or sulfuric acid. Salts can also be prepared by alkylation of a tertiary amine group in the molecule to form, for example, the trialkylammonium salt. N-Oxides of compounds of Formula I can be made by oxidizing the corresponding reduced nitrogen compound with a strong oxidizing agent such as etα-chloroperoxybenzoic acid. Synthesis of RU Groups
As alluded to above, other compounds of Formula I can be prepared by incorporation of the Rl 1 group after the synthesis of the quinazolinone ring system. A method for preparing the desired R1 group is to form the carbocycle or heterocycle from the quinazolinone wherein Rl = alkenyl or alkynyl, or R2 = alkenyl or alkynyl. Methods for preparing carbocycles or heterocycles from alkenes and alkynes are well-known in the literature.
The method of incorporating R1 1 into the corresponding alkenyl compound is generically illustrated in Scheme 21. The first reaction illustrates the method for preparing
Rl = Rl 1 compounds from the corresponding Rl = alkenyl compound. The second reaction illustrates how the same methodology can be used to prepare the R2 = Rl 1 compounds.
Scheme 21
Figure imgf000027_0001
q = l-8; r = 0-7; r + q = 1- G = a carbocyclic or heterocyclic ring system optionally substituted with R8, R9, and R10
The descriptions below refer to the preparation of the Rl = Rl 1 compounds, although one skilled in the art recognizes that the same procedures can be used to prepare the R2 = R1 materials as well. The starting R1 or R2 alkenes are prepared by the methods described above and illustrated in Schemes 1-7. 3-Membered Ring Heterocycles
Compounds of Formula Iv, compounds of Formula I wherein R is Rl 1 and Rl 1 comprises an epoxide, can be prepared as illustrated in Scheme 22.
Scheme 22
Figure imgf000028_0001
q =. ι-8; r = 0-7; r + q = l-8 Treatment of the alkene of Formula 14 with an oxidizing agent such as -chloroperoxybenzoic acid (MCPBA) in an inert solvent such as methylene chloride affords the epoxide of Formula Iv as described by Schwartz, N., inJ. Org. Chem., (1964), 29, 1976.
Similarly, the aziridines of Formula Iw can be prepared from the alkenes of Formula 14 by condensation with a nitrene as illustrated in Scheme 23 and described in Abramovitch, R. J. Chem. Soc, Chem. Commun., (1972), 1160.
Figure imgf000028_0002
q = l-8; r = 0-7; r + q = 1-
The NH aziridine compound of Formula Ix can be prepared from the corresponding epoxide by contact with sodium azide and triphenylphosphine as illustrated below in Scheme 24 and described by Ittah, Y. in J. Org. Chem. , ( 1978), 43, 4271. The episulfide of Formula Iy can also be prepared from the epoxide using triphenylphosphine sulfide using techniques taught by Chan, T. inJ Am. Chem. Soc, (1972), 94, 2880. Scheme 24
Figure imgf000029_0001
iy
In addition to the methods described above, methods for accessing compounds of Formulae Iv-Iy are taught in Calo, V.,J Chem. Soc, Chem. Commun., (1975), 621; Fujisawa, T., Chem. Lett., (1972), 935; and March, j. Advanced Organic Chemistry; 3rd ed., John Wiley: New York, (1985), p 741. 4-Membered Ring Heterocycles
The synthesis of oxetanes of Formula Iz may be achieved by ring expansion of the corresponding epoxide using dimethyloxosulfonium methylide as illustrated in Scheme 25 and described by J. Okuma inJ Org. Chem., (1983), 48, 5133. In some cases, a mixture of regioisomers will be obtained. Additional methods for preparing oxetanes, as well as other 4-membered ring heterocycles, from an alkene precursor are well-known in the art. For example, see: Buchi, G., J. Am. Chem. Soc, (1954), 76, 4327; and Pifferi, G., J Heterocyclic Chem., (1967), 4, 619.
Scheme 25
Figure imgf000029_0002
q = l-8, r = 0-7; r + q = l -8 lz
5-Memb< ϊϊred Ri ng Heterocycles
Compounds of Formula I wherein RU comprises a 5-membered ring heterocycle can be obtained in a variety of ways. For example, dioxolane compounds can be prepared from the glycol using known methods. A method exemplifying the preparation of the dimethyl - dioxolane is illustrated in Scheme 26 and described by A. Hampton inJ Am. Chem. Soc, (1961), 83, 3640. Scheme 26
Figure imgf000030_0001
15 Iaa q = l-8; r = 0-7; r + q = l-8
Reaction of the glycol of Formula 15 with 7-toluenesulfonic acid (TsOH) and 2,2-dimethoxypropane provides the desired material. The glycol of Formula 15 can be prepared from the alkene of Formula 14 using vicinal bis-hydroxylation reagents such as osmium tetroxide (see Wade, P., Tetrahedron Lett., (1989), 5969).
Some 5-membered ring compounds can be prepared from the alkene of Formula 14 using a 1,3-dipole cyclization. For example, reaction of 14 with bromonitrile oxide produces the dihydroisoxazole of Formula lab as illustrated in Scheme 27 (see Wade, P., in J. Org. Chem., (1990), 55, 3045).
Scheme 27
Figure imgf000030_0002
q -= l-8; r = 0-7; r + q ---- l-8
Cycloaddition of 1,3-dipoles with alkynes are also well-documented in the literature. For example, C. Kashima in Heterocycles, (1979), 12, 1343 teaches the condensation of an alkyne with benzene nitrile oxide to form the isoxazole. A similar process to prepare the isoxazole of Formula lac is illustrated in Scheme 28.
Scheme 28
Figure imgf000030_0003
q = l-8; r = 0-7; r + q = l-8
Many 1,3-dipoles are known to react with alkenes and alkynes of Formulae 14 and 16, respectively, in cycloaddition reactions. Dipoles and methods for generating them are described in 1,3-Dipolar Cycloaddition Reactions, A. Padwa, Ed., Wiley Interscience, NY, 1984, Vols. 1 and 2; and Comprehensive Heterocyclic Chemistry, Katritzky, A., Ed., Pergamon, NY, 1984, Vol. 5, p 143). Examples of known 1,3 dipoles are nitrile ylides, nitrile imines, nitrile sulfides, diazoalkanes, azides, azomethine ylides and nitrones.
One skilled in the art will recognize that the regiochemical outcome of the 1,3-dipolar addition will depend on the structures of both the 1,3-dipole and the dipolarophile. In many instances, a mixture of regioisomers will be obtained which can be separated by chromatography or recrystallization. 6-Membered Ring Heterocycles
Compounds of Formula I wherein R11 comprises a 6-membered ring heterocycle can be prepared from the alkene of Formula 14 by [4+2] cycloaddition with a suitable heterodiene. For example, conditions similar to those described by Krespan, C, inJ Am.
Chem. Soc, (1960), 82, 1515, can be employed to form dithianes of Formula lad as illustrated in Scheme 29.
Scheme 29
Figure imgf000031_0001
q = l-8; r = 0-7; r + q = l-8
As with the aforementioned 1 ,3-dipolar cycloadditions, alkynes can also engage in reactions with heterodiene systems to afford unsaturated ring compounds such as those of
Formula Iae.
Scheme 30
Figure imgf000031_0002
q = l-8; r = 0-7; r + q = l-8 Ia6
Ample literature exists citing various other heterodiene systems which are known to engage alkenes and alkynes of Formulae 14 and 16, respectively, to deliver 6-membered ring heterocyclic adducts. For example, sseHetero Diels-Alder Methodology in Organic Synthesis, Boger, D. and Weinreb, S., Eds., Academic, NY, (1987), pp 167-357; and Contemporary Heterocyclic Chemistry, Newkome, G. and Paudler, W., Wiley Interscience, NY, (1982), p 129. Examples of heterodienes known to undergo cycloaddition reactions are thiophene, furan, α,β-unsaturated aldehydes and ketones, α,β-unsaturated thiocarbonyl compounds, α,β-unsaturated imines, vinyl nitroso species, azoalkenes, acyldiimides, acyl sulfenes, ø-quinones, and thioamide-N-methylium salts.
Again, as in the previously mentioned case of 1 ,3-dipole cycloadditions, the regiochemical course of the [4+2] condensation depends on the structure of the alkene or alkyne and the heterodiene. Both regioisomers are often obtained in which case the desired regioisomer can be isolated by chromatography or recrystallization.
Compounds of Formula Iaf, wherein W is a direct bond and R2 is OH, may be assembled from anthranilic acids of Formula 3 as depicted in Scheme 31.
Scheme 31
Figure imgf000032_0001
Iaf Acids of Formula 3 are optimally reacted with isocyanates of Formula 17 at temperatures from ambient to about 150 °C in the presence of an inert solvent and base, followed by solvent distillation and heating of the subsequent residue to 200-250 °C for about 0.5 to 1 hour. Suitable solvents for this transformation include acetonitrile, DMF, or dioxane. Suitable bases include triethylamine or pyridine. Upon heating of the heat reaction residue for 0.5 hour- 1.0 hour at 200-250 °C, the reaction mass is brought to room temperature, triturated with water and or lower alkanol, and filtered to provide Iaf.
Phosphonates of Formula Iah are accessible by reacting halides of Formula lag with phosphites of Formula 18 (Scheme 32).
Scheme 32
Figure imgf000032_0002
halo = Cl, Br, I Such reactions are well-known in the art and are incorporated herein by reference
(Kaminski, J., J. Med. Chem., (1989), 32, 1686; March, J., Advanced Organic Chem., 3rd ed., John Wiley: New York, (1985), p 848). Compounds of Formula lag are preparable by methods described above in this disclosure. Phosphites of Formula 18 are available commercially, or readily prepared by established means. It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.
One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. IH NMR spectra are reported in ppm downfield from tetramethylsilane; s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets and br s = broad singlet.
EXAMPLE 1 Step A: Preparation of methyl 2-amino-5-iodobenzoate hydrochloride
To a solution of methyl anthranilate (25.0 g, 0.166 mol) in glacial acetic acid (3L) was added a second solution of iodine monochloride (26.82 g, 0.166 mol) in glacial acetic acid (250 mL) over 20-30 minutes. The resulting mixture was stirred at room temperature for 24 hours. The ensuing precipitate was filtered, washed with glacial acetic acid followed by diethyl ether, and dried to provide 43.2 g of the title compound, m.p. 188-192 °C; lH NMR (300 MHz, Me2SO-</6): δ 3.79 (s,3H); 6.67 (d,lH); 7.50 (dd,lH); 7.93 (d,lH). Anal. Calcd. for C8H9NO2ICl: C, 30.65;H, 2.89; N, 4.47; O, 10.21; Cl, 11.31; I, 40.48 Found: C, 31.19; H, 2.85; N, 4.48; O, 10.27; Cl, 11.72; I, 40.15.
