U.S. patent application number 13/144682 was filed with the patent office on 2012-06-14 for fungicidal compositions including hydrazone derivatives and copper.
This patent application is currently assigned to DOW AGROSCIENCES LLC. Invention is credited to Cruz Avila-Adame, Nneka T. Breaux, James M. Ruiz, Gerald Shaber, Steven Howard Shaber, Thomas L. Siddall, Jeffery D. Webster, David H. Young.
Application Number | 20120148682 13/144682 |
Document ID | / |
Family ID | 42244227 |
Filed Date | 2012-06-14 |
United States Patent
Application |
20120148682 |
Kind Code |
A1 |
Young; David H. ; et
al. |
June 14, 2012 |
FUNGICIDAL COMPOSITIONS INCLUDING HYDRAZONE DERIVATIVES AND
COPPER
Abstract
The present invention relates to the use of hydrazone compounds
and copper for controlling the growth of fungi.
Inventors: |
Young; David H.; (Camel,
IN) ; Shaber; Steven Howard; (Woodbury, NY) ;
Shaber; Gerald; (Woodbury, NY) ; Avila-Adame;
Cruz; (Carmel, IN) ; Breaux; Nneka T.;
(Indianapolis, IN) ; Ruiz; James M.; (Westfield,
IN) ; Siddall; Thomas L.; (Zionsville, IN) ;
Webster; Jeffery D.; (New Palestine, IN) |
Assignee: |
DOW AGROSCIENCES LLC
Indianapolis
IN
|
Family ID: |
42244227 |
Appl. No.: |
13/144682 |
Filed: |
January 14, 2010 |
PCT Filed: |
January 14, 2010 |
PCT NO: |
PCT/US10/21043 |
371 Date: |
February 8, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61144560 |
Jan 14, 2009 |
|
|
|
Current U.S.
Class: |
424/638 ; 556/35;
564/251 |
Current CPC
Class: |
A01N 31/04 20130101;
A01N 33/26 20130101; A01N 59/00 20130101; A61P 31/10 20180101; A01N
59/20 20130101; A01N 33/00 20130101; A01N 31/00 20130101; A01N
59/20 20130101; A01N 37/44 20130101; A01N 59/16 20130101; A01N
37/48 20130101; A01N 59/16 20130101; C07C 251/86 20130101; A01N
59/16 20130101; A01N 2300/00 20130101; A01N 37/40 20130101; A01N
37/44 20130101; A01N 43/30 20130101; A01N 37/28 20130101; A01N
37/28 20130101; A01N 37/48 20130101; A01N 43/30 20130101; A01N
2300/00 20130101; A01N 37/38 20130101; A01N 37/40 20130101; A01N
37/38 20130101; A01N 59/16 20130101; C07C 323/36 20130101; A01N
59/20 20130101 |
Class at
Publication: |
424/638 ;
564/251; 556/35 |
International
Class: |
A01N 59/20 20060101
A01N059/20; A01P 3/00 20060101 A01P003/00; C07F 1/08 20060101
C07F001/08; C07C 243/18 20060101 C07C243/18 |
Claims
1. A compound of Formula 1 ##STR00101## wherein R is H, C1-C4
alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, or C3-C6 halocycloalkyl;
X3, X4, X5, and X6 are 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, --SO.sub.2R1, SONR1R1, --CR1=NOR1, --CONR1R1,
NR1COOR1, --COOR1, substituted aryl, substituted heteroaryl,
unsubstituted aryl, and unsubstituted heteroaryl; Y2, Y3, Y4, Y5,
and Y6 are 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, --SO.sub.2R1, SONR1R1, --R1=NOR1, --CONR1R1,
NR1COOR1, --COOR1, substituted aryl, substituted heteroaryl,
unsubstituted aryl, unsubstituted heteroaryl, and phenoxy; and R1
is H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6
halocycloalkyl, substituted aryl, substituted heteroaryl,
unsubstituted aryl, or unsubstituted heteroaryl; 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; and
at least one X3, X4, X5, and X6 is C1-C4 haloalkyl.
2. The compound of claim 1, wherein R is H, C1-C4 alkyl, C3-C6
cycloalkyl, C1-C4 haloalkyl, or C3-C6 halocycloalkyl; R1 is H,
C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6
halocycloalkyl, substituted aryl, or unsubstituted aryl; X3, X4,
X5, and X6 are independently selected from the group consisting of
halogen, nitro, cyano, C1-C4 alkyl, C1-C4 haloalkyl C1-C4 alkoxy,
C2-C4 alkenyl, and C1-C4 alkylthio; and Y2, Y3, Y4, Y5, and Y6 are
independently selected from the group consisting of H, halogen,
nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio,
C1-C4 haloalkyl, C1-C4 haloalkoxy, C1-C4 haloalkylthio --NR1R1,
unsubstituted aryl, substituted aryl, and phenoxy; with the proviso
that X3 and X4, X5 and X6, 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 and N.
3. The compound of claim 2, wherein R is H or CH.sub.3; X3, X4, X5,
and X6 are independently selected from the group consisting of
halogen, nitro, cyano, C1-C4 alkyl, C1-C4 fluoroalkyl, and C1-C4
alkoxy; and Y2, Y3, Y4, Y5, and Y6 are independently selected from
the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4
alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; with
the proviso that at least one of X3, X4, X5, and X6 is C1-C4
fluoroalkyl; and 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 and N.
4. The compound of claim 3, wherein X3, X4, X5, and X6 are
independently selected from the group consisting of halogen, nitro,
cyano, trifluoromethyl, methyl, and methoxy; and Y2, Y3, Y4, Y5,
and Y6 are independently selected from the group consisting of H,
halogen, nitro, hydroxyl, trifluoromethyl, methyl, and methoxy;
with the proviso that at least one of X3, X4, X5, and X6 is
trifluoromethyl; and 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 and N.
5. The compound of claim 4, wherein X3, X4, X5, and X6 are
independently selected from the group consisting of halogen and
trifluoromethyl.
6. A synergistic mixture including a compound of claim 1 and
copper.
7. Use of the synergistic mixture of claim 6 for controlling the
growth of fungal pathogens of plants.
8. Use of the synergistic mixture of claim 6 for controlling the
growth of fungal of mammals.
9. Use of the synergistic mixture of claim 6 for controlling the
growth of fungi on inert substrates selected from the group
consisting essentially of wood, metal, and plastic.
10. Use of the synergistic mixture of claim 6 for controlling the
growth of fungi belonging to at least one of Ascomycete,
Basidiomycete, Oomycete, and Deuteromycete classes of fungi.
11. The mixture of synergistic claim 6 wherein the fungi is
selected from the group consisting of 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 and Podosphaera
leucotricha.
12. The synergistic mixture of claim 6, wherein a growth inhibiting
amount of a compound of Formula I in mixture with copper is
provided as a mixture in which the total molar ratio of copper to
the compound of claim 1 exceeds 1:1.
13. The synergistic mixture of claim 1, wherein a growth inhibiting
amount of a compound of Formula I is provided as an isolated
hydrazone-copper complex in which the molar ratio of the copper to
the compound of claim 1 is one of 1:1 and 1:2.
14. The synergistic mixture of claim 1, wherein the compound of
Formula I to be combined with copper is complexed with a metal.
15. The synergistic mixture of claim 14, wherein the metal
complexed with the compound of Formula I is selected from the group
consisting essentially of Cu.sup.+, Cu.sup.2+, Fe.sup.2+,
Fe.sup.3+, Zn.sup.2+, and Mn.sup.2+.
16. The synergistic mixture of claim 1, wherein the copper is
provided as at least one of the group consisting of 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.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] 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
[0002] The present disclosure relates to hydrazone compounds,
optionally with and without copper, and their use as fungicides.
The compounds of the present disclosure may offer protection
against ascomycetes, basidiomycetes, deuteromycetes and
oomycetes.
BACKGROUND
[0003] 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.
[0004] 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.
[0005] Fungicides are compounds, of natural or synthetic origin,
which act to protect and/or cure plants against damage caused by
agriculturally relevant fungi. Generally, no single fungicide is
useful in all situations. Consequently, research is ongoing to
produce fungicides that may have better performance, are easier to
use, and cost less.
