SUBSTTTUTED AROMATIC HETEROCYCLIC
COMPOUNDS AS FUNGICIDES
Shy-Fuh Lee, Micah Gliedt, and Richard J. Anderson
Related Applications
This application claims the benefit of United States provisional patent
application serial number 60/751,558, filed December 19, 2005, the disclosure of
which is incorporated by reference herein in its entirety.
Field of the Invention
The present invention concerns substituted aromatic heterocyclic compositions
such as thiophenes, furans and pyrroles, and methods of use thereof for the control of .
microbial pests, particularly fungal pests, on plants.
Background of the Invention
The incidence of serious fungal infections, either systemic or topical,
continues to increase for plants, animals, and humans. Many fungi are common in the
environment and not harmful to plants or mammals. However, some fungi can
produce disease in plants, humans and/or animals.
Fungicides are compounds, of natural or synthetic origin, which act to protect
plants against damage caused by fungi, including oomycetes. Current methods of
agriculture rely heavily on the use of fungicides. In fact, some crops cannot be grown
usefully without the use of fungicides. Using fungicides allows a grower to increase
the yield of the crop and consequently, increase the value of the crop. Numerous
fungicidal agents have been developed. However, the treatment of fungal infestations
and infections continues to be a major problem. Furthermore, fungicide and
antifungal drug resistance has become a serious problem, rendering these agents
ineffective for some agricultural and therapeutic uses. As such, a need exists for the
development of new fungicidal and antifungal compounds (see, e.g., US Patent No.
6,673,827; See also US Patent No. 6,617,330 to Walter, which describes pyrimidm-4-
enamine as fungicides).
Summary of the Invention
A first aspect of the invention is compounds of formula I:
(Formula Removed)
wherein:
X isS,O,or NRs;
R is H; alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted {e.g., 1,
2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloaikylthio, cyano, or nitro; aryloxyalkyl optionally
substituted {e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloaikylthio, cyano, or nitro;
arylthioalkyl optionally substituted {e.g., 1, 2, 3 or 4 times) with halogen, alkyL
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloaikylthio,
cyano, or nitro; aryl optionally substituted {e.g., 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloaikylthio, cyano, nitro; heteroaryl optionally substituted {e.g., 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloaikylthio, cyano, or nitro; or alkylsilyl;
R1 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted {e.g., 1, 2,
3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloaikylthio, cyano, or nitro; aryloxyalkyl optionally
substituted {e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloaikylthio, cyano, or nitro;
arylthioalkyl optionally substituted {e.g., 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloaikylthio,
cyano, or nitro; aryl optionally substituted {e.g., 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R2 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g., 1, 2,
3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryl optionally substituted (e.g.
1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; heteroaryl, especially 2-,
3- or 4-pyridy! optionally substituted (e.g. 1, 2,.3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; 5-pyrimidinyl optionally substituted (e.g. 1, 2, 3 or 4 times) with
halogen, alkyl, alkenyl,.alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkyllhio, cyano, or nitro; or 2- or 5-thiazolyl optionally substituted (e.g. 1,2, 3 or
4 times) with halogen, alkyl alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl,
haloalkenyl, haloalkoxy, haloalkylthio, cyano, or nitro;
R3 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g. I, 2, 3
or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryioxyalkyl optionally
substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
arylthioalkyl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; aryl optionally substituted (e.g. 1,2,3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, nitro; heteroaryl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; or alkylsilyl;
R4 is H; acyl (e.g., acetyl, benzoyl, phenylacetyl); haloacyl; alkoxycarbonyl;
aryloxycarbonyl; alkylaminocarbonyl; or dialkylaminocarbonyl;
R5 is H; alkyl; alkenyl; alkynyl; alkoxyalkyl; haloalkyl; arylalkyl optionally
substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryioxyalkyl
optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
arylthioalkyl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haioalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; aryl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haioalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl, haioalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
and salts thereof.
The present invention also concerns compositions comprising or consisting
essentially of an active compound as described herein in combination with a suitable
carrier (e.g., an agricultural carrier).
The compounds and compositions of the present invention are useful as crop
protection agents to combat or prevent fungal infestations, or to control other pests
such as weeds, insects, or acarids that are harmful to crops.
A second aspect of the present invention is a composition for controlling and
preventing plant pathogenic microorganisms comprising, in combination, an active
compound as described herein together with a suitable carrier.
A third aspect of the present invention is a method of controlling or preventing
infestation of cultivated plants by pathogenic microorganisms, comprising applying
an active compound as described herein to said plants, parts thereof or the locus
thereof in an amount effective to control said microorganisms.
A further aspect of the present invention is a method of controlling or
preventing infestation of technical materials by pathogenic microorganisms,
comprising applying an active compound as described herein to said technical
materials, parts thereof or the locus thereof in an amount effective to control said
microorganisms.
A further aspect of the present invention is a method of treating a fungal
infection in a subject in need thereof, comprising administering an active compound
as described herein to said subject in an amount effective to treat said fungal
infection.
A still further aspect of the present invention is the use of an active compound
as described herein for the preparation of a composition (e.g., an agricultural
formulation, a pharmaceutical formulation) for carrying out a method as described
herein (e.g., an agricultural treatment as described herein, the treatment of technical
materials as described herein, the treatment of a fungal infection in a subject as
described herein).
The foregoing and other objects and aspects of the present invention are
explained in greater detail below.
Detailed Description of the Preferred Embodiments
"Alkyl" as used herein refers to a saturated hydrocarbon radical which may be
straight-chain or branched-chain (for example, ethyl, isopropyl, t-amyl, or 2,5-
dimethylhexyl) or cyclic (for example cyclobutyl, cyclopropyl or cyclopentyl) and
contains from 1 to 24 carbon atoms. This definition applies both when the term is
used alone and when it is used as part of a compound term, such as "haloalkyl" and
similar terms. In some embodiments, preferred alkyl groups are those containing 1 to
4 carbon atoms, which are also referred to as "lower alkyl." In some embodiments
preferred alkyl groups are those comtaining 5 or 6 to 24 carbon atoms, which may also
be referred to as "higher alkyl".
"Alkenyl," as used herein, refers to a straight or branched chain hydrocarbon
containing from 2 to 24 carbons and containing at least one carbon-carbon double
bond formed by the removal of two hydrogens. Representative examples of "alkenyl"
include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,
4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, 3-decenyl and the like.
"Lower alkenyl" as used herein, is a subset of alkenyl and refers to a straight or
branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
"Alkynyl," as used herein, refers to a straight or branched chain hydrocarbon
group containing from 2 to 24 carbon atoms and containing at least one carbon-carbon
triple bond. Representative examples of alkynyl include, but are not limited, to
acetylenyl 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
"Lower alkynyl" as used herein, is a subset of alkyl and refers to a straight or
branched chain hydrocarbon group containing from 1 to 4 carbon atoms.
"Alkoxy" refers to an alkyl radical as described above which also bears an
oxygen substituent which is capable of covalent attachment to another hydrocarbon
radical (such as, for example, methoxy, ethoxy and t-butoxy).
"Alkylthio" as used herein refers to an alkyl group, as defined herein,
appended to the parent molecular moiety through a thio moiety, as defined herein.
Representative examples of alkylthio include, but are not limited, methylthio,
ethylthio, tert-butylthio, hexylthio, and the like.
"Aryl" or "aromatic ring moiety" refers to an aromatic substituent which may
be a single ring or multiple rings which are fused together, linked covalently or linked
to a common group such as an ethylene or methylene moiety. The aromatic rings may
each contain heteroatoms and hence "aryl encompasses "heteroaryl" as used herein.
Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl,
tetrahydronaphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-l-ethyl, thienyl, pyridyl
and quinoxalyl. "Aryl" means substituted or unsubstituted aryl unless otherwise
indicated and hence the aryl moieties may be optionally substituted with halogen
atoms, or other groups such as nitro, carboxyl, alkoxy, phenoxy and the like.
Additionally, the aryl radicals may be attached to other moieties at any position on the
aryl radical which would otherwise be occupied by a hydrogen atom (such as, for
example, 2-pyridyl 3-pyridyl and 4-pyridyl).
"Heteroaryl" means a cyclic, aromatic hydrocarbon in. which one or more
carbon atoms have been replaced with heteroatoms. If the heteroaryl group contains
more than one heteroatom, the heteroatoms may be the same or different Examples of
heteroaryl groups include pyridyl, pyrirnidinyl, imidazolyl, thienyl, furyl, pyrazinyl,
pyrrolyl pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl,
indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, •
qutnolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, isothiazolyl, and
benzo[b]thienyl. Preferred heteroaryl groups are five and six membered rings and
contain from one to three heteroatoms independently selected from O, N, and S. The
heteroaryl group, including each heteroatom, can be unsubstituted or substituted with
from 1 to 4 substituents, as chemically feasible. For example, the heteroatom S may
be substituted with one or two oxo groups, which may be shown as =O.