A 0.5 g sample of the above hydrochloride salt in dichloromethane (50 mL) was extracted with IN sodium hydroxide (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 0.4 g of the methyl-5-iodoanthranilate, mp 83-85 °C (lit1, mp 83-85 °C); lH NMR (300 MHz, Me2SO- d6): δ 3.79 (s,3H); 6.44 (d,lH); 6.79 (br s,2H); 7.49 (dd,lH); 7.93(d,lH). (U Med. Chem., 1988, 31, 2136 and references therein.)
Step B: Preparation of methyl 5-iodo-2-isothiocyanatobenzoate To methyl 2-amino-5-iodobenzoate hydrochloride (20.0 g, 0.063 mol) obtained above was added toluene (720 mL), water (180 mL), sodium bicarbonate (49 g, 0.583 mol) and thiophosgene (13.2 mL, 0.172 mol). The biphasic mixture was stirred at room temperature for 24 h, diluted with water (400 mL), and the phases separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 21.43 g of the title compound, ]H NMR (300 MHz, CDC13): δ 3.97
(s,lH); 7.02 (d,lH); 7.81 (dd,lH); 8.30 (d,lH). An analytical sample was prepared by taking 0.30 g of the crude material in 1-propanol (5 mL), followed by flie dropwise addition of water. The ensuing solid was filtered to deliver 259 mg of purified 5-iodo-2- isothiocyanatobenzoic acid methyl ester, mp 60-62 °C. Step C: Preparation of methyl 5-iodo-2-[(propoxythioxomethyl)amino]benzoate
To methyl 5-iodo-2-isothiocyanatobenzoate (18.66 g, 0.058 mol) was added 1- propanol (330 mL). The reaction solution was heated to reflux for 24 hours and cooled to room temperature. A 10 mL sample of the reaction mixture was removed and purified by flash chromatography on silica 95:5 v/v hexanes:ethyl acetate to give 0.48 g of the title compound, mp 45-47 °C; !H NMR (300 MHz, CDC13): δ 1.02 (t,3H); 1.84 (m,2H); 3.95
(s,3H); 4.51 (t,2H); 7.81 (m,lH); 8.33 (m,2H), 11.62 (br s,lH); m/e 378 deprotonated parent molecular ion (m e) measured by mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode (APCL). Step D: Preparation of 6-iodo-2-propoxy-4(3H)-quinazolinone Methyl 5-iodo-2-[(propoxythioxomethyl)amino]benzoate (1.0 g, 2.64 mmol) was combined with ammonia-saturated 1-propanol (20 mL) in a lightly-capped nalgene® vessel and stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure to provide 0.93 g of the title compound, mp 213-215 °C; JΗ NMR (300 MHz, CDC13): δ 1.04 (t,3H); 1.83 (m,2H); 4.41 (t,2H); 7.24 (d,lH); 7.92 (dd,lH); 8.51 (d,lH); 9.30 (br s, IH); m/e 331 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+).
EXAMPLE 2 Step A: Preparation of 6-iodo-2H-3 , 1 -benzoxazine-2 A( 1 HVdione A mixture of 2-amino-5-iodobenzoic acid (25 g, 95.05 mmol) and triphosgene (77.1 g,
260.4 mmol) in dioxane (316 mL) was heated to reflux for 8 hours. The resulting solid was filtered and washed with diethyl ether to give 28.1 g of the title compound, JΗ NMR (300 MHz, Me2SO-< 6): δ 6.96 (d,lH); 8.02 (dd,lH); 8.13 (d,lH); 11.82 (br s,lH); m/e 288 deprotonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode (APCL). Step B: Preparation of 2-amino-5-iodo-N-propylbenzamide
Propylamine (1.2 g, 20.3 mmol) and 6-iodo-2H-3,l-benzoxazine-2,4(lH)-dione (5.0 g, 17.3 mmol) were combine in pyridine (85 mL) and stirred at room temperature for 24 hours. The reaction was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200 mL) and 5% hydrochloric acid (200 mL). The phases were separated and the organic phase was washed with IN sodium hydroxide, water, and brine. Drying over anhydrous sodium sulfate and evaporation under reduced pressure afforded 3.9 g of the title compound, JΗ ΝMR (300 MHz, CDC13): δ 0.99 (t,3H); 1.63
(m,2H); 3.35 (m,2H); 5.52 (br s,2H); 5.95 (br s,lH); 6.47 (d,lH); 7.42 (dd,lH); 7.55(d,lH). Step C: Preparation of 2-(chloromethyl)-6-iodo-3-propyl-4(3H)-quinazolinone
To a solution of 2-amino-5-iodo-N-propylbenzamide (2.9 g, 9.54 mmol) in acetic acid (100 mL) was added chloroacetylchloride (3.2 g, 28.48 mmol) dropwise over a 5 minute. period. The reaction mixture was heated to 110 °C for 22 hour, concentrated to 1/4 volume, and added dropwise to 16% sodium hydroxide (100 mL) at -5 to 0 °C. The resulting precipitate was filtered, washed with water, and dried to deliver 2.59 g of the title compound, mp 140-144 °C; lΗ ΝMR (300 MHz, CDC13): δ 1.04 (t,3H); 1.84 (m,2H); 4.14 (t,2H); 4.59 (s,2H); 7.40 (d,lH); 8.03 (dd,lH); 8.62 (dd,lH). Step D: Preparation of 2-(ethoxymethyl)-6-iodo-3 -propyl -4(3H)-quinazolinone
A mixture of 2-(chloromethyl)-6-iodo-3 -propyl -4(3H)-quinazolinone (0.28 g, 0.77 mmol) and a 21% solution of sodium ethoxide/ethanol (0.278 g, 0.86 mmol) were combined in ethanol (7 mL) and stirred at room temperature for 1 hour. N,N- Dimethylformamide (2 mL) was added to the reaction mixture and stirring was continued for 48 hours. The reaction was quenched with 5% hydrochloric acid (1 mL), and concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give 0.37 g of crude product. Flash chromatography on silica using 80:20 v/v hexanes:ethyl acetate as eluent provided 0.20 g of the title compound, mp 99-102 °C; lΗ ΝMR (300 MHz, CDC13): δ 1.02 (t,3H); 1.26 (t,3H); 1.78 (m,2H); 3.64 (q,2H); 4.15 (t,2H), 4.58 (s,2H); 7.42 (d, IH); 7.98 (dd,lH); 8.62(d,lH).
EXAMPLE 3 Preparation of 3.4-dihvdro-4-oxo-2-propoxy-3-propyl-6-quinazolinyl thiocyanate A mixture of 2-amino-5-thiocyanatobenzoic acid (1.1 g, 5.67 mmol), S-methyl O- propyl propylcarbonimidothioate (2.0 g, 11.43 mmol), and triethylamine (0.55 g, 5.61 mmol) in benzene (57 mL) was heated at reflux for 24 hours. Following solvent removal under reduced pressure, the resulting residue was partitioned between dichloromethane (100 mL) and IN hydrochloric acid (100 mL). The organic phase was separated, washed with water and brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded 2.0 g of crude product. Column chromatography on silica gel using 90: 10 v/v hexanes:ethyl acetate as eluent, followed by trituration with hexanes, provided 0.14 g of the title compound, mp 117-120 °C; (300 MHz, CDC13): δ 0.98 (t,3H); 1.07 (t,3H); 1.75
(m,2H); 1.85 (m,2H); 4.05 (t,2H); 4.64 (t,2H); 7.54(d,lH); 7.79 (dd,lH); 8.35 (d,lH); m/e 304 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+).
EXAMPLE 4 Step A: Preparation of 2.3-dihvdro-6-hvdroxy-3-propyl-2-thioxo-4(lH)-quinazolinone
A mixture of 2-amino-5-hydroxybenzoic acid (1.0 g, 6.53 mmol), propyl isothiocyanate (0.63 g, 6.20 mmol), and triethylamine (0.66 g, 6.53 mmol) in ethanol (17 mL) was heated to reflux for 24 hours. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with ethanol followed by hexanes to provide 1.10 g of the title compound, mp 318-323 °C; 1 Η ΝMR (300 MHz, Me2SO-d6): δ 0.90 (t,3H); 1.62 (m,2H); 4.35 (t,2H); 7.22 (dd,lH); 7.28 (m,lH); 7.97 (d,lH); 9.98 (s,lH); 12.80 (s,lH). Step B: Preparation of 6-hvdroxy-3-propyl-2-(propylthio)-4(3H)-quinazolinone
Potassium carbonate (4.68 g, 33.90 mmol), iodopropane (6.6 g, 38.82 mmol) and 2,3- dihydro-6-hydroxy-3-propyl-2-thioxo-4(lH)-quinazolinone (8.0 g, 33.90 mmol) were combined in N,N-dimethylformamide (160 mL) and stirred at room temperature for 4 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the ensuing residue was partitioned between ethyl acetate (400 mL) and water (400 mL). The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was triturated with hexanes to deliver 8.4 g of the title compound, mp 155-157 °C; !Η ΝMR (300 MHz, CDC13): δ 1.05 (m,6H); 1.76 (m,4H); 3.25 (t,2H); 4.10 (t,2H); 7.28 (dd,lH); 7.46 (m,2H); 7.95 (d,lH). Step C: Preparation of 6.6'-[(fluoromethylene)bis(oxy)]bis[3-propyl-2-(propylthio)-
4(3H)-quinazolinone] A mixture of 6-hydroxy-3-propyl-2-(propylthio)-4(3H)-quinazolinone (0.5 g,
1.80 mmol) and potassium carbonate (0.66 g, 4.8 mmol) was combined inN.N- dimethylformamide (10 mL) and stirred at room temperature. A balloon charged with CF2CΗC1 was opened to the reaction mixture and an exotherm (23-30 °C) was observed as the contents of the balloon were consumed. The balloon was recharged several more times and stirring was continued for 48 hours. The reaction mixture was carefully poured into water (50 mL) and extracted twice with diethyl ether (25 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.54 g of a crude mixture. Column chromatography on silica gel (90:10 v/v hexanes:ethyl acetate) provided 0.27 g of 6-(difluoromethoxy)-3-propyl-2-(propylthio)-4(3H)-quinazolinone, mp 61-66 °C; ]Η NMR (300 MHz, CDC13): δ 1.04 (m,6H); 1.81 (m,4H); 3.25 (t,2H); 4.09 (t,2H); 6.59 (t,lH); 7.42 (dd,lH); 7.53(d,lH); 7.88 (d,lH); m/e 329 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+), in addition to 0.08 g of the title compound
6,6'-[(fluoromethylene)bis(oxy)]bis[3-propyl-2-(propylthio)-4(3H)-quinazolinone], mp 125-133 °C; *Η NMR (300 MHz, CDC13): δl .04 (m,12H); 1.81 (m,8H); 3.25 (t,4H); 4.09 (t,4H); 6.71 (d,lH); 7.42 (dd,2H); 7.53(d,2H); 7.88 (d,2H); m/e 587 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+). A 0.08 g sample of 6,6',6' '- [methylidynetris(oxy)]tris[3-propyl-2-(propylthio)-4(3H)-quinazolinone] was also isolated, mp 115-122 °C; lΗ NMR (300 MHz, CDC13): δl .00 (t,9H); 1.08 (t,9H); 1.81 (m,12H); 3.25 (t,6H); 4.09 (t,6H); 6.83 (d,lH); 7.50 (m,6H); 7.90 (m,3H); m/e 845 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+).
