CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/144,560 filed Jan. 14, 2009, which is expressly incorporated by reference herein.
FIELD OF THE INVENTION The present invention relates to the use of hydrazones in combination with copper, copper-based fungicides or other copper-containing materials as synergistic fungicidal mixtures.
BACKGROUND Copper is used to control the growth of organisms, especially microorganisms, in a variety of applications such as those described in the “Handbook of copper compounds and applications” edited by H. W. Richardson and published by Marcel Dekker, Inc. New York (1997), which is expressly incorporated by reference herein. These applications may include its use in agriculture to control a wide range of fungal and bacterial diseases of plants. Copper products may also be used as aquatic biocides in fresh or marine environments. Copper products may be used in antifouling applications and to control unwanted organisms in ponds and lakes based on the toxicity of copper towards algae, fungi, macrophytes and mollusks. Copper-based materials may also be used as wood preservatives and on other materials to inhibit fungal and bacterial growth. Other uses also include killing plant roots in sewer systems.
Ecological risk assessment studies have shown that copper products, which normally are applied at high use rates, may be toxic to birds, mammals, fish and other aquatic species (“Reregistration Eligibility Decision (RED) for Coppers”, EPA 738-R-06-020, July 2006, which is expressly incorporated by reference herein). Thus, while copper is a highly useful agent for controlling the growth of undesirable organisms in different environments, it is desirable to minimize the amount of copper applied.
SUMMARY OF THE INVENTION One exemplary embodiment of the present disclosure includes a synergistic mixture for controlling the growth of fungi, the synergistic mixture including copper and a hydrazone compound of Formula I:
wherein A is oxygen or sulfur;
Z is H or C1-C4 alkyl;
W is —CHR1-;
n is 0, 1, or 2;
R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl;
R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, C3-C6 halocycloalkyl, substituted aryl, unsubstituted aryl, substituted heteroaryl, or unsubstituted heteroaryl;
X3, X4, X5, and X6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 haloalkylthio, —SO2R1, SONR1R1, —CR1=NOR1, —CONR1R1, NR1COOR1, —COOR1, substituted aryl, substituted heteroaryl, unsubstituted aryl, and unsubstituted heteroaryl; and
Y2, Y3, Y4, Y5, and Y6 are each independently selected from the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4 haloalkylthio, —SO2R1, SONR1R1, —R1=NOR1, —CONR1R1, NR1COOR1, —COOR1, NR1R1, substituted aryl, substituted heteroaryl, unsubstituted aryl, unsubstituted heteroaryl, and phenoxy;
with the proviso that X3 and X4, X4 and X5, X5 and X6, Y2 and Y3, or Y3 and Y4 may form a 5 or 6 membered fused ring which may contain up to two heteroatoms selected from the group consisting of O, N, and S.
The term “alkyl” refers to a branched, unbranched, or cyclic carbon chain, including methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term “cycloalkyl” refers to a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen.
The term “alkenyl” refers to a branched, unbranched or cyclic carbon chain containing one or more double bonds including ethenyl, propenyl, butenyl, isopropenyl, isobutenyl, cyclohexenyl, and the like.
The term “alkynyl” refers to a branched or unbranched carbon chain containing one or more triple bonds including propynyl, butynyl and the like.
As used throughout this specification, the term ‘R’ refers to the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl, unless stated otherwise.
The term “alkoxy” refers to an —OR substituent.
The term “alkylthio” refers to an —S—R substituent.
The term “haloalkylthio” refers to an alkylthio, which is substituted with Cl, F, I, or Br or any combination thereof.
The term “cyano” refers to a —C≡N substituent.
The term “hydroxyl” refers to an —OH substituent.
The term “haloalkoxy” refers to an —OR—X substituent, wherein X is Cl, F, Br, or I, or any combination thereof.
The term “haloalkyl” refers to an alkyl, which is substituted with Cl, F, I, or Br or any combination thereof.
The term “halocycloalkyl” refers to a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, which is substituted with Cl, F, I, or Br or any combination thereof.
The term “haloalkenyl” refers to an alkenyl, which is substituted with Cl, F, I, or Br or any combination thereof.
The term “haloalkynyl” refers to an alkynyl which is substituted with Cl, F, I, or Br or any combination thereof.
The term “halogen” or “halo” refers to one or more halogen atoms, defined as F, Cl, Br, and I.
The term “aryl” refers to a cyclic, aromatic substituent consisting of hydrogen and carbon.
The term “heteroaryl” refers to a cyclic substituent that may be fully unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen.
The term “phenoxy” refers to an —O substituted with a six-membered fully unsaturated ring consisting of hydrogen and carbon.
The term “nitro” refers to a —NO2 substituent.
Certain compounds disclosed in this document can exist as one or more isomers. The various isomers include stereoisomers, geometric isomers, diastereomers, and enantiomers. Thus, the compounds disclosed in this invention include geometric isomers, racemic mixtures, individual stereoisomers, and optically active mixtures. It will be appreciated by those skilled in the art that one isomer may be more active than the others. The structures disclosed in the present disclosure are drawn in only one geometric form for clarity, but are intended to represent all geometric forms of the molecule.
Additional features and advantages of the present invention will become apparent to those skilled in the art upon consideration of the following detailed description of the illustrative embodiments exemplifying the best mode of carrying out the invention as presently perceived.
DETAILED DESCRIPTION OF THE DISCLOSURE The embodiments of the invention described herein are not intended to be exhaustive or to limit the invention to the precise forms disclosed. Rather, the embodiments selected for description have been chosen to enable one skilled in the art to practice the invention. Although the disclosure is described as a synergistic combination of copper, copper based fungicides, or other copper-containing materials and a hydrazone or hydrazone derivative it should be understood that the concepts presented herein may be used in various applications and should not be limited.
The mixtures of the present invention have fungitoxic activity against phytopathogenic fungi, against fungal pathogens of mammals, including humans, and against wood decay causing fungi. The mixtures of the present invention may have broad spectrum fungitoxic activity, particularly against phytopathogenic fungi. They are active against fungi of a number of classes including Deuteromycetes (Fungi Imperfecti), Basidiomycetes, Oomycetes and Ascomycetes. More particularly, the method of this invention provides for activity against organisms including, but not limited to, Phytophthora species, Plasmopara viticola, Pseudoperonospora cubensis, Pythium species, Pyricularia oryzae, Colletotrichum species, Helminthosporium species, Alternaria species, Septoria nodorum, Leptosphaeria nodorum, Ustilago maydis, Erysiphe graminis, Puccinia species, Sclerotinia species, Sphaerotheca fuliginea, Cercospora species, Rhizoctonia species, Uncinula necator, Septoria tritici, and Podosphaera leucotricha.
The method of the present invention also provides for activity against fungal pathogens of mammals (including humans) including, but not limited to, Candida species such as C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis, Aspergillus species such as Aspergillus fumigatus, Fusarium species, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Microsporum species, and Tricophyton species. The method of the present invention also provides for activity against fungi which cause wood decay such as Gleophyllum trabeur, Phialophora mutabilis, Poria palcenta and Trametes versicolor.
The present invention contemplates all vehicles by which the composition of the present invention can be formulated for delivery and use as a pesticide composition, including solutions, suspensions, emulsions, wettable powders and water dispersible granules, emulsifiable concentrates, granules, dusts, baits, and the like. Typically, formulations are applied following dilution of the concentrated formulation with water as aqueous solutions, suspensions or emulsions, or combinations thereof. Such solutions, suspensions or emulsions are produced from water-soluble, water-suspended or water-suspendable, water-emulsified or water-emulsifiable formulations or combinations thereof which are solids, including and usually known as wettable powders or water dispersible granules; or liquids including and usually known as emulsifiable concentrates, aqueous suspensions or suspension concentrates, and aqueous emulsions or emulsions in water, or mixtures thereof such as suspension-emulsions. As will be readily appreciated, any material to which this composition can be added may be used, provided they yield the desired utility without significant interference with the desired activity of the pesticidally active ingredients as pesticidal agents and improved residual lifetime or decreased effective concentration is achieved.
Wettable powders, which may be compacted to form water dispersible granules, comprise an intimate mixture of one or more of the pesticidally active ingredients, an inert carrier and surfactants. The concentration of the pesticidally active ingredient in the wettable powder is usually 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. In the preparation of wettable powder formulations, the pesticidally active ingredients can be compounded with any finely divided solid, such as prophyllite, talc, chalk, gypsum, Fuller's earth, bentonite, attapulgite, starch, casein, gluten, montmorillonite clays, diatomaceous earths, purified silicates or the like. In such operations, the finely divided carrier and surfactants are typically blended with the compound(s) and milled
Emulsifiable concentrates of the pesticidally active ingredient comprise a convenient concentration, such as from about 10 weight percent to about 50 weight percent of the pesticidally active ingredient, in a suitable liquid, based on the total weight of the concentrate. The pesticidally active ingredients are dissolved in an inert carrier, which is either a water miscible solvent or a mixture of water-immiscible organic solvents, and emulsifiers. The concentrates may be diluted with water and oil to form spray mixtures in the form of oil-in-water emulsions. Useful organic solvents include aromatics, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha. Other organic solvents may also be used, such as, for example, terpenic solvents, including rosin derivatives, aliphatic ketones, such as cyclohexanone, and complex alcohols, such as 2-ethoxyethanol.
Emulsifiers which can be advantageously employed herein can 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. Examples of 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 esterified with the polyol or polyoxyalkylene. Cationic emulsifiers include quaternary ammonium compounds and fatty amine salts. Anionic emul-sifiers include the oil-soluble salts (e.g., calcium) of alkylaryl sulfonic acids, oil-soluble salts of sulfated polyglycol ethers and appropriate salts of phosphated polyglycol ether.
Representative organic liquids which can be employed in preparing emulsifiable concentrates are the aromatic liquids such as xylene, propyl benzene fractions; or mixed naphthalene fractions, mineral oils, substituted aromatic organic liquids such as dioctyl phthalate; kerosene; dialkyl amides of various fatty acids, particularly the dim-ethyl amides; and glycol ethers such as the n-butyl ether, ethyl ether or methyl ether of diethylene glycol, and the methyl ether of triethylene glycol and the like. Mixtures of two or more organic liquids may also be employed in the preparation of the emulsifiable concentrate. Surface-active emulsifying 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 emulsifying agents. The formulations can also contain other compatible additives, for example, plant growth regulators and other biologically active compounds used in agriculture.
Aqueous suspensions comprise suspensions of one or more water-insoluble pesticidally active ingredients dispersed in an aqueous vehicle at a concentration in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous suspension. Suspensions are prepared by finely grinding one or more of the pesticidally active ingredients, and vigorously mixing the ground material into a vehicle comprised of water and surfactants chosen from the same types discussed above. Other components, such as inor-ganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous vehicle. It is often most effective to grind and mix at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
Aqueous emulsions comprise emulsions of one or more water-insoluble pesticidally active ingredients emulsified in an aqueous vehicle at a concentration typically in the range from about 5 to about 50 weight percent, based on the total weight of the aqueous emulsion. If the pesticidally active ingredient is a solid it must be dissolved in a suitable water-immiscible solvent prior to the preparation of the aqueous emulsion. Emulsions are prepared by emulsifying the liquid pesticidally active ingredient or water-immiscible solution thereof into an aqueous medium typically with inclusion of surfactants that aid in the formation and stabilization of the emulsion as described above. This is often accomplished with the aid of vigorous mixing provided by high shear mixers or homogenizers.
The compositions of the present invention can also be granular formulations, which are particularly useful for applications to the soil. Granular formulations usually contain from about 0.5 to about 10 weight percent, based on the total weight of the granular formulation of the pesticidally active ingredient(s), dispersed in an inert 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 are usually prepared by dissolving the pesticidally active ingredients in a suitable solvent and applying it to a granular carrier which has been preformed to the appropriate particle size, in the range of from about 0.5 to about 3 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 and solvent, and crushing and drying to obtain the desired granular particle.
Dusts can be prepared by intimately mixing one or more of the pesticidally active ingredients 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.
The formulations may additionally contain adjuvant surfactants to enhance deposition, wetting and penetration of the pesticidally active ingredients onto the target site such as a crop or organism. These 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 of the esters of sulfosuccinic acids, ethoxylated organosilicones, ethoxylated fatty amines and blends of surfactants with mineral or vegetable oils.
The formulations may optionally include combinations that contain other pesticidal compounds. Such additional pesticidal compounds may be fungicides, insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the mixtures of the present invention in the medium selected for application, and not antagonistic to the activity of the present mixtures. Accordingly, in such embodiments, the other pesticidal compound is employed as a supplemental toxicant for the same or for a different pesticidal use. The mixtures of the present invention, and the pesticidal compound in the combination can generally be present in a weight ratio of from 1:100 to 100:1.
For pharmaceutical use, the mixtures described herein may be taken up in pharmaceutically acceptable carriers, such as, for example, solutions, suspensions, tablets, capsules, ointments, elixirs and injectable compositions. Pharmaceutical preparations may contain from 0.1% to 99% by weight of active ingredient. Preparations which are in single dose form, “unit dosage form”, preferably contain from 20% to 90% active ingredient, and preparations which are not in single dose form preferably contain from 5% to 20% active ingredient. As used herein, the term “active ingredient” refers to mixtures described herein, salts thereof, hydrates, and mixtures with other pharmaceutically active compounds. Dosage unit forms such as, for example, tablets or capsules, typically contain from about 0.05 to about 1.0 g of active ingredient.
The mixtures of the present invention can also be combined with other agricultural fungicides to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal mixtures of the present invention are often applied in conjunction with one or more other fungicides to control a wider variety of undesirable diseases. When used in conjunction with other fungicide(s), the presently claimed mixtures can be formulated with the other fungicide(s), tank mixed with the other fungicide(s) or applied sequentially with the other fungicide(s). Such other fungicides include amisulbrom 2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol, 8-hydroxyquinoline sulfate, antimycin, Ampelomyces, quisqualis, azaconazole, azoxystrobin, Bacillus subtilis, benalaxyl, benomyl, benthiavalicarb-isopropyl, benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl, bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, boscalid, bromuconazole, bupirimate, BYF 1047, calcium polysulfide, captafol, captan, carbendazim, carboxin, carpropamid, carvone, chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans, cyazofamid, cyflufenamid, cymoxanil, cyproconazole, cyprodinil, coumarin, dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate), dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran, diethofencarb, difenoconazole, difenzoquat ion, diflumetorim, dimethomorph, dimoxystrobin, diniconazole, diniconazole-M, dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorph acetate, dodine, dodine free base, edifenphos, enestrobin, epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone, fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid, fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumorph, fluopicolide, fluopyram, fluoroimide, fluoxastrobin, fluquinconazole, flusilazole, flusulfamide, flutolanil, flutriafol, folpet, formaldehyde, fosetyl, fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine, guazatine acetates, GY-81, hexachlorobenzene, hexaconazole, hymexazol, imazalil, imazalil sulfate, imibenconazole, iminoctadine, iminoctadine triacetate, iminoctadine tris(albesilate), ipconazole, iprobenfos, iprodione, iprovalicarb, isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin hydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb, mandipropamid, maneb, mepanipyrim, mepronil, meptyldinocap, mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl, mefenoxam, metalaxyl-M, metam, metam-ammonium, metam-potassium, metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin, myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone, ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl, oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate, penconazole, pencycuron, pentachlorophenol, pentachlorophenyl laurate, penthiopyrad, phenylmercury acetate, phosphonic acid, phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim, potas-sium bicarbonate, potassium hydroxyquinoline sulfate, probenazole, prochloraz, procymidone, propamocarb, propamocarb hydrochloride, propiconazole, propineb, pro-quinazid, prothioconazole, pyraclostrobin, pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil, pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria sachalinensis extract, silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur, SYP-Z071, SYP-048, SYP-Z048, tar oils, tebuconazole, tecnazene, tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon, triadimenol, triazolopyrimidine, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triflumizole, triforine, triticonazole, validamycin, vinclozolin, zineb, ziram, zoxamide, Candida oleophila, Fusarium cocysporum, Gliocladium spp., Phlebiopsis gigantean, Streptomyces griseoviridis, Trichoderma spp., (RS)—N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide, 1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane, 2-(2-heptadecyl-2-imidazolin-1-yl)ethanol, 2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide, 2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride, 2-methoxyethylmercury silicate, 3-(4-chloro-phenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl thiocyanateme, ampropylfos, anilazine, azithiram, barium polysulfide, Bayer 32394, benodanil, benquinox, bentaluron, benzamacril; benzamacril-isobutyl, benzamorf, binapacryl, his (methylmercury) sulfate, his (tributyltin) oxide, buthiobate, cadmium calcium copper zinc chromate sulfate, carbamorph, CECA, chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox, climbazole, cyclafuramid, cypendazole, cyprofuram, decafentin, dichlone, dichlozo-line, diclobutrazol, dimethirimol, dinocton, dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin, drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf, fenapanil, fenitropan, 5-fluorocytosine and profungicides thereof, fluotrimazole, furcarbanil, furconazole, furconazole-cis, furmecyclox, furophanate, glyodine, griseofulvin, halacrinate, Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione, mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury dicyandiamide, metsulfovax, milneb, mucochloric anhydride, myclozolin, N-3,5-dichlorophenyl-succinimide, N-3-nitrophenyl-itaconimide, natamycin, N-ethylmercurio-4-toluenesulfonanilide, nickel bis(dimethyldithio-carbamate), OCH, phenylmercury dimethyldithiocarbamate, phenylmercury nitrate, phos-diphen, picolinamide UK-2A and derivatives thereof, prothiocarb; prothiocarb hydrochloride, pyracar-bolid, pyridinitril, pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid, quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen, tecoram, thiadifluor, thi-cyofen, thiochlorfenphim, thiophanate, thioquinox, tioxymid, triamiphos, triarimol, triazbutil, trichlamide, urbacid, XRD-563, and zarilamide, 1K-1140, propargyl amides and any combinations thereof.
The mixtures of the present invention can also be combined with other antifungal compounds used to control infections in mammals to form fungicidal mixtures and synergistic mixtures thereof. The fungicidal mixtures of the present invention can be applied in conjunction with one or more other antifungal compounds or their pharmaceutically acceptable salts to control a wider variety of undesirable diseases. When used in conjunction with other antifungal compounds, the presently claimed mixtures can be formulated with the other antifungal compound(s), coadministered with the other antifungal compound(s) or applied sequentially with the other antifungal compound(s). Typical antifungal compounds include, but are not limited to compounds selected from the group consisting of an azole such as fluconazole, voriconazole, itraconazole, ketoconazole, and miconazole, a polyene such as amphotericin B, nystatin or liposomal and lipid forms thereof such as Abelcet, AmBisome and Amphocil, a purine nucleotide inhibitor such as 5-fluorocytosine, a polyoxin such as nikkomycin, and pneumocandin or echinocandin derivatives such as caspofungin and micofungin.
Additionally, the mixtures of the present invention can be combined with other pesticides, including insecticides, nematocides, miticides, arthropodicides, bactericides or combinations thereof that are compatible with the mixtures of the present invention in the medium selected for application, and not antagonistic to the activity of the present mixtures to form pesticidal mixtures and synergistic mixtures thereof. The fungicidal mixtures of the present invention are often applied in conjunction with one or more other pesticides to control a wider variety of undesirable pests. When used in conjunction with other pesticides, the presently claimed mixtures can be formulated with the other pesticide(s), tank mixed with the other pesticide(s) or applied sequentially with the other pesticide(s). Typical insecticides include, but are not limited to: antibiotic insecticides such as allosamidin and thuringiensin; macrocyclic lactone insecticides such as spinosad; avermectin insecticides such as abamectin, doramectin, emamectin, eprinomectin, ivermectin and selamectin; milbemycin insecticides such as lepimectin, milbemectin, milbemycin oxime and moxidectin; arsenical insecticides such as calcium arsenate, copper acetoarsenite, copper arsenate, lead arsenate, potassium arsenite and sodium arsenite; botanical insecticides such as anabasine, azadirachtin, d-limonene, nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I, jasmolin II, pyrethrin I, pyrethrin II, quassia, rotenone, ryania and sabadilla; carbamate insecticides such as bendiocarb and carbaryl; benzofuranyl methylcarbamate insecticides such as benfuracarb, carbofuran, carbosulfan, decarbofuran and furathiocarb; dimethylcarbamate insecticides dimitan, dimetilan, hyquincarb and pirimicarb; oxime carbamate insecticides such as alanycarb, aldicarb, aldoxycarb, butocarboxim, butoxy-carboxim, methomyl, nitrilacarb, oxamyl, tazimcarb, thiocarboxime, thiodicarb and thiofanox; phenyl methylcarbamate insecticides such as allyxycarb, aminocarb, bufencarb, butacarb, carbanolate, cloethocarb, dicresyl, dioxacarb, EMPC, ethiofencarb, fenethacarb, fenobucarb, isoprocarb, methiocarb, metolcarb, mexacarbate, promacyl, promecarb, propoxur, trimethacarb, XMC and xylylcarb; dinitrophenol insecticides such as dinex, dinoprop, dinosam and DNOC; fluorine insecticides such as barium hexafluorosilicate, cryolite, sodium fluoride, sodium hexafluorosilicate and sulfluramid; formamidine insecticides such as amitraz, chlordimeform, formetanate and formparanate; fumigant insecticides such as acrylonitrile, carbon disulfide, carbon tetrachloride, chloroform, chloropicrin, para-dichlorobenzene, 1,2-dichloropropane, ethyl formate, ethylene dibromide, ethylene dichloride, ethylene oxide, hydrogen cyanide, iodomethane, methyl bromide, methylchloroform, methylene chloride, naphthalene, phosphine, sulfuryl fluoride and tetrachloroethane; inorganic insecticides such as borax, calcium polysulfide, copper oleate, mercurous chloride, potassium thiocyanate and sodium thiocyanate; chitin synthesis inhibitors such as bistrifluoron, buprofezin, chlorfluazuron, cyromazine, diflubenzuron, flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron, penfluoron, teflubenzuron and triflumuron; juvenile hormone mimics such as epofenonane, fenoxycarb, hydroprene, kinoprene, methoprene, pyriproxyfen and triprene; juvenile hormones such as juvenile hormone I, juvenile hormone II and juvenile hormone III; moulting hormone agonists such as chromafenozide, halofenozide, methoxyfenozide and tebufenozide; moulting hormones such as .alpha.-ecdysone and ecdysterone; moulting inhibitors such as diofenolan; precocenes such as precocene I, precocene II and precocene III; unclassified insect growth regulators such as dicyclanil; nereistoxin analogue insecticides such as bensultap, cartap, thiocyclam and thiosultap; nicotinoid insecticides such as flonicamid; nitroguanidine insecticides such as clothianidin, dinotefuran, imidacloprid and thiamethoxam; nitromethylene insecticides such as nitenpyram and nithiazine; pyridylmethyl-amine insecticides such as acetamiprid, imidacloprid, nitenpyram and thiacloprid; organochlorine insecticides such as bromo-DDT, camphechlor, DDT, pp'-DDT, ethyl-DDD, HCH, gamma-HCH, lindane, methoxychlor, pentachlorophenol and TDE; cyclodiene insecticides such as aldrin, bromocyclen, chlorbicyclen, chlordane, chlordecone, dieldrin, dilor, endosulfan, endrin, HEOD, heptachlor, HHDN, isobenzan, isodrin, kelevan and mirex; organophosphate insecticides such as bromfenvinfos, chlorfenvinphos, crotoxyphos, dichlorvos, dicrotophos, dimethylvinphos, fospirate, heptenophos, methocrotophos, mevinphos, monocrotophos, naled, naftalofos, phosphamidon, propaphos, TEPP and tetrachlorvinphos; organothiophosphate insecticides such as dioxabenzofos, fosmethilan and phenthoate; aliphatic organothiophosphate insecticides such as acethion, amiton, cadusafos, chlorethoxyfos, chlormephos, demephion, demephion-O, demephion-S, demeton, demeton-O, demeton-S, demeton-methyl, demeton-O-methyl, demeton-S-methyl, demeton-S-methylsulphon, disulfoton, ethion, ethoprophos, IPSP, isothioate, malathion, methacrifos, oxydemeton-methyl, oxydeprofos, oxydisulfoton, phorate, sulfotep, terbufos and thiometon; aliphatic amide organothiophosphate insecticides such as amidithion, cyanthoate, dimethoate, ethoate-methyl, formothion, mecarbam, omethoate, prothoate, sophamide and vamidothion; oxime organothiophosphate insecticides such as chlorphoxim, phoxim and phoxim-methyl; heterocyclic organothiophosphate insecticides such as azamethiphos, coumaphos, coumithoate, dioxathion, endothion, menazon, morphothion, phosalone, pyraclofos, pyridaphenthion and quinothion; benzothiopyran organothiophosphate insecticides such as dithicrofos and thicrofos; benzotriazine organothiophosphate insecticides such as azinphos-ethyl and azinphos-methyl; isoindole organothiophosphate insecticides such as dialifos and phosmet; isoxazole organothiophosphate insecticides such as isoxathion and zolaprofos; pyrazolopyrimidine organothiophosphate insecticides such as chlorprazophos and pyrazophos; pyridine organothiophosphate insecticides such as chlorpyrifos and chlorpyrifos-methyl; pyrimidine organothiophosphate insecticides such as butathiofos, diazinon, etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl, primidophos, pyrimitate and tebupirimfos; quinoxaline organothiophosphate insecticides such as quinalphos and quinalphos-methyl; thiadiazole organothiophosphate insecticides such as athidathion, lythidathion, methidathion and prothidathion; triazole organothiophosphate insecticides such as isazofos and triazophos; phenyl organothiophosphate insecticides such as azothoate, bromophos, bromophos-ethyl, carbophenothion, chlorthiophos, cyanophos, cythioate, dicapthon, dichlofenthion, etaphos, famphur, fenchlorphos, fenitrothion fensulfothion, fenthion, fenthion-ethyl, heterophos, jodfenphos, mesulfenfos, parathion, parathion-methyl, phenkapton, phosnichlor, profenofos, prothiofos, sulprofos, temephos, trichlormetaphos-3 and trifenofos; phosphonate insecticides such as butonate and trichlorfon; phosphonothioate insecticides such as mecarphon; phenyl ethylphosphonothioate insecticides such as fonofos and trichloronat; phenyl phenylphosphonothioate insecticides such as cyanofenphos, EPN and leptophos; phosphoramidate insecticides such as crufomate, fenamiphos, fosthietan, mephosfolan, phosfolan and pirimetaphos; phosphoramidothioate insecticides such as acephate, isocarbophos, isofenphos, methamidophos and propetamphos; phosphorodiamide insecticides such as dimefox, mazidox, mipafox and schradan; oxadiazine insecticides such as indoxacarb; phthalimide insecticides such as dialifos, phosmet and tetramethrin; pyrazole insecticides such as acetoprole, cyenopyrafen, ethiprole, fipronil, pyrafluprole, pyriprole, tebufenpyrad, tolfenpyrad and vaniliprole; pyrethroid ester insecticides such as acrinathrin, allethrin, bioallethrin, barthrin, bifenthrin, bioethanomethrin, cyclethrin, cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin, gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin, alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin, dimethrin, empenthrin, fenfluthrin, fenpirithrin, fenpropathrin, fenvalerate, esfenvalerate, flucythrinate, fluvalinate, taufluvalinate, furethrin, imiprothrin, metofluthrin, permethrin, biopermethrin, transpermethrin, phenothrin, prallethrin, profluthrin, pyresmethrin, resmethrin, bioresmethrin, cismethrin, tefluthrin, terallethrin, tetramethrin, tralomethrin and transfluthrin; pyrethroid ether insecticides such as etofenprox, flufenprox, halfenprox, protrifenbute and silafluofen; pyrimidinamine insecticides such as flufenerim and pyrimidifen; pyrrole insecticides such as chlorfenapyr; tetronic acid insecticides such as spiromesifen; thiourea insecticides such as diafenthiuron; urea insecticides such as flucofuron and sulcofuron; and unclassified insecticides such as closantel, crotamiton, EXD, fenazaflor, fenoxacrim, flubendiamide, hydramethylnon, isoprothiolane, malonoben, metaflumizone, metoxadiazone, nifluridide, pyridaben, pyridalyl, rafoxanide, triarathene, triazamate, meptyldinocap, pyribencarb and any combinations thereof.