"Agriculturally acceptable salt" means a salt the cation of which is known and
accepted in the art for the formation of salts for agricultural or horticultural use.
Preferably the salts are water-soluble.
"Cyano" as used herein refers to a -CN group.
"Halo" or "halogen," as used herein, refers to -Cl, -Br, -I or -F.
"Haloalkyl," as used herein, refers to at least one halogen, as defined herein,
appended to the parent molecular moiety through an alkyl group, as defined herein.
Representative examples of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and the like.
"Hydroxy," as used herein, refers to an -OH group.
"Nitro," as used herein, refers to a —NO2 group.
"Oxy," as used herein, refers to a -O- moiety.
"Thio," as used herein, refers to a -S- moiety.
The disclosures of all US Patent references cited herein are to be incorporated
herein in their entirety as if fully set forth.
2. Compounds. The compounds of this invention are represented by formula
I, including formulas Ia-Ic:

(Formula Removed)
wherein:
X is S,O,or NR5;
R is H; alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g., 1,
2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryloxyalkyl optionally
substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
arylthioalkyl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; aryl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylfhio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R1 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g., 1, 2,
3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryloxyalkyl optionally
substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
arylthioalkyl optionally substituted (e.g, 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; aryl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R2 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g., 1, 2,
3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryl optionally substituted (e.g.
1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; heteroaryl, especially 2-,
3- or 4-pyridyl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; 5-pyrimidinyl optionally substituted (e.g. 1, 2, 3 or 4 times) with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; or 2- or 5-thiazolyl optionally substituted (e.g. 1, 2,3 or
4 times) with halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl,
haloalkenyl, haloalkoxy, haloalkylthio, cyano, or nitro;
R3 is alkyl, alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g. 1,2,3
or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy',
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryloxyalkyl optionally
substituted (e.g. 1, 2, 3 or 4 times) with halogen alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylinio, cyano, or nitro;
arylthioalkyl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; aryl optionally substituted (e.g. 1,2,3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, nitro; heteroaryl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; or alkylsilyl;
R4 is H; acyl (e.g., acetyl, benzoyl, phenylacetyl); haloacyl; alkoxycarbonyl;
aryloxycarbonyl; alkylaminocarbonyl; or dialkylaminocarbonyl;
R5 is H; alkyl; alkenyl; alkynyl; alkoxyalkyl; haloalkyl; arylalkyl optionally
substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
aryloxyalkyl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; arylthioalkyl optionally substituted (e.g., 1, 2, 3 or 4 times) with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryl optionally substituted (e.g., 1, 2, 3 or 4 times) with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl,' haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano,.or nitro; or alkylsilyl.
Methods of making. Compositions of generic structure la wherein R. and R4 =
H may be prepared by the [3+2]-cycloaddition of an acetylenethiolate anion II and an
acetylenic ketone III to give thiophene ketone IV which upon reduction provides the
corresponding thiophene alcohol la (see L. S. Rodinova, M. L. Petrov, and A. A.
Petrov, Zhurnal Organicheskoi Khimii 1981, 17(10), 2071-2075 for a related
thiophene synthesis):
(Formula Removed)
The [3+2]-cycloaddition reaction is carried out by preforming the acetylenethiolate in
an inert solvent such as THF (tetrahydrofuran) at low temperature, preferably -78 °,
and then adding it to a solution of the acetylenic ketone HI in an inert solvent or
solvent mixture, such as THF and acetonitrile, at temperatures ranging from 0°C to -
20°C. The acetylenethiolate II is prepared from the reaction of sulfur with a lithium
salt (VI) of a terminal acetylene V (H. G. Raubenheimer, G. J. kruger, C. F. Marais,
R. Otte, and J. T. Z. Hattingh, Organometallics 1988,7,1853-1858) :
(Formula Removed)
Lithium acetylide VI is formed by the treatment of terminal acetylene V with
a strong base such as n-butyllithium in an inert solvent such as THF at low
temperature, preferably from -40°C to -78°C. Addition of sulfur to acetylide VT at
low temperature (~40°C to -78°C) and reaction for 1.5-3hr gives the acetylenethiolate
II. Reduction of thiophene ketone IV is effected with a reducing agent such as LiAIH4
in an inert solvent such as ether or THF, or NaBPL4 in a solvent such as ethanol at
temperatures in the range of 0°C to 20°C.
Alternatively, the Heck reaction may be employed to arylate activated
miophenes that are intermediates in the synthesis of la when R1 and R3 are aryl (L.
Lavenot, C. Gozzi, K. Dg, I Orlova, V. Penalva, and M. Lemaire, Journal of
Organometallic Chem. 1998, 567, 49-55). Thus, thiophene-3-carboxaldehyde VTI
may be selectively arylated with aryl iodide R3I in the presence of a transition metal
catalyst such as a palladium(n) catalyst to give a 2-arylated intermediate VDI. A
second palladium-catalyzed arylation with another aryl iodode R1I then gives the 2,4-
diarylthiophen-3-carboxaldehyde IX. Treatment of IX with
(Formula Removed)
an organometallic reagent R1M produces the compositions of generic structure la
(R and R4 = H).
(Formula Removed)
The Heck reaction is typically carried out in solvents such as acetonitrile or
water, or in mixtures of the two, at temperatures in the range of 20-80°C for 4-72hrs.
The typical palladium catalysts are palladium chloride, usually used in association
with lithium chloride, or palladium acetate used with tetra-n-butylammonium bromide
with or without a phosphine such as triphenylphosphine.
. The addition of the organometallic reagent R2M is typically conducted in an
inert solvent such as ether or THF under N2 atmosphere at 0-20°C for l-5hrs. The
organometallic reagent may be an organolithium reagent, or preferably an
organomagnesium reagent.
Compositions of generic structure la wherein R4 = H may also be prepared by
the Michael addition of a substituted α-mercaptoketone X (R1 = H) to acetylenic
ketone HI to give the dihydrothienyl intermediate XL Dehydration of XI to thiophene
XII and subsequent
(Formula Removed)
reduction of XII provides the composition la (R4 = H).
The Michael addition is carried out by reaction of the α-mercaptoketone X ( R1
= H) and the acetylenic ketone HI in the presence of a base, preferably an organic
base such as morpholine, and an inert solvent such as diethoxymethane at elevated
temperatures such as reflux temperature for l-8hrs. Alternatively, α-acetylthioketone
X (R1 = COCH3) may be used in the Michael addition wherein the base such as
morpholine cleaves the thioester to the requisite a-mercaptoketone X ( R' = H) in situ.
Intermediate XI is efficiently dehydrated by treatment with p-toluenesulfonic
acid or acetic anhydride in toluene at elevated temperatures (80-100°C) for 12-48hrs.
to produce the thienyl ketone Xll, reduction of which is accomplished as above with a
reducing agent such as LiAlH4 in an inert solvent such as ether or THF, or NaBH4 in a
solvent such as ethanol at temperatures in the range of 0°C to 20°C.
The a-acetylthioketones X (R' = COCH3) and α-mercaptoketones X ( R' = H)
are readily
(Table Removed)available by treatng the corresponding a-bromoketones XIII withthioaceticacidina
basic medium to give X (R' = COCH3), which upon treatment with aqueous base
(e.g., aqueous NaOH) produces X (R' = H).
The compositions lb may be prepared from XIII (R = H) or its chloro analog
by reaction with the p-ketoester XIV under base catalyzed conditions to give the
dihydrofuran XV (see F. Feist, Chem, Ber. 1902, 35, 1537-44), dehydration of which
produces the furan XVI. This dehydration is efficiently effected by treatment of XV
with p-toluenesulfonic acid or acetic anhydride in toluene at elevated temperatures
(80-100°C) for 12-48hrs. Reduction of furyl ester XVI to furyl alcohol XVII and
subsequent oxidation to furylcarboxaldehyde XVIH followed by addition of
organometallic reagent R2Li or R2MgX' gives compound lb (R4 = H) The reduction
of XVI to alcohol XVII is accomplished using a hydride reagent such as LiAlR4 or
diisobutylaluminum hydride (DIBAL) in an inert solvent such as ether of THF.
Oxidation of XVII to aldehyde my be effected with reagents including activated
MnO2, o-iodosobenzoic acid (EBX) in DMSO, or CrO3/pyr in inert solvents such as
dichloromethane . The addition of the organometallic reagent to aldehyde XVIII is
typically conducted in an inert solvent such as ether or THF under N2 atmosphere at
0-20°C for l-5hrs. The organometallic reagent may be an organolithium reagent, or
preferably an organomagnesium reagent.
