slide 1

Back to the List of the Granted Patents                                                                        Click here to download KE000443 PDF

(2l)Application Number:     KElP/ 2008/ 000765   
       
(22) Filing Date: 14/12/2006   
       
(30) Priority data: us 60/751558  19/12/2005   

(86)  PCT data     PCT/US06/04806514/12/200 wo 2007/075487    05/07/2007

(73) Owner: SYNGENTA LIMITED ofPristley Road, Surrey Research  Park, Guildford, Surrey GU2 7YH, United Kingdom

(72) Inventor:LEE,Shy-Fuh of228 Carbonera Avenue, Sunnyvale, California 94086, U.S.A.; GLIEDT, Micah of 1800 Stokes St., Apt 121, San Jose, California 95126, U.S.A. and ANDERSON, Richard of 3367 Kenneth Drive, Palo California 94303, U.S.A.

(74) Agent/address for correspondence: Hamilton Harrison & Mathews, ICEA Building, Kenyatta Avenue, P.O. Box 30333-00100, Nairobi
                   

(54) Title:  SUBSTITUTED AROMATIC HETEROCYCLE COMPOUNDS AS FUNGICIDES.

(57) Abstract: The present invention provides compounds of formula (!); wherein X is S, 0, or NR5, along with salts thereof and compositions containing the same. The compounds are useful as, among other things, 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.

SUBSTITUTED 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 inco:rporated by reference herein in its entirety.

5

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.

10

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 hannful to plants or mammals. However, some fungi can

15    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

20    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 25    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 pyrimidin-4-enamine as fungicides).

Summary of the Invention

5    A first aspect ofthe invention is compounds of formula I:


wherein:

10    XisS,O,orNRs;

R isH; alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally 1>ubstituted (e.g.,  1,

2, 3 or 4 times) with halogen. alkyl, alkenyl, alkynyl, haloalkyl, haloalkeny1, alkoxy,

alkylthio,    haloalkoxy,  haloalkylthio,   cyano,   or   nitro;   81Yloxyalkyl   optionally

substituted (e.g.,  1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl,

15    haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; arylthioalkyl optionally substituted (e.g., 1, 2, 3 or 4 times} with halogen, alkyl, alkeny1, alkynyl, haloalkyl, haloalkenyl, al~oxy, alkylthio, haloalkoxy, haloalkylthio,

cyano, or nitro; aryl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkeny1, alkynyl, haloalkyl, halo~enyl, alkoxy, alkylthio, haloalkoxy,

20    haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times} with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthlo, 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,

25    alkylthio, baloalkoxy, 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, haloalky1, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,

30    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 optional1y substituted (e.g., 1, 2, 3 or 4 ~ with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, a1kylthio, haloalkoxy, ha1oalky1thio, cyano, or nitro; or alkylsilyl;
R2 is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g., 1, 2,

5    3 or 4 times) with halogen, a1kyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, ha1oalkylthio, cyano, or nitro; aryl optionally substituted (e.g. I, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, ha1oalkenyl, alkoxy, a1kylthio, 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,

10    alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloa1kylthio, cyano, or nitro; 5-pyrimidinyl optiona1ly substituted (e.g. 1, 2, 3 or 4 times) with

halogen, alkyl, alkenyl, alkynyl, haloalkyl, ha1oalkenyl, alkoxy, a1kylthio, baloalkoxy, 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,

15 •   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,  lilkenyl,  alkynyl,  haloalkyl,  haloalkenyl,  alkoxy, alkylthio,  baloalkoxy,  haloalkylthio,    cyano,  or  nitro;  aryloxyalkyl  optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, halmilkyl, •20    haloalkenyl,   alkoxy,   alkylthio,   haloalkoxy,   haloalkylthio,   cyano,   or   nitro; arylthioalkyl  optionally  substituted  (e.g.  l,  2,  3  or  4  times)  with  halogen,  a1kyl, alkenyl, alkynyl, haloalkyl, ha.loalkenyl, alkoxy, alkylthio, haloalkoxy, ha1oalkylthio, cyano, or nitro; aryl optionally substituted (e.g. I, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, baloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,

25    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;

14 is H; acyl (e.g., acetyl, benzoyl, phenylacetyl); haloacyl; alkoxycarl>onyl; aryloxycarbonyl; alkylaminocarbonyl; or dialkylaminocarbonyl;

30 Rs is H; alkyl; alkenyl; alkynyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkertyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryloxyalkyl optionally substituted (e.g., I, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl,

haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkyltbio, 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,

5    alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, baloalkoxy, 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, 7yano, or nitro; or alkylsilyl;

and salts thereof.

1 0 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
15    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 acti'!e compound as described herein together with a suitable carrier.

A third aspect ofthe present invention is a method of controlling or preventing

20 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, 25 comprising applying an active compound as d~scribed 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

30    as described herein to said subject in an amount ef\ective 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).

5 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

10    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

15    4 carbon atoms, which are also referred to as "lower alkyl." In some embodiments preferred alkyl groups are those containing 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 ~hain hydrocarbon

containing from 2 to 24 carbons and containing at least one carbon-carbon double

20    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-1-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.

25 "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

30    branched chain hydrocarbon group containing from 1 to 4 carbon atoms.

"Alkoxy" ref~s 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 hel'bl• 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.

5 "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,

10    tetrahydronaphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-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

15    aryl radical which would othirrwise 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 saine or different. Examples of

20    heteroaryl groups include pyridyl, pyrirnidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrroly~, pyranyl, isobenzofuranyl, chrornenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, -

quinolyl,    phthalazinyl,    naphthyridinyl,    quinoxalinyl,    isothiazolyl,    and

benzo[b]thienyl. Preferred heteroaryl  groups are  five  and  six membered rings and

•    25 contain from one to three heteroatoms independently selected from 0, N, and S. The heteroaryl group, including each heteroatorn, can be unsubstituted or substituted with from 1 to 4 substituent&, as chemically feasible. For example, the heteroatom S may
be substituted with one or two oxo groups, .which may be shown as ==0.
'
"Agriculturally acceptable salt" means a salt the cation of which is known and

30    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, -1 or -F.

"Haloallcyl," as used herein, refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defmed herein. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, penta:fluoroethyl, 2-chloro-3-fluoropentyl, and the like.

s    "Hydroxy," as used herein, refers to an -OH group. "Nitro," as used herein, refers to a -NO:z group.

"Oxy," as used herein, refers to a -0- moiety. "Thio," as used herein, refers to a-S- moiety.

The disclosures of all US Patent references cited herein are to be incorporated 10 herein in their entirety as if fully set forth.

2. Compounds.  The compounds of this invention are represented by formula

I, including formulas la-Ic:

        R    OR   
        •~    4   
            ~       
15            I       
                    Rs
                    I
        ~    h        ~ h
R    OR4    "P)":R1OR4    •R-1p;OR4
"K~2        ~        R,
    Ia        lb        lc
20    wherein:               
    Xis S, O,orNRs;               
    R isH; alkyl; alkoxyalkyl; haloalkyl; acylalkyl optionally substituted (e.g.,  I,

2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; aryloxyalkyl optionally

25    substituted (e.g., l, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, baloalkyl, 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, haloal.kyl, haloalkenyl, alkoxy, alkyithio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., 1, 2, 3 or 4 times)

5    with  halogen,  alkyl,  alkenyl,  alkynyl,  haloalkyl,  haloalkenyl,  alk:oxy,  alkylthio,

haloalkoxy, haloalkylthio, cyano, or nitro; or alkylsilyl;

R 1 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

10    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, baloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio,

cyano, or nitro;  aryl optionally substituted (e.g.,  1, 2, 3 or 4  times) with halogen,

15.    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., I, 2,

20    3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthlo, haloalkoxy, haloalkylthio, cyano, or nitro; aryl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alk:ynyl, 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,

25    alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro; 5-pyrimidinyl optionally substituted (e.g. I, 2, 3 or 4 times) with

halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, baloalkoxy, 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,

30    baloalkenyl, haloalkoxy, haloalkylthio, cyano, or nitro;

RJ is alkyl; alkoxyalkyl; baloalkyl; arylalkyl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkyltbio, haloalkoxy, baloa!kylthio, 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. l, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alky!thio, haloalkoxy, haloalkylthio,

5    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;

10 ~ isH; acyl (e.g., acetyl, benzoyl, phenylacetyl); haloacyl; alkoxycarbonyl; aryloxycarbonyl; alk.ylaminocarbonyl; or dialkylaminocarbonyl;

Rs is H; alkyl; alkenyl; alkynyl; alkoxyalkyl; haloalkyl; aryla!kyl.optionally substituted (e.g., 1, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, or nitro;

15    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; arylthioalk.yl optionally substituted (e.g., 1, 2, 3 or 4 times) with

halogen, alkyl, alkenyl, .alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, halwalkylthio, cyano, or nitro; aryl optionally substituted (e.g., 1, 2, 3 or 4 times) with

20    halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g., I, 2, 3 or 4 times) with halogen, alkyl, alkenyl, alkynyl, • haloalkyl, haloalkenyl, alkoxy, alkylthio,

haloalkoxy, haloalkylthio, cyano,.or nitro; or alkylsilyl.

