Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
  • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
  • C07C257/12—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to hydrogen atoms
• • 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
  • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
  • A01N37/52—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing groups, e.g. carboxylic acid amidines
• • A—HUMAN NECESSITIES
  • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
  • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
  • A01P3/00—Fungicides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
  • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
  • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• Fungicides are compounds of natural or synthetic origin, which act to protect and/or cure plants against damage caused by agriculturally relevant fungi. Generally, no single fungicide is useful in all situations. Consequently, research is ongoing to produce fungicides that may have better performance (e.g., better efficacy at lower use rates), are easier to use, and cost less.
• the present disclosure relates to aryl amidines and their use as fungicides.
• the disclosure also relates to processes for the preparation of these compounds, to agricultural compositions comprising them, and to their use in the treatment and control of fungal diseases or disorders in agriculture.
• the ‘ 131 application” describes a series of fungicidal compounds.
• Three particular compounds disclosed in the ‘ 131 application are 3-(trifluoromethyl)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Example 25), 4- (trifluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Example 27), and 3-(trifluoromethyl)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5- dimethylbenzoate hydrochloride (Example 494), the structures of which are shown below.
• the compounds described in the ‘ 131 application have demonstrated activity against one or more agriculturally relevant fungi, such as Septoria leaf blotch of wheat caused by Zymoseptoria tritici, wheat brown rust caused by Puccinia triticina, Asian soybean rust caused by Phakopsora pachyrhizi, leaf blotch of barley caused by Rhynchosporium secalis, and spot blotch of barley caused by Cochliobolus sativus.
• one or more agriculturally relevant fungi such as Septoria leaf blotch of wheat caused by Zymoseptoria tritici, wheat brown rust caused by Puccinia triticina, Asian soybean rust caused by Phakopsora pachyrhizi, leaf blotch of barley caused by Rhynchosporium secalis, and spot blotch of barley caused by Cochliobolus sativus.
• antifungal compounds that demonstrate an improved fungicidal spectrum of activity and increased fungicidal activity at lower use rates, such as activity against Septoria leaf blotch of wheat caused by Zymoseptoria tritici, net blotch of barley caused by Pyrenophora teres, Ramularia leaf spot of barley caused by Ramularia collo-cygni, leaf blotch of barley caused by Rhynchosporium secalis, sugar beet leaf spot caused by Cercospora beiicola, anthracnose of cucurbits caused by Colletotrichum orbiculare, blast of rice caused by Magnaporthe oryzae, and brown rust of barley caused by Puccinia hordei.
• the present disclosure provides a compound of Formula I:
• Formula I or an acceptable salt, solvate, or hydrate thereof.
• the present disclosure provides a compound of Formula I, wherein the acceptable salts of Formula I include but are not limited to hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, formate, citrate, maleate, oxalate, tartrate, fumarate, benzenesulfonate, /9-toluenesulfonate, succinate, methanesulfonate, L- malate, acetate, benzoate, or 4-hydroxybenzoate.
• the acceptable salts of Formula I include but are not limited to hydrochloride, hydrobromide, sulfate, phosphate, trifluoroacetate, formate, citrate, maleate, oxalate, tartrate, fumarate, benzenesulfonate, /9-toluenesulfonate, succinate, methanesulfonate, L- malate, acetate, benzoate, or 4-hydroxybenzoate.
• the present disclosure provides a compound of Formula I, wherein the acceptable salt is the hydrochloride salt (Formula I-B):
• the present disclosure provides a compound of Formula I as defined herein, or an acceptable salt, solvate, or hydrate thereof, or an agricultural composition as defined herein, for use in the treatment or prevention of fungal diseases or disorders in or on a plant.
• Y et another embodiment of the present disclosure may include a method for the control or prevention of fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one of the compounds described above to at least one of the fungus, a seed, the plant, and an area adjacent to the plant.
• Another embodiment of the present disclosure may include a method for the control or prevention of fungal attack on a plant, the method including the steps of applying a fungicidally effective amount of one of the compounds described above to a growth medium adapted to grow a plant or a seed.
• Another embodiment of the present disclosure is a use of a compound of Formula I, as defined herein, or an acceptable salt, solvate, or hydrate thereof, for protection of a plant against attack by a phytopathogenic organism or the treatment of a plant infested by a phytopathogenic organism, comprising the application of a compound of Formula I, as defined herein, or an acceptable salt, solvate, or hydrate thereof, or a composition comprising the compound to soil, a plant, a part of a plant, foliage, and/or roots.
• composition useful for protecting a plant against attack by a phytopathogenic organism and/or treatment of a plant infested by a phytopathogenic organism comprising a compound of Formula I and a phytologically acceptable carrier material.
• the present disclosure further provides a method of synthesizing a compound of Formula I, or an acceptable salt, solvate, or hydrate thereof, as defined herein.
• the present disclosure provides a compound of Formula I, or an acceptable salt, solvate, or hydrate thereof, obtainable by, or obtained by, or directly obtained by a method of synthesis as defined herein.
• the present compounds have activity against one or more agriculturally relevant fungi, such as early blight of tomato caused by Alternaria solani, grey mold caused by Botrytis cinerea, cucumber powdery mildew caused by Podosphaera xanthii, Cercospora leaf blight caused by Cercospora kikuchii. target spot of soybean caused by Corynespora cassiicola, leaf spot of soybean caused by Septoria glycines, and wheat brown rust caused by Puccinia triticina.