EXAMPLE 5 Step A: Preparation of O- 3,4-dihvdro-4-oxo-3-propyl-2-(propylthio)-6-quinazolinyl] dimethylcarbamothioate A mixture of 60% sodium hydride (0.16 g, 4.0 mmol) and N,N-dimethylformamide
(18 mL) was stirred at room temperature for 10 minutes, cooled to 0 °C, and treated with 6-hydroxy-3-propyl-2-(propylthio)-4(3H)-quinazolinone (1.0 g, 3.60 mmol). The reaction mixture was stirred for 10 minutes and a solution of dimethylthiocarbamoyl chloride (0.45 g, 3.64 mmol) in tetrahydrofuran (5 mL) was added over 0.5 minutes. After stirring at 0 °C for 10 minutes and room temperature for 3 h, the reaction mixture was poured into water (200 mL) and extracted with diethyl ether (200 mL). The phases were separated and the aqueous phase was extracted with additional diethyl ether (100 mL). The organic extracts were combined, washed with brine, and dried over anhydrous sodium sulfate. Solvent removal under reduced pressure afforded 1.4 g of crude product. The crude material was recrystallized from hexanes to provide 1.39 g of the title compound, mp 84-87 °C; !Η ΝMR (300 MHz, CDC13): δ 1.05 (m,6H); 1.78 (m,4H); 3.25 (t,2H); 3.38(s,3H); 3.47(s,3H); 4.08 (t,2H); 7.40 (dd,lH); 7.54 (d,lH); 7.83 (d,lH).
Step B: Preparation of S-[3,4-dihvdro-4-oxo-3-propyl-2-rpropylthio)-6-quinazolinyl] dimethylcarbamothioate O-[3,4-dihydro-4-oxo-3-propyl-2-(propylthio)-6-quinazolinyl]dimethylcarbamo-thioate
(5.5 g, 15.07 mmol) was added to diphenyl ether (16.5 mL) at 270 °C. The temperature was raised to 320-330 °C for 3 hours then cooled to room temperature. The reaction mixture was adhered to silica and subjected to flash chromatography (solvent gradient of 95:5 to 80:20 v/v hexanes:ethyl acetate) to provide 3.5 g of the title compound, mp 77-79 °C; !H NMR (300 MHz, CDC13): δ 1.05 (m,6H); 1.78 (m,4H); 3.08 (br m,6H); 3.26 (t,2H); 4.08 (t,2H); 7.54 (d,lH); 7.75 (dd,lH); 8.30 (d,lH).
Step C: Preparation of 6-[(difluoromethyl)thio]-3-propyl-2-(propylthio -4(3H)- quinazolinone
A solution of 1-propanol (0.5 mL) in N,N-dimethylformamide (10 mL) was treated with 60% sodium hydride (0.14 g, 3.5 mmol) and stirred for 20 minutes at room temperature. A solution of S-[3,4-dihydro-4-oxo-3-propyl-2-(propylthio)-6-quinazolinyl] dimethyl- carbamothioate(0.5 g, 1.4 mmol) in N,N-dimethylformamide (1 mL) was added and the resulting mixture was stirred at room temperature for 4 hours. An additional equivalent of sodium propoxide in propanol was added, and stirring was continued for 15 minutes. Potassium carbonate (1.9 g, 13.8 mmol) was added and a balloon charged with CF2CΗC1 was opened to the reaction. The mixture was stirred for 24 hours, carefully poured into water (50 mL) and extracted twice with diethyl ether (25 mL). The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.6 g of crude mixture. Column chromatography on silica using 95:5 v/v hexanes:ethyl acetate as eluent afforded the following compounds (in order of elution): 0.12 g of 6-[(difluoromethyl)thio]-3-propyl-2- (propylthio)-4(3H)-quinazolinone, mp 65-68 °C; !H ΝMR (300 MHz, CDC13): δ 1.05 (m,6H); 1.79 (m,4H); 3.27 (t,2H); 4.10 (t,2H); 6.82 (t,lH); 7.53 (d,lH); 7.80 (dd,lH); 8.42 (d,lH); m/e 345 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+), 0.11 g of 6-[(difluoromethyl)thio]-2-propoxy-3-propyl-4(3H)-quinazolinone, mp 51-55 °C; lH ΝMR (300 MHz, CDC13): δ 0.97 (t,3H); 1.07 (t,3H); 1.75 (m,2H); 1.85 (m,2H); 4.04 (t,2H); 4.46 (t,2H); 6.81 (t,lH); 7.43 (d,lH); 7.78 (dd,lH); 8.40 (d,lH); m/e 329 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+), 0.10 g of 6-[(3,4-dihydro-4-oxo-2-propoxy-3- propyl-6-quinazolinyl)dithio]-3-propyl-2-(propylthio)-4(3H)-quinazolinone, lΗ ΝMR (300 MHz, CDC13): δ 1.04 (m,12H); 1.80 (m,8H); 3.23 (t,2H); 4.03 (m,4H); 4.42 (t,2H); 7.40 (d,lH); 7.43 (d,lH); 7.79 (m,2H); 8.28 (m,2H); m/e 571 protonated parent molecular ion
(m e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+), 0.17 g of 6,6'-dithiobis[2-propoxy-3-propyl-4(3H)- quinazolinone], *Η ΝMR (300 MHz, CDC13): δ 0.98 (t,6H); 1.05 (t,6H); 1.70 (m,4H); 1.81 (m,4H); 4.01 (t,4H); 4.42 (t,4H); 7.40 (d,2H); 7.78 (dd,2H); 8.28 (d,2H); m/e 555 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+), and 0.030 g of 6,6'-[methylenebis(thio)]bis[2-propoxy-3-propyl-4(3H)-quinazolinone], lΗ ΝMR (300 MHz, CDC13): δ 0.98 (t,6H); 1.07 (t,6H); 1.72 (m,4H); 1.85 (m,4H); 4.03 (t,4H); 4.40 (m,6H); 7.38 (d,2H); 7.64 (dd,2H); 8.21 (d,2H); m/e 569 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+).
EXAMPLE 6 Step A: Preparation of 6,6,-dithiobis[2,3-dihydro-3-propyl-2-thioxo-4(lH)- quinazolinonel A mixture of 2-amino-5-thiocyanatobenzoic acid (5.0 g, 25.77 mmol), propyl isothiocyanate (2.47 g, 24.48 mmol), and triethylamine (2.6 g, 25.74 mmol) in ethanol (68 mL) was heated to reflux for 24 hours. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with ethanol followed by hexanes to provide 2.2 g of the title compound, mp >300 °C; !Η NMR (300 MHz, Me2SO-d6): δ 0.89 (t,6H); 1.62 (m,4H); 4.29 (t,4H); 7.40 (d,2H); 7.87 (dd,2H); 7.97 (d,2H); 13.02 (br s,2H); m/e 501 deprotonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the negative ion mode (APCI-).
Step B: Preparation of 6.6'-dithiobis[3-propyl-2-(propylthio)-4(3H)-quinazolinone]
Potassium carbonate (0.60 g, 4.33 mmol), iodopropane (0.81 g, 4.76 mmol) and 6,6'- dithiobis[2,3-dihydro-3-propyl-2-thioxo-4(lH)-quinazolinone] (1.2 g, 2.40 mmol) were combined in NN-dimethylformamide (21 mL) and stirred at room temperature for 24 hours. The reaction mixture was then concentrated to dryness under reduced pressure, and the ensuing residue was partitioned between dichloromethane (150 mL) and water (150mL). The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to deliver 1.4 g of crude product. The crude material was purified by flash chromatography on silica gel using 80:20 v/v hexanes:ethyl acetate as eluent to afford 0.59 g of the title compound, mp 115-119 °C; ]Η ΝMR (300 MHz, CDC13): δ 0.99 (t,6H); 1.07 (t,6H); 1.78 (m,8H); 3.24 (t,4H); 4.06 (t,4H); 7.48 (d,2H); 7.79(dd,2H); 8.29 (d,2H); m/e 587 protonated parent molecular ion (m/e) measured by mass spectrometry using atmospheric pressure chemical ionization in the positive ion mode (APCI+). EXAMPLE 7
Preparation of 2-Chloro-6-iodo-3-»-propyl-4(3H)-quinazolinone
6-Iodo-3«-propyl-2-thio-4(3H)-quinazolinedione (5 g, 0.014 moles, prepared from propyl isothiocyanate in a manner similar to that described in Example 4, Step A using 2-amino-5-iodo benzoic acid in place of 2-amino-5-hydroxybenzoic acid) was slurried in n-propyl acetate and treated with phosgene (2.1 mL, 0.029 mol). The slurry was heated at reflux for 1 hour. The excess phosgene was removed by co-distillation with rø-propyl acetate at atmospheric pressure. The pot residue was then evaporated to dryness under vacuum. In this manner, 4.95 g of the title compound was obtained as a light pink solid, mp 98-100 °C; lU NMR (Me2SO-d6): δ 8.04 (d,lH); 8.16 (dd,lH); 7.31 (d,lH); 4.20 (m,2H); 1.78 (m,2H); 0.97 (t,3H).
