GB2327676A - Imidazoline-5-one compounds as anti-fungal agents - Google Patents

Imidazoline-5-one compounds as anti-fungal agents Download PDF

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GB2327676A
GB2327676A GB9816117A GB9816117A GB2327676A GB 2327676 A GB2327676 A GB 2327676A GB 9816117 A GB9816117 A GB 9816117A GB 9816117 A GB9816117 A GB 9816117A GB 2327676 A GB2327676 A GB 2327676A
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optionally substituted
c6h4ch2
c6h3ch2
alkyl
compound
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Brian Leslie Pilkington
Sally Elizabeth Russell
Alan John Whittle
William Roderick Mound
Michael Drysdale Turnbull
Anthony Marian Kozakiewicz
David John Hughes
William Guy Whittingham
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Syngenta Ltd
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Zeneca Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Compounds of formula (I) and fungicidal compositions thereof: wherein X is O, S or NH; R' is hydrogen or optionally substituted alkyl, aryl, heteroaryl, alkenyl or alkynyl; R<SP>2</SP> is optionally substituted hydrazido or hydroxylimino wherein these groups may form part of a ring, e.g. 1,2-diazolidine or 1,2-oxazolidine; R<SP>5</SP> is NH, NR<SP>11</SP> or NC(=O)R<SP>11</SP> and all other R groups comprise standard substituents, e.g. hydrogen, cyano or optionally substituted alkyl, alkoxy, thoialkyl, aryl, heteroaryl, alkenyl or alkynyl; processes for preparing said compounds, fungicidal compositions comprising them and methods of using them to combat fungi, especially fungal infections of plants.

Description

CHEMICAL COMPOUNDS The present invention relates to imidazolinone compounds, to processes for preparing them, to fungicidal compositions comprising them and to methods of using them to combat fungi, especially fungal infections of plants.
Fungicidal imidazolinone compounds are disclosed in WO 93/24467.
The present invention provides a compound of formula (I):
wherein R' is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl or optionally substituted alkynyl; R2 is R8ON=C(R') or R8HNN=C(R7); R3 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, haloalkoxy, cyano, SOAlkyl or SO2Alkyl; R4 is NH, NR6 or NC(=O)R6; R5 and R6 are, independently, hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted arylalkyl; R7 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, haloalkoxy, cyano, NR9R'0, optionally substituted aryl or optionally substituted heteroaryl; R8, R9 and R'O are, independently, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkyl, optionally substituted heteroaryl, acyl or haloacyl; or R7 and R8 join together to provide an optionally substituted 5- or 6-membered heterocyclic ring; and X is O, S or NH.
The compounds of formula a) can exist in several isomeric forms. This invention covers all such isomers and mixtures thereof in all proportions.
Halogen includes fluorine, chlorine, bromine and iodine.
Optionally substituted 5- or 6-membered heterocyclic ring includes rings containing two or three heteroatoms selected from the list comprising oxygen, nitrogen and sulphur with optional substituents including optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl.
Optionally substituted alkyl is, for example, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, cyanoalkyl or cycloalkylalkyl.
Alkyl moieties, and the alkyl moiety of alkoxy, haloalkoxy, alkylthio, haloalkyl, cycloalkylalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxyalkyl and optionally substituted heteroaryloxyalkyl, preferably contain from 1 to 6, more preferably from 1 to 4, carbon atoms. They can be in the form of straight or branched chains, for example methyl, ethyl, n- or iso-propyl, or n-, sec-, iso- or tert-butyl.
Cycloalkyl is preferably C34 cycloalkyl (such as cyclopentyl or cyclohexyl).
Haloalkyl moieties are preferably fluoroalkyl (for example, trifluoromethyl) or chloroalkyl moieties.
Haloalkoxy moieties are preferably fluoroalkoxy (for example trifluoromethoxy) or chloroalkoxy moieties.
Alkenyl and alkynyl moieties preferably contain from 2 to 6, more preferably from 2 to 4, carbon atoms. They can be in the form of straight or branched chains, and the alkenyl moieties, where appropriate, can be of either the (D- or ( > -configuration. Examples are vinyl, allyl and propargyl. Optional substituents on alkenyl or alkynyl include halogen, aryl or heteroaryl.
Acyl moieties are preferably alkanoyl (preferably containing from 1 to 6 carbon atoms, for example acetyl) or optionally substituted benzoyl (wherein the phenyl ring is optionally substituted as described below for aryl).
Haloacyl moieties are preferably fluoroacyl (for example, trifluoroacetyl) or chloroacyl moieties.
Aryl includes naphthyl but is preferably phenyl.
Heteroaryl includes 5- and 6-membered aromatic rings containing one, two, three or four heteroatoms selected from the list comprising oxygen, sulphur and nitrogen and can be fused to optionally substituted benzenoid ring systems. Examples of heteroaryl are pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl (1,2,3-, 1,2,4- and 1,3,5-), furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl (1,2,3- and 1,2,4-), tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, indolinyl, isoindolinyl, benzoxazolyl, benzofuryl, benzothienyl and benzimidazolinyl.
Substituents which may be present in optionally substituted benzenoid ring systems include halogen C1-4 alkyl or halo(C1-4)alkyl.
The alkyl moiety of arylalkyl, heteroarylalkyl, aryloxyalkyl and heteroaryloxyalkyl is optionally substituted with C1-6 alkoxy, optionally substituted aryl or optionally substituted heteroaryl. Arylalkyl is, for example, aryl(C1-4)alkyl (such as phenyl(C14)alkyl) and heteroarylalkyl is, for example, heteroaryl(C1-4)alkyl (such as pyridinyl(C1-4)alkyl or pyrimidinyl(C1-4)alkyl). Phenyl(C1-4)alkyl is especially benzyl, 1-phenyleth-1-yl or 2-phenylprop-2-yl.
Substituents which may be present in any optionally substituted aryl or heteroaryl ring include one or more of the following: halogen, hydroxy, mercapto, oxo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C2-5 alkenyloxy, C2-5 alkynyloxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, C1-4 alkylthio, halo(C1-4)alkylthio, hydroxy(C1-4)alkyl, C1-4 alkoxy(C1-4)alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl(C1-4)alkyl, phenyl, phenoxy, acyl, SF5, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR'R", -CONR'R", -COOR', -SOR', -SO2R', -(C1-6)alkyl SO2R', -SO2(C3-6)alkenyl, -OSO2R', -NHSO2R', -SO2NR'R", -COR', -CR'=NR", -CR'=NOR" or -N=CR'R"; two substituents, when they are in adjacent positions on the aryl or heteroaryl ring can join to form a fused aliphatic ring (especially to form a fused 6-membered carbon aliphatic ring); R' and R" are independently hydrogen, C1-4 alkyl, C1-4alkoxy, C1-4 alkylthio, C3-6 cycloalkyl, C3-6 cycloalkyl(C1-4)alkyl, acyl, phenyl or benzyl; the phenyl, phenoxy and benzyl groups being optionally substituted with halogen, C1-4 alkyl, halo(C1-4)alkyl, CIA alkoxy C1-4 haloalkoxy; when R' and R" are in -NR'R", -CONR'R", -NHCONR'R" or -SO2NR'R" they can together form a 5- or 6-membered heterocyclic ring (for example a pyrrole, imidazole, pyrrolidine, piperidine or morpholine ring).
In one particular aspect, the present invention provides a compound of formula (I) wherein R' is hydrogen or C1-4 alkyl (especially methyl); R3 is C1-4 alkylthio (especially methylthio) or C1-4 alkoxy (especially methoxy); R4 is NH; Ras is optionally substituted phenyl (especially unsubstituted phenyl); and X is oxygen.
In another aspect, the present invention provides a compound of formula (I) wherein Rl is hydrogen or C14 alkyl (especially methyl); R2 is R80N=C(R7); R3 is C14 alkylthio (especially methylthio) or C14 alkoxy (especially methoxy); R4 is NH; R5 is optionally substituted phenyl (especially unsubstituted phenyl); R7 is hydrogen or C,4 alkyl (especially methyl or ethyl); R8 is C14 alkyl, C24 alkenyl, optionally substituted phenyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted phenyl(C,4)alkyl, optionally substituted pyridinyl(C,4)alkyl, optionally substituted pyrimidinyl(C,4)alkyl, optionally substituted oxazolyl(C 14)alkyl, optionally substituted isoxazolyl(C1-4)alkyl, optionally substituted thiazolyl(C14)alkyl or optionally substituted isothiazolyl(C14)alkyl (the foregoing aryl and heteroaryl rings being optionally substituted with one or more of cyano, halogen, nitro, C14 alkyl, C,4 alkoxy, C14 alkylthio, C14 haloalkyl (for example CF3) or C, 4 haloalkoxy (for example OCF3)); and X is oxygen.
In a further aspect, the present invention provides a compound of formula (I) wherein Rl is C,4 alkyl (especially methyl); R2 is RSON=C(R7) or R8HNN=C(R7); R3 is C14 alkylthio (especially methylthio) or C14 alkoxy (especially methoxy); R4 is NH; R5 is optionally substituted phenyl (especially unsubstituted phenyl); R7 is hydrogen, C14 alkyl (especially methyl or ethyl) or phenyl; R8 is C1-4 alkyl, C24 alkenyl, optionally substituted phenyl, optionally substituted benzyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyridinyl(C14)alkyl or optionally substituted pyrimidinyl (C14)alkyl (the foregoing aryl and heteroaryl rings preferably being substituted with one or more of cyano, halogen, nitro, C14 alkyl (for example methyl), C14 alkoxy (for example OCH3) or C14 haloalkyl (for example CF3)); and X is oxygen. It is preferred that R2 is RSON=C(R7).
Table Ia provides examples of compounds of formula (I) wherein Rl is methyl; R3 is CH3S; R4 is NH; R5 is phenyl; X is oxygen; and R2 is R8ON=C(R7) wherein R7 and R8 are as defined in the Table.