SUMMARY OF THE INVENTION
[0006] One embodiment of the present disclosure may include
compounds of Formula I:
##STR00001##
[0007] wherein R is H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4
haloalkyl, or C3-C6 halocycloalkyl;
[0008] R1 is H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl,
C3-C6 halocycloalkyl, substituted aryl, substituted heteroaryl,
unsubstituted aryl, or unsubstituted heteroaryl;
[0009] X3, X4, X5, and X6 are 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, --SO.sub.2R1, SONR1R1, --CR1=NOR1, --CONR1R1,
NR1COOR1, --COOR1, substituted aryl, substituted heteroaryl,
unsubstituted aryl, and unsubstituted heteroaryl; and
[0010] Y2, Y3, Y4, Y5, and Y6 are 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, --SO.sub.2R1, SONR1R1, --R1=NOR1,
--CONR1R1, NR1COOR1, --COOR1, substituted aryl, substituted
heteroaryl, unsubstituted aryl, unsubstituted heteroaryl, and
phenoxy;
[0011] 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; and at least one X3, X4, X5, and X6 is
C1-C4 haloalkyl.
[0012] Another embodiment of the present disclosure may include a
fungicidal composition for the control or prevention of fungal
attack comprising the compounds described below and a
phytologically acceptable carrier material.
[0013] Yet another embodiment of the present disclosure may include
a method for the control or prevention of fungal attack on a plant,
the method including the steps of applying a fungicidally effective
amount of one or more of the compounds described below to at least
one of the fungus, the plant, an area adjacent to the plant, and
the seed adapted to produce the plant.
[0014] 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.
[0015] The term "cycloalkyl" refers to a monocyclic or polycyclic,
saturated substituent consisting of carbon and hydrogen.
[0016] 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.
[0017] The term "alkynyl" refers to a branched or unbranched carbon
chain containing one or more triple bonds including propynyl,
butynyl and the like.
[0018] As used throughout this specification, the term `R` refers
to the group consisting of C1-C4 alkyl, C2-C4 alkenyl, C2-C4
alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl,
C2-C4 haloalkynyl, or C3-C6 halocycloalkyl, unless stated
otherwise.
[0019] The term "alkoxy" refers to an --OR substituent.
[0020] The term "alkylthio" refers to an --S--R substituent.
[0021] The term "haloalkylthio" refers to an alkylthio, which is
substituted with Cl, F, I, or Br or any combination thereof.
[0022] The term "cyano" refers to a --C.ident.N substituent.
[0023] The term "hydroxyl" refers to an --OH substituent.
[0024] The term "haloalkoxy" refers to an --OR--X substituent,
wherein X is Cl, F, Br, or I, or any combination thereof.
[0025] The term "haloalkyl" refers to an alkyl, which is
substituted with Cl, F, I, or Br or any combination thereof.
[0026] 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.
[0027] The term "haloalkenyl" refers to an alkenyl, which is
substituted with Cl, F, I, or Br or any combination thereof.
[0028] The term "haloalkynyl" refers to an alkynyl which is
substituted with Cl, F, I, or Br or any combination thereof.
[0029] The term "halogen" or "halo" refers to one or more halogen
atoms, defined as F, Cl, Br, and I.
[0030] The term "nitro" refers to a --NO.sub.2 substituent.
[0031] The term "aryl" refers to a cyclic, aromatic substituent
consisting of hydrogen and carbon.
[0032] 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.
[0033] Throughout the disclosure, reference to the compounds of
Formula I is read as also including optical isomers and salts of
Formula I, and hydrates thereof. Specifically, when Formula I
contains a branched chain alkyl group, it is understood that such
compounds include optical isomers and racemates thereof. Exemplary
salts include: hydrochloride, hydrobromide, hydroiodide, and the
like.
[0034] 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.
[0035] It is also understood by those skilled in the art that
additional substitution is allowable, unless otherwise noted, as
long as the rules of chemical bonding and strain energy are
satisfied and the product still exhibits fungicidal activity.
[0036] Another embodiment of the present disclosure is a use of a
compound of Formula I, for protection of a plant against attack by
a phytopathogenic organism or the treatment of a plant infested by
a phytopathogenic organism, comprising the application of a
compound of Formula I, or a composition comprising the compound to
soil, a plant, a part of a plant, foliage, and/or seeds.
[0037] Additionally, another embodiment of the present disclosure
is a composition useful for protecting a plant against attack by a
phytopathogenic organism and/or treatment of a plant infested by a
phytopathogenic organism comprising a compound of Formula I and a
phytologically acceptable carrier material.
[0038] 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
[0039] The compounds of the present disclosure may be applied by
any of a variety of known techniques, either as the compounds or as
formulations comprising the compounds. For example, the compounds
may be applied to the roots, seeds or foliage of plants for the
control of various fungi, without damaging the commercial value of
the plants. The materials may be applied in the form of any of the
generally used formulation types, for example, as solutions, dusts,
wettable powders, flowable concentrates, or emulsifiable
concentrates.
[0040] 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.
[0041] The compounds of the present invention have fungitoxic
activity against phytopathogenic fungi, against fungal pathogens of
mammals, including humans, and against wood decay causing fungi.
The compounds 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, Septoria tritici, Leptosphaeria nodorum, Ustilago maydis,
Erysiphe graminis, Puccinia species, Sclerotinia species,
Sphaerotheca fuliginea, Cercospora species, Rhizoctonia species,
Uncinula necator and Podosphaera leucotricha.
[0042] 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.
[0043] Preferably, the compounds of the present disclosure are
applied in the form of a formulation, comprising one or more of the
compounds of Formula I with a phytologically acceptable carrier.
Concentrated formulations may be dispersed in water, or other
liquids, for application, or formulations may be dust-like or
granular, which may then be applied without further treatment. The
formulations can be prepared according to procedures that are
conventional in the agricultural chemical art.
[0044] The present disclosure contemplates all vehicles by which
one or more of the compounds may be formulated for delivery and use
as a fungicide. Typically, formulations are applied as aqueous
suspensions or emulsions. Such suspensions or emulsions may be
produced from water-soluble, water suspendible, or emulsifiable
formulations which are solids, usually known as wettable powders;
or liquids, usually known as emulsifiable concentrates, aqueous
suspensions, or suspension concentrates. As will be readily
appreciated, any material to which these compounds may be added may
be used, provided it yields the desired utility without significant
interference with the activity of these compounds as antifungal
agents.
[0045] Wettable powders, which may be compacted to form water
dispersible granules, comprise an intimate mixture of one or more
of the compounds of Formula I, an inert carrier and surfactants.
The concentration of the compound in the wettable powder may be
from about 10 percent to about 90 percent by weight based on the
total weight of the wettable powder, more preferably about 25
weight percent to about 75 weight percent. In the preparation of
wettable powder formulations, the compounds may 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.
[0046] Emulsifiable concentrates of the compounds of Formula I may
comprise a convenient concentration, such as from about 10 weight
percent to about 50 weight percent of the compound, in a suitable
liquid, based on the total weight of the concentrate. The compounds
may be 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, for example, terpenic solvents, including rosin derivatives,
aliphatic ketones, such as cyclohexanone, and complex alcohols,
such as 2-ethoxyethanool.
[0047] Emulsifiers which may be advantageously employed herein may
be readily determined by those skilled in the art and include
various nonionic, anionic, cationic and amphoteric emulsifiers, or
a blend of two or more emulsifiers. 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 solubilized with
the polyol or polyoxyalkylene. Cationic emulsifiers include
quaternary ammonium compounds and fatty amine salts. Anionic
emulsifiers include the oil-soluble salts (e.g., calcium) of
alkylaryl sulphonic acids, oil-soluble salts or sulfated polyglycol
ethers and appropriate salts of phosphated polyglycol ether.
[0048] Representative organic liquids which may be employed in
preparing the emulsifiable concentrates of the compounds of the
present invention 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
dimethyl amides of fatty glycols and glycol derivatives 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. Organic liquids
include xylene, and propyl benzene fractions, with xylene being
most preferred in some cases. Surface-active dispersing agents are
typically employed in liquid formulations and in an amount of from
0.1 to 20 percent by weight based on the combined weight of the
dispersing agent with one or more of the compounds. The
formulations can also contain other compatible additives, for
example, plant growth regulators and other biologically active
compounds used in agriculture.
[0049] Aqueous suspensions comprise suspensions of one or more
water-insoluble compounds of Formula I, 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 compounds, 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 inorganic 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.
[0050] 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.
[0051] The compounds of Formula I can also be applied as granular
formulations, which are particularly useful for applications to the
soil. Granular formulations generally contain from about 0.5 to
about 10 weight percent, based on the total weight of the granular
formulation of the compound(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 compounds 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.