The mixtures have broad ranges of efficacy as fungicides. The exact amounts of hydrazones and copper-containing materials to be applied is dependent not only on the specific materials being applied and relative amounts of hydrazone and copper in the mixtures, but also on the, 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 mixture. Thus, all the mixtures, and formulations containing the same, may not be equally effective at similar concentrations or against the same fungal species.
The mixtures are effective in use with plants in a disease-inhibiting and phytologically acceptable amount. The term “disease inhibiting and phytologically acceptable amount” refers to an amount of a mixture that kills or inhibits the plant disease for which control is desired, but is not significantly toxic to the plant. The exact amount of a mixture 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. The dilution and rate of application will depend upon the type of equipment employed, the method and frequency of application desired and diseases to be controlled. For foliar control of fungal infections on plants, the amount of copper used in mixture with hydrazone may range from 0.001 to 5 kg/ha, and preferably from 0.05 to 1 kg/ha. The amount of hydrazone used in mixture with copper may range from 0.001 to 5 kg/ha, and preferably from 0.05 to 1 kg/ha. The molar ratio of copper to hydrazone may range from 0.1:1 to 10, 000:1, preferably from 0.5:1 to 1000:1 and more preferably from 1:1 to 20:1.
It should be understood that the preferred amount of a copper material to be mixed with hydrazone in a given application may be influenced by availability of copper from other sources such as copper present in the soil or irrigation water, copper present on the foliage from natural sources, copper applied for fungal or bacterial disease control, copper applied as a fertilizer component, copper present in the water used in preparing fungicide solutions for application such as in spray application, copper present in formulations used in preparing spray solutions or dusts for application, or any other suitable copper source.
For fungal control the hydrazone may be applied before or after the application of copper such that the mixture is generated in the location where fungal control is desired. Additionally, multiple applications of copper or the hydrazone may be applied.
As a seed protectant, the amount of toxicant coated on the seed is usually at a dosage rate of about 10 to about 250 grams (g) and preferably from about 20 to about 60 g per 50 kilograms of seed. As a soil fungicide, the chemical can be incorporated in the soil or applied to the surface usually at a rate of 0.5 to about 20 kg and preferably about 1 to about 5 kg per hectare.
Methods for preparation of salicylaldehyde benzoylhydrazones and 2-hydroxyphenylketone benzoylhydrazones from salicylaldehydes or 2-hydroxyphenyl ketones and a benzoic hydrazide are well known in the literature. In addition the preparation of metal complexes of these materials is also well known (see for example Journal of Inorganic Biochemistry 1999, 77, 125-133, which is expressly incorporated by reference herein). Methods of preparation of precursor hydrazides are also well known. Hydrazides can be prepared, for example, from carboxylic acids such as in Maxwell et al., J. Med. Chem. 1984, 27, 1565-1570, and from carboxylic esters such as in Dydio et al., J. Org. Chem. 2009, 74, 1525-1530, which are expressly incorporated by reference herein. Thus, the synthesis of any benzoylhydrazone of the present invention and its metal complex(es) is fully described where the starting aldehyde or ketone, and the starting benzoic hydrazide, acid, or ester are described. The hydrazones disclosed may also be in the form of pesticidally acceptable salts and hydrates. Examples 23, 24, and 25 below provide typical methods for the preparation of such benzoylhydrazones. Example 31 below provides a general method for the preparation of their metal complexes.
Example 1 Preparation of 1-(3,5-dichloro-2-hydroxyphenyl)-2,2,2-trifluoroethanone
2,4-Dichloro-6-iodophenol (2.0 grams (g), 6.9 millimoles (mmol)) was dissolved in dry tetrahydrofuran (THF; 20 milliliters (mL)), cooled to −30 to −40° C., treated in portions with isopropyl magnesium chloride-lithium chloride complex (1.3 M in THF; 7.3 mmol) and stirred for 45 minutes (min) as the temperature was allowed to rise to 0° C. The mixture was cooled to −30° C., treated with 8 mL (10 mmol) of the Grignard reagent and stirred for 30 min at −30° C. Ethyl trifluoroacetate (2.4 mL, 2.8 g, 20 mmol) was added, and the mixture was stirred for 15 min at −30° C., warmed to 25° C. and stirred for 2 hours (h). The reaction was quenched by addition of saturated (satd) ammonium chloride (NH4C1; 10 mL), diluted with ethyl acetate (EtOAc; 50 mL) and washed with 1 M hydrochloric acid (HCl; 20 mL), satd sodium chloride (NaCl; 10 mL), dried over sodium sulfate (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (1.2 g): mp 50-52° C.; 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 5.92 (s, 1H); EIMS m/z 258.
Example 2 Preparation of cyclopropyl-(3,5-dichloro-2-hydroxyphenyl)-methanone
N-(3,5-Dichloro-2-hydroxybenzoyl)benzotriazole (prepared according to Katritizky et al., Synthesis 2007, 20, 3141-3146, which is expressly incorporated by reference herein; 2.0 g, 6.5 mmol) was stirred in dry THF (25 mL), cooled to −30° C., treated in portions with cyclopropylmagnesium bromide (0.5 M in THF; 28 mL, 14 mmol) and stirred at −30° C. for 30 min. The cooling bath was removed and the mixture was allowed to warm to 25° C. and stir for 3 h. The reaction was quenched by addition of 10 mL satd NH4Cl, and shaken with EtOAc (50 mL) plus 20% citric acid solution (30 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified ketone (450 mg): 1H NMR (400 MHz, CDCl3) δ 13.03 (s, 1H), 7.87 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H), 2.70-2.54 (m, 1H), 1.41-1.32 (m, 2H), 1.24-1.15 (m, 2H); EIMS m/z 230.
Example 3 Preparation of 1-(3,5-dichloro-2-hydroxyphenyl)-2-methylpropan-1-one
Methyl-3,5-dichlorosalicylate (prepared according to Ahmed et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in dry THF (30 mL), cooled to −40° C. and treated in portions with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol). The mixture was stirred at −20 to −40° C. for 45 min, warmed to 25° C. and stirred for 4 h. The excess reagent was quenched by addition of satd NH4Cl (10 mL). The mixture was diluted with EtOAc (50 mL) and the pH was adjusted to ˜1 by addition of 1 M HCl. The organic phase was washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by reverse-phase high-performance liquid chromatography (RP-HPLC) with 70% acetonitrile to give the purified ketone (1.1 g): mp: 102-104° C. 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z 232.
Example 4 Preparation of 2-hydroxy-3,5-bis-trifluoromethylbenzaldehyde
3,5-Bis(trifluoromethyl)anisaldehyde (prepared as in Sui and Macielag, Synth. Commun. 1997, 27, 3581-3590, which is expressly incorporated by reference herein; 2.0 g, 7.7 mmol) was dissolved in dry CH2Cl2 (15 mL), cooled to −78° C. and treated in portions with BBr3 (1 M solution in CH2Cl2; 8.0 mL, 8.0 mmol). The mixture was stirred and allowed to warm to 25° C. After 20 h, the mixture was cooled to −40° C., carefully treated with H2O (10 mL) and warmed to room temperature. The separated organic phase was washed with H2O (10 mL), satd NaCl solution (5 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with a 0 to 20% gradient of EtOAc in hexane to give the purified aldehyde (1.4 g, 70%) as an oil: 1H NMR (400 MHz, CDCl3) δ 12.05 (s, 1H), 10.02 (s, 1H), 8.07 (s, 2H). EIMS m/z 258.
Example 5 Preparation 5-chloro-2-hydroxy-3-trifluoromethylbenzaldehyde
5-Chloro-2-fluorobenzotrifluoride (1.5 g, 7.5 mmol) was dissolved in dry THF (10 mL), treated with tetramethylethylenediamine (TMEDA; 1.6 mL, 1.2 g, 11 mmol), cooled to −78° C. and treated in portions with n-butyl lithium (n-BuLi, 2.5 M in hexanes; 3.9 mL, 9.8 mmol). After stirring at −78° C. for 90 min, the mixture was treated with N,N-dimethylformamide (DMF; 770 μL, 730 mg, 10 mmol) and stirred for a further 30 min. The cooling bath was removed and mixture warmed to 25° C. over 30 min. The reaction was quenched by addition of satd NH4Cl solution then diluted with Et2O (30 mL). The separated organic phase was washed with satd NaCl (10 mL), dried (Na2SO4) and evaporated. The residue was dissolved in dry methanol (CH3OH; 10 mL) and treated with 30% sodium methoxide solution in CH3OH (14 g). The mixture was stirred at 25° C. for 20 h, diluted with H2O (50 mL) and extracted with Et2O (2×40 mL). The combined organic phases were washed with satd NaCl solution (20 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography using a 0 to 10% EtOAc gradient in hexane to give the benzaldehyde (1.1 g). This material (1.0 g, 4.2 mmol) was dissolved in dry CH2Cl2 (10 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 5 mL, 5 mmol). The mixture was allowed to warm to 25° C. and stir for 22 h. After cooling to −45° C., the mixture was treated with H2O (5 mL), warmed to 25° C. and extracted with EtOAc (2×15 mL). The combined extracts were washed with satd NaCl solution (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography using a 0 to 10% EtOAc gradient in hexane to give the aldehyde (950 mg): 1H NMR (400 MHz, CDCl3) δ 11.61 (s, 1H), 9.91 (s, 1H), 7.77 (dd, J=18.5, 2.6 Hz, 2H); EIMS m/z 224.
Example 6 Preparation of 3-chloro-2-hydroxy-5-trifluoromethylbenzaldehyde
3-Chloro-2-fluoro-5-trifluoromethylbenzaldehyde (5.0 g, 22 mmol) was dissolved in dry CH3OH (50 mL), treated with 25% sodium methoxide solution (30 mL) and heated to reflux for 2 h. After cooling the volatiles were removed by evaporation and the residue was taken up in H2O (20 mL) plus Et2O (80 mL). The aqueous phase was extracted with Et2O (50 mL), and the combined organic phases were washed with satd NaCl solution (15 mL), dried (Na2SO4) and evaporated. The residue was dissolved in dry CH2Cl2 (50 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 25 mL, 25 mmol). After warming to 25° C., the mixture was stirred for 21 h, cooled to −40° C. and quenched by addition of H2O (30 mL). After warming the aqueous phase was extracted with CH2Cl2 (30 mL), and the combined org. phases were washed with satd NaCl solution (30 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc gradient in hexane to give the purified aldehyde (2.7 g): 1H NMR (400 MHz, CDCl3) δ 11.81 (s, 1H), 9.96 (s, 1H), 7.87 (d, J=2.1 Hz, 1H), 7.84-7.77 (m, 1H); EIMS m/z 224.
Example 7 Preparation of 3-fluoro-5-formyl-4-hydroxybenzonitrile
4-Cyano-2-fluorophenol (5.0 g, 38 mmol) was dissolved in acetic acid (50 mL) and treated dropwise with stirring with bromine (6.4 g, 40 mmol). After 2 h at 25° C., H2O (100 mL) was added. The precipitated product was collected by filtration, washed well with H2O and then taken up in EtOAc (150 mL). The solution was washed with H2O (50 mL), satd NaCl solution (50 dmL), dried (Na2SO4) and evaporated. The residue was crystallized from aqueous ethanol (EtOH) to give the bromophenol (4.1 g). This material (3.4 g, 16 mmol) was dissolved in dry THF (100 mL), cooled to −78° C. and treated dropwise with n-BuLi (2.5 M in hexanes; 16 mL, 39 mmol) over 15 min. After stirring for 90 min at −78° C., DMF (3.5 mL, 3.3 g, 45 mmol) was added and stirring was continued for 30 min at −78° C. and then warmed to 25° C. over 2 h. Satd NH4Cl solution (25 mL) and Et2O (100 mL) were added, and the pH was adjusted to 2 with 1 M HCl. The separated organic phase was washed with satd NaCl solution, dried (Na2SO4) and evaporated. The residue was purified on silica gel chromatography with 10-50% EtOAc/hexane to give the aldehyde (2.1 g): 1H NMR (400 MHz, CDCl3) δ 11.48 (s, 1H), 9.96 (d, J=1.7 Hz, 1H), 7.78 (t, J=1.5 Hz, 2H), 7.61 (dd, J=9.8, 1.9 Hz, 2H); EIMS m/z 165.
Example 8 Preparation of 3-chloro-2-hydroxy-6-trifluoromethylbenzaldehyde
4-Chloro-3-fluoro-6-trifluoromethylbenzaldehyde (1.0 g, 4.4 mmol) was dissolved in dry CH3OH (10 mL), treated with 30% sodium methoxide solution in CH3OH (7.9 g, 44 mmol) and heated at reflux for 1 h. After cooling the mixture was diluted with H2O (15 mL) and extracted with Et2O (30 mL). The combined organic extracts were washed with satd NaCl solution (10 mL), dried (Na2SO4), and evaporated. The residue was purified by silica gel chromatography with 0-10% EtOAc/hexane to give the anisole intermediate (1.0 g). This material was dissolved in dry CH2Cl2 (15 mL), cooled to −78° C., treated with BBr3 (1 M in CH2Cl2; 5.0 mL, 5 mmol), allowed to warm to 25° C. and stir for 20 h. The reaction was cooled in ice and quenched by addition of H2O (10 mL). The separated organic phase was washed with satd NaCl solution (10 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-10% EtOAc/hexane to give the aldehyde (980 mg): 1H NMR (400 MHz, CDCl3) δ 12.78 (s, 1H), 10.28 (s, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.27 (d, J=8.5 Hz, 1H); EIMS m/z 224.
Example 9 Preparation of 5-chloro-2-hydroxy-4-trifluoromethylbenzaldehyde
2-Chloro-5-hydroxybenzotrifluoride (5.0 g, 25 mmol) was dissolved in acetic acid (50 mL) and treated with bromine (4.8 g, 30 mmol). The mixture was stirred at 25° C. for 6 h and poured into H2O (200 mL) with stirring. The precipitated phenol was collected by filtration and washed well with H2O. The solid was taken up in EtOAc (150 mL), washed with satd NaCl solution (50 mL), dried (Na2SO4) and evaporated to give product (6.0 g, circa 90% pure). This material (2.0 g, 7.3 mmol) was dissolved in dry THF (65 mL), cooled to −78° C. and treated dropwise with n-BuLi (2.5 M in hexanes; 6.4 mL, 16 mmol). The mixture was stirred for 90 min at −78° C. and treated with DMF (1.4 mL, 1.3 g, 18 mmol). After stirring at −78° C. for 30 min, the mixture was warmed to 25° C., quenched with satd NH4Cl solution (10 mL) and worked up with H2O (30 mL) and Et2O (75 mL). The organic phase was washed with satd NaCl (20 mL), dried (Na2SO4) and evaporated. The residue was purified by RP-HPLC to give the product (300 mg, ˜70% purity), which was used without further purification: EIMS m/z 224.
Example 10 Preparation of 2-hydroxy-4,6-bis-trifluoromethyl-benzaldehyde
3,5-Bis(trifluoromethyl)anisole (5.0 g 21 mmol) and TMEDA (4.0 mL, 3.0 g, 26 mmol) were dissolved in dry Et2O (60 mL), cooled to −10° C. and treated in portions with n-BuLi (2.5 M in hexanes; 10 mL, 25 mmol). The mixture was warmed to 25° C. and stirred for 90 min. The mixture was cooled to −78° C., treated dropwise with DMF (2.3 mL, 2.2 g, 30 mmol), stirred for 30 min, warmed to 25° C. and stirred for 30 min. The reaction was quenched by addition of H2O (50 mL) and extracted with Et2O (2×75 mL). The combined organic fractions were washed with satd NaCl solution (30 mL), dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography to give the anisaldehyde derivative (3.3 g). This material (3.0 g, 11 mmol) was dissolved in CH2Cl2 (75 mL), cooled to −78° C. and treated with BBr3 (1 M solution in CH2Cl2; 12 mL, 12 mmol). The mixture was stirred for 30 min at −78° C., warmed to 25° C. and stirred for 90 min H2O (100 mL) was added and stirring was continued for 30 min. The separated organic phase was washed with satd NaCl solution, dried (Na2SO4) and evaporated. The residue was purified by silica gel chromatography with 0-20% EtOAc/hexane to give the purified aldehyde (2.0 g): 1H NMR (400 MHz, CDCl3) δ 12.27 (s, 1H), 10.34 (s, 1H), 7.51 (s, 1H); EIMS m/z 258.
Example 11 Preparation of 1-(2-hydroxy-3-methoxyphenyl)-ethanone
1-(2-Hydroxy-3-methoxyphenyl)-ethanone was prepared from commercially available starting materials as described in US 038048, which is expressly incorporated by reference herein.
Example 12 Preparation of 1-(2-hydroxy-5-trifluoromethylphenyl)-ethanone
1-(2-Hydroxy-5-trifluoromethylphenyl)-ethanone was prepared from commercially available starting materials as described in EP 129812, which is expressly incorporated by reference herein.
Example 13 Preparation of 3,4-dichloro-2-hydroxybenzaldehyde
3,4-Dichloro-2-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Gu et al., J. Med. Chem. 2000, 43, 4868-4876, which is expressly incorporated by reference herein.
Example 14 Preparation of 3-bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde
3-Bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde was prepared from commercially available starting materials as described in Guiles et al., PCT Int. Appl. WO 2008039641 A2, which is expressly incorporated by reference herein.
Example 15 Preparation of 3-bromo-5-formyl-4-hydroxybenzonitrile
3-Bromo-5-formyl-4-hydroxybenzonitrile was prepared from commercially available starting materials as described in Sakaitani et al., PCT Int. Appl. WO 2004037816 A1, which is expressly incorporated by reference herein.
Example 16 Preparation of 3,6-dichloro-2-hydroxybenzaldehyde
3,6-Dichloro-2-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Rafferty et al., PCT Int. Appl. WO 2008121602 A1, which is expressly incorporated by reference herein.
Example 17 Preparation of 2-hydroxy-4-trifluoromethylbenzaldehyde
2-Hydroxy-4-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Faeh et al., U.S. Pat. Appl. Publ. 2007185113 A1, which is expressly incorporated by reference herein.
Example 18 Preparation of 2-hydroxy-5-trifluoromethylbenzaldehyde
2-Hydroxy-5-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Bonnert et al., PCT Int. Appl. WO 2006056752 A1, which is expressly incorporated by reference herein.
Example 19 Preparation of 2,3-dichloro-6-hydroxybenzaldehyde
2,3-Dichloro-6-hydroxybenzaldehyde was prepared from commercially available starting materials as described in Stokker et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly incorporated by reference herein.
Example 20 Preparation of 2-hydroxy-6-trifluoromethylbenzaldehyde
2-Hydroxy-6-trifluoromethylbenzaldehyde was prepared from commercially available starting materials as described in Stokker et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly incorporated by reference herein.
Example 21 Preparation of 2-hydroxy-6-methylbenzaldehyde
2-Hydroxy-6-methylbenzaldehyde was prepared from commercially available starting materials as described in Hofslokken and Skattebol, Acta Chemica Scandinavica 1999, 53, 258-262, which is expressly incorporated by reference herein.
Example 22 General Preparation of Ketone Compounds
Ketone compounds, wherein R2 is either i-propyl or t-butyl, were prepared from commercially available starting materials as described in Miller, J. A., J. Org. Chem. 1987, 52, 322-323, which is expressly incorporated by reference herein.
Example 23 Preparation of 3-trifluoromethoxy-benzoic acid [1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide
A suspension of 3,5-dichloro-2-hydroxy-benzaldehyde (0.200, 1.05 mmol) and 3-trifluoromethoxy-benzoic acid hydrazide (0.243 g, 1.05 mmol) in ethanol (3.3 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish 3-trifluoromethoxy-benzoic acid [1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide as an off-white solid (0.412 g, 99%): mp 180-182° C.; 1H NMR (400 MHz, DMSO) δ 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H); ESIMS m/z 393 ([M+H]+), 391 ([M−H]−).
Example 24 Preparation of benzoic acid [1-(3-chloro-2-hydroxyphenyl)-ethylidene]-hydrazide
A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100 g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to 60° C. for 18 hours. The reaction mixture was cooled to room temperature to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish benzoic acid [1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow solid (0.100 g, 59%): mp 202-203° C.; 1H NMR (400 MHz, DMSO) δ 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H), 6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H]+), 287 ([M−H]−.
Example 25 General Method for the Preparation of Benzoic Hydrazones of alkyl-o-hydroxyphenyl ketones The alkyl-o-hydroxyphenyl ketone (0.5 mmol) and benzoic hydrazide (0.75 mmol) were combined in n-propanol (5 mL) and acetic acid (4-5 drops) and heated to reflux for 20-24 h. Upon cooling the mixture was diluted with water (2-5 mL) in portions to induce precipitation. The solids were collected by filtration, washed with water and dried under vacuum at 80° C. After analysis by HPLC-MS most of the hydrazones were found to be sufficiently pure for testing. The less pure materials were purified by RP-HPLC using acetonitrile-water mixtures on a 10 mm×250 mm YMC-AQ column.
TABLE 1
Com- 1H NMR (400 MHz,
pound DMSO-d6
Num- ESIMS ESIMS unless otherwise
ber Structure mp (° C.) (+) (−) stated), δ
1 257 255
2 275 273
3 270 268
4 291 289
5 511 509
6 353 351
7 387 (+Na) 363
8 255 253
9 368 366
10 224-227 318 12.46 (s, 1H), 11.15 (s, 1H), 8.79 (d, J = 1.7 Hz, 1H), 8.68 (s, 1H), 8.51-8.35 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
11 323 321
12 259-262 320 318 12.43 (s, 1H), 11.15 (s, 1H), 8.67 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
13 381 379
14 311 309
15 197-198 259 257 12.27 (s, 1H), 11.64 (s, 1H), 8.67 (s, 1H), 8.02-7.89 (m, 2H), 7.68-7.52 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.35-7.24 (m, 1H), 6.99-6.88 (m, 1H)
16 309 307
17 209-213 356 354 14.30 (s, 1H), 11.43 (s, 1H), 7.61 (dd, J = 10.3, 2.5 Hz, 2H), 7.37 (dd, J = 7.7, 4.8 Hz, 2H), 7.16 (t, J = 8.9 Hz, 2H), 3.74 (s, 2H), 2.44 (s, 3H)
18 299 297
19 433 (+Na) 410
20 275 273
21 285 283
22 327 325
23 169-172 337 335 12.46 (s, 1H), 12.37 (s, 1H), 8.45 (s, 1H), 7.64 (dd, J = 7.5, 2.5 Hz, 2H), 7.34 (s, 1H), 7.28-7.20 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
24 241 239
25 271
26 381 379
27 246-247 337 335 12.51 (s, 1H), 12.34 (s, 1H), 8.45 (s, 1H), 7.64 (dd, J = 9.5, 2.5 Hz, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.18-7.10 (m, 2H), 2.38 (s, 3H), 2.33 (s, 3H)
28 447 (+Na) 423
29 283 281
30 159-160 297 295 13.48 (s, 1H), 11.43 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 7.17-7.09 (m, 2H), 6.94- 6.86 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 2.37 (s, 3H), 2.32 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H)
31 143-145 373 371 13.43 (s, 1H), 11.42 (s, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.33-7.26 (m, 6H), 7.25- 7.17 (m, 1H), 7.16-7.09 (m, 2H), 6.96-6.89 (m, 2H), 3.31-3.22 (m, 2H), 2.88-2.79 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
32 192-194 427 425 12.70 (s, 1H), 12.41 (s, 1H), 8.41 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.34 (s, 1H), 7.28-7.19 (m, 2H), 2.35 (s, 3H), 2.33 (s, 3H)
33 188-190 283 281 13.37 (s, 1H), 11.38 (s, 1H), 7.62 (dd, J = 7.8, 1.3 Hz, 1H), 7.35-7.27 (m, 2H), 7.26-7.15 (m, 2H), 6.94-6.86 (m, 2H), 2.42 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3H)
34 175-176 297 295 13.47 (s, 1H), 11.50 (s, 1H), 7.66-7.59 (m, 1H), 7.33- 7.27 (m, 2H), 7.26-7.16 (m, 2H), 6.95-6.87 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 2.33 (s, 6H), 1.11 (t, J = 7.5 Hz, 3H)
35 162-166 373 371 13.41 (s, 1H), 11.46 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 4.4 Hz, 5H), 7.25-7.20 (m, 3H), 7.16 (s, 1H), 6.96-6.89 (m, 2H), 3.32-3.24 (m, 2H), 2.87-2.80 (m, 2H), 2.33 (s, 3H), 2.32 (s, 3H)
36 269 267
37 300 298
38 269 267
39 283 281
40 297 295
41 261-263 349 12.58 (s, 1H), 12.46 (s, 1H), 8.57 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.2 Hz, 2H), 2.98 (hept, J = 6.7 Hz, 1H), 1.24 (d, J = 6.9 Hz, 6H)
42 270-272 441 439 12.80 (s, 1H), 12.49 (s, 1H), 8.53 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 7.0, 2.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 3.04-2.92 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H)
43 250-252 377 375 12.77, 12.67, 11.99, and 10.28 (4s, 2H), 8.45 and 8.31 (2s, 1H), 7.75-7.30 (m, 5H); Note: rotational isomers
44 148-163 361 359 13.37 (s, 1H), 11.41 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.48-7.41 (m, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.25 (dd, J = 8.1, 1.9 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 6.95- 6.87 (m, 2H), 3.02 (q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H)
45 204-208 413 411 13.08, 12.07, 12.00, 10.65 (4s, 2H), 7.70-7.40 (m, 4H), 7.38-7.14 (m, 6H), 7.00-6.65 (m, 2H), 3.29-3.18 (m, 2H), 2.80 (dd, J = 11.0, 5.3 Hz, 2H); Note: rotational isomers
46 170-171 401 399 12.54 (s, 1H), 12.47 (s, 1H), 8.57 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.28 (dd, J = 7.9, 2.2 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.12-7.06 (m, 2H)
47 178-180 347 345 13.31 (s, 1H), 11.37 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.67-7.62 (m, 1H), 7.60- 7.53 (m, 2H), 7.48-7.41 (m, 2H), 7.34-7.28 (m, 1H), 7.25 (dd, J = 7.9, 2.1 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.11-7.07 (m, 2H), 6.94-6.87 (m, 2H), 2.48 (s, 3H)
48 181-184 337 335 13.16, 11.95, 11.87, 10.73 (4s, 2H), 7.68-7.17 (m, 5H), 6.97-6.66 (m, 2H), 2.97-2.85 (m, 2H), 1.16-1.04 (m, 3H); Note: rotational isomers
49 173-177 379 377 13.24 (s, 1H), 11.74 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62-7.54 (m, 3H), 7.51- 7.47 (m, 1H), 7.35-7.28 (m, 5H), 7.24-7.19 (m, 1H), 6.97-6.89 (m, 2H), 3.30-3.22 (m, 2H), 2.87-2.79 (m, 2H)
50 303 301
51 270 268
52
53 285 283
54 289 287
55 333 (+Na) 309
56 106-111 377 375 12.62 (s, 1H), 12.17 (s, 1H), 8.45 (s, 1H), 7.92-7.88 (m, 1H), 7.83 (d, J = 7.0 Hz, 1H), 7.80-7.75 (m, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H)
57 220-222 403 401 14.32 (s, 1H), 11.91 (s, 1H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 1H), 7.55-7.45 (m, 2H), 2.45 (s, 3H)
58 208-210 323 321 13.18, 11.64, 11.59 (3s, 2H), 7.91-7.46 (m, 5H), 7.36- 7.14 (m, 1H), 6.95-6.60 (m, 2H), 2.40. 2.38 (2s, 3H); Note: rotational isomers
59 363 (+Na) 339
60 345 (+Na) 321
61 308 307
62 273 271
63 334
64 333 331
65 289
66 269 267
67 357 355
68 343 341
69 323
70 343 341
71 389 387
72 323
73 202-209 339 337 12.67 (s, 1H), 12.35 (s, 1H), 12.31 (s, 1H), 8.65 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 2.20 (s, 3H)
74 407 (+Na) 383
75 340
76 352
77 323 321
78 377
79 248-249 377 375 12.57 (s, 1H), 12.29 (s, 1H), 8.57 (s, 1H), 8.00-7.90 (m, 3H), 7.75- 7.61 (m, 2H)
80 385
81 238-240 377 375 12.71 (s, 1H), 12.37 (s, 1H), 8.61 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.68 (dd, J = 27.3, 2.5 Hz, 2H)
82 339 337
83 189-191 377 12.62 (s, 1H), 12.11 (s, 1H), 8.45 (s, 1H), 7.82 (t, J = 1.4 Hz, 1H), 7.71 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 1.4 Hz, 2H)
84 408 (+Na) 387
85 369 367
86 207-209 353 351 12.52 (s, 1H), 12.47 (s, 1H), 8.58 (s, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 7.55-7.50 (m, 1H), 7.50-7.43 (m, 2H), 7.19 (dd, J = 7.8, 1.9 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H)
87 364 363
88 369 367
89 325
90 399
91 324 322
92 215-217 359 12.70 (s, 1H), 12.60 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.13-8.07 (m, 2H), 8.06- 8.00 (m, 2H), 7.73-7.62 (m, 4H)
93 343
94 337
95 321
96 353
97 279-281 353 351 12.64 (s, 1H), 12.40 (s, 1H), 8.55 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H)
98 191-192 421 12.62, 12.57, 12.1, 10.35 (4s, 2H), 8.45, 8.28 (2s, 1H), 8.5-7.4 (m, 5H); Note: rotational isomers
99 192-194 353 351 12.40 (s, 2H), 8.44 (s, 1H), 7.64 (dd, J = 7.6, 2.5 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.19-7.03 (m, 2H), 3.84 (s, 3H), 2.20 (s, 3H)
100 220-229 393 391 12.61 (s, 1H), 12.44 (s, 1H), 8.58 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.75-7.49 (m, 4H)
101 327 325
102 207-209 339 337 12.56 (s, 1H), 12.44 (s, 1H), 8.56 (s, 1H), 7.65 (dd, J = 14.1, 2.5 Hz, 2H), 7.57 (s, 2H), 7.27 (s, 1H), 2.36 (s, 6H)
103 350
104 343
105 199-201 365 363 12.06 (s, 1H), 11.18 (s, 1H), 8.46 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.47-7.37 (m, 1H), 7.34-7.21 (m, 1H), 7.07 (dd, J = 27.1, 7.9 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H), 3.83 (s, 3H), 2.19 (s, 3H)
106 210-220 439 437 12.64 (s, 2H), 8.55 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.79-7.69 (m, 1H), 7.58 (d, J = 8.2 Hz, 1H)
107 191-195 345
108 188-189 443 12.65 (s, 1H), 12.43 (s, 1H), 8.40 (s, 1H), 7.81 (dd, J = 19.3, 2.3 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H), 7.19-7.02 (m, 2H), 3.84 (s, 3H), 2.14 (s, 3H)
109 224-230 483 481 12.66 (s, 2H), 8.54 (s, 1H), 8.09 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 16.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H)
110 209-211 427
111 237-239 449 447 12.81 (s, 1H), 12.74 (s, 1H), 8.60 (m, 2H), 8.19-7.97 (m, 4H), 7.85 (s, 2H), 7.72-7.54 (m, 2H)
112 430
113 475
114 427
115 413 411
116 415
117 267-269 465 12.76-12.63 (m, 1H), 12.59- 12.46 (m, 1H), 8.62-8.46 (m, 1H), 8.05-7.77 (m, 5H)
118 476
119 415
120 431
121 421 (+Na) 397
122 430
123 359 357
124 413 411
125 324 322
126 342 340
127 300 298
128 269 267
129 207-212 406 404 14.24 (s, 1H), 11.50 (s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 11.3, 2.5 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 3.88 (s, 2H), 2.45 (s, 3H)
130 269 267
131 283 281
132 187-189 397 395 12.63 (s, 1H), 12.43 (s, 1H), 8.41 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H),7.31 (t, J = 7.9 Hz, 1H), 7.18-7.04 (m, 2H), 3.84 (s, 3H), 2.20 (s, 3H)
133 122-128 317 12.06 (s, 1H), 11.17 (s, 1H), 8.46 (s, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.30 (ddd, J = 14.5, 7.7, 2.8 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 2.19 (s, 3H)
134 196-199 303 12.11 (s, 1H), 11.30 (s, 1H), 8.62 (s, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.56 (s, 2H), 7.32 (dd, J = 8.8, 2.7 Hz, 1H), 7.25 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.34 (s, 6H)
135 245-246 357 355 14.38 (s, 1H), 11.68 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H)
136 260-262 355 14.41 (s, 1H), 11.65 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.66-7.60 (m, 3H), 2.68-2.32 (m, 3H)
137 226-230 337 14.50 (s, 1H), 11.70 (s, 1H), 7.65 (dd, J = 11.7, 2.4 Hz, 2H), 7.53 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.39-7.29 (m, 2H), 2.45 (s, 3H), 2.41 (s, 3H).