Table Ia
Compound Number R7 R 1 H H 2 H CH3 3 H CH3CH2 4 H CH3CH2CH2 5 H (CH,XCH 6 H CH3CH2CH2CH2 7 H (CH3)2CHCH2 8 H CH3OCH2CH2
9 H C6H5OCH2CH2 10 H CH3O2CCH2 11 H CH2=CH-CH2 12 H CH3CH=CH-CH2 13 H C6H5CH=CHCH2 14 H (5-pyrimidinyl)CH=CHCH2 15 H CH#CCH2 16 H CH3C#CCH2 17 H C6H5 18 H 2-CN-C6H4 19 H 3-CN-C6H4 20 H 4-CN-C6H4 21 H 2-Br-C6H4 22 H 3-Br-C6H4 23 H 4-Br-C6H4 24 H 2-Cl-C6H4 25 H 3-Cl-C6H4 26 H 4-Cl-C6H4 27 H 2-F-C6H4 28 H 3-F-C6H4 29 H 4-F-C6H4 30 H 2-NO2-C6H4 31 H 3-NO2-C6H4 32 H 4-NO2-C6H4 33 H 2-CH3-C6H4 34 H 3-CH3-C6H4 35 H 4-CH3-C6H4 36 H 2-CH3O-C6H4 37 H 3-CH3O-C6H4 38 H 4-CH3O-C6H4 39 H 2-CH3S-C6H4 40 H 3-CH3S-C6H4 41 H 4CH3S-C6H4 42 H 2,3-diF-C6H3 43 H 2,4-diF-C6H3 44 H 2,5-diF-C6H3 45 H 2,6-diF-C6H3 46 H 3,4-diF-C6H3 47 H 3,5-diF-C6H3 48 H 2,3-diCl-C6H3 49 H 2,4-diCl-C6H3 50 H 2,5-diCl-C6H3 51 H 2,6-diCl-C6H3
52 H 3,4-diCl-C6H3 53 H 3,5diCl-C6H3 54 H 2-Cl-3-F-C6H3 55 H 2-F-3-Cl-C6H3 56 H 2-Cl-4-F-C6H3 57 H 2-F-4-Cl-C6H3 58 H 2-C1-5-F-C6H3 59 H 2-F-5-Cl-C6H3 60 H 2-Cl-6-F-C6H3 61 H 3-Cl-4-F-C6H3 62 H 3-F-4-Cl-C6H3 63 H 3-Cl-5-F-C6H3 64 H 2-Br-3-F-C6H3 65 H 2-F-3-Br-C6H3 66 H 2-Br-4-F-C6H3 67 H 2-F-4-Br-C6H3 68 H 2-Br-5-F-C6H3 69 H 2-F-5-Br-C6H3 70 H 2-Br-6-F-C6H3 71 H 3-Br-4-F-C6H3 72 H 3-F-4-Br-C6H3 73 H 3-Br-5-F-C6H3 74 H C6H5CH2 75 H 2-CH3-C6H4CH2 76 H 3-CH3-C6H4CH2 77 H 4-CH3-C6H4CH2 78 H 2-CH3CH2-C6H4CH2 79 H 3-CH3CH2-C6H4CH2 80 H 4-CH3CH2-C6H4CH2 81 H 2-(CH3)2CH-C6H4CH2 82 H 3-(CH3)2CH-C6H4CH2 83 H 4-(CH3)2CH-C6H4CH2 84 H 2-(CH3)3C-C6H4CH2 85 H 3-(CH3)3C-C6H4CH2 86 H 4-(CH3)3C-C6H4CH2 87 H 2-CF3-C6H4CH2 88 H 3-CF3-C6H4CH2 89 H 4-CF3-C6H4CH2 90 H 2,3-diCF3-C6H3CH2 91 H 2,4-diCF3-C6H3CH2 92 H 2,5 diCF3-C6H3CH2 93 H 2,6-diCF3-C6H3CH2 94 H 3,4-diCF3-C6H3CH2
95 H 3,5-diCF3-C6H3CH2 96 H 2-(CH3SO2CH2)-C6H4CH2 97 H 3-(CH3SO2CH2)-C6H4CH2 98 H 4-(CH3SO2CH2)-C6H4CH2 99 H 2-(C6H5SO2CH2)-C6H4CH2 100 H 3-(C6H5SO2CH2)-C6H4CH2 101 H 4-(C6H5SO2CH-C6H4CH2 102 H 2-NO2-C6H4CH2 103 H 3-NO2-C6H4CH2 104 H 4-NO2-C6H4CH2 105 H 2-CH3O-CJI4CH2 106 H 3-CH3O-C6H4CH2 107 H 4-CH3O-C6H4CH2 108 H 2-CH3O-5-NO2-C6H3CH2 109 H 2-NO2-4,5-diCH3O-C6H2CH2 110 H 2-CHF2O-C6H4CH2 111 H 3-CHF2O-C6H4CH2 112 H 4-CHF2O-C6H4CH2 113 H 2-CF3O-C6H4CH2 114 H 3-CF3O-C6H4CH2 115 H 4-CF3O-C6H4CH2 116 H 2-CH3S-C6H4CH2 117 H 3-CH3S-C6H4CH2 118 H 4-CH3S-C6h4CH2 119 H 2-CH3SO2-C6H4CH2 120 H 3-CH3SO2-C6H4CH2 121 H 4-CH3SQ-C6H,CH2 122 H 2-CH3NHSO2-C6H4CH2 123 H 3-CH3NHSO2-C6H4CH2 124 H 4-CH3NHSO2-C6H4CH2 125 H 2-CN-C6H4CH2 126 H 3-CN-C6H4CH2 127 H 4-CN-C6H4CH2 128 H CH3O2CC6H4CH2 129 H (CH3)3CCOC6H4CH2 130 H 2-F-C6H4CH2 131 H 3-F-C6H4CH2 132 H 4-F-C6H4CH2 133 H 2-C1-C6H4CH2 134 H 3-CI-C6H4CH2 135 H 4-Cl-C6H4CH2 136 H 2-Br-C6H4CH2 137 H 3-Br-C6H4CH2
138 H 4-Br-C6H4CH2 139 H 2-I-C6H4CH2 140 H 3-I-C6H4CH2 141 H 4-I-C6H4CH2 142 H 2,3-diF-C6H3CH2 143 H 2,4-diF-C6H3CH2 144 H 2,5-diF-C6H3CH2 145 H 2,6-diF-C6H3CH2 146 H 3,4 diF-C6H3CH2 147 H 3,5-diF-C6H3CH2 148 H 2,3-diCl-C6H3CH2 149 H 2,4-diCl-C6H3CH2 150 H 2,5-diCl-C6H3CH2 151 H 2,6-diCl-C6H3CH2 152 H 3,4-diCl-C6H3CH2 153 H 3,5-diCl-C6H3CH2 154 H 2-Cl-3-F-C6H3CH2 155 H 2-F-3-Cl-C6H3CH2 156 H 2-ClA-F-C6H3CH2 157 H 2-F-4-Cl-C6H3CH2 158 H 2-Cl-5-F-C6H3CH2 159 H 2-F-5-Cl-C6H3CH2 160 H 2-Cl-6-F-C6H3CH2 161 H 3-Cl-4-F-C6H3CH2 162 H 3-F4-Cl-C6H3CH2 163 H 3-Cl-5-F-C6H3CH2 164 H 2-Br-3-F-C6H3CH2 165 H 2-F-3-Br-C6H3CH2 166 H 2-Br-4-F-C6H3CH2 167 H 2-F-4-Br-C6H3CH2 168 H 2-Br-5-F-C6H3CH2 169 H 2-F-5-Br-C6H3CH2 170 H 2-Br-6-F-C6H3CH2 171 H 3-Br4-F-C6H3cH2 172 H 3-F-4-Br-C6H3CH2 173 H 3-Br-5-F-C6H3CH2 174 H 2-I-3-F-C6H3CH2 175 H 2-F-3-I-C6H3CH2 176 H 2-I-4-F-C6H3CH2 177 H 2-F-4-I-C6H3CH2 178 H 2-I-5-F-C6H3CH2 179 H 2-F-5-I-C6H3CH2 180 H 2-I-6-F-C6H3CH2
181 H 3-I-4-F-C6H3CH2 182 H 3-F4-I-C6H3CH2 183 H 3-I-5-F-C6H3CH2 184 H 2-Br-3-Cl-C6H3CH2 185 H 2-Cl-3-Br-C6H3CH2 186 H 2-Br-4-Cl-C6H3CH2 187 H 2-Cl-4-Br-C6H3CH2 188 H 2-Br-5-Cl-C6H3CH2 189 H 2-C1-5-Br-C6H3CH2 190 H 2-Br-6-Cl-C6H3CH2 191 H 3-Br-4-Cl-C6H3CH2 192 H 3-Cl-4-Br-C6H3CH2 193 H 3-Br-5-Cl-C6H,CH2 194 H C6F5CH2 195 H 2-F-3-CH3-C6H3CH2 196 H 2-F-5-CF3-C6H3CH2 197 H 4-CF3-C6F4CH2 198 H 4-CH2=CHCH2-C6F4CH2 199 H 2-C6H5-C6H4CH2 200 H 3-C6H5-C6H4CH2 201 H 4-C6H5-C6H4CH2 202 H (C6H5)2CH 203 H (C6H5)3C 204 H 2-NH2-C6H4CH2 205 H 3-NH2-C6H4CH2 206 H 4-NH2-C6H4CH2 207 H 2-CH3SO2NH-C6H4CH2 208 H 3-CH3SO2NH-C6H4CH2 209 H 4-CH3SO2NH-C6H4CH2 210 H 1-naphthyl-CH2 211 H 2-naphthyl-CH2 212 H fiir-2-yl 213 H thien-3-yl 214 H pyridin-2-yl 215 H 6-CH3O-pyridin-2-y1 216 H 4-CF3-pyridin-2-yl 217 H 6CF3-pyridin-2-yl 218 H 6-F-pyridin-2-yl 219 H pyridin-4-yl 220 H pyrimidin-2-yl 221 H 6-CH3O-pyrimidin-4-yl 222 CH3 H 223 CH3 CH3
224 CH3 CH3CH2 225 CH3 CH3CH2CH2 226 CH3 (CH3)2CH 227 CH3 CH3CH2CH2CH2 228 CH3 (CH3)2CHCH2 229 CH3 CH3OCH2CH2 230 CH3 C6H5OCH2CH2 231 CH3 CH3O2CCH2 232 CH3 CH2=CH-CH2 233 CH3 CH3CH=CH-CH2 234 CH3 C6H5CH=CHCH2 235 CH3 (5-pyrimidinyl)CH=CHCH2 236 CH3 CH#CCH2 237 CH3 CH3C#CCH2 238 CH3 C6H5 239 CH3 2-CN-C6H4 240 CH3 3-CN-C6H4 241 CH3 4-CN-C6H4 242 CH3 2-Br-C6H4 243 CH3 3-Br-C6H4 244 CH3 4-Br-C6H4 245 CH3 2-Cl-C6H4 246 CH3 3-C1-C6H4 247 CH3 4-Cl-C6H4 248 CH3 2-F-C6H4 249 CH3 3-F-C6H4 250 CH3 4-F-C6H4 251 CH3 2-NO2-C6H4 252 CH3 3-NO2-C6H4 253 CH3 4-NO2-C6H4 254 CH3 2-CH3-C6H4 255 CH3 3-CH3-C6H4 256 CH3 4-CH3-C6H4 257 CH3 2-CH3O-C6H4 258 CH3 3-CH3O-C6H4 259 CH3 4-CH3O-C6H4 260 CH3 2-CH3S-C6H4 261 CH3 3-CH3S-C6H4 262 CH3 4-CH3S-C6H4 263 CH3 2,3-diF-C6H3 264 CH3 2,4-diF-C6H3 265 CH3 2,5-diF-C6H3 266 CH3 2,6-diF-C6H3