[0052] Dusts containing the compounds of Formula I may be prepared
by intimately mixing one or more of the compounds in powdered form
with a suitable dusty agricultural carrier, such as, for example,
kaolin clay, ground volcanic rock, and the like. Dusts can suitably
contain from about 1 to about 10 weight percent of the compounds,
based on the total weight of the dust.
[0053] The formulations may additionally contain adjuvant
surfactants to enhance deposition, wetting and penetration of the
compounds onto the target crop and 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 or sulphosuccinic acids, ethoxylated
organosilicones, ethoxylated fatty amines and blends of surfactants
with mineral or vegetable oils. The formlulations may also include
oil-in-water emulsions such as those disclosed in U.S. patent
application Ser. No. 11/495,228, the disclosure of which is
expressly incorporated by reference herein.
[0054] The formulations may optionally include combinations that
contain other pesticidal compounds. Such additional pesticidal
compounds may be fungicides, insecticides, herbicides, nematocides,
miticides, arthropodicides, bactericides or combinations thereof
that are compatible with the compounds of the present invention in
the medium selected for application, and not antagonistic to the
activity of the present compounds. Accordingly, in such
embodiments, the other pesticidal compound is employed as a
supplemental toxicant for the same or for a different pesticidal
use. The compounds of Formula I and the pesticidal compound in the
combination can generally be present in a weight ratio of from
1:100 to 100:1.
[0055] For pharmaceutical use, the compounds 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 compounds described herein, salts thereof,
and mixtures of compounds described herein 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.
[0056] Suitable means of administering the pharmaceutical
preparations include oral, rectal, topical (including dermal,
buccal and sublingual), vaginal, parenteral (including
subcutaneous, intramuscular, intravenous, intradermal, intrathecal
and epidural) and by nasogastric tube. It will be understood by
those skilled in the art that the preferred route of administration
will depend upon the condition being treated and may vary with
factors such as the condition of the recipient.
[0057] The compounds of the present disclosure may also be combined
with other fungicides to form fungicidal mixtures and synergistic
mixtures thereof. The fungicidal compounds of the present
disclosure 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
compounds may 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 may include
2-(thiocyanatomethylthio)-benzothiazole, 2-phenylphenol,
8-hydroxyquinoline sulfate, ametoctradin, amisulbrom, antimycin,
Ampelomyces quisqualis, azaconazole, azoxystrobin, Bacillus
subtilis, benalaxyl, benomyl, benthiavalicarb-isopropyl,
benzylaminobenzene-sulfonate (BAB S) salt, bicarbonates, biphenyl,
bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, Bordeaux
mixture, boscalid, bromuconazole, bupirimate, calcium polysulfide,
captafol, captan, carbendazim, carboxin, carpropamid, carvone,
chloroneb, chlorothalonil, chlozolinate, Coniothyrium minitans,
copper hydroxide, copper octanoate, copper oxychloride, copper
sulfate, copper sulfate (tribasic), cuprous oxide, cyazofamid,
cyflufenamid, cymoxanil, cyproconazole, cyprodinil, 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, flutianil, flutolanil,
flutriafol, fluxapyroxad, 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, 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, penflufen, pentachlorophenol, pentachlorophenyl
laurate, penthiopyrad, phenylmercury acetate, phosphonic acid,
phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim,
potassium bicarbonate, potassium hydroxyquinoline sulfate,
probenazole, prochloraz, procymidone, propamocarb, propamocarb
hydrochloride, propiconazole, propineb, proquinazid,
prothioconazole, pyraclostrobin, pyrametostrobin, pyraoxystrobin,
pyrazophos, pyribencarb, pyributicarb, pyrifenox, pyrimethanil,
pyroquilon, quinoclamine, quinoxyfen, quintozene, Reynoutria
sachalinensis extract, sedaxane, silthiofam, simeconazole, sodium
2-phenylphenoxide, sodium bicarbonate, sodium pentachlorophenoxide,
spiroxamine, sulfur, SYP-Z071, SYP-Z048, tar oils, tebuconazole,
tebufloquin, tecnazene, tetraconazole, thiabendazole, thifluzamide,
thiophanate-methyl, thiram, tiadinil, tolclofos-methyl,
tolylfluanid, triadimefon, triadimenol, triazoxide, tricyclazole,
tridemorph, trifloxystrobin, triflumizole, triforine,
triticonazole, validamycin, valifenalate, valiphenal, vinclozolin,
zineb, ziram, zoxamide, Candida oleophila, Fusarium oxysporum,
Gliocladium spp., Phlebiopsis gigantea, 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-dithiine 1,1,4,4-tetraoxide,
2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,
2-methoxyethylmercury silicate,
3-(4-chlorophenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl
thiocyanateme, ampropylfos, anilazine, azithiram, barium
polysulfide, Bayer 32394, benodanil, benquinox, bentaluron,
benzamacril; benzamacril-isobutyl, benzamorf, binapacryl,
bis(methylmercury) sulfate, bis(tributyltin) oxide, buthiobate,
cadmium calcium copper zinc chromate sulfate, carbamorph, CECA,
chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox,
climbazole, cyclafuramid, cypendazole, cyprofuram, decafentin,
dichlone, dichlozoline, 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-nitrophenylitaconimide, natamycin,
N-ethylmercurio-4-toluenesulfonanilide, nickel
bis(dimethyldithiocarbamate), OCH, phenylmercury
dimethyldithiocarbamate, phenylmercury nitrate, phosdiphen,
picolinamide UK-2A and derivatives thereof, prothiocarb;
prothiocarb hydrochloride, pyracarbolid, pyridinitril, pyroxychlor,
pyroxyfur, quinacetol; quinacetol sulfate, quinazamid,
quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen,
tecoram, thiadifluor, thicyofen, thiochlorfenphim, thiophanate,
thioquinox, tioxymid, triamiphos, triarimol, triazbutil,
trichlamide, urbacid, XRD-563, and zarilamide, IK-1140, and any
combinations thereof.
[0058] The compounds 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 compounds 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 compounds 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.
[0059] Additionally, the compounds of the present invention may be
combined with other pesticides, including insecticides,
nematocides, miticides, arthropodicides, bactericides or
combinations thereof that are compatible with the compounds of the
present invention in the medium selected for application, and not
antagonistic to the activity of the present compounds to form
pesticidal mixtures and synergistic mixtures thereof. The
fungicidal compounds of the present disclosure may be 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 compounds may 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 and spinetoram; 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,
butoxycarboxim, 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; dessicant insecticides such as boric acid, diatomaceous
earth and silica gel; diamide insecticides such as
chlorantraniliprole, cyantraniliprole and flubendiamide;
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, alpha-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, isofenphos-methyl, methamidophos and
propetamphos; phosphorodiamide insecticides such as dimefox,
mazidox, mipafox and schradan; oxadiazine insecticides such as
indoxacarb; oxadiazoline insecticides such as metoxadiazone;
phthalimide insecticides such as dialifos, phosmet and
tetramethrin; pyrazole insecticides such as tebufenpyrad,
tolefenpyrad; phenylpyrazole insecticides such as acetoprole,
ethiprole, fipronil, pyrafluprole, pyriprole 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,
tau-fluvalinate, furethrin, imiprothrin, meperfluthrin,
metofluthrin, permethrin, biopermethrin, transpermethrin,
phenothrin, prallethrin, profluthrin, pyresmethrin, resmethrin,
bioresmethrin, cismethrin, tefluthrin, terallethrin, tetramethrin,
tetramethylfluthrin, 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; tetramic acid insecticides such as spirotetramat;
tetronic acid insecticides such as spiromesifen; thiourea
insecticides such as diafenthiuron; urea insecticides such as
flucofuron and sulcofuron; and unclassified insecticides such as
closantel, copper naphthenate, crotamiton, EXD, fenazaflor,
fenoxacrim, hydramethylnon, isoprothiolane, malonoben,
metaflumizone, nifluridide, plifenate, pyridaben, pyridalyl,
pyrifluquinazon, rafoxanide, sulfoxaflor, triarathene and
triazamate, and any combinations thereof.