138 247-253 403 401 14.38 (s, 1H), 11.68 (s, 1H), 8.14 (s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.87-7.83 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H)
139 401 399
140 199-204 338 336 14.27 (s, 1H), 11.44 (s, 1H), 7.61 (dd, J = 10.6, 2.5 Hz, 2H), 7.36-7.32 (m, 4H), 7.30-7.23 (m, 1H), 3.75 (s, 2H), 2.44 (s, 3H)
141 307-310 353 14.33 (s, 1H), 11.41 (s, 1H), 7.82-7.78 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.62- 7.56 (m, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 3.96 (s, 3H), 2.45 (s, 3H)
142 250-253 368 366 14.25 (s, 1H), 11.98 (s, 1H), 8.26-8.20 (m, 1H), 7.94- 7.88 (m, 1H), 7.85-7.78 (m, 2H), 7.67 (q, J = 2.5 Hz, 2H), 2.42 (s, 3H)
143 281
144 365 363
145 286 284
146 515 (+Na) 491
147 271 269
148 317
149 271 269
150 320 318
151 374 (+Na) 351
152 284
153 362
154 271 269
155 316 314
156 349 347
157 289 287
158 335 333
159 411 (+Na)
160 399 397
161 387
162 367
163 456 (+Na)
164 250-251 423 419 12.75 (s, 1H), 12.60 (s, 1H), 8.57 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 7.76 (q, J = 2.5 Hz, 2H)
165 218-221 385 383 12.58 (s, 1H), 12.35 (s, 1H), 8.61 (s, 1H), 7.85-7.77 (m, 1H), 7.75 (dd, J = 6.9, 2.5 Hz, 2H), 7.41 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 2.20 (s, 3H)
166 166-168 385 381 12.72 (s, 1H), 12.52 (s, 1H), 8.55 (s, 1H), 7.73 (dd, J = 14.6, 2.5 Hz, 2H), 7.59- 7.43 (m, 3H), 7.27-7.12 (m, 1H), 3.85 (s, 3H)
167 203-205 269 12.04 (s, 1H), 11.31 (s, 1H), 8.64 (s, 1H), 7.62-7.49 (m, 3H), 7.36-7.27 (m, 1H), 7.24 (s, 1H), 6.93 (t, J = 8.5 Hz, 2H), 2.36 (s, 6H)
168 223-226 382 380 12.76 (s, 1H), 12.47 (s, 1H), 8.53 (s, 1H), 7.73 (dd, J = 18.0, 2.5 Hz, 2H), 7.57 (s, 2H), 7.28 (s, 1H), 2.36 (s, 6H)
169 373 371
170 354
171 354
172 307
173 318 317
174 255 253
175 275 273
176 375 (+Na) 351
177
178 331 (+Na)
179 332
180 287
181 354
182 319 317
183 339 (+Na) 315
184 219-222 388 386 12.36 (s, 1H), 11.19 (s, 1H), 8.65 (s, 1H), 8.04 (dd, J = 80.4, 8.3 Hz, 4H), 7.83 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H)
185 349 347
186 196-202 389 387 12.25 (s, 1H), 10.99 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.80-7.76 (m, 1H), 7.66- 7.57 (m, 3H), 7.45 (dd, J = 8.8, 2.6 Hz, 1H), 7.37-7.31 (m, 1H)
187 213-218 343 341 12.36 (s, 1H), 11.18 (s, 1H), 8.66 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 2.6 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
188 305 303
189 185-188 344 342 12.25 (s, 1H), 10.98 (s, 1H), 8.47 (s, 1H), 7.81-7.67 (m, 1H), 7.66-7.57 (m, 2H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 7.23 (dt, J = 3.5, 2.3 Hz, 1H), 6.91 (dd, J = 42.1, 8.6 Hz, 1H)
190 353 351
191 351
192 385
193 432 431
194 369 367
195 367
196 169-173 423 421 12.67 (s, 1H), 12.32 (s, 1H), 8.42 (s, 1H), 7.82 (t, J = 1.3 Hz, 1H), 7.77 (dd, J = 12.0, 2.5 Hz, 2H), 7.65 (d, J = 1.3 Hz, 2H)
197 321 319
198 525
199 354 352
200 305 303
201 276-280 399 397 13.87 (s, 1H), 12.82 (s, 1H), 8.71 (s, 1H), 8.65 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.02 (t, J = 1.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.73 (dd, J = 8.0, 2.0 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H).
202 379
203 385 383
204 429 427
205 383 381
206 363 361
207 305 303
208 283-300 393 391 14.01 (s, 1H), 12.65 (s, 1H), 8.69 (s, 1H), 8.60 (d, J = 2.7 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 7.59 (s, 2H), 7.29 (s, 1H), 2.37 (s, 6H)
209 189-193 378 376 12.07 (s, 1H), 10.90 (s, 1H), 8.61 (s, 1H), 7.55 (s, 2H), 7.40 (d, J = 2.2 Hz, 1H), 7.24 (s, 1H), 7.17 (d, J = 2.2 Hz, 1H), 3.85 (s, 3H), 2.35 (s, 6H)
210 369 367
211 220-227 393 391 11.76 (s, 1H), 8.19 (s, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.6 Hz, 1H), 7.04 (s, 2H), 6.94 (s, 1H), 2.18 (s, 6H), 1.53 (s, 9H)
212 289 287
213 271 269
214 285 283
215 300 298
216 323 321
217 91-104 297 295 10.78 (s, 1H), 8.18 (s, 1H), 7.42-7.37 (m, 2H), 7.34 (dd, J = 7.7, 1.7 Hz, 1H), 7.32-7.24 (m, 4H), 6.80 (td, J = 8.3, 4.4 Hz, 2H), 1.53 (s, 9H)
218 222-225 354 352 12.17 (s, 1H), 10.94 (s, 6H), 7.78-7.71 (m, 15H), 7.62-7.57 (m, 9H), 7.53 (dd, J = 8.6, 2.6 Hz, 6H), 7.27 (dddd, J = 27.4, 15.4, 7.9, 1.7 Hz, 14H), 6.96- 6.89 (m, 12H), 6.83-6.76 (m, 7H)
219 228-231 423 421 12.60 (s, 1H), 12.10 (s, 1H), 7.80-7.75 (m, 2H), 7.69 (dd, J = 19.8, 2.6 Hz, 2H), 7.57 (dd, J = 2.5, 1.2 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H)
220 215-218 512 510 12.65 (s, 1H), 12.35 (s, 1H), 7.87 (q, J = 2.4 Hz, 2H), 7.82-7.75 (m, 3H), 7.64 (dd, J = 17.0, 2.4 Hz, 1H), 7.55 (ddd, J = 8.5, 6.0, 2.6 Hz, 1H)
221 202-205 446 444 12.14 (s, 1H), 10.95 (s, 1H), 8.48 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H), 7.80-7.72 (m, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.50 (dd, J = 12.0, 8.4 Hz, 1H), 7.35-7.18 (m, 1H), 6.96-6.89 (m, 1H), 6.80 (dd, J = 12.3, 5.2 Hz, 1H)
222 201-219 514 512 12.57 (s, 1H), 12.12 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.81 (ddd, J = 11.4, 10.0, 2.2 Hz, 2H), 7.71 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H)
223 215-216 603 601 12.62 (s, 1H), 12.36 (s, 1H), 8.40 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.86 (dd, J = 7.4, 2.3 Hz, 2H), 7.82-7.76 (m, 2H), 7.53 (d, J = 8.4 Hz, 1H)
224 222-226 401 399 12.15 (s, 1H), 10.94 (s, 1H), 8.49 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.88 (dd, J = 8.4, 2.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.59 (dd, J = 7.7, 1.6 Hz, 1H), 6.97-6.89 (m, 2H), 6.84-6.76 (m, 1H)
225 198-201 470 8.44 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.89 (td, J = 8.7, 2.1 Hz, 2H), 7.68 (dd, J = 16.4, 2.5 Hz, 2H), 7.43-7.36 (m, 2H)
226 205-212 559 12.64 (s, 1H), 12.36 (s, 1H), 8.40 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.93-7.83 (m, 3H), 7.40 (t, J = 5.0 Hz, 1H)
227 86-122 334 332 12.04 (d, J = 17.6 Hz, 1H), 11.05 (s, 1H), 7.62-7.52 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.34-7.26 (m, 2H), 6.96-6.88 (m, 2H), 6.80 (t, J = 6.0 Hz, 1H), 2.36 (s, 3H)
228 240-242 403 401 12.49 (s, 1H), 12.25 (s, 1H), 8.44 (s, 1H), 7.67 (dd, J = 13.6, 2.5 Hz, 2H), 7.60 (d, J = 4.1 Hz, 1H), 7.56-7.43 (m, 1H), 7.33 (dd, J = 6.3, 2.2 Hz, 1H), 2.37 (d, J = 2.8 Hz, 3H)
229 258-261 491 489 12.53 (s, 1H), 12.48 (s, 1H), 8.40 (s, 1H), 7.84 (dd, J = 11.5, 2.4 Hz, 2H), 7.60 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.34 (q, J = 7.8 Hz, 1H), 2.37 (d, J = 3.5 Hz, 3H)
230 185-187 255 253 (300 MHz, CDCl3) 12.73 (s, 1H), 9.00 (s, 1H), 7.90- 7.82 (m, 2H), 7.64-7.57 (m, 1H), 7.55-7.47 (m, 3H), 7.35-7.28 (m, 1H), 7.09-7.00 (m, 1H), 6.94- 6.87 (m, 1H), 2.42 (s, 3H)
231 188-189 275 273 12.47 (s, 1H), 12.40 (s, 1H), 8.63 (s, 1H), 8.07-7.91 (m, 2H), 7.70-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H)
232 186-188 255 12.24 (s, 1H), 11.96 (s, 1H), 8.59 (s, 1H), 8.08-7.89 (m, 2H), 7.71-7.43 (m, 3H), 7.26 (dd, J = 24.4, 7.4 Hz, 2H), 6.86 (t, J = 7.5 Hz, 1H), 2.23 (s, 3H)
233 218-219 275 273 12.16 (s, 1H), 11.60 (s, 1H), 8.65 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.59 (dt, J = 14.8, 7.7 Hz, 4H), 7.10-6.83 (m, 2H)
234 179-182 255 253 12.08 (s, 1H), 11.32 (s, 1H), 8.61 (s, 1H), 8.08-7.81 (m, 2H), 7.70-7.47 (m, 3H), 7.42 (d, J = 7.8 Hz, 1H), 6.89-6.68 (m, 2H), 2.29 (s, 3H)
235 192-193 255 253 12.11 (s, 1H), 11.06 (s, 1H), 8.61 (s, 1H), 8.01-7.84 (m, 2H), 7.59 (dt, J = 27.8, 7.2 Hz, 3H), 7.36 (d, J = 1.4 Hz, 1H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 2.26 (s, 3H)
236 247-248 275 273 12.53 (s, 1H), 12.48 (s, 1H), 9.06 (s, 1H), 8.08-7.90 (m, 2H), 7.62 (dt, J = 28.8, 7.2 Hz, 3H), 7.34 (t, J = 8.2 Hz, 1H), 7.06 (dd, J = 7.9, 0.7 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H)
237 215-216 271 269 12.26 (s, 1H), 12.21 (s, 1H), 8.98 (s, 1H), 8.03-7.90 (m, 2H), 7.66-7.49 (m, 3H), 7.28 (t, J = 8.3 Hz, 1H), 6.57 (dd, J = 8.3, 3.6 Hz, 2H), 3.86 (s, 3H)
238 249-252 289 287 12.88 (s, 1H), 12.46 (s, 1H), 8.61 (s, 1H), 8.04-7.89 (m, 2H), 7.60 (ddd, J = 12.6, 11.5, 6.4 Hz, 4H), 7.23 (d, J = 8.4 Hz, 1H)
239 206-208 289 287 12.18 (s, 1H), 11.29 (s, 1H), 8.59 (s, 1H), 7.95 (dd, J = 11.2, 4.0 Hz, 2H), 7.69- 7.47 (m, 4H), 6.94 (s, 1H), 2.30 (s, 3H)
240 238-241 309 307 12.25 (s, 1H), 11.61 (s, 1H), 8.62 (s, 1H), 8.08-7.71 (m, 2H), 7.68-7.29 (m, 4H), 7.19 (s, 1H)
241 273-274 309 307 12.76 (s, 1H), 12.55 (s, 1H), 9.06 (s, 1H), 8.09-7.90 (m, 2H), 7.62 (ddd, J = 22.7, 11.1, 7.0 Hz, 4H), 7.00 (d, J = 9.0 Hz, 1H)
242 273-274 309 307 12.92 (s, 1H), 12.52 (s, 1H), 8.98 (s, 1H), 8.09-7.88 (m, 2H), 7.73-7.52 (m, 3H), 7.22 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H)
243 187-189 349 347 12.77 (s, 1H), 12.50 (s, 1H), 9.00 (s, 1H), 8.11-7.87 (m, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.16 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H)
244 206-207 277 275 12.45 (d, J = 10.6 Hz, 1H), 12.42 (s, 1H), 8.77 (s, 1H), 7.97 (d, J = 7.5 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.44- 7.23 (m, 1H), 6.81 (td, J = 9.5, 3.4 Hz, 1H)
245 216-218 259 257 12.35 (s, 1H), 12.10 (s, 1H), 8.82 (s, 1H), 8.04-7.89 (m, 2H), 7.76-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.36 (dd, J = 15.2, 8.3 Hz, 1H), 6.91-6.70 (m, 2H)
246 212-213 255 253 12.19 (s, 2H), 8.92 (s, 1H), 8.03-7.90 (m, 2H), 7.69- 7.60 (m, 1H), 7.57 (t, J = 7.3 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 6.78 (dd, J = 14.2, 7.8 Hz, 2H), 2.43 (s, 3H)
247 204-205 309 307 13.45 (s, 1H), 12.61 (s, 1H), 9.02 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 8.6 Hz, 1H)
248 234-237 354 352 12.72 (s, 1H), 12.45 (s, 1H), 8.80 (t, J = 1.9 Hz, 1H), 8.62 (s, 1H), 8.51-8.37 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 24.9, 2.5 Hz, 2H)
249 165-169 375 12.70 (s, 1H), 12.38 (s, 1H), 8.60 (s, 1H), 8.32-8.23 (m, 2H), 8.02 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.68 (dd, J = 24.6, 2.5 Hz, 2H)
250 180-182 393 391 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 8.01 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H)
251 236-237 289 287 13.78 (s, 1H), 11.43 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.70-7.51 (m, 2H), 7.03- 6.92 (m, 4H), 2.49 (s, 3H)
252 214-215 303 301 13.77 (s, 1H), 11.51 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.43 (dd, J = 10.7, 4.3 Hz, 1H), 7.36-7.29 (m, 2H), 7.01-6.92 (m, 2H), 2.41 (s, 3H), 2.40 (s, 3H)
253 210-211 303 301 13.79 (s, 1H), 11.38 (s, 1H), 7.78-7.70 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48- 7.40 (m, 2H), 7.01-6.93 (m, 2H), 2.48 (s, 3H), 2.41 (s, 3H)
254 254-256 303 301 13.80 (s, 1H), 11.33 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.02-6.91 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H)
255 183-184 323 321 13.60 (s, 1H), 11.72 (s, 1H), 7.67-7.45 (m, 5H), 7.02- 6.94 (m, 2H), 2.41 (s, 3H)
256 222-223 323 321 13.69 (s, 1H), 11.52 (s, 1H), 8.02-7.97 (m, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.73-7.65 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.02-6.94 (m, 2H), 2.49 (s, 3H)
257 246-247 323 321 13.72 (s, 1H), 11.48 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.02-6.93 (m, 2H), 2.49 (s, 3H)
258 277-280 337 12.42 (s, 2H), 11.47 (s, 1H), 8.61 (s, 1H), 7.66 (d, J = 13.7 Hz, 3H), 7.28 (dd, J = 8.4, 1.9 Hz, 1H), 6.91 (d, J = 8.4 Hz, 1H), 2.28 (s, 3H)
259 245-253 336 12.81 (s, 1H), 12.16 (s, 1H), 8.51 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.61 (dd, J = 13.2, 2.5 Hz, 2H), 6.61 (d, J = 8.7 Hz, 2H), 6.50 (q, J = 4.8 Hz, 1H), 2.75 (d, J = 4.9 Hz, 3H)
260 286-289 337 335 12.58 (s, 1H), 12.48 (s, 1H), 8.57 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H)
261 150-152 285 283 12.85 (s, 1H), 11.33 (s, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.8 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.49 (s, 3H)
262 146-155 299 297 12.81 (s, 1H), 11.40 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.46-7.40 (m, 1H), 7.33 (dd, J = 7.5, 3.9 Hz, 2H), 7.11 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.41 (s, 3H), 2.40 (s, 3H)
263 131-141 299 297 12.84 (s, 1H), 11.29 (s, 1H), 7.78-7.70 (m, 2H), 7.43 (d, J = 5.2 Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H)
264 159-162 299 297 12.86 (s, 1H), 11.24 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.48 (s, 3H), 2.40 (s, 3H)
265 170-184 319 317 12.67 (s, 1H), 11.61 (s, 1H), 7.65-7.44 (m, 5H), 7.11 (d, J = 3.0 Hz, 1H), 7.01- 6.92 (m, 1H), 3.75 (s, 3H), 2.41 (s, 3H)
266 190-201 319 317 12.75 (s, 1H), 11.43 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.9 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.50 (s, 3H)
267 193-196 319 317 12.79 (s, 1H), 11.39 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.49 (s, 3H).