(Formula Removed)
Alternatively, furyl ester XVI may be hydrolyzed to furoic acid XIX under
aqueous basic conditions such as aqueous NaOH or LiOH. Conversion of the acid
XIX to the Weinreb amide XX may be accomplished by coupling XIX and N.O-
hydroxylamine hydrochloride using 1-hydroxybenzotriazole (HOBT) and
diisopropylcarbodiimide (DIC) in the presence of diisopropylethylamine (DIEA) in an
inert solvent such as dichloromethane (DCM) . Addition of organometallic agent
R2MgX' to XX in an inert solvent such as ether or THF under N2 atmosphere at 0-
20°C for l-5hrs gives the ketone XXI, reduction of which is accomplished as above
-14-
with a reducing agent such as LiAIH4 in an inert solvent such as ether or THF, or
NaBH4 in a solvent such as ethanol at temperatures in the range of 0°C to 20°C. to
produce compound lb (R4 = H).

(Formula Removed)
The compositions Ic may be prepared using an approach similar to that
employed for the thiophenes la, i.e., but adding a-aminoketones XXII to the
alkynylketone HI in the Michael addition. Dehydration of dihydropyrrole XXIII to
yield pyrrolyl ketone XXIV and subsequent reduction with LiAlH4 or NaBH4) gives Ic
(R4 = H). Reaction conditions similar to those used to prepare the aforementioned
furans lb may be employed.
w R5 R5 Rs
(Formula Removed)
Alternatively, condensation of a-aminoketone XXII and p-ketoester XTV
under basic conditions gives the dihydropyrrole XXV (see L. Knorr, Chem. Ber.
1884, 17, 1635; A. H. Corwin, Heterocyclic Compounds. 1950, 1, 287), dehydration
of which produces the pyrrolyl ester XXVI. Alkylation of XXVI with R5I yields the
N-substituted pyrrolyl ester XXWII. In reactions similar to those described for the
furan system, ester XXVII is converted to compound Ic (R4 = H).
}*"* + r^O^ base fcJL^R. R^v^*. ***
(Formula Removed)
Ester XXVn may also be hydrolyzed to its corresponding acid XXX and
converted to its Weinreb amide XXXI as above. Addition of organometallic agent
R2MgX' gives the ketone XXXII, reduction of which produces compound Ic (R4 =
H).
(Table & Formula Removed)
Exemplary compounds. Compounds la of the invention that are especially
useful for the control of fungal pathogens are those in which:
R = Horalkyl;
R, = aryl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen,alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro;
or heteroaryl optionally substituted (e.g. 1,2,3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, nitro;
R2 = heteroaryl, especially 2-, 3- or 4-pyridyl optionally substituted
(e.g. 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; or 5-
pyrimidinyl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro;
R3 = alkyl; aryloxyalkyl optionally substituted (e.g. 1, 2, 3 or 4 times)
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, or nitro; aryl optionally substituted (e.g. 1,2,
3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl
optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, nitro; or alkylsilyl;
R4 = H;and
Rs is H, alkyl, or haloalkyl.
Examples of compounds of the present invention include, but are not limited
to, the following:
(Structure Removed)
Salts. The compounds described herein and, optionally, all their isomers may
be obtained in the form of their salts. Because some of the compounds I have a basic
center they can, for example, form acid addition salts. Said acid addition salts are, for
example, formed with mineral acids, typically sulfuric acid, a phosphoric acid or a
hydrogen halide, with organic carboxylic acids, typically acetic acid, oxalic acid,
malonic acid, maleic acid, ftraiaric acid or phthalic acid, with hydroxyearboxylic
acids, typically ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or
with benzoic acid, or with organic sulfonic acids, typically methanesulfonic acid or p-
toiuenesulfonic acid. Together with at least one acidic group, the compounds of
formula I can also form salts with bases. Suitable salts with bases are, for example,
metal salts, typically alkali metal salts; or alkaline earth metal salts, e.g. sodium salts,
potassium salts or magnesium salts, or salts with ammonia or an organic amine, e.g.
morpholine, piperidine, pyrrolidine, a mono-, di- or trialkylamine, typically
ethylamine, diemylamine, triemylamine or dimethylpropylamine, or a mono-, di- or
trihydroxyalkylamine, typically mono-, di- or triethanolamine. Where appropriate, the
formation of corresponding internal salts is also possible. Within the scope of this
invention, agrochemical or phannaceutically acceptable salts are preferred.
3. Agrochemical compositions and use. Active compounds of the present
invention can be used to prepare agrochemical compositions and used to control fungi
in like manner as other antifungal compounds. See, e.g., US Patent No. 6,617,330;
see also US Patents Nos. 6,616,952; 6,569,875; 6,541,500, and 6,506,794.
Active compounds described herein can be used for protecting plants against
diseases that are caused by fungi. For the purposes herein, oomycetes shall be
considered fungi. The active compounds can be used in the agricultural sector and
related fields as active ingredients for controlling plant pests. The active compounds
can be used to inhibit or destroy the pests that occur on plants or parts of plants (fruit,
blossoms, leaves, stems, tubers, roots) of different crops of useful plants, optionally
while at the same time protecting also those parts of the plants that grow later e.g.
from phytopathogenic micro-organisms.
Active compounds may be used as dressing agents for the treatment of plant
propagation material, in particular of seeds (fruit, tubers, grains) and plant cuttings
(e.g. rice), for the protection against fungal infections as well as against
phytopathogenic fungi occurring in the soil.
The active compounds may be used, for example, against the phytopathogenic
fungi of the following classes: Fungi imperfecti (e.g. Botrytis, Pyricularia,
Helminthosporium, Fusarium, Septoria, Cercospora and Alternaria) and
Basidiomycetes (e.g. Rhizoctonia, Hemileia, Puccinia). Additionally, they may also
be used against the Ascomycetes classes (e.g. Venturia and Erysiphe, Podosphaera,'
Monilinia, Uncinula) and of the Oomycetes classes (e.g. Phytophthora, Pythium,
Plasmopara). Specific examples of fungi that may be treated include, but are not
limited to, Septoria tritici, Stagonospora nodorum, Phytophthora infestans, Botrytis
cinerea, and Monilinia fructicola.
Target crops to be protected with active compounds and compositions of the
invention typically comprise the following species of plants: cereal (wheat, barley,
rye, oat, rice, maize, sorghum and related species); beet (sugar beet and fodder beet);
pomes, drupes and soft fruit (apples, pears, plums, peaches, almonds, cherries,
strawberries, Taspberries and blackberries); leguminous plants (beans, lentils, peas,
soybeans); oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil
plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons);
fiber plants (cotton, flax, hemp, jute); citrus fruit (oranges, lemons, grapefruit,
mandarins); vegetables (spinach, lettuce, asparagus, cabbages, carrots, onions,
tomatoes, potatoes, paprika); lauraceae (avocado, cinnamon, camphor) or plants such
as tobacco, nuts, coffee, eggplants, sugar cane, tea, pepper, vines including grape-
bearing vines, hops, bananas, turf and natural rubber plants, as well as ornamentals
(flowers, shrubs, broad-leafed trees and evergreens, such as conifers). This list does
not represent any limitation.
The active compounds can be used in the form of compositions and can be
applied to the crop area or plant to be treated, simultaneously or in succession with
further compounds. These further compounds can be e.g. fertilizers or micronutrient
donors or other preparations which influence the growth of plants. They can also be
selective herbicides as well as insecticides, fungicides, bactericides, nematicides,
molluscicides, plant growth regulators, plant activators or mixtures of several of these
preparations, if desired together with further carriers, surfactants or application
promoting adjuvants customarily employed in the art of formulation.
The active compounds can be mixed with other fungicides, resulting in some
cases in unexpected synergistic activities.
