U.S. patent application number 13/144684 was filed with the patent office on 2012-01-12 for synergistic 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, Steven Howard Shaber, Thomas L. Siddall, Jeffery D. Webster, David H. Young.
Application Number | 20120010075 13/144684 |
Document ID | / |
Family ID | 42244227 |
Filed Date | 2012-01-12 |
United States Patent
Application |
20120010075 |
Kind Code |
A1 |
Young; David H. ; et
al. |
January 12, 2012 |
SYNERGISTIC FUNGICIDAL COMPOSITIONS INCLUDING HYDRAZONE DERIVATIVES
AND COPPER
Abstract
The present invention relates to the use of mixtures containing
hydrazone compounds and copper for controlling the growth of
fungi.
Inventors: |
Young; David H.; (Camel,
IN) ; Shaber; Steven Howard; (Zionsville, IN)
; 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.: |
13/144684 |
Filed: |
January 14, 2010 |
PCT Filed: |
January 14, 2010 |
PCT NO: |
PCT/US10/21040 |
371 Date: |
September 23, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61144560 |
Jan 14, 2009 |
|
|
|
Current U.S.
Class: |
504/101 ;
424/604; 424/632; 424/633; 424/635; 424/637; 424/638; 504/358;
514/162; 514/186; 514/466; 514/500 |
Current CPC
Class: |
A01N 59/20 20130101;
C07C 323/36 20130101; A01N 59/20 20130101; A01N 33/00 20130101;
C07C 251/86 20130101; A01N 33/26 20130101; A01N 59/20 20130101;
A01N 43/30 20130101; A01N 37/40 20130101; A01N 59/00 20130101; A01N
59/16 20130101; A01N 31/04 20130101; A01N 59/16 20130101; A01N
2300/00 20130101; A01N 31/00 20130101; A01N 37/40 20130101; A01N
37/28 20130101; A01N 2300/00 20130101; A01N 59/16 20130101; A01N
37/44 20130101; A01N 37/38 20130101; A01N 43/30 20130101; A01N
37/48 20130101; A01N 37/28 20130101; A01N 37/48 20130101; A01N
37/38 20130101; A01N 37/44 20130101; A01N 59/16 20130101; A61P
31/10 20180101 |
Class at
Publication: |
504/101 ;
424/632; 514/500; 424/604; 424/637; 424/638; 514/162; 424/633;
424/635; 514/466; 514/186; 504/358 |
International
Class: |
A01N 59/20 20060101
A01N059/20; A01N 59/26 20060101 A01N059/26; A01N 43/30 20060101
A01N043/30; A01P 3/00 20060101 A01P003/00; A01P 1/00 20060101
A01P001/00; A01P 5/00 20060101 A01P005/00; A01P 21/00 20060101
A01P021/00; A01P 13/00 20060101 A01P013/00; A01P 7/02 20060101
A01P007/02; A01P 11/00 20060101 A01P011/00; A01P 9/00 20060101
A01P009/00; A01P 7/00 20060101 A01P007/00; A01N 55/02 20060101
A01N055/02; A01P 7/04 20060101 A01P007/04 |
Claims
1. A synergistic mixture for controlling the growth of fungi, the
synergistic mixture including copper and a hydrazone compound of
Formula 1: ##STR00618## wherein A is oxygen or sulfur; Z is H or
C1-C4 alkyl; W is --CHR1-; n is 0, 1, or 2; R is H, C1-C6 alkyl,
C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl,
C2-C6 haloalkenyl C2-C6 haloalkynyl, or C3-C6 halocycloalkyl; R1 is
H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl,
C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl, C3-C6
halocycloalkyl, substituted aryl, unsubstituted aryl, substituted
heteroaryl, or unsubstituted heteroaryl; X3, X4, X5, and X6 are
each independently selected from the group consisting of H,
halogen, nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 alkoxy, C2-C4
alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4 haloalkyl, C1-C4
haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C1-C4
haloalkylthio, --SO.sub.2R1, SONR1R1, --CR1=NOR1, --CONR1R1,
NR1COOR1, --COOR1, substituted aryl, substituted heteroaryl,
unsubstituted aryl, and unsubstituted heteroaryl; and Y2, Y3, Y4,
Y5, and Y6 are each independently selected from the group
consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4 alkyl,
C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio, C1-C4
haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4 haloalkynyl,
C1-C4 haloalkylthio, --SO.sub.2R1, SONR1R1, --R1=NOR1, --CONR1R1,
NR1COOR1, --COOR1, NR1R1, substituted aryl, substituted heteroaryl,
unsubstituted aryl, unsubstituted heteroaryl, and phenoxy; with the
proviso that X3 and X4, X4 and X5, X5 and X6, Y2 and Y3, or Y3 and
Y4 may form a 5 or 6 membered fused ring which may contain up to
two heteroatoms selected from the group consisting of O, N, and
S.
2. Use of the synergistic mixture of claim 1 for controlling the
growth of fungal pathogens of plants.
3. Use of the synergistic mixture of claim 1 for controlling the
growth of fungal of mammals.
4. Use of the synergistic mixture of claim 1 for controlling the
growth of fungi on inert substrates selected from the group
consisting essentially of wood, metal, and plastic.
5. Use of the synergistic mixture of claim 1 for controlling the
growth of fungi belonging to at least one of Ascomycete,
Basidiomycete, Oomycete, and Deuteromycete classes of fungi.
6. The synergistic mixture of claim 1 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.
7. The synergistic mixture of claim 1, wherein a growth inhibiting
amount of the hydrazone compound of Formula I in mixture with
copper is provided as a mixture in which the total molar ratio of
copper to the hydrazone compound of Formula 1 exceeds 1:1.
8. The synergistic mixture of claim 1, wherein a growth inhibiting
amount of the hydrazone compound of Formula I is provided as an
isolated hydrazone-copper complex in which the molar ratio of the
copper to the hydrazone compound of Formula 1 is one of 1:1 and
1:2.
9. The synergistic mixture of claim 1, wherein the hydrazone
compound of Formula 1 to be combined with copper is complexed with
a metal.
10. The synergistic mixture of claim 8, wherein the metal complexed
with the hydrazone compound of Formula 1 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+.
11. 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.
12. The synergistic mixture of claim 1, wherein W is --CHR-- or
--CH(R)O--; n is 0 or 1; A is O or S; R is H, C1-C6 alkyl, C1-C6
fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C6 cycloalkyl; R1
is H, C1-C6 alkyl, C1-C6 fluoroalkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C6 cycloalkyl, substituted aryl, or unsubstituted aryl; Z is H
or --C(CH.sub.3).sub.3; X3, X4, X5, and X6 are each independently
selected from the group consisting of H, 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 each independently
selected from the group consisting of H, halogen, nitro, hydroxyl,
cyano, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy
C1-C4 alkylthio, --NR1R1, substituted aryl, unsubstituted 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.
13. The synergistic mixture of claim 12, wherein W is --CH.sub.2--;
n is 0 or 1; A is O or S; R is H, C1-C4 alkyl, or C3-C6 cycloalkyl;
Z is H; X3, X4, X5, and X6 are each independently selected from the
group consisting of H, halogen, nitro, C1-C2 alkyl, C1-C2
haloalkyl, and C1-C2 alkoxy; and Y2, Y3, Y4, Y5, and Y6 are each
independently selected from the group consisting of H, halogen,
nitro, hydroxyl, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy,
and C1-C4 haloalkoxy; with the proviso that 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.
14. The synergistic mixture of claim 13, wherein n is 0; A is 0; R
is H, C1-C4 alkyl, or cyclopropyl; Z is H; X3, X4, X5, and X6 are
each independently selected from the group consisting of H,
halogen, nitro, methyl, trifluoromethyl, and methoxy; Y2, Y3, Y4,
Y5, and Y6 are each independently selected from the group
consisting of H, halogen, nitro, hydroxyl, C1-C4 alkyl, C1-C4
alkoxy, C1-C4 haloalkyl, and C1-C4 haloalkoxy; with the proviso
that Y3 and Y4 may form a 5 or 6 membered fused ring which may
contain up to two oxygen atoms.
15. The synergistic mixture of claim 1, wherein a ratio of the
hydrazone to the copper is from 1:0.1 to 1:10,000.
16. An agriculturally active composition including the synergistic
mixture of claim 1 and at least one of a herbicide, an insecticide,
a bacteriocide, a nematocide, a miticide, a biocide, a termiticide,
a rodenticide, a molluscide, a arthropodicide, a fertilizer, a
growth regulator, and a pheromone.
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 invention relates to the use of hydrazones in
combination with copper, copper-based fungicides or other
copper-containing materials as synergistic fungicidal mixtures.
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.
SUMMARY OF THE INVENTION
[0005] One exemplary embodiment of the present disclosure includes
a synergistic mixture for controlling the growth of fungi, the
synergistic mixture including copper and a hydrazone compound of
Formula I:
##STR00001##
wherein A is oxygen or sulfur;
[0006] Z is H or C1-C4 alkyl;
[0007] W is --CHR1-;
[0008] n is 0, 1, or 2;
[0009] R is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6
cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl,
or C3-C6 halocycloalkyl;
[0010] R1 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6
cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6 haloalkynyl,
C3-C6 halocycloalkyl, substituted aryl, unsubstituted aryl,
substituted heteroaryl, or unsubstituted heteroaryl;
[0011] X3, X4, X5, and X6 are each independently selected from the
group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4
alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio,
C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4
haloalkynyl, C1-C4 haloalkylthio, --SO.sub.2R1, SONR1R1,
--CR1=NOR1, --CONR1R1, NR1COOR1, --COOR1, substituted aryl,
substituted heteroaryl, unsubstituted aryl, and unsubstituted
heteroaryl; and
[0012] Y2, Y3, Y4, Y5, and Y6 are each independently selected from
the group consisting of H, halogen, nitro, hydroxyl, cyano, C1-C4
alkyl, C1-C4 alkoxy, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkylthio,
C1-C4 haloalkyl, C1-C4 haloalkoxy, C2-C4 haloalkenyl, C2-C4
haloalkynyl, C1-C4 haloalkylthio, --SO.sub.2R1, SONR1R1, --R1=NOR1,
--CONR1R1, NR1COOR1, --COOR1, NR1R1, substituted aryl, substituted
heteroaryl, unsubstituted aryl, unsubstituted heteroaryl, and
phenoxy;
[0013] 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.
[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-C6 alkyl, C2-C6 alkenyl, C2-C6
alkynyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl C2-C6
haloalkynyl, or C3-C6 halocycloalkyl, unless stated otherwise.
[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 "aryl" refers to a cyclic, aromatic substituent
consisting of hydrogen and carbon.
[0031] 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.
[0032] The term "phenoxy" refers to an --O substituted with a
six-membered fully unsaturated ring consisting of hydrogen and
carbon.
[0033] The term "nitro" refers to a --NO.sub.2 substituent.
[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] 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
[0036] 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.
[0037] The mixtures of the present invention have fungitoxic
activity against phytopathogenic fungi, against fungal pathogens of
mammals, including humans, and against wood decay causing fungi.
The mixtures of the present invention may have broad spectrum
fungitoxic activity, particularly against phytopathogenic fungi.
They are active against fungi of a number of classes including
Deuteromycetes (Fungi Imperfecti), Basidiomycetes, Oomycetes and
Ascomycetes. More particularly, the method of this invention
provides for activity against organisms including, but not limited
to, Phytophthora species, Plasmopara viticola, Pseudoperonospora
cubensis, Pythium species, Pyricularia oryzae, Colletotrichum
species, Helminthosporium species, Alternaria species, Septoria
nodorum, Leptosphaeria nodorum, Ustilago maydis, Erysiphe graminis,
Puccinia species, Sclerotinia species, Sphaerotheca fuliginea,
Cercospora species, Rhizoctonia species, Uncinula necator, Septoria
tritici, and Podosphaera leucotricha.
[0038] 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.
[0039] The present invention contemplates all vehicles by which the
composition of the present invention can be formulated for delivery
and use as a pesticide composition, including solutions,
suspensions, emulsions, wettable powders and water dispersible
granules, emulsifiable concentrates, granules, dusts, baits, and
the like. Typically, formulations are applied following dilution of
the concentrated formulation with water as aqueous solutions,
suspensions or emulsions, or combinations thereof. Such solutions,
suspensions or emulsions are produced from water-soluble,
water-suspended or water-suspendable, water-emulsified or
water-emulsifiable formulations or combinations thereof which are
solids, including and usually known as wettable powders or water
dispersible granules; or liquids including and usually known as
emulsifiable concentrates, aqueous suspensions or suspension
concentrates, and aqueous emulsions or emulsions in water, or
mixtures thereof such as suspension-emulsions. As will be readily
appreciated, any material to which this composition can be added
may be used, provided they yield the desired utility without
significant interference with the desired activity of the
pesticidally active ingredients as pesticidal agents and improved
residual lifetime or decreased effective concentration is
achieved.
[0040] Wettable powders, which may be compacted to form water
dispersible granules, comprise an intimate mixture of one or more
of the pesticidally active ingredients, an inert carrier and
surfactants. The concentration of the pesticidally active
ingredient in the wettable powder is usually from about 10 percent
to about 90 percent by weight based on the total weight of the
wettable powder, more preferably about 25 weight percent to about
75 weight percent. In the preparation of wettable powder
formulations, the pesticidally active ingredients can be compounded
with any finely divided solid, such as prophyllite, talc, chalk,
gypsum, Fuller's earth, bentonite, attapulgite, starch, casein,
gluten, montmorillonite clays, diatomaceous earths, purified
silicates or the like. In such operations, the finely divided
carrier and surfactants are typically blended with the compound(s)
and milled
[0041] Emulsifiable concentrates of the pesticidally active
ingredient comprise a convenient concentration, such as from about
10 weight percent to about 50 weight percent of the pesticidally
active ingredient, in a suitable liquid, based on the total weight
of the concentrate. The pesticidally active ingredients are
dissolved in an inert carrier, which is either a water miscible
solvent or a mixture of water-immiscible organic solvents, and
emulsifiers. The concentrates may be diluted with water and oil to
form spray mixtures in the form of oil-in-water emulsions. Useful
organic solvents include aromatics, especially the high-boiling
naphthalenic and olefinic portions of petroleum such as heavy
aromatic naphtha. Other organic solvents may also be used, such as,
for example, terpenic solvents, including rosin derivatives,
aliphatic ketones, such as cyclohexanone, and complex alcohols,
such as 2-ethoxyethanol.
[0042] Emulsifiers which can be advantageously employed herein can
be readily determined by those skilled in the art and include
various nonionic, anionic, cationic and amphoteric emulsifiers, or
a blend of two or more emulsifiers. Examples of nonionic
emulsifiers useful in preparing the emulsifiable concentrates
include the polyalkylene glycol ethers and condensation products of
alkyl and aryl phenols, aliphatic alcohols, aliphatic amines or
fatty acids with ethylene oxide, propylene oxides such as the
ethoxylated alkyl phenols and carboxylic esters esterified with the
polyol or polyoxyalkylene. Cationic emulsifiers include quaternary
ammonium compounds and fatty amine salts. Anionic emul-sifiers
include the oil-soluble salts (e.g., calcium) of alkylaryl sulfonic
acids, oil-soluble salts of sulfated polyglycol ethers and
appropriate salts of phosphated polyglycol ether.
[0043] Representative organic liquids which can be employed in
preparing emulsifiable concentrates are the aromatic liquids such
as xylene, propyl benzene fractions; or mixed naphthalene
fractions, mineral oils, substituted aromatic organic liquids such
as dioctyl phthalate; kerosene; dialkyl amides of various fatty
acids, particularly the dim-ethyl amides; and glycol ethers such as
the n-butyl ether, ethyl ether or methyl ether of diethylene
glycol, and the methyl ether of triethylene glycol and the like.
Mixtures of two or more organic liquids may also be employed in the
preparation of the emulsifiable concentrate. Surface-active
emulsifying agents are typically employed in liquid formulations
and in an amount of from 0.1 to 20 percent by weight based on the
combined weight of the emulsifying agents. The formulations can
also contain other compatible additives, for example, plant growth
regulators and other biologically active compounds used in
agriculture.
[0044] Aqueous suspensions comprise suspensions of one or more
water-insoluble pesticidally active ingredients dispersed in an
aqueous vehicle at a concentration in the range from about 5 to
about 50 weight percent, based on the total weight of the aqueous
suspension. Suspensions are prepared by finely grinding one or more
of the pesticidally active ingredients, and vigorously mixing the
ground material into a vehicle comprised of water and surfactants
chosen from the same types discussed above. Other components, such
as inor-ganic salts and synthetic or natural gums, may also be
added to increase the density and viscosity of the aqueous vehicle.
It is often most effective to grind and mix at the same time by
preparing the aqueous mixture and homogenizing it in an implement
such as a sand mill, ball mill, or piston-type homogenizer.
[0045] 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.
[0046] The compositions of the present invention can also be
granular formulations, which are particularly useful for
applications to the soil. Granular formulations usually contain
from about 0.5 to about 10 weight percent, based on the total
weight of the granular formulation of the pesticidally active
ingredient(s), dispersed in an inert carrier which consists
entirely or in large part of coarsely divided inert material such
as attapulgite, bentonite, diatomite, clay or a similar inexpensive
substance. Such formulations are usually prepared by dissolving the
pesticidally active ingredients in a suitable solvent and applying
it to a granular carrier which has been preformed to the
appropriate particle size, in the range of from about 0.5 to about
3 mm A suitable solvent is a solvent in which the compound is
substantially or completely soluble. Such formulations may also be
prepared by making a dough or paste of the carrier and the compound
and solvent, and crushing and drying to obtain the desired granular
particle.
[0047] Dusts can be prepared by intimately mixing one or more of
the pesticidally active ingredients in powdered form with a
suitable dusty agricultural carrier, such as, for example, kaolin
clay, ground volcanic rock, and the like. Dusts can suitably
contain from about 1 to about 10 weight percent of the compounds,
based on the total weight of the dust.
[0048] The formulations may additionally contain adjuvant
surfactants to enhance deposition, wetting and penetration of the
pesticidally active ingredients onto the target site such as a crop
or organism. These adjuvant surfactants may optionally be employed
as a component of the formulation or as a tank mix. The amount of
adjuvant surfactant will typically vary from 0.01 to 1.0 percent by
volume, based on a spray-volume of water, preferably 0.05 to 0.5
volume percent. Suitable adjuvant surfactants include, but are not
limited to ethoxylated nonyl phenols, ethoxylated synthetic or
natural alcohols, salts of the esters of sulfosuccinic acids,
ethoxylated organosilicones, ethoxylated fatty amines and blends of
surfactants with mineral or vegetable oils.
[0049] The formulations may optionally include combinations that
contain other pesticidal compounds. Such additional pesticidal
compounds may be fungicides, insecticides, nematocides, miticides,
arthropodicides, bactericides or combinations thereof that are
compatible with the mixtures of the present invention in the medium
selected for application, and not antagonistic to the activity of
the present mixtures. Accordingly, in such embodiments, the other
pesticidal compound is employed as a supplemental toxicant for the
same or for a different pesticidal use. The mixtures of the present
invention, and the pesticidal compound in the combination can
generally be present in a weight ratio of from 1:100 to 100:1.
[0050] For pharmaceutical use, the mixtures described herein may be
taken up in pharmaceutically acceptable carriers, such as, for
example, solutions, suspensions, tablets, capsules, ointments,
elixirs and injectable compositions. Pharmaceutical preparations
may contain from 0.1% to 99% by weight of active ingredient.
Preparations which are in single dose form, "unit dosage form",
preferably contain from 20% to 90% active ingredient, and
preparations which are not in single dose form preferably contain
from 5% to 20% active ingredient. As used herein, the term "active
ingredient" refers to mixtures described herein, salts thereof,
hydrates, and mixtures with other pharmaceutically active
compounds. Dosage unit forms such as, for example, tablets or
capsules, typically contain from about 0.05 to about 1.0 g of
active ingredient.
[0051] The mixtures of the present invention can also be combined
with other agricultural fungicides to form fungicidal mixtures and
synergistic mixtures thereof. The fungicidal mixtures of the
present invention are often applied in conjunction with one or more
other fungicides to control a wider variety of undesirable
diseases. When used in conjunction with other fungicide(s), the
presently claimed mixtures can be formulated with the other
fungicide(s), tank mixed with the other fungicide(s) or applied
sequentially with the other fungicide(s). Such other fungicides
include amisulbrom 2-(thiocyanatomethylthio)-benzothiazole,
2-phenylphenol, 8-hydroxyquinoline sulfate, antimycin, Ampelomyces,
quisqualis, azaconazole, azoxystrobin, Bacillus subtilis,
benalaxyl, benomyl, benthiavalicarb-isopropyl,
benzylaminobenzene-sulfonate (BABS) salt, bicarbonates, biphenyl,
bismerthiazol, bitertanol, bixafen, blasticidin-S, borax, boscalid,
bromuconazole, bupirimate, BYF 1047, calcium polysulfide, captafol,
captan, carbendazim, carboxin, carpropamid, carvone, chloroneb,
chlorothalonil, chlozolinate, Coniothyrium minitans, cyazofamid,
cyflufenamid, cymoxanil, cyproconazole, cyprodinil, coumarin,
dazomet, debacarb, diammonium ethylenebis-(dithiocarbamate),
dichlofluanid, dichlorophen, diclocymet, diclomezine, dichloran,
diethofencarb, difenoconazole, difenzoquat ion, diflumetorim,
dimethomorph, dimoxystrobin, diniconazole, diniconazole-M,
dinobuton, dinocap, diphenylamine, dithianon, dodemorph, dodemorph
acetate, dodine, dodine free base, edifenphos, enestrobin,
epoxiconazole, ethaboxam, ethoxyquin, etridiazole, famoxadone,
fenamidone, fenarimol, fenbuconazole, fenfuram, fenhexamid,
fenoxanil, fenpiclonil, fenpropidin, fenpropimorph, fentin, fentin
acetate, fentin hydroxide, ferbam, ferimzone, fluazinam,
fludioxonil, flumorph, fluopicolide, fluopyram, fluoroimide,
fluoxastrobin, fluquinconazole, flusilazole, flusulfamide,
flutolanil, flutriafol, folpet, formaldehyde, fosetyl,
fosetyl-aluminium, fuberidazole, furalaxyl, furametpyr, guazatine,
guazatine acetates, GY-81, hexachlorobenzene, hexaconazole,
hymexazol, imazalil, imazalil sulfate, imibenconazole,
iminoctadine, iminoctadine triacetate, iminoctadine
tris(albesilate), ipconazole, iprobenfos, iprodione, iprovalicarb,
isoprothiolane, isopyrazam, isotianil, kasugamycin, kasugamycin
hydrochloride hydrate, kresoxim-methyl, mancopper, mancozeb,
mandipropamid, maneb, mepanipyrim, mepronil, meptyldinocap,
mercuric chloride, mercuric oxide, mercurous chloride, metalaxyl,
mefenoxam, metalaxyl-M, metam, metam-ammonium, metam-potassium,
metam-sodium, metconazole, methasulfocarb, methyl iodide, methyl
isothiocyanate, metiram, metominostrobin, metrafenone, mildiomycin,
myclobutanil, nabam, nitrothal-isopropyl, nuarimol, octhilinone,
ofurace, oleic acid (fatty acids), orysastrobin, oxadixyl,
oxine-copper, oxpoconazole fumarate, oxycarboxin, pefurazoate,
penconazole, pencycuron, pentachlorophenol, pentachlorophenyl
laurate, penthiopyrad, phenylmercury acetate, phosphonic acid,
phthalide, picoxystrobin, polyoxin B, polyoxins, polyoxorim,
potas-sium bicarbonate, potassium hydroxyquinoline sulfate,
probenazole, prochloraz, procymidone, propamocarb, propamocarb
hydrochloride, propiconazole, propineb, pro-quinazid,
prothioconazole, pyraclostrobin, pyrazophos, pyribencarb,
pyributicarb, pyrifenox, pyrimethanil, pyroquilon, quinoclamine,
quinoxyfen, quintozene, Reynoutria sachalinensis extract,
silthiofam, simeconazole, sodium 2-phenylphenoxide, sodium
bicarbonate, sodium pentachlorophenoxide, spiroxamine, sulfur,
SYP-Z071, SYP-048, SYP-Z048, tar oils, tebuconazole, tecnazene,
tetraconazole, thiabendazole, thifluzamide, thiophanate-methyl,
thiram, tiadinil, tolclofos-methyl, tolylfluanid, triadimefon,
triadimenol, triazolopyrimidine, triazoxide, tricyclazole,
tridemorph, trifloxystrobin, triflumizole, triforine,
triticonazole, validamycin, vinclozolin, zineb, ziram, zoxamide,
Candida oleophila, Fusarium cocysporum, Gliocladium spp.,
Phlebiopsis gigantean, Streptomyces griseoviridis, Trichoderma
spp., (RS)--N-(3,5-dichlorophenyl)-2-(methoxymethyl)-succinimide,
1,2-dichloropropane, 1,3-dichloro-1,1,3,3-tetrafluoroacetone
hydrate, 1-chloro-2,4-dinitronaphthalene, 1-chloro-2-nitropropane,
2-(2-heptadecyl-2-imidazolin-1-yl)ethanol,
2,3-dihydro-5-phenyl-1,4-dithi-ine 1,1,4,4-tetraoxide,
2-methoxyethylmercury acetate, 2-methoxyethylmercury chloride,
2-methoxyethylmercury silicate,
3-(4-chloro-phenyl)-5-methylrhodanine, 4-(2-nitroprop-1-enyl)phenyl
thiocyanateme, ampropylfos, anilazine, azithiram, barium
polysulfide, Bayer 32394, benodanil, benquinox, bentaluron,
benzamacril; benzamacril-isobutyl, benzamorf, binapacryl, his
(methylmercury) sulfate, his (tributyltin) oxide, buthiobate,
cadmium calcium copper zinc chromate sulfate, carbamorph, CECA,
chlobenthiazone, chloraniformethan, chlorfenazole, chlorquinox,
climbazole, cyclafuramid, cypendazole, cyprofuram, decafentin,
dichlone, dichlozo-line, diclobutrazol, dimethirimol, dinocton,
dinosulfon, dinoterbon, dipyrithione, ditalimfos, dodicin,
drazoxolon, EBP, ESBP, etaconazole, etem, ethirim, fenaminosulf,
fenapanil, fenitropan, 5-fluorocytosine and profungicides thereof,
fluotrimazole, furcarbanil, furconazole, furconazole-cis,
furmecyclox, furophanate, glyodine, griseofulvin, halacrinate,
Hercules 3944, hexylthiofos, ICIA0858, isopamphos, isovaledione,
mebenil, mecarbinzid, metazoxolon, methfuroxam, methylmercury
dicyandiamide, metsulfovax, milneb, mucochloric anhydride,
myclozolin, N-3,5-dichlorophenyl-succinimide,
N-3-nitrophenyl-itaconimide, natamycin,
N-ethylmercurio-4-toluenesulfonanilide, nickel
bis(dimethyldithio-carbamate), OCH, phenylmercury
dimethyldithiocarbamate, phenylmercury nitrate, phos-diphen,
picolinamide UK-2A and derivatives thereof, prothiocarb;
prothiocarb hydrochloride, pyracar-bolid, pyridinitril,
pyroxychlor, pyroxyfur, quinacetol; quinacetol sulfate, quinazamid,
quinconazole, rabenzazole, salicylanilide, SSF-109, sultropen,
tecoram, thiadifluor, thi-cyofen, thiochlorfenphim, thiophanate,
thioquinox, tioxymid, triamiphos, triarimol, triazbutil,
trichlamide, urbacid, XRD-563, and zarilamide, 1K-1140, propargyl
amides and any combinations thereof.
[0052] The mixtures of the present invention can also be combined
with other antifungal compounds used to control infections in
mammals to form fungicidal mixtures and synergistic mixtures
thereof. The fungicidal mixtures of the present invention can be
applied in conjunction with one or more other antifungal compounds
or their pharmaceutically acceptable salts to control a wider
variety of undesirable diseases. When used in conjunction with
other antifungal compounds, the presently claimed mixtures can be
formulated with the other antifungal compound(s), coadministered
with the other antifungal compound(s) or applied sequentially with
the other antifungal compound(s). Typical antifungal compounds
include, but are not limited to compounds selected from the group
consisting of an azole such as fluconazole, voriconazole,
itraconazole, ketoconazole, and miconazole, a polyene such as
amphotericin B, nystatin or liposomal and lipid forms thereof such
as Abelcet, AmBisome and Amphocil, a purine nucleotide inhibitor
such as 5-fluorocytosine, a polyoxin such as nikkomycin, and
pneumocandin or echinocandin derivatives such as caspofungin and
micofungin.
[0053] Additionally, the mixtures of the present invention can be
combined with other pesticides, including insecticides,
nematocides, miticides, arthropodicides, bactericides or
combinations thereof that are compatible with the mixtures of the
present invention in the medium selected for application, and not
antagonistic to the activity of the present mixtures to form
pesticidal mixtures and synergistic mixtures thereof. The
fungicidal mixtures of the present invention are often applied in
conjunction with one or more other pesticides to control a wider
variety of undesirable pests. When used in conjunction with other
pesticides, the presently claimed mixtures can be formulated with
the other pesticide(s), tank mixed with the other pesticide(s) or
applied sequentially with the other pesticide(s). Typical
insecticides include, but are not limited to: antibiotic
insecticides such as allosamidin and thuringiensin; macrocyclic
lactone insecticides such as spinosad; avermectin insecticides such
as abamectin, doramectin, emamectin, eprinomectin, ivermectin and
selamectin; milbemycin insecticides such as lepimectin,
milbemectin, milbemycin oxime and moxidectin; arsenical
insecticides such as calcium arsenate, copper acetoarsenite, copper
arsenate, lead arsenate, potassium arsenite and sodium arsenite;
botanical insecticides such as anabasine, azadirachtin, d-limonene,
nicotine, pyrethrins, cinerins, cinerin I, cinerin II, jasmolin I,
jasmolin II, pyrethrin I, pyrethrin II, quassia, rotenone, ryania
and sabadilla; carbamate insecticides such as bendiocarb and
carbaryl; benzofuranyl methylcarbamate insecticides such as
benfuracarb, carbofuran, carbosulfan, decarbofuran and
furathiocarb; dimethylcarbamate insecticides dimitan, dimetilan,
hyquincarb and pirimicarb; oxime carbamate insecticides such as
alanycarb, aldicarb, aldoxycarb, butocarboxim, butoxy-carboxim,
methomyl, nitrilacarb, oxamyl, tazimcarb, thiocarboxime, thiodicarb
and thiofanox; phenyl methylcarbamate insecticides such as
allyxycarb, aminocarb, bufencarb, butacarb, carbanolate,
cloethocarb, dicresyl, dioxacarb, EMPC, ethiofencarb, fenethacarb,
fenobucarb, isoprocarb, methiocarb, metolcarb, mexacarbate,
promacyl, promecarb, propoxur, trimethacarb, XMC and xylylcarb;
dinitrophenol insecticides such as dinex, dinoprop, dinosam and
DNOC; fluorine insecticides such as barium hexafluorosilicate,
cryolite, sodium fluoride, sodium hexafluorosilicate and
sulfluramid; formamidine insecticides such as amitraz,
chlordimeform, formetanate and formparanate; fumigant insecticides
such as acrylonitrile, carbon disulfide, carbon tetrachloride,
chloroform, chloropicrin, para-dichlorobenzene,
1,2-dichloropropane, ethyl formate, ethylene dibromide, ethylene
dichloride, ethylene oxide, hydrogen cyanide, iodomethane, methyl
bromide, methylchloroform, methylene chloride, naphthalene,
phosphine, sulfuryl fluoride and tetrachloroethane; inorganic
insecticides such as borax, calcium polysulfide, copper oleate,
mercurous chloride, potassium thiocyanate and sodium thiocyanate;
chitin synthesis inhibitors such as bistrifluoron, buprofezin,
chlorfluazuron, cyromazine, diflubenzuron, flucycloxuron,
flufenoxuron, hexaflumuron, lufenuron, novaluron, noviflumuron,
penfluoron, teflubenzuron and triflumuron; juvenile hormone mimics
such as epofenonane, fenoxycarb, hydroprene, kinoprene, methoprene,
pyriproxyfen and triprene; juvenile hormones such as juvenile
hormone I, juvenile hormone II and juvenile hormone III; moulting
hormone agonists such as chromafenozide, halofenozide,
methoxyfenozide and tebufenozide; moulting hormones such as
.alpha.-ecdysone and ecdysterone; moulting inhibitors such as
diofenolan; precocenes such as precocene I, precocene II and
precocene III; unclassified insect growth regulators such as
dicyclanil; nereistoxin analogue insecticides such as bensultap,
cartap, thiocyclam and thiosultap; nicotinoid insecticides such as
flonicamid; nitroguanidine insecticides such as clothianidin,
dinotefuran, imidacloprid and thiamethoxam; nitromethylene
insecticides such as nitenpyram and nithiazine; pyridylmethyl-amine
insecticides such as acetamiprid, imidacloprid, nitenpyram and
thiacloprid; organochlorine insecticides such as bromo-DDT,
camphechlor, DDT, pp'-DDT, ethyl-DDD, HCH, gamma-HCH, lindane,
methoxychlor, pentachlorophenol and TDE; cyclodiene insecticides
such as aldrin, bromocyclen, chlorbicyclen, chlordane, chlordecone,
dieldrin, dilor, endosulfan, endrin, HEOD, heptachlor, HHDN,
isobenzan, isodrin, kelevan and mirex; organophosphate insecticides
such as bromfenvinfos, chlorfenvinphos, crotoxyphos, dichlorvos,
dicrotophos, dimethylvinphos, fospirate, heptenophos,
methocrotophos, mevinphos, monocrotophos, naled, naftalofos,
phosphamidon, propaphos, TEPP and tetrachlorvinphos;
organothiophosphate insecticides such as dioxabenzofos, fosmethilan
and phenthoate; aliphatic organothiophosphate insecticides such as
acethion, amiton, cadusafos, chlorethoxyfos, chlormephos,
demephion, demephion-O, demephion-S, demeton, demeton-O, demeton-S,
demeton-methyl, demeton-O-methyl, demeton-S-methyl,
demeton-S-methylsulphon, disulfoton, ethion, ethoprophos, IPSP,
isothioate, malathion, methacrifos, oxydemeton-methyl, oxydeprofos,
oxydisulfoton, phorate, sulfotep, terbufos and thiometon; aliphatic
amide organothiophosphate insecticides such as amidithion,
cyanthoate, dimethoate, ethoate-methyl, formothion, mecarbam,
omethoate, prothoate, sophamide and vamidothion; oxime
organothiophosphate insecticides such as chlorphoxim, phoxim and
phoxim-methyl; heterocyclic organothiophosphate insecticides such
as azamethiphos, coumaphos, coumithoate, dioxathion, endothion,
menazon, morphothion, phosalone, pyraclofos, pyridaphenthion and
quinothion; benzothiopyran organothiophosphate insecticides such as
dithicrofos and thicrofos; benzotriazine organothiophosphate
insecticides such as azinphos-ethyl and azinphos-methyl; isoindole
organothiophosphate insecticides such as dialifos and phosmet;
isoxazole organothiophosphate insecticides such as isoxathion and
zolaprofos; pyrazolopyrimidine organothiophosphate insecticides
such as chlorprazophos and pyrazophos; pyridine organothiophosphate
insecticides such as chlorpyrifos and chlorpyrifos-methyl;
pyrimidine organothiophosphate insecticides such as butathiofos,
diazinon, etrimfos, lirimfos, pirimiphos-ethyl, pirimiphos-methyl,
primidophos, pyrimitate and tebupirimfos; quinoxaline
organothiophosphate insecticides such as quinalphos and
quinalphos-methyl; thiadiazole organothiophosphate insecticides
such as athidathion, lythidathion, methidathion and prothidathion;
triazole organothiophosphate insecticides such as isazofos and
triazophos; phenyl organothiophosphate insecticides such as
azothoate, bromophos, bromophos-ethyl, carbophenothion,
chlorthiophos, cyanophos, cythioate, dicapthon, dichlofenthion,
etaphos, famphur, fenchlorphos, fenitrothion fensulfothion,
fenthion, fenthion-ethyl, heterophos, jodfenphos, mesulfenfos,
parathion, parathion-methyl, phenkapton, phosnichlor, profenofos,
prothiofos, sulprofos, temephos, trichlormetaphos-3 and trifenofos;
phosphonate insecticides such as butonate and trichlorfon;
phosphonothioate insecticides such as mecarphon; phenyl
ethylphosphonothioate insecticides such as fonofos and
trichloronat; phenyl phenylphosphonothioate insecticides such as
cyanofenphos, EPN and leptophos; phosphoramidate insecticides such
as crufomate, fenamiphos, fosthietan, mephosfolan, phosfolan and
pirimetaphos; phosphoramidothioate insecticides such as acephate,
isocarbophos, isofenphos, methamidophos and propetamphos;
phosphorodiamide insecticides such as dimefox, mazidox, mipafox and
schradan; oxadiazine insecticides such as indoxacarb; phthalimide
insecticides such as dialifos, phosmet and tetramethrin; pyrazole
insecticides such as acetoprole, cyenopyrafen, ethiprole, fipronil,
pyrafluprole, pyriprole, tebufenpyrad, tolfenpyrad and vaniliprole;
pyrethroid ester insecticides such as acrinathrin, allethrin,
bioallethrin, barthrin, bifenthrin, bioethanomethrin, cyclethrin,
cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin,
gamma-cyhalothrin, lambda-cyhalothrin, cypermethrin,
alpha-cypermethrin, beta-cypermethrin, theta-cypermethrin,
zeta-cypermethrin, cyphenothrin, deltamethrin, dimefluthrin,
dimethrin, empenthrin, fenfluthrin, fenpirithrin, fenpropathrin,
fenvalerate, esfenvalerate, flucythrinate, fluvalinate,
taufluvalinate, furethrin, imiprothrin, metofluthrin, permethrin,
biopermethrin, transpermethrin, phenothrin, prallethrin,
profluthrin, pyresmethrin, resmethrin, bioresmethrin, cismethrin,
tefluthrin, terallethrin, tetramethrin, tralomethrin and
transfluthrin; pyrethroid ether insecticides such as etofenprox,
flufenprox, halfenprox, protrifenbute and silafluofen;
pyrimidinamine insecticides such as flufenerim and pyrimidifen;
pyrrole insecticides such as chlorfenapyr; tetronic acid
insecticides such as spiromesifen; thiourea insecticides such as
diafenthiuron; urea insecticides such as flucofuron and sulcofuron;
and unclassified insecticides such as closantel, crotamiton, EXD,
fenazaflor, fenoxacrim, flubendiamide, hydramethylnon,
isoprothiolane, malonoben, metaflumizone, metoxadiazone,
nifluridide, pyridaben, pyridalyl, rafoxanide, triarathene,
triazamate, meptyldinocap, pyribencarb and any combinations
thereof.