Methods ofmaking. Compositions of generic structure Ia wherein Rand R! =

25    H may be prepared by the [3+2]-cycloaddition of an acetylenethiolate anion II and an acetylenic ketone lll to give thiophene ketone IV which upon reduction provides the corresponding thiophene alcohol Ia (see L. S. Rodinova, M. L. Petrov, and A. A. Petrov, Zhurnal Orgonicheskoi K.himti 1981, 17(10), 2071-2075 for a related thiophene synthesis):

30
s~  Li+        Ra    -            -  R           OH   
R,f    +                       
                R    0       
        R;0        1        ?;1   
        1        ~R2        R2   
n        m        IV        Ia (R and~= H)   

5    The [3+2]-cycloaddition reaction is canied 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 m in an inert solvent or

solvent mixture, such as THF and acetonitrile, at temperatures ranging from o•c to - 2o•c. The acetylenethiolate n is prepared from the reaction of sulfur with a lithium

10    salt (VI) of a terminal acetylene V (H. G. R.aubenheimer, G. J. Kruger, C. F. Marais, R. Otte, and J. T. z. Hattingh, Organometallics 1988, 7, 1853-1858):
H        u+    -Ss    R,r       
    alkyl    R,~            M+   
R,~                       
    lithium                   
v        VI        n       

15

Lithium acetylide VI is formed by the treatment of tenninal acetylene V with a strong base such as n-butyllithium in an inert solvent such as THF at low temperature, prefembly from -4o•c to -7s•c. Addition of sulfur to acetylide VI at low temperature (-40°C to -78°C) and reaction for 1.5-3hr gives the acetylenethiolate

20    II. Reduction of thiophene ketone IV is effected with a reducing agent such as LiAII'L! in an inert solvent such as ether or TIIF, or NaBH, 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

thiophenes that are intermediates in the synthesis of Ia when R 1 and R3  are aryl (L.

25    Lavenot, C. Gozzi, K. llg, I Orlova, V. Penalva, and M Lemaire, Journal of Organometallic Chern. 1998, 567, 49-55). Thus, thiophene-3-carboxaldehyde VII may be selectively 8l")rlated with aryl iodide R3l in the presence of a transition metal

catalyst such as a  palladium(IT) catalyst to give a 2-arylated in
 

SR'        sR,'    R-p;•   
R~0    +           
R,        :~R10    -    R1    0   
    Ra10    -  ~        R::       
                       
X    m    XI        XII    •  Ia (R.t =H)   

reduction of XII provides the composition Ia (&!=H).

5    The Michael addition is carried out by reaction of the a-mercaptoketone X ( R'

=    H) and the acetylenic ketone m 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 1-Shrs. Alternatively, a-acetylthioketone X  (R' = COCH3) may  be used in the  Michael  addition  wherein the  base  such as I 0     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-lOO"C) for 12-48hrs.

to produce the thienyl ketone XII, reduction of which is accomplished as above with a reducing agent such as LiAJ~ in an inert solvent such as ether or THF, or NaB~ in a
15    solvent such as ethanol at temperatures in the range of o•c to 2o•c.

The a-acetylthioketones X (R' = COCH3) and a-mercaptoketones X ( R' = H) are readily
Br    -    s_/{_    R~0   
R~0        R~0       
R,        R,    R,   
XIII        X (R' = COCH3)    X(R'= H)   

20

available by treating the corresponding a-bromoketones XIII with thioacetic acid in a basic medium to give X (R' = COCH3), which upon treatment with aqueous base (e.g., aqueous NaOH) produces X (R' =H).

The compositions Ib may be prepared from XIII (R = H) or its chloro analog

25    by reaction with the fl-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. 1bis dehydration is efficiently effected by treatment of XV with p-toluenesulfonic acid or acetic anhydride in toluene at elevated temperatures
 
(80-lOO"C) for 12-48hrs. Reduction of fuzyl ester XVI to fury! alcohol XVII and subsequent oxidation to furylcarboxaldehyde XVIII followed by addition of organometallic reagent ~Li or R2MgX' gives compound Ib CR-4 = H) The reduction of XVI to alcohol XVU is accomplished using a hydride reagent such as Li.AII4 or

5    diisobutylalwninum hydride (DffiAL) in an inert solvent such as ether of THF. Oxidation of xvn to aldehyde my be effected with reagents including activated

Mn~, o-iodosobenzoic acid (IBX) in DMSO, or CrO:Ypyr in inert solvents such as dichloromethane . The addition of the organometallic reagent to aldehyde XVIU is typically conducted in an inert solvent such as ether or 1HF under Nz atmosphere at

10    0-20"C for 1-Shrs. The organometallic reagent may be an organolithium reagent. or preferably an l)rganomagnesium reagent.

R_j'  +    10............._    base                <eduction   
'ro    R3   o    -                -   
R,                               
xm        XIV                       
15                    R2li           
x~h    oxidation    Rp;~h_•        RK•~h   
    -        or       
R,            R;    H    -    R,    ~   
                0    R2MgX'        HO   
HO                               
XVII                XVIII        lb (R.s =H)   

20 Alternatively, fury! 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

25    inert solvent such as dichloromethane (DCM) . Addition of arganometallic agent R2MgX' to XX in an inert solvent such as ether or THF under N2 atmosphere at 0-20"C for 1-Shrs gives the ketone XXI, reduction ofwhich is accomplished as above

with a• reducing agent such as LiA1}4 in an inert solvent such as ether or 1JIF, or NaBIL! in a solvent such as ethanol at temperatures in the range of 0°C to 20°C. to produce compound lb (Itt= H).

                            MeONHMe.HCI               
        reduction    R-:pr;OR3    HOBT/DIC    R-:pr;OR,    RzMgX'   
    R-~p:;•t            ~    h    o    -    ~ t    o    -   
    R1 ro0    ~    HO        rn~    ~ Io-N\.           
5    XVI    XIX            XX           
-reduction

XXI    lb (R. =H)

10 The compositions Ic may be prepared using an approach similar to that . employed for the thiophenes Ia, i.e., but adding a-arninoketones xxn to the alkynylketone m in the Michael addition. Dehydration of dihydropyrrole XX1H to yield pyrrolyl ketone XXIV and subsequent reduction with LWIL! or NaB& gives lc

(R4 = H). Reaction conditions similar to those used to prepare the aforementioned 15 furans lb may be employed.
            R.        Ro       
~-R,            I        I           
R-'ro    +        R;p;~    ~    /;    ~ ;,   
            HO    -    RP:;'    R,OH   
R,        R;0    R,    0    R1    0    •fs~-'   
            ~            R>       
        1-                       
XXII        m    xxm        XXIV    lc(~=H)   

Alternatively, condensation of a-aminoketone XXII and f3-ketoester XIV under basic conditions gives the dihydropyrrole XXV (see L. Knorr, Chem. Ber.

20    1884, 17, 1635; A. H. Corwin. Heterocvclic Compounds, 1950, 1, 287), dehydration of which produces the pyrrolyl ester XXVI. Alkylation of XXVI with Rsi yields the N-substituted pyrrolyl ester XXVVll. In reactions similar to those described for the furan system, ester XXVII is converted to compound Ic (&, = H).
 
R == H or alkyl;

R1 =aryl optionally substituted (e.g. 1, 2, 3 or 4 ti:ines) with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkyltbio, haloalk:oxy, cyano, nitro; or heteroaryl optionally substituted (e.g. 1, 2; 3 or 4 times) with halogen, alkyl,

5    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,

10    alk.enyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthlo, 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, alko~, alkylthio,

haloalkoxy, haloalkylthio, cyano, or nitro; aryl optionally substituted (e.g. I, 2,

15    3 or 4 times) with halogen, alkyl, alkenyl, alkyny!, haloalkyl, haloalkenyl, alkoxy, • alkylthio, haloalkoxy, haloalkylthio, cyano, nitro; heteroaryl optionally substituted (e.g. 1, 2, 3 or 4 times) with halogen, aJkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, alkoxy, alkylthio, haloal.koxy, Iuiloalkylthio, cyano, nitro; or alkylsilyl;

2Q    ~=H;and

Rs is H. alkyl, or haloalkyl.

Examples of compounds of the present invention include, but are not limited

to, the following:

Compound    Structure        Chemical Name   
No.               
               