• agriculturally relevant fungi such as early blight of tomato caused by Alternaria solani, grey mold caused by Botrytis cinerea, cucumber powdery mildew caused by Podosphaera xanthii, Cercospora leaf blight caused by Cercospora kikuchii. target spot of soybean caused by Corynespora cassiicola, leaf spot of soybean caused by Septoria glycines, and wheat brown rust caused by Puccinia triti
• ambient temperature and “room temperature” refer to temperatures ranging from about 20 °C to about 24 °C.
• phytoly acceptable carrier refers to a carrier or an excipient that is useful in preparing an agricultural composition and is generally not phytotoxic to valuable crops.
• crystalline refers to a solid state form where the molecules are arranged to form a crystal lattice comprising distinguishable unit cells. A certain crystalline form can be identified by the specific diffraction peaks when subjected to X-ray radiation.
• the ratio of solvent molecules to the compound of Formula I or an acceptable salt thereof may be, but is not limited to, 1 :2, 1 :1, or 2: 1.
• the ratio of water molecules to the compound of Formula I or an acceptable salt or solvate thereof may be, but is not limited to, 1:2 (hemi-hydrate), 1: 1 (monohydrate), 2: 1 (dihydrate).
• reference to the compound of or compounds of Formula I is read as also including all regioisomers, structural isomers, geometrical isomers, rotational isomers, tautomers, and stereoisomers, for example diastereomers, enantiomers, and mixtures thereof.
• the compounds of the disclosure may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage e.g., restriction resulting from the presence of a ring or a double bond. Accordingly, any cis! trans and E/Z isomers are expressly included in the present disclosure.
• linkages e.g., carbon-carbon bonds
• the compounds of the disclosure may also be present in multiple tautomeric forms. Where one or more tautomeric forms exist, the disclosure expressly includes all such tautomeric forms of the compounds described herein, even though only a single tautomeric form may be represented.
• the compounds of the present disclosure may exist in an amorphous solid form or as an oil. [0030] The compounds of the present disclosure may exist in one or more crystalline or polymorphic forms. All crystalline forms and polymorphs of the compounds of the disclosure are expressly included in the present disclosure.
• the present disclosure provides a crystalline form of 4- (difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I).
• the crystalline form of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate is an anhydrous and solvent-free crystalline polymorph form.
• the crystalline form is crystalline polymorph Form A (referred to herein as Form A) of Formula I.
• the present disclosure provides one or more crystalline forms of 4-(difluoromethoxy)benzyl 4-(((ethyl(methyl)arnino)methylene)amino)-2,5- dimethylbenzoate hydrochloride (Formula I-B).
• the one or more crystalline forms are crystalline polymorph Forms 1, 2, and 3 (individually referred to herein as Form 1, Form 2, and Form 3, respectively) of Formula I-B.
• the crystalline polymorph Form 1 of 4- (difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride is a hemi-hydrate crystalline polymorph form.
• the crystalline polymorph Form 2 and Form 3 of 4- (difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride are anhydrous and solvent-free crystalline polymorph forms.
• FIG. 1 is a graph showing the combined biological efficacy in a greenhouse study against Septoria leaf blotch caused by Zymoseptoria tritici.
• FIG. 2 is a graph showing the biological efficacy in a cross-trial analysis of replicated field trials in three geographic locations against Septoria leaf blotch caused by Zymoseptoria tritici.
• FIG. 3 is a graph showing the biological efficacy in a cross-trial analysis of replicated field trials in three geographic locations against net blotch of barley caused by Pyrenophora teres.
• FIG. 4 is a graph showing the biological efficacy in a cross-trial analysis of replicated field trials in three geographic locations against Ramularia leaf spot of barley caused by Ramularia collo-cygni.
• FIG. 5 is a graph showing the biological efficacy in a cross-trial analysis of replicated field trials in three geographic locations against leaf blotch of barley caused by Rhynchosporium secalis.
• FIG. 6 is a graph showing the biological efficacy in a cross-trial analysis of replicated field trials in three geographic locations against brown rust of barley caused by Puccinia hordei.
• FIG. 7 shows a powder X-ray diffraction pattern of 4-(difluorom ethoxy )benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I), Form A (solvent- free and anhydrous), as prepared in Example 12 of the present disclosure.
• FIG. 8 shows a powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B), Form 1 (hemi -hydrate), as prepared in Example 17 of the present disclosure.
• FIG. 9 shows a powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B), Form 2 (solvent-free and anhydrous), as prepared in Example 19 of the present disclosure.
• FIG. 10 shows a powder X-ray diffraction pattern of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B, solvent-free and anhydrous), Form 3, as prepared in Example 24 of the present disclosure.
• the compounds of the present disclosure may be applied by any of a variety of known techniques, either as the compounds or as formulations comprising the compounds.
• the compounds may be applied to the roots or foliage of plants for the control of various fungi, without damaging the commercial value of the plants.
• the materials may be applied in the form of any of the generally used formulation types, for example, as solutions, dusts, wettable powders, flowable concentrates, or emulsifiable concentrates.
• the compounds of the present disclosure are applied in the form of a formulation, comprising one of the compounds of Formula I with a phytologically acceptable carrier.