[0054] The mixtures have broad ranges of efficacy as fungicides.
The exact amounts of hydrazones and copper-containing materials to
be applied is dependent not only on the specific materials being
applied and relative amounts of hydrazone and copper in the
mixtures, but also on the, the particular action desired, the
fungal species to be controlled, and the stage of growth thereof,
as well as the part of the plant or other product to be contacted
with the mixture. Thus, all the mixtures, and formulations
containing the same, may not be equally effective at similar
concentrations or against the same fungal species.
[0055] The mixtures are effective in use with plants in a
disease-inhibiting and phytologically acceptable amount. The term
"disease inhibiting and phytologically acceptable amount" refers to
an amount of a mixture that kills or inhibits the plant disease for
which control is desired, but is not significantly toxic to the
plant. The exact amount of a mixture required varies with the
fungal disease to be controlled, the type of formulation employed,
the method of application, the particular plant species, climate
conditions, and the like. The dilution and rate of application will
depend upon the type of equipment employed, the method and
frequency of application desired and diseases to be controlled. For
foliar control of fungal infections on plants, the amount of copper
used in mixture with hydrazone may range from 0.001 to 5 kg/ha, and
preferably from 0.05 to 1 kg/ha. The amount of hydrazone used in
mixture with copper may range from 0.001 to 5 kg/ha, and preferably
from 0.05 to 1 kg/ha. The molar ratio of copper to hydrazone may
range from 0.1:1 to 10, 000:1, preferably from 0.5:1 to 1000:1 and
more preferably from 1:1 to 20:1.
[0056] 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.
[0057] 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.
[0058] 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.
[0059] Methods for preparation of salicylaldehyde benzoylhydrazones
and 2-hydroxyphenylketone benzoylhydrazones from salicylaldehydes
or 2-hydroxyphenyl ketones and a benzoic hydrazide are well known
in the literature. In addition the preparation of metal complexes
of these materials is also well known (see for example Journal of
Inorganic Biochemistry 1999, 77, 125-133, which is expressly
incorporated by reference herein). Methods of preparation of
precursor hydrazides are also well known. Hydrazides can be
prepared, for example, from carboxylic acids such as in Maxwell et
al., J. Med. Chem. 1984, 27, 1565-1570, and from carboxylic esters
such as in Dydio et al., J. Org. Chem. 2009, 74, 1525-1530, which
are expressly incorporated by reference herein. Thus, the synthesis
of any benzoylhydrazone of the present invention and its metal
complex(es) is fully described where the starting aldehyde or
ketone, and the starting benzoic hydrazide, acid, or ester are
described. The hydrazones disclosed may also be in the form of
pesticidally acceptable salts and hydrates. Examples 23, 24, and 25
below provide typical methods for the preparation of such
benzoylhydrazones. Example 31 below provides a general method for
the preparation of their metal complexes.
Example 1
Preparation of
1-(3,5-dichloro-2-hydroxyphenyl)-2,2,2-trifluoroethanone
##STR00002##
[0061] 2,4-Dichloro-6-iodophenol (2.0 grams (g), 6.9 millimoles
(mmol)) was dissolved in dry tetrahydrofuran (THF; 20 milliliters
(mL)), cooled to -30 to -40.degree. C., treated in portions with
isopropyl magnesium chloride-lithium chloride complex (1.3 M in
THF; 7.3 mmol) and stirred for 45 minutes (min) as the temperature
was allowed to rise to 0.degree. C. The mixture was cooled to
-30.degree. C., treated with 8 mL (10 mmol) of the Grignard reagent
and stirred for 30 min at -30.degree. C. Ethyl trifluoroacetate
(2.4 mL, 2.8 g, 20 mmol) was added, and the mixture was stirred for
15 min at -30.degree. C., warmed to 25.degree. C. and stirred for 2
hours (h). The reaction was quenched by addition of saturated
(satd) ammonium chloride (NH.sub.4C1; 10 mL), diluted with ethyl
acetate (EtOAc; 50 mL) and washed with 1 M hydrochloric acid (HCl;
20 mL), satd sodium chloride (NaCl; 10 mL), dried over sodium
sulfate (Na.sub.2SO.sub.4) and evaporated. The residue was purified
by silica gel chromatography with 0-20% EtOAc/hexane to give the
purified ketone (1.2 g): mp 50-52.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.61 (d, J=2.4 Hz, 1H), 7.34 (d, J=2.4 Hz, 1H),
5.92 (s, 1H); EIMS m/z 258.
Example 2
Preparation of
cyclopropyl-(3,5-dichloro-2-hydroxyphenyl)-methanone
##STR00003##
[0063] N-(3,5-Dichloro-2-hydroxybenzoyl)benzotriazole (prepared
according to Katritizky et al., Synthesis 2007, 20, 3141-3146,
which is expressly incorporated by reference herein; 2.0 g, 6.5
mmol) was stirred in dry THF (25 mL), cooled to -30.degree. C.,
treated in portions with cyclopropylmagnesium bromide (0.5 M in
THF; 28 mL, 14 mmol) and stirred at -30.degree. C. for 30 min. The
cooling bath was removed and the mixture was allowed to warm to
25.degree. C. and stir for 3 h. The reaction was quenched by
addition of 10 mL satd NH.sub.4Cl, and shaken with EtOAc (50 mL)
plus 20% citric acid solution (30 mL). The organic phase was washed
with satd NaCl (20 mL), 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 ketone (450 mg): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 13.03 (s, 1H), 7.87 (d, J=2.5 Hz, 1H),
7.57 (d, J=2.5 Hz, 1H), 2.70-2.54 (m, 1H), 1.41-1.32 (m, 2H),
1.24-1.15 (m, 2H); EIMS m/z 230.
Example 3
Preparation of
1-(3,5-dichloro-2-hydroxyphenyl)-2-methylpropan-1-one
##STR00004##
[0065] Methyl-3,5-dichlorosalicylate (prepared according to Ahmed
et al., Medicinal Chemistry 2008, 4, 298-308, which is expressly
incorporated by reference herein; 2.0 g, 9.0 mmol) was dissolved in
dry THF (30 mL), cooled to -40.degree. C. and treated in portions
with isopropyl magnesium chloride, 2.0 M in THF; 10 mL, 20 mmol).
The mixture was stirred at -20 to -40.degree. C. for 45 min, warmed
to 25.degree. C. and stirred for 4 h. The excess reagent was
quenched by addition of satd NH.sub.4Cl (10 mL). The mixture was
diluted with EtOAc (50 mL) and the pH was adjusted to .about.1 by
addition of 1 M HCl. 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) with 70% acetonitrile to give the purified
ketone (1.1 g): mp: 102-104.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.69 (d, J=2.5 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H),
3.54 (dt, J=13.6, 6.8 Hz, 1H), 1.26 (d, J=6.8 Hz, 6H); EIMS m/z
232.
Example 4
Preparation of 2-hydroxy-3,5-bis-trifluoromethylbenzaldehyde
##STR00005##
[0067] 3,5-Bis(trifluoromethyl)anisaldehyde (prepared as in Sui and
Macielag, Synth. Commun. 1997, 27, 3581-3590, which is expressly
incorporated by reference herein; 2.0 g, 7.7 mmol) was dissolved in
dry CH.sub.2Cl.sub.2 (15 mL), cooled to -78.degree. C. and treated
in portions with 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 h, the mixture was cooled to -40.degree. C.,
carefully treated with H.sub.2O (10 mL) and warmed to room
temperature. The separated organic phase was washed with H.sub.2O
(10 mL), satd NaCl solution (5 mL), dried (Na.sub.2SO.sub.4) and
evaporated. The residue was purified by silica gel chromatography
with a 0 to 20% gradient of EtOAc in hexane to give the purified
aldehyde (1.4 g, 70%) as an oil: .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 5
Preparation 5-chloro-2-hydroxy-3-trifluoromethylbenzaldehyde
##STR00006##
[0069] 5-Chloro-2-fluorobenzotrifluoride (1.5 g, 7.5 mmol) was
dissolved in dry THF (10 mL), treated with
tetramethylethylenediamine (TMEDA; 1.6 mL, 1.2 g, 11 mmol), cooled
to -78.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 min, the mixture was treated with
N,N-dimethylformamide (DMF; 770 .mu.L, 730 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
addition of satd NH.sub.4Cl solution then diluted with Et.sub.2O
(30 mL). The separated organic phase was washed with satd NaCl (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 stir 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 6
Preparation of 3-chloro-2-hydroxy-5-trifluoromethylbenzaldehyde
##STR00007##
[0071] 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 org. 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
purified 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 7
Preparation of 3-fluoro-5-formyl-4-hydroxybenzonitrile
##STR00008##
[0073] 4-Cyano-2-fluorophenol (5.0 g, 38 mmol) was dissolved in
acetic acid (50 mL) and treated dropwise with stirring with bromine
(6.4 g, 40 mmol). After 2 h at 25.degree. C., H.sub.2O (100 mL) was
added. The precipitated product was collected by filtration, washed
well with H.sub.2O and then taken up in EtOAc (150 mL). The
solution was washed with H.sub.2O (50 mL), satd NaCl solution (50
dmL), dried (Na.sub.2SO.sub.4) and evaporated. The residue was
crystallized from aqueous ethanol (EtOH) to give the bromophenol
(4.1 g). This material (3.4 g, 16 mmol) was dissolved in dry THF
(100 mL), cooled to -78.degree. C. and treated dropwise with n-BuLi
(2.5 M in hexanes; 16 mL, 39 mmol) over 15 min. After stirring for
90 min at -78.degree. C., DMF (3.5 mL, 3.3 g, 45 mmol) was added
and stirring was continued for 30 min at -78.degree. C. and then
warmed to 25.degree. C. over 2 h. Satd NH.sub.4Cl solution (25 mL)
and Et.sub.2O (100 mL) were added, and the pH was adjusted to 2
with 1 M HCl. The separated organic phase was washed with satd NaCl
solution, dried (Na.sub.2SO.sub.4) and evaporated. The residue was
purified on silica gel chromatography with 10-50% EtOAc/hexane to
give the aldehyde (2.1 g): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 11.48 (s, 1H), 9.96 (d, J=1.7 Hz, 1H), 7.78 (t, J=1.5 Hz,
2H), 7.61 (dd, J=9.8, 1.9 Hz, 2H); EIMS m/z 165.
Example 8
Preparation of 3-chloro-2-hydroxy-6-trifluoromethylbenzaldehyde
##STR00009##
[0075] 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 solution 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 (30 mL). The combined
organic 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 stir 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 9
Preparation of 5-chloro-2-hydroxy-4-trifluoromethylbenzaldehyde
##STR00010##
[0077] 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
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.sup.2O (30
mL) and Et.sub.2O (75 mL). The organic phase was washed with satd
NaCl (20 mL), dried (Na.sub.2SO.sub.4) and evaporated. The residue
was purified by RP-HPLC to give the product (300 mg, .about.70%
purity), which was used without further purification: EIMS m/z
224.
Example 10
Preparation of 2-hydroxy-4,6-bis-trifluoromethyl-benzaldehyde
##STR00011##
[0079] 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). The mixture was 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 11
Preparation of 1-(2-hydroxy-3-methoxyphenyl)-ethanone
##STR00012##
[0081] 1-(2-Hydroxy-3-methoxyphenyl)-ethanone was prepared from
commercially available starting materials as described in US
038048, which is expressly incorporated by reference herein.
Example 12
Preparation of 1-(2-hydroxy-5-trifluoromethylphenyl)-ethanone
##STR00013##
[0083] 1-(2-Hydroxy-5-trifluoromethylphenyl)-ethanone was prepared
from commercially available starting materials as described in EP
129812, which is expressly incorporated by reference herein.
Example 13
Preparation of 3,4-dichloro-2-hydroxybenzaldehyde
##STR00014##
[0085] 3,4-Dichloro-2-hydroxybenzaldehyde was prepared from
commercially available starting materials as described in Gu et
al., J. Med. Chem. 2000, 43, 4868-4876, which is expressly
incorporated by reference herein.
Example 14
Preparation of 3-bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde
##STR00015##
[0087] 3-Bromo-2-hydroxy-5-methylsulfanyl-benzaldehyde was prepared
from commercially available starting materials as described in
Guiles et al., PCT Int. Appl. WO 2008039641 A2, which is expressly
incorporated by reference herein.
Example 15
Preparation of 3-bromo-5-formyl-4-hydroxybenzonitrile
##STR00016##
[0089] 3-Bromo-5-formyl-4-hydroxybenzonitrile was prepared from
commercially available starting materials as described in Sakaitani
et al., PCT Int. Appl. WO 2004037816 A1, which is expressly
incorporated by reference herein.
Example 16
Preparation of 3,6-dichloro-2-hydroxybenzaldehyde
##STR00017##
[0091] 3,6-Dichloro-2-hydroxybenzaldehyde was prepared from
commercially available starting materials as described in Rafferty
et al., PCT Int. Appl. WO 2008121602 A1, which is expressly
incorporated by reference herein.
Example 17
Preparation of 2-hydroxy-4-trifluoromethylbenzaldehyde
##STR00018##
[0093] 2-Hydroxy-4-trifluoromethylbenzaldehyde was prepared from
commercially available starting materials as described in Faeh et
al., U.S. Pat. Appl. Publ. 2007185113 A1, which is expressly
incorporated by reference herein.
Example 18
Preparation of 2-hydroxy-5-trifluoromethylbenzaldehyde
##STR00019##
[0095] 2-Hydroxy-5-trifluoromethylbenzaldehyde was prepared from
commercially available starting materials as described in Bonnert
et al., PCT Int. Appl. WO 2006056752 A1, which is expressly
incorporated by reference herein.
Example 19
Preparation of 2,3-dichloro-6-hydroxybenzaldehyde
##STR00020##
[0097] 2,3-Dichloro-6-hydroxybenzaldehyde was prepared from
commercially available starting materials as described in Stokker
et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly
incorporated by reference herein.
Example 20
Preparation of 2-hydroxy-6-trifluoromethylbenzaldehyde
##STR00021##
[0099] 2-Hydroxy-6-trifluoromethylbenzaldehyde was prepared from
commercially available starting materials as described in Stokker
et al., J. Med. Chem. 1980, 23, 1414-1427, which is expressly
incorporated by reference herein.
Example 21
Preparation of 2-hydroxy-6-methylbenzaldehyde
##STR00022##
[0101] 2-Hydroxy-6-methylbenzaldehyde was prepared from
commercially available starting materials as described in
Hofslokken and Skattebol, Acta Chemica Scandinavica 1999, 53,
258-262, which is expressly incorporated by reference herein.
Example 22
General Preparation of Ketone Compounds
##STR00023##
[0103] Ketone compounds, wherein R2 is either i-propyl or t-butyl,
were prepared from commercially available starting materials as
described in Miller, J. A., J. Org. Chem. 1987, 52, 322-323, which
is expressly incorporated by reference herein.
Example 23
Preparation of 3-trifluoromethoxy-benzoic acid
[1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide
##STR00024##
[0105] A suspension of 3,5-dichloro-2-hydroxy-benzaldehyde (0.200,
1.05 mmol) and 3-trifluoromethoxy-benzoic acid hydrazide (0.243 g,
1.05 mmol) in ethanol (3.3 mL) was heated to 60.degree. C. for 18
hours. The reaction mixture was cooled to room temperature to
precipitate the product. The solid was collected via suction
filtration and rinsed with ethanol to furnish
3-trifluoromethoxy-benzoic acid
[1-(3,5-dichloro-2-hydroxy-phenyl)-methylidene]-hydrazide as an
off-white solid (0.412 g, 99%): mp 180-182.degree. C.; .sup.1H NMR
(400 MHz, DMSO) .delta. 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s, 1H),
8.01 (d, J=7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H); ESIMS m/z
393 ([M+H].sup.+), 391 ([M-H].sup.-).
Example 24
Preparation of benzoic acid
[1-(3-chloro-2-hydroxyphenyl)-ethylidene]-hydrazide
##STR00025##
[0107] A suspension of 1-(3-chloro-2-hydroxyphenyl)-ethanone (0.100
g, 0.586 mmol), benzoic acid hydrazide (0.080 g, 0.586 mmol), and
glacial acetic acid (0.180 mL) in ethanol (1.8 mL) was heated to
60.degree. C. for 18 hours. The reaction mixture was cooled to room
temperature to precipitate the product. The solid was collected via
suction filtration and rinsed with ethanol to furnish benzoic acid
[1-(3-chloro-2-hydroxy-phenyl)-ethylidene]-hydrazide as a yellow
solid (0.100 g, 59%): mp 202-203.degree. C.; .sup.1H NMR (400 MHz,
DMSO) .delta. 14.36 (s, 1H), 11.50 (s, 1H), 7.96 (d, J=7.3 Hz, 2H),
7.68-7.61 (m, 2H), 7.56 (t, J=6.7 Hz, 2H), 7.49 (d, J=7.8 Hz, 1H),
6.92 (t, J=8.0 Hz, 1H), 2.52 (s, 3H); ESIMS m/z 289 ([M+H].sup.+),
287 ([M-H].sup.-.
Example 25
General Method for the Preparation of Benzoic Hydrazones of
alkyl-o-hydroxyphenyl ketones
[0108] The alkyl-o-hydroxyphenyl ketone (0.5 mmol) and benzoic
hydrazide (0.75 mmol) were combined in n-propanol (5 mL) and acetic
acid (4-5 drops) and heated to reflux for 20-24 h. Upon cooling the
mixture was diluted with water (2-5 mL) in portions to induce
precipitation. The solids were collected by filtration, washed with
water and dried under vacuum at 80.degree. C. After analysis by
HPLC-MS most of the hydrazones were found to be sufficiently pure
for testing. The less pure materials were purified by RP-HPLC using
acetonitrile-water mixtures on a 10 mm.times.250 mm YMC-AQ
column.
TABLE-US-00001 TABLE 1 Com- .sup.1H NMR (400 MHz, pound
DMSO-d.sub.6 Num- ESIMS ESIMS unless otherwise ber Structure mp
(.degree. C.) (+) (-) stated), .delta. 1 ##STR00026## 257 255 2
##STR00027## 275 273 3 ##STR00028## 270 268 4 ##STR00029## 291 289
5 ##STR00030## 511 509 6 ##STR00031## 353 351 7 ##STR00032## 387
(+Na) 363 8 ##STR00033## 255 253 9 ##STR00034## 368 366 10
##STR00035## 224-227 318 12.46 (s, 1H), 11.15 (s, 1H), 8.79 (d, J =
1.7 Hz, 1H), 8.68 (s, 1H), 8.51-8.35 (m, 2H), 7.86 (t, J = 8.0 Hz,
1H), 7.71 (d, J = 2.7 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97
(d, J = 8.8 Hz, 1H) 11 ##STR00036## 323 321 12 ##STR00037## 259-262
320 318 12.43 (s, 1H), 11.15 (s, 1H), 8.67 (s, 1H), 8.39 (d, J =
8.8 Hz, 2H), 8.18 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 2.7 Hz, 1H),
7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H) 13
##STR00038## 381 379 14 ##STR00039## 311 309 15 ##STR00040##
197-198 259 257 12.27 (s, 1H), 11.64 (s, 1H), 8.67 (s, 1H),
8.02-7.89 (m, 2H), 7.68-7.52 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H),
7.35-7.24 (m, 1H), 6.99-6.88 (m, 1H) 16 ##STR00041## 309 307 17
##STR00042## 209-213 356 354 14.30 (s, 1H), 11.43 (s, 1H), 7.61
(dd, J = 10.3, 2.5 Hz, 2H), 7.37 (dd, J = 7.7, 4.8 Hz, 2H), 7.16
(t, J = 8.9 Hz, 2H), 3.74 (s, 2H), 2.44 (s, 3H) 18 ##STR00043## 299
297 19 ##STR00044## 433 (+Na) 410 20 ##STR00045## 275 273 21
##STR00046## 285 283 22 ##STR00047## 327 325 23 ##STR00048##
169-172 337 335 12.46 (s, 1H), 12.37 (s, 1H), 8.45 (s, 1H), 7.64
(dd, J = 7.5, 2.5 Hz, 2H), 7.34 (s, 1H), 7.28-7.20 (m, 2H), 2.35
(s, 3H), 2.33 (s, 3H) 24 ##STR00049## 241 239 25 ##STR00050## 271
26 ##STR00051## 381 379 27 ##STR00052## 246-247 337 335 12.51 (s,
1H), 12.34 (s, 1H), 8.45 (s, 1H), 7.64 (dd, J = 9.5, 2.5 Hz, 2H),
7.43 (d, J = 7.6 Hz, 1H), 7.18-7.10 (m, 2H), 2.38 (s, 3H), 2.33 (s,
3H) 28 ##STR00053## 447 (+Na) 423 29 ##STR00054## 283 281 30
##STR00055## 159-160 297 295 13.48 (s, 1H), 11.43 (s, 1H), 7.62 (d,
J = 7.8 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.2 Hz,
1H), 7.17-7.09 (m, 2H), 6.94- 6.86 (m, 2H), 2.94 (q, J = 7.5 Hz,
2H), 2.37 (s, 3H), 2.32 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H) 31
##STR00056## 143-145 373 371 13.43 (s, 1H), 11.42 (s, 1H), 7.65 (d,
J = 7.7 Hz, 1H), 7.33-7.26 (m, 6H), 7.25- 7.17 (m, 1H), 7.16-7.09
(m, 2H), 6.96-6.89 (m, 2H), 3.31-3.22 (m, 2H), 2.88-2.79 (m, 2H),
2.35 (s, 3H), 2.33 (s, 3H) 32 ##STR00057## 192-194 427 425 12.70
(s, 1H), 12.41 (s, 1H), 8.41 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H),
7.79 (d, J = 2.3 Hz, 1H), 7.34 (s, 1H), 7.28-7.19 (m, 2H), 2.35 (s,
3H), 2.33 (s, 3H) 33 ##STR00058## 188-190 283 281 13.37 (s, 1H),
11.38 (s, 1H), 7.62 (dd, J = 7.8, 1.3 Hz, 1H), 7.35-7.27 (m, 2H),
7.26-7.15 (m, 2H), 6.94-6.86 (m, 2H), 2.42 (s, 3H), 2.35 (s, 3H),
2.33 (s, 3H) 34 ##STR00059## 175-176 297 295 13.47 (s, 1H), 11.50
(s, 1H), 7.66-7.59 (m, 1H), 7.33- 7.27 (m, 2H), 7.26-7.16 (m, 2H),
6.95-6.87 (m, 2H), 2.94 (q, J = 7.5 Hz, 2H), 2.33 (s, 6H), 1.11 (t,
J = 7.5 Hz, 3H) 35 ##STR00060## 162-166 373 371 13.41 (s, 1H),
11.46 (s, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 4.4 Hz, 5H),
7.25-7.20 (m, 3H), 7.16 (s, 1H), 6.96-6.89 (m, 2H), 3.32-3.24 (m,
2H), 2.87-2.80 (m, 2H), 2.33 (s, 3H), 2.32 (s, 3H) 36 ##STR00061##
269 267 37 ##STR00062## 300 298 38 ##STR00063## 269 267 39
##STR00064## 283 281 40 ##STR00065## 297 295 41 ##STR00066##
261-263 349 12.58 (s, 1H), 12.46 (s, 1H), 8.57 (s, 1H), 7.90 (d, J
= 8.2 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H),
7.44 (d, J = 8.2 Hz, 2H), 2.98 (hept, J = 6.7 Hz, 1H), 1.24 (d, J =
6.9 Hz, 6H) 42 ##STR00067## 270-272 441 439 12.80 (s, 1H), 12.49
(s, 1H), 8.53 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.83 (dd, J = 7.0,
2.2 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 3.04-2.92 (m, 1H), 1.24 (d,
J = 6.9 Hz, 6H) 43 ##STR00068## 250-252 377 375 12.77, 12.67,
11.99, and 10.28 (4s, 2H), 8.45 and 8.31 (2s, 1H), 7.75-7.30 (m,
5H); Note: rotational isomers 44 ##STR00069## 148-163 361 359 13.37
(s, 1H), 11.41 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.64 (d, J = 7.8
Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.48-7.41 (m, 2H),
7.30 (t, J = 7.4 Hz, 1H), 7.25 (dd, J = 8.1, 1.9 Hz, 1H), 7.21 (t,
J = 7.4 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 6.95- 6.87 (m, 2H), 3.02
(q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.5 Hz, 3H) 45 ##STR00070##
204-208 413 411 13.08, 12.07, 12.00, 10.65 (4s, 2H), 7.70-7.40 (m,
4H), 7.38-7.14 (m, 6H), 7.00-6.65 (m, 2H), 3.29-3.18 (m, 2H), 2.80
(dd, J = 11.0, 5.3 Hz, 2H); Note: rotational isomers 46
##STR00071## 170-171 401 399 12.54 (s, 1H), 12.47 (s, 1H), 8.57 (s,
1H), 7.75 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J
= 2.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.49-7.41 (m, 2H), 7.28 (dd, J =
7.9, 2.2 Hz, 1H), 7.21 (t, J = 7.4 Hz, 1H), 7.12-7.06 (m, 2H) 47
##STR00072## 178-180 347 345 13.31 (s, 1H), 11.37 (s, 1H), 7.73 (d,
J = 7.7 Hz, 1H), 7.67-7.62 (m, 1H), 7.60- 7.53 (m, 2H), 7.48-7.41
(m, 2H), 7.34-7.28 (m, 1H), 7.25 (dd, J = 7.9, 2.1 Hz, 1H), 7.20
(t, J = 7.4 Hz, 1H), 7.11-7.07 (m, 2H), 6.94-6.87 (m, 2H), 2.48 (s,
3H) 48 ##STR00073## 181-184 337 335 13.16, 11.95, 11.87, 10.73 (4s,
2H), 7.68-7.17 (m, 5H), 6.97-6.66 (m, 2H), 2.97-2.85 (m, 2H),
1.16-1.04 (m, 3H); Note: rotational isomers 49 ##STR00074## 173-177
379 377 13.24 (s, 1H), 11.74 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H),
7.62-7.54 (m, 3H), 7.51- 7.47 (m, 1H), 7.35-7.28 (m, 5H), 7.24-7.19