    S    Cl       
    Cl~    2,4-Bis-{3-chlorophenyr)-3-{(3-   
        pyridyl)hydmxymethyiJ-   
    VHO~        thiophene   
N

    Cl    4-(3-Ghlomphenyl)-2-(5-   
           
2        chlom-2-thlenyl)-3-[(3-   
        pyridyl)hydmxymethyl]-   
           
        thiophene   
 

Cl


~CI

Cl_..ll,.JHO>-o

N

~:
N

~CI

N

F~
N

~CI

Cl.)l,JHO~
N
 

4-{3-Chlorophenyl)-2-(3,5-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-thiophene

4-(4-Chlorophenyl)-2-{5-chloro-2-thlenyl)-3-[(3-pyridyl)hydroxymethyl)-thiophene

4-{4-Chlorophenyl)-2-(3,5-dffluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-thlophene

2-{4-Chlorophenyl)-4-(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-thiophene

4-(2,4-Difluorophenyl)-2-(1,1-dimethylethyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2,4-Bis-{4-chlorophenyl)-3-[(3• pyridyl)hydroxymethyl]-thiophene

4-{4-Chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]-2-(2-thienyl)thiophene

2-(4-Chlorophenyl)-4-{5-chloro-2-thienyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

4-(5-Chloro-2-thienyl)-2-(2,4-dlfluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene
 

0:8-" 2-(4-Chlorophenyl)-3-[(3-12 pyridyl)hydroxymethyl)-4-(2-
thienyl)thiophene
N

F

2-(2,4-Difluorophenyl)-3-[(3-13 pyridyl)hydroxymethyl]-4-(2-
thienyl)thiophene

14    -lf.#r•!

N
15    ~
N
16    ~ F
HO
N

17    Cl~•
N

18    ~N

19    ~•II
l
N

20    ~F

F    N

21    c ~N

Br

22

23    c ~
N
24    <:13:8F

N
 

2-(2,4-Difluorophenyl)-4-(i methyl-2-thienyl)-3-f(3-pyridyl)hydroxymethyl]-thiophene

2 - (4 - Butylphenyl} - 4 - (5-mett; 2 - thienyl) - 3 - [(3-
pyridyl)hydroxymethyl]-thiophene

2,4 - Bis - (2,4 - Difluorophenyl)• [(3 - pyridyl)hydroxymethyl]-thiophene

4 - (4 - Chlorophenyl)-2-(2,4-dffluorophenyl}-3-[(3-pyridyl)hydroxymethyl}-thiophene

2,4-Bis-(2-•trifluoromethylphenyl)-3-{(3-pyridyl)hydroxymethylj-thiophene

2,4-Bis-(3-trifluoromethylphenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2,4-Bis-(4-trifluoromethylphenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

4 - {4 - Chlorophenyl)-3-{(3-pyridyl)hydroxymethyl]-2-(3-thienyl)thiophene

2-(5-Bromo-2-thienyl)-4-(4-chlorophenyl)-3-{(3-pyridyl)hydroxymethyl]-thiophene

4 - (4 - Chlorophenyl)-2-(5-methyl - 2 - thien yl)-3-{ (3• pyridyl}hydroxymethyl]-thiophene

2•(3,5-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyiJ-4-(3-thien_yl)thiophene

f'

25

26    FdS8F
N

F

27
~ N"'

5 w:J:g-CI

28

~
N

29    ~c-o
&
N

30    Cl
31    Cl ~N

32    Fi;8g"""
N

F
33    ~F

~
N
 

2-{2,4-Difluorophenyl)-3-[(3-pyrldyl)hydroxymethyl]-4-(3-thienyl)thiophene

2-{3,5-Difluorophenyl)-4-{4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-thiophene

2-(2,4-Difluorophenyl)-4-(4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-thiophene

2-(4-Chlorophenyl)-3-{(3-pyridyl)hydroxymethyiJ-4-(3-thienyl)thiophene

3-[(3-Pyridyl)hydroxymethyl]-
2-(2-tetrahydropyranyloxy-methyl)-4-(3-thienyl)thiophene

4-(5-Chlor0-2-thienyl)-3-[(3-pyridyl)hydroxymethyl]-2-(2-thienyl)thiophene

4 - (5 - Chloro - 2 - thienyl)-3-[(3-pyridyl)hydroxymethyl]-2-(3-thienyl)thiophene

4-(2,4-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-2-(3-thlenyl)thiophene

2 - (2,4-Difluorophenyl)-3•[(3-pyridyl)hydroxymethyl)-4-(2-thienyl)thiophene
 

34    ~v-CI    2 - (4-Ghlorophenoxymethyl)-3-   
        [(3-pyridyl)hydroxymethyl)-4-   
    &    (2-thienyl)thiophene   
    N       
    ~av-CI    2 - (4-Chlorophenoxymethyl)-3-   
35        [(3-pyridyl)hydroxymethyl)-4-   
    0    (3-thienyl)thiophene   
    N       

            2 - (4 -Chlorophenylethyl)-3-[(3-
36    ~CI pyridyl)hydroxymethyl]-4-(2-
    HO    -N    thienyl)thiophene
            2 - (4 - Chlorophenylethyl)-3-[(3-•
37    ~CI pyridyl)hydroxymethyl]-4-(3-
N.    thienyl)thiophene   
       
 
I~

38



39



40

41 ~a. c

N

42    ~CI

0
N
ff]:Q-Q--c•

43
0

44    ~-Q-ct

F
N
45    ~ F
""
N
46    tYJ:g\ Cl
 

4-(4-Fiuorophenyl)-3-[(3-pyridyl)hydroxyme!hyl}-2-(2-thienyl)thiophene

4-(2,4-0ifluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-2-(2-thienyl)thiophene

4-(2,4-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl}-2-(trimethylsilyl)thlophene

4 - (4 - Chlorophenyl)-2-(4-chlorophenylethyl)-3-((3-pyridyl}hydroxymethyl]-thiophene

2 - (4-Chlorophenylethyl)-4-

(2,4-dlfluorophenyl)-3-((3-pyridyl)hydroxymethyl]-thiophene

2-(4-Chlorophenoxymethyl)-4-(4-chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]: thiophene

2 - (4-Chlorophenoxymethyl)-4-

(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyiJ-thiophene

2 - (2,4 - Difluorophenyl)-4-(2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl}-thiophene

2-(4-Chlorophenyl)-4-{2-fluorophenyl)-3-[(3-pyrldyl)hydroxymethyl]-thiophene
            - 21-   
    F~CI        2-(4-Chlorophenyl)-4-(3-   
47            fluorophenyl)-3-{(3-   
            pyridyl)hydroxymethyl)-   
    _.,  HO    ~ "           
        N        thiophene   
                4-(3-Fiuorophenyl)-3-[(3-   
48        ~ '""""..    pyrldyl)hydroxymethyl)-2-(2-   
                lhienyl)thiophene   
        . N           
    "'        2,4-Bis-(2-Chlorophenyl)-3-[(3-   
49                pyridyl)hydroxymethyl)-   
                thiophene   
    HO               
    C88N           
        S Cl           
    Clv:J:g    2,4-Bis-(3-Chlorophenyl)-3-[(3-   
50            pyridyl)hydroxymethyl)-   
    HO    ..,        thiophene   
        N           
                2,4-Bis-(Phenyl)-3-[(3-   
51                pyridyl)hydroxymethyl]-   
                thiophene   
            2,4 - Bis-(2,4-Dichlorophenyl)-   
52            3 - [(3 -pyridyl)hydroxymethyl)-   
    cm•N    thiophene   
    CI.J8N    2,4-Bis-(2-Fiuorophenyl)-3-[(3-   
53            pyrldyl)hydroxymethyl]-   
            thiophene   
               
    •d]:ff    2,4-Bis-(3-Fiuorophenyl)-3-[(3-   
54            pyridyl)hydroxymethyl]-   
            thiophene   
        N           
        -        2-(3-Chlorophenyl)-4,5-   
55        A        dimethyt-3-{(3-   
    J8"IN        pyrldyl)hydroxymethyl}-   
               
            thiophene   
    ;;    4 - (5 - Chloro - 2 - furanyl)-2-(4-   
            chlorophenyl)-3-[(3-   
56    Cl               
                pyridyl)hydroxymethyiJ•   
        <           
                thiophene   
    ~N           
            4 - (5 - Chloro-2-furanyl)-2-(2,4-   
57    Cl    f        difluorophenyl)-3-[(3-   
                pyridyl)hydroxymethyl]-   
~N                  thiophene
 

59

F

s    Cl
60    o3:8
N

61    ~FF

62    $%0N

    F
63    ~•
    F
64    ~
65   
618i
N

66    FF~
67    rfZ'
-o
68    F HRfu
N
2,4-Bis•(2-thienyl)-3-£(3-pyrldyl)hydroxymethyl} thiophene

2,4-Bis-(4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2-{3-Chlorophenyl)-4-phenyl-3-[(3-pyridyl)hydroxymethyl]-thiophene