Mixing components which are particularly preferred are azoles such as
azaconazole, bitertanol, propiconazole, difenoconazole, diniconazole, cyproconazole,
epoxiconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil,
imibenconazole, ipconazole, tebuconazole, tetraconazole, fenbuconazole,
metconazole, myclobutanil, perfurazoate, penconazole, bromuconazole, pyrifenox,
prochloraz, triadimefon, triadimenol, triflumizole or triticonazole; pyrimidinyl
carbinoles such as ancymidol, fenarimol or nuarimol; 2-amino-pyrimidine such as
bupirimate, dimethirimol or ethirimol; morpholines such as dodemorph, fenpropidin,
fenpropimorph, spiroxamin or tridemorph; anilinopyrirnidines such as cyprodinil,
pyrimethanil or mepampyrirn; pyrroles such as fenpiclonil or fludioxonil;
phenylamides such as benalaxyl, furalaxyl, metalaxyl, R-metalaxyl, ofurace or
oxadixyl; benzimidazoles such as benomyl, carbendazim, debacarb, Albendazole or
thiabendazole; dicarboximides such as chlozolinate, dichlozoiine, iprodine,
myclozoline, procymidone or vinclozolin; carboxamides such as carboxin, fenfuram,
flutolanil, mepronil, oxycarboxin or thifluzamide; guanidines such as guazatine,
dodine or iminoctadine; strobilurines such as azoxystrobin, kresoxim-methyl,
metominostrobin, pyraclostrobin, picoxystrobin, SSF-129, methyl 2[(2-
trifluoromethyl)-pyrid-6-yloxymethyl]-3-methoxy-acrylate or 2-[ {alpha, [(alpha-
memyl-3-trifluoromethyl-berizyl)imino]-oxy} -o-tolyl]- glyoxylic acid-methylester-O-
methyloxime (trifloxystrobin); ditbiocarbamates such as ferbam, mancozeb, maneb,
metiram, propineb, thiram, zineb or ziram; N-halomethylthio-dicarboximides such as
captafol, captan, dichlofluanid, fluoromide, folpet or tolyfluanid; copper compounds
such as Bordeaux mixture, copper hydroxide, copper oxychloride, copper sulfate,
cuprous oxide, mancopper or oxine-copper; .nitrophenol derivatives such as dinocap
or nitrothal-isopropyl; organo phosphorous derivatives such as edifenphos,
iprobenphos, isoprothiolane, phosdiphen, pyrazophos or toclofos-methyl; and other
compounds of diverse structures such as acibenzolar-S-methyl, harpin, anilazine,
blasticidin-S, chinomethionat, chloroneb, chlorothalonil, cymoxanil, dichlone,
diclomezine, dicloran, diethofencarb, dimethomorph, dithianon, etridiazole,
famoxadone, fenamidone, fentin, ferimzone, fluazinam, flusulfamide, fenhexamid,
fosetyl-aluminium, hymexazol, kasugamycin, methasulfocarb, pencycuron, phthalide,
polyoxins, probenazole, propamocarb, pyroquilon, quinoxyfen, quintozene, sulfur,
tiiazoxide, tricyclazole, triforine, validamycin, (S)-5-methyl-2-methylthio-5-phenyl-3-
phenylamino-3,5-di-hydroimidazol-4-on e (RPA 407213), 3,5-dichloro-N-(3-chloro-
1-ethyl-l -methyl-2-oxopropyl)-4-methylbenzarnide (RH-7281), N-allyl-4-,5-dimethyl-
2-trimethylsilylthiophene-3-carboxamide (MON 65500), 4-chloro-4-cyano-N,N-
dimethyl-5-p-tolylimidazole-l-sulfon-amide (IKF-916), N-(l-cyano-l,2-
dimethylpropyI)-2-(2,4-dichlorophenoxy)-propionamide (AC 382042) or iprovalicarb
(SZX 722).
The active compounds can be mixed with one or more systemically acquired
resistance inducer ("SAR" inducer), alone or in combination with a fungicide as
above. SAR inducers are known and described in, for example, US Patent No.
6,919,298. In general, a SAR inducer is any compound which has the ability to turn
on resistance in a plant to a disease-causing agent, including, but not limited to a
virus, a bacterium,, a fungus, or combinations of these agents. In addition, an SAR
inducer may induce resistance to insect feeding in a plant, as defined by Enyedi et al.
(1992; Cell 70: 879-886). Exemplary SAR inducers cover many structural families of
compounds, but are united by their ability to induce a resistance to plant diseases
and/or pest feeding. One class of SAR inducers is the salicylates. The commercial
SAR inducers acibenzolar-S-methyl (available as Actigard® from Syngenta), harpin
protein (available as Messenger™ from Eden Biosciences), yeast extract hydrolysate
from Saccharomyces cerevisiae (available as Keyplex® 350-DP® from Morse
Enterprises Limited, Inc. of Miami, Florida), and Oryzemate are useful in the present
invention. Elicitors, including the Goemar products are another class of SAR inducers
that can also be used. In addition, ethylene, its biosynthetic precursors, or ethylene
releasing compounds such as Ethrel are considered SAR inducers of utility in this
context. See also US Patent No. 6,919,298.
Suitable carriers and adjuvants can be solid or liquid and are substances useful
in formulation technology, e.g. natural or regenerated mineral substances, solvents,
dispersants, wetting agents, tackifiers, thickeners, binders or fertilizers.
A preferred method of applying an active compound of the invention, or an
agrpchemical composition which contains at least one of said compounds, is foliar
application. The frequency of application and the rate of application will depend on
the risk of infestation by the corresponding pathogen. However, the active compounds
can also penetrate the plant through the roots via the soil (systemic action) by
drenching the locus of the plant with a liquid formulation, or by applying the
compounds in solid form to the soil, e.g. in granular form (soil application). In crops
of water such as rice, such granulates can be applied to the flooded rice field. The
active compounds may also be applied to seeds (coating) by impregnating the seeds or
tubers either with a liquid formulation of the fungicide or coating them with a solid
formulation.
The term locus as used herein is intended to embrace the fields on which the
treated crop plants are growing, or where the seeds of cultivated plants are sown, or
the place where the seed will be placed into the soil. The term seed is intended to
embrace plant propagating material such as cuttings, seedlings, seeds, and germinated
or soaked seeds.
The active compounds are used in unmodified form or, preferably, together
with the adjuvants conventionally employed in the art of formulation. To this end they
are conveniently formulated in known manner to emulsifiable concentrates, coatable
pastes, directly sprayable or dilutable solutions, dilute emulsions, wettable powders,
soluble powders, dusts, granulates, and also encapsulations e.g. in polymeric
substances. As with the type of the compositions, the methods of application, such as
spraying, atomizing, dusting, scattering, coating or pouring, are chosen in accordance
with the intended objectives and the prevailing circumstances.
Advantageous rates of application are normally from 5 g to 2 kg of active
ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 .kg a.i/ha, most preferably
from 20 g to 600 g a.i./ha. When used as seed drenching agent, convenient dosages
are from 10 mg to 1 g of active substance per kg of seeds.
The formulation, i.e. the compositions containing the compound of formula I
and, if desired, a solid or liquid adjuvant, are prepared in known manner, typically by
intimately mixing and/or grinding the compound with extenders, e.g..solvents, solid
carriers and, optionally, surface active compounds (surfactants).
Suitable carriers and adjuvants may be solid or liquid and correspond to the
substances ordinarily employed in formulation technology, such as, e.g. natural or
regenerated mineral substances, solvents, dispersants, wetting agents, tackifiers,
thickeners binding agents or fertilizers. Such carriers are for example described in
WO 97/33890.
Further surfactants customarily employed in the art of formulation are known
to the expert or can be found in the relevant literature.
The agrochemical formulations will usually contain from 0.1 to 99% by
weight, preferably from 0.1 to 95% by weight, of the compound of formula I, 99.9 to
1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and
from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.
Whereas it is preferred to formulate commercial products as concentrates, the
end user will normally use dilute formulations.
The compositions may also contain further adjuvants such as stabilizers,
antifoams, viscosity regulators, binders or tackifiers as well as fertilizers,
micronutrient donors or other formulations for obtaining special effects.
4. Technical materials. The compounds and combinations of the present
invention may also be used in the area of controlling fungal infection (particularly by
mold and mildew) of technical materials, including protecting technical material
against attack of fungi and reducing or eradicating fungal infection of technical
materials after such infection has occurred. Technical materials include but are not
limited to organic and inorganic materials wood, paper, leather, natural and synthetic
fibers, composites thereof such as particle board, plywood, wall-board and the like,
woven and non-woven fabrics, construction surfaces and materials, cooling and
heating system surfaces and materials, ventilation and air conditioning system
surfaces and materials, and the like. The compounds and combinations according the
present invention can be applied to such materials or surfaces in an amount effective
to inhibit or prevent disadvantageous effects such as decay, discoloration or mold in
like manner as described above. Structures and dwellings constructed using or
incorporating technical materials in which such compounds or combinations have
been applied are likewise protected against attack by fungi.
5. Pharmaceutical uses. In addition to the foregoing, active compounds of
the present invention can be used in the treatment of fungal infections of human and
animal subjects (including but not limited to horses, cattle, sheep, dogs, cats, etc.) for
medical and veterinary purposes. Examples of such infections include but are not
limited to ailments such as Onychomycosis, sporotichosis, hoof rot, jungle rot,
Pseudallescheria boydii, scopulanopsis or athletes foot, sometimes generally referred
to as "white-line" disease, as well as fungal infections in immunocompromised
patients such as AIDS patients and transplant patients. Thus, fungal infections may be
of skin or of keratinaceous material such as hair, hooves, or nails, as well as systemic
infections such as those caused by Candida spp., Cryptococcus neoformans, and
Aspergillus spp., such as in pulmonary aspergillosis and Pneumocystis carinii
pneumonia. Active compounds as described herein may be combined with a
phannaceutically acceptable carrier and administered or applied to such subjects or
infections {e.g., topically, parenterally) in an amount effective to treat the infection in
accordance with known techniques, as (for example) described in US Patents No.