EXAMPLE 8 Preparation of 6-iodo-3-/7 -propyl -4(3H)-quinazoline-2,4-dione A mixture of 5.0 g (0.019 moles) 2-amino-5-iodobenzoic acid, 1.9 g (0.012 moles)
Η-propyl isocyanate, and 1.9 g (0.019 moles) triethylamine in 190 mL of acetonitrile was stirred at ambient temperature overnight. An additional 1.9 g (0.012 moles) of «-propyl isocyanate was added and stirring continued at ambient temperature for an additional 72 hours. The reaction was then concentrated by atmospheric pressure distillation to deliver 7.8 g of an oil which solidified upon standing in vacuo. A 3.6 g portion of this crude material was subjected to heating neat at 190 °C for 0.75 hours. The resulting reaction mass was cooled, treated with approximately 20 mL ethanol, agitated, and filtered. The filter cake was subsequently washed with ether and dried to deliver 1.8 g of the title compound, lΗ NMR (300 MHz, Me2SO-d6): δ 0.87 (s,3H); 1.50-1.69 (m,2H); 3.83 (t,2H); 6.99 (d,lH); 7.94 (dd, 1 H); 8.16 (d, 1 H); 11.02 (brs, NH).
By the procedures described herein together with methods known in the art, the following compounds of Tables 1 to 21 can be prepared. The following abbreviations are used in the Tables which follow: 5 = secondary, n - normal, / = iso, c = cyclo, Me = methyl, Et = ethyl, Pr = propyl, z'-Pr = isopropyl, Bu = butyl, Ph = phenyl, OMe = methoxy, OEt = ethoxy, SMe = methylthio, CN = cyano, SCN = thiocyanato, NO2 = nitro, S(O) Me = methylsulfonyl, 2-pyridinyl = 4-C1-2 -thienyl = 5 -benzofuranyl =
Figure imgf000040_0001
5-CF3 -3 -benzofuranyl 2 -furanyl = benzo[b]thiophen-2-yl =
Figure imgf000040_0002
benzo[b]thiophen-3-yl 4-CO2Me-2-quinolinyl 2-thienyl =
O
Figure imgf000040_0003
(4-morpholinyl)methyl = 3-quinolinyl : cyclopropylmethyl =
Figure imgf000041_0001
2-(THF)CH2 = 3-oxetanyl = 3 -furanyl
Figure imgf000041_0002
TABLE 1
Figure imgf000041_0003
Figure imgf000041_0004
TABLE 2 Compounds of Formula I wherein: Q = O, R1 = propyl, W = CH Q, R3 = 6-1, R4 = H, and p = 0.
Figure imgf000041_0005
Figure imgf000042_0001
TABLE 3
Figure imgf000042_0002
Figure imgf000042_0003
Figure imgf000043_0001
TABLE 4
Figure imgf000043_0002
TABLE 5 Compounds of Formula I wherein Q = O, R] = (2-THF)CH2, W = CH20, R3 = 6-1, R4 = H and p = 0.
Figure imgf000043_0003
Figure imgf000044_0001
TABLE 6 Compounds of Formula I wherein: Q = O, R2 = Et, W = CH2Q, R3 = 6-1, R4 = H, p = 0 and R J = Rl 1.
RU R8 R9 R 10
CH2(Y-96)*
(CH2)2CH(CH3)(CH2)2(Y-96) 2-CH3 3-CH3
(CH2)ι0(Y-96) 3-(CH2)5CH3 3-CH3
CH2(Y-97) 1-C6F5 3-CH2CH3
CH2(Y-98)
CH2(Y-99) 3-(4-Me-Ph) 2-OCH3
CH2(Y-100) 2-OCH3
CH2(Y-52)
(CH2)5(Y-52) 3-0(CH2)5CH3
(CH2)2CH(CH3)(CH2)2(Y-52) 4-CN
(CH2)10(Y-93) 3-CF3
CH2(Y-52) 4-(CF2)5CF3 5-F 5-F
CH2(Y-52) 3-C1 4-CF3
CH2(Y-93) 2-C≡CH 4-SCH3
CH2(Y-3)
CH2(Y-3) 4-C≡C(CH2)5CH3 5-1
(CH2)10(Y-4) 4-SCH3 5-C1
CH2(Y-2)
CH2(Y-2) 3-OCF3
CH2(Y-2) 3-0(CF2)5CF3 4-CH3
CH2(Y-1)
CH2(Y-1) 5-C1
(CH2)5(Y-5) 2-Br 4-Br 5-Br
CH2(Y-16) 2-CH3 3-CH2CH3
CH2(Y-15) 3-Br
CH2(Y-15) 3-C(=0)SCH2CH3
CH2(Y-15) 3-C(=0)N(CH3)2
Figure imgf000045_0001
Figure imgf000046_0001
1 Y-l to Y-l 00 are defined in Exhibit 1 of the Summary of the Invention.
TABLE 7 Compounds of Formula I wherein: Q = O, R1 = propyl, W = CH20, R3 = 6-1, R4 = H, p = 0 and R2 = Rl l .
RU R* R9 R 10
CH2(Y-96)*
(CH2)2CH(CH3)(CH2)2(Y-96) 2-CH3 3-CH3
(CH2)ιo(Y-96) 3-(CH2)5CH3 3-CH3
CH2(Y-97) 1-C6F5 3-CH2CH3
CH2(Y-98)
CH2(Y-99) 3-(4-Me-Ph) 2-OCH3
CH2(Y-100) 2-OCH3
CH2(Y-52)
(CH2)5(Y-52) 3-0(CH2)5CH3
(CH2)2CH(CH3)(CH2)2(Y-52) 4-CN
(CH2)10(Y-93) 3-CF3
CH2(Y-52) 4-(CF2)5CF3 5-F 5-F
CH2(Y-52) 3-C1 4-CF3
CH2(Y-93) 2-C≡CH 4-SCH3
CH2(Y-3)
CH2(Y-3) 4-C≡C(CH2)5CH3 5-1
(CH2)10(Y-4) 4-SCH3 5-C1
CH2(Y-2)
CH2(Y-2) 3-OCF3
CH2(Y-2) 3-0(CF2)5CF3 4-CH3
CH2(Y-1)
CH2(Y-1) 5-C1
Figure imgf000047_0001
Figure imgf000048_0001
: Y-l to Y-l 00 are defined in Exhibit 1 of the Summary of the Invention
TABLE 8
Figure imgf000048_0002
TABLE 9
Com ounds of Formula I wherein: = O, Rl = propyl, R3 = 6-1, R4 = H, = 0 and W is a direct bond.
Figure imgf000048_0003
Figure imgf000049_0002
TABLE 10
Figure imgf000049_0001
Figure imgf000050_0001
TABLE 11
Compounds of Formula I wherein: Q = O, W = O, Rl = propyl, R2 = propyl, R4 = H, p = 0 and R3 = = Rl4
R14 R14 R14
6-OH 6-(4-Cl-2-thienyl) 6-SH
6-(5-CF3-3-benzofuranyl) 6-CN 6-(benzo[b]thiophen-2-yl)
6-SCHF2 6-(2-quinolinyl) 6-SCF3
6-(4-C02Me-2-quinolinyl) 6-SOCHF2 6-0(0=)C0Me
6-SOCF3 6-S(0=)COC4H9 6-S02CHF2
6-MeN(0=)COPh 6-S02CF3 6-0(S=)COEt
6-SCN 6-S(S=)COCF3 6-SF5
6-0(0=)CSPr 6-(0=)CMe 6-0(S=)CS(3-ClPh)
6-(S=)CC4H9 6-S(S=)CSC4H9 6-(0=)CPh
6-HN(0=)CSMe 6-0(0=)CMe 6-HN(S=)CSC4F9
6-S(S=)CC4F9 6-(PhN(S=)CO(4-ClPh)) 6-0(S=)CPh
6-0(0=)CNPh(Me) 6-S(0=)C(3-ClPh) 6-0(S=)CNMe2
6-(0=)COMe 6-S(S=)CNMe2 6-(S=)CSC4F9 -S(0=)CNMe2 6-(0=)CSPh 6-0(0=)CNHC4F9
6-(S=)CO(3-ClPh) 6-0(S=)CNHCF3 6-0(0=)CCF3
6-HN(0=)CN(Pr)2 6-HN(0=)CC4F9 6-(i-Pr)N(S=)CNHPh -H (S=)CPh 6-HN(0=)CNH2 6-(0=)CNHMe
6-HN(S=)CNMe2 6-(2-pyridinyl) 6-S(0=)CC3F7 -(3-fiιranyl) 6-OC6H5 6-0(0=)P(OEt)2 -SC6H5 6-0(S=)P(OEt)2 6-C≡CC6H5 -0(0=)P(OMe)2 6-CH=CHCN 6-0(S=)P(OMe)2 -CH=CHC02Me 6-OS02CF3 6-NCS -B(OH)2 TABLE 12
Compounds of Formula I wherein: Q = 0, W = S, Rl = propyl, R2 = propyl, R4 = H, p = 0 and R3 = -= R14
R14 Ell ll
6-OH 6-(4-Cl-2-thienyl) 6-SH
6-(5-CF3-3-benzofuranyl) 6-CN 6-(benzo[b]thiophen-2-yl)
6-SCHF2 6-(2-quinolinyl) 6-SCF3
6-(4-C0 Me-2-quinolinyl) 6-SOCHF2 6-0(O-=)COMe
6-SOCF3 6-S(0=)COC4H9 6-S02CHF2
6-MeN(0=)COPh 6-S02CF3 6-0(S=)C0Et
6-SCN 6-S(S=)COCF3 6-SF5
6-0(0=)CSPr 6-(0=)CMe 6-0(S=)CS(3-ClPh)
6-(S=)CC4H9 6-S(S=)CSC H9 6-(0=)CPh
6-HN(0=)CSMe 6-0(0=)CMe 6-HN(S=)CSC4F9
6-S(S=)CC4F9 6-(PhN(S=)CO(4-ClPh)) 6-0(S=)CPh
6-0(0=)CNPh(Me) 6-S(0=)C(3-Cl-Ph) 6-0(S=)CNMe2
6-(0=)COMe 6-S(S=)CNMe2 6-(S=)CSC4F9
6-S(0=)CNMe2 6-(0=)CSPh 6-0(0=)CNHC4F9
6-(S=)CO(3-Cl-Ph) 6-0(S=)CNHCF3 6-0(0=)CCF3
6-HN(0=)CN(Pr)2 6-HN(0=)CC4F9 6-(i-Pr)N(S=)CNHPh
6-HN(S=)CPh 6-HN(0=)CNH2 6-(0=)CNHMe
6-HN(S=)CNMe2 6-(2-pyridinyl) 6-S(0=)CC3F7
6-(3-furanyl) 6-B(OH)2
TABLE 13
Figure imgf000051_0001
Figure imgf000051_0002
TABLE 14
Figure imgf000052_0001
Figure imgf000052_0004
TABLE 15
Figure imgf000052_0002
Figure imgf000052_0005
TABLE 16
Figure imgf000052_0003
Figure imgf000052_0006
TABLE 17
Figure imgf000053_0001
Figure imgf000053_0003
TABLE 18
Figure imgf000053_0002
Figure imgf000053_0004
TABLE 19
Compounds of Formula I wherein: Q = O, R4 = H and p = 0.