2,4-Bis-(3-chloro-5-trifluoromethy!phenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2,4-Bis-(2,5-difluoropheny!)-3-[(3-pyridyl)hydroxymethyl)-thiophene

2,4-Bis-(4-chloro-3-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2,4 - Bis - (3-Methoxyphenyl)-3- . [(3 - pyridyl)hydroxymethyl)-thiophene

4-{2-Fiuorophenyl)-3-((3-pyridyl)hydroxymethyl]-2-{2-thienyl)thiophene

2,4-Bis-(2-chlor0-4-trifluoromethylphenyl)-3-[(3-pyridyl)hydroxymethy!)-thiophene

2,4-Bis-(4-Methoxyphenyl)-3-[(3-pyrldyl}hydroxymethyl]-thiophene

2-{3-Chlorophenyt)-4-{2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

69    ~

0
N

~CI
70
F
 
2 -{5-Bromo-2-thlenyl}-4-(2,4-dlfluorophenyl)-3-[{3-pyridyl)hydroxymethyl]-thiophene

2-(5-Chloro-2-thlenyl)-4-(2,4-difluorophenyl)-3-[(3-pyrldyl)hydroxymethyl]-
 


71
 
N

~CI

I
N
 
thiophene

5-Chloro-2-(5-chloro-2-thienyl)-4-(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene
 

72    Cl ~N

73    Cl~N

Cl
74    JYJ8
N
. 75    ~.b
F
N
76    Cl#):gCl
N

77    c ~

78    ~F

N


79
Cl
 

4 - (4 - Chlorophenyl)-2-(2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

4 - (4 - Chlorophenyl)-2-(3-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2-{2-Chlorophenyl)-4-(2.4• difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

4 - {2,4 - Difluorophenyl)-2-(2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2-(4-Chlorophenyl)-4-{4-chloro-2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

2 - {3 - Chlorophenyl)-4-(4-chloro - 2 - fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

4 - (2,4-Difluorophenyl)-2-{4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-thiophene

4-{2,4-Dichlorophenyl)-3-[(3-pyridyl)hydroxymethyl]-2-{3-thienyl)thiophene
80
F


81
Cl


82

~CI
83 I c

N

F

84
c

85    ~N

86
87    Clo3:8.... Cl
N
88    ~....
c
N
 

4-(4-Fiuorophenyl)-3-1(3-pyridyl)hydroxymethyl)-2•(3-thienyl)thiophene

4-(4-Chloro-2-fluorophenyl}-3-[(3-pyridyl)hydroxymethyl]-2• {3-thieny!)thiophene

4-{2-Chlorophenyl)•3-{(3-pyridyl)hydroxymethyl]-2-(3-thtenyl)thioJ?hene

4-(4-Chlorophenyl)-2-(5-chloro-2-thlenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4-(4-Chlorophenyl)-2-(3,5-dlfluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4 - (4 - Chlorophenyl)-2-(2,4-dlfluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4-(4-Chlorophenyl}-3-[{3-pyridyl)hydroxymethyl]-2-(2• thienyl)furan


2,4-Bis-(4-chlorophenyl}-3-{(3-pyridyl)hydroxymethyl]furan


4 - (4 - Ghlorophenyl}-2-(4-chloro - 2 - fluorophenyl)-3-[{3• pyrfdyl)hydroxymethyl]furan
 

    Cl    2-(4-Chlorophenyl)-4-(2,4-   
89    F    dlfluorophenyl)-3-{(3-   
        pyridyl)hydroxymethyl]furan   
    hJ8N       
90    F    4-(2,4-Difluorophen yl)-2-( 4•   
        fluorophenyl)-3-[{3-   
    F    pyridyl)hydroxymethyl)furan   


91

92    ~N

93

~CI
94

N

M(:-o-c,
95    cJ~o>--()
 

4-(2,4-Dlfluorophenyl)-3-[(3-pyrldyl)hydroxymethyl]-2-(3-thienyl)furan

4-(2,4-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-2-(2-thlenyl)furan

2-(5-Chloro-2-thienyl}-4-(2,4-diftuorophenyl}-3-[(3-pyridyl)hydroxymethyl]furan

2-(3-Chlorophenyl}-4-(2,4-difluorophenyl}-3-[(3-pyrldyl}hydroxymethyl]furan

2-( 4-Chlorophenyl)-4-(4-chloro-2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan
 


96
 

~CI

cJ...V o>-Q
N
 

2-(3-Chlorophenyl)-4-(4-chloro-2-fluorophenyl}-3-[(3-pyridyl}hydroxymethyl}furan
 

97    ~

CI.J!...,..Io~•
N

98
Cl


99



100
101    c~
N
 

2-(2-Chlorophenyl)-4-(4-chloro-2-fluorophenyl)-3-[(3-pyridyl}hydroxymethyl]furan

4-( 4-Chloro-2-fluorophenyl}-2-(4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4-(4-Chloro-2-fluorophenyl)-2-(3-fluorophenyl}-3{(3-pyridyl}hydroxymethyl]furan

4-(4-Chloro-2-fluorophenyl)-2-(2-fluorophenyl)-3-[(3-pyridyl}hydroxymethyl]furan

4-(4-Chloro-2-fluorophenyl)-3-[(3-pyrldyl)hydroxymethyl]-2-(3-thienyl}furan


102
Cl
J;fJ:gCII.

103
c
N
104    Cl1/J:gCl
N
1/k?CI
105
Cl
N
106    ~
Cl
N

107
Cl

F

108

Cl

109    ~'~
N
110    ~
N

Cl
111


Cl
112

4-(4-Chloro-2-fluorophenyl)-3-[(3-pyrlclyl)hydroxymethyl]-2-(2-thienyl)furan

4-(4-Chloro-2-fluorophenyl)-2-(5-chloro-2-thienyl)-3-[(3-pyridyl)hyclroxymethyl)furan

2-(4-Chlorophenyl)-4-(2,4-dichlorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

2-(3-Chlorophenyl)-4-(2,4-dichlorophenyl)-3-((3-pyridyl)hydroxymethyl]furan

2 - (2 - Chlorophenyl)-4-(2,4-dichlorophenyi)-H(3-pyridyl)hydroxymethyl]furan

4-(2,4-Dlchlorophenyl)-2-(4-fluorophenyl)-3-{(3-pyridyl)hydroxymethyl)furan

. 4-(2,4-Dlchlorophenyl)-2-(3-fluorophenyl)-3-{(3-pyridyl)hydroxymethyijfuran

2 - {2,4-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl)-4-(2-thienyl)funan

2 - {2,4 - 0ichlorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-thlenyl)furan

2-(4-Chloro-2-fluorophimyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-thienyl)furan

2-(4-Chlorophenyl)-3-{(3-pyridyl)hydroxymethyl)-4-{2-thienyl)furan
 

113    «J:g"
~
N

Cl
114    oJ:80N
115    ~....,
N
118    ~NF
F
117    ~N
118    0:[1,F
N
119    ~
M

Cl
120    c1~a

M

121    Cl ~0
HO
N
122    Cl~ Cl
0
N
123    Cl -<:!]:g"

N'


2-(3-Chlorophenyl)-3-((3-pyridyl)hydroxymethyl]-4-(2-thienyl)furan

2-{2-Chlorophenyl)-3-{(3-pyridyl)hydroJtymethyl)-4-(2-thienyl)furan

2 - (4 - Fiuorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-thienyl}furan

2 - (3 - Fiuorophenyl)-3-[{3-pyridyl)hydroxymethyl]-4-{2-thienyl)furan

2 - (2 - Fiuorophenyl)-3-({3-pyridyl)hydroxymethyij-4-(2-thienyl)furan

2-(3,5-Difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]-4-{2-thlenyl)furan

4 - {5 - Chloro - 2 - thienyl)-2-(2,4-difluorophenyl)-3-{(3-pyrldyl)hydro:xymethyl]furan

4 - {5 -Chloro-2-thienyl)-2-(2,4-dichlorophenyl)-3-[(3-pyridyl)hydro:xymethyl]furan

2 - (4 - Chloro-2-fluorophenyl)-4-(5 -chloro-2-thienyl)-3-{(3-pyridyl)hydroxymethyl]furan

2 - (4 - Chlorophenyl)-4-(5• chloro - 2-thienyl)-3-[(3-pyridyl)hydroxymethyl)furan

2-(3-Chlorophenyl)-4-(5-chloro-2-thienyl)-3-[(3-pyridyl)hydroxymethyl}furan

124    Cl-«J80

N

125    ~•HO!
N
126    Cl-0:8~
N
127    Cl ~
!
N

128    Cl~•F.

N

I
129    ~~
Cl

N
130    Cl48-
N

131    c•~110
N

I
132 ~I c
N

133 ~CI-c

N

2-(2-Chlorophenyl)-4-(5-cl:lloro-2-thienyl)-3-[(3-pyridyl)hydroxymethyl]furan

4 - {5 -Chloro-2-thienyl)-2-(4-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4-(5-Chloro-2-thienyl)-2-{3-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4 - (5 - Chloro-2-thlenyl)-2-(2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]furan