6,680,073; 6,673,842; 6,664,292; 6,613,738; 6,423,519; 6,413,444; 6,403,063; and
6,042,845; the disclosures of which applicants specifically intend be incorporated by
reference herein in their entirety.
"Pharmaceutically acceptable" is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms which are, within the scope
of sound medical judgment, suitable for use in contact with the tissues of human
beings and animals without excessive toxicity, irritation, allergic response, or other
problem or complication, commensurate with a reasonable benefit/risk ratio.
"Pharmaceutically-acceptable carrier" as used herein means a
pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid
filler, diluent, excipient, solvent or encapsulating material, involved in carrying or
transporting the subject peptidomimetic agent from one organ, or portion of the body,
to another organ, or portion of the body. Each carrier must be "acceptable" in the
sense of being compatible with the other ingredients of the formulation and not
injurious to the patient. Some examples of materials which can serve as
pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and
sucrose; (2) starches, such as com starch and potato starch; (3). cellulose, and its
derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose
acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as
cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil,
safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as
propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene
glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid;
(16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl
alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible
substances employed in pharmaceutical formulations.
Formulations of the present invention include those suitable for oral, nasal,
topical (including buccal and sublingual), rectal, vaginal and/or parenteral
administration. The formulations may conveniently be presented in unit dosage form
and may be prepared by any methods well known in the art of pharmacy. The amount
of active ingredient which can be combined with a carrier material to produce a single
dosage form will vary depending upon the host being treated, Hie particular mode of
administration. The amount of active ingredient which can be combined with a carrier
material to produce a single dosage form will generally be that amount of the active
ingredient which produces a therapeutic effect Generally, out of one hundred percent,
this amount will range from about 1 percent to about ninety-nine percent of active
ingredient, preferably from about 5 percent to about 70 percent, most preferably from
about 10 percent to about 30 percent.
Methods of preparing these formulations or compositions include the step of
bringing into association a compound of the present invention with the carrier and,
optionally, one or more accessory ingredients. In general, the formulations are
prepared by uniformly and intimately bringing into association a peptide or
peptidomimetic of the present invention with liquid carriers, or finely divided solid
carriers, or both, and then, if necessary, shaping the product
The ointments, pastes, creams and gels may contain, in addition to the active
ingredient, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic
acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to a compound of this invention,
excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates
and polyamide powder, or mixtures of these, substances. Sprays can additionally
contain customary propellants, such as chlorofluorohydrocarbons and volatile
unsubstituted hydrocarbons, such as butane and propane.
Formulations suitable for oral administration may be presented in discrete
units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined
amount of the active compound; as a powder or granules; as a solution or a
suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil
emulsion: Such formulations may be prepared by any suitable method of pharmacy
which includes the step of bringing into association the active compound and a
suitable carrier (which may contain one or more accessory ingredients as noted
above). In general, the formulations of the invention are prepared by uniformly and
intimately admixing the active compound with a liquid or finely divided solid carrier,
or both, and then, if necessary, shaping the resulting mixture. For example, a tablet
may be prepared by compressing or molding a powder or granules containing the
active compound, optionally with one or more accessory ingredients. Compressed
tablets may be prepared by compressing, in a suitable machine, the compound in a
free-flowing form, such as a powder or granules optionally mixed with a binder,
lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may
be made by molding, in a suitable machine, the powdered compound moistened with
an inert liquid binder.
Pharmaceutical compositions of this invention suitable for parenteral
administration comprise one or more active compounds of the invention in
combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or
nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders
which may be reconstituted into sterile injectable solutions or dispersions just prior to
use, which may contain antioxidants, buffers, bacteriostats, solutes which render the
formulation isotonic with the blood of the intended recipient or suspending or
thickening agents.
Examples of suitable aqueous and nonaqueous carriers which may be
employed in the pharmaceutical compositions of the invention include water, ethanol,
polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and
suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic
esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use
of coating materials, such as lecithin, by the maintenance of the required particle size
in the case of dispersions, and by the use of surfactants. These compositions may also
contain adjuvants such as preservatives, wetting agents, emulsifying agents and
dispersing agents. Prevention of the action of microorganisms may be ensured by the
inclusion of various antibacterial and other antifungal agents, for example, paraben,
chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include
isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In
addition, prolonged absorption of the injectable pharmaceutical form may be brought
about by the inclusion of agents which delay absorption such as aluminum
monostearate and gelatin.
When the compounds of the present invention are administered as
pharmaceuticals, to humans and animals, they can be given per se or as a
pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably,
0.5 to 90%) of active ingredient in combination with a phaimaceutically acceptable
carrier.
The preparations of the present invention may be given by any suitable means
of administration including orally, parenterally, topically, transdermally, rectally, etc..
They are of course given by forms suitable for each administration route. For
example, they are administered in tablets or capsule form, by injection, inhalation, eye
lotion, ointment, suppository, etc. administration by injection, infusion or inhalation;
topical by lotion or ointment; and rectal by suppositories. Topical or parenteral
administration is preferred.
"Parenteral administration" and "administered parenterally" as used herein
means modes of administration other than enteral and topical administration, usually
by injection, and includes, without limitation, intravenous, intramuscular, intraarterial,
intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,
transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid,
intraspinal and intrasternal injection and infusion.
Actual dosage. levels of the active ingredients in the pharmaceutical
compositions of this invention may be varied so as to obtain an amount of the active
ingredient which is effective to achieve the desired therapeutic response, e.g.,
anthnycotic activity, for a particular patient, composition, and mode of administration,
without being toxic to the patient. The selected dosage level will depend upon a
variety of factors including the activity of the particular active compound employed,
the route of administration, the time of administration, the rate of excretion of the
particular active compound being employed, the duration of the treatment, other
drugs, compounds and/or materials used in combination with the particular inhibitor
employed, the age, sex, weight, condition, general health and prior medical history of
the patient being treated, and like factors well known in the medical arts. A physician
or veterinarian having ordinary skill in the art can readily determine and prescribe the
effective amount of the pharmaceutical composition required. For example, the
physician or veterinarian could start doses of the. compounds of the invention
employed in the pharmaceutical composition at levels lower than that required in
order to achieve the desired therapeutic effect and gradually increase the dosage until
the desired effect is achieved. As a general proposition, a dosage from about 0.01 or
0.1 to about 50, 100 or 200 mg/kg will have therapeutic efficacy, with all weights
being calculated based upon the weight of the active compound, including the cases
where a salt is employed.
The present invention is explained in greater detail in the following non-
limiting Examples.
LAMPLE1
2,4-Bis-(3-chlorophenyl)-3-i(3-pyridyI)hydroxymethyl] thiophene (Compound 1)
To a solution of 273mg (2.0mmol) of 3-chlorophenylacetylene in 4mL of
anhydrous THF under a N2 atmosphere at -78°C was added 1.25mL (2.0mmol) of a
1.6M solution of n-butyllithium in hexane. The solution was stirred for 1.5hr, and
then 64mg (2.0mmol) of sulfur was added. After an additional l.Shr at -780C, the red
solution was • warmed to room temperature and added to a solution of 400mg
(1.66mmol) of 3-{3-chlorophenyl)-l-(3-pyridyl)-2-propyn-l-one in 4mL of THF and
lmL of acetonitrile. The reaction solution was stirred for 2hr at room temperature,
and was then poured into water. The aqueous layer was extracted several times with
ether. The combined ether extracts were washed with saturated sodium chloride and
dried over magnesium sulfate. The drying agent was filtered off, and the ether was
removed by rotoevaporation. The crude product was purified by flash column
chromatography on silica gel to give 185mg (0.45mmol) of 2,4-bis-(3-chlorophenyl)-
3-[(3-pyridyl)carbonyl] thiophene. 1H NMR (CDC13): 7.95 (d of q, 1), 8.56 (d of d, 1),
and 8.73ppm (d, 1). MS m/z 410.0 (M+H). .