• Concentrated formulations may be dispersed in water, or other liquids, for application, or formulations may be dust-like or granular, which may then be applied as is by the end user.
• the formulations can be prepared according to procedures that are conventional in the agricultural chemical art.
• the present disclosure contemplates all vehicles by which one of the compounds may be formulated for delivery and used as a fungicide.
• formulations are applied as aqueous suspensions or emulsions.
• Such suspensions or emulsions may be produced from water- soluble, water-suspendible, or emulsifiable formulations which are solids, usually known as wettable powders; or liquids, usually known as emulsifiable concentrates, aqueous suspensions, or suspension concentrates.
• the compounds of the present disclosure may be added to any material, provided the material yields the desired utility without significant interference to the activity of these compounds as antifungal agents.
• Wettable powders which may be compacted to form water-dispersible granules, comprise an intimate mixture of one of the compounds of Formula I, an inert carrier, and optional additives such as surfactants.
• concentration of the compound of Formula I in the wettable powder may be from about 10 percent to about 90 percent by weight based on the total weight of the wettable powder, more preferably about 25 weight percent to about 75 weight percent.
• Emulsifiable concentrates comprise an active ingredient, such as the compounds of Formula I, dissolved in an inert carrier, which is either a water-miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers.
• Emulsifiable concentrates may comprise a convenient concentration, such as from about 1 weight percent to about 50 weight percent of the compound of Formula I, based on the total weight of the concentrate.
• the emulsifiable concentrates may be diluted with water to form spray mixtures in the form of oil-in-water emulsions.
• Emulsifiers which may be advantageously employed herein may be readily determined by those skilled in the art and include various nonionic, anionic, cationic and amphoteric emulsifiers, or a blend of two or more emulsifiers.
• nonionic emulsifiers useful in preparing the emulsifiable concentrates include the polyalkylene glycol ethers and condensation products of alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or fatty acids with ethylene oxide, propylene oxides such as the ethoxylated alkyl phenols and carboxylic esters solubilized with the polyol or polyoxyalkylene.
• Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts.
• Anionic emulsifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulfonic acids, oil-soluble salts or sulfated polyglycol ethers and appropriate salts of phosphated-polyglycol ether.
• Representative organic liquids which may be employed in preparing the emulsifiable concentrates of the compounds of the present disclosure are the aromatic liquids such as xylene, propyl benzene fractions, or mixed naphthalene fractions; substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dimethyl amides of fatty glycols and glycol derivatives such as the //-butyl ether, ethyl ether or methyl ether of diethylene glycol or the methyl ether of triethylene glycol; petroleum fractions or hydrocarbons such as mineral oil, aromatic solvents, paraffinic oils, and the like; terpenic solvents, including rosin derivatives; aliphatic ketones, such as cyclohexanone; complex alcohols, such as 2-ethoxy ethanol; vegetable oils such as soybean oil, rapeseed oil, olive oil, castor oil, sunflower seed oil, coconut oil
• Organic liquids include xylene, and propyl benzene fractions, with xylene being most preferred in some cases.
• Surface-active dispersing agents are typically employed in liquid formulations and in an amount of from 0.1 to 20 percent by weight based on the combined weight of the dispersing agent with one of the compounds.
• the formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.
• Aqueous suspensions comprise finely divided solids or powders of a water-insoluble active ingredient, such as a compound of Formula I, dispersed in an aqueous carrier at a concentration in the range from about 1 to about 50 weight percent, based on the total weight of the aqueous suspension.
• Suspensions are prepared by finely grinding the compound, and vigorously mixing the ground material into a carrier comprising water and surfactants chosen from the same types discussed above.
• Other components such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous carrier.
• the compounds of Formula I can also be applied as granular formulations, which are particularly useful for applications to the soil.
• Granular formulations generally contain from about 0.5 to about 10 weight percent of the active ingredient, based on the total weight of the granular formulation, dispersed in an inert solid carrier which consists entirely or in large part of coarsely divided inert material such as attapulgite, bentonite, diatomite, clay or a similar inexpensive substance.
• Such formulations may be prepared by dissolving the compounds in a suitable solvent and applying it to the solid carrier which has been preformed to the appropriate particle size, e.g., in the range of from about 0.5 to about 3 millimeters (mm).
• a suitable solvent is a solvent in which the compound is substantially or completely soluble.
• Such formulations may also be prepared by making a dough or paste of the carrier and the compound with a solvent, and crushing and drying the dough or paste to obtain the desired granular particle.
• Such formulations may also be prepared by making a dough or paste of the carrier and the compound with a solvent, then extruding the dough or paste to form granules of the formulation.
• Dusts containing the compounds of Formula I may be prepared by intimately mixing one of the compounds in powdered form with a suitable dusty agricultural carrier, such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.
• a suitable dusty agricultural carrier such as, for example, kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1 to about 10 weight percent of the compounds, based on the total weight of the dust.
• the formulations may additionally contain adjuvant surfactants to enhance deposition, wetting, and penetration of the compounds onto the target crop and organism.
• adjuvant surfactants may optionally be employed as a component of the formulation or as a tank mix.
• the amount of adjuvant surfactant will typically vary from 0.01 to 1.0 percent by volume, based on a spray-volume of water, preferably 0.05 to 0.5 volume percent.