[0060] Additionally, the compounds of the present invention may be
combined with herbicides that are compatible with the compounds of
the present invention in the medium selected for application, and
not antagonistic to the activity of the present compounds to form
pesticidal mixtures and synergistic mixtures thereof. The
fungicidal compounds of the present disclosure may be applied in
conjunction with one or more herbicides to control a wide variety
of undesirable plants. When used in conjunction with herbicides,
the presently claimed compounds may be formulated with the
herbicide(s), tank mixed with the herbicide(s) or applied
sequentially with the herbicide(s). Typical herbicides include, but
are not limited to: amide herbicides such as allidochlor,
beflubutamid, benzadox, benzipram, bromobutide, cafenstrole, CDEA,
cyprazole, dimethenamid, dimethenamid-P, diphenamid, epronaz,
etnipromid, fentrazamide, flupoxam, fomesafen, halosafen,
isocarbamid, isoxaben, napropamide, naptalam, pethoxamid,
propyzamide, quinonamid and tebutam; anilide herbicides such as
chloranocryl, cisanilide, clomeprop, cypromid, diflufenican,
etobenzanid, fenasulam, flufenacet, flufenican, mefenacet,
mefluidide, metamifop, monalide, naproanilide, pentanochlor,
picolinafen and propanil; arylalanine herbicides such as
benzoylprop, flampropand flamprop-M; chloroacetanilide herbicides
such as acetochlor, alachlor, butachlor, butenachlor, delachlor,
diethatyl, dimethachlor, metazachlor, metolachlor, S-metolachlor,
pretilachlor, propachlor, propisochlor, prynachlor, terbuchlor,
thenylchlor and xylachlor; sulfonanilide herbicides such as
benzofluor, perfluidone, pyrimisulfan and profluazol; sulfonamide
herbicides such as asulam, carbasulam, fenasulam and oryzalin;
thioamide herbicides such as chlorthiamid; antibiotic herbicides
such as bilanafos; benzoic acid herbicides such as chloramben,
dicamba, 2,3,6-TBA and tricamba; pyrimidinyloxybenzoic acid
herbicides such as bispyribac and pyriminobac;
pyrimidinylthiobenzoic acid herbicides such as pyrithiobac;
phthalic acid herbicides such as chlorthal; picolinic acid
herbicides such as aminopyralid, clopyralid and picloram;
quinolinecarboxylic acid herbicides such as quinclorac and
quinmerac; arsenical herbicides such as cacodylic acid, CMA, DSMA,
hexaflurate, MAA, MAMA, MSMA, potassium arsenite and sodium
arsenite; benzoylcyclohexanedione herbicides such as mesotrione,
sulcotrione, tefuryltrione and tembotrione; benzofuranyl
alkylsulfonate herbicides such as benfuresate and ethofumesate;
benzothiazole herbicides such as benzazolin; carbamate herbicides
such as asulam, carboxazole chlorprocarb, dichlormate, fenasulam,
karbutilate and terbucarb; carbanilate herbicides such as barban,
BCPC, carbasulam, carbetamide, CEPC, chlorbufam, chlorpropham,
CPPC, desmedipham, phenisopham, phenmedipham, phenmedipham-ethyl,
propham and swep; cyclohexene oxime herbicides such as alloxydim,
butroxydim, clethodim, cloproxydim, cycloxydim, profoxydim,
sethoxydim, tepraloxydim and tralkoxydim; cyclopropylisoxazole
herbicides such as isoxachlortole and isoxaflutole; dicarboximide
herbicides such as cinidon-ethyl, flumezin, flumiclorac,
flumioxazin and flumipropyn; dinitroaniline herbicides such as
benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin,
isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin,
prodiamine, profluralin and trifluralin; dinitrophenol herbicides
such as dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC,
etinofen and medinoterb; diphenyl ether herbicides such as
ethoxyfen; nitrophenyl ether herbicides such as acifluorfen,
aclonifen, bifenox, chlomethoxyfen, chlomitrofen, etnipromid,
fluorodifen, fluoroglycofen, fluoronitrofen, fomesafen,
furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen and
oxyfluorfen; dithiocarbamate herbicides such as dazomet and metam;
halogenated aliphatic herbicides such as alorac, chloropon,
dalapon, flupropanate, hexachloroacetone, iodomethane, methyl
bromide, monochloroacetic acid, SMA and TCA; imidazolinone
herbicides such as imazamethabenz, imazamox, imazapic, imazapyr,
imazaquin and imazethapyr; inorganic herbicides such as ammonium
sulfamate, borax, calcium chlorate, copper sulfate, ferrous
sulfate, potassium azide, potassium cyanate, sodium azide, sodium
chlorate and sulfuric acid; nitrile herbicides such as bromobonil,
bromoxynil, chloroxynil, dichlobenil, iodobonil, ioxynil and
pyraclonil; organophosphorus herbicides such as amiprofos-methyl,
anilofos, bensulide, bilanafos, butamifos, 2,4-DEP, DMPA, EBEP,
fosamine, glufosinate, glufosinate-P, glyphosate and piperophos;
phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB,
2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol and
trifopsime; oxadiazoline herbicides such as methazole, oxadiargyl,
oxadiazon; oxazole herbicides such as fenoxasulfone; phenoxyacetic
herbicides such as 4-CPA, 2,4-D, 3,4-DA, MCPA, MCPA-thioethyl and
2,4,5-T; phenoxybutyric herbicides such as 4-CPB, 2,4-DB, 3,4-DB,
MCPB and 2,4,5-TB; phenoxypropionic herbicides such as cloprop,
4-CPP, dichlorprop, dichlorprop-P, 3,4-DP, fenoprop, mecopropand
mecoprop-P; aryloxyphenoxypropionic herbicides such as chlorazifop,
clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P,
fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P,
isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P
and trifop; phenylenediamine herbicides such as dinitramine and
prodiamine; pyrazole herbicides such as pyroxasulfone;
benzoylpyrazole herbicides such as benzofenap, pyrasulfotole,
pyrazolynate, pyrazoxyfen, and topramezone; phenylpyrazole
herbicides such as fluazolate, nipyraclofen, pioxaden and
pyraflufen; pyridazine herbicides such as credazine, pyridafol and
pyridate; pyridazinone herbicides such as brompyrazon, chloridazon,
dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon and
pydanon; pyridine herbicides such as aminopyralid, cliodinate,
clopyralid, dithiopyr, fluoroxypyr, haloxydine, picloram,
picolinafen, pyriclor, thiazopyr and triclopyr; pyrimidinediamine
herbicides such as iprymidam and tioclorim; quaternary ammonium
herbicides such as cyperquat, diethamquat, difenzoquat, diquat,
morfamquat and paraquat; thiocarbamate herbicides such as butylate,
cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate,
methiobencarb, molinate, orbencarb, pebulate, prosulfocarb,
pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate and
vernolate; thiocarbonate herbicides such as dimexano, EXD and
proxan; thiourea herbicides such as methiuron; triazine herbicides
such as dipropetryn, indaziflam, triaziflam and trihydroxytriazine;
chlorotriazine herbicides such as atrazine, chlorazine, cyanazine,
cyprazine, eglinazine, ipazine, mesoprazine, procyazine,
proglinazine, propazine, sebuthylazine, simazine, terbuthylazine
and trietazine; methoxytriazine herbicides such as atraton,
methometon, prometon, secbumeton, simeton and terbumeton;
methylthiotriazine herbicides such as ametryn, aziprotryne,
cyanatryn, desmetryn, dimethametryn, methoprotryne, prometryn,
simetryn and terbutryn; triazinone herbicides such as ametridione,
amibuzin, hexazinone, isomethiozin, metamitron and metribuzin;
triazole herbicides such as amitrole, cafenstrole, epronaz and
flupoxam; triazolone herbicides such as amicarbazone, bencarbazone,
carfentrazone, flucarbazone, ipfencarbazone, propoxycarbazone,
sulfentrazone and thiencarbazone-methyl; triazolopyrimidine
herbicides such as cloransulam, diclosulam, florasulam,
flumetsulam, metosulam, penoxsulam and pyroxsulam; uracil
herbicides such as benzfendizone, bromacil, butafenacil,
flupropacil, isocil, lenacil, saflufenacil and terbacil; urea
herbicides such as benzthiazuron, cumyluron, cycluron,
dichloralurea, diflufenzopyr, isonoruron, isouron,
methabenzthiazuron, monisouron and noruron; phenylurea herbicides
such as anisuron, buturon, chlorbromuron, chloreturon,
chlorotoluron, chloroxuron, daimuron, difenoxuron, dimefuron,
diuron, fenuron, fluometuron, fluothiuron, isoproturon, linuron,
methiuron, methyldymron, metobenzuron, metobromuron, metoxuron,
monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron,
tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides
such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron,
cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron,
flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron,
mesosulfuron, metazosulfuron, nicosulfuron, orthosulfamuron,
oxasulfuron, primisulfuron, propyrisulfuron, pyrazosulfuron,
rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron;
triazinylsulfonylurea herbicides such as chlorsulfuron,
cinosulfuron, ethametsulfuron, iodosulfuron, metsulfuron,
prosulfuron, thifensulfuron, triasulfuron, tribenuron,
triflusulfuron and tritosulfuron; thiadiazolylurea herbicides such
as buthiuron, ethidimuron, tebuthiuron, thiazafluoron and
thidiazuron; and unclassified herbicides such as acrolein, allyl
alcohol, aminocyclopyrachlor, azafenidin, bentazone, benzobicyclon,
bicyclopyrone, buthidazole, calcium cyanamide, cambendichlor,
chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol,
cinmethylin, clomazone, CPMF, cresol, cyanamide,
ortho-dichlorobenzene, dimepiperate, endothal, fluoromidine,
fluridone, fluorochloridone, flurtamone, fluthiacet, indanofan,
methyl isothiocyanate, OCH, oxaziclomefone, pentachlorophenol,
pentoxazone, phenylmercury acetate, prosulfalin, pyribenzoxim,
pyriftalid, quinoclamine, rhodethanil, sulglycapin, thidiazimin,
tridiphane, trimeturon, tripropindan and tritac.