267 CH3 3,4-diF-C6H3 268 CH3 3,5-diF-C6H3 269 CH3 2,3-diCl-C6H3 270 CH3 2,4-diCl-C6H3 271 CH3 2,5-diCl-C6H3 272 CH3 2,6-diCl-C6H3 273 CH3 3,4-diCl-C6H3 274 CH3 3,5-diCl-C6H3 275 CH3 2-Cl-3-F-C6H3 276 CH3 2-F-3-C1-C6H3 277 CH3 2-Cl-4-F-C6H3 278 CH3 2-F-4-Cl-C6H3 279 CH3 2-Cl-5-F-C6H3 280 CH3 2-F-5-C1-C6H3 281 CH3 2-Cl-6-F-C6H3 282 CH3 3-Cl-4-F-C6H3 283 CH3 3-F-4-Cl-C6H3 284 CH3 3-Cl-5-F-C6H3 285 CH3 2-Br-3-F-C6H3 286 CH3 2-F-3-Br-C6H3 287 CH3 2-Br-4-F-C6H3 288 CH3 2-F-4-Br-C6H3 289 CH3 2-Br-5-F-C6H3 290 CH3 2-F-5-Br-C6H3 291 CH3 2-Br-6-F-C6H3 292 CH3 3-Br-4-F-C6H3 293 CH3 3-F-4-Br-C6H3 294 CH3 3-Br-5-F-C6H3 295 CH3 C6H5CH2 296 CH3 2-CH3-C6H4CH2 297 CH3 3-CH3-C6H4CH2 298 CH3 4-CH3-C6H4CH2 299 CH3 2-CH3CH2-C6H4CH2 300 CH3 3-CH3CH2-C6H4CH2 301 CH3 4-CH3CH2-C6H4CH2 302 CH3 2-(CH3)2CH-C6H4CH2 303 CH3 3-(CH3)2CH-C6H4CH2 304 CH3 4-(CH3)2CH-C6H4CH2 305 CH3 2-(CH3)3C-C6H4CH2 306 CH3 3-(CH3)3C-C6H4CH2 307 CH3 4-(CH3)3C-C6H4CH2 308 CH3 3-CF3-C6H4CH2 309 CH3 3-CF3-C6H4CH2
310 CH3 4-CF3-C6H4CH2 311 CH3 2,3-diCF3-C6H3CH2 312 CH3 2,4-diCF3-C6H3CH2 313 CH3 2,5-diCF3-C6H3CH2 314 CH3 2,6-diCF3-C6H3CH2 315 CH3 3,4-diCF3-C6H3CH2 316 CH3 3,5-diCF3-C6H3CH2 317 CH3 2-(CH3SO2CH2)-C6H4CH2 318 CH3 3-(CH3SO2CH2)-C6H4CH2 319 CH3 4-(CH3SO2CH2)-C6H4CH2 320 CH3 2-(C6H5SO2CH2)-C6H4CH2 321 CH3 3-(C6H5SO2CH2)-C6H4CH2 322 CH3 4-(C6H5SO2CH2)-C6H4CH2 323 CH3 2-NO2-C6H4CH2 324 CH3 3-NO2-C6H4CH2 325 CH3 4-NO2-C6H4CH2 326 CH3 2-CH3O-C6H4CH2 327 CH3 3-CH3O-C6H4CH2 328 CH3 4-CH3O-C6H4CH2 329 CH3 2-CH3O-5-NO2-C6H3CH2 330 CH3 2-NO2-4,5-diCH3O-C6H2CH2 331 CH3 2-CHF2O-C6H4CH2 332 CH3 3-CHF2O-C6H4CH2 333 CH3 4-CHF2O-C6H4CH2 334 CH3 2-CF3O-C6H4CH2 335 CH3 3-CF3O-C6H4CH2 336 CH3 4-CF3O-C6H4CH2 337 CH3 2-CH3S-C6H4CH2 338 CH3 3-CH3S-C6H4CH2 339 CH3 4-CH3S-C6H4CH2 340 CH3 2-CH3SO2-C6H4CH2 341 CH3 3-CH3SO2-C6H4CH2 342 CH3 4-CH3SO2-C6H4CH2 343 CH3 2-CH3NHSO2-C6H4CH2 344 CH3 3-CH3NHSO2-C6H4CH2 345 CH3 4-CH3NHSO2-C6H4CH2 346 CH3 2-CN-C6H4CH2 347 CH3 3-CN-C6H4CH2 348 CH3 4-CN-C6H4CH2 349 CH3 CH3O2CC6H4CH2 350 CH3 (CH3)3CCOC6H4CH2 351 CH3 2-F-C6H4CH2 352 CH3 3-F-C6H4CH2
353 CH3 4-F-C6H4CH2 354 CH3 2-Cl-C6H4CH2 355 CH3 3-Cl-C6H4CH2 356 CH3 4-Cl-C6H4CH2 357 CH3 2-Br-C6H4CH2 358 CH3 3-Br-C6H4CH2 359 CH3 4-Br-C6H4CH2 360 CH3 2-I-C6H4CH2 361 CH3 3-I-C6H4CH2 362 CH3 4-I-C6H4CH2 363 CH3 2,3-diF-C6H3CH2 364 CH3 2,4-diF-C6H3CH2 365 CH3 2,5-diF-C6H3CH2 366 CH3 2,6-diF-C6H3CH2 367 CH3 3,4-diF-C6H3CH2 368 CH3 3,5-diF-C6H3CH2 369 CH3 2,3-diCl-C6H3CH2 370 CH3 2,4-diCl-C6H3CH2 371 CH3 2,5-diCl-C6H3CH2 372 CH3 2,6-diCl-C6H3CH2 373 CH3 3,4-diCl-C6H3CH2 374 CH3 3,5-diCl-C6H3CH2 375 CH3 2-Cl-3-F-C6H3CH2 376 CH3 2-F-3-Cl-C6H3CH2 377 CH3 2-Cl-4-F-C6H3CH2 378 CH3 2-F-4-Cl-C6H3CH2 379 CH3 2-Cl-5-F-C6H3CH2 380 CH3 2-F-5-Cl-C6H3CH2 381 CH3 2-Cl-6-F-C6H3CH2 382 CH3 3-Cl-4-F-C6H3CH2 383 CH3 3-F-4-Cl-C6H3CH2 384 CH3 3-Cl-5-F-C6H3CH2 385 CH3 2-Br-3-F-C6H3CH2 386 CH3 2-F-3-Br-C6H3CH2 387 CH3 2-Br-4-F-C6H3CH2 388 CH3 2-F-4-Br-C6H3CH2 389 CH3 2-Br-5-F-C6H3CH2 390 CH3 2-F-5-Br-C6H3CH2 391 CH3 2-Br-6-F-C6H3CH2 392 CH3 3-Br-4-F-C6H3CH2 393 CH3 3-F-4-Br-C6H3CH2 394 CH3 3-Br-5-F-C6H3CH2 395 CH3 2-I-3-F-C6H3CH2
396 CH3 2-F-3-I-C6H3CH2 397 CH3 2-I-4-F-C6H3CH2 398 CH3 2-F-4-I-C6H3CH2 399 CH3 2-I-5-F-C6H3CH2 400 CH3 2-F-5-I-C6H3CH2 401 CH3 2-I-6-F-C6H3CH2 402 CH3 3-I-4-F-C6H3CH2 403 CH3 3-F-4-I-C6H3CH2 404 CH3 3-I-5-F-C6H3CH2 405 CH3 2-Br-3-Cl-C6H3CH2 406 CH3 2-Cl-3-Br-C6H3CH2 407 CH3 2-Br-4-Cl-C6H3CH2 408 CH3 2-Cl-4-Br-C6H3CH2 409 CH3 2-Br-5-Cl-C6H3CH2 410 CH3 2-Cl-5-Br-C6H3CH2 411 CH3 2-Br-6-Cl-C6H3CH2 412 CH3 3-Br-4-Cl-C6H3CH2 413 CH3 3-Cl-4-Br-C6H3CH2 414 CH3 3-Br-5-Cl-C6H3CH2 415 CH3 C6F5CH2 416 CH3 2-F-3-CH3-C6H3CH2 417 CH3 2-F-5-CF3-C6H3CH2 418 CH3 4-CF3-C6F4CH2 419 CH3 4-CH2=CHCH2-C6F4CH2 420 CH3 2-C6H5-C6H4CH2 421 CH3 3-C6H5-C6H4CH2 422 CH3 4-C6H5-C6H4CH2 423 CH3 (C6H5)2CH 424 CH3 (C6H5)3C 425 CH3 2-NH2-C6H4CH2 426 CH3 3-NH2-C6H4CH2 427 CH3 4-NH2-C6H4CH2 428 CH3 2-CH3SO2NH-C6H4CH2 429 CH3 3-CH3SO2NH-C6H4CH2 430 CH3 4-CH3SO2NH-C6H4CH2 431 CH3 1-naphthyl-CH2 432 CH3 2-naphthyl-CH2 433 CH3 fur-2-yl 434 CH3 thien-3-yl 435 CH3 pyridin-2-yl 436 CH3 6-CH3O-pyridin-2-yl 437 CH3 4-CF3-pyridin-2-yl 438 CH3 6-CF3-pyridin-2-yl
439 | CH3 6-F-pyridin-2-yl 440 CH3 pyridin-4-yl 441 CH3 pyrimidin-2-yl 442 CH3 6-CH3O-pyrimidin-4-yl 443 C6H5 H 444 C6115 CH3 445 C6H5 CH3CH2 446 C6115 CH3CH2CH2 447 C6H5 (CH3)2CH 448 C6H5 - CH3CH2CH2CH2 449 C6H5 (CH3)2CHCH2 450 C6H5 CH3OCH2CH2 451 C6H5 C6H5OCH2CH2 452 C6115 CM3O2CCM, 453 C6H5 CH2=CH-CH2 454 C6H5 CH3CH=CH-CH2 455 C6H5 C6H5CH=CHCH2 456 C6H5 (5-pyrimidinyl)CH=CHCH2 457
482 C6H5 3-CH3S-C6H4 483 C6H5 4-CH3S-C6H4 484 C6H5 2,3-diF-C6H3 485 C6H5 2,4-diF-C6H3 486 C6H5 2,5-diF-C6H3 487 C6H5 2,6-diF-C6H3 488 C6H5 3,4-diF-C6H3 489 C6H5 3,5-diF-C6H3 490 C6H5 2,3-diCl-C6H3 491 C6H5 2,4-diCl-C6H3 492 C6H5 2,5-diCl-C6H3 493 C6H5 2,6-diCl-C6H3 494 C6H5 3,4-diCl-C6H3 495 C6H5 3,5-diCl-C6H3 496 C6H5 2-Cl-3-F-C6H3 497 C6H5 2-F-3-Cl-C6H3 498 C6H5 2-Cl-4-F-C6H3 499 C6H5 2-F-4-Cl-C6H3 500 C6H5 2-Cl-5-F-C6H3 501 C6H5 2-F-5-Cl-C6H3 502 C6H5 2-Cl-6-F-C6H3 503 C6H5 3-Cl-4-F-C6H3 504 C6H5 3-F-4-Cl-C6H3 505 C6H5 3-Cl-5-F-C6H3 506 C6H5 2-Br-3-F-C6H3 507 C6H5 2-F-3-Br-C6H3 508 C6H5 2-Br-4-F-C6H3 509 C6H5 2-F-4-Br-C6H3 510 C6H5 2-Br-5-F-C6H3 511 C6H5 2-F-5-Br-C6H3 512 C6H5 2-Br-6-F-C6H3 513 C6H5 3-Br-4-F-C6H3 514 C6H5 3-F-4-Br-C6H3 515 C6H5 3-Br-5-F-C6H3 516 C6H5 C6H5CH2 517 C6H5 2-CH3-C6H4CH2 518 C6H5 3-CH3-C6H4CH2 519 C6H5 4-CH3-C6H4CH2 520 C6H5 2-CH3CH2-C6H4CH2 521 C6H5 3-CH3CH2-C6H4CH2 522 C6H5 4-CH3CH2-C6H4CH2 523 C6H5 2-(CH3)2CH-C6H4CH2 524 C6H5 3-(CH3)2CH-C6H4CH2