• Suitable adjuvant surfactants include, but are not limited to ethoxylated nonyl phenols, ethoxylated synthetic or natural alcohols, salts or the esters of sulfosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines, blends of surfactants with mineral or vegetable oils, crop oil concentrate (mineral oil (85%) + emulsifiers (15%)); nonylphenol ethoxylate; benzylcocoalkyldimethyl quaternary ammonium salt; blend of petroleum hydrocarbon, alkyl esters, organic acid, and anionic surfactant; C9- Cn alkylpolyglycoside; phosphated alcohol ethoxylate; natural primary alcohol (C12- Cie) ethoxylate; di-sec-butylphenol EO-PO block copolymer; polysiloxane-methyl cap; nonylphenol ethoxylate + urea ammonium
• Another embodiment of the present disclosure is a method for the control or prevention of fungal attack.
• This method comprises applying to the soil, plant, roots, foliage, or locus of the fungus, or to a locus in which the infestation is to be prevented (for example applying to cereal or grape plants), a fungicidally effective amount of one of the compounds of Formula I.
• the compounds are suitable for treatment of various plants at fungicidal levels, while exhibiting low phytotoxicity.
• the compounds may be useful both in a protectant and/or an eradicant fashion.
• the compounds of Formula I have broad ranges of activity against fungal pathogens.
• exemplary pathogens may include, but are not limited to, the causative agent of Septoria leaf blotch of wheat (Zymoseptoria ulcerici), spot blotch of barley (Cochliobolus sativus), wheat brown rust (Puccinia triticina), wheat stripe rust (Piiccinia striiformis) blister smut of maize (Ustilago maydis), powdery mildew of grapevine (Uncinula needier), leaf blotch of barley (Rhynchosporium secalis), blast of rice (Magnaporthe oryzae), Asian soybean rust (Phakopsora pachyrhizi), glume blotch of wheat (Parastagonospora nodorum), anthracnose of cucurbits (Colletotrichum orbiculare), brown rust of barley Puccinia hordei),
• the exact amount of the active material to be applied is dependent not only on the specific active material being applied, but also on the particular action desired, the fungal species to be controlled, and the stage of growth thereof, as well as the part of the plant or other product to be contacted with the active material. Thus, all the compounds, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.
• the compounds of Formula I are effective in use with plants in a disease-inhibiting and phytologically acceptable amount.
• the terms "disease-inhibiting amount” or " phytologically acceptable amount” refer to an amount of a compound that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. This amount will generally be from about 0.1 to about 1000 ppm (parts per million), with 1 to 500 ppm being preferred. The exact concentration of compound required varies with the fungal disease to be controlled, the type of formulation employed, the method of application, the particular plant species, climate conditions, and the like.
• a suitable application rate is typically in the range from about 0.10 to about 4 pounds per acre (about 0.01 to 0.45 grams per square meter, g/m 2 ).
• Crystalline forms disclosed herein may be prepared using a number of different solvents and solvent mixtures from solvent classes such as alcohols, ketones, esters, ethers, hydrocarbons, polar aprotic solvents, and water.
• solvent classes such as alcohols, ketones, esters, ethers, hydrocarbons, polar aprotic solvents, and water.
• crystalline Form A of Formula I may be prepared using ethyl acetate.
• crystalline Form 2 of Formula I-B may be prepared using a number of different solvents, including but not limited to isopropyl alcohol, methyl isobutyl ketone, methyl ethyl ketone, heptane, 2-methyl tetrahydrofuran, methyl tert-butyl ether, and mixtures thereof.
• crystalline Form 3 of Formula I-B may be prepared using a number of different solvents, including but not limited to ethyl acetate, tetrahydrofuran, methyl isobutyl ketone, acetone, methyl tert-butyl ether, and mixtures thereof.
• polymorph Form A (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I), polymorph Form A, has been prepared according to the methods described herein.
• the powder X-ray diffraction (PXRD) pattern of polymorph Form A is shown in FIG. 7, with corresponding tabulated data shown in Table A.
• the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.5 ⁇ 0.1, 5.6 ⁇ 0.1, 11.1 ⁇ 0.1, 12.4 ⁇ 0.1, 14.2 ⁇ 0.1, 15.1 ⁇ 0.1, 15.2 ⁇ 0.1, 16.1 ⁇ 0.1, 16.7 ⁇ 0.1, 17.6 ⁇ 0.1, 18.3 ⁇ 0.1, 18.8 ⁇ 0.1, 19.2 ⁇ 0.1,
• the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (29) as provided in the above embodiments. It will be appreciated that the diffraction angles (29) provided in Table A are within the experimental error of the values provided above and also referred to in the present disclosure.
• the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising a peak at diffraction angle (29) of 23.3 ⁇ 0.2. In a further embodiment, the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising peaks at diffraction angles (29) of 12.4 ⁇ 0.2 and 23.3 ⁇ 0.2. In a further embodiment, the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising peaks at diffraction angles (26) of 12.4 ⁇ 0.2, 23.3 ⁇ 0.2, and 27.1 ⁇ 0.2.
• the crystalline polymorph Form A of Formula I has a powder X- ray diffraction pattern comprising peaks at diffraction angles (29) of 12.4 ⁇ 0.2, 21.6 ⁇ 0.2, 23.3 ⁇ 0.2, and 27.1 ⁇ 0.2.