268 215-224 300 298 15.25 (s, 1H), 11.65 (s, 1H), 8.02-7.91 (m, 4H), 7.66 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
269 193-196 314 312 15.27 (s, 1H), 11.76 (s, 1H), 7.95 (dd, J = 13.4, 7.5 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.4 Hz, 1H), 7.35 (dd, J = 7.5, 4.3 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)
270 235-239 314 312 15.25 (d, J = 8.4 Hz, 1H), 11.60 (s, 1H), 7.96 (ddd, J = 21.0, 8.0, 1.4 Hz, 2H), 7.76 (d, J = 11.3 Hz, 2H), 7.46 (d, J = 6.3 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.42 (s, 3H)
271 242-249 314 312 15.28 (s, 1H), 11.55 (s, 1H), 7.96 (ddd, J = 20.2, 8.0, 1.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.41 (s, 3H)
272 196-205 334 332 15.04 (s, 1H), 11.97 (s, 1H), 8.00-7.92 (m, 2H), 7.68- 7.53 (m, 3H), 7.49 (td, J = 7.3, 1.3 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 2.48 (s, 3H)
273 251-286 334 332 15.13 (s, 1H), 11.73 (s, 1H), 8.04-7.89 (m, 4H), 7.73 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 2.57 (s, 3H)
274 241-251 334 332 15.17 (s, 1H), 11.70 (s, 1H), 7.99 (d, J = 8.5 Hz, 3H), 7.94 (dd, J = 8.1, 1.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
275 216-222 343 341 13.24 (s, 1H), 12.64 (s, 1H), 8.69 (s, 1H), 8.04-7.88 (m, 4H), 7.62 (dt, J = 31.2, 7.3 Hz, 3H)
276 144-193 377 375 13.34 (s, 1H), 12.74 (s, 1H), 8.97 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.72-7.65 (m, 2H), 7.60 (t, J = 7.5 Hz, 3H)
277 214-217 309 307 12.25 (s, 1H), 11.84 (s, 1H), 8.73 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 7.9 Hz, 2H), 7.59 (dt, J = 30.0, 7.5 Hz, 4H), 7.12 (d, J = 8.6 Hz, 1H)
278 221-223 337 335 14.48 (s, 1H), 11.54 (s, 1H), 7.79-7.72 (m, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.47- 7.42 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H)
279 262-264 337 335
280 211-213 285 283
281 170-172 299 297 13.65 (s, 1H), 11.29 (s, 1H), 7.53 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 6.9 Hz, 1H), 7.34-7.28 (m, 2H), 6.51- 6.44 (m, 2H), 3.78 (s, 3H), 2.40 (s, 3H), 2.37 (s, 3H)
282 184-185 299 297 13.68 (s, 1H), 11.19 (s, 1H), 7.77-7.68 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.46- 7.40 (m, 2H), 6.51-6.44 (m, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H)
283 206-207 299 297 13.69 (s, 1H), 11.14 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 6.52-6.44 (m, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.39 (s, 3H)
284 174-175 319 317
285 212-214 319 317
286 227-229 319 317
287 204-208 334 332 13.49 (s, 1H), 11.45 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.76 (d, J = 2.3 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H)
288 201-203 348 346 13.49 (s, 1H), 11.53 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.33 (dd, J = 7.4, 4.5 Hz, 2H), 6.90 (d, J = 8.7 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H)
289 227-233 348 346 13.50 (s, 1H), 11.40 (s, 1H), 7.75 (t, J = 5.9 Hz, 3H), 7.49-7.41 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)
290 245-248 348 346 13.51 (s, 1H), 11.36 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 2.48 (s, 3H), 2.40 (s, 3H)
291 198-201 368 366 13.31 (s, 1H), 11.73 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (dd, J = 13.1, 4.7 Hz, 3H), 6.91 (d, J = 8.7 Hz, 1H), 2.41 (s, 3H)
292 235-240 368 366 13.40 (s, 1H), 11.54 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.50 (s, 3H)
293 264-268 366 13.43 (s, 1H), 11.50 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H)
294 215-217 309 307 12.24 (s, 1H), 11.56 (s, 1H), 8.73 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.87 (d, J = 8.0 Hz, 1H), 7.67-7.60 (m, 1H), 7.60-7.52 (m, 2H), 7.29-7.20 (m, 2H)
295 232-234 377 375 13.92 (s, 1H), 12.78 (s, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.94 (s, 1H), 7.70-7.64 (m, 1H), 7.62-7.56 (m, 2H)
296 170-173 309 307 13.03 (s, 1H), 12.49 (s, 1H), 8.65 (s, 1H), 7.97 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.71-7.62 (m, 2H), 7.61-7.53 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H)
297 228-230 309 307 12.93 (s, 1H), 12.56 (s, 1H), 8.96 (s, 1H), 8.01-7.94 (m, 2H), 7.70-7.62 (m, 1H), 7.62-7.55 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H)
298 207-209 365 363 12.54 (s, 1H), 12.50 (s, 1H), 8.55 (s, 1H), 7.99-7.92 (m, 2H), 7.68-7.61 (m, 1H), 7.61-7.50 (m, 4H), 2.50 (s, 3H)
299 146-148 285 283 13.50 (s, 1H), 11.34 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.66-7.60 (m, 1H), 7.59-7.52 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H)
300 208-209 299 297 13.50 (s, 1H), 11.40 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.36- 7.27 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.41 (s, 6H)
301 121-123 299 297 13.51 (s, 1H), 11.28 (s, 1H), 7.79-7.68 (m, J = 9.6 Hz, 2H), 7.46-7.40 (m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H)
302 146-148 299 297 13.53 (s, 1H), 11.24 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.47 (s, 3H), 2.40 (s, 3H)
303 233-234 319 317 13.34 (s, 1H), 11.61 (s, 1H), 7.64 (dd, J = 7.5, 1.5 Hz, 1H), 7.61-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.25-7.20 (m, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H)
304 146-148 319 317 13.42 (s, 1H), 11.43 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.49 (s, 3H)
305 168-170 319 317 13.44 (s, 1H), 11.39 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H)
306 290-291 344 13.66 (s, 1H), 12.68 (s, 1H), 8.59 (s, 1H), 8.19 (dd, J = 8.5, 1.8 Hz, 2H), 7.97 (d, J = 7.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H)
307 262-263 384 382 12.70 (s, 1H), 12.48 (s, 1H), 8.67 (s, 1H), 8.07-7.80 (m, 4H), 7.65 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H)
308 262-269 339 337 12.44 (s, 1H), 12.31 (s, 1H), 11.71 (s, 1H), 8.62 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.65 (dd, J = 6.5, 2.4 Hz, 2H), 6.81 (d, J = 7.5 Hz, 2H), 2.31 (s, 3H)
309 252-271 334 332 12.66 (s, 1H), 12.33 (s, 1H), 8.58 (s, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.7 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 2.5 Hz, 1H)
310 234-270 332 12.82 (s, 1H), 12.37 (s, 1H), 8.11-8.02 (m, 4H), 7.76 (dd, J = 15.4, 2.6 Hz, 3H)
311 197-199 269 267 13.11 (s, 1H), 11.31 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.44 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.48 (s, 3H), 2.28 (s, 3H)
312 154-156 283 281 13.11 (s, 1H), 11.37 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 5.6 Hz, 2H), 7.32 (dd, J = 7.4, 4.2 Hz, 2H), 7.11 (dd, J = 8.3, 1.6 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.40 (s, 6H), 2.27 (s, 3H)
313 182-184 283 281 13.12 (s, 1H), 11.26 (s, 1H), 7.74 (d, J = 9.7 Hz, 2H), 7.43 (d, J = 5.2 Hz, 3H), 7.12 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.27 (s, 3H)
314 206-208 283 281 13.13 (s, 1H), 11.22 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H)
315 154-158 303 301 12.95 (s, 1H), 11.59 (s, 1H), 7.65-7.57 (m, 2H), 7.46 (ddd, J = 12.5, 9.1, 1.4 Hz, 3H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.40 (s, 3H), 2.27 (s, 3H)
316 231-241 303 301 13.02 (s, 1H), 11.41 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.45 (s, 1H), 7.13 (dd, J = 8.3, 1.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.49 (s, 3H), 2.28 (s, 3H)
317 203-210 303 301 13.05 (s, 1H), 11.37 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.45 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.48 (s, 3H), 2.27 (s, 3H)
318 242-243 343 341 12.33 (s, 1H), 11.64 (s, 1H), 8.69 (s, 1H), 7.96 (d, J = 6.2 Hz, 3H), 7.64 (t, J = 7.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.36 (s, 1H)
319 216-218 343 341 13.84 (s, 1H), 12.70 (s, 1H), 8.95 (d, J = 1.2 Hz, 1H), 8.03-7.95 (m, 2H), 7.76- 7.64 (m, 2H), 7.60 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H)
320 225-226 343 341 13.15 (s, 1H), 12.64 (s, 1H), 8.61 (s, 1H), 8.04-7.90 (m, 3H), 7.75-7.52 (m, 4H)
321 204-206 357 355 13.74-12.87 (m, 1H), 12.60 (s, 1H), 8.68 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 1.1 Hz, 1H), 7.82-7.72 (m, 2H), 7.46 (d, J = 5.0 Hz, 2H), 2.41 (s, 3H)
322 269-271 357 355 13.15 (s, 1H), 12.69 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (dd, J = 19.3, 8.7 Hz, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 2.40 (s, 3H)
323 210-212 361 359 13.15 (s, 1H), 12.69 (s, 1H), 8.69 (s, 1H), 8.03 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (dd, J = 19.3, 8.7 Hz, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H)
324 200-202 361 359 13.4 (s, 1H), 12.66 (s, 1H), 8.68 (s, 1H), 8.11-7.98 (m, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.35-7.24 (m, 1H)
325 210-212 377 375 13.1 (s, 1H), 12.71 (s, 1H), 8.68 (s, 1H), 8.02 (d, J = 7.2 Hz, 2H), 7.93 (d, J = 10.3 Hz, 2H), 7.72 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H)
326 208-210 377 13.25 (s, 1H), 12.70 (s, 1H), 8.68 (s, 1H), 8.07-7.95 (m, 3H), 7.90 (d, J = 1.7 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H)
327 237-238 388 386 12.95 (s, 2H), 8.80 (t, J = 1.8 Hz, 1H), 8.72 (s, 1H), 8.48 (dd, J = 8.2, 1.4 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.88 (dd, J = 13.6, 5.3 Hz, 2H)
328 253-255 388 386 12.96 (s, 2H), 8.71 (s, 1H), 8.41 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H), 8.04 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H)
329 258-260 359 357 13.11 (s, 1H), 12.35 (s, 1H), 11.45 (s, 1H), 8.73 (s, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.95-7.83 (m, 2H), 7.54-7.40 (m, 1H), 7.00 (dd, J = 14.0, 7.4 Hz, 2H)
330 169-171 411 409 12.84 (s, 1H), 12.73 (s, 1H), 8.56 (s, 1H), 8.03 (s, 1H), 7.94-7.56 (m, 5H)
331 255-257 373 371 13.09 (s, 1H), 12.37 (s, 1H), 11.63 (s, 1H), 8.72 (s, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.90 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 3H), 2.32 (d, J = 6.7 Hz, 3H)
332 210-213 391 389 13.92 (s, 1H), 12.73 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H), 7.81-7.74 (m, 2H), 7.50-7.43 (m, 2H), 2.42 (s, 3H)
333 274-277 391 389 13.94 (s, 1H), 12.70 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 7.93 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H)
334 240-242 395 393 13.81 (s, 1H), 12.83 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.69-7.61 (m, 1H), 7.53 (td, J = 8.4, 2.1 Hz, 1H)
335 226-228 395 393 13.87 (s, 1H), 12.79 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.06 (dd, J = 8.7, 5.5 Hz, 2H), 7.94 (s, 1H), 7.47-7.39 (m, 2H)
336 230-233 411 409 13.80 (s, 1H), 12.85 (s, 1H), 8.71 (s, 1H), 8.37 (s, 1H), 8.04-8.00 (m, 1H), 7.97- 7.91 (m, 2H), 7.74 (d, J = 9.1 Hz, 1H), 7.66-7.59 (m, 1H)
337 233-236 411 409 13.85 (s, 1H), 12.84 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.94 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H)
338 256-258 420 13.76 (s, 1H), 13.08 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.75 (s, 1H), 8.50 (dd, J = 8.2, 1.4 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.89 (t, J = 8.0 Hz, 1H)
339 244-247 420 13.75 (s, 1H), 13.07 (s, 1H), 8.75 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.39 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.96 (s, 1H)
340 231-235 393 391 13.79 (s, 1H), 12.50 (s, 1H), 11.47 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.44 (m, 1H), 7.05-6.96 (m, 2H)
341 210-214 445 443 13.59, 12.89, 12.70, 11.12 (4s, 2H), 8.60, 8.38 (2s, 1H), 8.36, 8.15 (2s, 1H), 7.97-7.63 (m, 5H); Note: rotational isomers
342 251-254 407 405 13.80 (s, 1H), 12.48 (s, 1H), 11.60 (s, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 6.87-6.78 (m, 2H), 2.32 (s, 3H)
343 188-190 323 321 (300 MHz, DMSO-d6) 13.03 (s, 1H), 12.44 (s, 1H), 8.64 (s, 1H), 7.82-7.72 (m, 3H), 7.67 (d, J = 7.3 Hz, 1H), 7.46 (d, J = 5.0 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 2.41 (s, 3H)
344 239-241 323 321 (300 MHz, DMSO-d6) 13.05 (s, 1H), 12.41 (s, 1H), 8.64 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H), 7.38 (d, J = 7.9 Hz, 2H), 7.10 (t, J = 7.8 Hz, 1H), 2.40 (s, 3H)
345 176-180 327 325 (300 MHz, DMSO-d6) 12.92 (s, 1H), 12.54 (s, 1H), 8.65 (s, 1H), 7.86-7.73 (m, 3H), 7.72-7.59 (m, 2H), 7.51 (td, J = 8.5, 2.2 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H)
346 187-188 327 (300 MHz, DMSO-d6) 12.96 (s, 1H), 12.52 (s, 1H), 8.64 (s, 1H), 8.10-8.00 (m, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.11 (t, J = 7.7 Hz, 1H)
347 185-187 343 341 (300 MHz, DMSO-d6) 12.91 (s, 1H), 12.56 (s, 1H), 8.65 (s, 1H), 8.04-7.98 (m, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.1 Hz, 1H), 7.76-7.71 (m, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H)
348 215-216 343 341 12.96 (s, 1H), 12.55 (s, 1H), 8.64 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.71-7.63 (m, 3H), 7.11 (t, J = 7.7 Hz, 1H)
349 215-217 354 352 12.84 (s, 2H), 8.83-8.77 (m, 1H), 8.68 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.12 (t, J = 1.1 Hz, 1H)
350 253-255 352 12.86 (s, 2H), 8.67 (s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 7.1 Hz, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H)
351 230-234 325 323 12.95 (s, 1H), 12.28 (s, 1H), 11.56 (s, 1H), 8.71 (s, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.52-7.44 (m, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.05-6.96 (m, 2H)
352 248-253 339 337 12.95 (s, 1H), 12.26 (s, 1H), 11.67 (s, 1H), 8.70 (s, 1H), 7.80 (t, J = 9.1 Hz, 2H), 7.67 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.83 (d, J = 7.4 Hz, 2H), 2.31 (s, 3H)
353 169-171 377 375 12.78, 12.63, 12.47, 10.39 (4s, 2H), 8.50, 8.29 (2s, 1H), 7.92-7.54 (m, 6H), 7.11, 7.04 (2t, J = 1.1 Hz, 1H); Note: rotational isomers
354 212-214 323 321 12.89 (s, 1H), 12.41 (s, 1H), 8.60 (s, 1H), 7.79-7.70 (m, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 4.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 2.41 (s, 3H)
355 254-256 323 321 12.92 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 2.40 (s, 3H)
356 215-218 327 325 12.75 (s, 1H), 12.50 (s, 1H), 8.61 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.79-7.73 (m, 1H), 7.67-7.59 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.51 (td, J = 8.4, 2.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
357 244-246 325 12.83 (s, 1H), 12.47 (s, 1H), 8.60 (s, 1H), 8.04 (dd, J = 8.7, 5.5 Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H)
358 219-222 343 341 12.73 (s, 1H), 12.52 (s, 1H), 8.60 (s, 1H), 8.00 (t, J = 1.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.74-7.69 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
359 260-262 343 341 12.79 (s, 1H), 12.51 (s, 1H), 8.60 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
360 269-271 352 12.70 (s, 2H), 8.79 (s, 1H), 8.65 (s, 1H), 8.50-8.46 (m, 1H), 8.42-8.37 (m, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H)
361 237-243 352 12.69 (s, 2H), 8.63 (s, 1H), 8.40 (d, J = 8.7 Hz, 2H), 8.19 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H)
362 280-282 325 323 12.78 (s, 1H), 12.26 (s, 1H), 11.57 (s, 1H), 8.66 (s, 1H), 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.50-7.44 (m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.03-6.96 (m, 2H)
363 209-213 377 375 12.56, 12.52, 12.41, 10.48 (4s, 2H), 8.47, 8.26 (2s, 1H), 7.92-7.59 (m, 4H), 7.57, 7.31 (2d, J = 8.5 Hz, 1H), 7.57, 7.31 (2d, J = 8.5 Hz, 1H); Note: rotational isomers
364 271-278 339 337 12.79 (s, 1H), 12.24 (s, 1H), 11.69 (s, 1H), 8.66 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.84-6.79 (m, 2H), 2.31 (s, 3H)
365 214-216 323 13.46 (s, 1H), 12.57 (s, 1H), 9.01 (s, 1H), 7.82-7.75 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.49-7.45 (m, 2H), 7.10 (d, J = 8.6 Hz, 1H), 2.42 (s, 3H)
366 267-269 323 321 13.48 (s, 1H), 12.54 (s, 1H), 9.01 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.6 Hz, 1H), 2.40 (s, 3H)
367 203-209 327 325 13.35 (s, 1H), 12.65 (s, 1H), 9.01 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.81-7.76 (m, 1H), 7.69-7.61 (m, 1H), 7.56-7.48 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H)
368 264-267 327 325 13.41 (s, 1H), 12.62 (s, 1H), 9.00 (s, 1H), 8.10-8.01 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H)
369 232-234 343 341 13.34 (s, 1H), 12.67 (s, 1H), 9.00 (s, 1H), 8.04-8.00 (m, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H)
370 271-273 343 13.38 (s, 1H), 12.66 (s, 1H), 9.00 (s, 1H), 8.00 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H)
371 273-277 354 352 13.33 (s, 1H), 12.91 (s, 1H), 9.03 (s, 1H), 8.84-8.81 (m, 1H), 8.50 (dd, J = 8.2, 1.4 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H)
372 260-262 325 323 13.43 (s, 1H), 12.46 (s, 1H), 11.48 (s, 1H), 9.06 (s, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.05-6.96 (m, 2H)
373 221-222 377 375 13.18, 12.73, 12.58, 10.82 (4s, 2H), 8.85, 8.65 (2s, 1H), 7.95-7.62 (m, 4H), 7.56, 7.44 (2d, J = 8.6 Hz, 1H), 7.11, 7.05 (2d, J = 8.6 Hz, 1H); Note: rotational isomers
374 248-254 339 337 13.42 (s, 1H), 12.44 (s, 1H), 11.61 (s, 1H), 9.05 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.85-6.81 (m, 2H), 2.32 (s, 3H)
375 250- 300 dec 354 352 13.31 (s, 1H), 12.87 (s, 1H), 9.03 (s, 1H), 8.45-8.39 (m, 2H), 8.24-8.18 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H)
376 199-201 357 355 13.21 (s, 1H), 12.61 (s, 1H), 8.60 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.82-7.72 (m, 2H), 7.69 (d, J = 2.4 Hz, 1H), 7.51-7.40 (m, 2H), 2.41 (s, 3H)
377 276-278 357 355 13.23 (s, 1H), 12.59 (s, 1H), 8.60 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H)
378 219-221 361 359 13.09 (s, 1H), 12.72 (s, 1H), 8.61 (s, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.79-7.74 (m, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.64 (td, J = 8.0, 5.9 Hz, 1H), 7.52 (td, J = 8.4, 2.2 Hz, 1H)
379 227-228 361 359 13.16 (s, 1H), 12.68 (s, 1H), 8.60 (s, 1H), 8.26-7.87 (m, 3H), 7.71 (d, J = 2.4 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H)
380 228-229 377 375 13.08 (s, 1H), 12.74 (s, 1H), 8.60 (s, 1H), 8.05-7.97 (m, 2H), 7.93 (d, J = 7.8 Hz, 1H), 7.72 (t, J = 5.3 Hz, 2H), 7.62 (t, J = 7.9 Hz, 1H)
381 232-234 377 375 13.13 (s, 1H), 12.72 (s, 1H), 8.60 (s, 1H), 8.00 (dd, J = 10.9, 5.5 Hz, 3H), 7.71 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H)
382 235-237 388 386 13.00 (s, 1H), 8.83-8.74 (m, 1H), 8.63 (s, 1H), 8.56- 8.44 (m, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H)
383 245-247 388 386 12.99 (d, J = 25.6 Hz, 2H), 8.63 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H)
384 258-260 359 357 13.10 (s, 1H), 12.43 (s, 1H), 11.51 (s, 1H), 8.66 (s, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.55-7.39 (m, 1H), 7.06-6.91 (m, 2H)
385 203-204 411 409 12.92 (s, 1H), 12.79 (s, 1H), 8.48 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.95- 7.55 (m, 5H)
386 252-254 373 371 13.10 (s, 1H), 12.37 (s, 1H), 11.63 (s, 1H), 8.65 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 7.6 Hz, 2H), 2.30 (d, J = 8.7 Hz, 3H)
387 201-203 289 287 12.10 (s, 1H), 11.58 (s, 1H), 8.63 (s, 1H), 7.78-7.69 (m, 2H), 7.62 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 4.7 Hz, 2H), 7.03-6.95 (m, 2H), 2.40 (s, 3H)
388 258-260 289 287 12.09 (s, 1H), 11.62 (s, 1H), 8.63 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.04-6.94 (m, 2H), 2.39 (s, 3H)
389 218-222 293 291
390 226-228 293 291 12.16 (s, 1H), 11.54 (s, 1H), 8.63 (s, 1H), 8.06-7.98 (m, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.44-7.35 (m, 2H), 7.03-6.95 (m, 2H)
391 212-214 307 12.20 (s, 1H), 11.45 (s, 1H), 8.64 (s, 1H), 8.01-7.96 (m, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.73-7.63 (m, 2H), 7.63-7.55 (m, 1H), 7.02-6.95 (m, 2H)
392 257-260 309 307 12.20 (s, 1H), 11.50 (s, 1H), 8.64 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.67-7.60 (m, 3H), 7.03-6.94 (m, 2H)
393 233-238 320 318 12.41 (s, 1H), 11.42 (s, 1H), 8.81-8.77 (m, 1H), 8.69 (s, 1H), 8.46 (dd, J = 8.1, 1.8 Hz, 1H), 8.39 (d, J = 7.8 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.04-6.96 (m, 2H)
394 278-281 320 318 12.40 (s, 1H), 11.41 (s, 1H), 8.68 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.03-6.96 (m, 2H)
395 210-213 291 289
396 197-200 343 341 12.20, 12.13, 11.27, 10.30 (4s, 2H), 8.47, 8.26 (2s, 1H), 7.90-7.16 (m, 5H), 7.01-6.80 (m, 2H); Note: rotational isomers
397 283-287 305 303 12.02 (s, 1H), 11.90 (s, 1H), 11.51 (s, 1H), 8.67 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.04-6.95 (m, 2H), 6.83- 6.76 (m, 2H), 2.31 (s, 3H)
398 245-248 289 287 12.57 (s, 1H), 12.43 (s, 1H), 9.05 (s, 1H), 7.83-7.73 (m, 2H), 7.46 (d, J = 4.8 Hz, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.06 (dd, J = 7.9, 0.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H)
399 250-252 289 287 12.59 (s, 1H), 12.40 (s, 1H), 9.04 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.33 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 2.40 (s, 3H)
400 257-259 293 291 12.52 (s, 1H), 12.48 (s, 1H), 9.04 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.80-7.75 (m, 1H), 7.68-7.60 (m, 1H), 7.52 (td, J = 8.5, 2.4 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H)
401 266-268 293 291 12.53 (s, 1H), 12.48 (s, 1H), 9.03 (s, 1H), 8.09-8.00 (m, 2H), 7.47-7.39 (m, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H)
402 250-253 309 307 12.54 (s, 1H), 12.47 (s, 1H), 9.04 (s, 1H), 8.05-7.98 (m, 1H), 7.96-7.90 (m, 1H), 7.76-7.69 (m, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 8.0, 1.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H)
403 273-277 309 307 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 7.9, 0.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H)
404 269-270 320 318 12.77 (s, 1H), 12.48 (s, 1H), 9.07 (s, 1H), 8.82 (t, J = 1.9 Hz, 1H), 8.52-8.45 (m, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.08 (dd, J = 7.9, 0.8 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H)
405 >300 320 318 12.73 (s, 1H), 12.44 (s, 1H), 9.06 (s, 1H), 8.46-8.38 (m, 2H), 8.25-8.16 (m, 2H), 7.36 (t, J = 8.2 Hz, 1H), 7.08 (dd, J = 8.0, 0.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H)
406 277-280 291 289 12.52 (s, 1H), 12.37 (s, 1H), 11.55 (s, 1H), 9.07 (s, 1H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.43 (m, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 7.9, 0.9 Hz, 1H), 7.03-6.95 (m, 3H)
407 222-226 343 341 12.57, 12.45, 12.30, 10.21 (4s, 2H), 8.88, 8.64 (2s, 1H), 7.92-6.70 (m, 7H); Note: rotational isomers
408 273-276 305 303 12.51 (s, 1H), 12.35 (s, 1H), 11.70 (s, 1H), 9.07 (s, 1H), 7.82-7.75 (m, 1H), 7.34 (t, J = 8.2 Hz, 1H), 7.09- 7.03 (m, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 4.2 Hz, 2H), 2.32 (s, 3H)
409 297-299 337 335 12.20 (s, 1H), 11.63 (s, 2H), 8.66 (s, 1H), 7.88 (dd, J = 7.9, 1.4 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.61 (dd, J = 10.4, 2.3 Hz, 1H), 7.53- 7.38 (m, 1H), 7.07-6.88 (m, 2H)
410 211-212 337 335 12.36 (s, 1H), 11.72 (s, 1H), 8.63 (s, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.72-7.48 (m, 5H)
411 228-229 351 349 12.30 (s, 1H), 11.76 (s, 1H), 8.62 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.59 (dd, J = 10.5, 2.1 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H)
412 240-241 405 403 12.51 (s, 1H), 11.58 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.73-7.67 (m, 1H), 7.61 (dd, J = 10.4, 2.3 Hz, 1H)
413 279-282 368 12.78 (s, 1H), 12.49 (s, 1H), 8.54 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.73 (dd, J = 13.1, 2.5 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H)
414 209-215 372 370 12.69 (s, 1H), 12.58 (s, 1H), 8.54 (s, 1H), 8.04 (dd, J = 8.7, 5.5 Hz, 2H), 7.74 (dd, J = 7.7, 2.5 Hz, 2H), 7.42 (t, J = 8.8 Hz, 2H)
415 200-211 372 370 12.62 (s, 2H), 8.55 (s, 1H), 7.86-7.71 (m, 4H), 7.67- 7.47 (m, 2H)
416 167-226 399 397 12.85 (s, 1H), 12.55 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.52-8.37 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.76 (dd, J = 6.4, 2.5 Hz, 2H)
417 237-250 399 397 12.68 (s, 2H), 8.58 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.77 (q, J = 2.5 Hz, 2H)
418 266-274 422 420 12.66 (s, 1H), 8.42 (s, 1H), 7.94-7.71 (m, 7H)
419 188-196 289 287 12.16 (s, 1H), 11.30 (s, 1H), 8.62 (s, 1H), 7.80-7.59 (m, 3H), 7.43 (d, J = 4.6 Hz, 2H), 7.33 (dd, J = 8.7, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.40 (s, 3H)
420 205-224 372 12.23 (s, 1H), 11.21 (s, 1H), 8.64 (s, 1H), 7.83-7.72 (m, 2H), 7.70 (d, J = 2.7 Hz, 1H), 7.61 (td, J = 8.0, 5.9 Hz, 1H), 7.48 (td, J = 8.4, 2.1 Hz, 1H), 7.33 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H)
421 234-243 372 12.21 (s, 1H), 11.26 (s, 1H), 8.62 (s, 1H), 8.03 (dd, J = 8.4, 5.6 Hz, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.45-7.27 (m, 3H), 6.96 (d, J = 8.8 Hz, 1H)
422 154-164 343 341 12.25 (s, 1H), 11.01 (s, 1H), 8.47 (s, 1H), 7.91-7.65 (m, 7H)
423 166-169 289 287 (400 MHz, CDCl3) 8.59 (d, J = 12.0 Hz, 1H), 7.76 (d, J = 10.0 Hz, 2H), 7.47 (dd, J = 15.6, 6.2 Hz, 4H), 6.97 (t, J = 7.8 Hz, 1H), 2.39 (d, J = 12.0 Hz, 3H)
424 230-232 289 287 (400 MHz, CDCl3) 8.60 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 6.97 (t, J = 7.8 Hz, 1H), 2.40 (s, 3H)
425 178-184 293 291 (400 MHz, CDCl3) 8.62 (s, 1H), 7.86-7.72 (m, 2H), 7.63 (dd, J = 13.8, 8.0 Hz, 1H), 7.51 (dd, J = 7.1, 5.5 Hz, 3H), 6.98 (t, J = 7.8 Hz, 1H)
426 194-198 293 291 (400 MHz, CDCl3) 8.60 (s, 1H), 8.08-7.99 (m, 2H), 7.54-7.46 (m, 2H), 7.42 (t, J = 8.8 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H)
427 174-178 309 307 (400 MHz, CDCl3) 8.61 (s, 1H), 8.00 (t, J = 1.7 Hz, 1H), 7.95-7.68 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.55- 7.47 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H)
428 217-219 309 307 (400 MHz, CDCl3) 8.61 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.50 (ddd, J = 7.9, 4.5, 1.4 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H)
429 236-239 320 318 (400 MHz, CDCl3) 8.80 (t, J = 1.9 Hz, 1H), 8.66 (s, 1H), 8.52-8.36 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.53 (ddd, J = 9.7, 7.9, 1.5 Hz, 2H), 6.99 (t, J = 7.8 Hz, 1H)
430 284-287 320 318 (400 MHz, CDCl3) 8.64 (s, 1H), 8.41 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.6 Hz, 2H), 7.56-7.47 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H)
431 266-268 291 289 (400 MHz, CDCl3) 8.66 (s, 1H), 7.87 (dd, J = 7.9, 1.6 Hz, 1H), 7.54-7.42 (m, 3H), 6.98 (ddd, J = 7.8, 5.6, 3.9 Hz, 3H)
432 118-121 343 341 (400 MHz, CDCl3) 8.36 (d, J = 82.5 Hz, 1H), 7.95- 7.24 (m, 6H), 6.92 (dt, J = 42.3, 7.9 Hz, 1H)
433 258-266 305 303 (400 MHz, CDCl3) 8.66 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 7.9, 2.1 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.3 Hz, 2H), 2.31 (s, 3H)
434 262-268 384 382 (400 MHz, CDCl3) 8.58 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.72 (dd, J = 27.0, 2.4 Hz, 2H), 6.81 (d, J = 7.7 Hz, 2H), 2.31 (s, 3H)
435 192-194 323 321 12.21 (s, 1H), 11.82 (s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.75 (dd, J = 9.3, 4.5 Hz, 2H), 7.64 (dd, J = 8.7, 1.8 Hz, 1H), 7.44 (d, J = 4.7 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H), 2.40 (s, 3H)
436 245-249 323 321 12.19 (s, 1H), 11.88 (s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.63 (dd, J = 8.6, 1.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.5 Hz, 1H), 2.39 (s, 3H)
437 188-196 327 325 12.28 (s, 1H), 11.75 (s, 1H), 8.73 (s, 1H), 8.03 (d, J = 1.3 Hz, 1H), 7.78 (dd, J = 18.8, 9.0 Hz, 2H), 7.68-7.57 (m, 2H), 7.49 (td, J = 8.7, 2.3 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H)
438 229-231 327 325 12.26 (s, 1H), 11.80 (s, 1H), 8.72 (s, 1H), 8.10-7.96 (m, 3H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H)
439 187-197 343 341 12.30 (s, 1H), 11.73 (s, 1H), 8.73 (s, 1H), 8.06-7.94 (m, 2H), 7.91 (dd, J = 7.8, 1.2 Hz, 1H), 7.74-7.54 (m, 3H), 7.12 (d, J = 8.6 Hz, 1H)
440 252-254 343 341 12.30 (s, 1H), 11.77 (s, 1H), 8.72 (s, 1H), 8.06-7.90 (m, 3H), 7.64 (d, J = 8.5 Hz, 3H), 7.12 (d, J = 8.6 Hz, 1H)
441 218-220 354 352 12.51 (s, 1H), 11.74 (s, 1H), 8.80 (dd, J = 6.6, 4.8 Hz, 2H), 8.51-8.35 (m, 2H), 8.05 (d, J = 1.8 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H)
442 259-265 354 352 12.47 (s, 1H), 11.71 (s, 1H), 8.76 (s, 1H), 8.44-8.36 (m, 2H), 8.23-8.15 (m, 2H), 8.05 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H)
443 277-281 325 323 12.15 (s, 1H), 11.78 (s, 2H), 8.75 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 7.8, 1.2 Hz, 1H), 7.65 (dd, J = 8.6, 2.1 Hz, 1H), 7.50-7.42 (m, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.03-6.94 (m, 2H)
444 174-176 377 375 12.30 (s, 1H), 11.55 (s, 1H), 8.57 (s, 1H), 8.03 (d, J = 2.1 Hz, 1H), 7.91-7.47 (m, 5H), 7.12 (d, J = 8.6 Hz, 1H)
445 264-271 339 337 12.12 (s, 1H), 11.89 (s, 1H), 11.78 (s, 1H), 8.75 (s, 1H), 8.00 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.80 (d, J = 7.0 Hz, 2H), 2.31 (s, 3H)
446 282-286 305 303 12.03 (s, 2H), 11.24 (s, 1H), 8.65 (s, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 7.3 Hz, 2H), 2.31 (d, J = 6.5 Hz, 3H)
447 219-221 357 355 13.85 (s, 1H), 12.65 (s, 1H), 8.94 (s, 1H), 7.79 (dd, J = 9.2, 3.4 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.47 (dd, J = 8.8, 4.1 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 2.42 (s, 3H)
448 216-218 357 355 13.86 (s, 1H), 12.62 (s, 1H), 8.93 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz, 1H), 7.37 (dd, J = 14.8, 8.2 Hz, 3H), 2.40 (s, 3H)
449 227-229 361 359 13.79 (s, 1H), 12.69 (s, 1H), 8.92 (s, 1H), 8.11-8.00 (m, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 12.2, 5.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H)
450 231-233 361 359 13.73 (s, 1H), 12.73 (s, 1H), 8.93 (s, 1H), 7.87-7.60 (m, 4H), 7.53 (td, J = 8.3, 2.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
451 242-245 377 375 13.73 (s, 1H), 12.74 (s, 1H), 8.92 (s, 1H), 8.02 (t, J = 1.7 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.78-7.67 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
452 236-238 377 375 13.76 (s, 1H), 12.73 (s, 1H), 8.92 (s, 1H), 8.00 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H)
453 277-279 388 386 13.71 (s, 1H), 12.96 (s, 1H), 8.94 (s, 1H), 8.80 (t, J = 1.8 Hz, 1H), 8.49 (dd, J = 8.2, 1.5 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
454 305-307 388 386 13.73 (s, 1H), 12.91 (s, 1H), 8.94 (s, 1H), 8.43 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H)
455 278-280 358 356 13.82 (s, 1H), 12.57 (s, 1H), 11.28 (s, 1H), 8.98 (d, J = 1.3 Hz, 1H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.53-7.45 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.01 (dd, J = 13.2, 7.7 Hz, 2H)
456 203-205 358 356 13.55 (s, 1H), 12.83 (s, 1H), 8.77 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.88-7.70 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H)
457 258-260 373 371 13.81 (s, 1H), 12.61 (s, 1H), 11.54 (s, 1H), 8.97 (s, 1H), 7.74 (dd, J = 18.2, 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 5.9 Hz, 2H), 2.31 (d, J = 7.9 Hz, 3H)
458 218-221 333 331 13.31 (s, 1H), 11.41 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.67-7.62 (m, 1H), 7.35-7.28 (m, 1H), 6.94-6.87 (m, 2H), 2.49 (s, 3H)
459 262-263 319 317 13.84 (s, 1H), 11.26 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.00-6.92 (m, 2H), 3.85 (s, 3H), 2.48 (s, 3H)
460 258-259 367 365 13.72 (s, 1H), 11.48 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.01-6.94 (m, 2H), 2.48 (s, 3H)
461 244-245 357 355 13.69 (s, 1H), 11.63 (s, 1H), 8.13 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.5 Hz, 1H), 7.03-6.94 (m, 2H), 2.50 (s, 3H)
462 187-188 367 13.61, 11.71, 11.04 (3s, 2H), 7.76-7.40 (m, 5H), 7.00, 6.76 (2d, J = 2.2 Hz, 1H), 6.97, 6.88 (2dd, J = 8.6. 2.2 Hz, 1H), 2.41, 2.37 (2s, 3H); Note: rotational isomers
463 311-312 305 13.59 (s, 1H), 11.64 (s, 2H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49-7.42 (m, 1H), 7.07-6.95 (m, 4H), 2.43 (s, 3H)
464 140-141 315 313 13.55 (s, 1H), 11.17 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 7.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.47 (s, 3H)
465 176-177 362 13.44 (s, 1H), 11.40 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H)
466 175-176 353 351 13.40 (s, 1H), 11.54 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.49 (s, 3H)
467 245-247 363 361 13.32, 11.61, 11.55, 10.72 (4s, 2H), 7.76-7.40 (m, 4H), 7.72, 7.10 (2dd, J = 8.2, 1.2 Hz, 1H), 7.05, 6.92 (2d, J = 7.5 Hz, 1H), 6.84, 6.76 (2t, J = 8.1 Hz, 1H), 3.80, 3.66 (2s, 3H), 2.41, 2.37 (2s, 3H). Note: rotational isomers.