4 - (5 -Chloro-2-thienyl)-2-(3,5-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl}furan

4-(4-Chlorophenyl)-2-(5-chloro-2-thlenyi)-1-{N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole

4-(4-Chlorophenyl)-2-(3,5-difluorophenyi)-1-(N-methyl)-3-[(3-pyrldyl)hydroxymethyl]pyrrole

4 - (4 - Chlorophenyl)-2-(2,4-difluorophenyi)-1-(N-methyl)-3-{(3-pyrldyl)hydroxymethyl]pyrrole

4 - (4 - Chlorophenyi)-1-(N-methyl) - 3•[(3-pyridyl)hydroxymethyl}-2-(2-thienyl)pyrrole

2,4 - Bis-(4-chlorophenyi)-1-(N-methyl)-3-((3-pyrldyl)hydroxymethyl]pyrrole
 
134 d,:t8o 4-(4-Chlorophenyl)-2-(4-chloro-2-fluorophenyl)-3-[(3-

Cl    pyridyl)hydroxymethyl]pyrrole

N


135    JY]:g-Cl
F
N

I
136    }48-F

~
N

/
137    F~•N
138    ~I
F
N

I
139    ~CI

    I   
    N   
    JX}gCI   
140    Q   
       
    F   
    N   

I
141    c J/3:8 Cl

142    JA8N.
I
143    c P18~
N


2-(4-Chlorophenyl)-4-(2,4-dlfluorophE!nyi)-1-(N-methyl)-3-((3-pyridyl)hydroxymethyl]pyrrole

4-(2,4-Difluorophenyl)-2-(4-fluorophenyl)-1-(N-methyl)-3-[(3-pyridyl)hy~roxymethyl]pyrrole

4 - {2,4-Difluorophenyl)-1•(N-methyl)-3-[(3-pyridyl)hydroxymethyl]-2-(3• thienyl)pyrrole

4 - (2,4 - Difluorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]-2-(2-thienyl)pyrrole

2-(5-Chloro-2-thienyl)-4-(2,4-difluorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole

2-(3-Chlorophertyl)-4-(2,4-difluorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole

2-(4-Chlorophenyl}-4-(4-chloro-2-fluorophenyi}-1-(N-methyl)-3-[(3-pyridyl}hydroxymethyl]pyrrole

~-(3-Chlorophenyl)-4-(4-chloro-2-fluorophenyi)-1-(N-methyl)-3-[(3-pyrldyl)hydroxymethyl](:lyrrole

2-(2-Chlorophenyl}-4-(4-chloro-2-fluorophenyi}-1-(N-methyl)•3-{(3-pyridyl)hydroxymethyl]pyrrole
 

    I    4- (4 -Chloro-2-fluorophenyl)-2•   
           
144        F(4 - fluorophenyi)-1-(N-methyl)•   
    ~    3-((3-   
    Clh:]:g-       
        pyridyl)hydroxymethyl]pyrrole   
    N       
        4-( 4-chloro-2-fluorophenyl)-2-   
145    Q    (3-fluorophenyi)-1-(N-methyl)-   
JY.}g    3-[(3-
Cl    pyridyl)hydroxymethyl]pyrrole
N


/
147    Cl~
N

148    CID1:g

N

~CI
149
CI~O~

I
150    Cl~
N

I    Cl
151    CJ/1:&
N
152    CP18
N
153    ~
N

154

Cl
155    ~
N
156    o§g-o

N
 

4-(4-Chloro-2-fluorophenyl)-2-(2-fluorophenyi)-1-(N-methyl)-3-[(3-pyridyl)~ydroxymethyl]pyrrole

4-(4-Chloro-2-fluorophenyi)-1-(N-m ethyl )-3 -{(3-pyridyl)hydroxymethyl]-2-(3-thienyl)pyrrole

4-(4-Chloro-2-fluorophenyi)-1-(N-methyl)-3-[(3-pyridyf)hydroxymethyl]-2-(2-thienyl)pyrrole

4-(4-Chloro-2-fluorophenyl)-2-(5-chloro-2-thienyi)-1-(N-methyl)-3-[(3-pyridyl)hydroliymethyl)pyrrole

2-(4-Chlorophenyl)-4-(2,4-dichlorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole

2-(3-Chlorophenyl)-4-(2,4-dichlorophenyi)-1-(N-methyl)-3-[(3-pyrldyl)hydroxymethyl)pyrrole

2-(2-Chlorophenyl)-4-(2,4-dichlorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl)pyrrole

4-(2,4-Dichlorophenyl)-2-(4-fluorophenyi)-1-(N-methyl)-3-

-    _[(3-.   -    --
pyridyl)hydroxymethyl]pyrrole

4-(2,4-Dichlorophenyl)-2-(3-fluorophenyi}-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole

2-(2,4-Difluorophenyi}-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-thienyl)pyrrole

2-(2,4-Dichlorophenyi)-1-(N-methyl)-3-{(3-pyridyf)hydroxymethyl]-4-(2-thienyl)pyrrole
 

157    ~
0
N
158    o:cgI-CI

oj:goN-
•159    I
i
N

160    ~•i
N
161    a:rgI-F

0

162    o:J8~
N
163    ~

i    N

164    o:J8,IF
N

I    F
165    CI~F
HO
166    Cl~N Cl
167    ~
0
N

2 - (4 - Chloro - 2 - fluorophenyl)-1-(N - methyl)-3-[(3-pyridyl)hydroxymethyl]-4-(2-thienyl)pyrrole

2-{4-Chlorophenyi)-1-(N-methyl)-3-{(3-pyridyl)hydroxymethyl]-4-{2-thienyl)pyrrofe

2-{3-Chlorophenyl)-1-{N-methyl)-3-[(3-pyridyl)hydroxymethyl]-4-{2-!hienyl)pyrrole

2 - (2 -Chlorophenyi)-1-(N-methyl)-3-[(3-pyridyi)hydroxymethyl]-4-{2-thieny!)pyrrole

2-{4-Fiuorophenyi)-1-(N-methyl)-3-[(3- • pyridyl)hydroxymethyl]-4-{2-thienyl)pyrrole

2-(3-Fluorophenyi)-1-(N-methyl)-3-{(3-pyridy!)hydroxymethyl]-4-{2-thienyl)pyrrole

2 - (2 - Fiuorophenyi)-1-(N-me!hyf)-3-[{3-pyridyl)hydroxymethyl]-4-(2-thienyl)pyrrole

2-{3,5-Dif!uorophenyi)-1•(N-methyi)-3-((3-pyrldy!)hydroxymethy!]-4-(2-thienyl)pyrrole

4-(5-Chloro-2-thienyi)-2-(2,4-difluorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymelhyijpyrrole

4 - (5 - Chloro-2-thienyl)-2-(2,4-dlchlorophenyi)-:1-{N-methyl)-3-[(3-pyridyl)hydroxymethyl}pyrrole

2 - (4 - Ch!oro - 2 - fluorophenyl)-4-(5 - chloro - 2 - lhienyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyijpyrrole

tf
168    c1~a

N

I    Cl
Cl-~~
169    --u HO>-o
N

2-(4-Chlorophenyl)-4-(5-chloro-2-thienyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole

2-(3-Chlorophenyl)-4-(5-chloro-2-thienyi)-1-(N-methyl}-3-[(3-pyridyl)hydroxymethyl]pyrrole

2-(2-Chlorophenyl)-4-( 5-chloro-2-lhienyi)-1-(N-melhyl)-3-[(3-pyridyl)hydroxymethyl)pyrrole

4-( 5-Ch loro-2-thienyl)-2-(4-fluorophenyi)-1-(N-methyl)-3-
[(3-pyridyl)hydroxymethyl]pyrrole

4-(5-Chloro-2-thienyl)-2-(3-fluorophenyi)-1-(N-methyl)•3-
[(3-pyridyl}hydroxymethyl]pyrrole

4-(5-Chloro-2-thienyl)-2-(2-fluorophenyi)-1-(N-melhyl)-3-[(3-pyridyl)hydroxymethyl)pyrrole

4-(5-Chloro-2-thienyl)-2-(3,5-dlfluorophenyi)-1-(N-methyl)-3-[(3-pyridyl)hydroxymethyl]pyrrole
 


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

5    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, fumaric acid or phthalic acid, with hydroxyearboxylic acids, typically ascorbic acid, lactic acid, malic acid, tartaric acid or citric acid, or

10    with benzoic acid, or with organic sulfonic acids, typically methanesulfonic acid or p-toluenesulfonic 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, ';fiethylamine, triethylamine or dimethylpropylamine, or a mono-, di- or trihydroxyalkylamine, typically mono-, di- or triethanolamine. Where appropriate, the

5    formation of corresponding internal salts is also possible. Within the scope of this invention, agrochemical or pharmaceutically 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;
,0    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
.5 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

~0 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,

~5 Helminthosporium, Fusarium, Septaria, 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
iO    limited to, Septaria 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

5    plants, cocoa beans, groundnuts); cucumber plants (pumpkins, cucumbers, melons); fiber plants (cotton, flax, hemp, jute); citrus :fiuit (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-1 0    bearing vines, hops, bananas, turf and natural rubber plants, as well as ornamentals (flowers, shrubs, broad-leafed trees and evergreens, such as conifers).  Tills list does

not represent any limitation.