525 C6H5 4-(CH3)2CH-C6H4CH2 526 C6H5 2-(CH3)3C-C6H4CH2 527 C6H5 3-(CH3)3C-C6H4CH2 528 C6H5 4-(CH3)3C-C6H4CH2 529 C6H5 2-CF3-C6H4CH2 530 C6H5 3-Cf3-C6H4CH2 531 C6H5 4-CF3-C6H4CH2 532 C6H5 2,3-diCF3-C6H3CH2 533 C6H5 2,4-diCF3-C6H3CH2 534 C6H5 2,5-diCF3-C6H3CH2 535 C6H5 2,6-diCF3-C6H3CH2 536 C6H5 3,4-diCF3-C6H3CH2 537 C6H5 3,5-diCF3-C6H3CH2 538 C6H5 2-(CH3SO2CH2)-C6H4CH2 539 C6H5 3-(CH3SO2CH2)-C6H4CH2 540 C6H5 4-(CH3SO2CH2)-C6H4CH2 541 C6H5 2-(C6H5SO2CH2)-C6H4CH2 542 C6H5 3-(C6H5SO2CH2)-C6H4CH2 543 C6H5 4-(C6H5SO2CH2)-C6H4CH2 544 C6H5 2-NO2-C6H4CH2 545 C6H5 3-NO2-C6H4CH2 546 C6H5 4-NO2-C6H4CH2 547 C6H5 2-CH3O-C6H4CH2 548 C6H5 3-CH3O-C6H4CH2 549 C6H5 4-CH3O-C6H4CH2 550 C6H5 2-CH3O-5-NO2-C6H3CH2 551 C6H5 2-NO2-4,5-diCH3O-C6H2CH2 552 C6H5 2-CHF2O-C6H4CH2 553 C6H5 3-CHF2O-C6H4CH2 554 C6H5 4-CHF2O-C6H4CH2 555 C6H5 2-CF3O-C6H4CH2 556 C6H5 3-CF3O-C6H4CH2 557 C6H5 4-CF3O-C6H4CH2 558 C6H5 2-CH3S-C6H4CH2 559 C6H5 3-CH3S-C6H4CH2 560 C6H5 4-CH3S-C6H4CH2 561 C6H5 2-CH3SO2-C6H4CH2 562 C6H5 3-CH3SO2-C6H4CH2 563 C6H5 4-CH3SO2-C6H4CH2 564 C6H5 2-CH3NHSO2-C6H4CH2 565 C6H5 3-CH3NHSO2-C6H4CH2 566 C6H5 4-CH3NHSO2-C6H4CH2 567 C6H5 2-CN-C6H4CH2
568 C6H% 3-CN-C6H4CH2 569 C6H5 4-CN-C6H4CH2 570 C6H5 CH3O2CC6H4CH2 571 C6H5 (CH3)3CCOC6H4CH2 572 C6H5 2-F-C6H4CH2 573 C6H5 3-F-C6H4CH2 574 C6H5 4-F-C6H4CH2 575 C6H5 2-Cl-C6H4CH2 576 C6H5 3-Cl-C6H4CH2 577 C6H5 4-Cl-C6H4CH2 578 C6H5 2-Br-C6H4CH2 579 C6H5 3-Br-C6H4CH2 580 C6H5 4-Br-C6H4CH2 581 C6H5 2-I-C6H4CH2 582 C6H5 3-I-C6H4CH2 583 C6H5 4-I-C6H4CH2 584 C6H5 2,3-diF-C6H3CH2 585 C6H5 2,4-diF-C6H3CH2 586 C6H5 2,5-diF-C6H3CH2 587 C6H5 2,6-diF-C6H3CH2 588 C6H5 3,4-diF-C6H3CH2 589 C6H5 3,5-diF-C6H3CH2 590 C6H5 2,3-diCl-C6H3CH2 591 C6H5 2,4-diCl-C6H3CH2 592 C6H5 2,5-diCl-C6H3CH2 593 C6H5 2,6-diCl-C6H3CH2 594 C6H5 3,4-diCl-C6H3CH2 595 C6H5 3,5-diCl-C6H3CH2 596 C6H5 2-Cl-3-F-C6H3CH2 597 C6H5 2-F-3-Cl-C6H3CH2 598 C6H5 2-Cl-4-F-C6H3CH2 599 C6H5 2-F-4-Cl-C6H3CH2 600 C6H5 2-Cl-5-F-C6H3CH2 601 C6H5 2-F-5-Cl-C6H3CH2 602 C6H5 2-Cl-6-F-C6H3CH2 603 C6H5 3-Cl-4-F-C6H3CH2 604 C6H5 3-F-4-Cl-C6H3CH2 605 C6H5 3-Cl-5-F-C6H3CH2 606 C6H5 2-Br-3-F-C6H3CH2 607 C6H5 2-F-3-Br-C6H3CH2 608 C6H5 2-Br-4-F-C6H3CH2 609 C6H5 2-F-4-Br-C6H3CH2 610 C6H5 2-Br-5-F-C6H3CH2
611 C6H5 2-F-5-Br-C6H3CH2 612 C6H5 2-Br-6-F-C6H3CH2 613 C6H5 3-Br-4-F-C6H3CH2 614 C6H5 3-F-4-Br-C6H3CH2 615 C6H5 3-Br-5-F-C6H3CH2 616 C6H5 2-I-3-F-C6H3CH2 617 C6H5 2-F-3-I-C6H3CH2 618 C6H5 2-I-4-F-C6H3CH2 619 C6H5 2-F-4-I-C6H3CH2 620 C6H5 2-I-5-F-C6H3CH2 621 C6H5 2-F-5-I-C6H3CH2 622 C6H5 2-I-6-F-C6H3CH2 623 C6H5 3-I-4-F-C6H3CH2 624 C6H5 3-F-4-I-C6H3CH2 625 C6H5 3-I-5-F-C6H3CH2 626 C6H5 2-Br-3-Cl-C6H3CH2 627 C6H5 2-Cl-3-Br-C6H3CH2 628 C6H5 2-Br-4-Cl-C6H3CH2 629 C6H5 2-Cl-4-Br-C6H3CH2 630 C6H5 2-Br-5-Cl-C6H3CH2 631 C6H5 2-Cl-5-Br-C6H3CH2 632 C6H5 2-Br-6-Cl-C6H3CH2 633 C6H5 3-Br-4-Cl-C6H3CH2 634 C6H5 3-Cl-4-Br-C6H3CH2 635 C6H5 3-Br-5-Cl-C6H3CH2 636 C6H5 C6F5CH2 637 C6H5 2-F-3-CH3-C6H3CH2 638 C6H5 2-F-5-CF3-C6H3CH2 639 C6H5 4-CF3-C6F4CH2 640 C6H5 4-CH2=CHCH2-C6F4CH2 641 C6H5 2-C6H5-C6H4CH2 642 C6H5 3-C6H5-C6H4CH2 643 C6H5 4-C6H5-C6H4CH2 644 C6H5 (C6H5)2CH 645 C6H5 (C6H5)3C 646 C6H5 2-NH2-C6H4CH2 647 C6H5 3-NH2-C6H4CH2 648 C6H5 4-NH2-C6H4CH2 649 C6H5 2-CH3SO2NH-C6H4CH2 650 C6H5 3-CH3SO2NH-C6H4CH2 651 C6H5 4-CH3SO2NH-C6H4CH2 652 C6H5 1-naphthyl-CH2 653 C6H5 2-naphthyl-CH2
654 C6H5 fur-2-yl 655 C6H5 thien-3-yl 656 C6H5 pyridin-2-yl 657 C6H5 6-CH3O-pyridin-2-yl 658 C6H5 4-CF3-pyridin-2-yl 659 C6115 6-CF3-pyridin-2-yl 660 C6H5 6-F-pyridin-2-yl 661 C6H5 pyridin-4-yl 662 C6H5 pyrimidin-2-yl 663 C6H5 6-CH3O-pyrimidin-4-yl 664 H fur-2-ylmethyl 665 CH3 fur-2-ylmethyl 666 C6115 fiir-2-ylmethyl 667 H thien-3-ylmethyl 668 CH3 thien-3-ylmethyl 669 C6H5 thien-3-ylmethyl 670 H 2-CH3-thiazol-4-ylmethyl 671 CH3 2-CH3-thiazol-4-ylmethyl 672 C6H5 2-CH3-thiazol-4-ylmethyl 673 H 2-C6H5-thiazol-4-ylmethyl 674 CH3 2-C6H5-thiazol-4-ylmethyl 675 C6H5 2-C6H5-thiazol-4-ylmethyl 676 H 5-CH3-isoxazol-3-ylmethyl 677 CH3 5-CM3-isoxazol-3-ylmethyl 678 C6H5 5-CH3-isoxazol-3-ylmethyl 679 H 3,5-diCH3-isoxazol-4-ylmethyl 680 CH3 3,5-diCH3-isoxazol-4-ylmethyl 681 C6H5 3,5-diCH3-isoxazol-4-ylmethyl 682 H 5-Cl-1,2,3-thiadiazol-4-ylmethyl 683 CH3 5-Cl-1,2,3-thiadiazol-4-ylmethyl 684 C6H5 5-Cl-1,2,3-thiadiazol-4-ylmethyl 685 H 5-Br-benzofur-2-ylmethyl 686 CH3 5-Br-benzofiir-2-ylmethyl 687 C6H5 5-Br-benzofur-2-ylmethyl 688 H 5-Cl-benzothien-3-ylmethyl 689 CH3 5-Cl-benzothien-3-ylmethyl 690 C6H5 5-Cl-benzothien-3-ylmethyl 691 H 6-Cl-benzoxazol-2-ylmethyl 692 CH3 6-Cl-benzoxazol-2-ylmethyl 693 C6H5 6-Cl-benzoxazol-2-ylmethyl 694 H 6-CH3-pyridin-2-ylmethyl 695 CH3 6-CH3-pyridin-2-ylmethyl 696 C6115 6-CH3-pyridin-2-ylmethyl
697 H 4-CF3-pyridin-2-ylmethyl 698 CH3 4-CF3-pyridin-2-ylmethyl 699 C6H5 4-CF3-pyridin-2-ylmethyl 700 H pyridin-4-ylmethyl 701 CH3 pyridin-4-ylmethyl 702 C6H5 pyridin-4-ylmethyl 703 H l-CH,O-6-CH,-pyrimidin-2-ylmethyl 704 CH3 4-CH3O-6-CH3-pyrimidin-2-ylmethyl 705 C6H5 4-CH3O-6-CH3-pyrimidin-2-ylmethyl 706 H pyrimidin-4-ylmethyl 707 CH3 pyrimidin-4-ylmethyl 708 C6H5 pyrimidin-4-ylmethyl 709 H 6-CH3O-pyrimidin4-ylmethyl 710 CH3 6-CH,O-pyrimidin4-ylmethyl 711 C6H5 6-CH3O-pyrimidin-4-ylmethyl 712 H 1,3-diCH3-2,6-dioxo-pyrimidin-4-ylmethyl 713 CH3 1,3 -diCH,-2,6aioxo-pyrimidin4-ylmethyl 714 C6H5 1,3-diCH3-2,6-dioxo-pyrimidin-4-ylmethyl 715 H pyrazin-2-ylmethyl 716 CH3 pyrazin-2-ylmethyl 717 C6H5 pyrazin-2-ylmethyl 718 H pyridazin-3-ylmethyl 719 CM, pyridazin-3-ylmethyl 720 C6H5 pyridazin-3-ylmethyl 721 H quinolin-2-ylmethyl 722 CH3 quinolin-2-ylmethyl 723 C6H5 quinolin-2-ylmethyl 724 H quinolin-5-ylmethyl 725 CH3 quinolin-5-ylmethyl 726 C6H5 quinolin-5-ylmethyl 727 H quinazolin-2-ylmethyl 728 CH3 quinazolin-2-ylmethyl 729 C6H5 quinazolin-2-ylmethyl 730 H quinazolin-4-ylmethyl 731 CH3 quinazolin-4-ylmethyl 732 C6H5 quinazolin-4-ylmethyl Table Ib provides 68 examples of compounds of formula (I) wherein R' is methyl; R3 is CH3S; R4 is NH; R5 is phenyl; X is oxygen; and R7 and R8 join together, therefore R2 is
wherein R7 and R8 are as defined in the Table.