(m, 1H), 6.97-6.89 (m, 2H), 3.30-3.22 (m, 2H), 2.87-2.79 (m, 2H) 50
##STR00075## 303 301 51 ##STR00076## 270 268 52 ##STR00077## 53
##STR00078## 285 283 54 ##STR00079## 289 287 55 ##STR00080## 333
(+Na) 309 56 ##STR00081## 106-111 377 375 12.62 (s, 1H), 12.17 (s,
1H), 8.45 (s, 1H), 7.92-7.88 (m, 1H), 7.83 (d, J = 7.0 Hz, 1H),
7.80-7.75 (m, 2H), 7.70 (d, J = 2.5 Hz, 1H), 7.66 (d, J = 2.5 Hz,
1H) 57 ##STR00082## 220-222 403 401 14.32 (s, 1H), 11.91 (s, 1H),
7.76 (dd, J = 7.8, 1.1 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.65 (d,
J = 2.4 Hz, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 1H), 7.55-7.45 (m, 2H),
2.45 (s, 3H) 58 ##STR00083## 208-210 323 321 13.18, 11.64, 11.59
(3s, 2H), 7.91-7.46 (m, 5H), 7.36- 7.14 (m, 1H), 6.95-6.60 (m, 2H),
2.40. 2.38 (2s, 3H); Note: rotational isomers 59 ##STR00084## 363
(+Na) 339 60 ##STR00085## 345 (+Na) 321 61 ##STR00086## 308 307 62
##STR00087## 273 271 63 ##STR00088## 334 64 ##STR00089## 333 331 65
##STR00090## 289 66 ##STR00091## 269 267 67 ##STR00092## 357 355 68
##STR00093## 343 341 69 ##STR00094## 323 70 ##STR00095## 343 341 71
##STR00096## 389 387 72 ##STR00097## 323 73 ##STR00098## 202-209
339 337 12.67 (s, 1H), 12.35 (s, 1H), 12.31 (s, 1H), 8.65 (s, 1H),
7.80 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.66 (d, J =
2.5 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H),
2.20 (s, 3H) 74 ##STR00099## 407 (+Na) 383 75 ##STR00100## 340 76
##STR00101## 352 77 ##STR00102## 323 321 78 ##STR00103## 377 79
##STR00104## 248-249 377 375 12.57 (s, 1H), 12.29 (s, 1H), 8.57 (s,
1H), 8.00-7.90 (m, 3H), 7.75- 7.61 (m, 2H) 80 ##STR00105## 385 81
##STR00106## 238-240 377 375 12.71 (s, 1H), 12.37 (s, 1H), 8.61 (s,
1H), 8.16 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.68 (dd,
J = 27.3, 2.5 Hz, 2H) 82 ##STR00107## 339 337 83 ##STR00108##
189-191 377 12.62 (s, 1H), 12.11 (s, 1H), 8.45 (s, 1H), 7.82 (t, J
= 1.4 Hz, 1H), 7.71 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H),
7.65 (d, J = 1.4 Hz, 2H) 84 ##STR00109## 408 (+Na) 387 85
##STR00110## 369 367 86 ##STR00111## 207-209 353 351 12.52 (s, 1H),
12.47 (s, 1H), 8.58 (s, 1H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J =
2.5 Hz, 1H), 7.55-7.50 (m, 1H), 7.50-7.43 (m, 2H), 7.19 (dd, J =
7.8, 1.9 Hz, 1H), 4.11 (q, J = 6.9 Hz, 2H), 1.37 (t, J = 7.0 Hz,
3H) 87 ##STR00112## 364 363
88 ##STR00113## 369 367 89 ##STR00114## 325 90 ##STR00115## 399 91
##STR00116## 324 322 92 ##STR00117## 215-217 359 12.70 (s, 1H),
12.60 (s, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.13-8.07 (m, 2H), 8.06-
8.00 (m, 2H), 7.73-7.62 (m, 4H) 93 ##STR00118## 343 94 ##STR00119##
337 95 ##STR00120## 321 96 ##STR00121## 353 97 ##STR00122## 279-281
353 351 12.64 (s, 1H), 12.40 (s, 1H), 8.55 (s, 1H), 7.94 (d, J =
8.7 Hz, 2H), 7.67 (d, J = 2.5 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H),
7.08 (d, J = 8.9 Hz, 2H), 4.13 (q, J = 7.0 Hz, 2H), 1.36 (t, J =
7.0 Hz, 3H) 98 ##STR00123## 191-192 421 12.62, 12.57, 12.1, 10.35
(4s, 2H), 8.45, 8.28 (2s, 1H), 8.5-7.4 (m, 5H); Note: rotational
isomers 99 ##STR00124## 192-194 353 351 12.40 (s, 2H), 8.44 (s,
1H), 7.64 (dd, J = 7.6, 2.5 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H),
7.19-7.03 (m, 2H), 3.84 (s, 3H), 2.20 (s, 3H) 100 ##STR00125##
220-229 393 391 12.61 (s, 1H), 12.44 (s, 1H), 8.58 (s, 1H), 8.09
(d, J = 8.8 Hz, 2H), 7.75-7.49 (m, 4H) 101 ##STR00126## 327 325 102
##STR00127## 207-209 339 337 12.56 (s, 1H), 12.44 (s, 1H), 8.56 (s,
1H), 7.65 (dd, J = 14.1, 2.5 Hz, 2H), 7.57 (s, 2H), 7.27 (s, 1H),
2.36 (s, 6H) 103 ##STR00128## 350 104 ##STR00129## 343 105
##STR00130## 199-201 365 363 12.06 (s, 1H), 11.18 (s, 1H), 8.46 (s,
1H), 7.78 (d, J = 2.4 Hz, 1H), 7.47-7.37 (m, 1H), 7.34-7.21 (m,
1H), 7.07 (dd, J = 27.1, 7.9 Hz, 2H), 6.90 (d, J = 7.6 Hz, 1H),
3.83 (s, 3H), 2.19 (s, 3H) 106 ##STR00131## 210-220 439 437 12.64
(s, 2H), 8.55 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.79-7.69 (m, 1H),
7.58 (d, J = 8.2 Hz, 1H) 107 ##STR00132## 191-195 345 108
##STR00133## 188-189 443 12.65 (s, 1H), 12.43 (s, 1H), 8.40 (s,
1H), 7.81 (dd, J = 19.3, 2.3 Hz, 2H), 7.31 (t, J = 7.9 Hz, 1H),
7.19-7.02 (m, 2H), 3.84 (s, 3H), 2.14 (s, 3H) 109 ##STR00134##
224-230 483 481 12.66 (s, 2H), 8.54 (s, 1H), 8.09 (d, J = 8.8 Hz,
2H), 7.83 (d, J = 16.3 Hz, 2H), 7.58 (d, J = 8.1 Hz, 2H) 110
##STR00135## 209-211 427 111 ##STR00136## 237-239 449 447 12.81 (s,
1H), 12.74 (s, 1H), 8.60 (m, 2H), 8.19-7.97 (m, 4H), 7.85 (s, 2H),
7.72-7.54 (m, 2H) 112 ##STR00137## 430 113 ##STR00138## 475 114
##STR00139## 427 115 ##STR00140## 413 411 116 ##STR00141## 415 117
##STR00142## 267-269 465 12.76-12.63 (m, 1H), 12.59- 12.46 (m, 1H),
8.62-8.46 (m, 1H), 8.05-7.77 (m, 5H) 118 ##STR00143## 476 119
##STR00144## 415 120 ##STR00145## 431 121 ##STR00146## 421 (+Na)
397 122 ##STR00147## 430 123 ##STR00148## 359 357 124 ##STR00149##
413 411 125 ##STR00150## 324 322 126 ##STR00151## 342 340 127
##STR00152## 300 298 128 ##STR00153## 269 267 129 ##STR00154##
207-212 406 404 14.24 (s, 1H), 11.50 (s, 1H), 7.71 (d, J = 8.2 Hz,
2H), 7.62 (dd, J = 11.3, 2.5 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H),
3.88 (s, 2H), 2.45 (s, 3H) 130 ##STR00155## 269 267 131
##STR00156## 283 281 132 ##STR00157## 187-189 397 395 12.63 (s,
1H), 12.43 (s, 1H), 8.41 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.68
(d, J = 2.5 Hz, 1H),7.31 (t, J = 7.9 Hz, 1H), 7.18-7.04 (m, 2H),
3.84 (s, 3H), 2.20 (s, 3H) 133 ##STR00158## 122-128 317 12.06 (s,
1H), 11.17 (s, 1H), 8.46 (s, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.30
(ddd, J = 14.5, 7.7, 2.8 Hz, 2H), 7.11 (d, J = 8.1 Hz, 1H), 7.04
(d, J = 7.4 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 3.83 (s, 3H), 2.19
(s, 3H) 134 ##STR00159## 196-199 303 12.11 (s, 1H), 11.30 (s, 1H),
8.62 (s, 1H), 7.66 (d, J = 2.6 Hz, 1H), 7.56 (s, 2H), 7.32 (dd, J =
8.8, 2.7 Hz, 1H), 7.25 (s, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.34 (s,
6H) 135 ##STR00160## 245-246 357 355 14.38 (s, 1H), 11.68 (s, 1H),
8.02 (s, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.72 (d, J = 9.1 Hz, 1H),
7.70 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.60 (t, J =
7.9 Hz, 1H), 2.53 (s, 3H) 136 ##STR00161## 260-262 355 14.41 (s,
1H), 11.65 (s, 1H), 7.99 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 2.5 Hz,
1H), 7.66-7.60 (m, 3H), 2.68-2.32 (m, 3H) 137 ##STR00162## 226-230
337 14.50 (s, 1H), 11.70 (s, 1H), 7.65 (dd, J = 11.7, 2.4 Hz, 2H),
7.53 (d, J = 7.5 Hz, 1H), 7.45 (t, J = 7.0 Hz, 1H), 7.39-7.29 (m,
2H), 2.45 (s, 3H), 2.41 (s, 3H). 138 ##STR00163## 247-253 403 401
14.38 (s, 1H), 11.68 (s, 1H), 8.14 (s, 1H), 7.95 (d, J = 7.9 Hz,
1H), 7.87-7.83 (m, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4
Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 2.53 (s, 3H) 139 ##STR00164##
401 399 140 ##STR00165## 199-204 338 336 14.27 (s, 1H), 11.44 (s,
1H), 7.61 (dd, J = 10.6, 2.5 Hz, 2H), 7.36-7.32 (m, 4H), 7.30-7.23
(m, 1H), 3.75 (s, 2H), 2.44 (s, 3H) 141 ##STR00166## 307-310 353
14.33 (s, 1H), 11.41 (s, 1H), 7.82-7.78 (m, 1H), 7.70 (d, J = 2.5
Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.62- 7.56 (m, 1H), 7.25 (d, J =
8.2 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H), 3.96 (s, 3H), 2.45 (s, 3H)
142 ##STR00167## 250-253 368 366 14.25 (s, 1H), 11.98 (s, 1H),
8.26-8.20 (m, 1H), 7.94- 7.88 (m, 1H), 7.85-7.78 (m, 2H), 7.67 (q,
J = 2.5 Hz, 2H), 2.42 (s, 3H) 143 ##STR00168## 281 144 ##STR00169##
365 363 145 ##STR00170## 286 284 146 ##STR00171## 515 (+Na) 491 147
##STR00172## 271 269 148 ##STR00173## 317 149 ##STR00174## 271 269
150 ##STR00175## 320 318 151 ##STR00176## 374 (+Na) 351 152
##STR00177## 284 153 ##STR00178## 362 154 ##STR00179## 271 269 155
##STR00180## 316 314 156 ##STR00181## 349 347 157 ##STR00182## 289
287 158 ##STR00183## 335 333 159 ##STR00184## 411 (+Na) 160
##STR00185## 399 397 161 ##STR00186## 387 162 ##STR00187## 367 163
##STR00188## 456 (+Na) 164 ##STR00189## 250-251 423 419 12.75 (s,
1H), 12.60 (s, 1H), 8.57 (s, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.96
(d, J = 8.3 Hz, 2H), 7.76 (q, J = 2.5 Hz, 2H) 165 ##STR00190##
218-221 385 383 12.58 (s, 1H), 12.35 (s, 1H), 8.61 (s, 1H),
7.85-7.77 (m, 1H), 7.75 (dd, J = 6.9, 2.5 Hz, 2H), 7.41 (d, J = 7.2
Hz, 1H), 6.91 (t, J = 7.7 Hz, 1H), 2.20 (s, 3H) 166 ##STR00191##
166-168 385 381 12.72 (s, 1H), 12.52 (s, 1H), 8.55 (s, 1H), 7.73
(dd, J = 14.6, 2.5 Hz, 2H), 7.59- 7.43 (m, 3H), 7.27-7.12 (m, 1H),
3.85 (s, 3H) 167 ##STR00192## 203-205 269 12.04 (s, 1H), 11.31 (s,
1H), 8.64 (s, 1H), 7.62-7.49 (m, 3H), 7.36-7.27 (m, 1H), 7.24 (s,
1H), 6.93 (t, J = 8.5 Hz, 2H), 2.36 (s, 6H) 168 ##STR00193##
223-226 382 380 12.76 (s, 1H), 12.47 (s, 1H), 8.53 (s, 1H), 7.73
(dd, J = 18.0, 2.5 Hz, 2H), 7.57 (s, 2H), 7.28 (s, 1H), 2.36 (s,
6H) 169 ##STR00194## 373 371 170 ##STR00195## 354 171 ##STR00196##
354 172 ##STR00197## 307 173 ##STR00198## 318 317 174 ##STR00199##
255 253 175 ##STR00200## 275 273 176 ##STR00201## 375 (+Na) 351 177
##STR00202## 178 ##STR00203## 331 (+Na) 179 ##STR00204## 332 180
##STR00205## 287 181 ##STR00206## 354 182 ##STR00207## 319 317 183
##STR00208## 339 (+Na) 315 184 ##STR00209## 219-222 388 386 12.36
(s, 1H), 11.19 (s, 1H), 8.65 (s, 1H), 8.04 (dd, J = 80.4, 8.3 Hz,
4H), 7.83 (d, J = 2.5 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H), 6.92
(d, J = 8.8 Hz, 1H)
185 ##STR00210## 349 347 186 ##STR00211## 196-202 389 387 12.25 (s,
1H), 10.99 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.80-7.76 (m, 1H),
7.66- 7.57 (m, 3H), 7.45 (dd, J = 8.8, 2.6 Hz, 1H), 7.37-7.31 (m,
1H) 187 ##STR00212## 213-218 343 341 12.36 (s, 1H), 11.18 (s, 1H),
8.66 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H),
7.71 (d, J = 2.6 Hz, 1H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.97 (d,
J = 8.8 Hz, 1H) 188 ##STR00213## 305 303 189 ##STR00214## 185-188
344 342 12.25 (s, 1H), 10.98 (s, 1H), 8.47 (s, 1H), 7.81-7.67 (m,
1H), 7.66-7.57 (m, 2H), 7.34 (dd, J = 8.8, 2.7 Hz, 1H), 7.23 (dt, J
= 3.5, 2.3 Hz, 1H), 6.91 (dd, J = 42.1, 8.6 Hz, 1H) 190
##STR00215## 353 351 191 ##STR00216## 351 192 ##STR00217## 385 193
##STR00218## 432 431 194 ##STR00219## 369 367 195 ##STR00220## 367
196 ##STR00221## 169-173 423 421 12.67 (s, 1H), 12.32 (s, 1H), 8.42
(s, 1H), 7.82 (t, J = 1.3 Hz, 1H), 7.77 (dd, J = 12.0, 2.5 Hz, 2H),
7.65 (d, J = 1.3 Hz, 2H) 197 ##STR00222## 321 319 198 ##STR00223##
525 199 ##STR00224## 354 352 200 ##STR00225## 305 303 201
##STR00226## 276-280 399 397 13.87 (s, 1H), 12.82 (s, 1H), 8.71 (s,
1H), 8.65 (d, J = 2.7 Hz, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.02 (t, J
= 1.8 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.73 (dd, J = 8.0, 2.0 Hz,
1H), 7.62 (t, J = 7.9 Hz, 1H). 202 ##STR00227## 379 203
##STR00228## 385 383 204 ##STR00229## 429 427 205 ##STR00230## 383
381 206 ##STR00231## 363 361 207 ##STR00232## 305 303 208
##STR00233## 283-300 393 391 14.01 (s, 1H), 12.65 (s, 1H), 8.69 (s,
1H), 8.60 (d, J = 2.7 Hz, 1H), 8.47 (d, J = 2.6 Hz, 1H), 7.59 (s,
2H), 7.29 (s, 1H), 2.37 (s, 6H) 209 ##STR00234## 189-193 378 376
12.07 (s, 1H), 10.90 (s, 1H), 8.61 (s, 1H), 7.55 (s, 2H), 7.40 (d,
J = 2.2 Hz, 1H), 7.24 (s, 1H), 7.17 (d, J = 2.2 Hz, 1H), 3.85 (s,
3H), 2.35 (s, 6H) 210 ##STR00235## 369 367 211 ##STR00236## 220-227
393 391 11.76 (s, 1H), 8.19 (s, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.39
(d, J = 2.6 Hz, 1H), 7.04 (s, 2H), 6.94 (s, 1H), 2.18 (s, 6H), 1.53
(s, 9H) 212 ##STR00237## 289 287 213 ##STR00238## 271 269 214
##STR00239## 285 283 215 ##STR00240## 300 298 216 ##STR00241## 323
321 217 ##STR00242## 91-104 297 295 10.78 (s, 1H), 8.18 (s, 1H),
7.42-7.37 (m, 2H), 7.34 (dd, J = 7.7, 1.7 Hz, 1H), 7.32-7.24 (m,
4H), 6.80 (td, J = 8.3, 4.4 Hz, 2H), 1.53 (s, 9H) 218 ##STR00243##
222-225 354 352 12.17 (s, 1H), 10.94 (s, 6H), 7.78-7.71 (m, 15H),
7.62-7.57 (m, 9H), 7.53 (dd, J = 8.6, 2.6 Hz, 6H), 7.27 (dddd, J =
27.4, 15.4, 7.9, 1.7 Hz, 14H), 6.96- 6.89 (m, 12H), 6.83-6.76 (m,
7H) 219 ##STR00244## 228-231 423 421 12.60 (s, 1H), 12.10 (s, 1H),
7.80-7.75 (m, 2H), 7.69 (dd, J = 19.8, 2.6 Hz, 2H), 7.57 (dd, J =
2.5, 1.2 Hz, 1H), 7.55 (d, J = 2.6 Hz, 1H) 220 ##STR00245## 215-218
512 510 12.65 (s, 1H), 12.35 (s, 1H), 7.87 (q, J = 2.4 Hz, 2H),
7.82-7.75 (m, 3H), 7.64 (dd, J = 17.0, 2.4 Hz, 1H), 7.55 (ddd, J =
8.5, 6.0, 2.6 Hz, 1H) 221 ##STR00246## 202-205 446 444 12.14 (s,
1H), 10.95 (s, 1H), 8.48 (s, 1H), 7.93 (d, J = 2.1 Hz, 1H),
7.80-7.72 (m, 1H), 7.59 (dd, J = 7.7, 1.5 Hz, 1H), 7.50 (dd, J =
12.0, 8.4 Hz, 1H), 7.35-7.18 (m, 1H), 6.96-6.89 (m, 1H), 6.80 (dd,
J = 12.3, 5.2 Hz, 1H) 222 ##STR00247## 201-219 514 512 12.57 (s,
1H), 12.12 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.81 (ddd, J = 11.4,
10.0, 2.2 Hz, 2H), 7.71 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 2.5 Hz,
1H), 7.53 (dd, J = 8.4, 2.2 Hz, 1H) 223 ##STR00248## 215-216 603
601 12.62 (s, 1H), 12.36 (s, 1H), 8.40 (s, 1H), 7.97 (d, J = 2.1
Hz, 1H), 7.86 (dd, J = 7.4, 2.3 Hz, 2H), 7.82-7.76 (m, 2H), 7.53
(d, J = 8.4 Hz, 1H) 224 ##STR00249## 222-226 401 399 12.15 (s, 1H),
10.94 (s, 1H), 8.49 (s, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.88 (dd, J
= 8.4, 2.2 Hz, 1H), 7.85-7.81 (m, 1H), 7.59 (dd, J = 7.7, 1.6 Hz,
1H), 6.97-6.89 (m, 2H), 6.84-6.76 (m, 1H) 225 ##STR00250## 198-201
470 8.44 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.89 (td, J = 8.7, 2.1
Hz, 2H), 7.68 (dd, J = 16.4, 2.5 Hz, 2H), 7.43-7.36 (m, 2H) 226
##STR00251## 205-212 559 12.64 (s, 1H), 12.36 (s, 1H), 8.40 (s,
1H), 8.01 (d, J = 2.1 Hz, 1H), 7.93-7.83 (m, 3H), 7.40 (t, J = 5.0
Hz, 1H) 227 ##STR00252## 86-122 334 332 12.04 (d, J = 17.6 Hz, 1H),
11.05 (s, 1H), 7.62-7.52 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H),
7.34-7.26 (m, 2H), 6.96-6.88 (m, 2H), 6.80 (t, J = 6.0 Hz, 1H),
2.36 (s, 3H) 228 ##STR00253## 240-242 403 401 12.49 (s, 1H), 12.25
(s, 1H), 8.44 (s, 1H), 7.67 (dd, J = 13.6, 2.5 Hz, 2H), 7.60 (d, J
= 4.1 Hz, 1H), 7.56-7.43 (m, 1H), 7.33 (dd, J = 6.3, 2.2 Hz, 1H),
2.37 (d, J = 2.8 Hz, 3H) 229 ##STR00254## 258-261 491 489 12.53 (s,
1H), 12.48 (s, 1H), 8.40 (s, 1H), 7.84 (dd, J = 11.5, 2.4 Hz, 2H),
7.60 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.34 (q, J = 7.8 Hz, 1H),
2.37 (d, J = 3.5 Hz, 3H) 230 ##STR00255## 185-187 255 253 (300 MHz,
CDCl.sub.3) 12.73 (s, 1H), 9.00 (s, 1H), 7.90- 7.82 (m, 2H),
7.64-7.57 (m, 1H), 7.55-7.47 (m, 3H), 7.35-7.28 (m, 1H), 7.09-7.00
(m, 1H), 6.94- 6.87 (m, 1H), 2.42 (s, 3H) 231 ##STR00256## 188-189
275 273 12.47 (s, 1H), 12.40 (s, 1H), 8.63 (s, 1H), 8.07-7.91 (m,
2H), 7.70-7.61 (m, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.50 (d, J = 7.9
Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H) 232 ##STR00257## 186-188 255
12.24 (s, 1H), 11.96 (s, 1H), 8.59 (s, 1H), 8.08-7.89 (m, 2H),
7.71-7.43 (m, 3H), 7.26 (dd, J = 24.4, 7.4 Hz, 2H), 6.86 (t, J =
7.5 Hz, 1H), 2.23 (s, 3H) 233 ##STR00258## 218-219 275 273 12.16
(s, 1H), 11.60 (s, 1H), 8.65 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H),
7.59 (dt, J = 14.8, 7.7 Hz, 4H), 7.10-6.83 (m, 2H) 234 ##STR00259##
179-182 255 253 12.08 (s, 1H), 11.32 (s, 1H), 8.61 (s, 1H),
8.08-7.81 (m, 2H), 7.70-7.47 (m, 3H), 7.42 (d, J = 7.8 Hz, 1H),
6.89-6.68 (m, 2H), 2.29 (s, 3H) 235 ##STR00260## 192-193 255 253
12.11 (s, 1H), 11.06 (s, 1H), 8.61 (s, 1H), 8.01-7.84 (m, 2H), 7.59
(dt, J = 27.8, 7.2 Hz, 3H), 7.36 (d, J = 1.4 Hz, 1H), 7.12 (dd, J =
8.3, 1.8 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 2.26 (s, 3H) 236
##STR00261## 247-248 275 273 12.53 (s, 1H), 12.48 (s, 1H), 9.06 (s,
1H), 8.08-7.90 (m, 2H), 7.62 (dt, J = 28.8, 7.2 Hz, 3H), 7.34 (t, J
= 8.2 Hz, 1H), 7.06 (dd, J = 7.9, 0.7 Hz, 1H), 6.97 (d, J = 8.3 Hz,
1H) 237 ##STR00262## 215-216 271 269 12.26 (s, 1H), 12.21 (s, 1H),
8.98 (s, 1H), 8.03-7.90 (m, 2H), 7.66-7.49 (m, 3H), 7.28 (t, J =
8.3 Hz, 1H), 6.57 (dd, J = 8.3, 3.6 Hz, 2H), 3.86 (s, 3H) 238
##STR00263## 249-252 289 287 12.88 (s, 1H), 12.46 (s, 1H), 8.61 (s,
1H), 8.04-7.89 (m, 2H), 7.60 (ddd, J = 12.6, 11.5, 6.4 Hz, 4H),
7.23 (d, J = 8.4 Hz, 1H) 239 ##STR00264## 206-208 289 287 12.18 (s,
1H), 11.29 (s, 1H), 8.59 (s, 1H), 7.95 (dd, J = 11.2, 4.0 Hz, 2H),
7.69- 7.47 (m, 4H), 6.94 (s, 1H), 2.30 (s, 3H) 240 ##STR00265##
238-241 309 307 12.25 (s, 1H), 11.61 (s, 1H), 8.62 (s, 1H),
8.08-7.71 (m, 2H), 7.68-7.29 (m, 4H), 7.19 (s, 1H) 241 ##STR00266##
273-274 309 307 12.76 (s, 1H), 12.55 (s, 1H), 9.06 (s, 1H),
8.09-7.90 (m, 2H), 7.62 (ddd, J = 22.7, 11.1, 7.0 Hz, 4H), 7.00 (d,
J = 9.0 Hz, 1H) 242 ##STR00267## 273-274 309 307 12.92 (s, 1H),
12.52 (s, 1H), 8.98 (s, 1H), 8.09-7.88 (m, 2H), 7.73-7.52 (m, 3H),
7.22 (d, J = 2.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H) 243 ##STR00268##
187-189 349 347 12.77 (s, 1H), 12.50 (s, 1H), 9.00 (s, 1H),
8.11-7.87 (m, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.4 Hz,
2H), 7.16 (d, J = 8.7 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 3.82 (s,
3H) 244 ##STR00269## 206-207 277 275 12.45 (d, J = 10.6 Hz, 1H),
12.42 (s, 1H), 8.77 (s, 1H), 7.97 (d, J = 7.5 Hz, 2H), 7.66 (t, J =
7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 7.44- 7.23 (m, 1H), 6.81
(td, J = 9.5, 3.4 Hz, 1H) 245 ##STR00270## 216-218 259 257 12.35
(s, 1H), 12.10 (s, 1H), 8.82 (s, 1H), 8.04-7.89 (m, 2H), 7.76-7.61
(m, 1H), 7.58 (t, J = 7.4 Hz, 2H), 7.36 (dd, J = 15.2, 8.3 Hz, 1H),
6.91-6.70 (m, 2H) 246 ##STR00271## 212-213 255 253 12.19 (s, 2H),
8.92 (s, 1H), 8.03-7.90 (m, 2H), 7.69- 7.60 (m, 1H), 7.57 (t, J =
7.3 Hz, 2H), 7.20 (t, J = 7.9 Hz, 1H), 6.78 (dd, J = 14.2, 7.8 Hz,
2H), 2.43 (s, 3H) 247 ##STR00272## 204-205 309 307 13.45 (s, 1H),
12.61 (s, 1H), 9.02 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.66 (t, J =
7.3 Hz, 1H), 7.59 (t, J = 7.5 Hz, 2H), 7.53 (d, J = 8.6 Hz, 1H),
7.09 (d, J = 8.6 Hz, 1H) 248 ##STR00273## 234-237 354 352 12.72 (s,
1H), 12.45 (s, 1H), 8.80 (t, J = 1.9 Hz, 1H), 8.62 (s, 1H),
8.51-8.37 (m, 2H), 7.88 (t, J = 8.0 Hz, 1H), 7.69 (dd, J = 24.9,
2.5 Hz, 2H) 249 ##STR00274## 165-169 375 12.70 (s, 1H), 12.38 (s,
1H), 8.60 (s, 1H), 8.32-8.23 (m, 2H), 8.02 (d, J = 7.8 Hz, 1H),
7.83 (t, J = 7.8 Hz, 1H), 7.68 (dd, J = 24.6, 2.5 Hz, 2H) 250
##STR00275## 180-182 393 391 12.63 (s, 1H), 12.39 (s, 1H), 8.60 (s,
1H), 8.01 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.76-7.63 (m, 4H) 251
##STR00276## 236-237 289 287 13.78 (s, 1H), 11.43 (s, 1H), 7.94 (d,
J = 7.3 Hz, 2H), 7.70-7.51 (m, 2H), 7.03- 6.92 (m, 4H), 2.49 (s,
3H) 252 ##STR00277## 214-215 303 301 13.77 (s, 1H), 11.51 (s, 1H),
7.64 (d, J = 8.5 Hz, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.43 (dd, J =
10.7, 4.3 Hz, 1H), 7.36-7.29 (m, 2H), 7.01-6.92 (m, 2H), 2.41 (s,
3H), 2.40 (s, 3H) 253 ##STR00278## 210-211 303 301 13.79 (s, 1H),
11.38 (s, 1H), 7.78-7.70 (m, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.48-
7.40 (m, 2H), 7.01-6.93 (m, 2H), 2.48 (s, 3H), 2.41 (s, 3H) 254
##STR00279## 254-256 303 301 13.80 (s, 1H), 11.33 (s, 1H), 7.86 (d,
J = 8.0 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.0 Hz,
2H), 7.02-6.91 (m, 2H), 2.48 (s, 3H), 2.40 (s, 3H) 255 ##STR00280##
183-184 323 321 13.60 (s, 1H), 11.72 (s, 1H), 7.67-7.45 (m, 5H),
7.02- 6.94 (m, 2H), 2.41 (s, 3H) 256 ##STR00281## 222-223 323 321
13.69 (s, 1H), 11.52 (s, 1H), 8.02-7.97 (m, 1H), 7.90 (d, J = 7.8
Hz, 1H), 7.73-7.65 (m, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.02-6.94 (m,
2H), 2.49 (s, 3H) 257 ##STR00282## 246-247 323 321 13.72 (s, 1H),
11.48 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.6 Hz, 1H),
7.63 (d, J = 8.5 Hz, 2H), 7.02-6.93 (m, 2H), 2.49 (s, 3H) 258
##STR00283## 277-280 337 12.42 (s, 2H), 11.47 (s, 1H), 8.61 (s,
1H), 7.66 (d, J = 13.7 Hz, 3H), 7.28 (dd, J = 8.4, 1.9 Hz, 1H),
6.91 (d, J = 8.4 Hz, 1H), 2.28 (s, 3H)
259 ##STR00284## 245-253 336 12.81 (s, 1H), 12.16 (s, 1H), 8.51 (s,
1H), 7.77 (d, J = 8.7 Hz, 2H), 7.61 (dd, J = 13.2, 2.5 Hz, 2H),
6.61 (d, J = 8.7 Hz, 2H), 6.50 (q, J = 4.8 Hz, 1H), 2.75 (d, J =
4.9 Hz, 3H) 260 ##STR00285## 286-289 337 335 12.58 (s, 1H), 12.48
(s, 1H), 8.57 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 2.4
Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 2.70
(q, J = 7.6 Hz, 2H), 1.22 (t, J = 7.6 Hz, 3H) 261 ##STR00286##
150-152 285 283 12.85 (s, 1H), 11.33 (s, 1H), 7.94 (d, J = 7.3 Hz,
2H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.4 Hz, 2H), 7.13 (d, J
= 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.8 Hz, 1H), 6.85 (d, J = 8.9 Hz,
1H), 3.75 (s, 3H), 2.49 (s, 3H) 262 ##STR00287## 146-155 299 297
12.81 (s, 1H), 11.40 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.46-7.40
(m, 1H), 7.33 (dd, J = 7.5, 3.9 Hz, 2H), 7.11 (d, J = 2.9 Hz, 1H),
6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75 (s,
3H), 2.41 (s, 3H), 2.40 (s, 3H) 263 ##STR00288## 131-141 299 297
12.84 (s, 1H), 11.29 (s, 1H), 7.78-7.70 (m, 2H), 7.43 (d, J = 5.2
Hz, 2H), 7.13 (d, J = 2.9 Hz, 1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H),
6.85 (d, J = 8.8 Hz, 1H), 3.75 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H)
264 ##STR00289## 159-162 299 297 12.86 (s, 1H), 11.24 (s, 1H), 7.86
(d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 2.9 Hz,
1H), 6.94 (dd, J = 8.9, 2.9 Hz, 1H), 6.84 (d, J = 8.9 Hz, 1H), 3.75
(s, 3H), 2.48 (s, 3H), 2.40 (s, 3H) 265 ##STR00290## 170-184 319
317 12.67 (s, 1H), 11.61 (s, 1H), 7.65-7.44 (m, 5H), 7.11 (d, J =
3.0 Hz, 1H), 7.01- 6.92 (m, 1H), 3.75 (s, 3H), 2.41 (s, 3H) 266
##STR00291## 190-201 319 317 12.75 (s, 1H), 11.43 (s, 1H), 8.00 (s,
1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.58 (t, J
= 7.9 Hz, 1H), 7.14 (d, J = 2.9 Hz, 1H), 6.95 (dd, J = 8.9, 2.9 Hz,
1H), 6.86 (d, J = 8.9 Hz, 1H), 3.75 (s, 3H), 2.50 (s, 3H) 267
##STR00292## 193-196 319 317 12.79 (s, 1H), 11.39 (s, 1H), 7.97 (d,
J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 2.9 Hz,
1H), 6.95 (dd, J = 8.9, 2.9 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 3.75
(s, 3H), 2.49 (s, 3H). 268 ##STR00293## 215-224 300 298 15.25 (s,
1H), 11.65 (s, 1H), 8.02-7.91 (m, 4H), 7.66 (t, J = 7.3 Hz, 1H),
7.57 (t, J = 7.6 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H)
269 ##STR00294## 193-196 314 312 15.27 (s, 1H), 11.76 (s, 1H), 7.95
(dd, J = 13.4, 7.5 Hz, 2H), 7.54 (d, J = 7.5 Hz, 1H), 7.45 (t, J =
7.4 Hz, 1H), 7.35 (dd, J = 7.5, 4.3 Hz, 2H), 7.06 (t, J = 8.0 Hz,
1H), 2.49 (s, 3H), 2.41 (s, 3H) 270 ##STR00295## 235-239 314 312
15.25 (d, J = 8.4 Hz, 1H), 11.60 (s, 1H), 7.96 (ddd, J = 21.0, 8.0,
1.4 Hz, 2H), 7.76 (d, J = 11.3 Hz, 2H), 7.46 (d, J = 6.3 Hz, 2H),
7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.42 (s, 3H) 271