468 255-257 301 299 13.29 (s, 1H), 11.75 (s, 1H), 11.58 (s, 1H), 7.99 (dd, J = 7.8, 1.4 Hz, 1H), 7.50-7.42 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.02 (dd, J = 17.9, 7.7 Hz, 3H), 6.84 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.43 (s, 3H)
469 226-227 353 351 14.53 (s, 1H), 11.43 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.52 (s, 3H)
470 237-238 389 14.37 (s, 1H), 11.80 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 2.54 (s, 3H)
471 306-308 339 337
472 251-252 352 13.59 (s, 1H), 11.45 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.7 Hz, 1H), 6.49 (dt, J = 5.8, 2.5 Hz, 2H), 3.78 (s, 3H), 2.46 (s, 3H)
473 276-278 301 299 13.49 (s, 1H), 11.75 (s, 1H), 11.49 (s, 1H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.48-7.41 (m, 1H), 7.06-6.96 (m, 2H), 6.53-6.45 (m, 2H), 3.78 (s, 3H), 2.40 (s, 3H)
474 276-279 359 357 12.45 (s, 2H), 11.90 (s, 1H), 8.60 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.68-7.62 (m, 2H), 7.08-7.02 (m, 2H)
475 287-92 359 357
476 205-206 363 363 13.50, 11.50, 11.05 (3s, 2H), 7.75-7.38 (m, 5H), 6.51- 6.22 (m, 2H), 3.78, 3.68 (2s, 3H), 2.37, 2.34 (2s, 3H); Note: rotational isomers
477 310-312 369 367 14.32 (s, 1H), 11.99 (s, 1H), 11.54 (s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 6.62 (dd, J = 8.9, 2.4 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H)
478 327-331 367 14.28 (s, 1H), 11.76 (s, 1H), 11.39 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.10 (dd, J = 8.9, 3.2 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.76 (s, 3H), 2.45 (s, 3H)
479 245 352 14.55, 11.80, 11.69, 11.46, 9.82, 9.72 (6s, 3H), 7.64- 7.50 (m, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.77-6.71 (m, 2H), 2.40, 2.38 (2s, 3H), 2.22, 2.14 (2s, 3H); Note: rotational isomers
480 264-246 387 14.34 (s, 1H), 13.31 (s, 1H), 11.83 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.72-7.65 (m, 2H), 7.64-7.58 (m, 1H), 7.50 (d, J = 8.9 Hz, 1H), 2.59 (s, 3H)
481 260-262 373 371 14.28 (s, 1H), 11.96 (s, 2H), 7.93-7.88 (m, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.70- 7.64 (m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 2.52 (s, 3H)
482 226-227 315 313 13.72 (s, 1H), 11.07 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.51-6.44 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 2.44 (s, 3H)
483 239-241 363 361 13.70 (s, 1H), 11.30 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H), 6.51-6.42 (m, 2H), 3.77 (s, 3H), 2.44 (s, 3H)
484 258-259 369 367 14.46 (s, 1H), 11.58 (s, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.45 (s, 3H)
485 217-219 339 337 12.48, 12.31, 12.12, 10.62, 9.85, 9.72 (6s, 3H), 8.37, 8.17 (2s, 1H), 7.64-7.46 (m, 2H), 7.16 (t, J = 7.9 Hz, 1H), 6.78-6.70 (m, 2H), 2.21, 2.14 (2s, 3H); Note: rotational isomers
486 267-269 355 353 12.46 (s, 1H), 12.30 (s, 1H), 12.17 (s, 1H), 8.60 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 6.59 (dd, J = 8.9, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H)
487 250-252 355 353 12.41 (s, 1H), 12.29 (s, 1H), 11.13 (s, 1H), 8.63 (s, 1H), 7.69-7.61 (m, 2H), 7.41 (d, J = 3.1 Hz, 1H), 7.11 (dd, J = 9.0, 3.1 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 3.76 (s, 3H)
488 276-278 375 373 13.74 (s, 1H), 12.79 (s, 1H), 12.41 (s, 1H), 8.70 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.73-7.68 (m, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.63-7.58 (m, 1H), 7.49 (d, J = 8.9 Hz, 1H)
489 314-317 375 373 14.26 (s, 1H), 12.18 (s, 1H), 11.66 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H),7.71 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.10-7.04 (m, 2H), 2.45 (s, 3H)
490 322-325 374 14.28 (s, 1H), 12.07-11.66 (m, 2H), 7.90 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.8, 2.8 Hz, 1H), 7.06 (d, J = 8.8 Hz, 1H), 2.46 (s, 3H)
491 320-323 353 14.31 (s, 1H), 11.69 (s, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.88-6.79 (m, 2H), 2.45 (s, 3H), 2.31 (s, 3H)
492 202-203 289 287 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.68-7.61 (m, 2H), 7.56 (t, J = 6.7 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H)
493 193-198 303 301 14.37 (s, 1H), 11.59 (s, 1H), 7.63 (dd, J = 8.0, 1.3 Hz, 1H), 7.55-7.41 (m, 3H), 7.34 (dd, J = 7.5, 4.3 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H)
494 164-178 303 301 14.36 (s, 1H), 11.45 (s, 1H), 7.76 (d, J = 9.6 Hz, 2H), 7.65 (dd, J = 8.1, 1.4 Hz, 1H), 7.48 (dt, J = 15.0, 3.6 Hz, 3H), 6.92 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H), 2.42 (s, 3H)
495 195-200 303 301 14.38 (s, 1H), 11.40 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.64 (dd, J = 8.1, 1.5 Hz, 1H), 7.49 (dd, J = 7.9, 1.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 2.51 (s, 3H), 2.40 (s, 3H)
496 189-193 323 321 14.19 (s, 1H), 11.81 (s, 1H), 7.68-7.53 (m, 4H), 7.52- 7.47 (m, 2H), 6.93 (t, J = 8.0 Hz, 1H), 2.44 (s, 3H)
497 197-219 323 321 14.26 (s, 1H), 11.59 (s, 1H), 8.01 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.75-7.55 (m, 3H), 7.50 (dd, J = 7.9, 1.1 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.53 (s, 3H)
498 208-209 323 321 14.29 (s, 1H), 11.55 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.65 (ddd, J = 4.9, 3.8, 1.7 Hz, 3H), 7.50 (dd, J = 7.9, 1.2 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H)
499 203-204 319 317 14.40 (s, 1H), 11.33 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.64 (dd, J = 8.0, 1.3 Hz, 1H), 7.48 (dd, J = 7.9, 1.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H), 2.51 (s, 3H)
500 226-232 368 366 14.29 (s, 1H), 11.55 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8.1, 1.4 Hz, 1H), 7.49 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 2.52 (s, 3H)
501 250-256 357 355 14.26 (s, 1H), 11.70 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 8.1, 1.3 Hz, 1H), 7.51 (dd, J = 7.9, 1.1 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.53 (s, 3H)
502 178-183 368 366 14.20 (s, 1H), 11.80 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.66-7.59 (m, 2H), 7.53- 7.46 (m, 3H), 6.93 (t, J = 8.0 Hz, 1H), 2.44 (s, 3H)
503 283-287 305 303 14.17 (s, 1H), 11.68 (s, 2H), 7.99 (dd, J = 7.9, 1.7 Hz, 1H), 7.67 (dd, J = 8.1, 1.4 Hz, 1H), 7.48 (ddd, J = 14.2, 7.4, 1.5 Hz, 2H), 7.09- 6.99 (m, 2H), 6.93 (t, J = 8.0 Hz, 1H), 2.46 (s, 3H)
504 207-208 289 287 13.46 (s, 1H), 11.45 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.64 (dd, J = 13.0, 4.9 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.34 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H)
505 192-193 303 301 13.46 (s, 1H), 11.53 (s, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.33 (dt, J = 7.3, 2.4 Hz, 3H), 6.95 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H)
506 222-228 303 301 13.47 (s, 1H), 11.40 (s, 1H), 7.75 (d, J = 10.4 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 5.9 Hz, 2H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H)
507 221-228 303 13.48 (s, 1H), 11.35 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.34 (dd, J = 13.8, 5.2 Hz, 3H), 6.94 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H), 2.40 (s, 3H)
508 210-217 323 321 13.28 (s, 1H), 11.73 (s, 1H), 7.56 (dddd, J = 30.0, 21.9, 7.6, 1.5 Hz, 5H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H)
509 244-249 323 321 13.37 (s, 1H), 11.53 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.69 (dd, J = 16.9, 5.2 Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H)
510 248-252 323 321 13.40 (s, 1H), 11.50 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.65 (dd, J = 11.0, 5.5 Hz, 3H), 7.35 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H)
511 203-228 319 317 13.51 (s, 1H), 11.28 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.6 Hz, 1H), 7.09 (t, J = 5.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 3.85 (s, 3H), 2.49 (s, 3H)
512 269-271 368 366 13.39 (s, 1H), 11.50 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H)
513 271-273 357 355 13.35 (s, 1H), 11.65 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 8.8, 2.5 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.51 (s, 3H)
514 222-225 368 366 13.29 (s, 1H), 11.73 (s, 1H), 7.75 (dd, J = 7.8, 1.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.49 (ddd, J = 9.5, 7.5, 1.5 Hz, 2H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H)
515 298-318 305 303 13.25 (s, 1H), 11.67 (d, J = 54.4 Hz, 2H), 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.50-7.42 (m, 1H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H), 7.08-6.93 (m, 3H), 2.43 (s, 3H)
516 202-252 364 362 13.56 (s, 1H), 11.28 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.7, 2.4 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.48 (s, 3H)
517 270-275 413 411 13.44 (s, 1H), 11.50 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.81-7.72 (m, 4H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H)
518 272-280 402 400 13.38 (s, 1H), 11.65 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.78 (d, J = 2.4 Hz, 1H), 7.47 (dd, J = 8.7, 2.3 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H)
519 216-218 413 411 13.31 (s, 1H), 11.73 (s, 1H), 7.75 (dd, J = 6.2, 1.7 Hz, 2H), 7.62-7.58 (m, 1H), 7.50-7.43 (m, 3H), 6.91 (d, J = 8.8 Hz, 1H), 2.41 (s, 3H)
520 281-303 350 348 13.27 (s, 1H), 11.67 (d, J = 51.7 Hz, 2H), 7.98 (dd, J = 7.9, 1.6 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.50-7.43 (m, 2H), 7.07-6.98 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H), 2.43 (s, 3H)
521 204-212 330 328 15.32 (s, 1H), 11.48 (s, 1H), 8.01-7.90 (m, 4H), 7.13- 7.01 (m, 3H), 3.86 (s, 3H), 2.56 (s, 3H)
522 244-252 379 15.16 (s, 1H), 11.70 (s, 1H), 8.02-7.87 (m, 4H), 7.79 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
523 267-278 368 366 15.11 (s, 1H), 11.85 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 8.00 (dd, J = 8.0, 1.4 Hz, 1H), 7.95 (d, J = 8.1 Hz, 3H), 7.08 (t, J = 8.0 Hz, 1H), 2.57 (s, 3H)
524 186-188 379 377 15.06 (s, 1H), 11.97 (s, 1H), 7.95 (dd, J = 8.3, 1.2 Hz, 2H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H), 7.62 (dd, J = 7.4, 1.8 Hz, 1H), 7.53 (ddd, J = 7.4, 6.8, 1.5 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H)
525 274-283 314 15.02 (s, 1H), 11.73 (s, 1H), 11.69 (s, 1H), 8.05-7.89 (m, 3H), 7.51-7.43 (m, 1H), 7.11-6.98 (m, 3H), 2.50 (s, 3H)
526 76.9-187 315 313 13.80 (s, 1H), 7.92 (d, J = 7.3 Hz, 1H), 7.64-7.42 (m, 2H), 6.15 (dd, J = 9.6, 7.4 Hz, 1H), 6.10 (dd, J = 12.6, 2.3 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.77 (s, 1H), 3.74 (d, J = 1.3 Hz, 1H), 2.55 (s, 3H)
527 226-229 323 321 14.07 (s, 1H), 11.53 (s, 1H), 8.02-7.87 (m, 3H), 7.69- 7.59 (m, 2H), 7.58-7.50 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H)
528 200-203 337 335 14.06 (s, 1H), 11.61 (s, 1H), 7.89 (s, 1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 6.9 Hz, 1H), 7.37-7.28 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 2.48 (s, 3H), 2.41 (s, 3H)
529 235-238 337 335 14.08 (s, 1H), 11.48 (s, 1H), 7.92 (s, 1H), 7.80-7.72 (m, 2H), 7.65 (d, J = 7.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 2.56 (s, 3H), 2.41 (s, 3H)
530 225-229 337 335 14.09 (s, 1H), 11.44 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.10 (d, J = 8.6 Hz, 1H), 2.55 (s, 3H), 2.40 (s, 3H)
531 189-191 357 355 13.86 (s, 1H), 11.82 (s, 1H), 7.90 (s, 1H), 7.69-7.45 (m, 5H), 7.12 (d, J = 8.6 Hz, 1H), 2.48 (s, 3H)
532 241-245 357 355 13.96 (s, 1H), 11.61 (s, 1H), 8.02 (s, 1H), 7.94-7.89 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.68-7.63 (m, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 2.57 (s, 3H)
533 263-265 357 355 14.00 (s, 1H), 11.58 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.92 (s, 1H), 7.68-7.61 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H), 2.56 (s, 3H)
534 228-231 353 351 14.12 (s, 1H), 11.36 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H), 7.64 (dd, J = 8.7, 1.9 Hz, 1H), 7.12-7.06 (m, 3H), 3.85 (s, 3H), 2.55 (s, 3H)
535 256-259 402 400 13.99 (s, 1H), 11.58 (s, 1H), 7.94-7.89 (m, 3H), 7.78 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H)
536 228-234 391 389 13.95 (s, 1H), 11.73 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.97-7.91 (m, 3H), 7.69-7.64 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 2.57 (s, 3H)
537 192-200 402 400 13.87, 11.81, 11.70, 11.28 (4s, 2H), 7.91-7.39 (m, 6H), 7.21, 6.87 (2d, J = 8.6 Hz, 1H), 2.48, 2.42 (2s, 3H); Note: rotational isomers
538 277-297 361 (+Na) 13.84 (s, 1H), 11.71 (s, 2H), 7.98 (dd, J = 7.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.68-7.63 (m, 1H), 7.50-7.43 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.08-6.98 (m, 2H), 2.49 (s, 3H)
539 242-245 414
540 221-222 425 14.64 (s, 1H), 11.71 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.49-7.41 (m, 1H), 7.37- 7.29 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H)
541 236-238 427 425 14.62 (s, 1H), 11.55 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.78-7.72 (m, 2H), 7.48-7.41 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H)
542 258-259 425 14.64 (s, 1H), 11.50 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 2.51 (s, 3H), 2.40 (s, 3H)
543 207-209 447 445 14.46 (s, 1H), 11.92 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.66-7.53 (m, 3H), 7.51-7.46 (m, 1H), 2.44 (s, 3H)
544 255-256 447 14.52 (s, 1H), 11.69 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H)
545 255-258 445 14.55 (s, 1H), 11.65 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.67-7.61 (m, 2H), 2.52 (s, 3H)
546 247-248 441 14.66 (s, 1H), 11.43 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m, 2H), 3.85 (s, 3H), 2.51 (s, 3H)
547 264-266 493 491 14.55 (s, 1H), 11.65 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.80-7.76 (m, 2H), 2.52 (s, 3H)
548 255-257 481 14.51 (s, 1H), 11.80 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.86 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 2.53 (s, 3H)
549 214-216 491 489 14.46 (s, 1H), 11.91 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 7.8, 1.2 Hz, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 1H), 7.53 (td, J = 7.4, 1.3 Hz, 1H), 7.47 (td, J = 7.6, 1.9 Hz, 1H), 2.44 (s, 3H)
550 305-306 427 14.43 (s, 1H), 11.71 (s, 2H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H), 7.86-7.82 (m, 2H), 7.50- 7.43 (m, 1H), 7.08-6.98 (m, 2H), 2.45 (s, 3H)
551 154-155 315 313 13.71 (s, 1H), 11.27 (s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.65-7.59 (m, 1H), 7.58- 7.51 (m, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H)
552 150-152 329 327 13.71 (s, 1H), 11.34 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.46-7.39 (m, 1H), 7.32 (dt, J = 11.7, 8.4 Hz, 3H), 6.60 (d, J = 9.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H)
553 158-162 329 327 13.70 (s, 1H), 11.22 (s, 1H), 7.77-7.68 (m, 2H), 7.46- 7.41 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H)
554 245-249 329 327 13.71 (s, 1H), 11.18 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.41-7.31 (m, 3H), 6.60 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H)
555 77-86 349 347 13.54, 11.55, 10.92 (3s, 2H), 7.63-7.44 (m, 4H), 7.36, 7.25 (2d, J = 9.1 Hz, 1H), 6.61, 6.53 (2d, J = 9.1 Hz, 1H), 3.82, 3.75, 3.71, 3.50 (4s, 6H), 2.38, 2.35 (2s, 3H); Note: rotational isomers
556 194-201 349 347 13.60 (s, 1H), 11.37 (s, 1H), 8.00-7.97 (m, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.72- 7.67 (m, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.46 (s, 3H)
557 230-235 349 347 13.63 (s, 1H), 11.33 (s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H)
558 230-232 345 343 13.73 (s, 1H), 11.11 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.0 Hz, 1H), 7.08 (d, J = 8.9 Hz, 2H), 6.60 (d, J = 9.1 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H)
559 241-245 393 391 13.62 (s, 1H), 11.33 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H)
560 229-233 383 381 13.60 (s, 1H), 11.48 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 9.0 Hz, 1H), 6.62 (d, J = 9.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.46 (s, 3H)
561 195-200 393 391 13.54, 11.55, 10.90 (3s, 2H), 7.76-7.42 (m, 4H), 7.36, 7.25 (2d, J = 9.1 Hz, 1H), 6.61, 6.53 (2d, J = 9.1 Hz, 1H), 3.82, 3.75, 3.71, 3.50 (4s, 6H), 2.38, 2.34 (2s, 3H); Note: rotational isomers
562 279-297 331 329 13.51 (s, 1H), 11.74 (s, 1H), 11.51 (s, 1H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H), 7.49-7.42 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H), 7.07-6.97 (m, 2H), 6.62 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 2.40 (s, 3H)
563 287-292 375 373 (300 MHz, DMSO-d6) 12.48 (s, 1H), 11.17 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.71-7.64 (m, 2H), 7.58-7.49 (m, 1H), 7.42-7.32 (m, 2H)
564 312-315 387 14.42 (s, 1H), 12.04-11.57 (m, 2H), 8.60 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.56-7.51 (m, 1H), 7.41-7.35 (m, 2H), 2.50 (s, 3H)
565 278-279 351 14.33 (s, 1H), 11.75 (s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 7.7 Hz, 1H), 2.54 (s, 3H), 2.23 (s, 3H)
566 177-184 329 327 12.89 (s, 1H), 11.04 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.9 Hz, 2H), 6.12 (d, J = 5.0 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.39 (s, 3H), 2.37 (s, 3H)
567 206-215 349 347 10.05 (s, 1H), 9.70 (s, 1H), 7.59 (dd, J = 8.9, 2.1 Hz, 2H), 7.47 (d, J = 5.7 Hz, 2H), 6.17 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 2.1 Hz, 1H), 3.74 (s, 6H), 2.15 (s, 2H)
568 136-140 349 347 12.80 (s, 1H), 11.19 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 6.14-6.09 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.38 (s, 3H)
569 143-146 345 343 12.91 (s, 1H), 10.98 (s, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.12 (dd, J = 7.6, 2.3 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H)
570 134-159 394 392 12.78 (s, 1H), 11.19 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 6.12 (dd, J = 7.8, 2.2 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H)
571 131-133 383 381 12.70 (s, 1H), 11.33 (s, 1H), 8.11 (d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 6.13 (dd, J = 7.1, 2.3 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.38 (s, 3H)
572 222-225 291 289 13.55 (s, 1H), 11.54 (s, 1H), 7.95 (d, J = 7.4 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 7.43- 7.34 (m, 2H), 2.50 (s, 3H)
573 186-188 305 303 13.56 (s, 1H), 11.63 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.40-7.29 (m, 4H), 2.42 (s, 3H), 2.40 (s, 3H)
574 215-216 305 303 13.56 (s, 1H), 11.49 (s, 1H), 7.75 (d, J = 11.6 Hz, 2H), 7.45 (d, J = 6.2 Hz, 2H), 7.39 (td, J = 8.9, 2.8 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H)
575 220-22 305 303 13.57 (s, 1H), 11.44 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.38 (dd, J = 13.4, 6.6 Hz, 4H), 2.49 (s, 3H), 2.40 (s, 3H)
576 205-209 325 323 13.38 (s, 1H), 11.83 (s, 1H), 7.60 (dddd, J = 15.2, 9.7, 7.7, 1.6 Hz, 3H), 7.48 (td, J = 7.3, 1.4 Hz, 1H), 7.44- 7.34 (m, 2H), 2.42 (s, 3H)
577 279-282 325 323 13.45 (s, 1H), 11.62 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.41 (dd, J = 9.5, 7.1 Hz, 2H), 2.50 (s, 3H)
578 276-280 325 323 13.48 (s, 1H), 11.59 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 7.43-7.36 (m, 2H), 2.50 (s, 3H)
579 243-247 321 319 13.59 (s, 1H), 11.36 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 9.4, 3.2 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.49 (s, 3H)
580 268-270 370 368 13.48 (s, 1H), 11.59 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.5 Hz, 2H), 7.44-7.36 (m, 2H), 2.49 (s, 3H)
581 287-291 359 357 13.44 (s, 1H), 11.73 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 9.5, 7.5 Hz, 2H), 2.51 (s, 3H)
582 190-195 370 368 13.38 (s, 1H), 11.84 (s, 1H), 7.75 (dd, J = 7.8, 1.0 Hz, 1H), 7.62 (d, J = 1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.55-7.48 (m, 2H), 7.37 (dd, J = 8.4, 2.2 Hz, 1H), 2.42 (s, 3H)
583 308-323 307 305 13.37 (s, 1H), 11.70 (s, 2H), 7.98 (dd, J = 7.9, 1.7 Hz, 1H), 7.44 (ddd, J = 28.3, 14.3, 6.0 Hz, 3H), 7.07-6.98 (m, 2H), 2.43 (s, 3H)
584 269-274 329 327 9.96 (s, 1H), 9.24 (s, 1H), 7.35- 7.27 (m, 2H), 7.19 (t, J = 3.6 Hz, 2H), 6.08 (d, J = 10.7 Hz, 2H), 3.72 (s, 3H), 3.69 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H)
585 207-209 329 327 12.87 (s, 1H), 11.09 (s, 1H), 7.72 (d, J = 9.4 Hz, 2H), 7.42 (d, J = 4.6 Hz, 2H), 6.12 (dd, J = 7.8, 2.1 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H)
586 182-199 331 329 13.80 (s, 1H), 12.50 (s, 1H), 11.54 (s, 1H), 7.96 (dd, J = 7.8, 1.5 Hz, 1H), 7.47- 7.35 (m, 1H), 7.08-6.91 (m, 2H), 6.14 (d, J = 2.3 Hz, 1H), 6.08 (d, J = 2.4 Hz, 1H), 3.80 (s, 3H), 3.77 (s, 3H), 2.35 (s, 3H)
587 195-96 377 375 11.38 (s, 1H), 10.47 (s, 1H), 7.71 (dd, J = 15.3, 4.9 Hz, 3H), 7.58 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.35 (d, J = 2.3 Hz, 1H)
588 gum 351 349 12.49 (s, 1H), 9.88 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.62-7.31 (m, 4H), 7.13 (s, 1H), 3.78-3.65 (m, 1H), 1.07 (d, J = 9.5 Hz, 6H)
589 218-219 349 347 13.96 (s, 1H), 11.71 (s, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.88 (s, 1H), 7.62 (dt, J = 23.1, 7.2 Hz, 4H), 2.08-1.91 (m, 1H), 1.28 (d, J = 7.4 Hz, 2H), 0.79 (d, J = 4.4 Hz, 2H)
590 214-215 337 335 14.55 (s, 1H), 11.67 (s, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.75-7.61 (m, 3H), 7.57 (t, J = 7.5 Hz, 2H), 3.06 (q, J = 7.4 Hz, 2H), 1.14 (t, J = 7.5 Hz, 3H)
591 208-210 309 307 10.75 (s, 1H), 10.47 (s, 1H), 7.73-7.63 (m, 2H), 7.62- 7.53 (m, 1H), 7.47 (dd, J = 10.4, 4.6 Hz, 2H), 7.43- 7.35 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.96 (td, J = 7.6, 0.9 Hz, 1H)
592 241-243 297 295 9.90 (s, 1H), 8.78 (s, 1H), 7.57-7.24 (m, 6H), 7.11- 6.87 (m, 3H), 1.18 (s, 9H)
As exemplified below, hydrazones of the present invention, or their metal complexes, in a mixture with inorganic or organic mono- or divalent copper salts or chelates (hereinafter referred to as “copper products”) increase the biological potency of copper products, enabling comparable or improved efficacy at lower copper use rates. While not intending to be all-inclusive, copper products which may be mixed with the compounds of the present invention to provide enhanced potency may include the following: copper oxychloride, copper octanoate, copper ammonium carbonate, copper arsenate, copper oxysulfate, copper formate, copper propionate, copper oxyacetate, copper citrate, copper chloride, copper diammonium chloride, copper nitrate, copper carbonate, copper phosphate, copper pyrophosphate, copper disodium EDTA, copper diammonium EDTA, copper oxalate, copper tartrate, copper gluconate, copper glycinate, copper glutamate, copper aspartate, copper adipate, copper palmitate, copper stearate, copper caprylate, copper decanoate, copper undecylenate, copper neodecanoate, copper linoleate, copper oleate, copper borate, copper methanesulfonate, copper sulfamate, copper acetate, copper hydroxide, copper oxide, copper oxychloride-sulfate, copper sulfate, basic copper sulfate, copper-oxine, copper 3-phenylsalicylate, copper chloride hydroxide, copper dimethyldithiocarbamate, ammonium copper sulfate, copper magnesium sulfate, coppernaphthenate, copper ethanolamine, chromated copper arsenate, ammoniacal copper arsenate, ammoniacal copper zinc arsenate, ammoniacal copper borate, Bordeaux mixture, copper zinc chromate, cufraneb, cupric hydrazinium sulfate, cuprobam, nano-copper materials and copper didecyldimethylammonium chloride and where appropriate the hydrates of such compounds.