Figure imgf000053_0005
Figure imgf000054_0002
TABLE 20
Figure imgf000054_0001
TABLE 21 Compounds of Formula I wherein: Q = O, W is a direct bond, R2 = Cl and p = 0. i
R1 = CH2CH = CH2> R3 = 6-C1 R4= H
R1 = CH2CH = CH2 R3 = 6-Br R4= H
R1 = CH3, R3 = 6-C1 R4= H
R1 = (CH2)3CH3; R3 = 6-C1 R4= H
R1 = CH2CH2CH3) R3 = 6-C1 R4= H
R1 = CH2CH2CH3; R3 = 6-Br R4= H
Rl = CH2CH2CH3; R3 = 6-1 R4= H Rl = CH2 < ' R3 = 6-I R4= H
R1 = CH2 — < R3 = 6-Br R4= H
R = CH2(2-THF), R3 = 6-1 R = H R1 = CH2(2-THF), R3 = 6-Br R = H
Figure imgf000055_0001
Formulation/Utility
Compounds of Formula I used in this invention will generally be used as a formulation or composition with an agriculturally suitable carrier comprising at least one of a liquid diluent, a solid diluent or a surfactant. The formulation or composition ingredients are selected to be consistent with the physical properties of the active ingredient, mode of application and environmental factors such as soil type, moisture and temperature. Useful formulations include liquids such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions) and the like which optionally can be thickened into gels. Useful formulations further include solids such as dusts, powders, granules, pellets, tablets, films, and the like which can be water-dispersible ("wettable") or water-soluble. Active ingredient can be (micro)encapsulated and further formed into a suspension or solid formulation; alternatively the entire formulation of active ingredient can be encapsulated (or "overcoated"). Encapsulation can control or delay release of the active ingredient.
Sprayable formulations can be extended in suitable media and used at spray volumes from about one to several hundred liters per hectare. High-strength compositions are primarily used as intermediates for further formulation.
The formulations will typically contain effective amounts of active ingredient, diluent and surfactant within the following approximate ranges which add up to 100 percent by weight. Weight Percent
Active
Ingredient Diluent Surfactant
Water-Dispersible and Water-soluble 5-90 0-94 1-15 Granules, Tablets and Powders.
Suspensions, Emulsions, Solutions 5-50 40-95 0-15 (including Emulsifiable Concentrates)
Dusts 1-25 70-99 0-5
Granules and Pellets 0.01-99 5-99.99 0-15
High Strength Compositions 90-99 0-10 0-2
Typical solid diluents are described in Watkins, et al., Handbook of Insecticide Dust Diluents and Carriers, 2nd Ed., Dorland Books, Caldwell, New Jersey. Typical liquid diluents are described in Marsden, Solvents Guide, 2nd Ed., Interscience, New York, 1950. McCutcheon 's Detergents and Emulsiβers Annual, Allured Publ. Corp., Ridgewood, New Jersey, as well as Sisely and Wood, Encyclopedia of Surface Active Agents, Chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended uses. All formulations can contain minor amounts of additives to reduce foam, caking, corrosion, microbiological growth and the like, or thickeners to increase viscosity.
Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, dialkyl sulfosuccinates, alkyl sulfates, alkylbenzene sulfonates, organosilicones, N,N-dialkyltaurates, lignin sulfonates, naphthalene sulfonate formaldehyde condensates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers. Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starch, sugar, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate, and sodium sulfate. Liquid diluents include, for example, water, N,N-dimethylformamide, dimethyl sulfoxide, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffins, alkylbenzenes, alkylnaphthalenes, oils of olive, castor, linseed, tung, sesame, corn, peanut, cotton-seed, soybean, rape-seed and coconut, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, decanol and tetrahydrofurfuryl alcohol.
Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. Dusts and powders can be prepared by blending and, usually, grinding as in a hammer mill or fluid-energy mill. Suspensions are usually prepared by wetmilling; see, for example, U.S. 3,060,084. Granules and pellets can be prepared by spraying the active material upon preformed granular carriers or by agglomeration techniques. See Browning, "Agglomeration", Chemical Engineering, December 4, 1967, pp 141-48, Perry's Chemical Engineer's Handbook, 4th Ed., McGraw-Hill, New York, 1963, pages 8-57 and following, and WO 91/13546. Pellets can be prepared as described in U.S. 4,172,714. Water-dispersible and water-soluble granules can be prepared as taught in U.S. 4,144,050, U.S. 3,920,442 and DE 3,246,493. Tablets can be prepared as taught in U.S. 5,180,587, U.S. 5,232,701 and U.S. 5,208,030. Films can be prepared as taught in GB 2,095,558 and U.S. 3,299,566.
For further information regarding the art of formulation, see U.S. 3,235,361, Col. 6, line 16 through Col. 7, line 19 and Examples 10-41; U.S. 3,309,192, Col. 5, line 43 through Col. 7, line 62 and Examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138-140, 162-164, 166, 167 and 169-182; U.S. 2,891,855, Col. 3, line 66 through Col. 5, line 17 and Examples 1-4; Klingman, Weed Control as a Science, John Wiley and Sons, Inc., New York, 1961, pp 81-96; and Hance et al., Weed Control Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.
In the following Examples, all percentages are by weight and all formulations are prepared in conventional ways. Compound numbers refer to compounds in Index Tables A-C.
Example A Wettable Powder
Compound 25 65.0% dodecylphenol polyethylene glycol ether 2.0% sodium ligninsulfonate 4.0% sodium silicoaluminate 6.0% montmorillonite (calcined) 23.0%.
Example B
Granule Compound 25 10.0% attapulgite granules (low volatile matter,
0.71/0.30 mm; U.S.S. No. 25-50 sieves) 90.0%.
Example C Extruded Pellet Compound 25 25.0% anhydrous sodium sulfate 10.0% crude calcium ligninsulfonate 5.0% sodium alkylnaphthalenesulfonate 1.0% calcium/magnesium bentonite 59.0%. Example D Emulsifiable Concentrate
Compound 25 20.0% blend of oil soluble sulfonates and polyoxyethylene ethers 10.0% isophorone 70.0%.
The compounds of Formula I are useful as plant disease control agents. The present invention therefore further comprises a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof to be protected, or to the plant seed or seedling to be protected, an effective amount of a compound of the invention or a fungicidal composition containing said compound. The compounds and compositions of this invention provide control of diseases caused by a broad spectrum of fungal plant pathogens in the Basidiomycete, Ascomycete, Oomycete and Deuteromycete classes. They are effective in controlling a broad spectrum of plant diseases, particularly foliar pathogens of ornamental, vegetable, field, cereal, and fruit crops. These pathogens include Plasmopara viticola, Phytophthora infestans, Peronospora tabacina, Pseudoperonospora cubensis, Pythium aphanidermatum, Alternaria brassicae, Septoria nodorum, Septoria tritici, Cercosporidium personatum, Cercospora arachidicola, Pseudocercosporella herpotrichoides, Cercospora beticola, Botrytis cinerea, Monilinia fructicola, Pyricularia oryzae, Podosphaera leucotricha, Venturia inaequalis, Erysiphe graminis, Uncinula necatur, Puccinia recondita, Puccinia graminis, Hemileia vastatrix, Puccinia striiformis, Puccinia arachidis, Rhizoctonia solani, Sphaerotheca fuliginea, Fusarium oxysporum, Verticillium dahliae, Pythium aphanidermatum, Phytophthora megasperma, Sclerotinia sclerotiorum, Sclerotium rolfsii, Erysiphe polygon!, Pyrenophora teres, Gaeumannomyces graminis, Rynchosporium secalis, Fusarium roseum, Bremia lactucae and other generea and species closely related to these pathogens.