##STR00296## 242-249 314 312 15.28 (s, 1H), 11.55 (s, 1H), 7.96
(ddd, J = 20.2, 8.0, 1.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H), 7.37
(d, J = 8.1 Hz, 2H), 7.06 (t, J = 8.0 Hz, 1H), 2.56 (s, 3H), 2.41
(s, 3H) 272 ##STR00297## 196-205 334 332 15.04 (s, 1H), 11.97 (s,
1H), 8.00-7.92 (m, 2H), 7.68- 7.53 (m, 3H), 7.49 (td, J = 7.3, 1.3
Hz, 1H), 7.07 (t, J = 8.0 Hz, 1H), 2.48 (s, 3H) 273 ##STR00298##
251-286 334 332 15.13 (s, 1H), 11.73 (s, 1H), 8.04-7.89 (m, 4H),
7.73 (d, J = 7.9 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.07 (t, J =
8.0 Hz, 1H), 2.57 (s, 3H) 274 ##STR00299## 241-251 334 332 15.17
(s, 1H), 11.70 (s, 1H), 7.99 (d, J = 8.5 Hz, 3H), 7.94 (dd, J =
8.1, 1.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 8.0 Hz,
1H), 2.56 (s, 3H) 275 ##STR00300## 216-222 343 341 13.24 (s, 1H),
12.64 (s, 1H), 8.69 (s, 1H), 8.04-7.88 (m, 4H), 7.62 (dt, J = 31.2,
7.3 Hz, 3H) 276 ##STR00301## 144-193 377 375 13.34 (s, 1H), 12.74
(s, 1H), 8.97 (s, 1H), 7.99 (d, J = 7.3 Hz, 2H), 7.72-7.65 (m, 2H),
7.60 (t, J = 7.5 Hz, 3H) 277 ##STR00302## 214-217 309 307 12.25 (s,
1H), 11.84 (s, 1H), 8.73 (s, 1H), 8.01 (s, 1H), 7.95 (d, J = 7.9
Hz, 2H), 7.59 (dt, J = 30.0, 7.5 Hz, 4H), 7.12 (d, J = 8.6 Hz, 1H)
278 ##STR00303## 221-223 337 335 14.48 (s, 1H), 11.54 (s, 1H),
7.79-7.72 (m, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz,
1H), 7.47- 7.42 (m, 2H), 2.52 (s, 3H), 2.41 (s, 3H) 279
##STR00304## 262-264 337 335 280 ##STR00305## 211-213 285 283 281
##STR00306## 170-172 299 297 13.65 (s, 1H), 11.29 (s, 1H), 7.53 (d,
J = 8.7 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 6.9 Hz,
1H), 7.34-7.28 (m, 2H), 6.51- 6.44 (m, 2H), 3.78 (s, 3H), 2.40 (s,
3H), 2.37 (s, 3H) 282 ##STR00307## 184-185 299 297 13.68 (s, 1H),
11.19 (s, 1H), 7.77-7.68 (m, 2H), 7.56 (d, J = 8.7 Hz, 1H), 7.46-
7.40 (m, 2H), 6.51-6.44 (m, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.41
(s, 3H) 283 ##STR00308## 206-207 299 297 13.69 (s, 1H), 11.14 (s,
1H), 7.84 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 7.35 (d, J
= 8.1 Hz, 2H), 6.52-6.44 (m, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 2.39
(s, 3H) 284 ##STR00309## 174-175 319 317 285 ##STR00310## 212-214
319 317 286 ##STR00311## 227-229 319 317 287 ##STR00312## 204-208
334 332 13.49 (s, 1H), 11.45 (s, 1H), 7.94 (d, J = 7.4 Hz, 2H),
7.76 (d, J = 2.3 Hz, 1H), 7.64 (t, J = 7.3 Hz, 1H), 7.55 (t, J =
7.5 Hz, 2H), 7.45 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz,
1H), 2.49 (s, 3H) 288 ##STR00313## 201-203 348 346 13.49 (s, 1H),
11.53 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 7.4 Hz, 1H),
7.47-7.41 (m, 2H), 7.33 (dd, J = 7.4, 4.5 Hz, 2H), 6.90 (d, J = 8.7
Hz, 1H), 2.42 (s, 3H), 2.40 (s, 3H) 289 ##STR00314## 227-233 348
346 13.50 (s, 1H), 11.40 (s, 1H), 7.75 (t, J = 5.9 Hz, 3H),
7.49-7.41 (m, 3H), 6.90 (d, J = 8.7 Hz, 1H), 2.49 (s, 3H), 2.41 (s,
3H) 290 ##STR00315## 245-248 348 346 13.51 (s, 1H), 11.36 (s, 1H),
7.86 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 2.3 Hz, 1H), 7.45 (dd, J =
8.7, 2.3 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.7 Hz,
1H), 2.48 (s, 3H), 2.40 (s, 3H) 291 ##STR00316## 198-201 368 366
13.31 (s, 1H), 11.73 (s, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.61-7.54
(m, 2H), 7.47 (dd, J = 13.1, 4.7 Hz, 3H), 6.91 (d, J = 8.7 Hz, 1H),
2.41 (s, 3H) 292 ##STR00317## 235-240 368 366 13.40 (s, 1H), 11.54
(s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 2.4
Hz, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.59 (t, J = 7.9 Hz, 1H), 7.46
(dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.50 (s, 3H)
293 ##STR00318## 264-268 366 13.43 (s, 1H), 11.50 (s, 1H), 7.98 (d,
J = 8.4 Hz, 2H), 7.76 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.5 Hz,
2H), 7.46 (dd, J = 8.7, 2.3 Hz, 1H), 6.90 (d, J = 8.7 Hz, 1H), 2.49
(s, 3H) 294 ##STR00319## 215-217 309 307 12.24 (s, 1H), 11.56 (s,
1H), 8.73 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.87 (d, J = 8.0 Hz,
1H), 7.67-7.60 (m, 1H), 7.60-7.52 (m, 2H), 7.29-7.20 (m, 2H) 295
##STR00320## 232-234 377 375 13.92 (s, 1H), 12.78 (s, 1H), 8.72 (s,
1H), 8.35 (s, 1H), 7.98 (d, J = 7.4 Hz, 2H), 7.94 (s, 1H),
7.70-7.64 (m, 1H), 7.62-7.56 (m, 2H) 296 ##STR00321## 170-173 309
307 13.03 (s, 1H), 12.49 (s, 1H), 8.65 (s, 1H), 7.97 (d, J = 7.3
Hz, 2H), 7.80 (d, J = 7.5 Hz, 1H), 7.71-7.62 (m, 2H), 7.61-7.53 (m,
2H), 7.11 (t, J = 7.7 Hz, 1H) 297 ##STR00322## 228-230 309 307
12.93 (s, 1H), 12.56 (s, 1H), 8.96 (s, 1H), 8.01-7.94 (m, 2H),
7.70-7.62 (m, 1H), 7.62-7.55 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H),
7.36 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H) 298 ##STR00323##
207-209 365 363 12.54 (s, 1H), 12.50 (s, 1H), 8.55 (s, 1H),
7.99-7.92 (m, 2H), 7.68-7.61 (m, 1H), 7.61-7.50 (m, 4H), 2.50 (s,
3H) 299 ##STR00324## 146-148 285 283 13.50 (s, 1H), 11.34 (s, 1H),
7.94 (d, J = 7.4 Hz, 2H), 7.66-7.60 (m, 1H), 7.59-7.52 (m, 2H),
7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J =
8.0 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H) 300 ##STR00325## 208-209
299 297 13.50 (s, 1H), 11.40 (s, 1H), 7.52 (d, J = 7.4 Hz, 1H),
7.43 (t, J = 7.5 Hz, 1H), 7.36- 7.27 (m, 2H), 7.22 (d, J = 8.1 Hz,
1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s,
3H), 2.41 (s, 6H) 301 ##STR00326## 121-123 299 297 13.51 (s, 1H),
11.28 (s, 1H), 7.79-7.68 (m, J = 9.6 Hz, 2H), 7.46-7.40 (m, 2H),
7.24 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J =
8.0 Hz, 1H), 3.79 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H) 302
##STR00327## 146-148 299 297 13.53 (s, 1H), 11.24 (s, 1H), 7.86 (d,
J = 7.9 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.6 Hz,
1H), 7.03 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.80 (s,
3H), 2.47 (s, 3H), 2.40 (s, 3H) 303 ##STR00328## 233-234 319 317
13.34 (s, 1H), 11.61 (s, 1H), 7.64 (dd, J = 7.5, 1.5 Hz, 1H),
7.61-7.51 (m, 2H), 7.50-7.44 (m, 1H), 7.25-7.20 (m, 1H), 7.05 (d, J
= 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H), 2.40 (s, 3H)
304 ##STR00329## 146-148 319 317 13.42 (s, 1H), 11.43 (s, 1H), 8.00
(s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.59
(t, J = 7.9 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.9 Hz,
1H), 6.84 (t, J = 8.1 Hz, 1H), 3.79 (s, 3H), 2.49 (s, 3H) 305
##STR00330## 168-170 319 317 13.44 (s, 1H), 11.39 (s, 1H), 7.98 (d,
J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.0 Hz,
1H), 7.04 (d, J = 7.8 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s,
3H), 2.48 (s, 3H) 306 ##STR00331## 290-291 344 13.66 (s, 1H), 12.68
(s, 1H), 8.59 (s, 1H), 8.19 (dd, J = 8.5, 1.8 Hz, 2H), 7.97 (d, J =
7.3 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H) 307
##STR00332## 262-263 384 382 12.70 (s, 1H), 12.48 (s, 1H), 8.67 (s,
1H), 8.07-7.80 (m, 4H), 7.65 (t, J = 7.3 Hz, 1H), 7.57 (t, J = 7.5
Hz, 2H) 308 ##STR00333## 262-269 339 337 12.44 (s, 1H), 12.31 (s,
1H), 11.71 (s, 1H), 8.62 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.65
(dd, J = 6.5, 2.4 Hz, 2H), 6.81 (d, J = 7.5 Hz, 2H), 2.31 (s, 3H)
309 ##STR00334## 252-271 334 332 12.66 (s, 1H), 12.33 (s, 1H), 8.58
(s, 1H), 8.38 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 7.7
Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.63 (d, J = 2.5
Hz, 1H) 310 ##STR00335## 234-270 332 12.82 (s, 1H), 12.37 (s, 1H),
8.11-8.02 (m, 4H), 7.76 (dd, J = 15.4, 2.6 Hz, 3H) 311 ##STR00336##
197-199 269 267 13.11 (s, 1H), 11.31 (s, 1H), 7.94 (d, J = 7.4 Hz,
2H), 7.63 (t, J = 7.3 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.44 (s,
1H), 7.12 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 2.48 (s,
3H), 2.28 (s, 3H) 312 ##STR00337## 154-156 283 281 13.11 (s, 1H),
11.37 (s, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.42 (d, J = 5.6 Hz, 2H),
7.32 (dd, J = 7.4, 4.2 Hz, 2H), 7.11 (dd, J = 8.3, 1.6 Hz, 1H),
6.81 (d, J = 8.3 Hz, 1H), 2.40 (s, 6H), 2.27 (s, 3H) 313
##STR00338## 182-184 283 281 13.12 (s, 1H), 11.26 (s, 1H), 7.74 (d,
J = 9.7 Hz, 2H), 7.43 (d, J = 5.2 Hz, 3H), 7.12 (d, J = 8.2 Hz,
1H), 6.81 (d, J = 8.2 Hz, 1H), 2.47 (s, 3H), 2.41 (s, 3H), 2.27 (s,
3H) 314 ##STR00339## 206-208 283 281 13.13 (s, 1H), 11.22 (s, 1H),
7.85 (d, J = 7.9 Hz, 2H), 7.44 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H),
7.11 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 2.47 (s, 3H),
2.40 (s, 3H), 2.27 (s, 3H) 315 ##STR00340## 154-158 303 301 12.95
(s, 1H), 11.59 (s, 1H), 7.65-7.57 (m, 2H), 7.46 (ddd, J = 12.5,
9.1, 1.4 Hz, 3H), 7.12 (dd, J = 8.3, 1.8 Hz, 1H), 6.82 (d, J = 8.3
Hz, 1H), 2.40 (s, 3H), 2.27 (s, 3H) 316 ##STR00341## 231-241 303
301 13.02 (s, 1H), 11.41 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 7.7
Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.45
(s, 1H), 7.13 (dd, J = 8.3, 1.5 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H),
2.49 (s, 3H), 2.28 (s, 3H) 317 ##STR00342## 203-210 303 301 13.05
(s, 1H), 11.37 (s, 1H), 7.97 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5
Hz, 2H), 7.45 (s, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 8.3
Hz, 1H), 2.48 (s, 3H), 2.27 (s, 3H) 318 ##STR00343## 242-243 343
341 12.33 (s, 1H), 11.64 (s, 1H), 8.69 (s,
1H), 7.96 (d, J = 6.2 Hz, 3H), 7.64 (t, J = 7.2 Hz, 1H), 7.56 (t, J
= 7.5 Hz, 2H), 7.36 (s, 1H) 319 ##STR00344## 216-218 343 341 13.84
(s, 1H), 12.70 (s, 1H), 8.95 (d, J = 1.2 Hz, 1H), 8.03-7.95 (m,
2H), 7.76- 7.64 (m, 2H), 7.60 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.4
Hz, 1H) 320 ##STR00345## 225-226 343 341 13.15 (s, 1H), 12.64 (s,
1H), 8.61 (s, 1H), 8.04-7.90 (m, 3H), 7.75-7.52 (m, 4H) 321
##STR00346## 204-206 357 355 13.74-12.87 (m, 1H), 12.60 (s, 1H),
8.68 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 1.1 Hz, 1H), 7.82-7.72 (m,
2H), 7.46 (d, J = 5.0 Hz, 2H), 2.41 (s, 3H) 322 ##STR00347##
269-271 357 355 13.15 (s, 1H), 12.69 (s, 1H), 8.69 (s, 1H), 8.03
(s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (dd, J = 19.3, 8.7 Hz, 2H),
7.64 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 2.40 (s, 3H)
323 ##STR00348## 210-212 361 359 13.15 (s, 1H), 12.69 (s, 1H), 8.69
(s, 1H), 8.03 (s, 1H), 7.91 (d, J = 1.8 Hz, 1H), 7.80 (dd, J =
19.3, 8.7 Hz, 2H), 7.64 (d, J = 5.8 Hz, 1H), 7.52 (d, J = 1.9 Hz,
1H) 324 ##STR00349## 200-202 361 359 13.4 (s, 1H), 12.66 (s, 1H),
8.68 (s, 1H), 8.11-7.98 (m, 2H), 7.90 (d, J = 2.1 Hz, 1H), 7.43 (t,
J = 8.8 Hz, 2H), 7.35-7.24 (m, 1H) 325 ##STR00350## 210-212 377 375
13.1 (s, 1H), 12.71 (s, 1H), 8.68 (s, 1H), 8.02 (d, J = 7.2 Hz,
2H), 7.93 (d, J = 10.3 Hz, 2H), 7.72 (s, 1H), 7.63 (d, J = 7.8 Hz,
1H) 326 ##STR00351## 208-210 377 13.25 (s, 1H), 12.70 (s, 1H), 8.68
(s, 1H), 8.07-7.95 (m, 3H), 7.90 (d, J = 1.7 Hz, 1H), 7.66 (d, J =
8.5 Hz, 2H) 327 ##STR00352## 237-238 388 386 12.95 (s, 2H), 8.80
(t, J = 1.8 Hz, 1H), 8.72 (s, 1H), 8.48 (dd, J = 8.2, 1.4 Hz, 1H),
8.40 (d, J = 7.9 Hz, 1H), 8.03 (d, J = 1.7 Hz, 1H), 7.88 (dd, J =
13.6, 5.3 Hz, 2H) 328 ##STR00353## 253-255 388 386 12.96 (s, 2H),
8.71 (s, 1H), 8.41 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.7 Hz, 2H),
8.04 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H) 329 ##STR00354## 258-260 359
357 13.11 (s, 1H), 12.35 (s, 1H), 11.45 (s, 1H), 8.73 (s, 1H), 7.98
(d, J = 1.7 Hz, 1H), 7.95-7.83 (m, 2H), 7.54-7.40 (m, 1H), 7.00
(dd, J = 14.0, 7.4 Hz, 2H) 330 ##STR00355## 169-171 411 409 12.84
(s, 1H), 12.73 (s, 1H), 8.56 (s, 1H), 8.03 (s, 1H), 7.94-7.56 (m,
5H) 331 ##STR00356## 255-257 373 371 13.09 (s, 1H), 12.37 (s, 1H),
11.63 (s, 1H), 8.72 (s, 1H), 7.97 (d, J = 1.1 Hz, 1H), 7.90 (d, J =
1.8 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 3H),
2.32 (d, J = 6.7 Hz, 3H) 332 ##STR00357## 210-213 391 389 13.92 (s,
1H), 12.73 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 7.94 (s, 1H),
7.81-7.74 (m, 2H), 7.50-7.43 (m, 2H), 2.42 (s, 3H) 333 ##STR00358##
274-277 391 389 13.94 (s, 1H), 12.70 (s, 1H), 8.71 (s, 1H), 8.33
(s, 1H), 7.93 (s, 1H), 7.89 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0
Hz, 2H), 2.40 (s, 3H) 334 ##STR00359## 240-242 395 393 13.81 (s,
1H), 12.83 (s, 1H), 8.72 (s, 1H), 8.37 (s, 1H), 7.95 (s, 1H), 7.83
(d, J = 7.8 Hz, 1H), 7.78 (d, J = 9.6 Hz, 1H), 7.69-7.61 (m, 1H),
7.53 (td, J = 8.4, 2.1 Hz, 1H) 335 ##STR00360## 226-228 395 393
13.87 (s, 1H), 12.79 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.06 (dd,
J = 8.7, 5.5 Hz, 2H), 7.94 (s, 1H), 7.47-7.39 (m, 2H) 336
##STR00361## 230-233 411 409 13.80 (s, 1H), 12.85 (s, 1H), 8.71 (s,
1H), 8.37 (s, 1H), 8.04-8.00 (m, 1H), 7.97- 7.91 (m, 2H), 7.74 (d,
J = 9.1 Hz, 1H), 7.66-7.59 (m, 1H) 337 ##STR00362## 233-236 411 409
13.85 (s, 1H), 12.84 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.00 (d,
J = 8.5 Hz, 2H), 7.94 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H) 338
##STR00363## 256-258 420 13.76 (s, 1H), 13.08 (s, 1H), 8.80 (t, J =
1.8 Hz, 1H), 8.75 (s, 1H), 8.50 (dd, J = 8.2, 1.4 Hz, 1H), 8.41 (d,
J = 7.9 Hz, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.89 (t, J = 8.0 Hz,
1H) 339 ##STR00364## 244-247 420 13.75 (s, 1H), 13.07 (s, 1H), 8.75
(s, 1H), 8.42 (d, J = 8.8 Hz, 2H), 8.39 (s, 1H), 8.21 (d, J = 8.8
Hz, 2H), 7.96 (s, 1H) 340 ##STR00365## 231-235 393 391 13.79 (s,
1H), 12.50 (s, 1H), 11.47 (s, 1H), 8.77 (s, 1H), 8.30 (s, 1H), 7.95
(s, 1H), 7.87 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.44 (m, 1H),
7.05-6.96 (m, 2H) 341 ##STR00366## 210-214 445 443 13.59, 12.89,
12.70, 11.12 (4s, 2H), 8.60, 8.38 (2s, 1H), 8.36, 8.15 (2s, 1H),
7.97-7.63 (m, 5H); Note: rotational isomers 342 ##STR00367##
251-254 407 405 13.80 (s, 1H), 12.48 (s, 1H), 11.60 (s, 1H), 8.76
(s, 1H), 8.30 (s, 1H), 7.94 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H),
6.87-6.78 (m, 2H), 2.32 (s, 3H) 343 ##STR00368## 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) 344 ##STR00369##
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) 345 ##STR00370## 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) 346 ##STR00371## 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) 347
##STR00372## 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) 348
##STR00373## 215-216 343 341 12.96 (s, 1H), 12.55 (s, 1H), 8.64 (s,
1H), 7.99 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.71-7.63
(m, 3H), 7.11 (t, J = 7.7 Hz, 1H) 349 ##STR00374## 215-217 354 352
12.84 (s, 2H), 8.83-8.77 (m, 1H), 8.68 (s, 1H), 8.49 (d, J = 8.2
Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.82
(d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.0 Hz, 1H), 7.12 (t, J = 1.1 Hz,
1H) 350 ##STR00375## 253-255 352 12.86 (s, 2H), 8.67 (s, 1H), 8.42
(d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 7.1 Hz,
1H), 7.69 (d, J = 7.3 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1H) 351
##STR00376## 230-234 325 323 12.95 (s, 1H), 12.28 (s, 1H), 11.56
(s, 1H), 8.71 (s, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (d, J =
7.6 Hz, 1H), 7.68 (d, J = 7.1 Hz, 1H), 7.52-7.44 (m, 1H), 7.12 (t,
J = 7.8 Hz, 1H), 7.05-6.96 (m, 2H) 352 ##STR00377## 248-253 339 337
12.95 (s, 1H), 12.26 (s, 1H), 11.67 (s, 1H), 8.70 (s, 1H), 7.80 (t,
J = 9.1 Hz, 2H), 7.67 (d, J = 7.4 Hz, 1H), 7.11 (t, J = 7.8 Hz,
1H), 6.83 (d, J = 7.4 Hz, 2H), 2.31 (s, 3H) 353 ##STR00378##
169-171 377 375 12.78, 12.63, 12.47, 10.39 (4s, 2H), 8.50, 8.29
(2s, 1H), 7.92-7.54 (m, 6H), 7.11, 7.04 (2t, J = 1.1 Hz, 1H); Note:
rotational isomers 354 ##STR00379## 212-214 323 321 12.89 (s, 1H),
12.41 (s, 1H), 8.60 (s, 1H), 7.79-7.70 (m, 2H), 7.54 (d, J = 8.5
Hz, 1H), 7.45 (d, J = 4.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 2.41
(s, 3H) 355 ##STR00380## 254-256 323 321 12.92 (s, 1H), 12.39 (s,
1H), 8.60 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.4 Hz,
1H), 7.38 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 2.40 (s,
3H) 356 ##STR00381## 215-218 327 325 12.75 (s, 1H), 12.50 (s, 1H),
8.61 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.79-7.73 (m, 1H),
7.67-7.59 (m, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.51 (td, J = 8.4, 2.4
Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H) 357 ##STR00382## 244-246 325
12.83 (s, 1H), 12.47 (s, 1H), 8.60 (s, 1H), 8.04 (dd, J = 8.7, 5.5
Hz, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 8.8 Hz, 2H), 7.24
(d, J = 8.4 Hz, 1H) 358 ##STR00383## 219-222 343 341 12.73 (s, 1H),
12.52 (s, 1H), 8.60 (s, 1H), 8.00 (t, J = 1.8 Hz, 1H), 7.92 (d, J =
7.8 Hz, 1H), 7.74-7.69 (m, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.57 (d,
J = 8.5 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H) 359 ##STR00384## 260-262
343 341 12.79 (s, 1H), 12.51 (s, 1H), 8.60 (s, 1H), 7.98 (d, J =
8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 1H),
7.24 (d, J = 8.4 Hz, 1H) 360 ##STR00385## 269-271 352 12.70 (s,
2H), 8.79 (s, 1H), 8.65 (s, 1H), 8.50-8.46 (m, 1H), 8.42-8.37 (m,
1H), 7.88 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.25 (d, J
= 8.4 Hz, 1H) 361 ##STR00386## 237-243 352 12.69 (s, 2H), 8.63 (s,
1H), 8.40 (d, J = 8.7 Hz, 2H), 8.19 (d, J = 8.7 Hz, 2H), 7.59 (d, J
= 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H) 362 ##STR00387## 280-282
325 323 12.78 (s, 1H), 12.26 (s, 1H), 11.57 (s, 1H), 8.66 (s, 1H),
7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.50-7.44
(m, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.03-6.96 (m, 2H) 363
##STR00388## 209-213 377 375 12.56, 12.52, 12.41, 10.48 (4s, 2H),
8.47, 8.26 (2s, 1H), 7.92-7.59 (m, 4H), 7.57, 7.31 (2d, J = 8.5 Hz,
1H), 7.57, 7.31 (2d, J = 8.5 Hz, 1H); Note: rotational isomers 364
##STR00389## 271-278 339 337 12.79 (s, 1H), 12.24 (s, 1H), 11.69
(s, 1H), 8.66 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.5
Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.84-6.79 (m, 2H), 2.31 (s, 3H)
365 ##STR00390## 214-216 323 13.46 (s, 1H), 12.57 (s, 1H), 9.01 (s,
1H), 7.82-7.75 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.49-7.45 (m,
2H), 7.10 (d, J = 8.6 Hz, 1H), 2.42 (s, 3H) 366 ##STR00391##
267-269 323 321 13.48 (s, 1H), 12.54 (s, 1H), 9.01 (s, 1H), 7.89
(d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.6 Hz, 1H), 7.39 (d, J = 8.0 Hz,
2H), 7.09 (d, J = 8.6 Hz, 1H), 2.40 (s, 3H) 367 ##STR00392##
203-209 327 325 13.35 (s, 1H), 12.65 (s, 1H), 9.01 (s, 1H), 7.83
(d, J = 7.8 Hz, 1H), 7.81-7.76 (m, 1H), 7.69-7.61 (m, 1H),
7.56-7.48 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H) 368 ##STR00393##
264-267 327 325 13.41 (s, 1H), 12.62 (s, 1H), 9.00 (s, 1H),
8.10-8.01 (m, 2H), 7.53 (d, J = 8.6 Hz, 1H), 7.44 (t, J = 8.8 Hz,
2H), 7.10 (d, J = 8.6 Hz, 1H) 369 ##STR00394## 232-234 343 341
13.34 (s, 1H), 12.67 (s, 1H), 9.00 (s, 1H), 8.04-8.00 (m, 1H), 7.94
(d, J = 7.8 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.63 (t, J = 7.9 Hz,
1H), 7.54 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H) 370
##STR00395## 271-273 343 13.38 (s, 1H), 12.66 (s, 1H), 9.00 (s,
1H), 8.00 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.53 (d, J
= 8.6 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H) 371 ##STR00396## 273-277
354 352 13.33 (s, 1H), 12.91 (s, 1H), 9.03 (s, 1H), 8.84-8.81 (m,
1H), 8.50 (dd, J = 8.2, 1.4 Hz, 1H), 8.42 (d, J = 7.8 Hz, 1H), 7.90
(t, J = 8.0 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.6 Hz,
1H) 372 ##STR00397## 260-262 325 323 13.43 (s, 1H), 12.46 (s, 1H),
11.48 (s, 1H), 9.06 (s, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.54
(d, J = 8.6 Hz, 1H), 7.52-7.45 (m, 1H), 7.10 (d, J = 8.6 Hz, 1H),
7.05-6.96 (m, 2H) 373 ##STR00398## 221-222 377 375 13.18, 12.73,
12.58, 10.82 (4s, 2H), 8.85, 8.65 (2s, 1H), 7.95-7.62 (m, 4H),
7.56, 7.44 (2d, J = 8.6 Hz, 1H), 7.11, 7.05 (2d, J = 8.6 Hz, 1H);
Note: rotational isomers 374 ##STR00399## 248-254 339 337 13.42 (s,
1H), 12.44 (s, 1H), 11.61 (s, 1H), 9.05 (s, 1H), 7.79 (d, J = 8.5
Hz, 1H), 7.53 (d, J = 8.6 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H),
6.85-6.81 (m, 2H), 2.32 (s, 3H) 375 ##STR00400## 250- 300 dec 354
352 13.31 (s, 1H), 12.87 (s, 1H), 9.03 (s, 1H), 8.45-8.39 (m, 2H),
8.24-8.18 (m, 2H), 7.55 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 8.6 Hz,
1H) 376 ##STR00401## 199-201 357 355 13.21 (s, 1H), 12.61 (s, 1H),
8.60 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.82-7.72 (m, 2H), 7.69 (d,
J = 2.4 Hz, 1H), 7.51-7.40 (m, 2H), 2.41 (s, 3H) 377 ##STR00402##
276-278 357 355 13.23 (s, 1H), 12.59 (s, 1H), 8.60 (s, 1H), 7.99
(d, J = 2.4 Hz, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 2.5 Hz,
1H), 7.38 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H) 378 ##STR00403##
219-221 361 359 13.09 (s, 1H), 12.72 (s, 1H), 8.61 (s, 1H), 8.03
(d, J = 2.5 Hz, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.79-7.74 (m, 1H),
7.72 (d, J = 2.4 Hz, 1H), 7.64 (td, J = 8.0, 5.9 Hz, 1H), 7.52 (td,
J = 8.4, 2.2 Hz, 1H)
379 ##STR00404## 227-228 361 359 13.16 (s, 1H), 12.68 (s, 1H), 8.60
(s, 1H), 8.26-7.87 (m, 3H), 7.71 (d, J = 2.4 Hz, 1H), 7.43 (t, J =
8.8 Hz, 2H) 380 ##STR00405## 228-229 377 375 13.08 (s, 1H), 12.74
(s, 1H), 8.60 (s, 1H), 8.05-7.97 (m, 2H), 7.93 (d, J = 7.8 Hz, 1H),
7.72 (t, J = 5.3 Hz, 2H), 7.62 (t, J = 7.9 Hz, 1H) 381 ##STR00406##
232-234 377 375 13.13 (s, 1H), 12.72 (s, 1H), 8.60 (s, 1H), 8.00
(dd, J = 10.9, 5.5 Hz, 3H), 7.71 (d, J = 2.4 Hz, 1H), 7.66 (d, J =
8.6 Hz, 2H) 382 ##STR00407## 235-237 388 386 13.00 (s, 1H),
8.83-8.74 (m, 1H), 8.63 (s, 1H), 8.56- 8.44 (m, 1H), 8.40 (d, J =
7.9 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H),
7.72 (d, J = 2.5 Hz, 1H) 383 ##STR00408## 245-247 388 386 12.99 (d,
J = 25.6 Hz, 2H), 8.63 (s, 1H), 8.41 (d, J = 8.8 Hz, 2H), 8.20 (d,
J = 8.8 Hz, 2H), 8.04 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H)
384 ##STR00409## 258-260 359 357 13.10 (s, 1H), 12.43 (s, 1H),
11.51 (s, 1H), 8.66 (s, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.87 (dd, J
= 7.9, 1.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.55-7.39 (m, 1H),
7.06-6.91 (m, 2H) 385 ##STR00410## 203-204 411 409 12.92 (s, 1H),
12.79 (s, 1H), 8.48 (s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.95- 7.55
(m, 5H) 386 ##STR00411## 252-254 373 371 13.10 (s, 1H), 12.37 (s,
1H), 11.63 (s, 1H), 8.65 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.80
(d, J = 8.4 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 7.6 Hz,
2H), 2.30 (d, J = 8.7 Hz, 3H) 387 ##STR00412## 201-203 289 287
12.10 (s, 1H), 11.58 (s, 1H), 8.63 (s, 1H), 7.78-7.69 (m, 2H), 7.62
(d, J = 8.1 Hz, 1H), 7.43 (d, J = 4.7 Hz, 2H), 7.03-6.95 (m, 2H),
2.40 (s, 3H) 388 ##STR00413## 258-260 289 287 12.09 (s, 1H), 11.62
(s, 1H), 8.63 (s, 1H), 7.85 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.2
Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.04-6.94 (m, 2H), 2.39 (s, 3H)
389 ##STR00414## 218-222 293 291 390 ##STR00415## 226-228 293 291
12.16 (s, 1H), 11.54 (s, 1H), 8.63 (s, 1H), 8.06-7.98 (m, 2H), 7.64
(d, J = 8.1 Hz, 1H), 7.44-7.35 (m, 2H), 7.03-6.95 (m, 2H) 391
##STR00416## 212-214 307 12.20 (s, 1H), 11.45 (s, 1H), 8.64 (s,
1H), 8.01-7.96 (m, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.73-7.63 (m,
2H), 7.63-7.55 (m, 1H), 7.02-6.95 (m, 2H) 392 ##STR00417## 257-260
309 307 12.20 (s, 1H), 11.50 (s, 1H), 8.64 (s, 1H), 7.96 (d, J =
8.5 Hz, 2H), 7.67-7.60 (m, 3H), 7.03-6.94 (m, 2H) 393 ##STR00418##
233-238 320 318 12.41 (s, 1H), 11.42 (s, 1H), 8.81-8.77 (m, 1H),
8.69 (s, 1H), 8.46 (dd, J = 8.1, 1.8 Hz, 1H), 8.39 (d, J = 7.8 Hz,
1H), 7.86 (t, J = 8.0 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.04-6.96
(m, 2H) 394 ##STR00419## 278-281 320 318 12.40 (s, 1H), 11.41 (s,
1H), 8.68 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.18 (d, J = 8.8 Hz,
2H), 7.68 (d, J = 8.0 Hz, 1H), 7.03-6.96 (m, 2H) 395 ##STR00420##
210-213 291 289 396 ##STR00421## 197-200 343 341 12.20, 12.13,
11.27, 10.30 (4s, 2H), 8.47, 8.26 (2s, 1H), 7.90-7.16 (m, 5H),
7.01-6.80 (m, 2H); Note: rotational isomers 397 ##STR00422##
283-287 305 303 12.02 (s, 1H), 11.90 (s, 1H), 11.51 (s, 1H), 8.67
(s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H),
7.04-6.95 (m, 2H), 6.83- 6.76 (m, 2H), 2.31 (s, 3H) 398
##STR00423## 245-248 289 287 12.57 (s, 1H), 12.43 (s, 1H), 9.05 (s,
1H), 7.83-7.73 (m, 2H), 7.46 (d, J = 4.8 Hz, 2H), 7.34 (t, J = 8.2
Hz, 1H), 7.06 (dd, J = 7.9, 0.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H),
2.41 (s, 3H) 399 ##STR00424## 250-252 289 287 12.59 (s, 1H), 12.40
(s, 1H), 9.04 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.0
Hz, 2H), 7.33 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.96
(d, J = 8.3 Hz, 1H), 2.40 (s, 3H) 400 ##STR00425## 257-259 293 291
12.52 (s, 1H), 12.48 (s, 1H), 9.04 (s, 1H), 7.83 (d, J = 7.8 Hz,
1H), 7.80-7.75 (m, 1H), 7.68-7.60 (m, 1H), 7.52 (td, J = 8.5, 2.4
Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 6.97
(d, J = 8.3 Hz, 1H) 401 ##STR00426## 266-268 293 291 12.53 (s, 1H),
12.48 (s, 1H), 9.03 (s, 1H), 8.09-8.00 (m, 2H), 7.47-7.39 (m, 2H),
7.34 (t, J = 8.2 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.96 (d, J =
8.3 Hz, 1H) 402 ##STR00427## 250-253 309 307 12.54 (s, 1H), 12.47
(s, 1H), 9.04 (s, 1H), 8.05-7.98 (m, 1H), 7.96-7.90 (m, 1H),
7.76-7.69 (m, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.35 (t, J = 8.2 Hz,
1H), 7.07 (dd, J = 8.0, 1.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 1H) 403
##STR00428## 273-277 309 307 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s,
1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J = 8.2 Hz,
1H), 7.07 (dd, J = 7.9, 0.9 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H) 404
##STR00429## 269-270 320 318 12.77 (s, 1H), 12.48 (s, 1H), 9.07 (s,
1H), 8.82 (t, J = 1.9 Hz, 1H), 8.52-8.45 (m, 1H), 8.41 (d, J = 7.9
Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 7.08
(dd, J = 7.9, 0.8 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H) 405
##STR00430## >300 320 318 12.73 (s, 1H), 12.44 (s, 1H), 9.06 (s,
1H), 8.46-8.38 (m, 2H), 8.25-8.16 (m, 2H), 7.36 (t, J = 8.2 Hz,
1H), 7.08 (dd, J = 8.0, 0.9 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H) 406
##STR00431## 277-280 291 289 12.52 (s, 1H), 12.37 (s, 1H), 11.55
(s, 1H), 9.07 (s, 1H), 7.86 (dd, J = 7.9, 1.5 Hz, 1H), 7.52-7.43
(m, 1H), 7.35 (t, J = 8.2 Hz, 1H), 7.07 (dd, J = 7.9, 0.9 Hz, 1H),
7.03-6.95 (m, 3H) 407 ##STR00432## 222-226 343 341 12.57, 12.45,
12.30, 10.21 (4s, 2H), 8.88, 8.64 (2s, 1H), 7.92-6.70 (m, 7H);
Note: rotational isomers 408 ##STR00433## 273-276 305 303 12.51 (s,
1H), 12.35 (s, 1H), 11.70 (s, 1H), 9.07 (s, 1H), 7.82-7.75 (m, 1H),
7.34 (t, J = 8.2 Hz, 1H), 7.09- 7.03 (m, 1H), 6.96 (d, J = 8.3 Hz,
1H), 6.82 (d, J = 4.2 Hz, 2H), 2.32 (s, 3H) 409 ##STR00434##
297-299 337 335 12.20 (s, 1H), 11.63 (s, 2H), 8.66 (s, 1H), 7.88
(dd, J = 7.9, 1.4 Hz, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.61 (dd, J =
10.4, 2.3 Hz, 1H), 7.53- 7.38 (m, 1H), 7.07-6.88 (m, 2H) 410
##STR00435## 211-212 337 335 12.36 (s, 1H), 11.72 (s, 1H), 8.63 (s,
1H), 7.96 (d, J = 7.3 Hz, 2H), 7.72-7.48 (m, 5H) 411 ##STR00436##
228-229 351 349 12.30 (s, 1H), 11.76 (s, 1H), 8.62 (s, 1H), 7.87
(d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.59 (dd, J = 10.5, 2.1 Hz, 1H),
7.36 (d, J = 8.0 Hz, 2H), 2.39 (s, 3H) 412 ##STR00437## 240-241 405
403 12.51 (s, 1H), 11.58 (s, 1H), 8.66 (s, 1H), 8.15 (d, J = 8.1
Hz, 2H), 7.95 (d, J = 8.3 Hz, 2H), 7.73-7.67 (m, 1H), 7.61 (dd, J =
10.4, 2.3 Hz, 1H) 413 ##STR00438## 279-282 368 12.78 (s, 1H), 12.49
(s, 1H), 8.54 (s, 1H), 7.88 (d, J = 8.1 Hz, 2H), 7.73 (dd, J =
13.1, 2.5 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 2.40 (s, 3H) 414
##STR00439## 209-215 372 370 12.69 (s, 1H), 12.58 (s, 1H), 8.54 (s,
1H), 8.04 (dd, J = 8.7, 5.5 Hz, 2H), 7.74 (dd, J = 7.7, 2.5 Hz,
2H), 7.42 (t, J = 8.8 Hz, 2H) 415 ##STR00440## 200-211 372 370
12.62 (s, 2H), 8.55 (s, 1H), 7.86-7.71 (m, 4H), 7.67- 7.47 (m, 2H)
416 ##STR00441## 167-226 399 397 12.85 (s, 1H), 12.55 (s, 1H), 8.80
(t, J = 1.8 Hz, 1H), 8.59 (s, 1H), 8.52-8.37 (m, 2H), 7.88 (t, J =
8.0 Hz, 1H), 7.76 (dd, J = 6.4, 2.5 Hz, 2H) 417 ##STR00442##
237-250 399 397 12.68 (s, 2H), 8.58 (s, 1H), 8.41 (d, J = 8.8 Hz,
2H), 8.20 (d, J = 8.8 Hz, 2H), 7.77 (q, J = 2.5 Hz, 2H) 418
##STR00443## 266-274 422 420 12.66 (s, 1H), 8.42 (s, 1H), 7.94-7.71
(m, 7H) 419 ##STR00444## 188-196 289 287 12.16 (s, 1H), 11.30 (s,
1H), 8.62 (s, 1H), 7.80-7.59 (m, 3H), 7.43 (d, J = 4.6 Hz, 2H),
7.33 (dd, J = 8.7, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.40 (s,
3H) 420 ##STR00445## 205-224 372 12.23 (s, 1H), 11.21 (s, 1H), 8.64
(s, 1H), 7.83-7.72 (m, 2H), 7.70 (d, J = 2.7 Hz, 1H), 7.61 (td, J =
8.0, 5.9 Hz, 1H), 7.48 (td, J = 8.4, 2.1 Hz, 1H), 7.33 (dd, J =
8.8, 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H) 421 ##STR00446## 234-243
372 12.21 (s, 1H), 11.26 (s, 1H), 8.62 (s, 1H), 8.03 (dd, J = 8.4,
5.6 Hz, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.45-7.27 (m, 3H), 6.96 (d,
J = 8.8 Hz, 1H) 422 ##STR00447## 154-164 343 341 12.25 (s, 1H),
11.01 (s, 1H), 8.47 (s, 1H), 7.91-7.65 (m, 7H) 423 ##STR00448##
166-169 289 287 (400 MHz, CDCl.sub.3) 8.59 (d, J = 12.0 Hz, 1H),
7.76 (d, J = 10.0 Hz, 2H), 7.47 (dd, J = 15.6, 6.2 Hz, 4H), 6.97
(t, J = 7.8 Hz, 1H), 2.39 (d, J = 12.0 Hz, 3H) 424 ##STR00449##
230-232 289 287 (400 MHz, CDCl.sub.3) 8.60 (s, 1H), 7.87 (d, J =
8.1 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H),
6.97 (t, J = 7.8 Hz, 1H), 2.40 (s, 3H) 425 ##STR00450## 178-184 293
291 (400 MHz, CDCl.sub.3) 8.62 (s, 1H), 7.86-7.72 (m, 2H), 7.63
(dd, J = 13.8, 8.0 Hz, 1H), 7.51 (dd, J = 7.1, 5.5 Hz, 3H), 6.98
(t, J = 7.8 Hz, 1H) 426 ##STR00451## 194-198 293 291 (400 MHz,
CDCl.sub.3) 8.60 (s, 1H), 8.08-7.99 (m, 2H), 7.54-7.46 (m, 2H),
7.42 (t, J = 8.8 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H) 427 ##STR00452##
174-178 309 307 (400 MHz, CDCl.sub.3) 8.61 (s, 1H), 8.00 (t, J =
1.7 Hz, 1H), 7.95-7.68 (m, 2H), 7.61 (t, J = 7.9 Hz, 1H), 7.55-
7.47 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H) 428 ##STR00453## 217-219 309
307 (400 MHz, CDCl3) 8.61 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.66
(d, J = 8.6 Hz, 2H), 7.50 (ddd, J = 7.9, 4.5, 1.4 Hz, 2H), 6.98 (t,
J = 7.8 Hz, 1H) 429 ##STR00454## 236-239 320 318 (400 MHz,
CDCl.sub.3) 8.80 (t, J = 1.9 Hz, 1H), 8.66 (s, 1H), 8.52-8.36 (m,
2H), 7.88 (t, J = 8.0 Hz, 1H), 7.53 (ddd, J = 9.7, 7.9, 1.5 Hz,
2H), 6.99 (t, J = 7.8 Hz, 1H) 430 ##STR00455## 284-287 320 318 (400
MHz, CDCl.sub.3) 8.64 (s, 1H), 8.41 (d, J = 8.5 Hz, 2H), 8.19 (d, J
= 8.6 Hz, 2H), 7.56-7.47 (m, 2H), 6.98 (t, J = 7.8 Hz, 1H) 431
##STR00456## 266-268 291 289 (400 MHz, CDCl.sub.3) 8.66 (s, 1H),
7.87 (dd, J = 7.9, 1.6 Hz, 1H), 7.54-7.42 (m, 3H), 6.98 (ddd, J =
7.8, 5.6, 3.9 Hz, 3H) 432 ##STR00457## 118-121 343 341 (400 MHz,
CDCl.sub.3) 8.36 (d, J = 82.5 Hz, 1H), 7.95- 7.24 (m, 6H), 6.92
(dt, J = 42.3, 7.9 Hz, 1H) 433 ##STR00458## 258-266 305 303 (400
MHz, CDCl.sub.3) 8.66 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.49 (dd,
J = 7.9, 2.1 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.3
Hz, 2H), 2.31 (s, 3H) 434 ##STR00459## 262-268 384 382 (400 MHz,
CDCl.sub.3) 8.58 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.72 (dd, J =
27.0, 2.4 Hz, 2H), 6.81 (d, J = 7.7 Hz, 2H), 2.31 (s, 3H) 435
##STR00460## 192-194 323 321 12.21 (s, 1H), 11.82 (s, 1H), 8.72 (s,
1H), 8.00 (s, 1H), 7.75 (dd, J = 9.3, 4.5 Hz, 2H), 7.64 (dd, J =
8.7, 1.8 Hz, 1H), 7.44 (d, J = 4.7 Hz, 2H), 7.12 (d, J = 8.6 Hz,
1H), 2.40 (s, 3H) 436 ##STR00461## 245-249 323 321 12.19 (s, 1H),
11.88 (s, 1H), 8.72 (s, 1H), 8.00 (s, 1H), 7.86 (d, J = 8.1 Hz,
2H), 7.63 (dd, J = 8.6, 1.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.12
(d, J = 8.5 Hz, 1H), 2.39 (s, 3H) 437 ##STR00462## 188-196 327 325
12.28 (s, 1H), 11.75 (s, 1H), 8.73 (s, 1H), 8.03 (d, J = 1.3 Hz,
1H), 7.78 (dd, J = 18.8, 9.0 Hz, 2H), 7.68-7.57 (m, 2H), 7.49 (td,
J = 8.7, 2.3 Hz, 1H), 7.12 (d, J = 8.5 Hz, 1H) 438 ##STR00463##
229-231 327 325 12.26 (s, 1H), 11.80 (s, 1H), 8.72 (s, 1H),
8.10-7.96 (m, 3H), 7.64 (dd, J = 8.6, 2.0 Hz, 1H), 7.40 (t, J = 8.8
Hz, 2H), 7.12 (d, J = 8.6 Hz, 1H) 439 ##STR00464## 187-197 343 341
12.30 (s, 1H), 11.73 (s, 1H), 8.73 (s, 1H), 8.06-7.94 (m, 2H), 7.91
(dd, J = 7.8, 1.2 Hz, 1H), 7.74-7.54 (m, 3H), 7.12 (d, J = 8.6 Hz,
1H) 440 ##STR00465## 252-254 343 341 12.30 (s, 1H), 11.77 (s, 1H),
8.72 (s, 1H), 8.06-7.90 (m, 3H), 7.64 (d, J = 8.5 Hz, 3H), 7.12 (d,
J = 8.6 Hz, 1H) 441 ##STR00466## 218-220 354 352 12.51 (s, 1H),
11.74 (s, 1H), 8.80 (dd, J = 6.6, 4.8 Hz, 2H), 8.51-8.35 (m, 2H),
8.05 (d, J = 1.8 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.65 (dd, J =
8.7, 2.2 Hz, 1H), 7.13 (d, J =
8.6 Hz, 1H) 442 ##STR00467## 259-265 354 352 12.47 (s, 1H), 11.71
(s, 1H), 8.76 (s, 1H), 8.44-8.36 (m, 2H), 8.23-8.15 (m, 2H), 8.05
(d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.7, 2.2 Hz, 1H), 7.13 (d, J =
8.6 Hz, 1H) 443 ##STR00468## 277-281 325 323 12.15 (s, 1H), 11.78
(s, 2H), 8.75 (s, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.89 (dd, J = 7.8,
1.2 Hz, 1H), 7.65 (dd, J = 8.6, 2.1 Hz, 1H), 7.50-7.42 (m, 1H),
7.13 (d, J = 8.6 Hz, 1H), 7.03-6.94 (m, 2H) 444 ##STR00469##
174-176 377 375 12.30 (s, 1H), 11.55 (s, 1H), 8.57 (s, 1H), 8.03
(d, J = 2.1 Hz, 1H), 7.91-7.47 (m, 5H), 7.12 (d, J = 8.6 Hz, 1H)
445 ##STR00470## 264-271 339 337 12.12 (s, 1H), 11.89 (s, 1H),
11.78 (s, 1H), 8.75 (s, 1H), 8.00 (s, 1H), 7.83 (d, J = 8.5 Hz,
1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.80
(d, J = 7.0 Hz, 2H), 2.31 (s, 3H) 446 ##STR00471## 282-286 305 303
12.03 (s, 2H), 11.24 (s, 1H), 8.65 (s, 1H), 7.82 (d, J = 8.6 Hz,
1H), 7.67 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.6 Hz, 1H), 6.96
(d, J = 8.8 Hz, 1H), 6.80 (d, J = 7.3 Hz, 2H), 2.31 (d, J = 6.5 Hz,
3H) 447 ##STR00472## 219-221 357 355 13.85 (s, 1H), 12.65 (s, 1H),
8.94 (s, 1H), 7.79 (dd, J = 9.2, 3.4 Hz, 2H), 7.72 (d, J = 8.3 Hz,
1H), 7.47 (dd, J = 8.8, 4.1 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H), 2.42
(s, 3H) 448 ##STR00473## 216-218 357 355 13.86 (s, 1H), 12.62 (s,
1H), 8.93 (s, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz,
1H), 7.37 (dd, J = 14.8, 8.2 Hz, 3H), 2.40 (s, 3H) 449 ##STR00474##
227-229 361 359 13.79 (s, 1H), 12.69 (s, 1H), 8.92 (s, 1H),
8.11-8.00 (m, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.44 (dd, J = 12.2,
5.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H) 450 ##STR00475## 231-233 361
359 13.73 (s, 1H), 12.73 (s, 1H), 8.93 (s, 1H), 7.87-7.60 (m, 4H),
7.53 (td, J = 8.3, 2.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H) 451
##STR00476## 242-245 377 375 13.73 (s, 1H), 12.74 (s, 1H), 8.92 (s,
1H), 8.02 (t, J = 1.7 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.78-7.67
(m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H) 452
##STR00477## 236-238 377 375 13.76 (s, 1H), 12.73 (s, 1H), 8.92 (s,
1H), 8.00 (d, J = 8.6 Hz, 2H), 7.72 (d, J = 8.3 Hz, 1H), 7.67 (d, J
= 8.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 1H) 453 ##STR00478## 277-279
388 386 13.71 (s, 1H), 12.96 (s, 1H), 8.94 (s, 1H), 8.80 (t, J =
1.8 Hz, 1H), 8.49 (dd, J = 8.2, 1.5 Hz, 1H), 8.41 (d, J = 7.8 Hz,
1H), 7.89 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.37 (d, J
= 8.4 Hz, 1H) 454 ##STR00479## 305-307 388 386 13.73 (s, 1H), 12.91
(s, 1H), 8.94 (s, 1H), 8.43 (d, J = 8.8 Hz, 2H), 8.22 (d, J = 8.9
Hz, 2H), 7.74 (d, J = 8.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H) 455
##STR00480## 278-280 358 356 13.82 (s, 1H), 12.57 (s, 1H), 11.28
(s, 1H), 8.98 (d, J = 1.3 Hz, 1H), 7.84 (dd, J = 7.9, 1.5 Hz, 1H),
7.73 (d, J = 8.3 Hz, 1H), 7.53-7.45 (m, 1H), 7.36 (d, J = 8.4 Hz,
1H), 7.01 (dd, J = 13.2, 7.7 Hz, 2H) 456 ##STR00481## 203-205 358
356 13.55 (s, 1H), 12.83 (s, 1H), 8.77 (s, 1H), 7.93 (d, J = 7.6
Hz, 1H), 7.88-7.70 (m, 4H), 7.38 (d, J = 8.4 Hz, 1H) 457
##STR00482## 258-260 373 371 13.81 (s, 1H), 12.61 (s, 1H), 11.54
(s, 1H), 8.97 (s, 1H), 7.74 (dd, J = 18.2, 8.4 Hz, 2H), 7.36 (d, J
= 8.4 Hz, 1H), 6.83 (d, J = 5.9 Hz, 2H), 2.31 (d, J = 7.9 Hz, 3H)
458 ##STR00483## 218-221 333 331 13.31 (s, 1H), 11.41 (s, 1H), 7.90
(d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.67-7.62 (m, 1H),
7.35-7.28 (m, 1H), 6.94-6.87 (m, 2H), 2.49 (s, 3H) 459 ##STR00484##
262-263 319 317 13.84 (s, 1H), 11.26 (s, 1H), 7.94 (d, J = 8.7 Hz,
2H), 7.65 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.00-6.92
(m, 2H), 3.85 (s, 3H), 2.48 (s, 3H) 460 ##STR00485## 258-259 367
365 13.72 (s, 1H), 11.48 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.77
(d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.01-6.94 (m, 2H),
2.48 (s, 3H) 461 ##STR00486## 244-245 357 355 13.69 (s, 1H), 11.63
(s, 1H), 8.13 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.68
(d, J = 8.5 Hz, 1H), 7.03-6.94 (m, 2H), 2.50 (s, 3H) 462
##STR00487## 187-188 367 13.61, 11.71, 11.04 (3s, 2H), 7.76-7.40
(m, 5H), 7.00, 6.76 (2d, J = 2.2 Hz, 1H), 6.97, 6.88 (2dd, J = 8.6.
2.2 Hz, 1H), 2.41, 2.37 (2s, 3H); Note: rotational isomers 463
##STR00488## 311-312 305 13.59 (s, 1H), 11.64 (s, 2H), 7.97 (dd, J
= 7.9, 1.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.49-7.42 (m, 1H),
7.07-6.95 (m, 4H), 2.43 (s, 3H) 464 ##STR00489## 140-141 315 313
13.55 (s, 1H), 11.17 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.23 (d, J
= 7.5 Hz, 1H), 7.08 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 1H),
6.83 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.47 (s, 3H)
465 ##STR00490## 176-177 362 13.44 (s, 1H), 11.40 (s, 1H), 7.90 (d,
J = 8.4 Hz, 2H), 7.77 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 7.7 Hz,
1H), 7.04 (d, J = 7.9 Hz, 1H), 6.83 (t, J = 8.1 Hz, 1H), 3.79 (s,
3H), 2.48 (s, 3H) 466 ##STR00491## 175-176 353 351 13.40 (s, 1H),
11.54 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H),
7.25 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 6.84 (t, J =
8.1 Hz, 1H), 3.80 (s, 3H), 2.49 (s, 3H) 467 ##STR00492## 245-247
363 361 13.32, 11.61, 11.55, 10.72 (4s, 2H), 7.76-7.40 (m, 4H),
7.72, 7.10 (2dd, J = 8.2, 1.2 Hz, 1H), 7.05, 6.92 (2d, J = 7.5 Hz,
1H), 6.84, 6.76 (2t, J = 8.1 Hz, 1H), 3.80, 3.66 (2s, 3H), 2.41,
2.37 (2s, 3H). Note: rotational isomers. 468 ##STR00493## 255-257
301 299 13.29 (s, 1H), 11.75 (s, 1H), 11.58 (s, 1H), 7.99 (dd, J =
7.8, 1.4 Hz, 1H), 7.50-7.42 (m, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.02
(dd, J = 17.9, 7.7 Hz, 3H), 6.84 (t, J = 8.1 Hz, 1H), 3.80 (s, 3H),
2.43 (s, 3H) 469 ##STR00494## 226-227 353 351 14.53 (s, 1H), 11.43
(s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.68 (d, J = 2.5 Hz, 1H), 7.63
(d, J = 2.5 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 2.52
(s, 3H) 470 ##STR00495## 237-238 389 14.37 (s, 1H), 11.80 (s, 1H),
8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.70 (d, J =
2.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 2.54 (s, 3H) 471
##STR00496## 306-308 339 337 472 ##STR00497## 251-252 352 13.59 (s,
1H), 11.45 (s, 1H), 8.12 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.2 Hz,
2H), 7.57 (d, J = 8.7 Hz, 1H), 6.49 (dt, J = 5.8, 2.5 Hz, 2H), 3.78
(s, 3H), 2.46 (s, 3H) 473 ##STR00498## 276-278 301 299 13.49 (s,
1H), 11.75 (s, 1H), 11.49 (s, 1H), 7.97 (dd, J = 7.9, 1.7 Hz, 1H),
7.58 (d, J = 8.6 Hz, 1H), 7.48-7.41 (m, 1H), 7.06-6.96 (m, 2H),
6.53-6.45 (m, 2H), 3.78 (s, 3H), 2.40 (s, 3H) 474 ##STR00499##
276-279 359 357 12.45 (s, 2H), 11.90 (s, 1H), 8.60 (s, 1H), 7.86
(d, J = 8.5 Hz, 1H), 7.68-7.62 (m, 2H), 7.08-7.02 (m, 2H) 475
##STR00500## 287-92 359 357 476 ##STR00501## 205-206 363 363 13.50,
11.50, 11.05 (3s, 2H), 7.75-7.38 (m, 5H), 6.51- 6.22 (m, 2H), 3.78,
3.68 (2s, 3H), 2.37, 2.34 (2s, 3H); Note: rotational isomers 477
##STR00502## 310-312 369 367 14.32 (s, 1H), 11.99 (s, 1H), 11.54
(s, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.63
(d, J = 2.5 Hz, 1H), 6.62 (dd, J = 8.9, 2.4 Hz, 1H), 6.55 (d, J =
2.4 Hz, 1H), 3.80 (s, 3H), 2.45 (s, 3H) 478 ##STR00503## 327-331
367 14.28 (s, 1H), 11.76 (s, 1H), 11.39 (s, 1H), 7.71 (d, J = 2.5
Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.48 (d, J = 3.2 Hz, 1H), 7.10
(dd, J = 8.9, 3.2 Hz, 1H), 7.00 (d, J = 8.9 Hz, 1H), 3.76 (s, 3H),
2.45 (s, 3H) 479 ##STR00504## 245 352 14.55, 11.80, 11.69, 11.46,
9.82, 9.72 (6s, 3H), 7.64- 7.50 (m, 2H), 7.16 (t, J = 7.9 Hz, 1H),
6.77-6.71 (m, 2H), 2.40, 2.38 (2s, 3H), 2.22, 2.14 (2s, 3H); Note:
rotational isomers 480 ##STR00505## 264-246 387 14.34 (s, 1H),
13.31 (s, 1H), 11.83 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.05 (d, J
= 8.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H),
7.72-7.65 (m, 2H), 7.64-7.58 (m, 1H), 7.50 (d, J = 8.9 Hz, 1H),
2.59 (s, 3H) 481 ##STR00506## 260-262 373 371 14.28 (s, 1H), 11.96
(s, 2H), 7.93-7.88 (m, 1H), 7.72 (d, J = 2.4 Hz, 1H), 7.70- 7.64
(m, 2H), 7.02 (t, J = 7.9 Hz, 1H), 2.52 (s, 3H) 482 ##STR00507##
226-227 315 313 13.72 (s, 1H), 11.07 (s, 1H), 7.93 (d, J = 8.7 Hz,
2H), 7.55 (d, J = 8.7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.51-6.44
(m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 2.44 (s, 3H) 483 ##STR00508##
239-241 363 361 13.70 (s, 1H), 11.30 (s, 1H), 7.88 (d, J = 8.5 Hz,
2H), 7.75 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.8 Hz, 1H), 6.51-6.42
(m, 2H), 3.77 (s, 3H), 2.44 (s, 3H) 484 ##STR00509## 258-259 369
367 14.46 (s, 1H), 11.58 (s, 2H), 7.69 (d, J = 2.5 Hz, 1H), 7.63
(d, J = 2.4 Hz, 1H), 7.53 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (d, J =
7.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.45 (s, 3H)
485 ##STR00510## 217-219 339 337 12.48, 12.31, 12.12, 10.62, 9.85,
9.72 (6s, 3H), 8.37, 8.17 (2s, 1H), 7.64-7.46 (m, 2H), 7.16 (t, J =
7.9 Hz, 1H), 6.78-6.70 (m, 2H), 2.21, 2.14 (2s, 3H); Note:
rotational isomers 486 ##STR00511## 267-269 355 353 12.46 (s, 1H),
12.30 (s, 1H), 12.17 (s, 1H), 8.60 (s, 1H), 7.89 (d, J = 8.9 Hz,
1H), 7.66 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 6.59 (dd,
J = 8.9, 2.4 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H) 487
##STR00512## 250-252 355 353 12.41 (s, 1H), 12.29 (s, 1H), 11.13
(s, 1H), 8.63 (s, 1H), 7.69-7.61 (m, 2H), 7.41 (d, J = 3.1 Hz, 1H),
7.11 (dd, J = 9.0, 3.1 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 3.76 (s,
3H) 488 ##STR00513## 276-278 375 373 13.74 (s, 1H), 12.79 (s, 1H),
12.41 (s, 1H), 8.70 (s, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.98 (d, J =
8.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H),
7.73-7.68 (m, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.63-7.58 (m, 1H),
7.49 (d, J = 8.9 Hz, 1H) 489 ##STR00514## 314-317 375 373 14.26 (s,
1H), 12.18 (s, 1H), 11.66 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H),7.71
(d, J = 2.5 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.10-7.04 (m, 2H),
2.45 (s, 3H) 490 ##STR00515## 322-325 374 14.28 (s, 1H),
12.07-11.66 (m, 2H), 7.90 (d, J = 2.8 Hz, 1H), 7.71 (d, J = 2.5 Hz,
1H), 7.65 (d, J = 2.4 Hz, 1H), 7.51 (dd, J = 8.8, 2.8 Hz, 1H), 7.06
(d, J = 8.8 Hz, 1H), 2.46 (s, 3H) 491 ##STR00516## 320-323 353
14.31 (s, 1H), 11.69 (s, 2H), 7.89 (d, J = 7.8 Hz, 1H), 7.71 (d, J
= 2.5 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 6.88-6.79 (m, 2H), 2.45
(s, 3H), 2.31 (s, 3H) 492 ##STR00517## 202-203 289 287 14.36 (s,
1H), 11.50 (s, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.68-7.61 (m, 2H),
7.56 (t, J = 6.7 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 6.92 (t, J =
8.0 Hz, 1H), 2.52 (s, 3H) 493 ##STR00518## 193-198 303 301 14.37
(s, 1H), 11.59 (s, 1H), 7.63 (dd, J = 8.0, 1.3 Hz, 1H), 7.55-7.41
(m, 3H), 7.34 (dd, J = 7.5, 4.3 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H),
2.45 (s, 3H), 2.41 (s, 3H) 494 ##STR00519## 164-178 303 301 14.36
(s, 1H), 11.45 (s, 1H), 7.76 (d, J = 9.6 Hz, 2H), 7.65 (dd, J =
8.1, 1.4 Hz, 1H), 7.48 (dt, J = 15.0, 3.6 Hz, 3H), 6.92 (t, J = 8.0
Hz, 1H), 2.52 (s, 3H), 2.42 (s, 3H) 495 ##STR00520## 195-200 303
301 14.38 (s, 1H), 11.40 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.64
(dd, J = 8.1, 1.5 Hz, 1H), 7.49 (dd, J = 7.9, 1.3 Hz, 1H), 7.37 (d,
J = 8.0 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 2.51 (s, 3H), 2.40 (s,
3H) 496 ##STR00521## 189-193 323 321 14.19 (s, 1H), 11.81 (s, 1H),
7.68-7.53 (m, 4H), 7.52- 7.47 (m, 2H), 6.93 (t, J = 8.0 Hz, 1H),
2.44 (s, 3H) 497 ##STR00522## 197-219 323 321 14.26 (s, 1H), 11.59
(s, 1H), 8.01 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.75-7.55 (m, 3H),
7.50 (dd, J = 7.9, 1.1 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.53 (s,
3H) 498 ##STR00523## 208-209 323 321 14.29 (s, 1H), 11.55 (s, 1H),
7.99 (d, J = 8.5 Hz, 2H), 7.65 (ddd, J = 4.9, 3.8, 1.7 Hz, 3H),
7.50 (dd, J = 7.9, 1.2 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 2.52 (s,
3H) 499 ##STR00524## 203-204 319 317 14.40 (s, 1H), 11.33 (s, 1H),
7.96 (d, J = 8.7 Hz, 2H), 7.64 (dd, J = 8.0, 1.3 Hz, 1H), 7.48 (dd,
J = 7.9, 1.2 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.92 (t, J = 8.0
Hz, 1H), 3.85 (s, 3H), 2.51 (s, 3H) 500 ##STR00525## 226-232 368
366 14.29 (s, 1H), 11.55 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78
(d, J = 8.5 Hz, 2H), 7.65 (dd, J = 8.1, 1.4 Hz,
1H), 7.49 (dd, J = 7.9, 1.1 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 2.52
(s, 3H) 501 ##STR00526## 250-256 357 355 14.26 (s, 1H), 11.70 (s,