To a solution of 32mg (0.08mmol) of 2,4-bis-(3-chlorophenyl)-3-[(3-
pyridyl)carbonyl] thiophene in 2mL of anhydrous THF was added l0mg (0.26inmol)
of lithium aluminum hydride. The mixture was stirred at 0°C for 0.5hr and was then
diluted with ethyl acetate. The ethyl acetate solution was washed with water and dried
over magnesium sulfate. The drying agent was filtered off, and the solvent was
removed by rotoevaporation. The crude product was purified by preparative thin
layer chromatography (prep TLC) to give 30mg (0.073mmol) 2,4-bis-(3-
ch]orophenyl)-3-[(3-pyridyl)hydroxy-methyl} thiophene (Compound 1) in 91% yield.
lH NMR (CDCI3): 5.98 (br s, 1), 7.44 (br d, 1), 8.08 (br s, 1), and 8.21ppm (br d, 1).
MS m/z 412.0 (M+H).
EXAMPLE 2
4-(4-Chlorophenyl)-2-(5-chIoro-2-thienyl)-3-
f(3-pyridyl)hydroxymethylJthiophene (Compound 4)
To a solution of 137mg (1.0mmol) of 4-chlorophenylacetylene in 2mL of
anhydrous THF under a N2 atmosphere at -78°C was added 0.063mL (1.0mmol) of a
1.6M solution of n-butyllithium in hexane. The solution was stirred for 1.5hr., and
then 32mg (l.0mmol) of sulfur was added. After an additional 1.5hr at -78°C, the red
solution was warmed to -10°C. One half of the solution was added to a solution of
99mg (0.39mmol) of 3-(5-chloro-2-thienyl)-l-(3-pyridyl)-2-propyn-l-one in 2mL of
THF and 0.5mL of acetonitrile. After an additional 0.5hr, the reaction was diluted
with ethyl acetate. The ethyl acetate solution was washed with saturated sodium
chloride and dried over magnesium sulfate. The drying agent was filtered off, and the
solvent was removed by rotoevaporation. The crude product was purified by flash
column chromatography on silica gel to give 70mg (0.17mmol) of 4-(4-
chlorophenyl)-2-(5-chloro-2-thienyI)-3-[(3-pyridyl)carbonyl]-thiophene. 'H NMR.
(CDCl3): 6.76 (d, 1), 6.95 (d, 1), 7.96 (br d, I), 8.59 (br d, 1), and 8.73ppm (br s, 1).
MS m/z 415.9 (M+H).'
To a solution of 70mg (0.17mmol) of 4-(4-chlorophenyl)-2-(5-chloro-2-
thienyl)-3-[(3-pyridyl)carbonyl]thiophene in 3mL of anhydrous THF was added 13mg •
(0.34mmol) of lithium aluminum hydride. The mixture was stirred at 0°C for 0.5hr
and was then diluted with ethyl acetate and a minimum amount of water to
decompose the LiAIH4. The ethyl acetate solution was decanted off and evaporated to
dryness. The crude product was purified by preparative thin layer chromatography
(prep TLC) to give 60mg (0.14mmol) 4-(4-chlorophenyl>2-(5-chloro-2-thienyl)-3-
[(3-pyridyl)hydroxymethyl]thiophene (Compound 4) in 84% yield. 1H NMR (CDCI3):
6.08 (br s, 1), 6.81 (d, 1), 6.87 (d, 1), 7.39 (br d, 1), 8.18 (br s, 1), and 8.30 ppm (br d,
1). MS m/z 417.9 (M+H).
EXAMPLE 3
3-(3-ChlorophenyL)-l-(3-pyridyl)-2-propyn-l-one
To a solution of 5.0gm (36.6mmol) of 3-chlorophenylacetylene in 30mL of
anhydrous THE under a N2 atmosphere at -78°C was added 23mL (36.6mmol) of a
1.6M solution of n-butyllitbium in hexane. The solution was stirred for 2hr, and then a
solution of 3.9gm (36.6mmol) of pyridine-3-carboxaldehyde in 5mL of THF was
added. The reaction mixture was stirred at -78°C for 2hr and then was poured into ice
water. The solution was extracted several times with ether. The combined ether
extracts were washed twice with aqueous sodium bisulfite solution to remove any
remaining aldehyde, then with water, and finally with saturated sodium chloride
solution. The ether layer was dried over magnesium sulfate. The drying agent was
filtered off, and the ether was removed by rotoevaporation to give 8.5gm (34.7mmol)
of oily product, 3-(3-chlorophenyl)-l-(3-pyridyl)-2-propyn-l-ol.
The 8.5gm of 3-(3-chlorophenyl)-l-(3-pyridyl)-2-propyn-l-ol in 50mL of •
DMSO was added 10.7gm (38mmoI) of o-iodosobenzoic acid (IBX) in portions. The
resulting mixture was stirred for 2hr at room temperature, and then was diluted with
ethyl acetate and water. The solution was filtered and the filtrate was extracted with
ethyl acetate. The combined ethyl acetate extracts were washed consecutively with
water and saturated sodium chloride solution. The ethyl acetate layer was dried over
magnesium sulfate, the drying agent was filtered off, and the solvent was removed by
rotoevaporation to give 6.84gm (28.3mmol) of brown solid 3-(3-chlorophenyl)-l-(3-
pyridyl)-2-propyn-l-one in an overall 77% crude yield. ]H NMR (CDC13): 8.40 (d of
m, 1), 8.84 (d of d, 1), and 9.40ppm (d, 1). MS m/z 242.0 (M+H).
EXAMPLE 4
2,4-Bis-(2,4-diflaorophenyI)-3-[(3-pyridyl)hydroxymethyI]thiophene
To a suspension of 1.54gm (11.lmmol) of potassium carbonate, 1.44gm
(4.46mmol) of tetrabutylammonium bromide, and .05gm (0.22mmol) of palladium(II)
diacetate in 1.1 mL of acetonitrile/H2O (9:1) under a N2 atmosphere was added
1.83gm (6.69mmol) of 2,4-difluofo-l-iodobenzene and 0.50gm (4.46mmol) of
thiophene-3-carboxaldehyde. The mixture was heated at 80°C for 3days, and then
diluted with ethyl acetate. The ethyl acetate solution was washed with water and dried
over magnesium sulfate. The drying agent was filtered off, and the solvent was-
removed by .rotoevaporation to give a red-brown solid which was purified by flash
column chromatography on silica gel to give a mixture of 2-(2,4-
difluorophenyl)thiophene-3-carboxaldehyde and 2,4-bis-(2,4-
difluorophenyl)thiophene-3-carboxaldehyde which was used in the next reaction.
To a solution of 0.41gm (2.6mmol) of 3-bromopyridine in 1.7mL of
anhydrous THF under a N2 atmosphere was added 1.3mL (2.6mmol) of 2M
i-propylmagnesium chloride in THF. After 2 hr of stirring, 0.39gm of the above
mixture of aldehydes in 2mL of THF was added. After another 2hrs, the reaction was
diluted with water, and ethyl acetate was added to extract the products. The ethyl
acetate extract was washed with saturated sodium chloride and dried over magnesium
sulfate. The drying agent was filtered off, and the solvent was removed by
rctoevaporation to give a mixture of products that were purified by preparative HPLC.
From this reaction, I67mg of 2-(2,4-difluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene and 96mg of the desired 2,4-bis-(2,4-
difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene were isolated. For the latter,
'H NMR (CDCI3): 7.67 (br d oft, 1), 8.55 (d of d, 1), and 8.49 ppm (or d, 1). MS m/z
416.0(M+H).EXAMPLES
2-(3-Chlorophenyl)-4,5-dimethyI-4-hydroxy-3-[(3-pyridyl)carbonylJ-4,5-
dihydrothiophene
A solution of 0.20gm (0.83mmol) of 3-(3-chlorophenyl)-l-(3-pyridyl)-2-
propyn-l-one, 0.l0gm (0.99mmol) of 3-mercapto-2-butanone, and 0.072mL
(0.83mmol) of morpholine in 3mL of diethoxyrnethane was heated to reflux under a
N2 atmosphere for 8hrs. The reaction mixture was diluted with ethyl acetate, and the
organic solution was washed with saturated sodium chloride solution. The ethyl
acetate layer was dried over magnesium sulfate, the drying agent was filtered off, and
the solvent was removed by rotoevaporation. The crude product was purified by silica
gel column chromatography to yield 0.18gm (0.53mmol) of 2-(3-chlorophenyl)-4,5-
dimemyl-4-hydroxy-3-[(3-pyridyl)carbonyl]-4,5-dihydrothiophene as a mixture of
two isomers. 1H NMR (CDCI3): 1.56 (d,3), 1.64 (s, 3), 3.80 (t, 1), 7.82 (d of m, 1),
8.45 (d of d, 1), and 8.64ppm (d, 1). MS m/z 346.0 (M+H).