Compounds of Formula I can also be mixed with one or more other insecticides, fungicides, nematocides, bactericides, acaricides, growth regulators, chemosterilants, semiochemicals, repellents, attractants, pheromones, feeding stimulants or other biologically active compounds to form a multi-component pesticide giving an even broader spectrum of agricultural protection. Examples of such agricultural protectants with which compounds of this invention can be formulated are: insecticides such as abamectin, acephate, azinphos-methyl, bifenthrin, buprofezin, carbofuran, chlorfenapyr, chlorpyrifos, chlorpyrifos-methyl, cyfluthrin, beta-cyfluthrin, cyhalothrin, lambda-cyhalothrin, deltamethrin, diafenthiuron, diazinon, diflubenzuron, dimethoate, esfenvalerate, fenoxycarb, fenpropathrin, fenvalerate, fipronil, flucythrinate, tau-fluvalinate, fonophos, imidacloprid, isofenphos, malathion, metaldehyde, methamidophos, methidathion, methomyl, methoprene, methoxychlor, methyl 7-chloro-2,5-dihydro-2-[[N-(methoxycarbonyl)-N-[4- (trifluoromethoxy)phenyl]amino]carbonyl]indeno[l,2-e][l,3,4]oxadiazine-4a(3H)- carboxylate (DPX-JW062), monocrotophos, oxamyl, parathion, parathion-methyl, permethrin, phorate, phosalone, phosmet, phosphamidon, pirimicarb, profenofos, rotenone, sulprofos, tebufenozide, tefluthrin, terbufos, tetrachlorvinphos, thiodicarb, tralomethrin, trichlorfon and triflumuron; fungicides such as azoxystrobin, benomyl, blasticidin-S,
Bordeaux mixture (tribasic copper sulfate), bromuconazole, captafol, captan, carbendazim, chloroneb, chlorothalonil, copper oxychloride, copper salts, cymoxanil, cyproconazole, cyprodinil (CGA 219417), diclomezine, dicloran, difenoconazole, dimethomorph, diniconazole, diniconazole-M, dodine, edifenphos, epoxiconazole (BAS 480F), famoxadone, fenarimol, fenbuconazole, fenpiclonil, fenpropidin, fenpropimorph, fluazinam, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fosetyl-aluminum, furalaxyl, hexaconazole, ipconazole, iprobenfos, iprodione, isoprothiolane, kasugamycin, kresoxim-methyl, mancozeb, maneb, mepronil, metalaxyl, metconazole, S-methyl 7-benzothiazolecarbothioate (CGA 245704), myclobutanil, neo-asozin (ferric methanearsonate), oxadixyl, penconazole, pencycuron, probenazole, prochloraz, propiconazole, pyrifenox, pyroquilon, quinoxyfen, spiroxamine (KWG4168), sulfur, tebuconazole, tetraconazole, thiabendazole, thiophanate-methyl, thiram, triadimefon, triadimenol, tricyclazole, triticonazole, validamycin and vinclozolin; nematocides such as aldoxycarb and fenamiphos; bactericides such as streptomycin; acaricides such as amitraz, chinomethionat, chlorobenzilate, cyhexatin, dicofol, dienochlor, etoxazole, fenazaquin, fenbutatin oxide, fenpropathrin, fenpyroximate, hexythiazox, propargite, pyridaben and tebufenpyrad; and biological agents such as Bacillus thuringiensis, Bacillus thuringiensis delta endotoxin, baculovirus, and entomopathogenic bacteria, virus and fungi.
In certain instances, combinations with other fungicides having a similar spectrum of control but a different mode of action will be particularly advantageous for resistance management.
Preferred for better control of plant diseases caused by fungal plant pathogens (e.g., lower use rate or broader spectrum of plant pathogens controlled) or resistance management are mixtures of a compound of this invention with a fungicide selected from the group: flusilazole, epoxiconazole, fenpropimorph, fenpropidin, azoxystrobin, kresoxim methyl, benomyl, mancozeb and cymoxanil.
Plant disease control is ordinarily accomplished by applying an effective amount of a compound of this invention either pre- or post-infection, to the portion of the plant to be protected such as the roots, stems, foliage, fruit, seeds, tubers or bulbs, or to the media (soil or sand) in which the plants to be protected are growing. The compounds can also be applied to the seed to protect the seed and seedling.
Rates of application for these compounds can be influenced by many factors of the environment and should be determined under actual use conditions. Foliage can normally be protected when treated at a rate of from less than 1 g/ha to 5,000 g/ha of active ingredient. Seed and seedlings can normally be protected when seed is treated at a rate of from 0.1 to 10 g per kilogram of seed.
The following TESTS demonstrate the control efficacy of compounds of this invention on specific pathogens. The pathogen control protection afforded by the compounds is not limited, however, to these species. See Index Tables A-C for compound descriptions. The following abbreviations are used in the Index Tables which follow: H = hydrogen, O = oxygen, N = nitrogen, S = sulfur, F = fluorine, Cl = chlorine, Br = bromine, I = iodine, Ph = phenyl, OH = hydroxy and SCN = thiocyanato. The abbreviation "d" indicates that the compound appeared to decompose on melting. The abbreviation "Ex." stands for "Example" and is followed by a number indicating in which example the compound is prepared.
INDEX TABLE A
Figure imgf000060_0001
Cmpd El W R2 R3 El mp (°C)
No.
(Ex.)
1 (CH2)2CH3 direct bond (CH2)2CH3 Br H 79-84
3 (CH2)2CH3 S (CH2)2CH3 OH H 155-157
(Ex. 4B)
7 (CH2)2CH3 direct bond (CH2)2CH3 H 95-97
8 (CH2)2CH3 S (CH2)2CH3 SCHF2 H 65-68
(Ex. 5C)
9 (CH2)2CH3 O (CH2)2CH3 SCHF2 H 51-55
(Ex. 5C)
10 (CH2)2CH3 S (CH2)2CH3 OC(=S)N(CH3)2 H 84-87
(Ex. 5A)
11 (CH2)2CH3 s (CH2)2CH3 SC(=0)N(CH3)2 H 77-79
(Ex. 5B)
12 (CH2)3CH3 direct bond CH3 H 71-72 Cmpd El W Ef R3 El mp (°C)
No.
(Ex.)
13 (CH2)2CH3 CH20 CH2CH3 I H 99-102
(Ex. . 2D)
14 (CH2)2CH3 direct bon 1 CH2C1 I H 140-144
15 (CH2)2CH3 CH20 I H 63-66
Figure imgf000061_0001
16 (CH2)2CH3 O (CH2)2CH3 SCN H 117-120
(Ex. 3)
17 (CH2)2CH3 direct bond ' I H 124-127
Figure imgf000061_0002
18 (CH2)2CH3 CH2S02 CH3 I H 193-195
19 (CH2)2CH3 CH2NH (CH2)2CH3 I H oil*
20 CH2— <] CH20 CH2CH3 I H oil*
Figure imgf000061_0003
2 (CH2)2CH3 CH20 CH2 <] I H 74-80
3 CH2-<] direct bond CH2C1 I H 135-138 4 direct bond CH2C1 I H 110-115
Figure imgf000061_0004
5 (CH2)2CH3 O HC — CH2 I H 109-111
H2C 1— O 1
9 (CH2)2CH3 0 (CH2)2CH3 OH H 128-132 2 (CH2)2CH3 OC(=0) 2-NH2-5-I-Ph I H 184- 185 d 4 CH2CH2CH3 O CH2CH2CH3 C02CH3 H 91-93 5 CH2CH=CH2 direct bond OH Cl H 230-232 7 CH2-C≡CH direct bond OH Cl H 242- 245 d 8 CH2CH2CH3 direct bond OH Cl H 240-242 9 CH2CH2CH3 direct bond OH H Me >230* Cmpd El W R R3 El mp (°Q
No.
(Ex.)
50 CH2CH2CH3 direct bond OH Me H >220*
53 CH2CH(CH3)2 direct bond OH Br H 250-253
54 CH2CH2CH3 direct bond OH Br H >210*
55 CH2 direct bond OH Br H 206-208
CH3(CH2)20
56
/ \ direct bond OH Br H 208-211
CH2CH N 0 \ /
57 CH2CH2CH3 direct bond OH H >220*
(Ex. 8)
58 direct bond OH H 195-197
59 direct bond OH H 195-197
60
Figure imgf000062_0001
direct bond Cl Cl H 93-95
61 CH2CH=CH2 direct bond Cl Br H 79-81
62 CH3 direct bond Cl Cl H 152-154
64 (CH2)3CH3 direct bond Cl Cl H 62-64
65 CH2CH2CH3 direct bond Cl Cl H 236-240
66 CH2CH2CH3 direct bond Cl Br H 110-116
67 CH2CH2CH3 direct bond Cl I H 98-100
(Ex. 7)
68 CH2CH2CH3 direct bond Cl I I 170-173
75 CH2CH2CH3 direct bond OH I I >230*
80 CH2Ph direct bond OH Cl H >250*
81 CH2CH2CH3 NHC(=0) CF3 Cl H 172-174
83 CH2CH2CH3 direct bond CH(C02CH3)2 Cl H 138-142
84 CH2CH2CH3 direct bond CH(CN)2 Cl H 256-260 Cmpd Rl W R R3 El mp (°Q No. (Ex.)
85 CH2CH2CH3 direct bond CHCC^O^ Cl H 214-215
CN
86 (CH2)3CH3 direct bond OH Cl Cl 202-205
88 CH2-CH2 direct bond OH Cl H 256-258 / \ CH CH2
CH2 CH2
90 CH2CH=CH2 direct bond OH Br H 231.5- 232.5
91 CH2CH3 direct bond OH Cl H 220-222
93 CH2CH=CH2 direct bond Cl Br H 79-81
94 CH3 direct bond OH Br H >280
95 CH3 direct bond OH Cl H 267-268
96 CH3 direct bond OH I H >300
100 (CH2)3CH3 direct bond OH Cl H 193-195
101 OCH2CH3 direct bond CH2C1 Cl H 156-158
102 CH(CH3)2 direct bond CF3 Cl H 91-93
106 OCH2CH3 direct bond (CH2)3CH3 Br H 86-88
107 OCH2CH3 direct bond CH CH3 Br H 104-107
108 OCH2CH3 direct bond CH2CH2CH3 Br H 83-86
109 OCH2CH3 direct bond Ph Br H 128-130
111 direct bond Cl I I 150-155
Figure imgf000063_0001
112 CH2CH=CH2 NHC(=0) OCH2CH3 Cl H 157-159
113 CH2 <^ direct bond OH I H 261-264
114 CH2CH2CH3 direct bond CH(CH2CH3) H *
115 CH2 <^ direct bond Cl H 235-240
116
Figure imgf000063_0002
117 direct bond OH H 233-235
Figure imgf000063_0003
118 CH2CH2CH3 O CH2CH2CH2OH H 128-130 Cmpd R1 W R2 R3 El mp (°Q
No.
(Ex.)
119 CH2CH(OH)CH3 direct bond OH I H 238-240
120 CH2CH2CH2OH direct bond OH I H 212-215
121 CH2CH2CH3 O CH2CH(OH)CH2OH I H 109-110
122 CH2CH(OH)CH3 0 CH2CH(OH)CH3 I H 137-139
123
Figure imgf000064_0001
124 CH2- ] direct bond Cl I I 235-237
125 CH2CH(OH)CH3 O CH2CH2CH3 I H 103-105
126 CH2CH2CH2OH 0 CH2CH2CH3 I H 78-80
127 CH2CH=CH2 NHC(=0) CH3 Cl H 184- 185.5
128 OC(=0)OCH3 direct bond CH(CH3)2 Cl H 90-93
129 CH2Ph direct bond OH C02CH3 H 100-102
130 CH2CH=CH2 direct bond OH I H 239-240
131 OCH2CH3 direct bond OH Br H 243-245
*See Index Table C for IH NMR data.