1H), 8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.66 (dd,
J = 8.1, 1.3 Hz, 1H), 7.51 (dd, J = 7.9, 1.1 Hz, 1H), 6.93 (t, J =
8.0 Hz, 1H), 2.53 (s, 3H) 502 ##STR00527## 178-183 368 366 14.20
(s, 1H), 11.80 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.66-7.59 (m,
2H), 7.53- 7.46 (m, 3H), 6.93 (t, J = 8.0 Hz, 1H), 2.44 (s, 3H) 503
##STR00528## 283-287 305 303 14.17 (s, 1H), 11.68 (s, 2H), 7.99
(dd, J = 7.9, 1.7 Hz, 1H), 7.67 (dd, J = 8.1, 1.4 Hz, 1H), 7.48
(ddd, J = 14.2, 7.4, 1.5 Hz, 2H), 7.09- 6.99 (m, 2H), 6.93 (t, J =
8.0 Hz, 1H), 2.46 (s, 3H) 504 ##STR00529## 207-208 289 287 13.46
(s, 1H), 11.45 (s, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.64 (dd, J =
13.0, 4.9 Hz, 2H), 7.55 (t, J = 7.5 Hz, 2H), 7.34 (dd, J = 8.8, 2.5
Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H) 505 ##STR00530##
192-193 303 301 13.46 (s, 1H), 11.53 (s, 1H), 7.64 (d, J = 2.6 Hz,
1H), 7.52 (d, J = 7.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.33
(dt, J = 7.3, 2.4 Hz, 3H), 6.95 (d, J = 8.8 Hz, 1H), 2.42 (s, 3H),
2.40 (s, 3H) 506 ##STR00531## 222-228 303 301 13.47 (s, 1H), 11.40
(s, 1H), 7.75 (d, J = 10.4 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.44
(d, J = 5.9 Hz, 2H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H), 6.95 (d, J =
8.8 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H) 507 ##STR00532## 221-228
303 13.48 (s, 1H), 11.35 (s, 1H), 7.86 (d, J = 7.9 Hz, 2H), 7.65
(d, J = 2.5 Hz, 1H), 7.34 (dd, J = 13.8, 5.2 Hz, 3H), 6.94 (d, J =
8.8 Hz, 1H), 2.49 (s, 3H), 2.40 (s, 3H) 508 ##STR00533## 210-217
323 321 13.28 (s, 1H), 11.73 (s, 1H), 7.56 (dddd, J = 30.0, 21.9,
7.6, 1.5 Hz, 5H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8
Hz, 1H), 2.42 (s, 3H) 509 ##STR00534## 244-249 323 321 13.37 (s,
1H), 11.53 (s, 1H), 8.01 (s, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.69
(dd, J = 16.9, 5.2 Hz, 2H), 7.59 (t, J = 7.9 Hz, 1H), 7.35 (dd, J =
8.8, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.50 (s, 3H) 510
##STR00535## 248-252 323 321 13.40 (s, 1H), 11.50 (s, 1H), 7.98 (d,
J = 8.5 Hz, 2H), 7.65 (dd, J = 11.0, 5.5 Hz, 3H), 7.35 (dd, J =
8.7, 2.5 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 2.49 (s, 3H) 511
##STR00536## 203-228 319 317 13.51 (s, 1H), 11.28 (s, 1H), 7.95 (d,
J = 8.7 Hz, 2H), 7.65 (d, J = 2.6 Hz, 1H), 7.33 (dd, J = 8.8, 2.6
Hz, 1H), 7.09 (t, J = 5.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 3.85
(s, 3H), 2.49 (s, 3H) 512 ##STR00537## 269-271 368 366 13.39 (s,
1H), 11.50 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.5 Hz,
2H), 7.66 (d, J = 2.5 Hz, 1H), 7.35 (dd, J = 8.8, 2.5 Hz, 1H), 6.95
(d, J = 8.8 Hz, 1H), 2.49 (s, 3H) 513 ##STR00538## 271-273 357 355
13.35 (s, 1H), 11.65 (s, 1H), 8.14 (d, J = 8.1 Hz, 2H), 7.94 (d, J
= 8.3 Hz, 2H), 7.67 (d, J = 2.5 Hz, 1H), 7.36 (dd, J = 8.8, 2.5 Hz,
1H), 6.96 (d, J = 8.8 Hz, 1H), 2.51 (s, 3H) 514 ##STR00539##
222-225 368 366 13.29 (s, 1H), 11.73 (s, 1H), 7.75 (dd, J = 7.8,
1.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.49 (ddd, J = 9.5, 7.5, 1.5 Hz,
2H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 2.42
(s, 3H) 515 ##STR00540## 298-318 305 303 13.25 (s, 1H), 11.67 (d, J
= 54.4 Hz, 2H), 7.98 (dd, J = 7.8, 1.6 Hz, 1H), 7.67 (d, J = 2.5
Hz, 1H), 7.50-7.42 (m, 1H), 7.34 (dd, J = 8.7, 2.5 Hz, 1H),
7.08-6.93 (m, 3H), 2.43 (s, 3H) 516 ##STR00541## 202-252 364 362
13.56 (s, 1H), 11.28 (s, 1H), 7.95 (d, J = 8.7 Hz, 2H), 7.75 (d, J
= 2.4 Hz, 1H), 7.44 (dd, J = 8.7, 2.4 Hz, 1H), 7.08 (d, J = 8.8 Hz,
2H), 6.89 (d, J = 8.7 Hz, 1H), 3.85 (s, 3H), 2.48 (s, 3H) 517
##STR00542## 270-275 413 411 13.44 (s, 1H), 11.50 (s, 1H), 7.90 (d,
J = 8.4 Hz, 2H), 7.81-7.72 (m, 4H), 6.90 (d, J = 8.7 Hz, 1H), 2.49
(s, 3H) 518 ##STR00543## 272-280 402 400 13.38 (s, 1H), 11.65 (s,
1H), 8.14 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.78 (d, J
= 2.4 Hz, 1H), 7.47 (dd, J = 8.7, 2.3 Hz, 1H), 6.91 (d, J = 8.8 Hz,
1H), 2.50 (s, 3H) 519 ##STR00544## 216-218 413 411 13.31 (s, 1H),
11.73 (s, 1H), 7.75 (dd, J = 6.2, 1.7 Hz, 2H), 7.62-7.58 (m, 1H),
7.50-7.43 (m, 3H), 6.91 (d, J = 8.8 Hz, 1H), 2.41 (s, 3H) 520
##STR00545## 281-303 350 348 13.27 (s, 1H), 11.67 (d, J = 51.7 Hz,
2H), 7.98 (dd, J = 7.9, 1.6 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H),
7.50-7.43 (m, 2H), 7.07-6.98 (m, 2H), 6.91 (d, J = 8.7 Hz, 1H),
2.43 (s, 3H) 521 ##STR00546## 204-212 330 328 15.32 (s, 1H), 11.48
(s, 1H), 8.01-7.90 (m, 4H), 7.13- 7.01 (m, 3H), 3.86 (s, 3H), 2.56
(s, 3H) 522 ##STR00547## 244-252 379 15.16 (s, 1H), 11.70 (s, 1H),
8.02-7.87 (m, 4H), 7.79 (d, J = 8.5 Hz, 2H), 7.06 (t, J = 8.0 Hz,
1H), 2.56 (s, 3H) 523 ##STR00548## 267-278 368 366 15.11 (s, 1H),
11.85 (s, 1H), 8.15 (d, J = 8.1 Hz, 2H), 8.00 (dd, J = 8.0, 1.4 Hz,
1H), 7.95 (d, J = 8.1 Hz, 3H), 7.08 (t, J = 8.0 Hz, 1H), 2.57 (s,
3H) 524 ##STR00549## 186-188 379 377 15.06 (s, 1H), 11.97 (s, 1H),
7.95 (dd, J = 8.3, 1.2 Hz, 2H), 7.76 (dd, J = 7.8, 1.1 Hz, 1H),
7.62 (dd, J = 7.4, 1.8 Hz, 1H), 7.53 (ddd, J = 7.4, 6.8, 1.5 Hz,
2H), 7.07 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H) 525 ##STR00550##
274-283 314 15.02 (s, 1H), 11.73 (s, 1H), 11.69 (s, 1H), 8.05-7.89
(m, 3H), 7.51-7.43 (m, 1H), 7.11-6.98 (m, 3H), 2.50 (s, 3H) 526
##STR00551## 76.9-187 315 313 13.80 (s, 1H), 7.92 (d, J = 7.3 Hz,
1H), 7.64-7.42 (m, 2H), 6.15 (dd, J = 9.6, 7.4 Hz, 1H), 6.10 (dd, J
= 12.6, 2.3 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.77 (s, 1H), 3.74
(d, J = 1.3 Hz, 1H), 2.55 (s, 3H) 527 ##STR00552## 226-229 323 321
14.07 (s, 1H), 11.53 (s, 1H), 8.02-7.87 (m, 3H), 7.69- 7.59 (m,
2H), 7.58-7.50 (m, 2H), 7.11 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H) 528
##STR00553## 200-203 337 335 14.06 (s, 1H), 11.61 (s, 1H), 7.89 (s,
1H), 7.65 (dd, J = 8.6, 2.0 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.44
(t, J = 6.9 Hz, 1H), 7.37-7.28 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H),
2.48 (s, 3H), 2.41 (s, 3H) 529 ##STR00554## 235-238 337 335 14.08
(s, 1H), 11.48 (s, 1H), 7.92 (s, 1H), 7.80-7.72 (m, 2H), 7.65 (d, J
= 7.0 Hz, 1H), 7.48-7.43 (m, 2H), 7.11 (d, J = 8.6 Hz, 1H), 2.56
(s, 3H), 2.41 (s, 3H) 530 ##STR00555## 225-229 337 335 14.09 (s,
1H), 11.44 (s, 1H), 7.91 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.64
(dd, J = 8.6, 1.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.10 (d, J =
8.6 Hz, 1H), 2.55 (s, 3H), 2.40 (s, 3H) 531 ##STR00556## 189-191
357 355 13.86 (s, 1H), 11.82 (s, 1H), 7.90 (s, 1H), 7.69-7.45 (m,
5H), 7.12 (d, J = 8.6 Hz, 1H), 2.48 (s, 3H) 532 ##STR00557##
241-245 357 355 13.96 (s, 1H), 11.61 (s, 1H), 8.02 (s, 1H),
7.94-7.89 (m, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.68-7.63 (m, 1H),
7.59 (t, J = 7.9 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 2.57 (s, 3H)
533 ##STR00558## 263-265 357 355 14.00 (s, 1H), 11.58 (s, 1H), 7.99
(d, J = 8.5 Hz, 2H), 7.92 (s, 1H), 7.68-7.61 (m, 3H), 7.11 (d, J =
8.7 Hz, 1H), 2.56 (s, 3H) 534 ##STR00559## 228-231 353 351 14.12
(s, 1H), 11.36 (s, 1H), 7.96 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H),
7.64 (dd, J = 8.7, 1.9 Hz, 1H), 7.12-7.06 (m, 3H), 3.85 (s, 3H),
2.55 (s, 3H) 535 ##STR00560## 256-259 402 400 13.99 (s, 1H), 11.58
(s, 1H), 7.94-7.89 (m, 3H), 7.78 (d, J = 8.4 Hz, 2H), 7.66 (d, J =
8.8 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 2.56 (s, 3H) 536
##STR00561## 228-234 391 389 13.95 (s, 1H), 11.73 (s, 1H), 8.15 (d,
J = 8.1 Hz, 2H), 7.97-7.91 (m, 3H), 7.69-7.64 (m, 1H), 7.12 (d, J =
8.6 Hz, 1H), 2.57 (s, 3H) 537 ##STR00562## 192-200 402 400 13.87,
11.81, 11.70, 11.28 (4s, 2H), 7.91-7.39 (m, 6H), 7.21, 6.87 (2d, J
= 8.6 Hz, 1H), 2.48, 2.42 (2s, 3H); Note: rotational isomers 538
##STR00563## 277-297 361 (+Na) 13.84 (s, 1H), 11.71 (s, 2H), 7.98
(dd, J = 7.9, 1.6 Hz, 1H), 7.93 (s, 1H), 7.68-7.63 (m, 1H),
7.50-7.43 (m, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.08-6.98 (m, 2H),
2.49 (s, 3H) 539 ##STR00564## 242-245 414 540 ##STR00565## 221-222
425 14.64 (s, 1H), 11.71 (s, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.79
(d, J = 2.3 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.49-7.41 (m, 1H),
7.37- 7.29 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H) 541 ##STR00566##
236-238 427 425 14.62 (s, 1H), 11.55 (s, 1H), 7.84 (d, J = 2.3 Hz,
1H), 7.81 (d, J = 2.3 Hz, 1H), 7.78-7.72 (m, 2H), 7.48-7.41 (m,
2H), 2.52 (s, 3H), 2.41 (s, 3H) 542 ##STR00567## 258-259 425 14.64
(s, 1H), 11.50 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 2.3
Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.0 Hz, 2H), 2.51
(s, 3H), 2.40 (s, 3H) 543 ##STR00568## 207-209 447 445 14.46 (s,
1H), 11.92 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz,
1H), 7.66-7.53 (m, 3H), 7.51-7.46 (m, 1H), 2.44 (s, 3H) 544
##STR00569## 255-256 447 14.52 (s, 1H), 11.69 (s, 1H), 8.02 (s,
1H), 7.91 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J
= 2.3 Hz, 1H), 7.74-7.70 (m, 1H), 7.60 (t, J = 7.9 Hz, 1H), 2.53
(s, 3H) 545 ##STR00570## 255-258 445 14.55 (s, 1H), 11.65 (s, 1H),
7.99 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 2.2 Hz, 1H), 7.82 (d, J =
2.3 Hz, 1H), 7.67-7.61 (m, 2H), 2.52 (s, 3H) 546 ##STR00571##
247-248 441 14.66 (s, 1H), 11.43 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H),
7.83 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.12-7.06 (m,
2H), 3.85 (s, 3H), 2.51 (s, 3H) 547 ##STR00572## 264-266 493 491
14.55 (s, 1H), 11.65 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.85 (d, J
= 2.2 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.80-7.76 (m, 2H), 2.52
(s, 3H) 548 ##STR00573## 255-257 481 14.51 (s, 1H), 11.80 (s, 1H),
8.15 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.86 (d, J =
2.2 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 2.53 (s, 3H) 549
##STR00574## 214-216 491 489 14.46 (s, 1H), 11.91 (s, 1H), 7.86 (d,
J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.76 (dd, J = 7.8, 1.2
Hz, 1H), 7.61 (dd, J = 7.4, 1.8 Hz, 1H), 7.53 (td, J = 7.4, 1.3 Hz,
1H), 7.47 (td, J = 7.6, 1.9 Hz, 1H), 2.44 (s, 3H) 550 ##STR00575##
305-306 427 14.43 (s, 1H), 11.71 (s, 2H), 7.97 (dd, J = 7.9, 1.7
Hz, 1H), 7.86-7.82 (m, 2H), 7.50- 7.43 (m, 1H), 7.08-6.98 (m, 2H),
2.45 (s, 3H) 551 ##STR00576## 154-155 315 313 13.71 (s, 1H), 11.27
(s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.65-7.59 (m, 1H), 7.58- 7.51
(m, 2H), 7.38 (d, J = 9.0 Hz, 1H), 6.60 (d, J = 9.0 Hz, 1H), 3.82
(s, 3H), 3.71 (s, 3H), 2.45 (s, 3H) 552 ##STR00577## 150-152 329
327 13.71 (s, 1H), 11.34 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H),
7.46-7.39 (m, 1H), 7.32 (dt, J = 11.7, 8.4 Hz, 3H), 6.60 (d, J =
9.0 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H)
553 ##STR00578## 158-162 329 327 13.70 (s, 1H), 11.22 (s, 1H),
7.77-7.68 (m, 2H), 7.46- 7.41 (m, 2H), 7.37 (d, J = 9.0 Hz, 1H),
6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s, 3H),
2.41 (s, 3H) 554 ##STR00579## 245-249 329 327 13.71 (s, 1H), 11.18
(s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.41-7.31 (m, 3H), 6.60 (d, J =
9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H)
555 ##STR00580## 77-86 349 347 13.54, 11.55, 10.92 (3s, 2H),
7.63-7.44 (m, 4H), 7.36, 7.25 (2d, J = 9.1 Hz, 1H), 6.61, 6.53 (2d,
J = 9.1 Hz, 1H), 3.82, 3.75, 3.71, 3.50 (4s, 6H), 2.38, 2.35 (2s,
3H); Note: rotational isomers 556 ##STR00581## 194-201 349 347
13.60 (s, 1H), 11.37 (s, 1H), 8.00-7.97 (m, 1H), 7.89 (d, J = 7.8
Hz, 1H), 7.72- 7.67 (m, 1H), 7.58 (t, J = 7.9 Hz, 1H), 7.39 (d, J =
9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H),
2.46 (s, 3H) 557 ##STR00582## 230-235 349 347 13.63 (s, 1H), 11.33
(s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.38
(d, J = 9.0 Hz, 1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71
(s, 3H), 2.45 (s, 3H) 558 ##STR00583## 230-232 345 343 13.73 (s,
1H), 11.11 (s, 1H), 7.93 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 9.0 Hz,
1H), 7.08 (d, J = 8.9 Hz, 2H), 6.60 (d, J = 9.1 Hz, 1H), 3.85 (s,
3H), 3.82 (s, 3H), 3.71 (s, 3H), 2.44 (s, 3H)
559 ##STR00584## 241-245 393 391 13.62 (s, 1H), 11.33 (s, 1H), 7.89
(d, J = 8.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 9.0 Hz,
1H), 6.61 (d, J = 9.1 Hz, 1H), 3.82 (s, 3H), 3.71 (s, 3H), 2.45 (s,
3H) 560 ##STR00585## 229-233 383 381 13.60 (s, 1H), 11.48 (s, 1H),
8.12 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.39 (d, J =
9.0 Hz, 1H), 6.62 (d, J = 9.1 Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H),
2.46 (s, 3H) 561 ##STR00586## 195-200 393 391 13.54, 11.55, 10.90
(3s, 2H), 7.76-7.42 (m, 4H), 7.36, 7.25 (2d, J = 9.1 Hz, 1H), 6.61,
6.53 (2d, J = 9.1 Hz, 1H), 3.82, 3.75, 3.71, 3.50 (4s, 6H), 2.38,
2.34 (2s, 3H); Note: rotational isomers 562 ##STR00587## 279-297
331 329 13.51 (s, 1H), 11.74 (s, 1H), 11.51 (s, 1H), 7.98 (dd, J =
7.9, 1.5 Hz, 1H), 7.49-7.42 (m, 1H), 7.40 (d, J = 9.0 Hz, 1H),
7.07-6.97 (m, 2H), 6.62 (d, J = 9.0 Hz, 1H), 3.83 (s, 3H), 3.71 (s,
3H), 2.40 (s, 3H) 563 ##STR00588## 287-292 375 373 (300 MHz,
DMSO-d.sub.6) 12.48 (s, 1H), 11.17 (s, 1H), 8.63 (s, 1H), 8.44 (s,
1H), 7.94 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.71-7.64
(m, 2H), 7.58-7.49 (m, 1H), 7.42-7.32 (m, 2H) 564 ##STR00589##
312-315 387 14.42 (s, 1H), 12.04-11.57 (m, 2H), 8.60 (s, 1H), 8.00
(d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 2.5 Hz,
1H), 7.66 (d, J = 2.5 Hz, 1H), 7.56-7.51 (m, 1H), 7.41-7.35 (m,
2H), 2.50 (s, 3H) 565 ##STR00590## 278-279 351 14.33 (s, 1H), 11.75
(s, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.66
(d, J = 2.4 Hz, 1H), 7.41 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 7.7 Hz,
1H), 2.54 (s, 3H), 2.23 (s, 3H) 566 ##STR00591## 177-184 329 327
12.89 (s, 1H), 11.04 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.34 (d, J
= 7.9 Hz, 2H), 6.12 (d, J = 5.0 Hz, 2H), 3.80 (s, 3H), 3.76 (s,
3H), 2.39 (s, 3H), 2.37 (s, 3H) 567 ##STR00592## 206-215 349 347
10.05 (s, 1H), 9.70 (s, 1H), 7.59 (dd, J = 8.9, 2.1 Hz, 2H), 7.47
(d, J = 5.7 Hz, 2H), 6.17 (d, J = 2.0 Hz, 1H), 6.14 (d, J = 2.1 Hz,
1H), 3.74 (s, 6H), 2.15 (s, 2H) 568 ##STR00593## 136-140 349 347
12.80 (s, 1H), 11.19 (s, 1H), 7.95 (d, J = 8.4 Hz, 2H), 7.61 (d, J
= 8.3 Hz, 2H), 6.14-6.09 (m, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.38
(s, 3H) 569 ##STR00594## 143-146 345 343 12.91 (s, 1H), 10.98 (s,
1H), 7.92 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 6.12 (dd,
J = 7.6, 2.3 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 3.76 (s, 3H),
2.37 (s, 3H) 570 ##STR00595## 134-159 394 392 12.78 (s, 1H), 11.19
(s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 6.12
(dd, J = 7.8, 2.2 Hz, 2H), 3.80 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H)
571 ##STR00596## 131-133 383 381 12.70 (s, 1H), 11.33 (s, 1H), 8.11
(d, J = 8.1 Hz, 2H), 7.92 (d, J = 8.3 Hz, 2H), 6.13 (dd, J = 7.1,
2.3 Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.38 (s, 3H) 572
##STR00597## 222-225 291 289 13.55 (s, 1H), 11.54 (s, 1H), 7.95 (d,
J = 7.4 Hz, 2H), 7.65 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz,
2H), 7.43- 7.34 (m, 2H), 2.50 (s, 3H) 573 ##STR00598## 186-188 305
303 13.56 (s, 1H), 11.63 (s, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.45
(t, J = 8.0 Hz, 1H), 7.40-7.29 (m, 4H), 2.42 (s, 3H), 2.40 (s, 3H)
574 ##STR00599## 215-216 305 303 13.56 (s, 1H), 11.49 (s, 1H), 7.75
(d, J = 11.6 Hz, 2H), 7.45 (d, J = 6.2 Hz, 2H), 7.39 (td, J = 8.9,
2.8 Hz, 2H), 2.49 (s, 3H), 2.41 (s, 3H) 575 ##STR00600## 220-22 305
303 13.57 (s, 1H), 11.44 (s, 1H), 7.87 (d, J = 7.9 Hz, 2H), 7.38
(dd, J = 13.4, 6.6 Hz, 4H), 2.49 (s, 3H), 2.40 (s, 3H) 576
##STR00601## 205-209 325 323 13.38 (s, 1H), 11.83 (s, 1H), 7.60
(dddd, J = 15.2, 9.7, 7.7, 1.6 Hz, 3H), 7.48 (td, J = 7.3, 1.4 Hz,
1H), 7.44- 7.34 (m, 2H), 2.42 (s, 3H) 577 ##STR00602## 279-282 325
323 13.45 (s, 1H), 11.62 (s, 1H), 8.02 (s, 1H), 7.91 (d, J = 7.7
Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.41
(dd, J = 9.5, 7.1 Hz, 2H), 2.50 (s, 3H) 578 ##STR00603## 276-280
325 323 13.48 (s, 1H), 11.59 (s, 1H), 7.98 (d, J = 8.5 Hz, 2H),
7.64 (d, J = 8.5 Hz, 2H), 7.43-7.36 (m, 2H), 2.50 (s, 3H) 579
##STR00604## 243-247 321 319 13.59 (s, 1H), 11.36 (s, 1H), 7.96 (d,
J = 8.7 Hz, 2H), 7.37 (dd, J = 9.4, 3.2 Hz, 2H), 7.09 (d, J = 8.9
Hz, 2H), 3.85 (s, 3H), 2.49 (s, 3H) 580 ##STR00605## 268-270 370
368 13.48 (s, 1H), 11.59 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.78
(d, J = 8.5 Hz, 2H), 7.44-7.36 (m, 2H), 2.49 (s, 3H) 581
##STR00606## 287-291 359 357 13.44 (s, 1H), 11.73 (s, 1H), 8.14 (d,
J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 9.5, 7.5
Hz, 2H), 2.51 (s, 3H) 582 ##STR00607## 190-195 370 368 13.38 (s,
1H), 11.84 (s, 1H), 7.75 (dd, J = 7.8, 1.0 Hz, 1H), 7.62 (d, J =
1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.55-7.48 (m, 2H), 7.37 (dd,
J = 8.4, 2.2 Hz, 1H), 2.42 (s, 3H) 583 ##STR00608## 308-323 307 305
13.37 (s, 1H), 11.70 (s, 2H), 7.98 (dd, J = 7.9, 1.7 Hz, 1H), 7.44
(ddd, J = 28.3, 14.3, 6.0 Hz, 3H), 7.07-6.98 (m, 2H), 2.43 (s, 3H)
584 ##STR00609## 269-274 329 327 9.96 (s, 1H), 9.24 (s, 1H), 7.35-
7.27 (m, 2H), 7.19 (t, J = 3.6 Hz, 2H), 6.08 (d, J = 10.7 Hz, 2H),
3.72 (s, 3H), 3.69 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H) 585
##STR00610## 207-209 329 327 12.87 (s, 1H), 11.09 (s, 1H), 7.72 (d,
J = 9.4 Hz, 2H), 7.42 (d, J = 4.6 Hz, 2H), 6.12 (dd, J = 7.8, 2.1
Hz, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H) 586
##STR00611## 182-199 331 329 13.80 (s, 1H), 12.50 (s, 1H), 11.54
(s, 1H), 7.96 (dd, J = 7.8, 1.5 Hz, 1H), 7.47- 7.35 (m, 1H),
7.08-6.91 (m, 2H), 6.14 (d, J = 2.3 Hz, 1H), 6.08 (d, J = 2.4 Hz,
1H), 3.80 (s, 3H), 3.77 (s, 3H), 2.35 (s, 3H) 587 ##STR00612##
195-96 377 375 11.38 (s, 1H), 10.47 (s, 1H), 7.71 (dd, J = 15.3,
4.9 Hz, 3H), 7.58 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H),
7.35 (d, J = 2.3 Hz, 1H) 588 ##STR00613## gum 351 349 12.49 (s,
1H), 9.88 (s, 1H), 7.96 (d, J = 2.2 Hz, 1H), 7.86 (d, J = 2.2 Hz,
1H), 7.62-7.31 (m, 4H), 7.13 (s, 1H), 3.78-3.65 (m, 1H), 1.07 (d, J
= 9.5 Hz, 6H) 589 ##STR00614## 218-219 349 347 13.96 (s, 1H), 11.71
(s, 1H), 7.95 (d, J = 7.1 Hz, 2H), 7.88 (s, 1H), 7.62 (dt, J =
23.1, 7.2 Hz, 4H), 2.08-1.91 (m, 1H), 1.28 (d, J = 7.4 Hz, 2H),
0.79 (d, J = 4.4 Hz, 2H) 590 ##STR00615## 214-215 337 335 14.55 (s,
1H), 11.67 (s, 1H), 7.91 (d, J = 7.4 Hz, 2H), 7.75-7.61 (m, 3H),
7.57 (t, J = 7.5 Hz, 2H), 3.06 (q, J = 7.4 Hz, 2H), 1.14 (t, J =
7.5 Hz, 3H) 591 ##STR00616## 208-210 309 307 10.75 (s, 1H), 10.47
(s, 1H), 7.73-7.63 (m, 2H), 7.62- 7.53 (m, 1H), 7.47 (dd, J = 10.4,
4.6 Hz, 2H), 7.43- 7.35 (m, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.03 (d,
J = 8.3 Hz, 1H), 6.96 (td, J = 7.6, 0.9 Hz, 1H) 592 ##STR00617##
241-243 297 295 9.90 (s, 1H), 8.78 (s, 1H), 7.57-7.24 (m, 6H),
7.11- 6.87 (m, 3H), 1.18 (s, 9H)
[0109] As exemplified below, hydrazones of the present invention,
or their metal complexes, in a mixture with inorganic or organic
mono- or divalent copper salts or chelates (hereinafter referred to
as "copper products") increase the biological potency of copper
products, enabling comparable or improved efficacy at lower copper
use rates. While not intending to be all-inclusive, copper products
which may be mixed with the compounds of the present invention to
provide enhanced potency may include the following: copper
oxychloride, copper octanoate, copper ammonium carbonate, copper
arsenate, copper oxysulfate, copper formate, copper propionate,
copper oxyacetate, copper citrate, copper chloride, copper
diammonium chloride, copper nitrate, copper carbonate, copper
phosphate, copper pyrophosphate, copper disodium EDTA, copper
diammonium EDTA, copper oxalate, copper tartrate, copper gluconate,
copper glycinate, copper glutamate, copper aspartate, copper
adipate, copper palmitate, copper stearate, copper caprylate,
copper decanoate, copper undecylenate, copper neodecanoate, copper
linoleate, copper oleate, copper borate, copper methanesulfonate,
copper sulfamate, copper acetate, copper hydroxide, copper oxide,
copper oxychloride-sulfate, copper sulfate, basic copper sulfate,
copper-oxine, copper 3-phenylsalicylate, copper chloride hydroxide,
copper dimethyldithiocarbamate, ammonium copper sulfate, copper
magnesium sulfate, coppernaphthenate, copper ethanolamine,
chromated copper arsenate, ammoniacal copper arsenate, ammoniacal
copper zinc arsenate, ammoniacal copper borate, Bordeaux mixture,
copper zinc chromate, cufraneb, cupric hydrazinium sulfate,
cuprobam, nano-copper materials and copper didecyldimethylammonium
chloride and where appropriate the hydrates of such compounds.
[0110] Salicylaldehyde benzoylhydrazones such as those of the
current invention are known in the literature as chelators of metal
cations (Inorganica Chimica Acta 1982, 67, L25-L27, which is
expressly incorporated by reference herein), including copper.
Antimicrobial activity has been reported for
o-hydroxybenzaldehyde-N-salicyloylhydrazone and its copper, nickel
and cobalt complexes towards Staphylococcus aureus, Escherichia
coli, Aspergillus niger and A. flavus (Proceedings of the National
Academy of Sciences, India 1991, Section A Part IV, Vol. LXI, pp.
447-452, which is expressly incorporated by reference herein).
However, data in this report showed that the copper complex of
o-hydroxybenzaldehyde-N-salicyloylhydrazone had a similar level of
antimicrobial activity to that of
o-hydroxybenzaldehyde-N-salicyloylhydrazone alone and the nickel
and cobalt complexes, and provided no indication that
salicylaldehyde benzoylhydrazones might show any synergistic
antimicrobial effect in combination with copper.
Example 26
Effect of Copper on Fungitoxicity of Hydrazones Towards
Leptosphaeria nodorum
[0111] 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 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.
[0112] 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.
[0113] Results for growth inhibition by test compounds in
copper-plus medium ("% Inhn. Plus Copper Observed") were compared
with predicted values ("% Inhn. Plus Copper Predicted") that were
calculated using the formula set forth by S. R. Colby in Weeds
1967, 15, 20-22 based on results obtained for the same compounds in
copper-minus medium ("% Inhn. Minus Copper Observed") and the
inhibition attributed to copper chloride alone, as determined by
comparing growth in copper-minus and copper-plus media without any
test compound across experiments. Data are presented in Table 3.
Results illustrate that hydrazones and copper produce a synergistic
fungitoxic effect towards LEPTNO.