Table
Compound Number -R7-R8 1 -CH2-CH(C6H5)- 2 -CH2-CH(2-CN-C6H4) 3 -CH2-CH(3-CN-C6H4) 4 -CH2-CH(4-CN-C6H4) S -CM2-CM(2-Br-C6H4)- 6 -CH2-CH(3-Br-C6H4) 7 -CH2-CH(4-Br-C6H4) 8 -CH2-CH(2-Cl-C6H4) 9 -CH2-CH(3-Cl-C6H4) 10 -CH2-CH(4-C1-C6H4)- 11 -CH2-CH(2-F-C6H4) 12 -CH2-CH(3-F-C6H4) 13 -CH2-CH(4-F-C6H4) 14 -CH2-CH(2-NO2-C6H4) 15 -CH2-CH(3-NO2-C6H4) 16 -CH2-CH(4-NO2-C6H4) 17 -CH2-CH(2-CH3-C6H4) 18 -CH2-CH(3-CH3-C6H4) 19 -CH2-CH(4-CH3-C6H4) 20 -CH2-CH(2-CH3O-C6H4) 21 -CH2-CH(3-CH3O-C6H4) 22 -CH2-CH(4-CH3O-C6H 23 -CH2-CH(2-CH3S-C6H4) 24 -CH2-CH(3-CH3S-C6H4) 25 -CH2-CH(4-CH3S-C6H4)- 26 -CH2-CH(2,3-diF-C6H3) 27 -CH2-CH(2,4-diF-C6H3) 28 -CH2-CH(2,5-diF-C6H3)- 29 -CH2-CH(2,6-diF-C6H3)- 30 -CH2-CH(3,4-diF-C6H3) 31 -CH2-CH(3,5-diF-C6H3) 32 -CH2-CH(2,3-diCl-C6H3) 33 -CH2-CH(2,4-diCl-C6H3)
34 -CH2-CH(2,5-diCl-C6H3) 35 -CH2-CH(2,6-diCl-C6H3) 36 -CH2-CH(3,4-diCl-C6H3) 37 -CH2-CH(3,5-diCl-C6H3) 38 -CH2-CH(2-Cl-3-F-C6H3) 39 -CH2-CH(2-F-3-Cl-C6H3) 40 -CH2-CH(2-Cl-4-F-C6H3) 41 -CH2-CH(2-F-4-Cl-C6H3) 42 -CH2-CH(2-Cl-5-F-C6H3) 43 -CH2-CH(2-F-5-Cl-C6H3) 44 -CH2-CH(2-Cl-6-F-C6H3) 45 -CH2-CH(3-Cl-4-F-C6H3) 46 -CH2-CH(3-F-4-Cl-C6H3) 47 -CM2-CH(3-C1-5-F-CEM3)- 48 -CH2-CH(2-Br-3-F-C6H3) 49 -CH2-CH(2-F-3-Br-C6H3) 50 -CH2-CH(2-Br-4-F-C6H3) 51 -CH2-CH(2-F-4-Br-C6H3) 52 -CH2-CH(2-Br-5 -F-C6H3)- 53 -CH2-CH(2-F-5-Br-C6H3) 54 -CH2-CH(2-Br-6-F-C6H3) 55 -CH2-CH(3-Br-4-F-C6H3) 56 -CH2-CH(3-F-4-Br-C6H3) 57 -CH2-CH(3-Br-5-F-C6H3)- 58 -CH2-CH(2-NH2-C6H4) 59 -CM,-CM(3 -NH2-C6M4)- 60 -CH2-CH(4-NH2-C6H4) 61 -CH2-CH(4-C6H5O-C6H4) 62 -CH2-CH(fur-2-yl) 63 -CH2-CH(thien-3-yl) 64 -CH2-CH($CH3-thiazol-5-yl} 65 -CM,-CH(pyridin-2-yl)- 66 -CH2-CH(pyrimidin-4-yl) 67 -CH2-CH(pyrazin-2-yl) 68 -CH2-CH(quinolin-2-yl)- Table Ila Table IIa provides 732 examples of compounds of formula (I) wherein R' is methyl; R3 is CH3S; R4 is NH; R5 is phenyl; X is oxygen; and R2 is R8HNN=C(R7) wherein the values of R7 and R8 match the correspondingly numbered compounds in Table Ia.
Table IIb Table lIb provides 68 examples of compounds of formula (I) wherein Rl is methyl; R3 is CH3S; R4 is NH; R5 is phenyl; X is oxygen; and R7 and Rejoin together such that R2 is
wherein the values of R7 and R8 match the correspondingly numbered compounds in Table Ib.
Table IIIa Table IIIa provides 732 examples of compounds of formula (I) wherein R' is methyl; R3 is CH3O; R4 is NH; R5 is phenyl; X is oxygen; and R2 is R8ON=C(R7) wherein the values of R7 and R8 match the correspondingly numbered compounds in Table Ia.
Table IIIb Table IIIb provides 68 examples of compounds of formula (I) wherein R' is methyl; R3 is CH3O; R4 is NH; R5 is phenyl; X is oxygen; and R7 and R8 join together such that R2 is
wherein the values of R7 and R8 match the correspondingly numbered compounds in Table Ib.
Table IVa Table IVa provides 732 examples of compounds of formula (I) wherein R' is methyl; R3 is CH30; R4 is NH; R5 is phenyl; X is oxygen; and R2 is R8HNN=C(R7) wherein the values of R7 and R8 match the correspondingly numbered compounds in Table Ia.
Table-l;Vb Table IVb provides'68 examples of compounds of formula (I) wherein R' is methyl; R3 is CH3O; R4 is NH; R5 is phenyl; X is oxygen; and R7 and R8 join together such that R2 is
wherein the values of R7 and R8 match the correspondingly numbered compounds in Table Ib.
The following abbreviations are used throughout this description: mp = melting point ppm = parts per million s = singlet br = broad d = doublet dd = doublet of doublets t = triplet dt = doublet of triplets q= quartet m= multiplet 2s = two singlets (due to isomers) 2d = two doublets (due to isomers) 2t = two triplets (due to isomers) MW = Molecular weight Table V shows selected melting point and selected NMR data, all with CDCl3 as the solvent, (no attempt is made to list every absorption in all cases) for compounds of Tables Ia, Ib, IIa, IIb, IIIa, IIIb, IVa and IVb.
Table V
Compound No Melting NMR proton shifts (/ppm). Isomers (Table No) point (PC) 1 (Ia) 1.62(3H,s); 2.51(3H,s); 6.21(1H,s); One 6.76(2H,d); 6.99(1H,t); 7.26(2H,t); isomer 7.46(1H,s); 7.73(1H,s). E 2 (Ia) 1.61(3H,s); 2.51(3H,s); 3.89(3H,s); One 6.14(1H,s); 6.80(2H,d); 6.99(1H,t); | isomer 7.27(2H,t); 7.37(1H,s). E 3 (Ia) 1.25(3H,t); 1.61(3H,s); 2.52(3H,s); One 4.12(2H,q); 6.18(1H,s); 6.80(2H,d); | isomer 6.99(1M,t); 7.26(2H,t); 7.38(1H,s). E 9 (Ia) 1.61(3H,s); 2.51(3H,s); 4.18(2H,t); One 4.42(2H,t); 6.16(1H,s); 6.78(2H,d); isomer 6.84(6H,m); 7.25(2H,m); 7.43(1H,s).
10 (Ia) 4.66(2H,s). One isomer E 11 (Ia) 1.61(3H,s); 2.50(3H,s); 4.59(2H,m); One 5.19-5.34(2H,m); 5.90-6.05(1H,m); | isomer 6.31(1H,s); 6.77(2H,d); 6.97(1H,t); E 7.23(2H,m); 7.40(1H,s).
11 (Ia) 4.44-4.65(2H,m). One isomer Z
13 (Ia) 1.60(3H,s); 2.48(3H,s); 4.62(1H,dd); One 4.75(1H,dd); 5.89(1H,s); 6.27(1H,dt); isomer 6.54-6.68(3H,m); 6.83(1H,s): EE 6.89(1H,m): 7.19(2H,t); 7.28 7.47(5H,m); 14 (Ia) 1.62(3H,s); 2.52(3H,s); 4.78(2H,d); 22:3 6.18(1H,s); 6.47-6.53(2H,m); EE:ZE 6.79(2H,d); 6.99(1H,t); 7.25(2H,m); 7.45(1H,s); 8.73(2H,s); 9.09(1H,s).
15 (Ia) 1.62(3H,s); 2.49(1H,t); 2.52(3H,s); One 4.69(2H,d); 6.26(1H,s); 6.79(2H,d); isomer 6.99(1H,t); 7.27(2H,m); 7.44(1H,s). E 17 (Ia) 1.71(3H,s); 2.52(3H,s); 6.17(1H,s); One 6.82(2H,d); isomer 6.95-7.09(2H,m); 7.10-7.16(2H,m); | E 7.19-7.35(4H,m); 7.74(1H,s).
17 (IIIa) 1.71(3H,s); 4.05(3H,s); 6.09(1H,s); One 6.80(2H,d); 6.99(1H,t); 7.01(1H,t); isomer 7.13(2H,dd); 7.19-7.33(4H,m); E 7.75(1H,s).