Salicylaldehyde benzoylhydrazones such as those of the current invention are known in the literature as chelators of metal cations (Inorganica Chimica Acta 1982, 67, L25-L27, which is expressly incorporated by reference herein), including copper. Antimicrobial activity has been reported for o-hydroxybenzaldehyde-N-salicyloylhydrazone and its copper, nickel and cobalt complexes towards Staphylococcus aureus, Escherichia coli, Aspergillus niger and A. flavus (Proceedings of the National Academy of Sciences, India 1991, Section A Part IV, Vol. LXI, pp. 447-452, which is expressly incorporated by reference herein). However, data in this report showed that the copper complex of o-hydroxybenzaldehyde-N-salicyloylhydrazone had a similar level of antimicrobial activity to that of o-hydroxybenzaldehyde-N-salicyloylhydrazone alone and the nickel and cobalt complexes, and provided no indication that salicylaldehyde benzoylhydrazones might show any synergistic antimicrobial effect in combination with copper.
Example 26 Effect of Copper on Fungitoxicity of Hydrazones Towards Leptosphaeria nodorum In vitro fungitoxicity assays against Leptosphaeria nodorum (LEPTNO) were conducted using the liquid growth medium described by Coursen and Sisler (American Journal of Botany 1960, 47, 541-549) except that copper micronutrient, normally included as CuSO4, was omitted. The medium, termed “copper-minus”, was prepared by dissolving 10 g glucose, 1.5 g K2HPO4, 2 g KH2PO4 and 1 g (NH4)2SO4 in 1 liter of deionized water and treating the solution with 0.5 g Chelex 100 resin (Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822) by stiffing at room temperature for 1 h. MgSO4.7H2O (0.5 g) was added, and stiffing continued for a further hour. Trace elements (minus CuSO4), and vitamins described by Coursen and Sisler were added from concentrated stock solutions and the entire medium was sterilized by filtration. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus medium at 20 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus and copper-plus growth media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates.
LEPTNO was grown on potato dextrose agar in 9 cm diameter petri dishes for 7 days. Sterile deionized water (20 mL) was added to a culture plate and spores suspended by scraping the surface gently with a sterile plastic loop. The resulting suspension was filtered through a double layer of sterile cheesecloth. Filtered spore suspension (5 mL) was centrifuged in a bench centrifuge at 2000 rpm for 2 min. The resulting spore pellet was resuspended in 10 mL sterile deionized water (which had been treated with Chelex 100 resin using 0.5 g resin per liter of water by stirring at room temperature for 1 h), and recentrifuged. The spores were resuspended in copper-minus medium, and the suspension adjusted to 2×105 spores per mL. Microtiter plates were inoculated with 100 μL of this spore suspension and the plates incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
Results for growth inhibition by test compounds in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 3. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards LEPTNO.
Example 27 Efficacy of Hydrazones in Mixture with Copper Against Tomato Blight (Phytophthora infestans) Hydrazone compounds at 50 ppm in combination with 50 μM CuCl2.2H2O were evaluated as prophylactic treatments applied 24 h before inoculation. Efficacy was determined based on percentage of disease control against tomato late blight (TLB), causal agent Phytophthora infestans. Treatments were arranged in a completely randomized design with 3 repetitions each. A pot with one tomato plant was considered as an experimental unit. Hydrazones were dissolved in acetone and re-suspended in water containing 0.01% Triton® X-100, 0.1% Atlox 4913 and 50 μM CuCl2.2H2O to a final concentration of 10% acetone. All treatments were applied to run off 24 h before inoculation using a spin-table sprayer. Inoculation with an aqueous suspension of P. infestans sporangia was performed using a Delta painting sprayer. Percentage of disease control was determined 7 days after inoculation. Data are presented in Table 2, and illustrate the efficacy of hydrazones in mixture with copper for control of tomato late blight.
TABLE 2
LEPTNO LEPTNO LEPTNO
% Inhn. % Inhn. % Inhn.
Minus Plus Plus
Compound Concn. Copper Copper Copper TLB %
Number (μg/mL) Observed Observed Predicted Control
1 0.05 0.7 96.2 7.8 64.0
2 0.05 0.0 95.1 7.1 61.4
3 0.05 2.3 93.0 9.3 47.0
4 0.05 4.4 94.5 11.2 67.8
5 0.05 4.8 56.1 11.6 22.0
6 0.05 3.9 96.4 10.7 88.1
7 0.05 2.6 97.2 9.5 54.6
8 0.05 0.0 92.6 7.1 59.6
9 0.05 0.0 93.6 7.1 67.3
10 0.05 6.9 97.2 13.5 96.0
11 0.05 0.3 97.2 7.4 42.1
12 0.05 0.5 97.4 7.6 94.0
13 0.05 0.0 96.2 7.1 33.3
14 0.156 2.9 59.1 9.8 7.5
15 0.05 4.4 96.6 11.1 58.5
16 0.05 0.0 97.1 7.1 94.0
17 0.05 9.4 95.9 15.9 69.0
18 0.05 0.0 96.9 7.1 38.6
19 0.05 2.9 88.8 9.8 25.0
20 0.05 2.8 96.5 9.7 96.5
21 0.05 0.1 94.1 7.2 65.5
22 0.05 16.0 97.6 22.0 93.2
23 0.05 2.3 95.4 9.2 53.3
24 0.05 7.6 92.8 14.1 8.9
25 0.05 0.0 97.3 7.1 35.1
26 0.05 2.1 98.4 9.1 12.3
27 0.05 16.5 97.9 22.4 43.3
28 0.05 7.0 96.8 13.6 62.7
29 0.05 0.0 98.0 7.1 50.8
30 0.05 0.0 97.0 7.1 40.7
31 0.05 2.2 89.0 9.2 33.3
32 0.05 0.0 94.4 7.1 74.6
33 0.05 0.0 93.1 7.1 50.9
34 0.05 0.0 97.8 7.1 68.4
35 0.05 3.8 96.5 10.6 0.0
36 0.05 5.9 98.4 12.6 33.9
37 0.05 3.3 97.0 10.2 33.0
38 0.05 2.4 98.3 9.4 17.0
39 0.05 1.3 97.9 8.3 18.6
40 0.05 0.0 94.8 7.1 64.9
41 0.05 0.0 97.2 7.1 87.0
42 0.05 9.2 93.2 15.6 60.0
43 0.156 14.2 75.4 20.3 68.8
44 0.05 0.3 93.0 7.3 0.7
45 0.05 0.0 96.2 7.1 49.0
46 0.05 20.5 95.9 26.1 72.7
47 0.05 0.0 97.1 7.1 33.0
48 0.05 0.3 94.6 7.4 40.0
49 0.05 14.6 97.1 20.7 0.7
50 0.05 3.5 97.4 10.4 43.5
51 0.05 0.0 97.6 7.1 4.8
52 0.2 12.3 96.4 18.5 NT
53 0.05 0.0 96.8 7.1 62.0
54 0.05 0.0 95.7 7.1 17.0
55 0.05 0.0 95.5 7.1 43.9
56 0.05 2.1 96.3 9.1 81.3
57 0.05 0.0 97.3 7.1 89.5
58 0.05 0.0 95.0 7.1 49.0
59 0.05 12.8 97.5 19.0 79.7
60 0.05 7.3 97.5 13.9 85.0
61 0.05 3.8 93.6 10.6 60.0
62 0.05 0.0 96.3 7.1 56.1
63 0.05 0.0 96.7 7.1 40.4
64 0.05 0.0 97.8 7.1 43.0
65 0.05 0.0 98.3 7.1 10.0
66 0.05 0.1 97.4 7.2 51.0
67 0.05 2.6 91.8 9.5 75.0
68 0.05 15.8 97.0 21.8 75.9
69 0.05 19.3 96.9 25.1 90.8
70 0.05 19.6 98.2 25.3 93.1
71 0.05 2.6 91.2 9.5 78.0
72 0.05 14.1 91.3 20.2 81.3
73 0.05 8.6 98.0 15.1 87.3
74 0.05 3.0 95.7 9.8 63.6
75 0.05 0.0 98.4 7.1 15.8
76 0.05 0.0 97.0 7.1 89.8
77 0.05 7.6 96.1 14.1 55.5
78 0.05 7.9 96.3 14.4 70.9
79 0.05 12.2 97.1 18.4 84.4
80 0.05 0.0 98.4 7.1 91.5
81 0.05 2.4 96.1 9.3 97.0
82 0.05 8.4 97.4 14.9 60.6
83 0.05 5.9 98.0 12.5 60.6
84 0.05 5.6 95.5 12.3 83.6
85 0.05 5.3 90.0 12.0 51.5
86 0.05 0.3 97.6 7.4 80.7
87 0.05 8.1 98.6 14.7 69.5
88 0.05 10.7 96.7 17.0 4.8
89 0.05 17.5 95.9 23.3 85.8
90 0.05 9.5 96.4 15.9 54.6
91 0.05 0.0 79.3 7.1 18.0
92 0.05 1.9 98.2 8.8 71.9
93 0.05 6.0 95.2 12.7 77.2
94 0.05 0.0 92.9 7.1 37.0
95 0.05 14.1 94.0 20.2 81.2
96 0.05 1.2 93.6 8.2 78.2
97 0.05 18.2 98.3 24.0 76.3
98 0.05 16.8 98.1 22.7 79.7
99 0.05 8.9 94.5 15.4 50.3
100 0.05 8.2 97.0 14.7 74.2
101 0.05 7.8 97.3 14.3 85.3
102 0.05 0.0 93.4 7.1 74.0
103 0.05 17.9 98.1 23.8 63.2
104 0.05 27.7 98.2 32.8 70.2
105 0.05 5.8 95.2 12.5 74.6
106 0.05 0.0 94.6 7.1 88.7
107 0.05 0.0 97.2 7.1 74.6
108 0.05 21.3 97.6 26.9 50.9
109 0.05 27.8 98.3 32.9 89.1
110 0.05 19.9 98.2 25.6 76.4
111 0.05 16.8 97.4 22.7 63.6
112 0.05 8.1 97.8 14.6 78.2
113 0.05 17.0 98.0 22.9 94.7
114 0.05 0.0 36.9 7.1 7.5
115 0.05 6.1 97.4 12.7 78.2
116 0.05 8.4 98.2 14.9 88.8
117 0.05 28.8 98.5 33.9 89.5
118 0.05 10.6 98.3 16.9 85.3
119 0.05 2.2 95.7 9.1 91.9
120 0.05 19.9 98.2 25.6 92.6
121 0.05 0.0 98.3 7.1 88.1
122 0.05 13.5 98.7 19.6 92.7
123 0.05 7.5 95.5 14.1 71.0
124 0.05 0.0 88.2 7.1 23.0
125 0.05 2.4 94.4 9.3 87.0
126 0.05 13.2 92.4 19.4 73.0
127 0.05 0.0 97.1 7.1 40.0
128 0.05 10.8 88.6 17.1 38.0
129 0.05 5.5 97.8 12.2 49.0
130 0.05 1.2 98.6 8.2 50.8
131 0.05 0.0 96.8 7.1 62.0
132 0.05 9.1 97.7 15.5 65.5
133 0.05 8.8 98.5 15.3 71.9
134 0.05 4.2 95.3 11.0 57.0
135 0.05 0.2 98.6 7.3 96.0
136 0.05 9.7 98.6 16.2 95.0
137 0.05 4.5 98.5 11.3 74.0
138 0.05 4.0 98.1 10.8 91.0
139 0.05 1.7 97.1 8.6 93.0
140 0.05 6.7 96.7 13.3 81.0
141 0.05 1.5 96.2 8.5 52.0
142 0.05 1.1 98.2 8.1 79.0
143 0.05 2.1 98.2 9.0 64.4
144 0.05 0.0 98.5 7.1 87.0
145 0.05 2.4 97.2 9.3 55.9
146 0.05 0.0 96.2 7.1 71.2
147 0.05 0.0 95.6 7.1 13.5
148 0.05 15.4 97.9 21.5 72.9
149 0.05 0.0 97.1 7.1 22.1
150 0.05 10.0 97.5 16.4 87.5
151 0.05 11.8 97.6 18.1 83.0
152 0.05 0.0 89.1 7.1 26.0
153 0.05 0.0 97.0 7.1 34.6
154 0.05 3.4 70.7 10.3 36.6
155 0.05 1.9 78.3 8.9 32.0
156 0.05 7.4 94.8 14.0 51.5
157 0.05 7.8 96.9 14.3 61.8
158 0.05 6.2 96.9 12.9 84.7
159 0.05 11.4 98.5 17.7 91.9
160 0.05 3.4 96.1 10.2 65.5
161 0.05 7.0 97.7 13.6 58.2
162 0.05 0.0 96.9 7.1 94.0
163 0.05 5.9 98.0 12.6 87.7
164 0.05 10.8 98.6 17.1 96.5
165 0.05 14.9 98.4 21.0 88.4
166 0.05 2.6 97.9 9.5 71.9
167 0.05 0.0 95.8 7.1 67.3
168 0.05 13.3 97.7 19.5 59.6
169 0.05 2.7 98.1 9.6 78.9
170 0.05 0.0 94.5 7.1 65.5
171 0.05 4.0 98.3 10.8 15.8
172 0.05 13.2 97.9 19.4 27.1
173 0.05 8.3 97.7 14.8 12.2
174 0.05 0.0 97.0 7.1 72.7
175 0.05 4.9 97.9 11.6 80.0
176 0.05 8.8 98.2 15.2 61.4
177 0.05 12.5 95.2 18.7 91.0
178 0.05 8.5 98.3 15.0 59.3
179 0.05 18.7 98.0 24.4 35.1
180 0.05 10.8 95.1 17.1 43.9
181 0.05 16.0 97.6 22.0 90.5
182 0.05 0.0 97.6 7.1 74.6
183 0.05 0.0 96.7 7.1 66.7
184 0.05 7.1 97.0 13.7 70.9
185 0.05 0.0 95.2 7.1 54.6
186 0.05 0.0 97.6 7.1 61.8
187 0.05 20.7 97.5 26.3 92.7
188 0.05 7.9 96.5 14.5 74.6
189 0.05 19.2 95.9 24.9 72.7
190 0.05 5.6 95.7 12.3 70.9
191 0.05 15.4 98.1 21.4 29.8
192 0.05 7.8 94.7 14.3 84.2
193 0.05 0.0 95.1 7.1 80.0
194 0.05 16.1 96.9 22.0 80.4
195 0.05 19.2 97.9 24.9 89.5
196 0.05 4.4 97.7 11.2 94.5
197 0.05 0.0 97.1 7.1 43.7
198 0.05 11.8 97.7 18.1 75.4
199 0.05 4.0 98.0 10.8 56.1
200 0.05 0.0 95.0 7.1 78.9
201 0.05 4.0 96.0 10.8 50.9
202 0.05 2.0 96.6 9.0 49.1
203 0.05 6.9 95.7 13.5 56.4
204 0.05 7.3 95.5 13.8 77.2
205 0.05 15.4 97.2 21.5 78.9
206 0.05 16.4 98.4 22.3 80.7
207 0.05 0.0 95.3 7.1 52.7
208 0.05 5.4 97.0 12.1 32.8
209 0.05 17.6 95.9 23.4 67.3
210 0.05 1.9 94.1 8.9 37.0
211 0.05 7.0 97.1 13.6 16.0
212 0.05 0.0 95.2 7.1 14.0
213 0.05 3.7 98.8 10.6 56.1
214 0.05 7.0 98.0 13.6 60.0
215 0.05 0.5 98.6 7.5 37.0
216 0.05 6.3 98.4 12.9 57.9
217 0.05 0.0 92.7 7.1 0.0
218 0.05 0.0 92.5 7.1 70.9
219 0.05 34.5 97.9 39.2 68.4
220 0.05 0.0 95.3 7.1 89.1
221 0.05 0.0 92.4 7.1 66.0
222 0.05 0.0 94.5 7.1 67.3
223 0.05 26.9 97.2 32.1 54.0
224 0.05 0.0 91.0 7.1 67.3
225 0.05 0.0 96.6 7.1 78.2
226 0.05 0.0 94.5 7.1 71.0
227 0.05 5.0 95.0 11.7 52.7
228 0.05 2.6 97.0 9.6 68.4
229 0.05 6.0 98.0 12.7 70.9
230 0.05 9.0 98.3 15.5 65.0
231 0.05 0.0 98.5 7.1 81.3
232 0.05 2.3 97.5 9.3 57.6
233 0.05 5.6 98.1 12.3 88.1
234 0.05 0.0 94.3 7.1 72.9
235 0.05 0.0 96.3 7.1 80.0
236 0.05 3.5 97.0 10.4 88.1
237 0.05 0.0 91.8 7.1 45.0
238 0.05 0.5 97.6 7.5 92.5
239 0.05 0.1 97.8 7.2 66.1
240 0.05 0.0 98.1 7.1 74.6
241 0.05 0.5 97.0 7.5 62.7
242 0.05 6.9 98.0 13.5 78.0
243 0.05 5.3 96.7 12.1 86.4
244 0.05 0.0 96.1 7.1 62.7
245 0.05 0.0 96.7 7.1 52.7
246 0.05 0.0 95.3 7.1 50.9
247 0.05 10.1 94.0 16.5 84.7
248 0.05 12.4 96.3 18.7 98.0
249 0.05 27.8 95.8 32.9 100.0
250 0.05 8.7 98.1 15.2 97.0
251 0.05 3.5 98.1 10.3 33.0
252 0.05 7.8 98.4 14.4 28.0
253 0.05 4.9 98.0 11.6 14.0
254 0.05 8.3 98.1 14.8 0.0
255 0.05 3.6 98.2 10.4 28.0
256 0.05 3.0 98.7 9.8 18.0
257 0.05 6.0 94.4 12.6 21.0
258 0.05 34.1 97.4 38.8 87.0
259 0.05 9.9 97.9 16.3 32.0
260 0.05 11.2 97.1 17.5 81.0
261 0.05 2.7 97.9 9.6 10.0
262 0.05 3.1 94.0 9.9 4.6
263 0.05 4.1 97.9 10.9 14.0
264 0.05 6.0 98.4 12.7 21.0
265 0.05 0.0 98.1 7.1 15.0
266 0.05 4.5 95.4 11.3 28.0
267 0.05 5.7 98.3 12.4 33.0
268 0.05 1.2 98.7 8.2 31.0
269 0.05 0.0 98.8 7.1 21.0
270 0.05 6.9 98.6 13.5 61.0
271 0.05 6.9 98.9 13.5 61.0
272 0.05 2.0 98.1 8.9 37.0
273 0.05 0.4 97.7 7.5 44.0
274 0.05 0.0 96.3 7.1 89.0
275 0.05 0.0 98.4 7.1 79.7
276 0.05 5.5 97.8 12.2 71.2
277 0.05 1.9 97.5 8.9 86.4
278 0.05 1.7 97.7 8.7 90.0
279 0.05 5.1 98.6 11.8 96.0
280 0.05 2.2 98.2 9.1 88.0
281 0.05 1.4 98.4 8.4 67.0
282 0.05 0.0 94.7 7.1 52.0
283 0.05 0.0 95.9 7.1 67.0
284 0.05 0.0 97.1 7.1 74.0
285 0.05 3.4 97.5 10.3 51.0
286 0.05 2.3 98.4 9.2 75.0
287 0.05 0.0 98.3 7.1 65.0
288 0.05 1.8 98.2 8.8 26.0
289 0.05 0.0 97.6 7.1 45.0
290 0.05 0.4 95.5 7.5 21.0
291 0.05 2.2 95.4 9.2 67.0
292 0.05 5.0 97.6 11.7 21.0
293 0.05 7.9 95.7 14.4 19.0
294 0.05 1.7 94.2 8.7 72.9
295 0.05 5.8 98.0 12.5 89.8
296 0.05 8.3 97.7 14.8 84.7
297 0.05 0.0 96.4 7.1 69.5
298 0.05 0.7 95.0 7.8 74.6
299 0.05 0.0 97.9 7.1 74.0
300 0.05 0.0 97.2 7.1 70.0
301 0.05 0.0 97.9 7.1 82.0
302 0.05 0.0 96.4 7.1 82.0
303 0.05 0.0 98.0 7.1 45.0
304 0.05 0.0 97.9 7.1 77.0
305 0.05 0.5 98.3 7.5 61.0
306 0.05 0.0 95.2 7.1 35.0
307 0.05 0.0 91.3 7.1 25.0
308 0.05 37.2 97.7 41.6 96.0
309 0.05 5.5 97.4 12.2 74.0
310 0.05 2.4 96.6 9.3 64.0
311 0.05 3.3 98.3 10.2 37.0
312 0.05 3.8 97.8 10.6 1.4
313 0.05 8.5 98.5 15.0 28.0
314 0.05 0.0 97.7 7.1 8.8
315 0.05 2.7 95.8 9.6 18.0
316 0.05 4.5 97.1 11.3 14.0
317 0.05 16.3 97.9 22.3 24.0
318 0.05 3.1 97.3 10.0 71.2
319 0.05 18.1 96.6 23.9 78.0
320 0.05 17.1 96.4 23.0 100.0
321 0.05 11.7 96.6 18.0 100.0
322 0.05 20.9 97.9 26.5 95.0
323 0.05 16.1 98.1 22.1 100.0
324 0.05 2.3 96.3 9.2 98.0
325 0.05 0.0 95.7 7.1 100.0
326 0.05 6.9 95.6 13.5 93.0
327 0.05 1.2 95.7 8.3 98.0
328 0.05 0.0 95.1 7.1 99.0
329 0.05 14.0 93.5 20.1 99.0
330 0.05 5.3 92.9 12.1 99.0
331 0.05 22.8 97.8 28.2 100.0
332 0.05 2.0 93.9 8.9 89.0
333 0.05 16.2 93.2 22.1 85.0
334 0.05 10.9 97.8 17.2 98.0
335 0.05 10.2 96.8 16.6 95.0
336 0.05 16.6 97.8 22.5 98.0
337 0.05 22.4 98.0 27.9 97.0
338 0.05 9.0 98.1 15.5 96.0
339 0.05 1.5 95.4 8.5 100.0
340 0.05 18.0 96.2 23.8 95.0
341 0.05 1.2 88.9 8.2 63.0
342 0.05 9.1 98.3 15.6 86.0
343 0.05 2.8 95.4 9.7 97.0
344 0.05 31.5 91.8 36.4 100.0
345 0.05 18.8 97.9 24.6 97.0
346 0.05 30.0 96.7 34.9 96.0
347 0.05 13.8 98.4 19.9 97.0
348 0.05 16.3 98.3 22.2 100.0
349 0.05 17.4 96.9 23.3 97.0
350 0.05 11.3 94.9 17.6 97.0
351 0.05 7.7 96.1 14.3 100.0
352 0.05 8.8 98.4 15.3 100.0
353 0.05 0.0 94.8 7.1 81.0
354 0.05 18.4 95.4 24.2 98.0
355 0.05 19.6 89.8 25.3 87.0
356 0.05 18.6 98.0 24.4 93.0
357 0.05 56.7 97.4 59.7 93.0
358 0.05 12.7 98.3 18.9 100.0
359 0.05 41.4 97.3 45.6 92.0
360 0.05 17.6 96.9 23.4 97.0
361 0.05 3.3 96.4 10.2 97.0
362 0.05 11.1 97.2 17.4 97.0
363 0.05 4.3 94.7 11.1 92.0
364 0.05 8.4 95.8 14.9 97.0
365 0.05 13.8 95.6 19.9 95.0
366 0.05 14.2 96.6 20.3 100.0
367 0.05 13.1 97.9 19.2 95.0
368 0.05 0.0 96.9 7.1 98.0
369 0.05 7.0 95.5 13.6 98.0
370 0.05 3.5 97.5 10.4 91.0
371 0.05 12.6 96.1 18.8 98.0
372 0.05 15.1 97.4 21.1 98.0
373 0.05 0.0 97.3 7.1 90.0
374 0.05 11.1 98.2 17.4 98.0
375 0.05 7.2 98.2 13.7 90.0
376 0.05 13.6 96.5 19.8 98.0
377 0.05 29.9 97.6 34.9 100.0
378 0.05 26.3 98.4 31.6 97.0
379 0.05 26.7 98.2 31.9 100.0
380 0.05 36.1 98.3 40.6 100.0
381 0.05 31.8 98.6 36.6 100.0
382 0.05 19.3 98.5 25.0 96.0
383 0.05 20.3 95.7 25.9 100.0
384 0.05 28.6 95.8 33.6 100.0
385 0.05 5.4 94.6 12.1 100.0
386 0.05 41.1 98.4 45.3 100.0
387 0.05 13.5 96.9 19.6 87.0
388 0.05 17.2 98.1 23.1 61.0
389 0.05 7.7 97.6 14.2 95.0
390 0.05 4.2 97.5 11.0 95.0
391 0.05 6.0 96.9 12.7 92.0
392 0.05 15.8 97.9 21.8 46.0
393 0.05 4.3 96.1 11.1 73.0
394 0.05 8.0 95.9 14.6 71.0
395 0.05 8.2 93.9 14.8 76.0
396 0.05 0.0 95.5 7.1 49.0
397 NT NT NT 6.7
398 0.05 5.4 94.7 12.1 98.0
399 0.05 5.8 97.1 12.5 88.0
400 0.05 0.5 97.9 7.6 96.0
401 0.05 0.0 94.8 7.1 98.0
402 0.05 0.0 95.2 7.1 100.0
403 0.05 0.0 97.3 7.1 97.0
404 0.05 0.0 94.9 7.1 97.0
405 0.05 2.8 96.2 9.7 98.0
406 0.05 6.7 96.1 13.3 98.0
407 0.05 0.0 92.0 7.1 70.0
408 0.05 8.4 79.7 14.9 94.0
409 0.05 7.9 96.3 14.4 98.0
410 0.05 1.9 97.6 8.9 95.0
411 0.05 8.2 97.9 14.7 85.0
412 0.05 7.7 97.8 14.3 100.0
413 0.05 18.9 97.9 24.7 94.0
414 0.05 14.6 97.9 20.7 90.0
415 0.05 2.9 96.1 9.8 100.0
416 0.05 4.3 97.5 11.1 93.0
417 0.05 10.7 98.2 17.0 100.0
418 0.05 0.0 97.3 7.1 93.0
419 0.05 3.2 94.9 10.1 90.0
420 0.05 11.4 97.5 17.7 100.0
421 0.05 8.2 96.6 14.7 94.0
422 0.05 0.0 95.5 7.1 90.0
423 0.05 0.8 98.0 7.9 98.0
424 0.05 22.3 97.0 27.8 100.0
425 0.05 17.5 97.6 23.4 95.0
426 0.05 34.8 97.3 39.5 98.0
427 0.05 26.1 97.9 31.3 98.0
428 0.05 44.1 98.4 48.1 97.0
429 0.05 10.4 97.4 16.8 94.0
430 0.05 16.6 98.2 22.5 100.0
431 0.05 8.5 95.1 15.0 91.0
432 0.05 0.0 95.9 7.1 72.0
433 0.05 10.8 97.8 17.2 100.0
434 0.05 25.6 97.4 30.9 100.0
435 0.05 4.7 97.2 11.5 100.0
436 0.05 14.6 98.2 20.7 94.0
437 0.05 9.2 97.0 15.6 100.0
438 0.05 0.0 94.2 7.1 98.0
439 0.05 0.0 100.0 7.1 96.0
440 0.05 2.9 100.0 9.8 98.0
441 0.05 0.0 100.0 7.1 96.0
442 0.05 0.0 100.0 7.1 98.0
443 0.05 14.6 100.0 20.7 83.0
444 0.05 0.0 100.0 7.1 91.0
445 0.05 13.2 100.0 19.4 90.0
446 0.05 23.5 95.4 29.0 57.0
447 0.05 20.0 96.6 25.7 100.0
448 0.05 27.1 97.5 32.3 100.0
449 0.05 7.2 98.5 13.8 92.0
450 0.05 1.1 93.5 8.1 100.0
451 0.05 4.6 100.0 11.4 100.0
452 0.05 12.9 100.0 19.1 100.0
453 0.05 5.6 100.0 12.3 100.0
454 0.05 12.4 100.0 18.6 100.0
455 0.05 16.7 100.0 22.6 100.0
456 0.05 0.0 100.0 7.1 100.0
457 0.05 6.7 100.0 13.3 100.0
458 0.05 3.7 96.6 10.6 46.0
459 0.05 7.3 96.9 13.8 20.0
460 0.05 0.0 97.6 7.1 39.0
461 0.05 3.4 96.7 10.3 54.0
462 0.05 0.0 95.0 7.1 86.0
463 0.05 5.1 96.3 11.9 61.0
464 0.05 6.7 94.8 13.4 93.0
465 0.05 1.7 96.5 8.6 93.0
466 0.05 2.7 97.9 9.6 69.0
467 0.05 0.0 95.7 7.1 80.0
468 0.05 6.2 98.1 12.8 92.0
469 0.05 1.0 97.8 8.1 95.0