Example 27
Efficacy of Hydrazones in Mixture with Copper Against Tomato Blight
(Phytophthora infestans)
[0114] 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 Compound Concn. Copper Copper Copper TLB % Number
(.mu.g/mL) Observed Observed Predicted Control 1 0.05 0.7 96.2 7.8
64.0 2 0.05 0.0 95.1 7.1 61.4 3 0.05 2.3 93.0 9.3 47.0 4 0.05 4.4
94.5 11.2 67.8 5 0.05 4.8 56.1 11.6 22.0 6 0.05 3.9 96.4 10.7 88.1
7 0.05 2.6 97.2 9.5 54.6 8 0.05 0.0 92.6 7.1 59.6 9 0.05 0.0 93.6
7.1 67.3 10 0.05 6.9 97.2 13.5 96.0 11 0.05 0.3 97.2 7.4 42.1 12
0.05 0.5 97.4 7.6 94.0 13 0.05 0.0 96.2 7.1 33.3 14 0.156 2.9 59.1
9.8 7.5 15 0.05 4.4 96.6 11.1 58.5 16 0.05 0.0 97.1 7.1 94.0 17
0.05 9.4 95.9 15.9 69.0 18 0.05 0.0 96.9 7.1 38.6 19 0.05 2.9 88.8
9.8 25.0 20 0.05 2.8 96.5 9.7 96.5 21 0.05 0.1 94.1 7.2 65.5 22
0.05 16.0 97.6 22.0 93.2 23 0.05 2.3 95.4 9.2 53.3 24 0.05 7.6 92.8
14.1 8.9 25 0.05 0.0 97.3 7.1 35.1 26 0.05 2.1 98.4 9.1 12.3 27
0.05 16.5 97.9 22.4 43.3 28 0.05 7.0 96.8 13.6 62.7 29 0.05 0.0
98.0 7.1 50.8 30 0.05 0.0 97.0 7.1 40.7 31 0.05 2.2 89.0 9.2 33.3
32 0.05 0.0 94.4 7.1 74.6 33 0.05 0.0 93.1 7.1 50.9 34 0.05 0.0
97.8 7.1 68.4 35 0.05 3.8 96.5 10.6 0.0 36 0.05 5.9 98.4 12.6 33.9
37 0.05 3.3 97.0 10.2 33.0 38 0.05 2.4 98.3 9.4 17.0 39 0.05 1.3
97.9 8.3 18.6 40 0.05 0.0 94.8 7.1 64.9 41 0.05 0.0 97.2 7.1 87.0
42 0.05 9.2 93.2 15.6 60.0 43 0.156 14.2 75.4 20.3 68.8 44 0.05 0.3
93.0 7.3 0.7 45 0.05 0.0 96.2 7.1 49.0 46 0.05 20.5 95.9 26.1 72.7
47 0.05 0.0 97.1 7.1 33.0 48 0.05 0.3 94.6 7.4 40.0 49 0.05 14.6
97.1 20.7 0.7 50 0.05 3.5 97.4 10.4 43.5 51 0.05 0.0 97.6 7.1 4.8
52 0.2 12.3 96.4 18.5 NT 53 0.05 0.0 96.8 7.1 62.0 54 0.05 0.0 95.7
7.1 17.0 55 0.05 0.0 95.5 7.1 43.9 56 0.05 2.1 96.3 9.1 81.3 57
0.05 0.0 97.3 7.1 89.5 58 0.05 0.0 95.0 7.1 49.0 59 0.05 12.8 97.5
19.0 79.7 60 0.05 7.3 97.5 13.9 85.0 61 0.05 3.8 93.6 10.6 60.0 62
0.05 0.0 96.3 7.1 56.1 63 0.05 0.0 96.7 7.1 40.4 64 0.05 0.0 97.8
7.1 43.0 65 0.05 0.0 98.3 7.1 10.0 66 0.05 0.1 97.4 7.2 51.0 67
0.05 2.6 91.8 9.5 75.0 68 0.05 15.8 97.0 21.8 75.9 69 0.05 19.3
96.9 25.1 90.8 70 0.05 19.6 98.2 25.3 93.1 71 0.05 2.6 91.2 9.5
78.0 72 0.05 14.1 91.3 20.2 81.3 73 0.05 8.6 98.0 15.1 87.3 74 0.05
3.0 95.7 9.8 63.6 75 0.05 0.0 98.4 7.1 15.8 76 0.05 0.0 97.0 7.1
89.8 77 0.05 7.6 96.1 14.1 55.5 78 0.05 7.9 96.3 14.4 70.9 79 0.05
12.2 97.1 18.4 84.4 80 0.05 0.0 98.4 7.1 91.5 81 0.05 2.4 96.1 9.3
97.0 82 0.05 8.4 97.4 14.9 60.6 83 0.05 5.9 98.0 12.5 60.6 84 0.05
5.6 95.5 12.3 83.6 85 0.05 5.3 90.0 12.0 51.5 86 0.05 0.3 97.6 7.4
80.7 87 0.05 8.1 98.6 14.7 69.5 88 0.05 10.7 96.7 17.0 4.8 89 0.05
17.5 95.9 23.3 85.8 90 0.05 9.5 96.4 15.9 54.6 91 0.05 0.0 79.3 7.1
18.0 92 0.05 1.9 98.2 8.8 71.9 93 0.05 6.0 95.2 12.7 77.2 94 0.05
0.0 92.9 7.1 37.0 95 0.05 14.1 94.0 20.2 81.2 96 0.05 1.2 93.6 8.2
78.2 97 0.05 18.2 98.3 24.0 76.3 98 0.05 16.8 98.1 22.7 79.7 99
0.05 8.9 94.5 15.4 50.3 100 0.05 8.2 97.0 14.7 74.2 101 0.05 7.8
97.3 14.3 85.3 102 0.05 0.0 93.4 7.1 74.0 103 0.05 17.9 98.1 23.8
63.2 104 0.05 27.7 98.2 32.8 70.2 105 0.05 5.8 95.2 12.5 74.6 106
0.05 0.0 94.6 7.1 88.7 107 0.05 0.0 97.2 7.1 74.6 108 0.05 21.3
97.6 26.9 50.9 109 0.05 27.8 98.3 32.9 89.1 110 0.05 19.9 98.2 25.6
76.4 111 0.05 16.8 97.4 22.7 63.6 112 0.05 8.1 97.8 14.6 78.2 113
0.05 17.0 98.0 22.9 94.7 114 0.05 0.0 36.9 7.1 7.5 115 0.05 6.1
97.4 12.7 78.2 116 0.05 8.4 98.2 14.9 88.8 117 0.05 28.8 98.5 33.9
89.5 118 0.05 10.6 98.3 16.9 85.3 119 0.05 2.2 95.7 9.1 91.9 120
0.05 19.9 98.2 25.6 92.6 121 0.05 0.0 98.3 7.1 88.1 122 0.05 13.5
98.7 19.6 92.7 123 0.05 7.5 95.5 14.1 71.0 124 0.05 0.0 88.2 7.1
23.0 125 0.05 2.4 94.4 9.3 87.0 126 0.05 13.2 92.4 19.4 73.0 127
0.05 0.0 97.1 7.1 40.0 128 0.05 10.8 88.6 17.1 38.0 129 0.05 5.5
97.8 12.2 49.0 130 0.05 1.2 98.6 8.2 50.8 131 0.05 0.0 96.8 7.1
62.0 132 0.05 9.1 97.7 15.5 65.5 133 0.05 8.8 98.5 15.3 71.9 134
0.05 4.2 95.3 11.0 57.0 135 0.05 0.2 98.6 7.3 96.0 136 0.05 9.7
98.6 16.2 95.0 137 0.05 4.5 98.5 11.3 74.0 138 0.05 4.0 98.1 10.8
91.0 139 0.05 1.7 97.1 8.6 93.0 140 0.05 6.7 96.7 13.3 81.0 141
0.05 1.5 96.2 8.5 52.0 142 0.05 1.1 98.2 8.1 79.0 143 0.05 2.1 98.2
9.0 64.4 144 0.05 0.0 98.5 7.1 87.0 145 0.05 2.4 97.2 9.3 55.9 146
0.05 0.0 96.2 7.1 71.2 147 0.05 0.0 95.6 7.1 13.5 148 0.05 15.4
97.9 21.5 72.9 149 0.05 0.0 97.1 7.1 22.1 150 0.05 10.0 97.5 16.4
87.5 151 0.05 11.8 97.6 18.1 83.0 152 0.05 0.0 89.1 7.1 26.0 153
0.05 0.0 97.0 7.1 34.6 154 0.05 3.4 70.7 10.3 36.6 155 0.05 1.9
78.3 8.9 32.0 156 0.05 7.4 94.8 14.0 51.5 157 0.05 7.8 96.9 14.3
61.8 158 0.05 6.2 96.9 12.9 84.7 159 0.05 11.4 98.5 17.7 91.9 160
0.05 3.4 96.1 10.2 65.5 161 0.05 7.0 97.7 13.6 58.2 162 0.05 0.0
96.9 7.1 94.0 163 0.05 5.9 98.0 12.6 87.7 164 0.05 10.8 98.6 17.1
96.5 165 0.05 14.9 98.4 21.0 88.4 166 0.05 2.6 97.9 9.5 71.9 167
0.05 0.0 95.8 7.1 67.3 168 0.05 13.3 97.7 19.5 59.6 169 0.05 2.7
98.1 9.6 78.9 170 0.05 0.0 94.5 7.1 65.5 171 0.05 4.0 98.3 10.8
15.8 172 0.05 13.2 97.9 19.4 27.1 173 0.05 8.3 97.7 14.8 12.2 174
0.05 0.0 97.0 7.1 72.7 175 0.05 4.9 97.9 11.6 80.0 176 0.05 8.8
98.2 15.2 61.4 177 0.05 12.5 95.2 18.7 91.0 178 0.05 8.5 98.3 15.0
59.3 179 0.05 18.7 98.0 24.4 35.1 180 0.05 10.8 95.1 17.1 43.9 181
0.05 16.0 97.6 22.0 90.5 182 0.05 0.0 97.6 7.1 74.6 183 0.05 0.0
96.7 7.1 66.7 184 0.05 7.1 97.0 13.7 70.9 185 0.05 0.0 95.2 7.1
54.6 186 0.05 0.0 97.6 7.1 61.8 187 0.05 20.7 97.5 26.3 92.7 188
0.05 7.9 96.5 14.5 74.6 189 0.05 19.2 95.9 24.9 72.7 190 0.05 5.6
95.7 12.3 70.9 191 0.05 15.4 98.1 21.4 29.8 192 0.05 7.8 94.7 14.3
84.2 193 0.05 0.0 95.1 7.1 80.0 194 0.05 16.1 96.9 22.0 80.4 195
0.05 19.2 97.9 24.9 89.5 196 0.05 4.4 97.7 11.2 94.5 197 0.05 0.0
97.1 7.1 43.7 198 0.05 11.8 97.7 18.1 75.4 199 0.05 4.0 98.0 10.8
56.1 200 0.05 0.0 95.0 7.1 78.9 201 0.05 4.0 96.0 10.8 50.9 202
0.05 2.0 96.6 9.0 49.1 203 0.05 6.9 95.7 13.5 56.4 204 0.05 7.3
95.5 13.8 77.2 205 0.05 15.4 97.2 21.5 78.9 206 0.05 16.4 98.4 22.3
80.7 207 0.05 0.0 95.3 7.1 52.7 208 0.05 5.4 97.0 12.1 32.8 209
0.05 17.6 95.9 23.4 67.3 210 0.05 1.9 94.1 8.9 37.0 211 0.05 7.0
97.1 13.6 16.0 212 0.05 0.0 95.2 7.1 14.0 213 0.05 3.7 98.8 10.6
56.1 214 0.05 7.0 98.0 13.6 60.0 215 0.05 0.5 98.6 7.5 37.0 216
0.05 6.3 98.4 12.9 57.9 217 0.05 0.0 92.7 7.1 0.0 218 0.05 0.0 92.5
7.1 70.9 219 0.05 34.5 97.9 39.2 68.4 220 0.05 0.0 95.3 7.1 89.1
221 0.05 0.0 92.4 7.1 66.0 222 0.05 0.0 94.5 7.1 67.3 223 0.05 26.9
97.2 32.1 54.0 224 0.05 0.0 91.0 7.1 67.3 225 0.05 0.0 96.6 7.1
78.2 226 0.05 0.0 94.5 7.1 71.0 227 0.05 5.0 95.0 11.7 52.7 228
0.05 2.6 97.0 9.6 68.4 229 0.05 6.0 98.0 12.7 70.9 230 0.05 9.0
98.3 15.5 65.0 231 0.05 0.0 98.5 7.1 81.3 232 0.05 2.3 97.5 9.3
57.6 233 0.05 5.6 98.1 12.3 88.1 234 0.05 0.0 94.3 7.1 72.9 235
0.05 0.0 96.3 7.1 80.0 236 0.05 3.5 97.0 10.4 88.1 237 0.05 0.0
91.8 7.1 45.0 238 0.05 0.5 97.6 7.5 92.5 239 0.05 0.1 97.8 7.2 66.1
240 0.05 0.0 98.1 7.1 74.6 241 0.05 0.5 97.0 7.5 62.7
242 0.05 6.9 98.0 13.5 78.0 243 0.05 5.3 96.7 12.1 86.4 244 0.05
0.0 96.1 7.1 62.7 245 0.05 0.0 96.7 7.1 52.7 246 0.05 0.0 95.3 7.1
50.9 247 0.05 10.1 94.0 16.5 84.7 248 0.05 12.4 96.3 18.7 98.0 249
0.05 27.8 95.8 32.9 100.0 250 0.05 8.7 98.1 15.2 97.0 251 0.05 3.5
98.1 10.3 33.0 252 0.05 7.8 98.4 14.4 28.0 253 0.05 4.9 98.0 11.6
14.0 254 0.05 8.3 98.1 14.8 0.0 255 0.05 3.6 98.2 10.4 28.0 256
0.05 3.0 98.7 9.8 18.0 257 0.05 6.0 94.4 12.6 21.0 258 0.05 34.1
97.4 38.8 87.0 259 0.05 9.9 97.9 16.3 32.0 260 0.05 11.2 97.1 17.5
81.0 261 0.05 2.7 97.9 9.6 10.0 262 0.05 3.1 94.0 9.9 4.6 263 0.05
4.1 97.9 10.9 14.0 264 0.05 6.0 98.4 12.7 21.0 265 0.05 0.0 98.1
7.1 15.0 266 0.05 4.5 95.4 11.3 28.0 267 0.05 5.7 98.3 12.4 33.0
268 0.05 1.2 98.7 8.2 31.0 269 0.05 0.0 98.8 7.1 21.0 270 0.05 6.9
98.6 13.5 61.0 271 0.05 6.9 98.9 13.5 61.0 272 0.05 2.0 98.1 8.9
37.0 273 0.05 0.4 97.7 7.5 44.0 274 0.05 0.0 96.3 7.1 89.0 275 0.05
0.0 98.4 7.1 79.7 276 0.05 5.5 97.8 12.2 71.2 277 0.05 1.9 97.5 8.9
86.4 278 0.05 1.7 97.7 8.7 90.0 279 0.05 5.1 98.6 11.8 96.0 280
0.05 2.2 98.2 9.1 88.0 281 0.05 1.4 98.4 8.4 67.0 282 0.05 0.0 94.7
7.1 52.0 283 0.05 0.0 95.9 7.1 67.0 284 0.05 0.0 97.1 7.1 74.0 285
0.05 3.4 97.5 10.3 51.0 286 0.05 2.3 98.4 9.2 75.0 287 0.05 0.0
98.3 7.1 65.0 288 0.05 1.8 98.2 8.8 26.0 289 0.05 0.0 97.6 7.1 45.0
290 0.05 0.4 95.5 7.5 21.0 291 0.05 2.2 95.4 9.2 67.0 292 0.05 5.0
97.6 11.7 21.0 293 0.05 7.9 95.7 14.4 19.0 294 0.05 1.7 94.2 8.7
72.9 295 0.05 5.8 98.0 12.5 89.8 296 0.05 8.3 97.7 14.8 84.7 297
0.05 0.0 96.4 7.1 69.5 298 0.05 0.7 95.0 7.8 74.6 299 0.05 0.0 97.9
7.1 74.0 300 0.05 0.0 97.2 7.1 70.0 301 0.05 0.0 97.9 7.1 82.0 302
0.05 0.0 96.4 7.1 82.0 303 0.05 0.0 98.0 7.1 45.0 304 0.05 0.0 97.9
7.1 77.0 305 0.05 0.5 98.3 7.5 61.0 306 0.05 0.0 95.2 7.1 35.0 307
0.05 0.0 91.3 7.1 25.0 308 0.05 37.2 97.7 41.6 96.0 309 0.05 5.5
97.4 12.2 74.0 310 0.05 2.4 96.6 9.3 64.0 311 0.05 3.3 98.3 10.2
37.0 312 0.05 3.8 97.8 10.6 1.4 313 0.05 8.5 98.5 15.0 28.0 314
0.05 0.0 97.7 7.1 8.8 315 0.05 2.7 95.8 9.6 18.0 316 0.05 4.5 97.1
11.3 14.0 317 0.05 16.3 97.9 22.3 24.0 318 0.05 3.1 97.3 10.0 71.2
319 0.05 18.1 96.6 23.9 78.0 320 0.05 17.1 96.4 23.0 100.0 321 0.05
11.7 96.6 18.0 100.0 322 0.05 20.9 97.9 26.5 95.0 323 0.05 16.1
98.1 22.1 100.0 324 0.05 2.3 96.3 9.2 98.0 325 0.05 0.0 95.7 7.1
100.0 326 0.05 6.9 95.6 13.5 93.0 327 0.05 1.2 95.7 8.3 98.0 328
0.05 0.0 95.1 7.1 99.0 329 0.05 14.0 93.5 20.1 99.0 330 0.05 5.3
92.9 12.1 99.0 331 0.05 22.8 97.8 28.2 100.0 332 0.05 2.0 93.9 8.9
89.0 333 0.05 16.2 93.2 22.1 85.0 334 0.05 10.9 97.8 17.2 98.0 335
0.05 10.2 96.8 16.6 95.0 336 0.05 16.6 97.8 22.5 98.0 337 0.05 22.4
98.0 27.9 97.0 338 0.05 9.0 98.1 15.5 96.0 339 0.05 1.5 95.4 8.5
100.0 340 0.05 18.0 96.2 23.8 95.0 341 0.05 1.2 88.9 8.2 63.0 342
0.05 9.1 98.3 15.6 86.0 343 0.05 2.8 95.4 9.7 97.0 344 0.05 31.5
91.8 36.4 100.0 345 0.05 18.8 97.9 24.6 97.0 346 0.05 30.0 96.7
34.9 96.0 347 0.05 13.8 98.4 19.9 97.0 348 0.05 16.3 98.3 22.2
100.0 349 0.05 17.4 96.9 23.3 97.0 350 0.05 11.3 94.9 17.6 97.0 351
0.05 7.7 96.1 14.3 100.0 352 0.05 8.8 98.4 15.3 100.0 353 0.05 0.0
94.8 7.1 81.0 354 0.05 18.4 95.4 24.2 98.0 355 0.05 19.6 89.8 25.3
87.0 356 0.05 18.6 98.0 24.4 93.0 357 0.05 56.7 97.4 59.7 93.0 358
0.05 12.7 98.3 18.9 100.0 359 0.05 41.4 97.3 45.6 92.0 360 0.05
17.6 96.9 23.4 97.0 361 0.05 3.3 96.4 10.2 97.0 362 0.05 11.1 97.2
17.4 97.0 363 0.05 4.3 94.7 11.1 92.0 364 0.05 8.4 95.8 14.9 97.0
365 0.05 13.8 95.6 19.9 95.0 366 0.05 14.2 96.6 20.3 100.0 367 0.05
13.1 97.9 19.2 95.0 368 0.05 0.0 96.9 7.1 98.0 369 0.05 7.0 95.5
13.6 98.0 370 0.05 3.5 97.5 10.4 91.0 371 0.05 12.6 96.1 18.8 98.0
372 0.05 15.1 97.4 21.1 98.0 373 0.05 0.0 97.3 7.1 90.0 374 0.05
11.1 98.2 17.4 98.0 375 0.05 7.2 98.2 13.7 90.0 376 0.05 13.6 96.5
19.8 98.0 377 0.05 29.9 97.6 34.9 100.0 378 0.05 26.3 98.4 31.6
97.0 379 0.05 26.7 98.2 31.9 100.0 380 0.05 36.1 98.3 40.6 100.0
381 0.05 31.8 98.6 36.6 100.0 382 0.05 19.3 98.5 25.0 96.0 383 0.05
20.3 95.7 25.9 100.0 384 0.05 28.6 95.8 33.6 100.0 385 0.05 5.4
94.6 12.1 100.0 386 0.05 41.1 98.4 45.3 100.0 387 0.05 13.5 96.9
19.6 87.0 388 0.05 17.2 98.1 23.1 61.0 389 0.05 7.7 97.6 14.2 95.0
390 0.05 4.2 97.5 11.0 95.0 391 0.05 6.0 96.9 12.7 92.0 392 0.05
15.8 97.9 21.8 46.0 393 0.05 4.3 96.1 11.1 73.0 394 0.05 8.0 95.9
14.6 71.0 395 0.05 8.2 93.9 14.8 76.0 396 0.05 0.0 95.5 7.1 49.0
397 NT NT NT 6.7 398 0.05 5.4 94.7 12.1 98.0 399 0.05 5.8 97.1 12.5
88.0 400 0.05 0.5 97.9 7.6 96.0 401 0.05 0.0 94.8 7.1 98.0 402 0.05
0.0 95.2 7.1 100.0 403 0.05 0.0 97.3 7.1 97.0 404 0.05 0.0 94.9 7.1
97.0 405 0.05 2.8 96.2 9.7 98.0 406 0.05 6.7 96.1 13.3 98.0 407
0.05 0.0 92.0 7.1 70.0 408 0.05 8.4 79.7 14.9 94.0 409 0.05 7.9
96.3 14.4 98.0 410 0.05 1.9 97.6 8.9 95.0 411 0.05 8.2 97.9 14.7
85.0 412 0.05 7.7 97.8 14.3 100.0 413 0.05 18.9 97.9 24.7 94.0 414
0.05 14.6 97.9 20.7 90.0 415 0.05 2.9 96.1 9.8 100.0 416 0.05 4.3
97.5 11.1 93.0 417 0.05 10.7 98.2 17.0 100.0 418 0.05 0.0 97.3 7.1
93.0 419 0.05 3.2 94.9 10.1 90.0 420 0.05 11.4 97.5 17.7 100.0 421
0.05 8.2 96.6 14.7 94.0 422 0.05 0.0 95.5 7.1 90.0 423 0.05 0.8
98.0 7.9 98.0 424 0.05 22.3 97.0 27.8 100.0 425 0.05 17.5 97.6 23.4
95.0 426 0.05 34.8 97.3 39.5 98.0 427 0.05 26.1 97.9 31.3 98.0 428
0.05 44.1 98.4 48.1 97.0 429 0.05 10.4 97.4 16.8 94.0 430 0.05 16.6
98.2 22.5 100.0 431 0.05 8.5 95.1 15.0 91.0 432 0.05 0.0 95.9 7.1
72.0 433 0.05 10.8 97.8 17.2 100.0 434 0.05 25.6 97.4 30.9 100.0
435 0.05 4.7 97.2 11.5 100.0 436 0.05 14.6 98.2 20.7 94.0 437 0.05
9.2 97.0 15.6 100.0 438 0.05 0.0 94.2 7.1 98.0 439 0.05 0.0 100.0
7.1 96.0 440 0.05 2.9 100.0 9.8 98.0 441 0.05 0.0 100.0 7.1 96.0
442 0.05 0.0 100.0 7.1 98.0 443 0.05 14.6 100.0 20.7 83.0 444 0.05
0.0 100.0 7.1 91.0 445 0.05 13.2 100.0 19.4 90.0 446 0.05 23.5 95.4
29.0 57.0 447 0.05 20.0 96.6 25.7 100.0 448 0.05 27.1 97.5 32.3
100.0 449 0.05 7.2 98.5 13.8 92.0 450 0.05 1.1 93.5 8.1 100.0 451
0.05 4.6 100.0 11.4 100.0 452 0.05 12.9 100.0 19.1 100.0 453 0.05
5.6 100.0 12.3 100.0 454 0.05 12.4 100.0 18.6 100.0 455 0.05 16.7
100.0 22.6 100.0 456 0.05 0.0 100.0 7.1 100.0 457 0.05 6.7 100.0
13.3 100.0 458 0.05 3.7 96.6 10.6 46.0 459 0.05 7.3 96.9 13.8 20.0
460 0.05 0.0 97.6 7.1 39.0 461 0.05 3.4 96.7 10.3 54.0 462 0.05 0.0
95.0 7.1 86.0 463 0.05 5.1 96.3 11.9 61.0 464 0.05 6.7 94.8 13.4
93.0 465 0.05 1.7 96.5 8.6 93.0 466 0.05 2.7 97.9 9.6 69.0 467 0.05
0.0 95.7 7.1 80.0 468 0.05 6.2 98.1 12.8 92.0 469 0.05 1.0 97.8 8.1
95.0 470 0.05 4.0 98.0 10.8 93.0 471 0.05 7.9 97.8 14.4 83.0 472
0.05 0.0 97.7 7.1 49.0 473 0.05 0.0 97.5 7.1 78.0 474 0.05 39.2
97.6 43.5 100.0 475 0.05 33.8 97.1 38.5 100.0 476 0.05 0.0 93.9 7.1
69.0 477 0.05 6.2 83.4 12.8 93.0 478 0.05 0.7 94.7 7.7 65.0 479
0.05 0.0 97.5 7.1 97.0 480 0.05 9.5 95.3 15.9 4.7 481 0.05 10.3
97.8 16.7 76.0 482 0.05 0.0 96.4 7.1 66.0 483 0.05 0.0 97.9 7.1
63.0 484 0.05 12.6 93.2 18.8 88.0 485 0.05 8.0 96.7 14.5 95.0 486
0.05 12.8 96.6 19.0 95.0 487 0.05 11.2 93.9 17.5 100.0 488 0.05
20.1 92.6 25.7 72.0 489 0.05 15.8 97.8 21.8 85.0 490 0.05 31.5 97.0
36.4 55.0 491 0.05 25.0 97.5 30.3 75.0 492 0.05 0.0 98.1 7.1
93.0
493 0.05 0.0 97.8 7.1 95.0 494 0.05 0.0 97.7 7.1 96.0 495 0.05 0.0
97.3 7.1 91.0 496 0.05 0.7 97.8 7.8 94.0 497 0.05 0.0 98.1 7.1 75.0
498 0.05 0.0 97.5 7.1 85.0 499 0.05 0.0 97.4 7.1 85.0 500 0.05 9.2
93.2 15.6 80.0 501 0.05 0.5 98.0 7.6 89.0 502 0.05 4.2 97.2 11.0
85.0 503 0.05 5.2 97.0 11.9 66.0 504 0.05 1.3 97.6 8.3 94.0 505
0.05 7.1 97.3 13.7 46.0 506 0.05 2.7 97.5 9.6 44.0 507 0.05 7.6
97.0 14.1 66.0 508 0.05 9.4 97.1 15.9 92.0 509 0.05 0.0 96.2 7.1
85.0 510 0.05 6.2 95.5 12.8 56.0 511 0.05 0.0 97.8 7.1 73.0 512
0.05 7.4 97.8 13.9 59.0 513 0.05 14.0 98.0 20.1 53.0 514 0.05 0.0
97.7 7.1 75.0 515 0.05 0.0 97.6 7.1 47.0 516 0.05 0.0 97.9 7.1 59.0
517 0.05 0.0 96.7 7.1 56.0 518 0.05 24.2 97.4 29.6 58.0 519 0.05
9.1 95.7 15.6 88.0 520 0.05 14.9 96.7 20.9 49.0 521 0.05 5.0 95.9
11.8 83.0 522 0.05 9.4 97.3 15.9 95.0 523 0.05 7.0 97.7 13.6 92.0
524 0.05 9.3 95.8 15.7 39.0 525 0.05 5.4 97.4 12.1 78.0 526 0.05
1.8 16.2 8.7 41.0 527 0.05 7.6 97.6 14.2 78.0 528 0.05 8.7 97.7
15.2 73.0 529 0.05 15.3 97.7 21.3 46.0 530 0.05 9.8 96.2 16.2 59.0
531 0.05 0.0 97.3 7.1 80.0 532 0.05 4.9 91.4 11.7 56.0 533 0.05 6.2
97.0 12.9 34.0 534 0.05 5.1 95.7 11.9 61.0 535 0.05 10.1 97.7 16.5
56.0 536 0.05 21.1 93.4 26.7 24.0 537 0.05 12.2 96.2 18.5 90.0 538
0.05 12.4 96.5 18.6 44.0 539 0.05 1.6 98.0 8.6 100.0 540 0.05 0.0
97.5 7.1 95.0 541 0.05 0.0 97.5 7.1 93.0 542 0.05 0.0 95.8 7.1
100.0 543 0.05 1.3 93.9 8.3 100.0 544 0.05 6.9 97.6 13.5 97.0 545
0.05 19.6 97.9 25.3 95.0 546 0.05 7.6 97.7 14.2 100.0 547 0.05 10.8
97.7 17.1 88.0 548 0.05 6.7 97.5 13.3 98.0 549 0.05 0.0 97.3 7.1
94.0 550 0.05 4.6 97.2 11.4 63.0 551 0.05 1.7 96.0 8.7 90.0 552
0.05 0.0 94.2 7.1 71.0 553 0.05 0.0 93.2 7.1 88.0 554 0.05 0.0 97.3
7.1 100.0 555 0.05 3.7 92.5 10.5 46.0 556 0.05 7.7 95.9 14.2 75.0
557 0.05 13.0 95.7 19.2 90.0 558 0.05 3.8 95.7 10.6 80.0 559 0.05
10.0 97.3 16.4 93.0 560 0.05 1.3 90.7 8.3 65.0 561 0.05 0.0 92.2
7.1 60.0 562 0.05 1.4 97.3 8.4 91.0 563 0.05 20.6 96.9 26.2 70.0
564 0.05 17.4 94.2 23.3 1.3 565 0.05 12.2 97.4 18.4 98.0 566 0.05
6.8 95.9 13.4 70.0 567 0.05 2.5 42.3 9.5 14.0 568 0.05 8.0 94.3
14.6 61.0 569 0.05 6.1 15.8 12.7 70.0 570 0.05 3.2 97.2 10.1 39.0
571 0.05 0.0 84.7 7.1 31.0 572 0.05 2.5 97.4 9.5 94.0 573 0.05 2.4
98.4 9.3 93.0 574 0.05 2.8 98.3 9.7 93.0 575 0.05 0.0 98.1 7.1
100.0 576 0.05 0.7 97.9 7.7 90.0 577 0.05 1.9 97.9 8.8 100.0 578
0.05 7.2 98.0 13.8 100.0 579 0.05 0.0 97.6 7.1 97.0 580 0.05 3.1
98.1 10.0 97.0 581 0.05 13.6 98.2 19.7 93.0 582 0.05 12.2 97.8 18.4
94.0 583 0.05 13.2 98.0 19.4 100.0 584 0.05 3.0 11.8 9.9 7.6 585
0.05 6.3 86.3 13.0 62.0 586 0.05 0.0 87.3 7.1 31.0 587 0.05 6.2
96.6 12.8 2.4 588 0.05 7.6 96.3 14.2 5.6 589 0.05 8.7 97.9 15.2
61.0 590 0.05 10.0 98.6 16.4 88.0 591 0.05 0.0 9.9 7.1 11.0 592
0.05 0.0 25.4 7.1 1.4 CuCl.sub.2 10 .mu.M 7.1 .+-. 6.0 NT = not
tested
Example 28
Effect of Copper on Fungitoxicity of Hydrazones Towards
Phytophthora capsici
[0115] 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.
[0116] 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 stiffing 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.
[0117] 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 % Inhn % Inhn Minus Plus Plus
Compound Concentration copper copper copper Number (.mu.g/mL)
Observed Observed Predicted 1 0.039 9.7 87.2 13.8 3 0.039 0.0 88.5
4.5 5 0.039 18.6 93.9 22.3 6 0.039 28.8 95.8 32.0 14 0.039 0.0 87.2
4.5 15 0.039 80.4 91.8 81.2 16 0.050 0.0 91.9 4.5 20 0.050 2.1 90.4
6.5 21 0.039 0.0 90.0 4.5 23 0.039 10.8 93.8 14.8 24 0.039 10.2
92.4 14.2 28 0.039 11.4 93.8 15.4 43 0.039 54.2 90.3 56.2 52 0.039
40.6 91.2 43.3 56 0.039 57.5 94.1 59.4 60 0.050 4.1 76.4 8.4 61
0.039 17.6 95.6 21.3 69 0.050 0.0 87.6 4.5 74 5 17.2 89.4 20.9 83
0.039 27.9 96.2 31.1 84 0.039 47.5 95.0 49.8 91 0.039 52.1 93.2
54.3 96 0.039 55.2 91.9 57.2 99 0.039 23.6 94.0 27.1 100 0.039 10.0
88.8 14.0 101 0.039 70.0 88.2 71.4 102 0.039 15.7 93.6 19.4 119
0.039 37.9 95.1 40.7 121 0.050 0.0 90.4 4.5 123 0.039 16.3 94.8
20.0 124 0.039 25.0 89.7 28.3 125 0.039 66.6 89.4 68.1 129 0.039
10.6 96.3 14.6 131 0.039 5.6 93.7 9.9 140 0.050 0.0 91.4 4.5 143
0.039 6.0 94.5 10.3 146 0.039 11.8 91.4 15.8 162 0.050 5.2 91.6 9.5
177 0.050 0.0 92.4 4.5 182 0.039 25.9 90.9 29.2 183 0.039 0.0 88.9
4.5 204 0.050 6.0 81.9 10.2 207 0.039 0.0 88.9 4.5 210 0.039 36.6
92.7 39.4 218 0.050 10.7 93.3 14.7 219 0.050 15.3 90.6 19.1 220
0.050 13.4 85.5 17.3 221 0.050 12.0 92.2 15.9 222 0.050 11.3 76.8
15.3 223 0.050 2.5 51.3 6.9 224 0.050 6.2 93.3 10.4 225 0.050 11.4
82.8 15.4 226 0.050 2.3 62.1 6.7 227 0.050 1.7 93.4 6.2 228 0.050
10.0 86.9 14.0 229 0.050 1.6 89.1 6.0 230 0.050 5.8 93.6 10.1 275
0.050 0.0 91.2 4.5 277 0.050 0.0 88.2 4.5 320 0.050 2.9 81.4 7.3
337 0.050 4.7 42.1 9.0 351 0.050 0.0 87.9 4.5 364 0.050 0.0 23.2
4.5 369 0.050 0.0 44.5 4.5 384 0.050 0.0 71.1 4.5 405 0.050 0.6
85.9 5.1 427 0.050 9.1 88.6 13.2 443 0.050 2.4 91.2 6.8 455 0.050
0.0 30.8 4.5 578 0.050 2.8 90.4 7.2 CuCl.sub.2, 50 .mu.M 4.5 .+-.
7.9
Example 29
Effect of Copper on Fungitoxicity of Hydrazones Towards Ustilago
maydis
[0118] In vitro fungitoxicity assays against Ustilago maydis were
conducted using the copper-minus medium described in Example 26.
Medium containing copper was prepared by adding
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.
[0119] 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.
[0120] 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
16 0.0 80.0 11.9 20 1.2 91.0 12.9 60 0.0 93.5 11.9 69 0.0 96.2 11.9
121 0.0 96.9 11.9 140 0.0 95.7 11.9 162 8.8 96.4 19.7 177 0.0 33.3
11.9 204 0.0 77.0 11.9 230 11.9 94.4 22.4 275 0.0 92.2 11.9 277 1.7
83.5 13.4 320 0.0 95.2 11.9 329 16.2 41.8 26.2 337 22.0 97.8 31.3
351 27.1 97.7 35.8 364 65.5 92.9 69.6 369 3.1 93.6 14.7 384 13.6
96.6 23.9 405 9.6 90.0 20.4 427 34.3 89.3 42.1 443 10.2 35.3 20.9
455 0.0 96.0 11.9 578 47.4 93.8 53.6 CuCl.sub.2, 10 .mu.M 11.9
Example 30
Effect of Copper on Fungitoxicity of Hydrazones Towards Septoria
tritici
[0121] In vitro fungitoxicity assays against Septoria tritici were
conducted using the copper-minus medium described in Example 26.
Medium containing copper was prepared by adding
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.
[0122] 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.
[0123] 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 16 35.8 93.6 35.8 20 0.0 95.3 0.0 60 20.6 94.8
20.6 69 0.0 96.7 0.0 121 9.7 96.5 9.7 140 0.0 96.6 0.0 162 36.3
97.1 36.3 177 0.2 95.2 0.2 204 0.0 84.4 0.0 230 43.6 96.7 43.6 275
16.2 93.5 16.2 277 3.6 88.0 3.6 320 9.5 92.1 9.5 329 14.9 55.1 14.9
337 46.8 97.1 46.8 351 44.4 97.1 44.4 364 22.4 93.7 22.4 369 9.3
93.2 9.3 384 57.5 97.0 57.5 405 18.8 89.9 18.8 427 43.8 96.7 43.8
443 5.8 92.0 5.8 455 27.5 92.4 27.5 578 26.7 90.7 26.7 CuCl.sub.2,
1 .mu.M 0
Example 31
Comparative Efficacy of Isolated Metal-Hydrazone Complexes and
Parent Hydrazones Towards Leptosphaeria nodorum
[0124] Hydrazones and their isolated metal complexes were compared
with respect to their in vitro fungitoxicity towards LEPTNO. Metal
complexes of hydrazones were prepared by precipitation from ethanol
with various metal salts, at 1:1, 2:1 or 3:1 molar ratios, as
described in general by Ainscough, Brodie, Dobbs, Ranford, and
Waters (Inorganica Chimica Acta 1998, 267, 27-38, which is
expressly incorporated by reference herein).
[0125] 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 metal complexes of hydrazones are provided in Table 6
below.
TABLE-US-00006 TABLE 6 Ratio Com- Hydra- plex Com- zone: Num- pound
Metal ber Number Metal Salt Salt Description mp (.degree. C.) 593
77 FeCl.sub.3.cndot.6H.sub.2O 1:1 brown 199-202 black solid 594 77
FeCl.sub.3.cndot.6H.sub.2O 2:1 dark green 258-260 solid 595 78
FeCl.sub.3.cndot.6H.sub.2O 3:1 dark green 258-261 solid 596 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 dark green solid 597 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 2:1 tan solid 310-312 598 16
CuSO.sub.4.cndot.5H.sub.2O 1:1 dark green 307-308 solid 599 16
CuSO.sub.4.cndot.5H.sub.2O 2:1 dark green 310-312 solid 600 16
CuCl.sub.2.cndot.2H.sub.2O 1:1 light green 311-312 olive solid 601
16 CuCl.sub.2.cndot.2H.sub.2O 2:1 light green 288-290 solid 602 69
CuCl.sub.2.cndot.2H.sub.2O 1:1 olive- 250-255 brown solid 603 84
CuCl.sub.2.cndot.2H.sub.2O 1:1 olive green 278-280 solid 604 83
CuCl.sub.2.cndot.2H.sub.2O 1:1 olive 282-285 brown solid 605 77
CuCl.sub.2.cndot.2H.sub.2O 1:1 olive green 273-274 solid 606 96
CuCl.sub.2.cndot.2H.sub.2O 1:1 olive green 258-260 solid 607 70
CuCl.sub.2.cndot.2H.sub.2O 1:1 olive 278-279 brown glass 608 43
CuCl.sub.2.cndot.2H.sub.2O 1:1 green black 310-312 solid 609 76
CuCl.sub.2.cndot.2H.sub.2O 1:1 brown 272-273 solid 610 100
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 brown 315-317 black solid
611 16 MnCl.sub.2 2:1 mustard- 250 colored solid 612 16 ZnCl.sub.2
2:1 yellow- 250 green solid 613 299 CuCl.sub.2.cndot.2H.sub.2O 1:1
dark green 160-163 solid 614 300 CuCl.sub.2.cndot.2H.sub.2O 1:1
dark green 129-132 solid 615 301 CuCl.sub.2.cndot.2H.sub.2O 1:1
dark brown 73-78 solid 616 302 CuCl.sub.2.cndot.2H.sub.2O 1:1 dark
green 167-170 solid 617 303 CuCl.sub.2.cndot.2H.sub.2O 1:1 dark
green 137-139 solid 618 304 CuCl.sub.2.cndot.2H.sub.2O 1:1 dark
green 177-225 solid 619 305 CuCl.sub.2.cndot.2H.sub.2O 1:1 dark
brown 201-211 solid 620 16 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 293-302 solid 621 151 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 283-294 solid 622 238 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 299-308 solid 623 231 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 260-275 solid 624 233 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 286-290 solid 625 20 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 286-288 solid 626 236 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 259-263 solid 627 277 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 286-289 solid 628 320 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 280-286 solid 629 68 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 226-228 solid 630 159 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 224-235 solid 631 359 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 240-254 solid 632 370 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 257-267 solid 633 428 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 212-270 solid 634 392 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 262-293 solid 635 348 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 295-305 solid 636 440 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 259-281 solid 637 337 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 279-281 solid 638 381 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 279-281 solid 639 452 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 270-274 solid 640 69 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 298-299 solid 641 151 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 287-289 solid 642 172 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 311-313 solid 643 403 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 296-297 solid 644 60 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 215-219 solid 645 137 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 207-211 solid 646 278 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 242-246 solid 647 279 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 236-239 solid 648 67 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 176-87 solid 649 135 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 245-248 solid 650 136 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 242-247 solid 651 411 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 292-295 solid 652 412 CuCl.sub.2.cndot.2H.sub.2O 1:1 olive
green 309-310 solid 653 68 Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1
brown- >350 black solid
[0126] In vitro fungitoxicity assays were conducted using the
copper-minus medium described in Example 26. Test compounds were
dissolved in dimethylsulfoxide (DMSO) then dilutions in
copper-minus medium were prepared as 100 .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 26. 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.