• the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising peaks at diffraction angles (29) of 5.5 ⁇ 0.2, 12.4 ⁇ 0.2, 21.6 ⁇ 0.2, 23.3 ⁇ 0.2, and 27.1 ⁇ 0.2.
• the crystalline polymorph Form A of Formula I has a powder X-ray diffraction pattern comprising peaks at diffraction angles (29) essentially the same as shown in FIG. 7.
• a unique physical form of 4-(difluorom ethoxy )benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B), polymorph Form 1, has been prepared according to the methods described herein.
• the powder X-ray diffraction (PXRD) pattern of polymorph Form 1 is shown in FIG. 8, with corresponding tabulated data shown in Table B.
• the crystalline polymorph Form 1 of Formula I-B has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.9 ⁇ 0.2, 9.4 ⁇ 0.2, 10.5 ⁇ 0.2, 12.1 ⁇ 0.2, 12.6 ⁇ 0.2, 13.8 ⁇ 0.2, 15.1 ⁇ 0.2, 15.8 ⁇ 0.2, 16.9 ⁇ 0.2, 18.0 ⁇ 0.2, 18.7 ⁇ 0.2, 20.6 ⁇ 0.2, 21.1 ⁇ 0.2, 21.9 ⁇ 0.2, 23.0 ⁇ 0.2, 23.6 ⁇ 0.2, 24.8 ⁇ 0.2, 25.3 ⁇ 0.2, 25.9 ⁇ 0.2, 26.7 ⁇ 0.2, 27.4 ⁇ 0.2, 28.9 ⁇ 0.2, 29.7 ⁇ 0.2, 30.3 ⁇ 0.2, 30.8 ⁇ 0.2, 31.6 ⁇ 0.2, and 33.8 ⁇ 0.2.
• the crystalline polymorph Form 1 of Formula I-B has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table B are within the experimental error of the values provided above and also referred to in the present disclosure.
• the crystalline polymorph Form 1 of Formula I-B has a powder X-ray diffraction pattern comprising a peak at diffraction angle (29) of 23.6 ⁇ 0.2.
• the crystalline polymorph Form 1 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 12.1 ⁇ 0.2 and 23.6 ⁇ 0.2.
• the crystalline polymorph Form 1 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (26) of 12.1 ⁇ 0.2, 18.7 ⁇ 0.2, and 23.6 ⁇ 0.2.
• the crystalline polymorph Form 1 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 8.
• the crystalline polymorph Form 2 of Formula I-B has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.9 ⁇ 0.1, 9.6 ⁇ 0.1, 12.2 ⁇ 0.1, 12.8 ⁇ 0.1, 12.9 ⁇ 0.1, 13.4 ⁇ 0.1, 14.3 ⁇ 0.1, 14.9 ⁇ 0.1, 14.9 ⁇ 0.1, 16.1 ⁇ 0.1, 17.0 ⁇ 0.1, 17.5 ⁇ 0.1,
• the crystalline polymorph Form 2 of Formula I-B has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table C are within the experimental error of the values provided above and also referred to in the present disclosure.
• the crystalline polymorph Form 2 of Formula I-B has a powder X- ray diffraction pattern comprising peaks at diffraction angles (20) of 4.9 ⁇ 0.2, 9.6 ⁇ 0.2, 21.6 ⁇ 0.2, and 24.5 ⁇ 0.2.
• the crystalline polymorph Form 2 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.9 ⁇ 0.2,
• the crystalline polymorph Form 2 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 9.
• the crystalline polymorph Form 3 of Formula I-B has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.7 ⁇ 0.2, 4.7 ⁇ 0.2, 9.4 ⁇ 0.2, 12.8 ⁇ 0.2, 12.9 ⁇ 0.2, 13.5 ⁇ 0.2, 14.1 ⁇ 0.2, 14.4 ⁇ 0.2, 15.8 ⁇ 0.2, 16.5 ⁇ 0.2, 17.2 ⁇ 0.2, 17.9 ⁇ 0.2, 19.0 ⁇ 0.2, 20.3 ⁇ 0.2, 21.1 ⁇ 0.2, 22.3 ⁇ 0.2, 22.7 ⁇ 0.2, 23.3 ⁇ 0.2, 24.7 ⁇ 0.2, 25.1 ⁇ 0.2, 25.7 ⁇ 0.2, 26.9 ⁇ 0.2, 27.4 ⁇ 0.2, 28.0 ⁇ 0.2, 29.2 ⁇ 0.2, 29.8 ⁇ 0.2, 30.2 ⁇ 0.2, 30.8 ⁇ 0.2, 33.4 ⁇ 0.2,
• the crystalline polymorph Form 3 of Formula I-B has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (29) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table D are within the experimental error of the values provided above and also referred to in the present disclosure.
• the crystalline polymorph Form 3 of Formula I-B has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 9.4 ⁇ 0.2. In a further embodiment, the crystalline polymorph Form 3 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.7 ⁇ 0.2 and 9.4 ⁇ 0.2. In a further embodiment, the crystalline polymorph Form 3 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.7 ⁇ 0.2, 9.4 ⁇ 0.2, and 19.0 ⁇ 0.2.
• the crystalline polymorph Form 3 of Formula I-B has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 10.