20 (Ia) 1.71(3H,s); 2.53(3H,s); 6.80(2H,s); One 7.01(1H,t); 7.19(2H,dt); 7.24(2H,t); isomer 7.58(2H,dt); 7.79(1M,s). E 21 (Ia) 109.5- 1.71(3H,s); 2.53(3H,s); 6.17(1H,br.s); One 110.5 | 6.82(2H,d); 6.91(1H,dt); 6.99(1H,t); | isomer 7.18-7.30(2H,m); 7.22(2H,dt); E 7.36(1H,dd); 7.51(1H,dd); 7.89(1H,s).
42 (Ia) 144-145 1.71 & 1.82(3H,2s); 2.53 & 2.54(3H,2s); 2:1 6.23 & 6.27(1H,2s); E:Z 6.74 & 6.80(1H,2d); 6.85(1H,dt); 6.99 & 7.01(1H,2t); 7.16(1H,m); 7.23 & 7.29(2H,2t); 7.83(1H,s).
74 (Ia) 1.61(3H,s); 2.51(3H,s); 5.11(2H,s); One 6.17(1H,s); 6.77(2H,d); 6.98(1H,t); isomer 7.23(2H,t); 7.34(5H,m); 7.42(1H,s). E 75 (Ia) 5.14(2H,s).
76 (Ia) 5.08(2H,s).
77 (Ia) 1.62(3H,s); 2.35(3H,s); 2.52(3H,s); One 5.08(2H,s); 6.19(1H,s); 6.79(2H,d); isomer 6.99(1H,t); 7.13-7.31(6H,m); E 7.42(1H,s).
83 (Ia) 5.09(2H,s).
86 (Ia) 5.09(2H,s).
87 (Ia) 5.33(2H,s).
88 (Ia) 5.15(2H,s).
89 (Ia) 5.15(2H,s). One isomer E 91 (Ia) 5.37(2H,s).
99 (Ia) 4.95(2H,s).
102 (Ia) 5.53(2H,s).
104 (Ia) 1.62(3H,s); 2.52(3H,s); 5.19(2H,s); One 6.17(1H,s); 6.76(2H,d); 6.99(1H,t); isomer 7.21(2H,d); 7.47(1H,s); 7.49(2H,d); E 8.21(2H,d).
108 (Ia) 5.28(2H,s).
109 (Ia) 5.53(2H, ABq) One isomer B 110 (Ia) 5.19(2H,s).
112 (Ia) 5.08(2H,s).
113 (Ia) 5.20(2H,s).
114 (Ia) 5.10(2H,s).
115 (Ia) 5.10(2H,s).
121 (Ia) 5.19(2H,s).
125 (Ia) 5.29(2H,s).
126 (Ia) 5.10(2H,s).
127 (Ia) 5.15(2H,s).
128 (Ia) 5.17(2H,s).
129 (Ia) 5.12(2H,s).
130 aa) 5.19(2H,s).
131 (Ia) 5.10(2H,s).
132 (Ia) 5.07(2H,s).
133 (Ia) 5.22(2H,s).
134 (Ia) 5.07(2H,s).
135 (Ia) 1.62(3H,s); 2.52(3H,s); 5.08(2H,s); One 6.18(1H,s); 6.78(2H,d); 6.99(1H,t); isomer 7.18-7.36(6H,m); 7.42(1H,s). E
136 (Ia) 5.20(2H,s).
140 (Ia) 5.03(2H,s).
143 (Ia) 5.10(2H,s).
144 (Ia) 5.15(2H,s).
146 (Ia) 5.03(2H,s).
151 (Ia) 5.40(2H,s).
152 (Ia) 5.03(2H,s).
155 (Ia) 5.19(2H,s).
165 (Ia) 5.01(2H,s).
171 (Ia) 5.01(2H,s).
173 (Ia) 5.18(2H,s).
176 (Ia) 5.10(2H,s).
194 (Ia) 153.6 - 1.59(3H,s); 2.49(3H,s); 5.17(2H,m); One 154.4 6.11(1H,s); 6.72(2H,d); 6.98(1H,t); isomer 7.23(2H,t); 7.32(1H,s). E 195 (Ia) 5.17(2H,s).
196 (Ia) 5.20(2H,s).
197 (Ia) 5.22(2H,s).
198 (Ia) 5.10(2H,s); 5.20(2H,s).
199 (Ia) 5.05(2H,s).
203 (Ia) 1.47(3H,s); 2.44(3H,s); 5.96(1H,s); One 6.69(2H,d); 6.92(1H,t); 7.10(2H,m); isomer 7.20-7.32(15,m); 7.52(1H,s). E 210 (Ia) 5.56(2H,s).
211 (Ia) 5.27(2H,s).
217 (Ia) 158.0- 1.71(3H,s); 2.52(3H,s); 6.36(1H,br.s); One 161.1 6.79(2H,d); 6.99(1H,t); 7.21(2H,t); isomer 7.40(1H,d); 7.41(1H,d); 7.81(1H,t); | E 7.89(1H,s).
218 (Ia) 1.70(3H,s); 2.52(3H,s); 6.46(1H,s); One 6.62(1H,dd); 6.79(2H,d); 6.98(1H,t); isomer 7.03(1H,dd); 7.22(2H,t); 7.71(1H,q); E 7.82(1H,s).
222 (Ia) 1.60(3H,s); 1.94(3H,s); 2.49(3H,s); One 6.76(1H,br s); 6.70(2H,d); 6.94(1H,t); isomer 7.24(2H,t); 9.64(1H,br s).
223 (Ia) | | 1.59(3H,s); 1.88(3H,s); 2.50(3H,s); One 3.88(3H,s); 6.16(1H,s); 6.82(2H,d); isomer 6.99(1H,t); 7.26(2H,t).
224 (Ia) 1 .25(3M,t); 1 .59(3H,s); 1.88(3H,s); One 2.51(3H,s); 4.12(2H,q); 6.14(1H,s); isomer 6.82(2H,d); 6.98(1H,t); 7.25(2H,t).
232 (Ia) 1.59(3H,s); 1.90(3H,s); 2.50(3H,s); One 4.59(2H,dd); 5.16-5.32(2H,m); 5.91- isomer 6.08(1H,m); 6.29(1H,s); 6.81(2H,d); 6.98(1H,t); 7.25(2H,t).
238 (Ia) 1.68(3H,s); 2.12(3H,s); 2.52(3H,s); One 6.18(1H,s); 6.83(2H,d); 6.93- isomer 7.04(2H,m); 7.10-7.30(6H,m). E 238 (IIa) 1.51(3H,s); 2.08(3H,s); 2.42(3H,s); One 4.46(1H,s); isomer 6.54-6.65(3H,m); 6.86(2H,t); 6.98(1H,s); 7.18(1H,t); 7.40(2H,t); 8.00(2H,d).
241 (Ia) 1.68(3H,s); 2.15(3H,s); 2.51(3H,s); One 6.34(1H,s); 6.80(2H,d); 6.99(1H,t); isomer 7.1 9(2H,m); 7.20(2H,t); 7.54(2H,m).
242 (Ia) 1.69(3H,s); 2.22(3H,s); 2.52(3H,s); One 6.18(1H,br.s); 6.82(2H,d); isomer 6.87(1H,dt); 6.98(1H,t); 7.19(1H,dt); 7.21(2H,t); 7.37(1H,br.d); 7.50(1H,dd).
257 (Ia) 1.68(3H,s); 2.19(3H,s); 2.50(3H,s); One 3 .87(3H,s); 6.14(1H,s); 6.81(2H,d); isomer 6.82(1M,m); 6.87-7.0(3H,m); 7.18(2H,t); 7.31(1H,dd).
263 (Ia) 143.8- 1.69(3H,s); 2.19(3H,s); 2.53(3H,s); One 145.0 6.18(1H,br.s); 6.80(1H,m); isomer 6.82(2H,d); 6.90(1H,m); 6.98(1H,t); 7.10-7.31(3H,m).
295 (Ia) 1.60(3H,s); 1.90(3H,
372 (Ia) 1.54(3H,s); 1.81(3H,s); 2.50(3H,s); One 5.39(2H, ABq); 6.15(1H,br s); isomer, 6.80(2H,d); 6.99(1H,t); 7.23(5H,m). 50% pure 432 (Ia) 1.60(3H,s); 1 .92(3H,s); 2.50(3H,s); One 5.28(2H, ABq); 6.19(1H,br s); isomer 6.80(2H,d); 6.95(1H,t); 7.21(2H,t); 7.46(3H,m); 7.82(4H,m).
437 (Ia) 1.71(3H,s); 2.20(3M,s); 2.53(3M,s); One 6.23(1H,s); 6.80(2H,d); 6.98(1H,t); isomer 7.21(2H,t); 7.21(1H,d); 7.47(1H,s); 8.41(1H,d).
438 (Ia) < 80 1.69(3H,s); 2.23(3H,s); 2.51(3H,s); One 6.45(1H,br.s); 6.79(2H,d); 6.96(1H,t); isomer 7.18(2H,t); 7.38(1H,d); 7.41(1H,d); 7.76(1H,t).
439 (Ia) 162.4- 1.68(3H,s); 2.19(3H,s); 2.51(3H,s); One 163.5 6.34(1H,br.s); 6.59(1H,dd); isomer 6.80(2H,d); 6.97(1H,t); 7.02(1H,d); 7.20(2H,t); 7.68(1H,q).
667 (Ia) 138 - 141 1.63(3H,s); 2.51(3H,s); One 5.24(2H,ABq); 6.17(1H,br s); isomer 6.78(2H,d); 7.01 (3H,m); 7.26(3H,m); 7.39(1H,s).
670 (Ia) 1.60(3H,s); 2.48(3H,s); 2.70(3H,s); One 5.19(2H,s); 6.62(1H,br s); isomer 6.75(2H,d); 6.94(1H,t); 7.06(1H,s); 7.21(2H,t); 7.45(1H,s).
673 (Ia) 1.63(3H,s); 2.50(3H,s); 5.28(2H,s); One 6.30(1H,br s); 6.78(2H,d); 6.96(1H,t); isomer 7.23(3H,m); 7.42(3H,m); 7.49(1H,s); 7.94(2H,m).
676 (Ia) 1.62(3H,s), 2.39(3H,s); 2.52(3H,s); 1:1 mix 5.12(2H,s); 6.03(1H,s); 6.25(1H,br s); with 6.76(2H,d); 6.98(1H,t); 7.24(2H,t); compd.
7.44(1H,s). 1 (Ia) 679 (Ia) 1.59(3H,s); 2.25(3H,s); 2.32(3H,s); One 2.51(3H,s); 4.82(2H,ABq); isomer 6.20(1H,br s); 6.74(2H,d); 6.99(1H,t); 7.25(2H,t); 7.32(1H,s).
682 (Ia) 1.60(3H,s); 2.49(3H,s); 5.47(2H,s); One 6.27(1H,br s); 6.75(2H,d); 6.98(1H,t); | isomer 7.26(2H,t); 7.39(1H,s).