EXAMPLE 6
2-(3-Chlorophenyl)-4,S-dimethyl-3-{(3-pyridyl)hydroxymethyl]thiophene
(Compound 55)
A mixture of 0.050gm (0.14mmol) of 2-(3-chlorophenyl)-4,5-dimethyl-4-
hydroxy-3-[(3-pyridyl)carbonylJ-4,5-dihydrothiophene as a mixture of two isomers
and 0.024mL of acetic anhydride in l.0mL of toluene was placed in a sealed vial and
heated to 100°C in a sand bath for 48hrs. The crude reaction product was purified by
preparative thin layer chromatography (prep TLC) to give 0.037gm (0.1 Immol) of 2-
(3-chlorophenyl)-4,5-dimethyl-3-[3-pyridylcarbonyl]thiophene. 1H NMR (CDCI3):
2.09 (s, 3), 2.43 (s, 3), 8.00 (d of m, 1), 8.58 (d of d, 1), and 8.78ppm (d, 1). MS m/z
328.0 (M+H).
To a solution of 0.037gm (0.11mmol) of the preceding ketone, 2-(3-
chlorophenyl)-4,5-diniethyl-3-[3-pyridylcarbonyl]thiophene, in 3mL of diethyl ether
was added 0.020gm (0.45mmol) of lithium aluminum hydride. The mixture was
stirred at 0°C for 0.5hr and was then diluted with ethyl acetate and a minimum
amount of water to decompose the LiAlH4-. The ethyl acetate solution was decanted
off and evaporated to dryness. The crude product was purified by preparative thin
layer chromatography (prep TLC) to give 0.032gm (0.10mmol) of 2-(3-
chlorophenyl)^,5-dimemyl-3-[(3-pyridyl)hydroxymethyl]thiophene (Compound 55).
1H NMR (CDCI3): 1.82 (s, 3), 2.31 (s, 3), 7.64 (d of m, 1), 8.41 (d of d, 1), and
8.46ppm (br s, 1). MS m/z 330.0.0 (M+H).
EXAMPLE 7
Biological Screening
Fungicidal activity for the compounds described in this invention was
determined using a microtiter plate format. In primary screening, test compounds in
1 µL of dimethylsulfoxide (DMSO) are delivered to individual wells of a 96-well
microtjter plate. Then 100µL of minimal media consisting of 1.5% agar is delivered.to
each well and allowed to cool. Finally, inoculation is carried out by the addition of
10µL of an aqueous suspension of fungal spores to the surface of the solid agar. The
plates are covered and incubated in a controlled environment at 20 °C. Fungicidal
activity is determined by visual inspection and photometric analysis of fungal growth
after 3-5 days, depending on the pathogen. Commercial standards (azoxystrobin,
benomyl, captan, chlorothalonil, famoxadone, fiusilazole, and propiconazole) are
included in all assays. Test pathogens include Septoria tritici, Stagonospora nodorum,
Phytophthora infestans, Moniliniafructicola and Botrytis cinerea. Dose response data
for compounds found to be fungicidal in primary screening are obtained by screening
3-fold serial dilutions of the test compound. Fungicidal activity, noted as IC50 values
in uM concentration, for certain of the compounds covered in this invention is
included in the following Table 1. The coefficient of variation (ratio of standard
deviation to the mean) expressed in percentage is given in parentheses.

(Table Removed)
IC50(µM): A= <0.1;B = 0.11-1.0;C=1.1-10;D = 11-100;
E = >100; ND = Not determined
C.V. (%): (a) = 0-5; (b) = 6-15; (c) = 16-30 (d) = >30
The foregoing is illustrative of the present invention, and is not to be construed
as limiting thereof. The invention is defined by the following claims, with
equivalents of the claims to be included therein.

THAT WHICH IS CLAIMED IS:
1. A compound of formula I:
(Formula Removed)
wherein:
R is H; alkyl; alkoxyalkyl; haloalkyi; arylalkyl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyi, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl,
alkenyl, alkynyl, haloalkyi, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; arylthioalkyl optionally substituted with, halogen, alkyl, alkenyl,
alkynyl, haloalkyi, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or
nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyi,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl
optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyi, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
Ri is alkyl; alkoxyalkyl; haloalkyi; arylalkyl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyi, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl,
alkenyl, alkynyl, haloalkyi, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl,
alkynyl, haloalkyi, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkyluiio, cyano, or
nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyi,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl
optionally substituted with halogen, alkyl, alkenyl alkynyl, haloalkyi, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R2 is alkyl; alkoxyalkyl; haloalkyl; arylalkyi optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or
nitro; heteroaryl, especially 2-, 3- or 4-pyridyl optionally substituted with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; 5-pyrimidinyl optionally substituted with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; or 2- or 5-thiazolyl optionally substituted with halogen,
alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, haloalkenyl, haloalkoxy,
haloalkylthio, cyano, or nitro;
R.3 is alkyl; alkoxyalkyl; haloalkyl; arylalkyi optionally substituted with -
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or •
nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl
optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R4 is H; acyl; haloacyl; alkoxycarbonyl; aryloxycarbonyl; .
alkylaminocarbonyl; or dialkylaminocarbonyl;
R5 is H; alkyl; alkenyl; alkynyl; alkoxyalkyl; haloalkyl; arylalkyi optionally
substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryloxyalkyl optionally
substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; arylthioalkyl optionally
substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, eyano, nitro; heteroaryl optionally substituted with halogen, alkyl,

alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; or alkylsilyl;
or a salt thereof.
2. The compound of claim 1, wherein said compound is selected from the
group consisting of compounds of formula la, compounds of formula lb, and
compounds of formula Ic:
(Formula Removed)
wherein R1, R2, R3, R4 and Rs are as given above.
3. The compound of claim 1 wherein R'is H or alkyl.
4. The compound of claim 1 wherein R1 is aryl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, nitro; or heteroaryl optionally substituted with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro.
5. The compound of claim 1 wherein R1 is 2-chlorophenyl, 4-chlorophenyl,
2,4-dichlorophenyl, 2-fluorophenyl, 2,4-difmorophenyl, 3,5-difluorophenyl, 4-
trifluoro-methylphenyl, 4-trifluoromethoxyphenyl, 2-thienyl, 3-thienyl, 5-chloro-2-
thienyl, or 5-chloro-2-furyl.
6. The compound of claim 1 wherein R1 is alkyl or arylalkyl optionally
substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy,
alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro.
7. The compound of claim 1 wherein R2 is heteroaryl optionally substituted
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, or nitro.
8. The compound of claim 1 wherein R2 is 3-pyridyl or 5-pyrimidinyl
optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro.
9. The compound of claim 1 wherein R3 is alkyl; aryl optionally substituted
with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio,
haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, nitro; or alkylsilyl.
10. The compound of claim 1 wherein R3 is phenyl, 3-chlorophenyl, 4-
chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-mediylphenyl, 2-thienyl, 5-
chloro-2-thienyl, 5-methyl-2-thienyl, 3-thienyl, /-butyl, or trimethylsilyl.
11. The compound of claim 1 wherein R4 is H.
12. The compound of claim 1 wherein:
R is H or alkyl;
R1 is aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; or
heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
R2 is heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;
R3 is alkyl; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl,
haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro;
heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; or alkylsilyl;
and
R4 isH;
Rs is alkyl and haloalkyl;
or a salt thereof.
13. The compound of claim 12 wherein R1 is 2-chlorophenyl, 4-chlorophenyl,
2,4-dichlorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4-
trifluoro-methylphenyl, 4-trifluoromethoxyphenyl, 2-thienyl, 3-thienyl, 5-chloro-2-
thienyl, or 5-chloro-2-furyI.
14. The compound of claim 12 wherein R2 is 3-pyridyl or 5-pyrimidinyl
optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro.
15. The compound of claim 12 wherein R3 is phenyl, 3-chlorophenyl, 4-
chlorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, . 3,5-difluorophenyl, 4-
methylphenyl, 2-thienyl, 5-chloro-2-thienyI, 5-methyl-2-thienyl, 3-thienyl, t-butyl, or
trimethylsilyl.