• H NMR spectral data are in ppm (6) and were recorded at 396, 400 and 500 MHz; 19 F NMR spectral data are in ppm (8) and were recorded at 376 or 471 MHz; and 31 P NMR spectral data are in ppm (8) and were recorded at 202 MHz, unless otherwise stated.
• the combined organic phases were passed through a phase separator and concentrated to a pale-yellow oil.
• the residue was dissolved in DCM (0.5 mL), and A'-ethyl- Ahn ethyl amine (66.0 mg, 1.12 mmol) was added dropwise via syringe.
• the solution was heated to 40 °C and stirred for 3 hours.
• the reaction was quenched with water (10 mL), and the mixture was extracted with DCM (3 x 10 mL).
• the combined organic phases were passed through a phase separator and concentrated.
• the title compound can also be prepared as follows.
• a 500 mL jacketed reactor was equipped with a nitrogen inlet, temperature probe, agitator and outlet attached to a scrubber.
• the reaction was charged with A-ethyl-A-methylformamide (8.83 g, 97.4 mmol, 96.0 wt %) and anhydrous DCM (130 mL).
• the jacket was set to 20 °C, and the mixture was stirred at 250 revolutions per minute (rpm).
• Oxalyl chloride (8.17 mL, 93.4 mmol) was added over 30 minutes. The mixture was stirred for an additional hour after complete addition.
• Example 12 Crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate (Formula I) as Form A - evaporative crystallization from ethyl acetate
• Example 13 Crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 1 - evaporative crystallization from isopropyl alcohol
• Example 14 Alternate crystallization of 4-(difluoromethoxy)henzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 1 - slow evaporative crystallization from acetone or combinations of dichloromethane, ethyl acetate and/or heptane
• Example 15 Alternate crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 1 - solvent/antisolvent crystallization from ethanol/methyl tert-butyl ether, acetonitrile/isopropyl acetate, chloroform/heptane, or chlor oform/m ethyl isobutyl ketone
• Example 16 Alternate crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 1 -fast cooling crystallization fiom toluene/acetonitrile
• Example 17 Alternate crystallization of 4-(difhioromethoxy)benzyl 4- (((ethyl(methyl)amino)methy ene)amino)-2f -dimethylbenzoate hydrochloride (Formula I-B) as Form 1 - slow cooling crystallization from methyl isobutyl ketone/acetone, ethanol /heptane, toluene/acetonitrile, ethyl acetate/heptane, or ethyl acetate/chloroform
• Example 18 Alternate crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 1 - stagnant cooling crystallization from methyl ethyl ketone or mixtures of dichloromethane and heptane
• Example 19 Crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 2 - evaporative crystallizations from 2-methyl tetrahydrofuran or methyl isobutyl ketone [0102] A saturated solution of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) in 2-methyl tetrahydrofuran and an undersaturated solution of Formula I-B in methyl isobutyl ketone were prepared.
• Example 20 Alternate crystallization of 4-(difhioromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2f -dimethylbenzoate hydrochloride (Formula I-B) as Form 2 - solvent dntisolvent crystallization from isopropyl alcohol/methyl tert-butyl ether
• Example 21 Alternate crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 2 - slow cooling crystallization from methyl isobutyl ketone or heptane, Isopropyl alcohol [0104] 4-(Difluoromethoxy)benzyl 4-(((ethyl(methyl)amino)methylene)amino)-2,5- dimethylbenzoate hydrochloride (Formula I-B, 25 mg) was added to vials.
• Methyl isobutyl ketone or a mixture of heptane and isopropyl alcohol was added incrementally at 50 °C until the material fully dissolved.
• the solutions were cooled slowly to room temperature over ⁇ 12 hours. If solids did not precipitate after reaching room temperature, the solutions were cooled further to 0 °C or even further to -20 °C by placing in a freezer overnight. Once precipitation occurred, the samples were filtered to provide crystalline solids. Samples were analyzed by powder X-ray diffraction (PXRD) according to Method 2 and assigned the designation Form 2.
• PXRD powder X-ray diffraction
• Example 22 Crystallization of 4-(difhioromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 3 - evaporative crystallization from methyl isobutyl ketone
• Example 24 Alternate crystallization of 4-(difluoromethoxy)benzyl 4- (((ethyl(methyl)amino)methylene)amino)-2,5-dimethylbenzoate hydrochloride (Formula I-B) as Form 3 - slow cooling crystallization from ethyl acetate or tetrahydrofuran/methyl tert-butyl ether
• Samples were analyzed using a Bruker D2 Phaser using Cu Kot radiation (30 kilovolts (kV), 10 milliamps (mA)) and a 0-0 goniometer.
• the incident beam passed through a 0.2 millimeter (mm) divergence slit.
• a 1 mm air scatter screen was placed above the sample, and the beam stop was removed.
• the diffracted beam passed through a 3 mm air scatter slit, 2.5° Seller slits, and a 0.5 K(3 filter followed by a Lynxeye SSD160 Detector with a position sensitive detector (PSD) opening of 1.5°.
• Samples were measured under ambient conditions as flat plate specimens using powder as received.
• the samples were prepared on a polished, zero-background (510) silicon wafer by gently pressing onto the flat surface or packed into a cut cavity. The sample was rotated in its own plane at 15 rpm. Data were collected from 3 to 40° 29 with a step size of 0.03° 29 and collection time of 9.5 seconds.