685 (Ia) 1.61(3H,s); 2.50(3H,s); 5.18(2H,s); One 6.15(1H,s); 6.66(1H,s); 6.77(2H,d); isomer 6.97(1H,t); 7.22(2H,t); 7.34(2H,m); 7.44(1H,s); 7.68(1H,d).
688 (Ia) 1.62(3H,s); 2.51(3H,s); 5.29(2H,s); One 6.21(1H,br s); 6.78(2H,d); 6.98(1H,t); isomer 7.24(2H,t); 7.33(1H,dd); 7.41(1H,s); 7.48(1H,s); 7.75(1H,d); 7.84(1H,d).
691 (Ia) 1 .60(3H,s); 2.49(3H,s); 5.32(2H,s); One 6.13(1H,br s); 6.75(2H,d); 6.96(1H,t); isomer 7.22(2H,t); 7.33(1H,dd); 7.45(1H,d); 7.72(1H,d).
703 (Ia) 1.60(3H,s); 2.42(3H,s); 2.50(3H,s); One 3.90(3H,s); 5.20(2H,s); 6.30(1H,br s); isomer 6.44(1H,s); 6.75(2H,d); 6.94(1H,t); 7.19(2H,t); 7.57(1H,s).
706 (Ia) 5.22(2H,s). 3:2 mix MW 370 and 449/451 R5=C6H5 :R5=4- Br-C6H4 712 (Ia) 1.60(3H,s); 2.50(3H,s); 3.35(3H,s); One 3.39(311,s); 4.89(2H,s); 5.80(1H,s); isomer 6.25(1H,br s); 6.75(2H,d); 6.99(1H,t); 7.25(2H,t); 7.45(1H,s).
1 (Ib) 1.71(3H,s); 2.50(3H,s); 2.88- Mixture 3.10(111,m); 3.31-3.56(111,m); 5.53- 1:1 5.64(1H,m); 6.26-6.35(1H,br m); 6.70-6.80(2H,m); 6.92-7.01(1H,m); 7.19-7.39(7H,m).
13 (Ib) 1.70(3H,s); 2.50(3H,s); 2.83- Mixture 3.07(1H,m); 3.32-3.53(1H,m);5.51- 1:1 5.62(1H,m); 6.32-6.41(1H,br m); 6.69-6.79(2H,m); 6.92-7.08(3H,m); 7.18-7.32(4H,m).
60 (Ib) 1.71(3H,s); 2.51(3H,s); 2.89- Mixture 3.09(1H,m); 3.24-3.46(1H,m); 5.45- 1:1 5.52(1 M,m); 6.40-6.47(1 H,br m); 6.60-6.67(2H,m); 6.70-6.80(2H,m); 6.92-7.01(1H,m); 7.05-7.12(2H,m); 7.16-7.31(2H,m).
61 (Ib) 1.72(3H,s); 2.51(3H,s); 2.88- Mixture 3.12(1H,m); 3.30-3.54(1H,m); 5.52- 1:1 5.63(1H,m); 6.27-6.35(1H,br m); 6.70-6.80(2H,m); 6.92-7.03(5H,m); 7.07-7.16(1H,m); 7.19-7.39(6H,m).
64 (Ib) 1.71(3H,s); 2.44(3H,s); 2.52(3H,s); Mixture 2.90-3.10(1H,m); 3.36-3.59(1H,m); 1:1 5.79-5.92(1H,m); 6.57(1H,br s); 6.71 6.80(2H,m); 6.92-7.02(1H,m); 7.18 7.30(2H,m); 8.64(1H,s).
67 (Ib) 1 .72(3H,s); 2.52(3H,s); 2.44- Mixture 2.57(1H,m); 3.32-3.66(1H,m); 5.70- 1:1 5.81(1H,m); 6A06.50(111,br m); 6.69-6.80(2H,m); 6.91-7.01(1H,m); 7.18-7.30(2H,m); 8.48-8.58(2H,m); 8.76-8.81(1H,m).
68 (Ib) 1.72(3H,s); 2.49(3H,s); 2.30- Mixture 3.68(2H,m); 5.87-5.94(1H,m); 6.47- 1:1 6.52(1H,br m); 6.70-6.80(2H,m); 6.89-7.01(1H,m); 7.15-7.29(2H,m); 7.34-7.85(4H,m); 8.00-8.07(1H,m); 8.13-8.20(1H,m).
Throughout this description, compounds are named according to the IUPAC system, with the ring atoms numbered as shown below.
The compounds of the present invention can be made using the processes below or alternatively they can be made by adapting processes disclosed in the art (for example W093/24467).
Compounds of formula (I), wherein R' is alkyl; R2 is R80N=C(R7); R3 is alkylthio; R4 is NH; R5 is optionally substituted phenyl; R7 is hydrogen, alkyl or phenyl; R8 is as defined above; and X is oxygen, can be prepared as described below. In the process schemes shown below, R is hydrogen or a substituent for R5 as defined above; and R* is hydrogen or an aryl substituent as described above. R" is optionally substituted alkyl or optionally substituted aryl as described above.
NHNH H S CS2!MeI!NaOH C02Me R1NH .HCI HoO, SOCI, HO R\k-- cs ~~~~~ MeOH AjcQMe NH2.HCI MeOH NH'zHC/ Hç Alkyl lodide 2co R' R1 R NSAkyl R (3) RS Hç 7 Hç Alkyl Iodide 1 K2CO3\ /LDA /R7CHO R1 N Alkyl HOR7N R (4) H o Compounds of formula (1) can be prepared by the method of Anthoni (Acta Chem.
Scand. 1966, vol. 20, p2742) whereby a phenyl hydrazine is reacted with iodomethane and carbon disulphide in water, in the presence of a strong base (such as sodium or potassium hydroxide). Substitution on the aryl ring of the starting phenyl hydrazine enables variation in that portion of the molecule.
The compound of formula (1) can be reacted with an amino acid ester hydrochloride (which can be prepared, for example, according to the procedure of Guttmann (Helv.
Chimica Acta, 1958, vol 16, p1852)) to give a thionoimidazolin-5-one (a compound of formula (2) or (5)). It is preferred that the reaction is carried out in an inert solvent (such as dimethylformamide) and in the presence of an organic base (such as triethylamine). The temperature of the reaction is preferably between 20"C and 1200C and it is preferred that an inert atmosphere of nitrogen or argon is employed to minimise aerial decomposition.
Since the amino acid ester hydrochloride chosen has a direct bearing on the 4substituent of the imidazolin-5-one ring, it will be appreciated that a range of different 4substituted imidazolin-5-ones can be prepared. For example, use of methyl serine as amino acid ester hydrochloride provides 4-hydroxymethyl-4-methyl thionoimidazolin-5-one, while the use of alanine provides a 4-methyl thionoimidazolin-5-one which is open to further substitution at the 4-position.
An alternative preparation of the thioimidazolinone heterocycle (2) is to adapt the work of Jefferys (J. Chem. Soc., 1954, p2227), whereby a phenyl hydrazine is reacted with an N-thiocarbamylglycine (6) (or other N-thiocarbamyl amino acid).
A compound of formula (3) or (4) can be prepared by reacting a compound of formula (2) or (5) with an alkylating agent (such as iodomethane) in the presence of an inorganic base (such as sodium or potassium carbonate) in a suitable solvent (such as acetone or tetrahydrofuran) at a temperature up to the boiling point of the solvent. It is particularly important to exclude atmospheric oxygen, by use of an inert gas such as nitrogen or argon, to prevent oxidation of the product under the alkaline conditions of the reaction.
A compound of formula (4) can also be prepared by reacting a compound of formula (3) with an aldehyde (for example formaldehyde) in the presence of a strong base (such as lithium diisopropylamide, potassium carbonate or diisopropylethylamine) in a suitable solvent (for example tetrahydrofuran or diethyl ether). The use of other aldehydes, for example acetaldehyde, in the presence of for example, potassium carbonate as base, gives rise to compounds substituted on the newly added carbon sidechain (for example a compound of formula (7)).
R' R: R1 R SAikyl N - R OH3CHO /k2CO3 NOR O HO0 (3) (7) Swem > alkyl R1N\ SAlkyl RSN 0k0% 0o Rv. H (9) (10) (8) Swern oxidation (Swern at al, Synthesis, 1981, p165 and references therein) of a compound of formula (7) provides a compound of formula (8), which when reacted with a hydroxylamine (10) gives a final compound of formula (9).
Hydroxylamines of formula (10) are commercially available; others can be prepared using the procedure of Castellino and Rapoport (JOC, 1984, vol 49, p1348), whereby a substituted phenol is reacted with 2,4-dinitrophenoxyamine, which can be prepared according to the methods of Sheradsky (J. Heterocyclic Chem., 1967, vol 4, p413) or Tamura et al (JOC, 1793, vol 38, p1239).
Other hydroxylamines (for example 6-fluoropyridylhydroxylamine) can be made (for example as shown below) by adapting these methods.
,C1 KOH / ethanoi s H CF3CO2H , > F KOH F N ethanol - F CF3CO2H F OINH, /t-'C 0 H Similarly, the compound of formula (4a) can be oxidised using Swern conditions and then reacted with a hydroxylamine (10). In this case, however, the oxidation and hydroxylamine condensation must be done in a "one pot", in situ, manner, as the aldehyde (11) is unstable and would otherwise decompose to give a compound of formula (3).
HO- Nf SAlkyl Swem N SAlkyl HO }{\N%SAIkYl Swem R 0 00NR (4a) (11) j R8 ONH2 (10) R1 N R8\OIN\ 0 N -R 0 (9a) A compound of formula (12) can be prepared by reaching a compound of formula (9b) with a base (such as potassium hydroxide) and a halide (for example bromide) of formula (13), following the method of Goya (Heterocycles; 1991, vol. 32, p279).
Halides of formula (13) are commercially available, or can be prepared by standard methods known in the literature.
A compound of formula (16), wherein Ar = aryl or heteroaryl, can be prepared by the method of Ono et al (Tetrahedron Lett. 1994, vol.35, p.4133) whereby a compound of formula (14) is reacted with a halide (for example bromide or iodide) of formula (15) in the presence of a palladium species (for example palladium diacetate) and a base (such as potassium carbonate) in a suitable solvent (such as dimethylformamide).
A compound of formula (18) can be prepared using the method of Paton (J. Chem Soc., Perkin Trans 1; 1994, p.2841), whereby a compound of formula (9c) is treated with a halogenating agent (such as N-chiorosuccinimide) in the presence of a catalytic base (for example pyridine) and then with a compound of formula (17) and a further base (for example triethylamine).
A compound of formula (I) wherein R3 is alkoxy can be prepared by reacting a compound of formula (I) wherein R3 is alkylthio, with an alkoxide (such as sodium methoxide).
In a further aspect the present invention provides processes, as hereinbefore described, for preparing a compound of formula (I) and a process for preparing a compound of formula (5) from a compound of formula (1).
In a still further aspect the present invention provides the intermediate compounds of formulae (2), (3), (4), (5), (8) and (11).