470 0.05 4.0 98.0 10.8 93.0
471 0.05 7.9 97.8 14.4 83.0
472 0.05 0.0 97.7 7.1 49.0
473 0.05 0.0 97.5 7.1 78.0
474 0.05 39.2 97.6 43.5 100.0
475 0.05 33.8 97.1 38.5 100.0
476 0.05 0.0 93.9 7.1 69.0
477 0.05 6.2 83.4 12.8 93.0
478 0.05 0.7 94.7 7.7 65.0
479 0.05 0.0 97.5 7.1 97.0
480 0.05 9.5 95.3 15.9 4.7
481 0.05 10.3 97.8 16.7 76.0
482 0.05 0.0 96.4 7.1 66.0
483 0.05 0.0 97.9 7.1 63.0
484 0.05 12.6 93.2 18.8 88.0
485 0.05 8.0 96.7 14.5 95.0
486 0.05 12.8 96.6 19.0 95.0
487 0.05 11.2 93.9 17.5 100.0
488 0.05 20.1 92.6 25.7 72.0
489 0.05 15.8 97.8 21.8 85.0
490 0.05 31.5 97.0 36.4 55.0
491 0.05 25.0 97.5 30.3 75.0
492 0.05 0.0 98.1 7.1 93.0
493 0.05 0.0 97.8 7.1 95.0
494 0.05 0.0 97.7 7.1 96.0
495 0.05 0.0 97.3 7.1 91.0
496 0.05 0.7 97.8 7.8 94.0
497 0.05 0.0 98.1 7.1 75.0
498 0.05 0.0 97.5 7.1 85.0
499 0.05 0.0 97.4 7.1 85.0
500 0.05 9.2 93.2 15.6 80.0
501 0.05 0.5 98.0 7.6 89.0
502 0.05 4.2 97.2 11.0 85.0
503 0.05 5.2 97.0 11.9 66.0
504 0.05 1.3 97.6 8.3 94.0
505 0.05 7.1 97.3 13.7 46.0
506 0.05 2.7 97.5 9.6 44.0
507 0.05 7.6 97.0 14.1 66.0
508 0.05 9.4 97.1 15.9 92.0
509 0.05 0.0 96.2 7.1 85.0
510 0.05 6.2 95.5 12.8 56.0
511 0.05 0.0 97.8 7.1 73.0
512 0.05 7.4 97.8 13.9 59.0
513 0.05 14.0 98.0 20.1 53.0
514 0.05 0.0 97.7 7.1 75.0
515 0.05 0.0 97.6 7.1 47.0
516 0.05 0.0 97.9 7.1 59.0
517 0.05 0.0 96.7 7.1 56.0
518 0.05 24.2 97.4 29.6 58.0
519 0.05 9.1 95.7 15.6 88.0
520 0.05 14.9 96.7 20.9 49.0
521 0.05 5.0 95.9 11.8 83.0
522 0.05 9.4 97.3 15.9 95.0
523 0.05 7.0 97.7 13.6 92.0
524 0.05 9.3 95.8 15.7 39.0
525 0.05 5.4 97.4 12.1 78.0
526 0.05 1.8 16.2 8.7 41.0
527 0.05 7.6 97.6 14.2 78.0
528 0.05 8.7 97.7 15.2 73.0
529 0.05 15.3 97.7 21.3 46.0
530 0.05 9.8 96.2 16.2 59.0
531 0.05 0.0 97.3 7.1 80.0
532 0.05 4.9 91.4 11.7 56.0
533 0.05 6.2 97.0 12.9 34.0
534 0.05 5.1 95.7 11.9 61.0
535 0.05 10.1 97.7 16.5 56.0
536 0.05 21.1 93.4 26.7 24.0
537 0.05 12.2 96.2 18.5 90.0
538 0.05 12.4 96.5 18.6 44.0
539 0.05 1.6 98.0 8.6 100.0
540 0.05 0.0 97.5 7.1 95.0
541 0.05 0.0 97.5 7.1 93.0
542 0.05 0.0 95.8 7.1 100.0
543 0.05 1.3 93.9 8.3 100.0
544 0.05 6.9 97.6 13.5 97.0
545 0.05 19.6 97.9 25.3 95.0
546 0.05 7.6 97.7 14.2 100.0
547 0.05 10.8 97.7 17.1 88.0
548 0.05 6.7 97.5 13.3 98.0
549 0.05 0.0 97.3 7.1 94.0
550 0.05 4.6 97.2 11.4 63.0
551 0.05 1.7 96.0 8.7 90.0
552 0.05 0.0 94.2 7.1 71.0
553 0.05 0.0 93.2 7.1 88.0
554 0.05 0.0 97.3 7.1 100.0
555 0.05 3.7 92.5 10.5 46.0
556 0.05 7.7 95.9 14.2 75.0
557 0.05 13.0 95.7 19.2 90.0
558 0.05 3.8 95.7 10.6 80.0
559 0.05 10.0 97.3 16.4 93.0
560 0.05 1.3 90.7 8.3 65.0
561 0.05 0.0 92.2 7.1 60.0
562 0.05 1.4 97.3 8.4 91.0
563 0.05 20.6 96.9 26.2 70.0
564 0.05 17.4 94.2 23.3 1.3
565 0.05 12.2 97.4 18.4 98.0
566 0.05 6.8 95.9 13.4 70.0
567 0.05 2.5 42.3 9.5 14.0
568 0.05 8.0 94.3 14.6 61.0
569 0.05 6.1 15.8 12.7 70.0
570 0.05 3.2 97.2 10.1 39.0
571 0.05 0.0 84.7 7.1 31.0
572 0.05 2.5 97.4 9.5 94.0
573 0.05 2.4 98.4 9.3 93.0
574 0.05 2.8 98.3 9.7 93.0
575 0.05 0.0 98.1 7.1 100.0
576 0.05 0.7 97.9 7.7 90.0
577 0.05 1.9 97.9 8.8 100.0
578 0.05 7.2 98.0 13.8 100.0
579 0.05 0.0 97.6 7.1 97.0
580 0.05 3.1 98.1 10.0 97.0
581 0.05 13.6 98.2 19.7 93.0
582 0.05 12.2 97.8 18.4 94.0
583 0.05 13.2 98.0 19.4 100.0
584 0.05 3.0 11.8 9.9 7.6
585 0.05 6.3 86.3 13.0 62.0
586 0.05 0.0 87.3 7.1 31.0
587 0.05 6.2 96.6 12.8 2.4
588 0.05 7.6 96.3 14.2 5.6
589 0.05 8.7 97.9 15.2 61.0
590 0.05 10.0 98.6 16.4 88.0
591 0.05 0.0 9.9 7.1 11.0
592 0.05 0.0 25.4 7.1 1.4
CuCl2 10 μM 7.1 ± 6.0
NT = not tested
Example 28 Effect of Copper on Fungitoxicity of Hydrazones Towards Phytophthora capsici In vitro fungitoxicity assays against Phytophthora capsici were conducted using the asparagine-sucrose (AS) medium described in Canadian Journal of Microbiology 1961, 7, 15-25, except that copper micronutrient, normally included as CuSO4, was omitted. The medium, termed “copper-minus AS”, was prepared by dissolving 2 g asparagine, 0.43 g KH2PO4, 0.3 g K2HPO4, 0.4 mL of a 0.5 mg/mL thiamine-HCl solution and 15 g sucrose in 1 liter of deionized water and treating the solution with 0.5 g Chelex 100 resin (Bio-Rad Analytical grade, 50-100 mesh, sodium form, cat# 142-2822) by stiffing at room temperature for 1 h. The pH was adjusted to 6.4, then MgSO4.7H2O (100 μg/mL), FeSO4.7H2O (1 μg/mL), CaCl2 (50 μg/mL), ZnSO4.7H2O (1 μg/mL), NaMoO4.2H2O (0.2 μg/mL) and MnCl2.4H2O (0.2 μg/mL) were added and the entire medium was sterilized by filtration. “Copper-plus AS” medium was prepared by adding CuCl2.2H2O to the copper-minus AS medium at 100 μM. Test compounds were dissolved in DMSO then dilutions in copper-minus AS and copper-plus AS media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates.
Phytophthora capsici was grown on petri plates, 9 cm in diameter, containing 15 mL V-8 agar, pH 7.0, containing 200 mL V-8 juice, 4 g CaCO3, and 20 g agar per liter. Plates were inoculated with 7-mm plugs from a 1-week old culture, incubated at 25° C. in the dark for 3 days, and then placed under fluorescent lights for 4 days to induce sporulation. Zoospore release from sporangia was induced by adding 15 mL of sterile deionized water (which had been treated with Chelex 100 resin using 0.5 g resin per liter of water by stiffing at room temperature for 1 h) to each plate, and incubating for 10 min at 25° C. followed by 20 min at 4° C. The plates were returned to 25° C. for 10 min and the aqueous suspension of released zoospores was recovered. The zoospore suspension was adjusted to 5×104 spores/mL by dilution into Chelex 100-treated water. Microtiter plates were inoculated with 100 μL of spore suspension and incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
Results for growth inhibition by test compounds in copper-plus AS medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds (1967), 15, 20-22 based on results obtained for the same compounds in copper-minus AS medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus AS and copper-plus AS media without any test compound across experiments. Data are presented in Table 3. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Phytophthora capsici.
TABLE 3
% Inhn % Inhn % Inhn
Minus Plus Plus
Compound Concentration copper copper copper
Number (μg/mL) Observed Observed Predicted
1 0.039 9.7 87.2 13.8
3 0.039 0.0 88.5 4.5
5 0.039 18.6 93.9 22.3
6 0.039 28.8 95.8 32.0
14 0.039 0.0 87.2 4.5
15 0.039 80.4 91.8 81.2
16 0.050 0.0 91.9 4.5
20 0.050 2.1 90.4 6.5
21 0.039 0.0 90.0 4.5
23 0.039 10.8 93.8 14.8
24 0.039 10.2 92.4 14.2
28 0.039 11.4 93.8 15.4
43 0.039 54.2 90.3 56.2
52 0.039 40.6 91.2 43.3
56 0.039 57.5 94.1 59.4
60 0.050 4.1 76.4 8.4
61 0.039 17.6 95.6 21.3
69 0.050 0.0 87.6 4.5
74 5 17.2 89.4 20.9
83 0.039 27.9 96.2 31.1
84 0.039 47.5 95.0 49.8
91 0.039 52.1 93.2 54.3
96 0.039 55.2 91.9 57.2
99 0.039 23.6 94.0 27.1
100 0.039 10.0 88.8 14.0
101 0.039 70.0 88.2 71.4
102 0.039 15.7 93.6 19.4
119 0.039 37.9 95.1 40.7
121 0.050 0.0 90.4 4.5
123 0.039 16.3 94.8 20.0
124 0.039 25.0 89.7 28.3
125 0.039 66.6 89.4 68.1
129 0.039 10.6 96.3 14.6
131 0.039 5.6 93.7 9.9
140 0.050 0.0 91.4 4.5
143 0.039 6.0 94.5 10.3
146 0.039 11.8 91.4 15.8
162 0.050 5.2 91.6 9.5
177 0.050 0.0 92.4 4.5
182 0.039 25.9 90.9 29.2
183 0.039 0.0 88.9 4.5
204 0.050 6.0 81.9 10.2
207 0.039 0.0 88.9 4.5
210 0.039 36.6 92.7 39.4
218 0.050 10.7 93.3 14.7
219 0.050 15.3 90.6 19.1
220 0.050 13.4 85.5 17.3
221 0.050 12.0 92.2 15.9
222 0.050 11.3 76.8 15.3
223 0.050 2.5 51.3 6.9
224 0.050 6.2 93.3 10.4
225 0.050 11.4 82.8 15.4
226 0.050 2.3 62.1 6.7
227 0.050 1.7 93.4 6.2
228 0.050 10.0 86.9 14.0
229 0.050 1.6 89.1 6.0
230 0.050 5.8 93.6 10.1
275 0.050 0.0 91.2 4.5
277 0.050 0.0 88.2 4.5
320 0.050 2.9 81.4 7.3
337 0.050 4.7 42.1 9.0
351 0.050 0.0 87.9 4.5
364 0.050 0.0 23.2 4.5
369 0.050 0.0 44.5 4.5
384 0.050 0.0 71.1 4.5
405 0.050 0.6 85.9 5.1
427 0.050 9.1 88.6 13.2
443 0.050 2.4 91.2 6.8
455 0.050 0.0 30.8 4.5
578 0.050 2.8 90.4 7.2
CuCl2, 50 μM 4.5 ± 7.9
Example 29 Effect of Copper on Fungitoxicity of Hydrazones Towards Ustilago maydis In vitro fungitoxicity assays against Ustilago maydis were conducted using the copper-minus medium described in Example 26. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus medium at 20 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) at 200 μg/mL and 1 μL aliquots were added to two wells of flat-bottomed 96-well microtiter plates. Copper-minus medium (100 μL) was added to one of the wells and copper-plus medium to the second well. Control wells, included for each medium, received 1 uL DMSO and 100 μL of medium.
Ustilago maydis was grown in 50 mL potato dextrose broth with shaking at 25° C. for 24 h. A 10 mL aliquot of the culture was centrifuged at 2000 rpm for 2 min, resuspended in 10 mL of sterile Chelex 100-treated water, and centrifuged again. The spores were resuspended in copper-minus medium, and the suspension adjusted to a concentration of 1×105 spores per mL. Microtiter plate wells containing test compound of DMSO (control) as described above were inoculated with 100 μL of this spore suspension and the plates incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
Results for growth inhibition by test compounds at 1 μg/mL in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted results (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound. Data are presented in Table 4. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Ustilago maydis.
TABLE 4
% Inhn. % Inhn. % Inhn.
Compound Minus copper Plus copper Plus copper
Number Observed Observed Predicted
16 0.0 80.0 11.9
20 1.2 91.0 12.9
60 0.0 93.5 11.9
69 0.0 96.2 11.9
121 0.0 96.9 11.9
140 0.0 95.7 11.9
162 8.8 96.4 19.7
177 0.0 33.3 11.9
204 0.0 77.0 11.9
230 11.9 94.4 22.4
275 0.0 92.2 11.9
277 1.7 83.5 13.4
320 0.0 95.2 11.9
329 16.2 41.8 26.2
337 22.0 97.8 31.3
351 27.1 97.7 35.8
364 65.5 92.9 69.6
369 3.1 93.6 14.7
384 13.6 96.6 23.9
405 9.6 90.0 20.4
427 34.3 89.3 42.1
443 10.2 35.3 20.9
455 0.0 96.0 11.9
578 47.4 93.8 53.6
CuCl2, 10 μM 11.9
Example 30 Effect of Copper on Fungitoxicity of Hydrazones Towards Septoria tritici In vitro fungitoxicity assays against Septoria tritici were conducted using the copper-minus medium described in Example 26. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus medium at 2 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) at 10 μg/mL and 1 μL aliquots were added to two wells of flat-bottomed 96-well microtiter plates. Copper-minus medium (100 μL) was added to one of the wells and copper-plus medium to the second well. Control wells, included for each medium, received 1 uL DMSO and 100 μL of medium.
Septoria tritici isolate USA-184 was grown on potato dextrose agar at 18° C. under black lights for 3 days. A loopful of spores was transferred from the culture to a 15 mL tube containing 5 mL of sterile Chelex-treated water. The spores were centrifuged at 2000 rpm for 2 min, resuspended in 10 mL water, and centrifuged again. The spores were resuspended in copper-minus medium, and the suspension adjusted to a concentration of 1×105 spores per mL. Microtiter plate wells containing test compound of DMSO (control) as described above were inoculated with 100 μL of this spore suspension and the plates incubated at 25° C. for 90 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
Results for growth inhibition by test compounds at 0.05 μg/mL in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted results (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound. In this experiment, copper chloride alone (1 μM) had no effect on growth. Data are presented in Table 5. Results illustrate that hydrazones and copper produce a synergistic fungitoxic effect towards Septoria tritici.
TABLE 5
% Inhibition % Inhibition % Inhibition
Compound Minus copper Plus copper Plus copper
Number Observed Observed Predicted
16 35.8 93.6 35.8
20 0.0 95.3 0.0
60 20.6 94.8 20.6
69 0.0 96.7 0.0
121 9.7 96.5 9.7
140 0.0 96.6 0.0
162 36.3 97.1 36.3
177 0.2 95.2 0.2
204 0.0 84.4 0.0
230 43.6 96.7 43.6
275 16.2 93.5 16.2
277 3.6 88.0 3.6
320 9.5 92.1 9.5
329 14.9 55.1 14.9
337 46.8 97.1 46.8
351 44.4 97.1 44.4
364 22.4 93.7 22.4
369 9.3 93.2 9.3
384 57.5 97.0 57.5
405 18.8 89.9 18.8
427 43.8 96.7 43.8
443 5.8 92.0 5.8
455 27.5 92.4 27.5
578 26.7 90.7 26.7
CuCl2, 1 μM 0
Example 31 Comparative Efficacy of Isolated Metal-Hydrazone Complexes and Parent Hydrazones Towards Leptosphaeria nodorum Hydrazones and their isolated metal complexes were compared with respect to their in vitro fungitoxicity towards LEPTNO. Metal complexes of hydrazones were prepared by precipitation from ethanol with various metal salts, at 1:1, 2:1 or 3:1 molar ratios, as described in general by Ainscough, Brodie, Dobbs, Ranford, and Waters (Inorganica Chimica Acta 1998, 267, 27-38, which is expressly incorporated by reference herein).
A general synthesis of 1:1 metal-hydrazone complexes is as follows. The starting salicylaldehyde benzoylhydrazone or 2-hydroxyphenylketone benzoylhydrazone is dissolved (or suspended) in EtOH (generally 0.1 mmol hydrazone per mL solvent) and agitated at a temperature ranging from room temperature to 80° C. for 30 min. To this solution (or suspension) is added 1 equivalent of the metal salt (generally as a 1 M solution in EtOH). The mixture is agitated for a period ranging from 1 to 24 h at a temperature ranging from room temperature to 80° C. The metal-hydrazone complex generally precipitates during the reaction or upon cooling and is isolated by filtration, washed with EtOH and finally washed with Et2O. In the instances where the complex does not precipitate, the solvent is removed and the resulting solid metal-hydrazone complex is washed with Et2O. Properties of particular metal complexes of hydrazones are provided in Table 6 below.
TABLE 6
Ratio
Com- Hydra-
plex Com- zone:
Num- pound Metal
ber Number Metal Salt Salt Description mp (° C.)
593 77 FeCl3•6H2O 1:1 brown 199-202
black solid
594 77 FeCl3•6H2O 2:1 dark green 258-260
solid
595 78 FeCl3•6H2O 3:1 dark green 258-261
solid
596 16 Cu(OCOCH3)2•H2O 1:1 dark green
solid
597 16 Cu(OCOCH3)2•H2O 2:1 tan solid 310-312
598 16 CuSO4•5H2O 1:1 dark green 307-308
solid
599 16 CuSO4•5H2O 2:1 dark green 310-312
solid
600 16 CuCl2•2H2O 1:1 light green 311-312
olive solid
601 16 CuCl2•2H2O 2:1 light green 288-290
solid
602 69 CuCl2•2H2O 1:1 olive- 250-255
brown
solid
603 84 CuCl2•2H2O 1:1 olive green 278-280
solid
604 83 CuCl2•2H2O 1:1 olive 282-285
brown
solid
605 77 CuCl2•2H2O 1:1 olive green 273-274
solid
606 96 CuCl2•2H2O 1:1 olive green 258-260
solid
607 70 CuCl2•2H2O 1:1 olive 278-279
brown
glass
608 43 CuCl2•2H2O 1:1 green black 310-312
solid
609 76 CuCl2•2H2O 1:1 brown 272-273
solid
610 100 Cu(OCOCH3)2•H2O 1:1 brown 315-317
black solid
611 16 MnCl2 2:1 mustard- 250
colored
solid
612 16 ZnCl2 2:1 yellow- 250
green solid
613 299 CuCl2•2H2O 1:1 dark green 160-163
solid
614 300 CuCl2•2H2O 1:1 dark green 129-132
solid
615 301 CuCl2•2H2O 1:1 dark brown 73-78
solid
616 302 CuCl2•2H2O 1:1 dark green 167-170
solid
617 303 CuCl2•2H2O 1:1 dark green 137-139
solid
618 304 CuCl2•2H2O 1:1 dark green 177-225
solid
619 305 CuCl2•2H2O 1:1 dark brown 201-211
solid
620 16 CuCl2•2H2O 1:1 olive green 293-302
solid
621 151 CuCl2•2H2O 1:1 olive green 283-294
solid
622 238 CuCl2•2H2O 1:1 olive green 299-308
solid
623 231 CuCl2•2H2O 1:1 olive green 260-275
solid
624 233 CuCl2•2H2O 1:1 olive green 286-290
solid
625 20 CuCl2•2H2O 1:1 olive green 286-288
solid
626 236 CuCl2•2H2O 1:1 olive green 259-263
solid
627 277 CuCl2•2H2O 1:1 olive green 286-289
solid
628 320 CuCl2•2H2O 1:1 olive green 280-286
solid
629 68 CuCl2•2H2O 1:1 olive green 226-228
solid
630 159 CuCl2•2H2O 1:1 olive green 224-235
solid
631 359 CuCl2•2H2O 1:1 olive green 240-254
solid
632 370 CuCl2•2H2O 1:1 olive green 257-267
solid
633 428 CuCl2•2H2O 1:1 olive green 212-270
solid
634 392 CuCl2•2H2O 1:1 olive green 262-293
solid
635 348 CuCl2•2H2O 1:1 olive green 295-305
solid
636 440 CuCl2•2H2O 1:1 olive green 259-281
solid
637 337 CuCl2•2H2O 1:1 olive green 279-281
solid
638 381 CuCl2•2H2O 1:1 olive green 279-281
solid
639 452 CuCl2•2H2O 1:1 olive green 270-274
solid
640 69 CuCl2•2H2O 1:1 olive green 298-299
solid
641 151 CuCl2•2H2O 1:1 olive green 287-289
solid
642 172 CuCl2•2H2O 1:1 olive green 311-313
solid
643 403 CuCl2•2H2O 1:1 olive green 296-297
solid
644 60 CuCl2•2H2O 1:1 olive green 215-219
solid
645 137 CuCl2•2H2O 1:1 olive green 207-211
solid
646 278 CuCl2•2H2O 1:1 olive green 242-246
solid
647 279 CuCl2•2H2O 1:1 olive green 236-239
solid
648 67 CuCl2•2H2O 1:1 olive green 176-87
solid
649 135 CuCl2•2H2O 1:1 olive green 245-248
solid
650 136 CuCl2•2H2O 1:1 olive green 242-247
solid
651 411 CuCl2•2H2O 1:1 olive green 292-295
solid
652 412 CuCl2•2H2O 1:1 olive green 309-310
solid
653 68 Cu(OCOCH3)2•H2O 1:1 brown- >350
black solid
In vitro fungitoxicity assays were conducted using the copper-minus medium described in Example 26. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus medium were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 μL of spore suspension at a concentration of 2×105 spores per mL, prepared as in Example 26. The plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
Results for growth inhibition by hydrazones and corresponding isolated metal complexes (each at 0.1 μg/mL) are shown in Table 7. The results illustrate that isolated Cu complexes of hydrazones are much more fungitoxic than the corresponding hydrazones and also are much more active than isolated Fe, Mn and Zn complexes of hydrazones.