The active compotmds 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 1-5    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

20    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,

25    epoxiconazole, fluquinconazole, flusilazole, flutriafol, hexaconazole, imazalil, imibenconazole, ipconazole, tebuconazole, tetraconazole, fenbuconazole, metconazole, myclobutanil, perfuTa:z.oate, penconazole, bromuconazole, pyrifenox,

prochloraz,    triadimefon,  triadimenol,  tri:flumizole   or  triticonazole;  pyrimidinyl

carbinoles such as ancymidol,  fenarimol  or nuarimol; 2-amino-pyrlmidine such  as

30    bupirimate, dimethirimol or ethirimol; morpholines such as dodemorph, fenpropidin, fenpropimorph, spiroxamin or tridemorph; anilinopyrimidines such as cyprodinil, pyrimethanil or mepanipyrim; pyrroles •such as fenpiclonil or fludioxonil; phenylamides such as benalaxyl, furalax:yl, metalaxyl, R-metalaxyl, ofurace or


oxadixyl; benzimidazoles such as benomyl, carbendazim, debacarb, fuberidazole or thiabendazole; dicarboximides such as chlozolinate, dichlozoline, iprodine, myclozoline, procymidone or vinclozolin; carboxamides such as carboxin, fenfuram, flutolanil, mepronil, oxycarboxin or thifluzamide; guanidines such as guazatine,

5    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-[{alpba.[(alpha-methyl-3-trifluoromethyl-benzyl)im.ino]-oxy}-o-tolyl]- glyoxylic acid-methylester-0-methyloxime (trifloxystrobin); dithiocarbamaies such as ferbam, mancozeb, maneb,

10    metiram, propineb, ~. zinebor 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;   org~o phosphorous   derivatives   such   as   edifenphos,

15    iprobenphos, isoprothiolane, phosdiphen, pyrazophos or toclofos-methyl; and other compounds of diverse structures such as acibenzo1ar-S-methyl. harpin, anilazine, blasticidin-S, chinomethionat, chloroneb, chlorothalonil, cymoxanil, dicblone, diclomezine, dicloran, diethofencarb, dimethomorph, dithianon, etridiazole, famoxadone, fenamidone, fentin, ferimzone, fluazinam, flusulfarnide, fenhexamid,

20    fosetyl-aluminium, hymexazol, kasugamycin, methasulfocarb, pencycuron, phthalide, polyoxins, probenazole, propamocarb, pyroquilon, quinoxyfen, quintozene, sulfur, triazoxide, 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-cbloro-1-ethyl-1-methy1-2-oxopropyl)-4-methylbenzamide (RH-7281 ), N-allyl-4,5-dimethyl-

25    2-ttimethylsilylthiopbene-3-carboxamide (MON 65500), 4-chloro-4-cyano-N,N-dimethyl-5-p-tolylimidaz.ole-1-sulfon-amide (IKF-916), N-( 1-cyano-1 ,2-dimethylpropyl)-2-{2,4-dichlorophenoxy)-propionamide (AC 382042) or iprovalicarb (SZX722).

The active compounds can be mixed with one•or more systemically acquired

30    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 tum 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; Cell70: 879-886). Exemplary SAR inducers cover many structural families of compounds, but are united by their ability to induce a resistance to plant diseases

5    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 MessengerTM from Eden Biosciences), yeast extract hydrolysate from Saccharomyces cerevisiae (available as Keyplex® 350-DP® from Morse

Enterprises Limited, Inc. of Miami, Florida), and O~emate are useful in the present

10    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

1 5 • in fol'II)ulation technology, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tacki:tiers, thickeners, binders or fertilizers.

A preferred method of applying an active compound of the invention, or an agrc:>cbemical composition which contains at least one of said compounds, is foliar application..The frequency of application and the rate of application will depend on

20    the risk of~estation 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 s•oJ'id 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

25 • active compoun~s 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

30    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, qoatable pastes, directly sprayable or dilutable solutions, dilute emulsions, wettable powders,

5    soluble powders, dusts, granulaies, 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

10    ingredient (a.i.) per hectare (ha), preferably from 10 g to 1.kg a.i.lha, 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

15    mtunately 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 cotrespond to the substances ordinarily employed in formulation technology, such as, e.g. natural or regenerated mineral substances, solvents, dispersants, wetting agents, tacki:fiers,

20    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

25    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.

30 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

5    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

10    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

15    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

20    limited to aihnents such as Onychomycosis, sporotichosis, hoof rot, jungle rot, Pseudallescheria boydii, scopulariopsis or athletes foot, sometimes generally referred to as "white-line" disease, as well as fungal infections in immunocomprornised 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

25    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 pharmaceutically acceptable carrier and administered or applied to such subjects or

infections (e.g., topically, parenterally) in an amount effective to treat the infection in

30    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 ofwhlch applicants specifically intend be incorporated by reference herein in their entirety.


"Phannaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms ~ch are, within the scope of sound medical judgment, suitable f~ use in contact with the tissues of human beings and mUmals without excessive toxicity, irritation, allergic response, or other

5 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,

10    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 corn  starch and potato  starch;  (3). cellulose,  and its

15    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, safilower 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

20    glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magneshun 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 phannaceutical formulations.

25 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

30    dosage form will vary depending upon the host being treated, •the 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,

fu.is amount will range from about I 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

5    bringing into association a ciomp.ound 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.

10 The ointmentS, pastes, creams and gels may contain, in addition to the active ingredient, excipients, such as animal and vegetable fats, oils, waxes, paraffms, 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,

15    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 20 •   units, such as Cllflsules, 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

25    suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the formulations ofthe 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

30    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 ~mpositions of this invention suitable for parenteral administration comprise one or more active compounds of the invention in

5    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

10    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

15    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, emulseying agents and dispei:sing agents. Prevention of the action of microorganisms may be ensured by the

20 incl~ion 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, sodi~ 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

25    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 pharmaceutically acceptable

30    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 iJUection, 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.

5 "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,
10    intraspinal and intrastemal injection and infusion.

Actual dosage . levels of the active ingredients in the phannaceutical 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., antimycotic activity, for a particular patient, composition, and mode of a.cl.niinistration,
15    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

20    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 detennine 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

25    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

30    where a salt is employed.

The. present invention is  explained  in  greater detail  in the  following  non-

limiting Examples.

EXAMPLE I

2,4-Bis-(3-cblorophenyl)-3-((3-pyridyl)bydroxymethyl] 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

5    1.6M solution of n-butyllithium in hexane. The solution was stirred for l.Shr, and then 64mg (2.0mmol) of sulfur was added. After an additional l.Shr at -78°C, the red solution was • warmed to room temperature and added to• a solution of 400mg (1.66mmol) of 3-(3-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one in 4mL of THF and
lroL of acetonitrile .. The reaction solution was stirred for 2hr at room temperature,

10    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) of2,4-bis-(3-cblorophenyl)-

15    3-[(3-pyridyl)=bonyl) thiophene. 1HNMR (CDC13): 7.95 (d ofq, 1), 8.56 (d ofd, 1), arid 8.73ppm (d, I). MS m/z410.0 (M+H).

To  a  solution  of  32mg  (0.08mmol) • of  2,4-bis-(3-chlorophenyl)-3-[(3-

pyridyl)Cllrbonyl] thiophene in 2mL of~ydrous THF was adde~ lOmg (0.26tnmol) of lithium aluminum hydride. The mixture was stirred at ooc for 0.5hr and was then

20    diluted with ethyl acetate. The ethyl acetate solution was washed with water and dried over magnesium sulfate. •The drying agent was filtered '0~ 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-chlorophenyl)-3-[(3-pyridyl)hydroxy-methyl} thiophene (Compound I) in 91%. yield.
25    1H NMR (CDCh): 5.98 (br s, I), 7.44 (br d, 1), 8.08 (br s, 1), and 8.21ppm (br d, 1).

MS m/z 412.0 (M+H).