• FIG. 1 shows the percent disease control at 3 days prior to fungicide treatment (3-day curative; 3DC) or 1 day after fungicide treatment (1-day protectant; 1DP) against test concentrations of Formula I (—•—), Example 25 (--•—), Example 27 ( - A- -), Example 494 (— ⁇ ), and Formula I-B (- ⁇ -).
• Example B Evaluation of Fungicidal Activity in Microplot Field Trials: Seploria Leaf Blotch of Wheat (Zymoseptoria tritici; EPPO code SEPTTR)
• Wheat plants (varieties ‘Lancer’, ‘Barrel’, and ‘Tobak’) were established in microplots of 1-meter by 2-meters and materials applied at a curative application timing between growth stages 39 and 55 or at a protectant timing between growth stages 37 and 39 depending on geographic region. Four replicates were used in a random block design. Disease severity on a scale of 0 to 100 percent disease was visually assessed at multiple time points at approximately a 7-to-14-day interval to generate percent disease control based on the area under the disease progress curve. Trials were conducted at up to three geographical locations. Data are shown in FIG. 2.
• FIG. 2 shows the percent disease control against test concentrations of Formula I (— ⁇ — ) and Example 25 (--*- ) in a cross-trial analysis of replicated field trials.
• Barley plants (varieties ‘Snakebite’, ‘Planet’, and ‘LG Caspari’) were established in microplots of 1-meter by 2-meters and materials applied at a protectant application timing between growth stages 45 and 49 depending on geographic region. Four replicates were used in a random block design. Disease severity on a scale of 0 to 100 percent disease was visually assessed at multiple time points at approximately a 7-day interval to generate percent disease control based on the area under the disease progress curve. Trials were conducted at up to three geographical locations. Data are shown in FIG. 3.
• FIG. 3 shows the percent disease control against test concentrations of Formula I (— ⁇ — ) and Example 25 - ) in a cross-trial analysis of replicated field trials.
• Example D Evaluation of Fungicidal Activity in Microplot Field Trials: Ramularia Leaf Spot of Barley (Ramularia collo-cygni; EPPO code RAMUCC)
• Barley plants (varieties ‘Taverna’, ‘Lomerit’ and ‘LG Caspari’) were established in microplots of 1-meter by 2-meters and materials applied at a protectant application timing between growth stages 33 and 41 depending on geographic region. Four replicates were used in a random block design. Disease severity on a scale of 0 to 100 percent disease was visually assessed at multiple time points at approximately a 7-to-14-day interval to generate percent disease control based on the area under the disease progress curve. Trials were conducted at up to three geographical locations. Data are shown in FIG. 4.
• FIG. 4 shows the percent disease control against test concentrations of Formula I (— ⁇ — ) and Example 25 (-- « ⁇ - ) in a cross-trial analysis of replicated field trials.
• Example E Evaluation of Fungicidal Activity in Microplot Field Trials: Leaf Blotch of Barley (Rhynchosporium secalis; EPPO code RHYNSE)
• Barley plants (varieties ‘Snakebite’ and ‘Pixel’) were established in microplots of 1- meter by 2-meters and materials applied at a protectant application timing between growth stages 33 and 41 depending on geographic region. Four replicates were used in a random block design. Disease severity on a scale of 0 to 100 percent disease was visually assessed at multiple time points at approximately a 7-to-14-day interval to generate percent disease control based on the area under the disease progress curve. Trials were conducted at up to three geographical locations. Data are shown in FIG. 5,
• FIG. 5 shows the percent disease control against test concentrations of Formula I (— ⁇ — ) and Example 25 (--•- - ) in a cross-trial analysis of replicated field trials.
• Example F Evaluation of Fungicidal Activity in Microplot Field Trials: Brown Rust of Barley (Puccinia hordei; EPPO code PUCCHD)
• Barley plants (varieties ‘Pixel’ and ‘Faro’) were established in microplots of 1-meter by 2-meters and materials applied at a protectant application timing between growth stages 41 and 65 depending on geographic region. Four replicates were used in a random block design. Disease severity on a scale of 0 to 100 percent disease was visually assessed at multiple time points at approximately a 7-to-14-day interval to generate percent disease control based on the area under the disease progress curve. Trials were conducted at up to three geographical locations. Data are shown in FIG. 6.
• FIG. 6 shows the percent disease control against test concentrations of Formula I ( ⁇ *— ) and Example 25 (- ⁇ - ) in a cross-trial analysis of replicated field trials.
• Example G Evaluation of Fungicidal Activity : Sugar Beet Leaf Spot (Cercospora beticola; EPPO code CERCBE)
• Example H Evaluation of Fungicidal Activity: Anthracnose of Cucurbits (Colletotrichum orbicular e; EPPO code COLLLA)
• Cucumber seedlings (variety ‘Bush Pickle’) were propagated in soil-less potting mix, with each pot having 1 plant, and used for testing when the first leaf was fully emerged. Test plants were inoculated with a spore suspension of Colletotrichum orbiculare one day after fungicide treatments (1-day protectant; 1DP). After inoculation, the plants were kept in 100% relative humidity for two days to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse for disease to develop. Fungicide formulation and application were made as described in Example G. Disease assessment was conducted as described in Example A. Data are shown in Table 2.