[0127] Results for growth inhibition by hydrazones and
corresponding isolated metal complexes (each at 0.1 .mu.g/mL) are
shown in Table 7. The results illustrate that isolated Cu complexes
of hydrazones are much more fungitoxic than the corresponding
hydrazones and also are much more active than isolated Fe, Mn and
Zn complexes of hydrazones.
TABLE-US-00007 TABLE 7 Com- Com- Hydrazone Complex plex pound Ra- %
Inhibi- % Inhibi- Number Number Metal Salt tio* tion tion 593 77
FeCl.sub.3.cndot.6H.sub.2O 1:1 10.6 7.1 594 77
FeCl.sub.3.cndot.6H.sub.2O 2:1 10.6 4.9 595 77
FeCl.sub.3.cndot.6H.sub.2O 3:1 10.6 3.1 596 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 19.9 98.4 597 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 2:1 19.9 94.6 599 16
CuSO.sub.4.cndot.5H.sub.2O 2:1 19.9 97.3 600 16
CuCl.sub.2.cndot.2H.sub.2O 1:1 19.9 95.3 601 16
CuCl.sub.2.cndot.2H.sub.2O 2:1 19.9 97.0 602 69
CuCl.sub.2.cndot.2H.sub.2O 1:1 32.4 94.9 603 84
CuCl.sub.2.cndot.2H.sub.2O 1:1 6.7 95.6 604 83
CuCl.sub.2.cndot.2H.sub.2O 1:1 27.9 95.1 605 77
CuCl.sub.2.cndot.2H.sub.2O 1:1 10.6 97.2 606 96
CuCl.sub.2.cndot.2H.sub.2O 1:1 10.7 90.3 607 70
CuCl.sub.2.cndot.2H.sub.2O 1:1 29.4 48.3 608 43
CuCl.sub.2.cndot.2H.sub.2O 1:1 3.6 21.2 609 76
CuCl.sub.2.cndot.2H.sub.2O 1:1 92.8 95.5 610 100
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 24.7 96.7 611 16
MnCl.sub.2.cndot.4H.sub.2O 2:1 19.9 31.3 612 16 ZnCl.sub.2 2:1 19.9
21.4 613 299 CuCl.sub.2.cndot.2H.sub.2O 1:1 18.6 96.3 614 300
CuCl.sub.2.cndot.2H.sub.2O 1:1 2.5 66.9 615 301
CuCl.sub.2.cndot.2H.sub.2O 1:1 3.5 87.3 616 302
CuCl.sub.2.cndot.2H.sub.2O 1:1 22.9 95.5 617 303
CuCl.sub.2.cndot.2H.sub.2O 1:1 10.6 88.0 618 304
CuCl.sub.2.cndot.2H.sub.2O 1:1 13.3 94.1 619 305
CuCl.sub.2.cndot.2H.sub.2O 1:1 27.1 96.3 621 151
CuCl.sub.2.cndot.2H.sub.2O 1:1 30.9 97.4 622 238
CuCl.sub.2.cndot.2H.sub.2O 1:1 20.0 97.5 623 231
CuCl.sub.2.cndot.2H.sub.2O 1:1 10.7 98.0 624 233
CuCl.sub.2.cndot.2H.sub.2O 1:1 8.4 96.8 625 20
CuCl.sub.2.cndot.2H.sub.2O 1:1 14.7 96.9 626 236
CuCl.sub.2.cndot.2H.sub.2O 1:1 4.7 94.9 627 277
CuCl.sub.2.cndot.2H.sub.2O 1:1 0.6 91.9 628 320
CuCl.sub.2.cndot.2H.sub.2O 1:1 22.1 94.6 629 68
CuCl.sub.2.cndot.2H.sub.2O 1:1 7.1 97.8 630 159
CuCl.sub.2.cndot.2H.sub.2O 1:1 27.4 97.8 631 359
CuCl.sub.2.cndot.2H.sub.2O 1:1 24.1 98.0 632 370
CuCl.sub.2.cndot.2H.sub.2O 1:1 23.1 97.5 633 428
CuCl.sub.2.cndot.2H.sub.2O 1:1 29.9 97.3 634 392
CuCl.sub.2.cndot.2H.sub.2O 1:1 22.8 75.8 635 348
CuCl.sub.2.cndot.2H.sub.2O 1:1 23.9 91.8 636 440
CuCl.sub.2.cndot.2H.sub.2O 1:1 23.8 95.8 637 337
CuCl.sub.2.cndot.2H.sub.2O 1:1 39.9 97.9 638 381
CuCl.sub.2.cndot.2H.sub.2O 1:1 43.9 97.1 639 452
CuCl.sub.2.cndot.2H.sub.2O 1:1 19.3 96.7 641 195
CuCl.sub.2.cndot.2H.sub.2O 1:1 21.7 95.2 642 172
CuCl.sub.2.cndot.2H.sub.2O 1:1 28.7 97.2 643 403
CuCl.sub.2.cndot.2H.sub.2O 1:1 12.1 93.9 644 60
CuCl.sub.2.cndot.2H.sub.2O 1:1 23.3 98.0 645 137
CuCl.sub.2.cndot.2H.sub.2O 1:1 27.2 97.7 646 278
CuCl.sub.2.cndot.2H.sub.2O 1:1 16.2 97.5 647 279
CuCl.sub.2.cndot.2H.sub.2O 1:1 19.9 96.9 648 67
CuCl.sub.2.cndot.2H.sub.2O 1:1 4.2 95.9 649 135
CuCl.sub.2.cndot.2H.sub.2O 1:1 20.6 96.0 650 136
CuCl.sub.2.cndot.2H.sub.2O 1:1 34.7 98.3 651 411
CuCl.sub.2.cndot.2H.sub.2O 1:1 32.1 97.5 652 412
CuCl.sub.2.cndot.2H.sub.2O 1:1 40.4 97.0 653 68
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 7.1 96.9 *Molar ratio of
hydrazone:metal used to prepare complexes.
Example 32
Comparative efficacy of isolated Cu-hydrazone complexes and parent
hydrazones against glume blotch of wheat (Leptosphaeria
nodorum)
[0128] Hydrazones and their copper complexes were compared with
respect to their ability to control glume blotch of wheat. Compound
formulation was accomplished by dissolving technical materials in
acetone and adding 9 volumes de-ionized water containing 0.01%
Triton.RTM. X-100.
[0129] Wheat (cultivar Yuma) was grown in a soilless peat-based
potting mixture ("Metromix") until the seedlings were 10-20 cm
tall. These plants were then sprayed to run-off with the test
compound at a rate of 200 ppm. After 24 h, the test plants were
inoculated by spraying with an aqueous suspension of LEPTNO spores
and kept in a dew chamber overnight. The plants were then
transferred to the greenhouse until disease developed in the
untreated control plants. Results, shown in Table 8, show that
copper complexes of hydrazones have higher fungicidal activity
towards glume blotch than the corresponding hydrazones without
copper.
TABLE-US-00008 TABLE 8 Com- Com- plex pound Ra- Hydrazone Complex
Number Number Metal Salt tio* % Control % Control 600 16
CuCl.sub.2.cndot.2H.sub.2O 1:1 41 93 602 69
CuCl.sub.2.cndot.2H.sub.2O 1:1 25 83 603 84
CuCl.sub.2.cndot.2H.sub.2O 1:1 37 92 604 83
CuCl.sub.2.cndot.2H.sub.2O 1:1 38 75 605 77
CuCl.sub.2.cndot.2H.sub.2O 1:1 0 75 606 96
CuCl.sub.2.cndot.2H.sub.2O 1:1 0 91 607 70
CuCl.sub.2.cndot.2H.sub.2O 1:1 0 91 608 43
CuCl.sub.2.cndot.2H.sub.2O 1:1 0 84 609 76
CuCl.sub.2.cndot.2H.sub.2O 1:1 0 97 610 100
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 0 94 *Molar ratio of
hydrazone:metal used to prepare complexes.
Example 33
Effect of Copper on Fungitoxicity of Metal-Hydrazone Complexes
Towards Leptosphaeria nodorum
[0130] In vitro fungitoxicity assays against LEPTNO were conducted
using the copper-minus medium described in Example 26. 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 media 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 26. 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. Results for growth inhibition by test compounds in
copper-plus medium ("% Inhn. Plus Copper Observed") were compared
with predicted values ("% Inhn. Plus Copper Predicted") that were
calculated using the formula set forth by S. R. Colby in Weeds
1967, 15, 20-22 based on results obtained for the same compounds in
copper-minus medium ("% Inhn. Minus Copper Observed") and the
inhibition attributed to copper chloride alone, as determined by
comparing growth in copper-minus and copper-plus media without any
test compound across experiments. Data are presented in Table 9.
Results show that fungitoxicity of metal complexes of hydrazones
towards LEPTNO is synergistically enhanced in the presence of added
copper. Furthermore, the fungitoxicity of copper complexes of
hydrazones is synergistically enhanced in the presence of added
copper.
TABLE-US-00009 TABLE 9 % Inhn. % Inhn. % Inhn. Minus Plus Plus
Complex Compound Concn. copper copper copper Number Number Metal
salt Ratio* (.mu.g/mL) Observed Observed Predicted 593 77
FeCl.sub.3.cndot.6H.sub.2O 1:1 0.05 31.3 93.7 33.6 594 77
FeCl.sub.3.cndot.6H.sub.2O 2:1 0.05 0.8 92.7 4.1 595 77
FeCl.sub.3.cndot.6H.sub.2O 3:1 0.05 9.8 93.3 12.8 596 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 0.0125 4.5 56.7 7.7 596 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 0.0125 6.4 85.4 9.5 598 16
CuSO.sub.4.cndot.5H.sub.2O 1:1 0.10 57.3 91.2 58.7 599 16
CuSO.sub.4.cndot.5H.sub.2O 2:1 0.0125 28.6 55.2 31.0 600 16
CuCl.sub.2.cndot.2H.sub.2O 1:1 0.0125 29.6 84.3 31.9 601 16
CuCl.sub.2.cndot.2H.sub.2O 2:1 0.0125 27.2 68.9 29.6 611 16
MnCl.sub.2.cndot.4H.sub.2O 2:1 0.05 36.6 96.1 38.8 612 16
ZnCl.sub.2 2:1 0.05 36.3 67.5 38.5 CuCl.sub.2, 10 3.3 .mu.M *Molar
ratio of hydrazone:metal used to prepare complexes.
Example 34
Effect of Copper on Fungitoxicity of Metal-Hydrazone Complexes
Towards Phytophthora capsici
[0131] In vitro fungitoxicity assays against Phytophthora capsici
were conducted using the copper-minus AS medium described in
Example 28. Medium containing copper was prepared by adding
CuCl.sub.2.2H.sub.2O to the copper-minus AS medium at 100 .mu.M.
Test compounds were dissolved in dimethylsulfoxide (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.
Microtiter plates were inoculated with 100 .mu.L of zoospore
suspension at a concentration of 5.times.10.sup.4 spores per mL,
prepared as in Example 28. The plates were 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.
[0132] Results for growth inhibition by test compounds in
copper-plus AS medium ("% Inhn. Plus Copper Observed") were
compared with predicted values ("% Inhn. Plus Copper Predicted")
that were calculated using the formula set forth by S. R. Colby in
Weeds 1967, 15, 20-22 based on results obtained for the same
compounds in copper-minus AS medium ("% Inhn. Minus Copper
Observed") and the inhibition attributed to copper chloride alone,
as determined by comparing growth in copper-minus and copper-plus
media without any test compound across experiments. Data are
presented in Table 10. Results show that fungitoxicity of metal
complexes of hydrazones towards Phytophthora capsici is
synergistically enhanced in the presence of added copper.
Furthermore, the fungitoxicity of copper complexes of hydrazones is
synergistically enhanced in the presence of added copper.
TABLE-US-00010 TABLE 10 % Inhn. % Inhn. % Inhn. Minus Plus Plus
Complex Compound Concn. copper copper copper Number Number Metal
salt Ratio* (.mu.g/mL) Observed Observed Predicted 593 77
FeCl.sub.3.cndot.6H.sub.2O 1:1 0.025 7.0 93.7 11.3 594 77
FeCl.sub.3.cndot.6H.sub.2O 2:1 0.025 0.0 93.6 4.6 595 77
FeCl.sub.3.cndot.6H.sub.2O 3:1 0.025 0.0 93.7 4.6 596 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 0.0125 0.9 95.4 5.5 596 16
Cu(OCOCH.sub.3).sub.2.cndot.H.sub.2O 1:1 0.025 10.1 95.8 14.3 598
16 CuSO.sub.4.cndot.5H.sub.2O 1:1 0.025 0.0 94.8 4.6 599 16
CuSO.sub.4.cndot.5H.sub.2O 2:1 0.025 8.4 96.1 12.6 601 16
CuCl.sub.2.cndot.2H.sub.2O 2:1 0.025 4.1 94.0 8.5 602 16
CuCl.sub.2.cndot.2H.sub.2O 1:1 0.025 12.7 94.4 16.7 611 16
MnCl.sub.2.cndot.4H.sub.2O 2:1 0.025 9.3 95.1 13.5 612 16
ZnCl.sub.2 2:1 0.025 5.2 90.2 9.6 CuCl.sub.2, 50 0.025 4.6 .mu.M
*Molar ratio of hydrazone:metal used to prepare complexes.
Example 35
Fungitoxicity of Copper-Hydrazone Mixtures Containing Different
Ratios of Components Towards Leptosphaeria nodorum
[0133] In vitro fungitoxicity assays against LEPTNO were conducted
using the copper-minus medium described in Example 26. Mixtures
containing hydrazone compound 16 at 200 nM and CuCl.sub.2 at 0.2
.mu.M (1:1 molar ratio), 0.8 .mu.M (1:4 ratio), 12.5 .mu.M (1:62.5
ratio) and 200 .mu.M (1:1000 ratio) were prepared in copper-minus
medium. Two-fold dilution series of these mixtures were then
prepared in 100 .mu.L aliquots of copper-minus medium in
flat-bottomed 96-well microtiter plates. A suspension of LEPTNO
spores in copper-minus medium at 2.times.10.sup.5 spores per mL was
prepared as in Example 26. Microtiter plates were inoculated with
100 .mu.L of the spore suspension and the plates were incubated at
25.degree. C. for 72 h before assessing fungal growth by measuring
light scattering in a NepheloStar plate reader.
[0134] Growth inhibition was determined by comparing growth in the
presence of copper-hydrazone mixture with growth in control wells
lacking the copper-hydrazone mixture. EC50 values were calculated
from dose-response curves, and are expressed as the amounts of
hydrazone or copper in each test mixture at the rates providing 50%
inhibition of growth as compared to a control lacking the
copper-hydrazone mixture. Data are presented in Table 11. The
results show that copper-hydrazone mixtures representing a wide
range of molar ratios of copper:hydrazone are substantially more
efficacious against LEPTNO than either hydrazone or copper
alone.
TABLE-US-00011 TABLE 11 Amounts of hydrazone and CuCl.sub.2 at EC50
values Hydrazone CuCl.sub.2 Hydrazone:Cu ratio EC50 (nM) EC50
(.mu.M) Hydrazone without CuCl.sub.2 >3200 1 to 1 72.2 0.072 1
to 4 43.0 0.172 1 to 62.5 28.4 1.77 1 to 1000 14.0 14.0 CuCl.sub.2
without hydrazone 117.9
Example 36
Fungitoxicity of Copper-Hydrazone Mixtures Containing Different
Ratios of Components Towards Phytophthora capsici
[0135] In vitro fungitoxicity assays against Phytophthora capsici
were conducted using the copper-minus AS medium described in
Example 28. Mixtures containing hydrazone compound 16 at 200 nM and
CuCl.sub.2.2H.sub.2O at 0.2 .mu.M (1:1 molar ratio), 0.8 .mu.M (1:4
ratio), 3.2 .mu.M (1:16 ratio), 12.5 .mu.M (1:62.5 ratio), 50 .mu.M
(1:200 ratio) and 200 .mu.M (1:1000 ratio) were prepared in
copper-minus AS medium. Two-fold dilution series of these mixtures
were then prepared in 100 .mu.L aliquots of copper-minus AS medium
in flat-bottomed 96-well microtiter plates. A suspension of P.
capsici zoospores in Chelex-treated water at 5.times.10.sup.4
spores per mL was prepared as in Example 28. Microtiter plates were
inoculated with 100 .mu.L of the spore suspension and incubated at
25.degree. C. for 48 h before assessing fungal growth by measuring
light scattering in a NepheloStar plate reader.
[0136] Growth inhibition was determined by comparing growth in the
presence of copper-hydrazone mixture with growth in control wells
lacking the copper-hydrazone mixture. EC50 values were calculated
from dose-response curves, and are expressed as the amounts of
hydrazone or copper in each test mixture at the rates providing 50%
inhibition of growth as compared to a control lacking the
copper-hydrazone mixture. Data are presented in Table 12. The
results show that copper-hydrazone mixtures representing a wide
range of molar ratios of copper:hydrazone are substantially more
efficacious against Phytophthora capsici than either hydrazone or
copper alone.
TABLE-US-00012 TABLE 12 Amounts of hydrazone and CuCl.sub.2 at EC50
values Hydrazone CuCl.sub.2 Hydrazone:Cu ratio EC50 (nM) EC50
(.mu.M) Hydrazone without CuCl.sub.2 143.2 1 to 1 71.1 0.071 1 to 4
47.1 0.189 1 to 16 27.5 0.441 1 to 62.5 16.6 1.04 1 to 250 7.6 1.90
1 to 1000 4.6 4.56 CuCl.sub.2 without hydrazone 720.0
Example 37
Synergistic Effect Between Hydrazone Compound 16 and Various Copper
Materials Against Tomato Late Blight (Phytophthora infestans),
Tomato Early Blight (Alternaria solani), and Cucumber Anthracnose
(Colletotrichum lagenarium)
[0137] Hydrazone compound 16 was tested alone or in combination
with CuCl.sub.2.2H.sub.2O, CuSO.sub.4.5H.sub.2O, Kocide.RTM. 2000
(copper hydroxide), or CUREX 3 (tribasic copper sulfate). All
materials and mixtures were evaluated as prophylactic treatments
applied 24 h before inoculation. Efficacy was determined based on
percentage of disease control against tomato late blight
(Phytophthora infestans), tomato early blight (Alternaria solani),
and anthracnose on cucumbers (Colletotrichum lagenarium).
Treatments were arranged as a factorial experiment in a completely
randomized design. Hydrazone and copper were regarded as factors
with hydrazone at 10, 50, 200, and 400 .mu.M, and copper materials
at 10, 50, 200, 400, and 800 .mu.M with respect to their copper
content. All treatments were performed in triplicate. Plant
varieties used were Outdoor Girl and Bush Pickle, for tomato and
cucumber, respectively. Treatments were prepared in 0.01%
Triton.RTM. X-100 and applied to run-off 24 h before inoculation
using a spin-table sprayer. Inoculation was performed with aqueous
spore suspensions using a Delta painting sprayer. Percentage of
disease control was determined 7 days after inoculation.
[0138] Results (Tables 13-24) for disease control by
hydrazone-copper mixtures were compared with predicted values
(shown in brackets) which were calculated using the Colby formula
based on disease control by the hydrazone alone and copper material
alone. The data show that hydrazone-copper mixtures provided
greater disease control than predicted based on control delivered
by the individual components of the mixtures.
TABLE-US-00013 TABLE 13 Synergistic fungicidal effect between
hydrazone Compound 16 and CuCl.sub.2.cndot.2H.sub.2O against tomato
late blight (Phytophthora infestans) % Control of Tomato Late
Blight CuCl.sub.2 Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0.0
1.5 11.3 21.4 25.7 10 1.7 33.5 (3.1) 41.9 (12.8) 67.8 (22.7) 64.4
(26.9) 50 8.5 39.7 (9.9) 63.0 (18.8) 96.6 (28.1) 91.7 (32.0) 200
38.2 69.0 (39.2) 91.5 (45.2) 95.8 (51.5) 91.7 (54.1) 400 56.0 75.7
(56.6) 91.7 (60.9) 90.8 (65.4) 99.8 (67.3) 800 70.2 94.2 (70.7)
98.3 (73.6) 96.7 (76.6) 100.0 (77.9)
TABLE-US-00014 TABLE 14 Synergistic fungicidal effect between
hydrazone Compound 16 and CuSO.sub.4.cndot.5H.sub.2O against tomato
late blight (Phytophthora infestans) % Control of Tomato Late
Blight CuSO.sub.4 Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 1.5
11.3 21.4 25.7 10 1.7 26.3 (3.1) 56.8 (12.8) 78.0 (22.7) 41.5
(26.9) 50 4.8 28.1 (6.2) 67.7 (15.5) 81.3 (25.1) 54.5 (29.2) 200
49.7 56.0 (50.4) 72.9 (55.4) 93.2 (60.4) 87.2 (62.6) 400 76.0 77.3
(76.4) 78.0 (78.8) 95.8 (81.2) 96.6 (82.2) 800 82.9 72.2 (83.1)
91.6 (84.8) 97.5 (86.5) 98.3 (87.3)
TABLE-US-00015 TABLE 15 Synergistic fungicidal effect between
hydrazone Compound 16 and Kocide .RTM. 2000 against tomato late
blight (Phytophthora infestans) % Control of Tomato Late Blight
Kocide .RTM. Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 1.5 11.3
21.4 25.7 10 5.8 26.8 (7.2) 41.2 (16.4) 53.4 (26.0) 65.3 (30.0) 50
6.8 43.1 (8.2) 46.4 (17.3) 77.3 (26.7) 79.6 (30.8) 200 30.4 51.6
(31.4) 65.8 (38.3) 94.8 (45.3) 93.2 (48.3) 400 63.1 64.9 (63.7)
78.3 (67.3) 89.9 (71.0) 94.9 (72.6) 800 67.4 80.8 (67.9) 95.6
(71.1) 100 (74.4) 100 (75.8)
TABLE-US-00016 TABLE 16 Synergistic fungicidal effect between
hydrazone Compound 16 and CUREX 3 against tomato late blight
(Phytophthora infestans) % Control of Tomato Late Blight CUREX 3
Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 1.5 11.3 21.4 25.7 10
0.0 42.4 (1.5) 72.9 (11.3) 77.9 (21.4) 61.7 (25.7) 50 0.0 61.0
(1.5) 88.0 (11.3) 88.0 (21.4) 85.5 (25.7) 200 26.2 63.6 (27.3) 88.9
(34.5) 100.0 (42.0) 93.5 (45.1) 400 41.2 77.3 (42.0) 96.7 (47.8)
96.7 (53.8) 98.3 (56.3) 800 60.8 89.8 (61.4) 97.4 (65.3) 99.5
(69.2) 99.1 (70.9)
TABLE-US-00017 TABLE 17 Synergistic fungicidal effect between
hydrazone Compound 16 and CuCl.sub.2.cndot.2H.sub.2O against tomato
early blight (Alternaria solani) % Control of Tomato Early Blight
CuCl.sub.2 Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0.0 3.9 8.0
28.4 32.4 10 0.0 38.4 (3.9) 39.8 (8.0) 46.1 (28.4) 59.2 (32.4) 50
0.0 44.5 (3.9) 56.0 (8.0) 69.9 (28.4) 86.3 (32.4) 200 50.4 62.1
(52.4) 73.2 (54.5) 82.0 (64.5) 94.7 (66.5) 400 72.5 80.3 (73.6)
79.7 (74.7) 94.2 (80.3) 98.1 (81.4) 800 83.3 86.0 (83.9) 89.6
(84.6) 98.8 (88.0) 98.3 (88.7)
TABLE-US-00018 TABLE 18 Synergistic fungicidal effect between
hydrazone Compound 16 and CuSO.sub.4.cndot.5H.sub.2O against tomato
early blight (Alternaria solani) % Control of Tomato Early Blight
CuSO.sub.4 Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 3.9 8.0
28.4 32.4 10 0.0 48.7 (3.9) 53.8 (8.0) 55.6 (28.4) 54.7 (32.4) 50
7.1 53.0 (10.7) 70.5 (14.5) 74.6 (33.5) 80.9 (37.2) 200 54.4 66.0
(56.2) 83.0 (58.1) 89.7 (67.4) 89.4 (69.2) 400 64.1 82.1 (65.5)
89.5 (67.0) 93.3 (74.3) 96.8 (75.7) 800 71.6 83.5 (72.7) 93.0
(73.9) 96.0 (79.7) 97.7 (80.8)
TABLE-US-00019 TABLE 19 Synergistic fungicidal effect between
hydrazone Compound 16 and Kocide .RTM. 2000 against tomato early
blight (Alternaria solani) % Control of Tomato Early Blight Kocide
.RTM. Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 3.9 8 28.4 32.4
10 1.1 35.6 (5.0) 52.4 (9.0) 29.8 (29.2) 27.2 (33.1) 50 3.9 55.4
(7.6) 77.6 (11.6) 69.8 (31.2) 75.3 (35.0) 200 36 66.1 (38.5) 92.4
(41.1) 84.8 (54.2) 81.4 (56.7) 400 52.7 74.7 (54.5) 92.2 (56.5)
92.4 (66.1) 90.6 (68.0) 800 62.9 83.4 (64.3) 93.6 (65.9) 93.4
(73.4) 95.1 (74.9)
TABLE-US-00020 TABLE 20 Synergistic fungicidal effect between
hydrazone Compound 16 and CUREX 3 against tomato early blight
(Alternaria solani) % Control of Tomato Early Blight CUREX 3
Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 3.9 8.0 28.4 32.4 10
0.0 39.6 (3.9) 29.2 (8.0) 46.0 (28.4) 44.2 (32.4) 50 4.9 48.5 (8.6)
64.4 (12.5) 74.8 (31.9) 65.1 (35.7) 200 36.6 54.7 (39.1) 74.7
(41.7) 85.1 (54.6) 82.3 (57.2) 400 49.1 65.6 (51.1) 80.0 (53.2)
94.9 (63.6) 93.4 (65.6) 800 40.2 63.6 (42.5) 88.0 (45.0) 96.6
(57.2) 94.9 (59.6)
TABLE-US-00021 TABLE 21 Synergistic fungicidal effect between
hydrazone Compound 16 and CuCl.sub.2.cndot.2H.sub.2O against
cucumber anthracnose (Colletotrichum lagenarium). % Control of
Cucumber Anthracnose CuCl.sub.2 Hydrazone (.mu.M) (.mu.M) 0 10 50
200 400 0 0 10.0 33.8 63.8 70.8 10 9.6 46.9 (18.6) 72.5 (40.1) 82.8
(67.3) 83.6 (73.6) 50 1.4 47.8 (11.3) 81.0 (34.8) 86.2 (64.3) 89.0
(71.2) 200 37.2 73.0 (43.5) 85.3 (58.4) 95.4 (77.3) 98.9 (81.7) 400
76.2 87.2 (78.6) 94.9 (84.2) 98.8 (91.4) 99.6 (93.0) 800 90.0 91.0
(91.0) 97.5 (93.4) 97.8 (96.4) 98.6 (97.1)
TABLE-US-00022 TABLE 22 Synergistic fungicidal effect between
hydrazone Compound 16 and CuSO.sub.4.cndot.5H.sub.2O against
cucumber anthracnose (Colletotrichum lagenarium). % Control of
Cucumber Anthracnose CuSO.sub.4 Hydrazone (.mu.M) (.mu.M) 0 10 50
200 400 0 0 10.0 33.8 63.8 70.8 10 1.4 55.8 (11.2) 67.5 (34.7) 94.5
(64.3) 90.7 (71.2) 50 0.0 58.9 (10.0) 78.3 (33.8) 92.0 (63.8) 98.7
(70.8) 200 61.3 70.6 (65.2) 89.8 (74.4) 97.5 (86.0) 99.6 (88.7) 400
75.7 92.0 (78.1) 95.2 (83.9) 98.4 (91.2) 99.7 (92.9) 800 87.1 96.2
(88.4) 95.6 (91.5) 96.5 (95.3) 99.6 (96.2)
TABLE-US-00023 TABLE 23 Synergistic fungicidal effect between
hydrazone Compound 16 and Kocide .RTM. 2000 against cucumber
anthracnose (Colletotrichum lagenarium) % Control of Cucumber
Anthracnose Kocide .RTM. Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400
0 0 10 33.8 63.8 70.8 10 15.9 40.4 (24.3) 56.5 (44.3) 83.7 (69.6)
72.2 (75.4) 50 15 64.9 (23.5) 83.7 (43.7) 93.9 (69.2) .sup. 97
(75.2) 200 28.9 .sup. 80 (36.0) 95.3 (52.9) 97.2 (74.3) 97.5 (79.2)
400 68.8 79.9 (71.9) 89.5 (79.3) 99.4 (88.7) 98.5 (90.9) 800 67.5
90.3 (70.8) 95.9 (78.5) 99.2 (88.2) 99.3 (90.5)
TABLE-US-00024 TABLE 24 Synergistic fungicidal effect between
hydrazone Compound 16 and CUREX 3 against cucumber anthracnose
(Colletotrichum lagenarium) % Control of Cucumber Anthracnose CUREX
3 Hydrazone (.mu.M) (.mu.M) 0 10 50 200 400 0 0 10.0 33.8 63.8 70.8
10 7.8 42.1 (17.0) 78.0 (39.0) 84.4 (66.6) 93.0 (73.1) 50 10.9 51.9
(19.8) 91.4 (41.0) 92.8 (67.7) 95.8 (74.0) 200 23.0 58.6 (30.7)
93.5 (49.0) 99.1 (72.1) 99.2 (77.5) 400 38.7 71.1 (44.8) 92.9
(59.4) 99.4 (77.8) 98.3 (82.1) 800 31.5 55.2 (38.4) 84.0 (54.7)
96.2 (75.2) 95.0 (80.0)
Example 38
Control of Grape Downy Mildew (Plasmopara viticola) and Tomato Late
Blight (Phytophthora infestans) by Compound 16, its Copper Complex,
and Copper Chloride
[0139] Test compounds were hydrazone Compound 16, the complex of
Compound 16 with copper ("hydrazone-copper") prepared by
precipitation with CuCl.sub.2.2H.sub.2O using a 1:1 molar ratio,
and CuCl.sub.2.2H.sub.2O alone. Hydrazone and hydrazone-copper were
formulated in 10% acetone/0.1% Trycol 5941 in de-ionized water.
CuCl.sub.2.2H.sub.2O was formulated with 0.1% Trycol 5941 in
de-ionized water. Grape and tomato plants were sprayed with 160
.mu.M suspensions of the formulated test compounds at a spray
volume of 0.8 mL per plant. After 24 h, the undersides of the grape
leaves were inoculated with an aqueous suspension of Plasmopara
viticola sporangia and tomato plants were inoculated with an
aqueous suspension of Phytophthora infestans sporangia. Plants were
kept in high humidity overnight, then transferred to a greenhouse
(grapes) or growth room (tomatoes) until disease developed on
untreated control plants.
[0140] Results for disease control by hydrazone-copper were
compared with predicted results calculated using the Colby formula
based on disease control by the hydrazone alone and CuCl.sub.2
alone. Results, shown in Table 25, show that hydrazone-copper
provided greater disease control than predicted based on control
observed for hydrazone and CuCl.sub.2 alone.
TABLE-US-00025 TABLE 25 % Control % Control Disease Treatment .mu.M
Observed Predicted Downy mildew Hydrazone 16 160 29
Hydrazone-copper 600 160 78 30 CuCl.sub.2 160 1 Late blight
Hydrazone 16 160 49 Hydrazone-coppper 600 160 100 84 CuCl.sub.2 160
69
[0141] While this disclosure has been described as having exemplary
compounds, the present disclosure can be further modified within
the spirit and scope of this disclosure. For example, all of the
disclosed components of the preferred and alternative embodiments
are interchangeable providing disclosure herein of many systems
having combinations of all the preferred and alternative embodiment
components. This application is therefore intended to cover any
variations, uses, or adaptations of the disclosure using its
general principles. Further, this application is intended to cover
such departures from the present disclosure as come within known or
customary practice in the art to which this disclosure pertains and
which fall within the limits of the appended claims.
* * * * *