EXAMPLE2

4-(4-Chlorophenyl)-2-(5-ehloro-2-tbienyl)-3-

30    [(3-pyridyl)bydroxymetbyl)tbiopbene (Compound 4)

To a solution of 137mg (l.Ommol) of 4-chlorophenylacetylene in 2mL of anhydrous THF under a N2 atmosphere at -78°C was added O.Q63mL (l.Ommol) of a I.6M solution of n-butyllithium in hexane. The solution was stirred for I.Shr, and
 
then 32mg (l.Ommol) of sulfur was added. After an additiona11.5hr at -78•c, the red

solution was warmed to -to•c. One half of the solution was added to a solution of
.    .
99mg (0.39mmol) of 3-(5-chloro-2-thienyl)-1-(3-pyridyl)-2-propyn-1-one in 2mL of THF and O.SmL of acetonitrile. After an additional O.Shr, the reaction was diluted

5    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-thienyl)-3-[(3-pyridyl)carbonyl]-thiophene. 1H NMR 10 (CDC13): 6.76 (d, 1), 6.95 (d, 1), 7.96 (br d, 1), 8.59 (br d, 1), and 8.73ppm (br s, I).

MS mlz 415.9 (M+H).

To a solution of 70mg (0.17nunol) of 4-(4-chlorophenyl)-2-(5-chloro-2-thienyl)-3-[(3-pyridyl)carbonyl]thiophene in 3mL of anhydrous 1HF was added 13mg • (0.34mmol) of lithium aluminum hydride. The mixture was stirred at o•c for O.Shr

15    and •was then diluted with ethyl acetate and a minimum amount of water to decompose the LiAilf4. 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  (0.14nunol)  4-(4-chlorophenyl)-2-(5-chloro-2-thienyl)-3-

[(3-pyridyl)hydroxymethyl]thiophene (Compound 4) in 84% yield. 1H NMR (CDC])):

20    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,

I)    . MS mlz 417.9 '(M+H).

EXAMPLE3

3-(3-Chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one

25 To a solution of 5.0gm (36.6mmol) of 3-cblorophenylacetylene in 30mL of anhydrous THF. under a N2 atmosphere at -?s•c was added 23mL (36.6mmol) of a 1.6M solution ofn-butyllithluni in hexane. The solution was stirred for 2hr, and then a solution of 3.9gm (36.6mmol) of pyridine-3-carboxaldebyde in 5mL of THF was added. The reaction mixture was stirred at -?s•c for 2hr and then was poured into ice

30    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)-1-(3-pyridyl)-2-propyn-1-ol.

The 8.5gm of 3-(3-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol in 50mL of DMSO was added 10.7gm (38mmol) of o-iodosobenzoic acid (IBX) in portions. The

5    resulting mi:!cture 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

10    rotoevaporation to give 6.84gm (28.3mmol) of brown solid 3-(3-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one in an overall 77% crude yield. 1H NMR (CDCh): 8.40 (d of m, 1), 8.84 (d ofd, 1), and 9.40ppm (d, 1). MS mlz 242.0 (M+H).

    EXAMPLE4
15    2,4-Bis-(2,4-ditluorophenyl)-3-((3-pyridyl)bydroxymetbyi]tbiopbene
    To  a  suspension  of  l.54gm  (ll.lmmol)  of potassium  carbonate,  1.44gm
    (4.46mmol) oftetrabutylammonium bromide, and .OSgm (0.22mmol) of palladimn(II)
    diacetate  in  l.lmL  of acetonitrile/H20  (9:1)  under  a  N2  atmosphere  was  added
    !.83gm  (6.69mmol)  of  2,4-difluoto-1-iodobenzene  and  0.50gm.  (4.46mmol)  of
20    thiophene-3-carboxaldehyde. The mixture was heated at  so•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
    colwnn   chromatography   on   silica   gel   to   give   a   mixture   of   2-(2,4-

25    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 0.4lgD1 (2.6mmol) of 3-bromopyridine in 1.7mL of anhydrous THF under a N2 almosphere was added 1.3mL (2.6mrnol) of 2M i-propy!magnesium chloride in THF. After 2 hr of stirring, 0.39gm of the above

30    mixture of aldehydes in 2mL ofTIIF 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

rotoevaporation to give a mixture ofproducts that were purified by preparative HPLC. From this reaction, 167mg of 2-(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiopbene and 96mg of the desired 2,4-bis-(2,4-difluorophenyl)-3-((3-pyridyl)hydrox:ymethyl]thiophene were isolated. For the latter,
5    1H NMR. (CDCl3): 7.67 (br d oft,.1), 8.55 (d of d, 1), and 8.49 ppm (br d,.l). MS mlz

416.0 (M+H).

EXAMPLES

2-(3-Chloropbenyl)- 4,5-dimethyJ-4-hydroxy-3-[(3-pyridyl)carbonyl]-4,5-10 dihydrothiophene

A solution of 0.20gm. (0.83mmol) of 3-(3-chlorophenyl)-1-(3-pyridyl)-2-propyn-l-one, O.lOgm (0.99mmol) of 3-mercapto-2-butanone, and 0.072mL (0.83mmol) of morpholine in 3mL of diethoxymethane was heated to reflux under a

N2 atmosphere for 8brs. The reaction mixture was diluted with ethyl acetate, and the

15    orgaclc 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 0.18grn (0.53mmol) of 2-(3-chlorophenyl)-4,5-dimethyl-4-hydroxy-3-[(3-pyridyl)carbonyl]-4,5-dihydrothiophene as a mixture of

20    two isomers. 1H NMR (CDCh): 1.56 (d,3), 1.64 (s, 3), 3.80 (t, 1), 7.82 (d of m, 1), 8.45 (d ofd, 1), and 8.64ppm (d, 1). MS m/z346.0 (M+H).

EXAMPLE6

2-(3-Chlorophenyl)-4,5-dimethyl-3-[(3-pyridyl)hydroxymethyl)thiophene 25 (Compound 55)

A mixture of O.OSOgm (0.14mmol) of 2:(3-chlorophenyl)-4,5-dimethyl-4-hydroxy-3-[(3-pyridyl)carbonyl]-4,5-dihydrothiophene as a mixture of two isomers and 0.024mL of acetic anhydride in l.OmL 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

30    preparative thin layer chromatography (prep TLC) to give 0.037gm (O.llmmol) of 2-(3-chlorophenyl)-4,5-dimethyl-3-[3-pyridylcarbonyl]thiophene. 1H NMR. (CDC~)):
2.9    (s, 3), 2.43 (s, 3), 8.00 (d ofm. 1), 8.58 (d ofd, 1), and 8.78ppm (d, 1). MS mlz

328.0    (M+H).

To a solution of 0.037gm (O.llmmol) of the preceding ketone, 2-(3-chlorophenyl)-4,5-dimethyl-3-[3-pyridylcarbonyl]thiophene, in 3mL of diethyl ether was added 0.020gm (0.45mmol) of lithium aluminum hydride. The mixture was stirred at ooc for O.Shr and was then diluted with ethyl acetate and a minimum
5    amount of water to decompose the LiAIRa. 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)-4,5-dimethyl-3-[(3-pyridyl)hydroxymethyl]thiophene (Compound 55). 1H NMR (CDCh): 1.82 (s, 3), 2.31 (s, 3), 7.64 (d o~m, 1), 8.41 (d of d, 1), and
10    8.46ppm (br s, 1). MS mlz 330.0.0 (M+H).

EXAMPLE?

Biological Screening

Fungicidal  activity  for  the  compounds  described  in  this  invention  was

15    determined using a microtiter plate format. In primary screening, test compounds in IJ.!L of dirriethylsulfoxide (DMSO) are delivered to individual wells of a 96-well microtiter plate. Then I OOJ.1L 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 1OJ.LL of an aqueous suspension of fimgal spores to the surface of the solid agar. The

20    plates are covered and incubated in a controlled environment at 20 °C. Fungicidal activity is detennined by visual inspection and photometric analysis of fungal growth after 3-5 days, depending on the pathogen. Commercial standards (azoxystrobin. benomyl, captan, chlorothalonil, famoxadone, flusilazole, and propiconazole) are

included in all assays. Test pathogens include Septaria tritici, Stagonospora nodor.um,

25    Plrytophthora infestans, Monilinia.fructicola 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 J.IM concentration, for certain of the compounds covered in this invention is included in the following Table 1. The coefficient of variation (ratio of standard

30    deviation to the mean) expressed in percentage is given in parentheses.

ifable 1.