[0061] The compounds have broad ranges of efficacy as fungicides.
The exact amount of the hydrazones and copper-containing materials
to be applied is dependent not only on the specific active
materials being applied and relative amounts of hydrazone and
copper in the mixtures, but also on the particular action desired,
the fungal species to be controlled, and the stage of growth
thereof, as well as the part of the plant or other product to be
contacted with the compound. Thus, all the compounds, and
formulations containing the same, may not be equally effective at
similar concentrations or against the same fungal species.
[0062] Another embodiment of the present disclosure is a method for
the control or prevention of fungal attack. This method comprises
applying to the soil, plant, roots, foliage, seed or locus of the
fungus, or to a locus in which the infestation is to be prevented
(for example applying to cereal or grape plants), a fungicidally
effective amount of one or more of the compounds of Formula I. The
compounds are suitable for treatment of various plants at
fungicidal levels, while exhibiting low phytotoxicity. The
compounds may be useful both in a protectant and/or an eradicant
fashion.
[0063] The compounds have been found to have significant fungicidal
effect particularly for agricultural use. Many of the compounds are
particularly effective for use with agricultural crops and
horticultural plants.
[0064] It will be understood by those in the art that the efficacy
of the compound for the foregoing fungi establishes the general
utility of the compounds as fungicides.
[0065] The compounds 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 compound that kills or inhibits the plant disease
for which control is desired, but is not significantly toxic to the
plant. This amount will generally be from about 0.1 to about 1000
ppm (parts per million), with 1 to 500 ppm being preferred. The
exact amount of a compound required varies with the fungal disease
to be controlled, the type of formulation employed, the method of
application, the particular plant species, climate conditions, and
the like. A suitable application rate is typically in the range
from about 0.10 to about 4 pounds/acre (about 0.01 to 0.45 grams
per square meter, g/m.sup.2).
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] The compounds 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, Septoria tritici, Leptosphaeria nodorum,
Ustilago maydis, Erysiphe graminis, Puccinia species, Sclerotinia
species, Sphaerotheca fuliginea, Cercospora species, Rhizoctonia
species, Uncinula necator and Podosphaera leucotricha.
[0071] Any range or desired value given herein may be extended or
altered without losing the effects sought, as is apparent to the
skilled person for an understanding of the teachings herein.
[0072] The compounds of Formula I may be made using well-known
chemical procedures. Intermediates not specifically mentioned in
this disclosure are either commercially available, may be made by
routes disclosed in the chemical literature, or may be readily
synthesized from commercial starting materials utilizing standard
procedures. 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 and
Inorganica Chimica Acta 2007, 360, 1753-1761, which are 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, both of
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. Example 11 below
provides a typical method for the preparation of such
benzoylhydrazones. Example 15 below provides a general method for
the preparation of their metal complexes.
[0073] The following examples are presented to illustrate the
various aspects of the compounds of the present disclosure and
should not be construed as limitations to the claims.
Example 1
Preparation of 2-hydroxy-3,5-bis-trifluoromethylbenzaldehyde
##STR00002##
[0075] 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 grams (g), 7.7 millimoles
(mmol)) was dissolved in dry dichloromethane (CH.sub.2Cl.sub.2; 15
milliliters (mL), cooled to -78.degree. C. and treated in portions
with boron tribromide (BBr.sub.3, 1 M solution in CH.sub.2Cl.sub.2;
8.0 mL, 8.0 mmol). The mixture was stirred and allowed to warm to
25.degree. C. After 20 hours (h), the mixture was cooled to
-40.degree. C., carefully treated with water (H.sub.2O; 10 mL) and
warmed to room temperature. The separated organic phase was washed
with H.sub.2O (10 mL), saturated (satd) sodium chloride (NaCl)
solution (5 mL), dried over sodium sulfate (Na.sub.2SO.sub.4) and
evaporated. The residue was purified by silica gel chromatography
with a 0 to 20% gradient of ethyl acetate (EtOAc) in hexane to give
the aldehyde (1.4 g, 70%) as an oil: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 12.05 (s, 1H), 10.02 (s, 1H), 8.07 (s, 2H).
EIMS m/z 258.
Example 2
Preparation 5-chloro-2-hydroxy-3-trifluoromethylbenzaldehyde
##STR00003##
[0077] 5-Chloro-2-fluorobenzotrifluoride (1.5 grams (g), 7.5
millimoles (mmol)) was dissolved in dry tetrahydrofuran (THF; 10
milliliters (mL)), treated with tetramethylethylene-diamine (TMEDA;
1.6 mL, 1.2 g, 11 mmol), cooled to -78.degree. 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.degree. C. for 90 minutes (min),
the mixture was treated with N,N-dimethylformamide (DMF; 770
microliters (.mu.L), 730 milligrams (mg), 10 mmol) and stirred for
a further 30 min. The cooling bath was removed and mixture warmed
to 25.degree. C. over 30 min. The reaction was quenched by the
addition of satd ammonium chloride (NH.sub.4Cl) solution and then
diluted with diethyl ether (Et.sub.2O; 30 mL). The separated
organic phase was washed with satd NaCl solution (10 mL), dried
(Na.sub.2SO.sub.4) and evaporated. The residue was dissolved in dry
methanol (CH.sub.3OH; 10 mL) and treated with 30% sodium methoxide
solution in CH.sub.3OH (14 g). The mixture was stirred at
25.degree. C. for 20 h, diluted with H.sub.2O (50 mL) and extracted
with Et.sub.2O (2.times.40 mL). The combined organic phases were
washed with satd NaCl solution (20 mL), dried (Na.sub.2SO.sub.4)
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 CH.sub.2Cl.sub.2 (10 mL), cooled to -78.degree. C.
and treated with BBr.sub.3 (1 M solution in CH.sub.2Cl.sub.2; 5 mL,
5 mmol). The mixture was allowed to warm to 25.degree. C. and
stirred for 22 h. After cooling to -45.degree. C., the mixture was
treated with H.sub.2O (5 mL), warmed to 25.degree. C. and extracted
with EtOAc (2.times.15 mL). The combined extracts were washed with
satd NaCl solution (10 mL), dried (Na.sub.2SO.sub.4) 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): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 11.61 (s, 1H), 9.91
(s, 1H), 7.77 (dd, J=18.5, 2.6 Hz, 2H); EIMS m/z 224.
Example 3
Preparation of 3-chloro-2-hydroxy-5-trifluoromethylbenzaldehyde
##STR00004##
[0079] 3-Chloro-2-fluoro-5-trifluoromethylbenzaldehyde (5.0 g, 22
mmol) was dissolved in dry CH.sub.3OH (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 H.sub.2O (20 mL) plus Et.sub.2O (80 mL).