INDEX TABLE B
Figure imgf000064_0002
Cmpd
No. W El mp (°C)
(Ex.)
Figure imgf000064_0003
Cmpd
No. W R3 mp(°C)
(Ex.)
Figure imgf000065_0001
Cmpd
No. W R3 mp (°C) (Ex.)
Figure imgf000066_0001
*See Index Table C for ]H NMR data.
INDEX TABLE C
Cmpd No. IH NMR Data (CDC13 solution unless indicated otherwise)3
19 δ 1.00 (t,6H), 1.62 (m,2H). 1.76 (m,2H), 2.20 (br s, IH), 2.72 (t,2H), 3.90 (s,2H), 4.05
(t,2H), 7.38 (d,lH), 7.95 (dd,lH), 8.60 (d,lH) and m/e 386 (APCI) +
20 δ 0.55 (m,4H), 1.25 (m,4H), 3.64 (q,2H), 4.18 (d,2H), 4.63 (s,2H), 7.42 (d,lH), 8.00
(dd,lH), 8.63 (d,lH) and m/e 385 (APCI) +
35 δ 1.04 (m,12H), 1.80 (m,8H), 3.23 (t,2H), 4.03 (m,4H), 4.42 (t,2H), 7.40 (d,lH), 7.43
(d, lH), 7.79 (m,2H), 8.28 (m,2H) and m/e 571 (APCI) +
36 δ 0.98 (t,6H), 1.05 (t,6H), 1.70 (m,4H), 1.81 (m,4H), 4.01 (t,4H), 4.42 (t,4H), 7.40 (d,2H),
7.78 (dd,2H), 8.28 (d,2H) and m/e 555 (APCI) +
37 δ 0.98 (t,6H), 1.07 (t,6H), 1.72 (m,4H), 1.85 (m,4H), 4.03 (t,4H), 4.40 (m,6H), 7.38
(d,2H), 7.64 (dd,2H), 8.21 (d,2H) and m/e 569 (APCI) + 49b δ 0.89 (t,3H); 1.60 (m,2H); 2.35 (s,3H); 3.86 (t,2H); 7.13 (t,lH); 7.51 (d,lH); 7.81 (d,lH),
10.67 (s,lH) 50c δ 0.90 (t,3H); 1.66 (m,2H); 2.38 (s,3H); 3.93 (t,2H); 7.18 (d,lH); 7.49 (d,lH); 7.82 (s,lH)
54b δ 0.90 (t,3H); 1.60 (m,2H); 3.85 (t,2H); 7.14 (d,lH); 7.82 (d,lH); 7.99 (s,lH); 11.58
(MH). 57b δ 0.87 (s,3H); 1.50-1.69 (m,2H), 3.83 (t,2H); 6.99 (d,lH); 7.94 (dd,lH); 8.16 (d, lH) 11.02
(br s,NH) 75b δ 0.85 (t,3H); 1.57 (m,2H); 3.81 (m,2H); 8.13 (d,lH); 8.39 (d,lH); 9.98 (s, lH)
80b δ 5.08 (s,2H), 2-7.4 (m,6H), 7.73 (d, lH), 7.88 (d,lH), 11.64 (s,lH)
114 δ 0.89-0.94(m,6H); 1.03(t,3H); 1.3(m,2H); 1.62-1.98(m,6H); 1.8(m,lH); 4.1(m,2H);
7.36(d, lH); 7.95(dd,2H); 8.58(d,lH)
132 δ 0.99(m,6H); 1.07(t,6H); 1.73(m,4H); 1.85(m,4H); 4.07(t,4H); 4.43(t,4H); 6.70(d, lH); 7.46(m,4H); 7.91(m,2H)
133 δ 0.96(t,9H); 1.08(t,9H); 1.70(m,6H); 1.84(m,6H); 4.04(t,6H); 4.42(t,6H); 6.80(s,lH); 7.44(m,6H); 7.91(m,3H) a iH NMR data are in ppm downfield from tetramethylsilane. Couplings are designated by (s)-singlet,
(d)-doublet, (t)-triplet, (q)-quartet, (m)-multiplet, (dd)-doublet of doublets and (br s)-broad singlet. b *H NMR solvent is Me2S0-rf6. c IH NMR solvent is acetone-rfg.
BIOLOGICAL EXAMPLES OF THE INVENTION Test compounds were first dissolved in acetone in an amount equal to 3% of the final volume and then suspended at a concentration of 200 ppm in purified water containing 250 ppm of the surfactant Trem® 014 (polyhydric alcohol esters). The resulting test suspensions were then used in the following tests. Spraying these 200 ppm test suspensions to the point of run-off on the test plants is the equivalent of a rate of 500 g/ha.
TEST A The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore dust of Erysiphe graminis f. sp. tritici, (the causal agent of wheat powdery mildew) and incubated in a growth chamber at 20°C for 7 days, after which disease ratings were made.
TEST B The test suspension was sprayed to the point of run-off on wheat seedlings. The following day the seedlings were inoculated with a spore suspension of Puccinia recondita (the causal agent of wheat leaf rust) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 6 days, after which disease ratings were made. TEST C
The test suspension was sprayed to the point of run-off on rice seedlings. The following day the seedlings were inoculated with a spore suspension of Pyricularia oryzae (the causal agent of rice blast) and incubated in a saturated atmosphere at 27°C for 24 h, and then moved to a growth chamber at 30°C for 5 days, after which disease ratings were made. TEST D
The test suspension was sprayed to the point of run-off on tomato seedlings. The following day the seedlings were inoculated with a spore suspension of Phytophthora infestans (the causal agent of potato and tomato late blight) and incubated in a saturated atmosphere at 20°C for 24 h, and then moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
TEST E The test suspension was sprayed to the point of run-off on grape seedlings. The following day the seedlings were inoculated with a spore suspension of Plasmopara viticola (the causal agent of grape downy mildew) and incubated in a saturated atmosphere at 20°C for 24 h, moved to a growth chamber at 20°C for 6 days, and then incubated in a saturated atmosphere at 20°C for 24 h, after which disease ratings were made. TEST F The test suspension was sprayed to the point of run-off on cucumber seedlings. The following day the seedlings were inoculated with a spore suspension of Botrytis cinerea (the causal agent of gray mold on many crops) and incubated in a saturated atmosphere at 20°C for 48 h, and moved to a growth chamber at 20°C for 5 days, after which disease ratings were made.
Results for Tests A-F are given in Table A. In the table, a rating of 100 indicates 100% disease control and a rating of 0 indicates no disease control (relative to the controls). A dash (-) indicates no test results. ND indicates disease control not determined due to phytotoxicity.
TABLE A
Cmpd No. Test A Test B Test C Test D Test E Test F
1 100* 20 0 0 - 0
7 100* 0 0 0 - 0
8 53* 93 0 0 - 0
9 83* 0 0 0 - 0
10 0* 85 0 2 - 0
11 86* 0 0 2 - 0
15 63* 67 0 43 - 0
16 95* 0 0 20 - 0
17 95* 27 0 0 - 0
18 0* 0 0 0 - 0
19 95* 0 0 20 - 0
20 93* 28 0 0 - 0
23 84* 68 0 0 - 0
24 0* 86 0 0 - 0
25 100* 0 0 0 - 0
29 40* 68 0 23 - 0
32 98* 0 0 0 - 0
33 ø** 26 0 19 - 0
34 0* 0 0 0 - 0
35 90* 0 0 23 - 0
36 71* 0 0 0 - 0
38 83* 0 0 69 - 0
44 93* 28 0 0 - 0
45 0 6 34 0 0 0
47 0 0 36 0 0 0
48 98 0 0 0 28 0 Cmpd No. Test A Test B Test C Test D Test E Test F
49 55 3 0 0 50 0
50 0 0 0 21 28 0
53 65* 23 0 0 34 0
54 97* 0 0 0 0 0
57 91 - 0 0 - -
58 85*** 0 0 0 - 0
59 59*** 0 0 0 - 0
65 97 0 0 0 0 0
66 99* 58 0 0 99 0
67 99* 0 0 0 - 9
68 98* 0 0 0 - 0
75 99* 28 0 4 - 0
80 0 0 0 22 0 0
83 87 57 0 0 11 0
84 49 59 0 76 92 0
85 0 0 0 0 0 0
86 66 0 0 0 22 50
100 0* 24 0 0 22 71
106 100 0 0 0 - 0
107 96 0 0 0 - 0
108 99 26 0 22 - 0
109 87* 0 0 25 - 0
113 32 0 0 0 - 0
114 97 68 0 18 - 0
117 0 0 0 68 - 0
118 100 26 74 0 - 0
123 98 0 0 0 - 0
124 100* 0 0 68 - 0
125 100*** 0** 0** ø** - 0**
126 100 0 0 60 - 0
130 0 0 0 0 - 0
131 0* 66 0 46 - 0
132 60* 86 0 0 - 86
Sprayed at 10 ppm.