Compound    lB. cinerea    P. lnfestans    ~- nodorum    ~- tritici    M. fructicola   
Number                       
                       
                       
4    B (c)    E    B    A (d)    A   
                       
6    B (d)    •E    B(c)    A (b)    A   
                       
8    ND    E    B (d)    A(d)    ND   
                       
9    B (d)    E    A(d)    A (c)    A   
                       
12    A (d)    E    A(d)    A    A   
                       
14    B (d)    E    A (b)    A    A   
                       

ICSO(J.&M):  A= S0.1; 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:

wherein:

X is S, 0, or NR5 ;

R is H; 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;
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, 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;
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;

~ is H; acyl; haloacyl; alkoxycarbonyl; aryloxycarbonyl; alkylaminocarbonyl; or dialkylaminocarbonyl;

R5 is H; alkyl; alkenyl; alkynyl; 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;

or a salt thereof.

with the proviso that the compound of formula (l) is not 2.4-diphenyl-3-(alpha-hydroxyethyl)pvrrole 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 formulaIc:


Ia    Ib    lc

wherein R1, Rz, R3, ~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 I 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-furyl.
6.    The compound of claim I 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 I 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 I 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 I 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-methylphenyl, 2-thienyl, 5-chloro-2-thienyl, 5-methyl-2-thienyl, 3-thienyl, t-butyl, or trimethylsilyl.

11.    The compound of claim 1 wherein ~ is H.

12.    The compound of claim I wherein:

R is H or alkyl;

R 1 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

~isH;

R5 is alkyl and haloalkyl; or a salt thereo£

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-furyl.

14.    The compound of claim 12 wherein R2 is 3-pyridyl or 5-pyrimidinyl optionally substituted with halogen, alkyl, alkeny1, alkynyl, haloalky1, 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-thienyl, 5-methyl-2-thienyl, 3-thienyl, t-butyl, or trimethylsilyl.



I6. The compound of claim I2 selected from the group consisting of: 2,4-Bis-(3-chlorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound I); 4-(3-Chlorophenyl)-2-(5-chloro-2-thienyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 2); 4-(3-Chlorophenyl)-2-(3,5-difluorophenyl)-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-pyridyl)hydroxymethyl]thiophene (compound 5); 2-(4-Chlorophenyl)-4-(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 6); 4-(2,4-Difluorophenyl)-2-( I, I-dimethylethyl)-3-[(3-pyridyl)hydroxymethyl]thiophene( compound 7); 2,4-Bis-( 4-chlorophenyi)-3-[ (3-

pyridy1)hydroxymethy1]thiophene (compound 8); 4-(4-Ch1oropheny1)-3-[(3-pyridy1)hydroxymethy1]-2-(2-thieny1)thiophene (compound 9); 2-( 4-Ch1oropheny1)-4-( S-ch1oro-2-thieny1)-3-[ (3-pyridy1)hydroxymethy1]thiophene (compound 10); 4-(S-Ch1oro-2-thieny1)-2-(2,4-difluoropheny1)--3-[(3-pyridy1)hydroxymethy1]thiophene (compound 11 ); 2-( 4-Ch1oropheny1)-3-[(3-pyridy1)hydroxymethy1]-4-(2-thieny1)thiophene (compound 12); 2-(2,4-Difluoropheny1)-3-[(3-pyridy1)hydroxymethy1]-4-(2-thieny1)thiophene (compound 13 ); 2-(2,4-Difluoropheny1)-3-[ (3-pyridy1 )hydroxymethy1 ]-4-(2-thieny1)thiophene (compound 14); 2-( 4-Buty1pheny1)-4-( 5-methy1-2-thieny1)-3-[(3-pyridy1)hydroxymethy1]thiophene (compound 15); 2,4-Bis-(2,4-Difluoropheny1)-3-[(3-pyridy1)hydroxymethy1]thiophene (compound 16); 4-( 4-Ch1oropheny1)-2-(2,4-difluoropheny1)-3-[(3-pyridy1)hydroxymethy1]thiophene (compound 17); 2,4-Bis-(2-trifluoromethy1pheny1)-3-[ (3-pyridy1)hydroxymethy1]thiophene (compound 18); 2,4-Bis-(3-trifluoromethy1pheny1)-3-[ (3-pyridy1)hydroxymethy1 ]thiophene (compound 19); 2,4-Bis-( 4-trifluoromethy1pheny1)-3-[ (3-pyridy1)hydroxymethy1]thiophene (compound 20); 4-( 4-Ch1oropheny1)-3-[ (3-pyridy1)hydroxymethy1]-2-(3-thieny1)thiophene (compound 21 ); 2-(S-Bromo-2-thieny1)-4-(4-ch1oropheny1)-3-[ (3-pyridy1)hydroxymethy1]thiophene (compound 22); 4-( 4-Ch1oropheny1)-2-( 5-methy1-2-thieny1)-3-[(3-pyridy1)hydroxymethy1]thiophene (compound 23); 2-(3,5-Difluoropheny1)-3 -[ (3-pyridy1)hydroxymethy1]-4-(3-thieny1)thiophene (compound 24); 2-(2,4-Difluoropheny1)-3-[(3-pyridy1)hydroxymethy1]-4-(3-thieny1)thiophene (compound 25); 2-(3,5-Difluoropheny1)-4-( 4-fluoropheny1)-3-[ (3-pyridy1)hydroxymethy1]thiophene (compound 26); 2-(2,4-Difluoropheny1)-4-( 4-fluoropheny1)-3-[(3-pyridy1)hydroxymethy1]thiophene (compound 27); 2-( 4-Ch1oropheny1)-3-[ (3-pyridy1)hydroxymethy1 ]-4-(3-thieny1)thiophene (compound 28); 3-[(3-Pyridy1)hydroxymethy1]-2-(2-tetrahydropyrany1oxy-methy1)-4-(3-thieny1)thiophene (compound 29); 4-(2,4-Difluoropheny1)-3-[(3-pyridy1)hydroxymethy1]-2-(3-thieny1)thiophene (compound 32); 4-(2,4-Difluoropheny1)-3-[(3-pyridy1)hydroxymethy1]-2-(2-thieny1)thiophene (compound 39); 2-(2,4-Difluoropheny1)-4-(2-fluoropheny1)-3-[(3-pyridy1)hydroxymethy1 ]thiophene (compound 45); 2,4-Bis-(2-Ch1oropheny1)-3-[ (3-pyridy1)hydroxymethy1]-thiophene (compound 49); 2,4-Bis-(3-Ch1oropheny1)-3-[(3-pyridy1)hydroxymethy1]thiophene (compound SO); 2,4-Bis-(Pheny1)-3-[(3-

pyridyl)hydroxymethyl]thiophene (compound 51); 2,4-Bis-(2,4-Dichlorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 52); 2,4-Bis-(2-Fluorophenyl)-3-[ (3-pyridyl)hydroxymethyl]thiophene (compound 53); 2,4-Bis-(3-Fluorophenyl)-3-[ (3-pyridyl)hydroxymethyl]thiophene (compound 54); 2-(3-Chlorophenyl)-4,5-dimethyl-3-[ (3-pyridyl)hydroxymethyl]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-trifluoromethylphenyl)-3-[ (3-pyridyl)hydroxymethyl]-thiophene (compound 61 ); 2,4-Bis-(2,5-difluorophenyl)-3-[ (3-pyridyl)hydroxymethyl ]thiophene (compound 62); 2,4-Bis-(4-chloro-3-fluorophenyl)- 3-[ (3-pyridyl)hydroxymethyl]thiophene (compound 63 ); 2,4-Bis-(3-Methoxyphenyl)-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)hydroxymethyl]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-difluorophenyl)-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-difluorophenyl)-3-[ (3-pyridyl)hydroxymethyl]-thiophene (compound 71 ); 4-( 4-Chlorophenyl)-2-(2-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 72); 4-(4-Chlorophenyl)-2-(3-fluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 73); 2-(2-Chlorophenyl)-4-(2,4-difluorophenyl)-3-[(3-pyridyl)hydroxymethyl]thiophene (compound 74); 4-(2,4-Difluorophenyl)-2-(2-fluorophenyl)-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 Septaria 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.


25.    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 said 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 thereofto 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 Ia:

R    S    R

~••R,

Ia

wherein:

RisH;

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, 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;

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;

~ is H; acyl (e.g., acetyl, benzoyl, phenylacetyl); haloacyl; alkoxycarbonyl; aryloxycarbonyl; alkylaminocarbonyl; or dialkylaminocarbonyl;
said method comprising:

(a) reacting an acetylenethiolate of formula II


where R1 is as given above with an acetylenic ketone of formula IIl:


where R2  and R3  are as given above in an inert solvent to produce a compound of

formula IV,
and then:

(b) reducing said compound of Formula IV to produce said compound of

Formula Ia

(R=H).


29. The method of claim 28, wherein said reducing step is carried out with

LiAl~ in an inert solvent or with NaB~ in an alcoholic solvent.

Newsletter

Join our newsletter for CIPIT news through subscriptions!

SEND

Social Media

    

Contact Us

TEL : (254) 703 034 612