The aqueous phase was extracted with Et.sub.2O (50 mL), and the
combined organic phases were washed with satd NaCl solution (15
mL), dried (Na.sub.2SO.sub.4) and evaporated. The residue was
dissolved in dry CH.sub.2Cl.sub.2 (50 mL), cooled to -78.degree. C.
and treated with BBr.sub.3 (1 M solution in CH.sub.2Cl.sub.2; 25
mL, 25 mmol). After warming to 25.degree. C., the mixture was
stirred for 21 h, cooled to -40.degree. C. and quenched by addition
of H.sub.2O (30 mL). After warming, the aqueous phase was extracted
with CH.sub.2Cl.sub.2 (30 mL) and the combined organic phases were
washed with satd NaCl solution (30 mL), dried (Na.sub.2SO.sub.4)
and evaporated. The residue was purified by silica gel
chromatography with 0-20% EtOAc gradient in hexane to give the
aldehyde (2.7 g): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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 4
Preparation of 3-chloro-2-hydroxy-6-trifluoromethylbenzaldehyde
##STR00005##
[0081] 4-Chloro-3-fluoro-6-trifluoromethylbenzaldehyde (1.0 g, 4.4
mmol) was dissolved in dry CH.sub.3OH (10 mL), treated with 30%
sodium methoxide in CH.sub.3OH (7.9 g, 44 mmol) and heated at
reflux for 1 h. After cooling, the mixture was diluted with
H.sub.2O (15 mL) and extracted with Et.sub.2O (2.times.30 mL). The
combined ether extracts were washed with satd NaCl solution (10
mL), dried (Na.sub.2SO.sub.4), 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 CH.sub.2Cl.sub.2 (15 mL), cooled to -78.degree. C., treated
with BBr.sub.3 (1 M in CH.sub.2Cl.sub.2; 5.0 mL, 5 mmol), allowed
to warm to 25.degree. C. and stirred for 20 h. The reaction was
cooled in ice and quenched by addition of H.sub.2O (10 mL). The
separated organic phase was washed with satd NaCl solution (10 mL),
dried (Na.sub.2SO.sub.4) and evaporated. The residue was purified
by silica gel chromatography with 0-10% EtOAc/hexane to give the
aldehyde (980 mg): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 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 5
Preparation of 5-chloro-2-hydroxy-4-trifluoromethylbenzaldehyde
##STR00006##
[0083] 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.degree. C. for 6 h and
poured into H.sub.2O (200 mL) with stirring. The precipitated
phenol was collected by filtration and washed well with H.sub.2O.
The solid was taken up in EtOAc (150 mL), washed with satd NaCl
solution (50 mL), dried (Na.sub.2SO.sub.4) and evaporated to give
the 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.degree. 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.degree. C. and
treated with DMF (1.4 mL, 1.3 g, 18 mmol). After stirring at
-78.degree. C. for 30 min, the mixture was warmed to 25.degree. C.,
quenched with satd NH.sub.4Cl solution (10 mL) and worked up with
H.sub.2O (30 mL) and Et.sub.2O (75 mL). The organic phase was
washed with satd NaCl solution (20 mL), dried (Na.sub.2SO.sub.4)
and evaporated. The residue was purified by reverse-phase
high-performance liquid chromatography (RP-HPLC) to give the
product (300 mg, circa 70% purity), which was used without further
purification: EIMS m/z 224.
Example 6
Preparation of 2-hydroxy-4,6-bis-trifluoromethyl-benzaldehyde
##STR00007##
[0085] 3,5-Bis(trifluoromethyl)anisole (5.0 g 21 mmol) and TMEDA
(4.0 mL, 3.0 g, 26 mmol) were dissolved in dry Et.sub.2O (60 mL),
cooled to -10.degree. C. and treated in portions with n-BuLi (2.5 M
in hexanes; 10 mL, 25 mmol) warmed to 25.degree. C. and stirred for
90 min. The mixture was cooled to -78.degree. C., treated dropwise
with DMF (2.3 mL, 2.2 g, 30 mmol), stirred for 30 min, warmed to
25.degree. C. and stirred for 30 min. The reaction was quenched by
addition of H.sub.2O (50 mL) and extracted with Et.sub.2O
(2.times.75 mL). The combined organic fractions were washed with
satd NaCl solution (30 mL), dried (Na.sub.2SO.sub.4) 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 CH.sub.2Cl.sub.2 (75 mL), cooled to
-78.degree. C. and treated with BBr.sub.3 (1 M solution in
CH.sub.2Cl.sub.2; 12 mL, 12 mmol). The mixture was stirred for 30
min at -78.degree. C., warmed to 25.degree. C. and stirred for 90
min H.sub.2O (100 mL) was added and stirring was continued for 30
min. The separated organic phase was washed with satd NaCl
solution, dried (Na.sub.2SO.sub.4) and evaporated. The residue was
purified by silica gel chromatography with 0-20% EtOAc/hexane to
give the purified aldehyde (2.0 g): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 12.27 (s, 1H), 10.34 (s, 1H), 7.51 (s, 1H);
EIMS m/z 258.
Example 7
Preparation of 1-(2-hydroxy-5-trifluoromethylphenyl)-ethanone
##STR00008##
[0087] 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 8
Preparation of 2-hydroxy-4-trifluoromethylbenzaldehyde
##STR00009##
[0089] 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 9
Preparation of 2-hydroxy-5-trifluoromethylbenzaldehyde
##STR00010##
[0091] 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 10
Preparation of 2-hydroxy-6-trifluoromethylbenzaldehyde
##STR00011##
[0093] 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 11
Preparation of 3-chloro-benzoic acid
[1-(2-hydroxy-3-trifluoromethyl-phenyl)-methylidine]-hydrazide
##STR00012##
[0095] 2-Hydroxy-3-(trifluoromethyl)benzaldehyde (100 mg, 0.53
mmol) and 3-chlorobenzhydrazide (90 mg, 53 mmol) were shaken
together and heated to 60.degree. C. in absolute ethanol (EtOH; 3
mL) for 24 h. After cooling to room temperature, H.sub.2O
(.about.0.5 mL) was added and the resulting solid was filtered,
washed with H.sub.2Oand Et.sub.2O and dried in a vacuum oven at
50.degree. C. for several hours to give the desired product (145
mg, 80%) as a white solid: mp 185-187.degree. C.; .sup.1H NMR (300
MHz, solvent) .delta. 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); ESIMS m/z 343 ([M+H].sup.+), 341
([M-H].sup.-).
TABLE-US-00001 TABLE 1 Com- pound Num- mp ESIMS ESIMS .sup.1H NMR
(400 MHz, DMSO-d.sub.6 unless otherwise ber Structure (.degree. C.)
(+) (-) stated), .delta. 1 ##STR00013## 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) 2 ##STR00014## 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) 3 ##STR00015## 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) 4 ##STR00016## 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) 5
##STR00017## 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) 6 ##STR00018## 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) 7 ##STR00019## 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) 8 ##STR00020## 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) 9 ##STR00021## 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) 10
##STR00022## 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) 11 ##STR00023## 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 = 1.7 Hz, 1H), 7.82-7.72 (m, 2H), 7.46 (d, J =
5.0 Hz, 2H), 2.41 (s, 3H) 12 ##STR00024## 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) 13 ##STR00025## 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) 14 ##STR00026##
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) 15 ##STR00027## 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) 16
##STR00028## 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) 17 ##STR00029## 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) 18 ##STR00030## 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) 19 ##STR00031## 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) 20 ##STR00032## 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) 21
##STR00033## 255- 257 373 371 13.09 (s, 1H), 12.37 (s, 1H), 11.63
(s, 1H), 8.72 (s, 1H), 7.97 (d, J = 1.7 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) 22 ##STR00034## 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) 23 ##STR00035## 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) 24 ##STR00036## 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) 25 ##STR00037## 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) 26 ##STR00038## 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) 27 ##STR00039## 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) 28 ##STR00040## 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) 29
##STR00041## 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) 30 ##STR00042## 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, 1H) 31 ##STR00043## 210- 214 445 443 13.59, 12.89, 12.70, 11.2
(4s, 2H), 8.60, 8.38 (2s, 1H), 8.36, 8.15 (2s, 1H), 7.97-7.63 (m,
5H); Note: rotational isomers 32 ##STR00044## 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) 33 ##STR00045## 188- 190 323 321 (300 MHz,
DMSO-d.sub.6) 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) 34 ##STR00046## 239- 241 323 321
(300 MHz, DMSO-d.sub.6) 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) 35 ##STR00047## 176- 180 327 325 (300 MHz,
DMSO-d.sub.6) 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) 36 ##STR00048## 187- 188 327 (300 MHz,
DMSO-d.sub.6) 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) 37 ##STR00049## 185-
187 343 341 (300 MHz, DMSO-d.sub.6) 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) 38 ##STR00050## 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) 39 ##STR00051## 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 = 7.7 Hz, 1H) 40
##STR00052## 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) 41 ##STR00053##
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) 42 ##STR00054## 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) 43 ##STR00055## 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 = 7.7 Hz, 1H); Note: rotational isomers
44 ##STR00056## 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) 45 ##STR00057## 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) 46 ##STR00058## 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) 47 ##STR00059## 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) 48 ##STR00060## 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) 49
##STR00061## 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) 50 ##STR00062## 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) 51 ##STR00063## 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)
52 ##STR00064## 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) 53 ##STR00065## 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) 54 ##STR00066## 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) 55 ##STR00067## 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) 56 ##STR00068##
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) 57
##STR00069## 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) 58 ##STR00070## 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) 59
##STR00071## 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)
60 ##STR00072## 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) 61 ##STR00073## 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) 62 ##STR00074## 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) 63 ##STR00075## 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)
64 ##STR00076## 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) 65 ##STR00077## 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), 6.30 (d, J = 7.0 Hz, 2H), 2.31 (s, 3H) 66 ##STR00078## 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) 67 ##STR00079##
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) 68 ##STR00080## 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) 69 ##STR00081## 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) 70 ##STR00082## 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) 71 ##STR00083## 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) 72 ##STR00084## 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) 73 ##STR00085##
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) 74 ##STR00086## 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) 75 ##STR00087## 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) 76 ##STR00088## 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) 77 ##STR00089## 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, dH) 78
##STR00090## 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) 79 ##STR00091## 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) 80 ##STR00092## 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) 81 ##STR00093## 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) 82 ##STR00094##
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) 83
##STR00095## 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) 84 ##STR00096## 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) 85 ##STR00097## 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) 86 ##STR00098##
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) 87 ##STR00099## 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 88
##STR00100## 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)
[0096] As exemplified below, hydrazones of the present invention,
or their metal complexes, in a mixture with copper or 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, copper naphthenate, 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.