TABLE 7
Com- Com- Hydrazone Complex
plex pound Ra- % Inhibi- % Inhibi-
Number Number Metal Salt tio* tion tion
593 77 FeCl3•6H2O 1:1 10.6 7.1
594 77 FeCl3•6H2O 2:1 10.6 4.9
595 77 FeCl3•6H2O 3:1 10.6 3.1
596 16 Cu(OCOCH3)2•H2O 1:1 19.9 98.4
597 16 Cu(OCOCH3)2•H2O 2:1 19.9 94.6
599 16 CuSO4•5H2O 2:1 19.9 97.3
600 16 CuCl2•2H2O 1:1 19.9 95.3
601 16 CuCl2•2H2O 2:1 19.9 97.0
602 69 CuCl2•2H2O 1:1 32.4 94.9
603 84 CuCl2•2H2O 1:1 6.7 95.6
604 83 CuCl2•2H2O 1:1 27.9 95.1
605 77 CuCl2•2H2O 1:1 10.6 97.2
606 96 CuCl2•2H2O 1:1 10.7 90.3
607 70 CuCl2•2H2O 1:1 29.4 48.3
608 43 CuCl2•2H2O 1:1 3.6 21.2
609 76 CuCl2•2H2O 1:1 92.8 95.5
610 100 Cu(OCOCH3)2•H2O 1:1 24.7 96.7
611 16 MnCl2•4H2O 2:1 19.9 31.3
612 16 ZnCl2 2:1 19.9 21.4
613 299 CuCl2•2H2O 1:1 18.6 96.3
614 300 CuCl2•2H2O 1:1 2.5 66.9
615 301 CuCl2•2H2O 1:1 3.5 87.3
616 302 CuCl2•2H2O 1:1 22.9 95.5
617 303 CuCl2•2H2O 1:1 10.6 88.0
618 304 CuCl2•2H2O 1:1 13.3 94.1
619 305 CuCl2•2H2O 1:1 27.1 96.3
621 151 CuCl2•2H2O 1:1 30.9 97.4
622 238 CuCl2•2H2O 1:1 20.0 97.5
623 231 CuCl2•2H2O 1:1 10.7 98.0
624 233 CuCl2•2H2O 1:1 8.4 96.8
625 20 CuCl2•2H2O 1:1 14.7 96.9
626 236 CuCl2•2H2O 1:1 4.7 94.9
627 277 CuCl2•2H2O 1:1 0.6 91.9
628 320 CuCl2•2H2O 1:1 22.1 94.6
629 68 CuCl2•2H2O 1:1 7.1 97.8
630 159 CuCl2•2H2O 1:1 27.4 97.8
631 359 CuCl2•2H2O 1:1 24.1 98.0
632 370 CuCl2•2H2O 1:1 23.1 97.5
633 428 CuCl2•2H2O 1:1 29.9 97.3
634 392 CuCl2•2H2O 1:1 22.8 75.8
635 348 CuCl2•2H2O 1:1 23.9 91.8
636 440 CuCl2•2H2O 1:1 23.8 95.8
637 337 CuCl2•2H2O 1:1 39.9 97.9
638 381 CuCl2•2H2O 1:1 43.9 97.1
639 452 CuCl2•2H2O 1:1 19.3 96.7
641 195 CuCl2•2H2O 1:1 21.7 95.2
642 172 CuCl2•2H2O 1:1 28.7 97.2
643 403 CuCl2•2H2O 1:1 12.1 93.9
644 60 CuCl2•2H2O 1:1 23.3 98.0
645 137 CuCl2•2H2O 1:1 27.2 97.7
646 278 CuCl2•2H2O 1:1 16.2 97.5
647 279 CuCl2•2H2O 1:1 19.9 96.9
648 67 CuCl2•2H2O 1:1 4.2 95.9
649 135 CuCl2•2H2O 1:1 20.6 96.0
650 136 CuCl2•2H2O 1:1 34.7 98.3
651 411 CuCl2•2H2O 1:1 32.1 97.5
652 412 CuCl2•2H2O 1:1 40.4 97.0
653 68 Cu(OCOCH3)2•H2O 1:1 7.1 96.9
*Molar ratio of hydrazone:metal used to prepare complexes.
Example 32 Comparative efficacy of isolated Cu-hydrazone complexes and parent hydrazones against glume blotch of wheat (Leptosphaeria nodorum) Hydrazones and their copper complexes were compared with respect to their ability to control glume blotch of wheat. Compound formulation was accomplished by dissolving technical materials in acetone and adding 9 volumes de-ionized water containing 0.01% Triton® X-100.
Wheat (cultivar Yuma) was grown in a soilless peat-based potting mixture (“Metromix”) until the seedlings were 10-20 cm tall. These plants were then sprayed to run-off with the test compound at a rate of 200 ppm. After 24 h, the test plants were inoculated by spraying with an aqueous suspension of LEPTNO spores and kept in a dew chamber overnight. The plants were then transferred to the greenhouse until disease developed in the untreated control plants. Results, shown in Table 8, show that copper complexes of hydrazones have higher fungicidal activity towards glume blotch than the corresponding hydrazones without copper.
TABLE 8
Com- Com-
plex pound Ra- Hydrazone Complex
Number Number Metal Salt tio* % Control % Control
600 16 CuCl2•2H2O 1:1 41 93
602 69 CuCl2•2H2O 1:1 25 83
603 84 CuCl2•2H2O 1:1 37 92
604 83 CuCl2•2H2O 1:1 38 75
605 77 CuCl2•2H2O 1:1 0 75
606 96 CuCl2•2H2O 1:1 0 91
607 70 CuCl2•2H2O 1:1 0 91
608 43 CuCl2•2H2O 1:1 0 84
609 76 CuCl2•2H2O 1:1 0 97
610 100 Cu(OCOCH3)2•H2O 1:1 0 94
*Molar ratio of hydrazone:metal used to prepare complexes.
Example 33 Effect of Copper on Fungitoxicity of Metal-Hydrazone Complexes Towards Leptosphaeria nodorum In vitro fungitoxicity assays against LEPTNO were conducted using the copper-minus medium described in Example 26. Medium containing copper was prepared by adding CuCl2.2H2O to the copper minus medium at 20 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus and copper-plus media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 μL of spore suspension at a concentration of 2×105 spores per mL, prepared as in Example 26. The plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound. Results for growth inhibition by test compounds in copper-plus medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 9. Results show that fungitoxicity of metal complexes of hydrazones towards LEPTNO is synergistically enhanced in the presence of added copper. Furthermore, the fungitoxicity of copper complexes of hydrazones is synergistically enhanced in the presence of added copper.
TABLE 9
% Inhn. % Inhn. % Inhn.
Minus Plus Plus
Complex Compound Concn. copper copper copper
Number Number Metal salt Ratio* (μg/mL) Observed Observed Predicted
593 77 FeCl3•6H2O 1:1 0.05 31.3 93.7 33.6
594 77 FeCl3•6H2O 2:1 0.05 0.8 92.7 4.1
595 77 FeCl3•6H2O 3:1 0.05 9.8 93.3 12.8
596 16 Cu(OCOCH3)2•H2O 1:1 0.0125 4.5 56.7 7.7
596 16 Cu(OCOCH3)2•H2O 1:1 0.0125 6.4 85.4 9.5
598 16 CuSO4•5H2O 1:1 0.10 57.3 91.2 58.7
599 16 CuSO4•5H2O 2:1 0.0125 28.6 55.2 31.0
600 16 CuCl2•2H2O 1:1 0.0125 29.6 84.3 31.9
601 16 CuCl2•2H2O 2:1 0.0125 27.2 68.9 29.6
611 16 MnCl2•4H2O 2:1 0.05 36.6 96.1 38.8
612 16 ZnCl2 2:1 0.05 36.3 67.5 38.5
CuCl2, 10 3.3
μM
*Molar ratio of hydrazone:metal used to prepare complexes.
Example 34 Effect of Copper on Fungitoxicity of Metal-Hydrazone Complexes Towards Phytophthora capsici In vitro fungitoxicity assays against Phytophthora capsici were conducted using the copper-minus AS medium described in Example 28. Medium containing copper was prepared by adding CuCl2.2H2O to the copper-minus AS medium at 100 μM. Test compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions in copper-minus AS and copper-plus AS media were prepared as 100 μL aliquots in flat-bottomed 96-well microtiter plates. Microtiter plates were inoculated with 100 μL of zoospore suspension at a concentration of 5×104 spores per mL, prepared as in Example 28. The plates were incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader. Growth inhibition was determined by comparing growth in the presence of test compound with growth in control wells lacking test compound.
Results for growth inhibition by test compounds in copper-plus AS medium (“% Inhn. Plus Copper Observed”) were compared with predicted values (“% Inhn. Plus Copper Predicted”) that were calculated using the formula set forth by S. R. Colby in Weeds 1967, 15, 20-22 based on results obtained for the same compounds in copper-minus AS medium (“% Inhn. Minus Copper Observed”) and the inhibition attributed to copper chloride alone, as determined by comparing growth in copper-minus and copper-plus media without any test compound across experiments. Data are presented in Table 10. Results show that fungitoxicity of metal complexes of hydrazones towards Phytophthora capsici is synergistically enhanced in the presence of added copper. Furthermore, the fungitoxicity of copper complexes of hydrazones is synergistically enhanced in the presence of added copper.
TABLE 10
% Inhn. % Inhn. % Inhn.
Minus Plus Plus
Complex Compound Concn. copper copper copper
Number Number Metal salt Ratio* (μg/mL) Observed Observed Predicted
593 77 FeCl3•6H2O 1:1 0.025 7.0 93.7 11.3
594 77 FeCl3•6H2O 2:1 0.025 0.0 93.6 4.6
595 77 FeCl3•6H2O 3:1 0.025 0.0 93.7 4.6
596 16 Cu(OCOCH3)2•H2O 1:1 0.0125 0.9 95.4 5.5
596 16 Cu(OCOCH3)2•H2O 1:1 0.025 10.1 95.8 14.3
598 16 CuSO4•5H2O 1:1 0.025 0.0 94.8 4.6
599 16 CuSO4•5H2O 2:1 0.025 8.4 96.1 12.6
601 16 CuCl2•2H2O 2:1 0.025 4.1 94.0 8.5
602 16 CuCl2•2H2O 1:1 0.025 12.7 94.4 16.7
611 16 MnCl2•4H2O 2:1 0.025 9.3 95.1 13.5
612 16 ZnCl2 2:1 0.025 5.2 90.2 9.6
CuCl2, 50 0.025 4.6
μM
*Molar ratio of hydrazone:metal used to prepare complexes.
Example 35 Fungitoxicity of Copper-Hydrazone Mixtures Containing Different Ratios of Components Towards Leptosphaeria nodorum In vitro fungitoxicity assays against LEPTNO were conducted using the copper-minus medium described in Example 26. Mixtures containing hydrazone compound 16 at 200 nM and CuCl2 at 0.2 μM (1:1 molar ratio), 0.8 μM (1:4 ratio), 12.5 μM (1:62.5 ratio) and 200 μM (1:1000 ratio) were prepared in copper-minus medium. Two-fold dilution series of these mixtures were then prepared in 100 μL aliquots of copper-minus medium in flat-bottomed 96-well microtiter plates. A suspension of LEPTNO spores in copper-minus medium at 2×105 spores per mL was prepared as in Example 26. Microtiter plates were inoculated with 100 μL of the spore suspension and the plates were incubated at 25° C. for 72 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader.
Growth inhibition was determined by comparing growth in the presence of copper-hydrazone mixture with growth in control wells lacking the copper-hydrazone mixture. EC50 values were calculated from dose-response curves, and are expressed as the amounts of hydrazone or copper in each test mixture at the rates providing 50% inhibition of growth as compared to a control lacking the copper-hydrazone mixture. Data are presented in Table 11. The results show that copper-hydrazone mixtures representing a wide range of molar ratios of copper:hydrazone are substantially more efficacious against LEPTNO than either hydrazone or copper alone.
TABLE 11
Amounts of hydrazone and CuCl2
at EC50 values
Hydrazone CuCl2
Hydrazone:Cu ratio EC50 (nM) EC50 (μM)
Hydrazone without CuCl2 >3200
1 to 1 72.2 0.072
1 to 4 43.0 0.172
1 to 62.5 28.4 1.77
1 to 1000 14.0 14.0
CuCl2 without hydrazone 117.9
Example 36 Fungitoxicity of Copper-Hydrazone Mixtures Containing Different Ratios of Components Towards Phytophthora capsici In vitro fungitoxicity assays against Phytophthora capsici were conducted using the copper-minus AS medium described in Example 28. Mixtures containing hydrazone compound 16 at 200 nM and CuCl2.2H2O at 0.2 μM (1:1 molar ratio), 0.8 μM (1:4 ratio), 3.2 μM (1:16 ratio), 12.5 μM (1:62.5 ratio), 50 μM (1:200 ratio) and 200 μM (1:1000 ratio) were prepared in copper-minus AS medium. Two-fold dilution series of these mixtures were then prepared in 100 μL aliquots of copper-minus AS medium in flat-bottomed 96-well microtiter plates. A suspension of P. capsici zoospores in Chelex-treated water at 5×104 spores per mL was prepared as in Example 28. Microtiter plates were inoculated with 100 μL of the spore suspension and incubated at 25° C. for 48 h before assessing fungal growth by measuring light scattering in a NepheloStar plate reader.
Growth inhibition was determined by comparing growth in the presence of copper-hydrazone mixture with growth in control wells lacking the copper-hydrazone mixture. EC50 values were calculated from dose-response curves, and are expressed as the amounts of hydrazone or copper in each test mixture at the rates providing 50% inhibition of growth as compared to a control lacking the copper-hydrazone mixture. Data are presented in Table 12. The results show that copper-hydrazone mixtures representing a wide range of molar ratios of copper:hydrazone are substantially more efficacious against Phytophthora capsici than either hydrazone or copper alone.
TABLE 12
Amounts of hydrazone and CuCl2
at EC50 values
Hydrazone CuCl2
Hydrazone:Cu ratio EC50 (nM) EC50 (μM)
Hydrazone without CuCl2 143.2
1 to 1 71.1 0.071
1 to 4 47.1 0.189
1 to 16 27.5 0.441
1 to 62.5 16.6 1.04
1 to 250 7.6 1.90
1 to 1000 4.6 4.56
CuCl2 without hydrazone 720.0
Example 37 Synergistic Effect Between Hydrazone Compound 16 and Various Copper Materials Against Tomato Late Blight (Phytophthora infestans), Tomato Early Blight (Alternaria solani), and Cucumber Anthracnose (Colletotrichum lagenarium) Hydrazone compound 16 was tested alone or in combination with CuCl2.2H2O, CuSO4.5H2O, Kocide® 2000 (copper hydroxide), or CUREX 3 (tribasic copper sulfate). All materials and mixtures were evaluated as prophylactic treatments applied 24 h before inoculation. Efficacy was determined based on percentage of disease control against tomato late blight (Phytophthora infestans), tomato early blight (Alternaria solani), and anthracnose on cucumbers (Colletotrichum lagenarium). Treatments were arranged as a factorial experiment in a completely randomized design. Hydrazone and copper were regarded as factors with hydrazone at 10, 50, 200, and 400 μM, and copper materials at 10, 50, 200, 400, and 800 μM with respect to their copper content. All treatments were performed in triplicate. Plant varieties used were Outdoor Girl and Bush Pickle, for tomato and cucumber, respectively. Treatments were prepared in 0.01% Triton® X-100 and applied to run-off 24 h before inoculation using a spin-table sprayer. Inoculation was performed with aqueous spore suspensions using a Delta painting sprayer. Percentage of disease control was determined 7 days after inoculation.
Results (Tables 13-24) for disease control by hydrazone-copper mixtures were compared with predicted values (shown in brackets) which were calculated using the Colby formula based on disease control by the hydrazone alone and copper material alone. The data show that hydrazone-copper mixtures provided greater disease control than predicted based on control delivered by the individual components of the mixtures.
TABLE 13
Synergistic fungicidal effect between hydrazone Compound 16 and
CuCl2•2H2O against tomato late blight (Phytophthora infestans)
% Control of Tomato Late Blight
CuCl2 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0.0 1.5 11.3 21.4 25.7
10 1.7 33.5 (3.1) 41.9 (12.8) 67.8 (22.7) 64.4 (26.9)
50 8.5 39.7 (9.9) 63.0 (18.8) 96.6 (28.1) 91.7 (32.0)
200 38.2 69.0 (39.2) 91.5 (45.2) 95.8 (51.5) 91.7 (54.1)
400 56.0 75.7 (56.6) 91.7 (60.9) 90.8 (65.4) 99.8 (67.3)
800 70.2 94.2 (70.7) 98.3 (73.6) 96.7 (76.6) 100.0 (77.9)
TABLE 14
Synergistic fungicidal effect between hydrazone Compound 16 and
CuSO4•5H2O against tomato late blight (Phytophthora infestans)
% Control of Tomato Late Blight
CuSO4 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 1.5 11.3 21.4 25.7
10 1.7 26.3 (3.1) 56.8 (12.8) 78.0 (22.7) 41.5 (26.9)
50 4.8 28.1 (6.2) 67.7 (15.5) 81.3 (25.1) 54.5 (29.2)
200 49.7 56.0 (50.4) 72.9 (55.4) 93.2 (60.4) 87.2 (62.6)
400 76.0 77.3 (76.4) 78.0 (78.8) 95.8 (81.2) 96.6 (82.2)
800 82.9 72.2 (83.1) 91.6 (84.8) 97.5 (86.5) 98.3 (87.3)
TABLE 15
Synergistic fungicidal effect between hydrazone Compound 16 and Kocide ® 2000
against tomato late blight (Phytophthora infestans)
% Control of Tomato Late Blight
Kocide ® Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 1.5 11.3 21.4 25.7
10 5.8 26.8 (7.2) 41.2 (16.4) 53.4 (26.0) 65.3 (30.0)
50 6.8 43.1 (8.2) 46.4 (17.3) 77.3 (26.7) 79.6 (30.8)
200 30.4 51.6 (31.4) 65.8 (38.3) 94.8 (45.3) 93.2 (48.3)
400 63.1 64.9 (63.7) 78.3 (67.3) 89.9 (71.0) 94.9 (72.6)
800 67.4 80.8 (67.9) 95.6 (71.1) 100 (74.4) 100 (75.8)
TABLE 16
Synergistic fungicidal effect between hydrazone Compound 16 and
CUREX 3 against tomato late blight (Phytophthora infestans)
% Control of Tomato Late Blight
CUREX 3 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 1.5 11.3 21.4 25.7
10 0.0 42.4 (1.5) 72.9 (11.3) 77.9 (21.4) 61.7 (25.7)
50 0.0 61.0 (1.5) 88.0 (11.3) 88.0 (21.4) 85.5 (25.7)
200 26.2 63.6 (27.3) 88.9 (34.5) 100.0 (42.0) 93.5 (45.1)
400 41.2 77.3 (42.0) 96.7 (47.8) 96.7 (53.8) 98.3 (56.3)
800 60.8 89.8 (61.4) 97.4 (65.3) 99.5 (69.2) 99.1 (70.9)
TABLE 17
Synergistic fungicidal effect between hydrazone Compound 16 and
CuCl2•2H2O against tomato early blight (Alternaria solani)
% Control of Tomato Early Blight
CuCl2 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0.0 3.9 8.0 28.4 32.4
10 0.0 38.4 (3.9) 39.8 (8.0) 46.1 (28.4) 59.2 (32.4)
50 0.0 44.5 (3.9) 56.0 (8.0) 69.9 (28.4) 86.3 (32.4)
200 50.4 62.1 (52.4) 73.2 (54.5) 82.0 (64.5) 94.7 (66.5)
400 72.5 80.3 (73.6) 79.7 (74.7) 94.2 (80.3) 98.1 (81.4)
800 83.3 86.0 (83.9) 89.6 (84.6) 98.8 (88.0) 98.3 (88.7)
TABLE 18
Synergistic fungicidal effect between hydrazone Compound 16 and
CuSO4•5H2O against tomato early blight (Alternaria solani)
% Control of Tomato Early Blight
CuSO4 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 3.9 8.0 28.4 32.4
10 0.0 48.7 (3.9) 53.8 (8.0) 55.6 (28.4) 54.7 (32.4)
50 7.1 53.0 (10.7) 70.5 (14.5) 74.6 (33.5) 80.9 (37.2)
200 54.4 66.0 (56.2) 83.0 (58.1) 89.7 (67.4) 89.4 (69.2)
400 64.1 82.1 (65.5) 89.5 (67.0) 93.3 (74.3) 96.8 (75.7)
800 71.6 83.5 (72.7) 93.0 (73.9) 96.0 (79.7) 97.7 (80.8)
TABLE 19
Synergistic fungicidal effect between hydrazone Compound 16 and Kocide ® 2000
against tomato early blight (Alternaria solani)
% Control of Tomato Early Blight
Kocide ® Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 3.9 8 28.4 32.4
10 1.1 35.6 (5.0) 52.4 (9.0) 29.8 (29.2) 27.2 (33.1)
50 3.9 55.4 (7.6) 77.6 (11.6) 69.8 (31.2) 75.3 (35.0)
200 36 66.1 (38.5) 92.4 (41.1) 84.8 (54.2) 81.4 (56.7)
400 52.7 74.7 (54.5) 92.2 (56.5) 92.4 (66.1) 90.6 (68.0)
800 62.9 83.4 (64.3) 93.6 (65.9) 93.4 (73.4) 95.1 (74.9)
TABLE 20
Synergistic fungicidal effect between hydrazone Compound 16 and
CUREX 3 against tomato early blight (Alternaria solani)
% Control of Tomato Early Blight
CUREX 3 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 3.9 8.0 28.4 32.4
10 0.0 39.6 (3.9) 29.2 (8.0) 46.0 (28.4) 44.2 (32.4)
50 4.9 48.5 (8.6) 64.4 (12.5) 74.8 (31.9) 65.1 (35.7)
200 36.6 54.7 (39.1) 74.7 (41.7) 85.1 (54.6) 82.3 (57.2)
400 49.1 65.6 (51.1) 80.0 (53.2) 94.9 (63.6) 93.4 (65.6)
800 40.2 63.6 (42.5) 88.0 (45.0) 96.6 (57.2) 94.9 (59.6)
TABLE 21
Synergistic fungicidal effect between hydrazone
Compound 16 and CuCl2•2H2O against cucumber
anthracnose (Colletotrichum lagenarium).
% Control of Cucumber Anthracnose
CuCl2 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 10.0 33.8 63.8 70.8
10 9.6 46.9 (18.6) 72.5 (40.1) 82.8 (67.3) 83.6 (73.6)
50 1.4 47.8 (11.3) 81.0 (34.8) 86.2 (64.3) 89.0 (71.2)
200 37.2 73.0 (43.5) 85.3 (58.4) 95.4 (77.3) 98.9 (81.7)
400 76.2 87.2 (78.6) 94.9 (84.2) 98.8 (91.4) 99.6 (93.0)
800 90.0 91.0 (91.0) 97.5 (93.4) 97.8 (96.4) 98.6 (97.1)
TABLE 22
Synergistic fungicidal effect between hydrazone
Compound 16 and CuSO4•5H2O against cucumber
anthracnose (Colletotrichum lagenarium).
% Control of Cucumber Anthracnose
CuSO4 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 10.0 33.8 63.8 70.8
10 1.4 55.8 (11.2) 67.5 (34.7) 94.5 (64.3) 90.7 (71.2)
50 0.0 58.9 (10.0) 78.3 (33.8) 92.0 (63.8) 98.7 (70.8)
200 61.3 70.6 (65.2) 89.8 (74.4) 97.5 (86.0) 99.6 (88.7)
400 75.7 92.0 (78.1) 95.2 (83.9) 98.4 (91.2) 99.7 (92.9)
800 87.1 96.2 (88.4) 95.6 (91.5) 96.5 (95.3) 99.6 (96.2)
TABLE 23
Synergistic fungicidal effect between hydrazone Compound 16 and Kocide ® 2000
against cucumber anthracnose (Colletotrichum lagenarium)
% Control of Cucumber Anthracnose
Kocide ® Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 10 33.8 63.8 70.8
10 15.9 40.4 (24.3) 56.5 (44.3) 83.7 (69.6) 72.2 (75.4)
50 15 64.9 (23.5) 83.7 (43.7) 93.9 (69.2) 97 (75.2)
200 28.9 80 (36.0) 95.3 (52.9) 97.2 (74.3) 97.5 (79.2)
400 68.8 79.9 (71.9) 89.5 (79.3) 99.4 (88.7) 98.5 (90.9)
800 67.5 90.3 (70.8) 95.9 (78.5) 99.2 (88.2) 99.3 (90.5)
TABLE 24
Synergistic fungicidal effect between hydrazone Compound 16 and CUREX
3 against cucumber anthracnose (Colletotrichum lagenarium)
% Control of Cucumber Anthracnose
CUREX 3 Hydrazone (μM)
(μM) 0 10 50 200 400
0 0 10.0 33.8 63.8 70.8
10 7.8 42.1 (17.0) 78.0 (39.0) 84.4 (66.6) 93.0 (73.1)
50 10.9 51.9 (19.8) 91.4 (41.0) 92.8 (67.7) 95.8 (74.0)
200 23.0 58.6 (30.7) 93.5 (49.0) 99.1 (72.1) 99.2 (77.5)
400 38.7 71.1 (44.8) 92.9 (59.4) 99.4 (77.8) 98.3 (82.1)
800 31.5 55.2 (38.4) 84.0 (54.7) 96.2 (75.2) 95.0 (80.0)
Example 38 Control of Grape Downy Mildew (Plasmopara viticola) and Tomato Late Blight (Phytophthora infestans) by Compound 16, its Copper Complex, and Copper Chloride Test compounds were hydrazone Compound 16, the complex of Compound 16 with copper (“hydrazone-copper”) prepared by precipitation with CuCl2.2H2O using a 1:1 molar ratio, and CuCl2.2H2O alone. Hydrazone and hydrazone-copper were formulated in 10% acetone/0.1% Trycol 5941 in de-ionized water. CuCl2.2H2O was formulated with 0.1% Trycol 5941 in de-ionized water. Grape and tomato plants were sprayed with 160 μM suspensions of the formulated test compounds at a spray volume of 0.8 mL per plant. After 24 h, the undersides of the grape leaves were inoculated with an aqueous suspension of Plasmopara viticola sporangia and tomato plants were inoculated with an aqueous suspension of Phytophthora infestans sporangia. Plants were kept in high humidity overnight, then transferred to a greenhouse (grapes) or growth room (tomatoes) until disease developed on untreated control plants.
Results for disease control by hydrazone-copper were compared with predicted results calculated using the Colby formula based on disease control by the hydrazone alone and CuCl2 alone. Results, shown in Table 25, show that hydrazone-copper provided greater disease control than predicted based on control observed for hydrazone and CuCl2 alone.
TABLE 25
% Control % Control
Disease Treatment μM Observed Predicted
Downy mildew Hydrazone 16 160 29
Hydrazone-copper 600 160 78 30
CuCl2 160 1
Late blight Hydrazone 16 160 49
Hydrazone-coppper 600 160 100 84
CuCl2 160 69
While this disclosure has been described as having exemplary compounds, the present disclosure can be further modified within the spirit and scope of this disclosure. For example, all of the disclosed components of the preferred and alternative embodiments are interchangeable providing disclosure herein of many systems having combinations of all the preferred and alternative embodiment components. This application is therefore intended to cover any variations, uses, or adaptations of the disclosure using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this disclosure pertains and which fall within the limits of the appended claims.