16. The compound of claim 12 selected from the group consisting of: 2,4-Bis-
(3-chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]miophene (compound 1); 4-(3-
Chlorophenyl)-2-(5-chIoro-2-thienyl)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 2); 4-(3-Chlorophenyl)-2-(3,5-difiuorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 3); 4-(4-Chlorophenyl)-2-(5-chloro-2-
thienyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 4); 4-(4-Chlorophenyl)-
2-(3,5-difluorophenyl)-3-[(3-pyridyI)hydroxymethyl]thiophene (compound 5); 2-(4-
Chlorophenyl)-4-(2,4-difluorophenyl)-3-[(3-pyridyI)hydroxymethyl]thiophene
(compound 6); 4-(2,4-Difluorophenyl)-2-(l,l-dimethylethyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene(compound 7); 2,4-Bis-(4-chlorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 8); 4-(4-Chlorophenyl)-3-[(3-
pyridyl)hydroxymethyl]-2-(2-thienyl)thiophene (compound 9); 2-(4-Chlorophenyl)-4-
(5-chloro-2-thienyl)-3-[(3-pyridyl)hydroxyrnethyl]thiophene (compound 10); 4-(5-
Chloro-2-thienyl)-2-(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 11); 2-(4-Chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-
thienyl)thiophene (compound 12); 2-(2,4-Difluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]-4-(2-thienyl)thiophene (compound 13); 2-(2,4-
Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-thienyl)thiophene (compound
14); 2-(4-Butylphenyl)-4-(5-methyl-2-thienyl)-3-t(3-
pyridyl)hydroxymethyl]thiophene (compound 15); 2,4-Bis-(2,4-Difluorophenyl)-3-
[(3-pyridyl)hydroxymemyl]thiopliene (compound 16); 4-(4-Chlorophenyl)-2-(2,4-
difluorophenyl)-3-[-3-pyridyl)hydroxymethyl]thiophene (compound 17): 2,4-Bis-(2-
trifluoromethylphenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 18); 2,4-
Bis-(3-trifluoromethylphenyI)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound
19); 2,4-Bis-(4-trifluoromemylphenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 20); 4-(4-Chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]-2-(3-
thienyl)thiophene (compound 21); 2-(5-Bromo-2-thienyl)-4-(4-chlorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 22); 4-(4-Chlorophenyl)-2-(5-methyl-
2-thienyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 23); 2-(3,5-
Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(3-thienyl)thiophene (compound
24); 2-(2,4-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(3-thienyl)thiophene
(compound 25); 2-(3,5-Difluorophenyl)-4-(4-fluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 26); 2-(2,4-Difluorophenyl)-4-(4-
fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 27); 2-(4-
Chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(3-thienyl)thiophene (compound 28);
3-[(3-Pyridyl)hydroxymethyl]-2-(2-tetrahydropyranyIoxy-methyl)-4-(3-
thienyl)thiophene (compound 29); 4-(2,4-Difluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]-2-(3-thienyl)thiophene (compound 32); 4-(2,4-
Difluorcphenyl)-3-[(3-pyridyI)hydroxymethyI]-2-(2-thienyl)thiophene (compound
3 9); 2-(2,4-Difluorophenyl)-4-(2-fluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 45); 2,4-Bis-(2-Chlorophenyl)-3-[(3-
pyridyl)hydroxymethyl]-thiophene (compound 49); 2,4-Bis-(3-Chlorophenyl)-3-[(3-
pyridyl)hydroxymefhyl]thiophene (compound 50); 2,4-Bis-(Phenyl)-3-[(3-
pyridyl)hydroxymethyI]thiophene (compound 51); 2,4-Bis-(2,4-Dichlorophenyl)-3-
[(3-pyridyl)hydroxymemyl]thiophene (compound 52); 2,4-Bis-(2-Fluorophenyl)-3-
[(3-pyridyl)hydroxymethyl]thiophene (compound 53): 2,4-Bis-(3-Fluoropheny1)~3-
[(3-pyridyl)hydroxymethyl]thiophene (compound 54); 2-(3-Chlorophenyl)-4,5-
dimethyl-3-[(3-pyridyl)hydroxymethiyl]thiophene (compound 55); 4-(5-Chloro-2-
furanyl)-2-(4-chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 56);
4-(5-Chloro-2-furanyl)-2-(2,4-difluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 57); 2,4-Bis-(2-thienyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 58); 2,4-Bis-(4-Fluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 59); and 2-(3-Chlorophenyl)-4-phenyl-
3-[(3-pyridyl)hydroxymethyl]thiophene -(compound 60); 2,4-Bis-(3-chloro-5-
trifluoromethylphenyI)-3-[(3-pyridyl)hydroxymefhyI]-thiophene (compound 61); 2,4-
Bis-(2,5-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 62);
2,4-Bis-(4-chloro-3-fluorophenyI)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 63); 2,4-Bis-(3-Memoxyphenyl)-3-[(3-pyridyl)hydroxymethyl}-thiophene
(compound 64); • 4-(2-Fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-2-(2-
thienyl)thiophene (compound 65); 2,4-Bis-(2-chloro-4-trifluoromethylphenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 66); 2,4-Bis-(4-Methoxyphenyl)-3-[(3-
pyridyl)hydroxymethyI]thiophene (compound 67); 2-(3-Chlorophenyl)-4-(2,4-
difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene (compound 68); 2-(5-
Bromo-2-thienyl)-4-(2,4-difluoropheny])-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 69); 2-(5-Chloro-2-thienyl)-4-(2)4-difluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 70); 5-Chloro-2-(5-chloro-2-thienyl)-4-
(2,4-dif]uorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene (compound 71); 4-(4-
ChlorophenyI)-2-(2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 72); 4-(4-Chlorophenyl)-2-(3-fluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]diiophene (compound 73); 2-(2-Chlorophenyl)-4-(2,4-
difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 74); 4-(2,4-
Difluorophenyl)-2-(2-£luorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 75); 2-(4-Chlorophenyl)-4-(4-chloro-2-fluorophenyl)-3-[(3-
pyridyl)hydroxymethyl]thiophene (compound 76); 2-(3-Chlorophenyl)-4-(4-chloro-2-
fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene (compound 77); 4-(2,4-
Difluorophenyl)-2-(4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene
(compound 78); and salts thereof.
17. A composition for controlling and preventing plant pathogenic
microorganisms comprising, in combination, a compound of claim 1 together with a
suitable carrier. •
18. The composition of claim 17, further comprising at least one additional
fungicide or SAR inducer.
19. A method of controlling or preventing infestation of cultivated plants by
pathogenic microorganisms, comprising:
applying a compound according to claim 1 to said plants, parts thereof or the
locus thereof in an amount effective to control said microorganisms.
20. A method according to claim 19, wherein the microorganism is a fungal
organism.
21. The method of claim 20,-wherein said fungal organism is selected from the
group consisting of Septoria tritici, Stagonospora nodorum,.Phytophthora infestans,
Botrytis cinerea, and Moniliniafructicola..
22. A method of controlling or preventing infestation of plant propagation
material by pathogenic microorganisms, comprising:
applying a compound according to claim 1 to said plant propagation material
in an amount effective to control said microorganisms.
23. The method of claim 22, wherein said plant propagation material
comprises seeds.
24. A method according to claim 22, wherein the microorganism is a fungal
organism.A method of controlling or preventing infestation of a technical material
by pathogenic microorganisms, comprising:
applying a compound according to claim 1 to said technical material in an
amount effective to control s?id microorganisms.
26. A method of treating a fungal infection in a subject in need thereof,
comprising:
administering a compound of claim 1 or a pharmaceutically acceptable salt
thereof to said subject in an amount effective to treat said fungal infection.
27. A composition for treating a fungal infection in a subject in need thereof,
comprising, in combination, a compound of claim 1 or a pharmaceutically acceptable
salt thereof together with a pharmaceutically acceptable carrier.
28. A method of making a compound of formula la:
(Formula Removed)
wherein:
R isH;
R1 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl,
alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or
nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl
optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R2 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with
halogen, alkyl, alkenyl, alkyny], haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or
nitro; heteroaryl, especially 2-, 3- or 4-pyridyl optionally substituted with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; 5-pyrimidinyl optionally substituted with halogen,
alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; or 2- or 5-thiazolyl optionally substituted with halogen,
alkyl, alkenyl, alkynyl, alkoxy, alkylthio, haloalkyl, haloalkenyl, haloalkoxy,
haloalkylthio, cyano, or nitro;
R3 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with
halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy,
haloalkylthio, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl,
alkenyl, alkynyl, haloalkyl; haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,
cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl,
alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or
nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl,
haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl
optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,
alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;
R4 is H; acyl (e.g., acetyl, benzoyl, phenylacetyi); haloacyl; aikoxycarbonyl;
aryloxycarbonyl; alkylaminocarbonyl; or dialkylaminocarbonyl;
said method comprising:
(a) reacting an acetylenethiolate of formula II
(Formula Removed)
where R1 is as given above with an acerylenic ketone of formula HI:
(Formula Removed)
where R2 and R3 are as given above in an inert solvent to produce a" c6mpbund of
(Formula Removed)
formula IV,

and then:
(b) reducing said compound of Formula IV to produce said compound of
Formula la (R=H)
29. The method of claim 28, wherein said reducing step is carried out with
LiAlR4 in an inert solvent or with NaBH1 in an alcoholic solvent.