• Example I Evaluation of Fungicidal Activity: Blast of Rice (Magnaporthe oryzae; EPPO code PYRIOR)
• Rice seedlings (variety ‘M202’) were propagated in soil-less potting mix, with each pot having 8 to 10 plants, and used for testing when the first leaf was fully emerged.
• Test plants were inoculated with a spore suspension of Magnaporthe oryzae one day after fungicide treatments (1-day protectant; 1DP). After inoculation the plants were kept in 100% relative humidity for two days to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse for disease to develop. Fungicide formulation and application were made as described in Example G. Disease assessment was conducted as described in Example A. Data are shown in Table 2.
• Example J Evaluation of Fungicidal Activity: Asian Soybean Rust (Phakopsora pachyrhizi;
• Soybean plants (variety ‘Williams 82’) were propagated in soil-less potting mix, with each pot having 1 plant, and used for testing when the first leaf was fully emerged. Test plants were inoculated as described in Example A. After inoculation plants were kept in 100% relative humidity for 24 hours to permit spores to germinate and infect the leaf. The plants were transferred to a growth room for disease to develop. Fungicide application and disease assessment were made as described in Example A. Data are shown in Table 3.
• Example K Evaluation of Fungicidal Activity: Early Blight of Tomato (Alternaria solani;
• Tomato plants (variety ‘Brandywine’) were propagated in soil-less potting mix, with each pot having 1 plant, and used for testing when the first leaf was fully emerged. Test plants were inoculated with a spore suspension of Alternaria solani one day after fungicide treatments (1-day protectant; 1DP). After inoculation, the plants were kept in a dark dew room with 100% relative humidity for 2 days to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse for disease to develop. Fungicide formulation and application were made as described in Example G. Disease assessment was conducted as described in Example A. Data are shown in Table 4.
• Example L Evaluation of Fungicidal Activity: Grey Mold (Botrytis cinerea; EPPO code BOTRCI)
• Grape plants (variety ‘Pinot noir’) were propagated in soil-less potting mix, with each pot having 1 plant, and trimmed to the first fully emerged leaf.
• Test plants were inoculated with a spore suspension of Botrytis cinerea one day after fungicide treatments (1-day protectant; 1DP). After inoculation the plants were kept in a dark dew room with 100% relative humidity for 4 days to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse for disease to develop.
• Fungicide formulation and application were made as described in Example G. Disease assessment was conducted as described in Example A. Data are shown in Table 5. Table 5.
• Fungicidal activity as percent disease control in a 1-day protectant (1DP) application at 200 and 50 ppm.
• Example M Evaluation of Fungicidal Activity: Cucumber Powdery Mildew (Podosphaera xanthii; EPPO code PODOXA)
• Cucumber plants (variety ‘Straight eight’) were propogated in soil-less potting mix, with each pot having 1 plant, and used for testing when the first leaf was fully emerged. Test plants were inoculated with a spore suspension of Podosphaera xanthii one day after fungicide treatments (1-day protectant; 1DP). After inoculation the plants were then transferred to a greenhouse for disease to develop. Fungicide formulation and application were made as described in Example G. Disease assessment was conducted as described in Example A. Data are shown in Table 6.
• Example N Evaluation of In vitro Fungicidal Activity: Cercospora kikuchii, EPPO code CERCKI; Corynespora cassiicola, EPPO code CORYCA; and Septoria glycines, EPPO code SEPTGL
• Test compounds were serially diluted in dimethyl sulfoxide (DMSO), and 2 microliter ( L) aliquots were added to 96-well flat-bottomed microtiter plates (Falcon Products).
• DMSO dimethyl sulfoxide
• L microliter
• Example O Evaluation of Fungicidal Activity: Wheat Brown Rust (Puccinia triticina; Synonym: Puccinia recondita f sp. tritici; Bayer code PUCCRT):
• Wheat plants (variety ‘Yuma’) were grown from seed in a greenhouse in soil-less potting mix until the first leaf was fully emerged, with 7-10 seedlings per pot. These plants were inoculated with an aqueous spore suspension of Puccinia triticina after fungicide treatments. After inoculation, the plants were kept in a dark dew room with 100% relative humidity overnight to permit spores to germinate and infect the leaf. The plants were then transferred to a greenhouse for disease to develop. Fungicide formulation and application were made as described in Example G. Disease assessment was conducted as described in Example A. Data are shown in Table 8.
• Test compounds were diluted in dimethyl sulfoxide (DMSO), and 2 microliter (pL) aliquots were added to 96-well flat-bottomed microtiter plates (Falcon Products).
• DMSO dimethyl sulfoxide
• pL microliter
• Spore suspensions were prepared in Difco YNB (6.7 g/L, yeast nitrogen base without amino acids; BD Diagnostic Systems) supplemented with 2 g of glucose and 3 g each of potassium dihydrogen phosphate and dipotassium hydrogen phosphate per liter (L). Total assay volume was 200 pL per well.
• Initial inoculum density was adjusted to 100,000 spores/mL for BOTRCI, CORYCA and SEPTTR, 250,000 spores/mL for COLLLA, 40,000 spores/mL for PYRIOR, 50,000 spores/mL for USTIMA and 10,000-20,000 spores/mL for ALTESO.

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