[0097] 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 12
Effect of Copper on Fungitoxicity of Hydrazones Towards
Leptosphaeria nodorum
[0098] 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 CuSO.sub.4,
was omitted. The medium, termed "copper-minus", was prepared by
dissolving 10 g glucose, 1.5 g K.sub.2HPO.sub.4, 2 g
KH.sub.2PO.sub.4 and 1 g (NH.sub.4).sub.2SO.sub.4 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.
MgSO.sub.4.7H.sub.2O (0.5 g) was added, and stiffing was continued
for a further hour. Trace elements (minus CuSO.sub.4), 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
CuCl.sub.2.2H.sub.2O to the copper-minus medium at 20 .mu.M. Test
compounds were dissolved in dimethylsulfoxide (DMSO) then dilutions
in copper-minus and copper-plus growth media were prepared as 100
.mu.L aliquots in flat-bottomed 96-well microtiter plates.
[0099] 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.times.10.sup.5 spores per mL. Microtiter plates were inoculated
with 100 .mu.L of this spore suspension and the plates incubated at
25.degree. 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.
[0100] 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 2.
Results illustrate that hydrazones and copper produce a synergistic
fungitoxic effect towards LEPTNO.
Example 13
Efficacy of Hydrazones in Mixture with Copper Against Tomato Blight
(Phytophthora infestans)
[0101] Hydrazone compounds at 50 ppm in combination with 50 .mu.M
CuCl.sub.2.2H.sub.2O 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.RTM. X-100, 0.1% Atlox 4913 and 50 .mu.M
CuCl.sub.2.2H.sub.2O 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-US-00002 TABLE 2 LEPTNO LEPTNO LEPTNO % Inhn. % Inhn. % Inhn.
Minus Plus Plus TLB Compound Concn. Copper Copper Copper % Number
(.mu.g/mL) Observed Observed Predicted Control 1 0.05 0.0 98.4 7.1
79.7 2 0.05 5.5 97.8 12.2 71.2 3 0.05 1.9 97.5 8.9 86.4 4 0.05 1.7
94.2 8.7 72.9 5 0.05 5.8 98.0 12.5 89.8 6 0.05 8.3 97.7 14.8 84.7 7
0.05 0.0 96.4 7.1 69.5 8 0.05 3.1 97.3 10.0 71.2 9 0.05 18.1 96.6
23.9 78.0 10 0.05 17.1 96.4 23.0 100.0 11 0.05 11.7 96.6 18.0 100.0
12 0.05 20.9 97.9 26.5 95.0 13 0.05 16.1 98.1 22.1 100.0 14 0.05
2.3 96.3 9.2 98.0 15 0.05 0.0 95.7 7.1 100.0 16 0.05 6.9 95.6 13.5
93.0 17 0.05 1.2 95.7 8.3 98.0 18 0.05 0.0 95.1 7.1 99.0 19 0.05
14.0 93.5 20.1 99.0 20 0.05 5.3 92.9 12.1 99.0 21 0.05 22.8 97.8
28.2 100.0 22 0.05 2.0 93.9 8.9 89.0 23 0.05 16.2 93.2 22.1 85.0 24
0.05 10.9 97.8 17.2 98.0 25 0.05 10.2 96.8 16.6 95.0 26 0.05 16.6
97.8 22.5 98.0 27 0.05 22.4 98.0 27.9 97.0 28 0.05 9.0 98.1 15.5
96.0 29 0.05 1.5 95.4 8.5 100.0 30 0.05 18.0 96.2 23.8 95.0 31 0.05
1.2 88.9 8.2 63.0 32 0.05 9.1 98.3 15.6 86.0 33 0.05 2.8 95.4 9.7
97.0 34 0.05 31.5 91.8 36.4 100.0 35 0.05 18.8 97.9 24.6 97.0 36
0.05 30.0 96.7 34.9 96.0 37 0.05 13.8 98.4 19.9 97.0 38 0.05 16.3
98.3 22.2 100.0 39 0.05 17.4 96.9 23.3 97.0 40 0.05 11.3 94.9 17.6
97.0 41 0.05 7.7 96.1 14.3 100.0 42 0.05 8.8 98.4 15.3 100.0 43
0.05 0.0 94.8 7.1 81.0 44 0.05 13.6 96.5 19.8 98.0 45 0.05 29.9
97.6 34.9 100.0 46 0.05 26.3 98.4 31.6 97.0 47 0.05 26.7 98.2 31.9
100.0 48 0.05 36.1 98.3 40.6 100.0 49 0.05 31.8 98.6 36.6 100.0 50
0.05 19.3 98.5 25.0 96.0 51 0.05 20.3 95.7 25.9 100.0 52 0.05 28.6
95.8 33.6 100.0 53 0.05 5.4 94.6 12.1 100.0 54 0.05 41.1 98.4 45.3
100.0 55 0.05 4.7 97.2 11.5 100.0 56 0.05 14.6 98.2 20.7 94.0 57
0.05 9.2 97.0 15.6 100.0 58 0.05 0.0 94.2 7.1 98.0 59 0.05 0.0
100.0 7.1 96.0 60 0.05 2.9 100.0 9.8 98.0 61 0.05 0.0 100.0 7.1
96.0 62 0.05 0.0 100.0 7.1 98.0 63 0.05 14.6 100.0 20.7 83.0 64
0.05 0.0 100.0 7.1 91.0 65 0.05 13.2 100.0 19.4 90.0 66 0.05 20.0
96.6 25.7 100.0 67 0.05 27.1 97.5 32.3 100.0 68 0.05 7.2 98.5 13.8
92.0 69 0.05 1.1 93.5 8.1 100.0 70 0.05 4.6 100.0 11.4 100.0 71
0.05 12.9 100.0 19.1 100.0 72 0.05 5.6 100.0 12.3 100.0 73 0.05
12.4 100.0 18.6 100.0 74 0.05 16.7 100.0 22.6 100.0 75 0.05 0.0
100.0 7.1 100.0 76 0.05 6.7 100.0 13.3 100.0 77 0.05 7.6 97.6 14.2
78.0 78 0.05 8.7 97.7 15.2 73.0 79 0.05 15.3 97.7 21.3 46.0 80 0.05
9.8 96.2 16.2 59.0 81 0.05 0.0 97.3 7.1 80.0 82 0.05 4.9 91.4 11.7
56.0 83 0.05 6.2 97.0 12.9 34.0 84 0.05 5.1 95.7 11.9 61.0 85 0.05
10.1 97.7 16.5 56.0 86 0.05 21.1 93.4 26.7 24.0 87 0.05 12.2 96.2
18.5 90.0 88 0.05 12.4 96.5 18.6 44.0 CuCl.sub.2, 7.1 .+-. 6.0 10
.mu.M
Example 14
Effect of Copper on Fungitoxicity of Hydrazones Towards
Phytophthora capsici
[0102] 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 CuSO.sub.4, was omitted.