Claims

CLAIMSWhat is claimed is:
1. A method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of a compound of Formula I or an N-oxide or an agriculturally suitable salt thereof:
Figure imgf000070_0001
wherein R3 is Cl, Br, I, CrC8 alkyl, C3-C8 cycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, CrC8 haloalkyl, C3-C8 haloalkenyl, C3-C8 haloalkynyl, Cj-C8 alkoxy, Cι-C8 haloalkoxy, C3-C8 alkenyloxy, C3-C8 alkynyloxy, CrC alkylthio, CrC8 alkylsulfonyl, C^-Cg alkoxyalkyl, C3-C8 trialkylsilyl, ΝR6R7, C5-C8 trialkylsilylalkynyl, R!4 or phenyl optionally substituted with at least one Rl3;
R4 is hydrogen, Cl, Br, I, CrC4 alkyl, CrC haloalkyl, Cj-C4 alkoxy or
Cj-C haloalkoxy; or when R3 and R4 are on adjacent atoms they can be taken together as -OC(Rl6)2O-; Rl4 is B(OH)2; OH; SH; cyano; CF3SO3; CrC4 haloalkylthio; CrC4 haloalkylsulfinyl; C C4 haloalkylsulfonyl; thiocyanato; C3-C8 trialkylsilyloxy,
Rl OCHRl6O; (Ri5O)2CHO; Rl SS; Rl5SCH(Rl6)S; SF5; Rl?C(=Y); Rl 8C(=Y)X; Rl7XC(=Y); (Rl7)XC(=Y)X; O(Y=)P(ORl )2; isothiocyanato; pyridinyl, furanyl, thienyl, benzofuranyl, benzo[b]thiophenyl, aryloxy, arylthio or quinolinyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with Rl°; C2-alkenyl or C2-alkynyl each substituted with
CN, CO2R6 or phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; each R15 is
Figure imgf000070_0002
each W is independently defined as -O-, -S(O)n-, -NR5-, -CH2O-, -CH2S(O)n-, -CH2NR5-, -C(=O)-, -C(=Y)O-, -OC(=Y)-, -OC(=Y)O-, -NHC(=Y)NH-, -NHC(=Y)O-, -OC(=Y)NH-, -C(=Y)NH-, -NHC(=Y)- or a direct bond; the directionality of the W linkage is defined such that the moiety depicted on the left side of the linkage is bonded to the quinazolinone heterocycle and the moiety on the right side is bonded to R ; each n is independently 0, 1 or 2; each Q is independently defined as O or S; each R1 is independently defined as -CJO alkyl; C3-C6 cycloalkyl; C3-C10 alkenyl; 3-Cιø alkynyl; CrC10 haloalkyl; C3-C10 haloalkenyl; C3-C10 haloalkynyl;
C2-C10 alkoxyalkyl; C2-C10 alkylthioalkyl; C2-C10 alkylsulfonylalkyl; C -C10 cycloalkylalkyl; C4-CIQ alkenyloxyalkyl; C4-Cι0 alkynyloxyalkyl; -CJQ alkenylthioalkyl; C -C10 alkynylthioalkyl; -Cjø haloalkoxyalkyl; C4-CJO alkoxyalkenyl; C -Cjø alkylthioalkenyl; C4-C10 trialkylsilylalkyl; Cj-C10 alkoxy; Rl 1; Rl7C(=S); Rl8C(=S)X; Rl7XC(=Y); (Rl7)XC(=Y)X; pyridinyl, furanyl, thienyl, benzofuranyl, benzo[b]thiophenyl or quinolinyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with Rl ; or CrC10 alkyl substituted with NR6R7, nitro, cyano, OH, SH, OC(=O)R20, C(=O)SR6 or phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; each X is independently O, NRΪ7 or S; each Y is independently O or S; each R2 is independently defined as CrC 10 alkyl; C3-C7 cycloalkyl; C3-Cι0 alkenyl; C3-Cιø alkynyl; CJ-CJO haloalkyl; C3-Cι0 haloalkenyl; C3-C10 haloalkynyl; C2-Cιø alkoxyalkyl; C2-C10 alkylthioalkyl; C2-C10 alkylsulfonylalkyl; C4-C10 cycloalkylalkyl; -CJO alkenyloxyalkyl; C -Cjø alkynyloxyalkyl; C -Cι0 alkenylthioalkyl; C -C10 alkynylthioalkyl; -CJO haloalkoxyalkyl; C4-C10 alkoxyalkenyl; C4-C10 alkylthioalkenyl; C4-Cι0 trialkylsilylalkyl; R1 1; phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or Cj-Ciø alkyl substituted with one or more substituents selected from the group NR6R7, cyano, nitro, OH, SH, OC(=O)R20, CO2R6, O(Y=)P(OR18)2, (O=)P(ORl8)2 or phenyl optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or when a W is -NR5-, then the R2 attached to said W can additionally be selected from -OR7; -N=CR6R6; -NR6R7; and pyridinyl, furanyl and thienyl each optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; or when a W is -O-, then the R2 attached to said W can additionally be selected from
-N=CR6R6 and -NR6R7; or when a W is -O-, -S(O)n-, -NR5- or -CH2O-, then the R2 attached to said W can additionally be
Figure imgf000072_0001
; or when a W is a direct bond and R is other than CF3; then the R2 attached to said W can additionally be selected from OH and halogen; or when a W is a direct bond, then the R2 attached to said W can additionally be selected from O(Y=)P(ORl )2, S(Y=)P(ORl )2, O-S(O)R18, O-S(O)2Rl8, O-S(O)2ORl8 and thiocyanato; each R5 is independently defined as hydrogen, Cj-C4 alkyl or C(=O)R12; each R6 is independently hydrogen; Cj-C4 alkyl; or phenyl optionally substituted with at least one Rl3; each R7 is independently hydrogen; Cj-C8 alkyl; or phenyl optionally substituted with at least one RJ3; or each pair of R6 and R7, when attached to the same nitrogen atom, can independently be taken together as -CH2CH2CH2CH2-, -CH2(CH2)3CH2-, -CH2CH2OCH2CH2-, -CH2CH(CH3)CH2CH(CH3)CH2- or -CH2CH(CH3)OCH(CH3)CH2-; each R8 is independently C Cg alkyl; Cj-Cg alkoxy; Cj-Cg haloalkyl; halogen; C2-Cg alkynyl; C Cg alkylthio; phenyl or phenoxy each optionally substituted with at least one Ri3; cyano; nitro; C Cg haloalkoxy; Cj-Cg haloalkylthio; C2-C6 alkenyl; C2-C6 haloalkenyl; acetyl; C(=O)SMe; or N(CrC2 alkyl)2; each R9 is independently methyl, ethyl, methoxy, methylthio, halogen, C(=O)S(CrC3 alkyl), C(O)NR6R7 or trifluoromethyl; each R10 is independently halogen; each R11 is independently CJ-CJQ alkyl substituted with an 8-, 9- or 10-membered fused carbobicyclic or fused heterobicyclic ring; or Rl 1 is CJ-CIQ alkyl substituted with a 3-, 4-, 5- or 6-membered heteromonocyclic ring; wherein said heterobicyclic or heteromonocyclic rings contain 1 to 4 heteroatoms independently selected from the group nitrogen, oxygen and sulfur, provided that each heterobicyclic or heteromonocyclic ring contains no more than 4 nitrogens, no more than 2 oxygens and no more than 2 sulfurs, wherein said heterobicyclic or heteromonocyclic ring is bonded to the alkyl group through a carbon atom of the ring, and wherein said carbobicyclic, heterobicyclic or heteromonocyclic ring is optionally substituted with R8, optionally substituted with R9 and optionally substituted with R10; each Rl is independently defined as hydrogen, Cj-C4 alkyl, CrC4 alkoxy or NR6R7; each Rl3 is independently halogen, Cj-C4 alkyl, Cj-C alkoxy, Cj-C4 haloalkyl, nitro or cyano; each Rl6 is independently hydrogen, halogen, Cι-C4 alkyl or Cj-Cg haloalkyl; each Ri7 is independently hydrogen, C C4 alkyl or Cj-Cg haloalkyl; each Rl8 is C Cg alkyl, C C6 haloalkyl or phenyl optionally substituted with R!3; Rl9 is Cl, Br or I; each R20 is independently Cj-C4 alkyl or C C4 haloalkyl; m is 1, 2 or 3; and p is O, l or 2; provided that when W is -O-, -S(O)n- or -NR5-; R2 is other than and CrC10 alkyl
Figure imgf000073_0001
substituted with one or more substituents selected from the group cyano, nitro, OH, SH, OC(=O)R20, O(Y=)P(ORl8)2 or (O=)P(ORl )2; and Rl is other than Rl7C(=S), Rl8C(=S)X, Rl7XC(=Y), (Rl7)XC(=Y)X, and CrC10 alkyl substituted with OH, SH, OC(=O)R20 or C(=O)SR6; then R3 is R14; when R is R17OC(=O)O, R17OC(=O)S or Rl7OC(=O)NH; then W is other than
-CH2O-, -CH2S(O)n-, -CH2NR5- and a direct bond; and when WR2 is NHCF3, then R1 is other than CrC6 alkyl and C3-C6 cycloalkyl.
2. The method of Claim 1 wherein for said applied compound, each W is -O-, -S- or -NR5-; each R1 is CrC10 alkyl, C4-C10 cycloalkylalkyl or Rπ; each R2 is CJ-CIQ alkyl, C4-Cι0 cycloalkylalkyl or R 1; and R3 is R14.
3. The method of Claim 1 wherein for said applied compound,
W is a direct bond;
Rl is CrC10 alkyl, C4-C10 cycloalkylalkyl or RU; R2 is OH or halogen;
R3 is halogen, CrC8 alkyl, C3-C8 cycloalkyl or R14; and R14 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or Cj-C4 haloalkylsulfonyl.
4. The method of Claim 1 wherein for said applied compound, each W is -CH2O-, -CH2S(O)n- or -CH2NR5-; each Rl is Cj-C10 alkyl, C4-Cj0 cycloalkylalkyl or R1 1; and each R2 is CJ-CJO alkyl, C -C10 cycloalkylalkyl or RU.
5. The method of Claim 1 wherein for said applied compound, each W is a direct bond; each Rl is C]-Cι0 alkyl, C4-CJO cycloalkylalkyl or Rl 1; and each R2 is CJ-CJO alkyl, C4-C10 cycloalkylalkyl, C2-C10 alkylsulfonylalkyl, CrC10 alkyl substituted with NR6R7, cyano, nitro, OH, OC(=O)R20, CO2R6, R11 or phenyl optionally substituted with R8, R9 or Rl°.
6. The method of Claim 4 or Claim 5 wherein for said applied compound,
R3 is halogen, Cj-Cg alkyl, C3-C8 cycloalkyl or Rl4; and Rl4 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or Cj-C haloalkylsulfonyl.
7. The method of Claim 1 wherein for said applied compound,
Rl, R2 or both R1 and R2 are CrC4 alkyl substituted with OH; R3 is halogen, CrC8 alkyl, C3-C8 cycloalkyl or RM; R4 is hydrogen, Cl, Br or I; and Rl4 is OH, SH, cyano, CF3SO3, CrC4 haloalkylthio, CrC4 haloalkylsulfinyl or Cj-C4 haloalkylsulfonyl.
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