The medium, termed "copper-minus AS", was prepared by dissolving 2
g asparagine, 0.43 g KH.sub.2PO.sub.4, 0.3 g K.sub.2HPO.sub.4, 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 MgSO.sub.4.7H.sub.2O (100 .mu.g/mL),
FeSO.sub.4.7H.sub.2O (1 .mu.g/mL), CaCl.sub.2 (50 .mu.g/mL),
ZnSO.sub.4.7H.sub.2O (1 .mu.g/mL), NaMoO.sub.4.2H.sub.2O (0.2
.mu.g/mL) and MnCl.sub.2.4H.sub.2O (0.2 .mu.g/mL) were added and
the entire medium was sterilized by filtration. "Copper-plus AS"
medium was prepared by adding CuCl.sub.2.2H.sub.2O to the
copper-minus AS medium at 100 .mu.M. Test compounds were dissolved
in DMSO then dilutions in copper-minus AS and copper-plus AS media
were prepared as 100 .mu.L aliquots in flat-bottomed 96-well
microtiter plates.
[0103] 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 CaCO.sub.3, and 20 g agar per liter. Plates were
inoculated with 7-mm plugs from a 1-week old culture, incubated at
25.degree. 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 stirring at room temperature for
1 h) to each plate, and incubating for 10 min at 25.degree. C.
followed by 20 min at 4.degree. C. The plates were returned to
25.degree. C. for 10 min and the aqueous suspension of released
zoospores was recovered. The zoospore suspension was adjusted to
5.times.10.sup.4 spores/mL by dilution into Chelex 100-treated
water. Microtiter plates were inoculated with 100 .mu.L of spore
suspension and incubated at 25.degree. 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.
[0104] 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-US-00003 TABLE 3 % Inhn Minus % Inhn % Inhn Compound
Concentration copper Plus copper Plus copper Number (.mu.g/mL)
Observed Observed Predicted 1 0.050 0.0 91.2 4.5 3 0.050 0.0 88.2
4.5 10 0.050 2.9 81.4 7.3 27 0.050 4.7 42.1 9.0 41 0.050 0.0 87.9
4.5 52 0.050 0.0 71.1 4.5 63 0.050 2.4 91.2 6.8 74 0.050 0.0 30.8
4.5 CuCl.sub.2, 4.5 .+-. 7.9 50 uM
Example 15
Effect of Copper on Fungitoxicity of Hydrazones Towards Ustilago
maydis
[0105] In vitro fungitoxicity assays against Ustilago maydis were
conducted using the copper-minus medium described in Example 12.
Medium containing copper was prepared by adding
CuCl.sub.2.2H.sub.2O to the copper-minus medium at 20 .mu.M. Test
compounds were dissolved in dimethylsulfoxide (DMSO) at 200
.mu.g/mL and 1 .mu.L aliquots were added to two wells of
flat-bottomed 96-well microtiter plates. Copper-minus medium (100
.mu.L) 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 .mu.L of medium.
[0106] Ustilago maydis was grown in 50 mL potato dextrose broth
with shaking at 25.degree. 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.times.10.sup.5 spores per mL.
Microtiter plate wells containing test compound of DMSO (control)
as described above were inoculated with 100 .mu.L of this spore
suspension and the plates incubated at 25.degree. 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.
[0107] Results for growth inhibition by test compounds at 1
.mu.g/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-US-00004 TABLE 4 % Inhn. % Inhn. % Inhn. Compound Minus
copper Plus copper Plus copper Number Observed Observed Predicted 1
0.0 92.2 11.9 3 1.7 83.5 13.4 10 0.0 95.2 11.9 19 16.2 41.8 26.2 27
22.0 97.8 31.3 41 27.1 97.7 35.8 52 13.6 96.6 23.9 63 10.2 35.3
20.9 74 0.0 96.0 11.9 CuCl.sub.2, 11.9 10 .mu.M
Example 16
Effect of Copper on Fungitoxicity of Hydrazones Towards Septoria
tritici
[0108] In vitro fungitoxicity assays against Septoria tritici were
conducted using the copper-minus medium described in Example 12.
Medium containing copper was prepared by adding
CuCl.sub.2.2H.sub.2O to the copper-minus medium at 2 .mu.M. Test
compounds were dissolved in dimethylsulfoxide (DMSO) at 10 .mu.g/mL
and 1 .mu.L aliquots were added to two wells of flat-bottomed
96-well microtiter plates. Copper-minus medium (100 .mu.L) 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 .mu.L of medium.
[0109] Septoria tritici isolate USA-184 was grown on potato
dextrose agar at 18.degree. 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.times.10.sup.5 spores per mL. Microtiter plate wells containing
test compound of DMSO (control) as described above were inoculated
with 100 .mu.L of this spore suspension and the plates incubated at
25.degree. 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.
[0110] Results for growth inhibition by test compounds at 0.05
.mu.g/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 .mu.M) 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-US-00005 TABLE 5 % Inhibition % Inhibition % Inhibition
Compound Minus copper Plus copper Plus copper Number Observed
Observed Predicted 1 16.2 93.5 16.2 3 3.6 88.0 3.6 10 9.5 92.1 9.5
19 14.9 55.1 14.9 27 46.8 97.1 46.8 41 44.4 97.1 44.4 52 57.5 97.0
57.5 63 5.8 92.0 5.8 74 27.5 92.4 27.5 CuCl.sub.2, 0 1 .mu.M
Example 15
Comparative Efficacy of Isolated Copper-Hydrazone Complexes and
Parent Hydrazones Towards Leptosphaeria nodorum
[0111] Hydrazones and their isolated copper complexes were compared
with respect to their in vitro fungitoxicity towards LEPTNO. Copper
complexes of hydrazones were prepared by precipitation from ethanol
with CuCl.sub.2.2H.sub.2O, at a 1:1 molar ratio, 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).
[0112] 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.degree. 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.degree. 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 Et.sub.2O. In the instances where the complex does not
precipitate, the solvent is removed and the resulting solid
metal-hydrazone complex is washed with Et.sub.2O. Properties of
particular copper complexes of hydrazones are provided in Table 6
below.
TABLE-US-00006 TABLE 6 Com- Com- Ratio plex pound Hydrazone:Metal
mp Number Number Metal Salt Salt Description (.degree. C.) 89 3
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 286- solid 289 90 10
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 280- solid 286 91 27
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 279- solid 281 92 38
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 295- solid 305 93 49
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 279- solid 281 94 60
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 259- solid 281 95 71
CuCl.sub.2 .cndot. 2H.sub.2O 1:1 olive green 270- solid 274
[0113] In vitro fungitoxicity assays were conducted using the
copper-minus medium described in Example 12. Test compounds were
dissolved in dimethylsulfoxide (DMSO) then dilutions in
copper-minus medium were prepared as 100 .mu.L aliquots in
flat-bottomed 96-well microtiter plates. Microtiter plates were
inoculated with 100 .mu.L of spore suspension at a concentration of
2.times.10.sup.5 spores per mL, prepared as in Example 12. The
plates were incubated at 25.degree. 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.
[0114] Results for growth inhibition by hydrazones and
corresponding isolated copper complexes (each at 0.1 .mu.g/mL) are
shown in Table 7. The results illustrate that isolated copper
complexes of hydrazones are much more fungitoxic than the
corresponding hydrazones.
TABLE-US-00007 TABLE 7 Com- Complex pound Hydrazone Complex Number
Number Metal Salt Ratio* % Inhibition % Inhibition 89 3 CuCl.sub.2
.cndot. 2H.sub.2O 1:1 0.6 91.9 90 10 CuCl.sub.2 .cndot. 2H.sub.2O
1:1 22.1 94.6 91 27 CuCl.sub.2 .cndot. 2H.sub.2O 1:1 39.9 97.9 92
38 CuCl.sub.2 .cndot. 2H.sub.2O 1:1 23.9 91.8 93 49 CuCl.sub.2
.cndot. 2H.sub.2O 1:1 43.9 97.1 94 60 CuCl.sub.2 .cndot. 2H.sub.2O
1:1 23.8 95.8 95 71 CuCl.sub.2 .cndot. 2H.sub.2O 1:1 19.3 96.7
*Molar ratio of hydrazone:metal used to prepare complexes.
* * * * *