The compounds of formula (I) are active fungicides and may be used to control one or more of the following pathogens: Pyricularia oryzae (Magnaporthe grisea) on rice and wheat and other Pyricularia spp. on other hosts; Puccinia recondita, Puccinia strifformis and other rusts on wheat, Puccinia hordei, Puccinia striiformis and other rusts on barley, and rusts on other hosts (for example turf, rye, coffee, pears, apples, peanuts, sugar beet, vegetables and ornamental plants); Erysiphe cichoracearum on cucurbits (for example melon); Erysiphe graminis (powdery mildew) on barley, wheat, rye and turf and other powdery mildews on various hosts, such as Sphaerotheca macularis on hops, Sphaerotheca firliginea on cucurbits (for example cucumber), Leveillula taurica on tomatoes, aubergine and green pepper, Podosphaera leucotricha on apples and Uncinula necator on vines; Cochliobolus spp., Helminthosporium spp., Drechslera spp. (Pyrenophora spp.), Rhynchosporium spp., Mycosphaerella graminicola (Septoria tritici) and Phaeosphaeria nodorum (Stagonospora nodorum), Pseudocercosporella herpotrichoides and Gaeumannomyces gram in is on cereals (for example wheat, barley, rye), turf and other hosts; Cercospora arachidicola and Cercosporidiumpersonatum on peanuts and other Cercospora spp. on other hosts, for example sugar beet, bananas, soya beans and rice; Botrytis cinerea (grey mould) on tomatoes, strawberries, vegetables, vines and other hosts and other Botrytis spp. on other hosts; Alternaria spp. on vegetables (for example carrots), oil-seed rape, apples, tomatoes, cereals (for example wheat) and other hosts; Venturia spp. (including Venturia inaequalis (scab)) on apples, pears, stone fruit, tree nuts and other hosts; Cladosporium spp. on a range of hosts including cereals (for example wheat) and tomatoes; Monilinia spp. on stone fruit, tree nuts and other hosts; Didymella spp. on tomatoes, turf, wheat and other hosts; Phoma spp. on oil-seed rape, turf, rice, potatoes, wheat and other hosts; Aspergillus spp. and Aureobasidium spp. on wheat, lumber and other hosts; Ascochyta spp. on peas, wheat, barley and other hosts; Stemphylium spp. (Pleospora spp.) on apples, pears, onions and other hosts; summer diseases (for example bitter rot (Glomerella cingulata), black rot or frogeye leaf spot (Botryosphaeria obtusa), Brooks fruit spot (Mycosphaerella pomi), Cedar apple rust (Gymnosporangium juniperi-virginianae), sooty blotch (Gloeodes pomigena), flyspeck (Schizothyrium pomi) and white rot (Botryosphaeria dothidea)) on apples and pears; Plasmopara viticola on vines; other downy mildews, such as Bremia lactucae on lettuce, Peronospora spp. on soybeans, tobacco, onions and other hosts, Pseudoperonospora humuli on hops and Pseudoperonospora cubensis on cucurbits; Pythium spp. (including Pythium ultimum) on turf and other hosts; Phytophthora infestans on potatoes and tomatoes and other Phytophthora spp. on vegetables, strawberries, avocado, pepper, omamentals, tobacco, cocoa and other hosts; Thanatephorus cucumeris on rice and turf and other Rhizoctonia spp. on various hosts such as wheat and barley, peanuts, vegetables, cotton and turf; Sclerotinia spp. on turf, peanuts, oil-seed rape and other hosts; Sclerotium spp. on turf, peanuts and other hosts; Gibberella fujikuroi on rice; Colletotrichum spp. on a range of hosts including turf, coffee and vegetables; Laetisaria fuciformis on turf; Mycosphaerella spp. on bananas, peanuts, citrus, pecans, papaya and other hosts; Diaporthe spp. on citrus, soybean, melon, pears, lupin and other hosts; Elsinoe spp. on citrus, vines, olives, pecans, roses and other hosts; Verticillium spp. on a range of hosts including hops, potatoes and tomatoes; Pyrenopeziza spp. on oil-seed rape and other hosts; Oncobasidium theobromae on cocoa causing vascular streak dieback; Fusarium spp., Typhula spp., Microdochium nivale, Ustilago spp., Urocystis spp., Tilletia spp. and Clavicepspurpurea on a variety of hosts but particularly wheat, barley, turf and maize; Ramularia spp. on sugar beet and other hosts; post-harvest diseases particularly of fruit (for example Penicillium digitatum, Penicillium italicum and Trichoderma viride on oranges, Colletotrichum musae and Gloeosporium musarum on bananas and Botrytis cinerea on grapes); other pathogens on vines, notably Eutypa lata, Guignardia bidweliji, Phellinus igniarus, Phomopsis viticola, Pseudopeziza tracheiphila and Stereum hirsutum; other pathogens on trees (for example Lophodermium seditiosum) or lumber, notably Cephaloascusfragrans, Ceratocystis spp., Ophiostoma piceae, Penicillium spp., Trichodermapseudokoningii, Trichoderma viride, Trichoderma harzianum, Aspergillus niger, Leptographium lindbergi and A ureobasidium pullulans; and fungal vectors of viral diseases (for example Polymyxa gram in is on cereals as the vector of barley yellow mosaic virus (BYMV) and Polymyxa betae on sugar beet as the vector of rhizomania).
A compound of formula (I) may move acropetally, basipetally or locally in plant tissue. Moreover, a compound of formula (I) may be volatile enough to be active in the vapour phase against one or more fungi on the plant.
The invention therefore provides a method of combating fungi which comprises applying to a plant, to a seed of a plant, to the locus of the plant or seed or to soil a fungicidally effective amount of a compound of formula (I), or a composition containing a compound of formula (I).
The term "plant" as used herein includes seedlings, bushes and trees. Furthermore, the fungicidal method of the invention includes protectant, curative, systemic, eradicant and antisporulant treatments.
The compounds of formula (I) are preferably used for agricultural, horticultural and turfgrass purposes in the form of a composition.
In order to apply a compound of formula (I), it is usually formulated into a composition which includes, in addition to the compound of formula (I), a suitable inert diluent or carrier and, optionally, a surface active agent. Surface active agents are chemicals which are able to modify the properties of an interface (for example, liquid/solid, liquid/air or liquid/liquid interfaces) by lowering the interfacial tension and thereby leading to changes in other properties (for example dispersibility and wetting). It is preferred that all compositions (both solid and liquid formulations) comprise, by weight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%, of a compound of formula (I). The composition is generally used for the control of fungi such that a compound of formula (I) is applied at a rate of from 0.1 g tolOkg per hectare, preferably from 1 g to 6kg per hectare, more preferably from 1 g to lkg per hectare.
When used in a seed dressing, a compound of formula (I) is used at a rate of 0.0001 g to 10g (for example 0.001g or 0.05g), preferably 0.005g to 10g, more preferably 0.005g to 4g, per kilogram of seed.
In another aspect the present invention provides a fungicidal composition comprising a fungicidally effective amount of a compound of formula (I), a suitable carrier or diluent therefor and, optionally, a surface active agent.
The compositions can be chosen from a number of formulation types, including dustable powders (DP), soluble powders (SP), water soluble granules (SG), water dispersible granules (WG), wettable powders (WP), granules (GR) (slow or fast release), soluble concentrates (SL), oil miscible liquids (OL), ultra low volume liquids (UL), emulsifiable concentrates (EC), emulsions (both oil in water (W) and water in oil (EO)), suspension concentrates (SC), aerosols, fogging/smoke formulations, capsule suspensions (CS) and seed dressings. The formulation type chosen in any instance will depend upon the particular purpose envisaged and the physical, chemical and biological properties of the compound of formula (I).
Dustable powders (DP) may be prepared by mixing a compound of formula (I) with one or more solid diluents (for example natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulphur, lime, flours, talc and other organic and inorganic solid carriers) and mechanically grinding the mixture to a fine powder.
Soluble powders (SP) can be prepared by mixing a compound of formula (I) with one or more water-soluble inorganic salts (such as sodium bicarbonate, sodium carbonate or magnesium sulphate) or one or more water-soluble organic solids (such as a polysaccharide) and, optionally, one or more wetting agents, one or more dispersing agents or a mixture of said agents to improve water dispersibility/solubility. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water soluble granules (SG).
Wettable powders (WP) can be prepared by mixing a compound of formula (I) with one or more solid diluents or carriers, one or more wetting agents and, preferably, one or more dispersing agents and, optionally, one or more suspending agents to facilitate the dispersion in liquids. The mixture is then ground to a fine powder. Similar compositions may also be granulated to form water dispersible granules (WG).
Granules (GR) may be formed either by granulating a mixture of a compound of formula (I) and one or more powdered solid diluents or carriers, or from pre-formed blank granules by absorbing a compound of formula (I) (or a solution thereof, in a suitable agent) in a porous granular material (such as pumice, attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing a compound of formula (I) (or a solution thereof, in a suitable agent) on to a hard core material (such as sands, silicates, mineral carbonates, sulphates or phosphates) and drying if necessary. Agents which are commonly used to aid absorption or adsorption include aliphatic and aromatic petroleum solvents, alcohols, polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugars and vegetable oils. One or more other additives may also be included in granules (for example an emulsifying agent, wetting agent or ,dispersing agent).
Soluble concentrat s (SL) can be prepared by dissolving a compound of formula (I) in water or an organic solvent, such as a ketone, alcohol or glycol ether. These solutions may contain a surface active agent (for example to improve water dilution or prevent crystallisation in a spray tank).
Emulsifiable concentrates (EC) or oil in water emulsions (EW) may be prepared by dissolving a compound of formula (I) in an organic solvent (optionally containing one or more wetting agents, one or more emulsifying agents or a mixture of said agents) and, for an emulsion, subsequently adding, under high shear agitation, the mixture to water (which may contain one or more wetting agents, one or more emulsifying agents or a mixture of said agents). Suitable organic solvents for use in ECs include ketones (such as cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl alcohol, furfuryl alcohol or butanol).
Suitable organic solvents for use in ECs or EWs include vegetable oils, N-substituted pyrrolidones, glycol ethers, chlorinated hydrocarbons (such as chlorobenzenes) and aromatic solvents (such as alkylbenzenes or alkylnaphthalenes).
Suspension concentrates (SC) may comprise aqueous or non-aqueous suspensions of finely divided insoluble solid particles of a compound of formula (I). SCs may be prepared by ball or bead milling the solid compound of formula (I) in a suitable medium with one or more dispersing agents, to produce a fine particle suspension of the compound. One or more wetting agents may be included in the composition and a suspending agent may be included to reduce the rate at which the particles settle.
Aerosol formulations comprise a compound of formula (I) and a suitable propellant (for example n-butane). A compound of formula (I) may also be dissolved or dispersed in a suitable medium (for example water or a water misc
A compound of formula (I) may also be formulated for use as a seed treatment, for example as a powder composition, including a powder for dry seed treatment (DS), a water soluble powder (SS) or a water dispersible powder for slurry treatment (WS), or as a liquid composition, including a flowable concentrate (FS), a solution (LS) or a capsule suspension (CS). The preparations of DS, SS, WS, FS and LS compositions are very similar to those of, respectively, DP, SP, WP, SC and SL compositions described above. Compositions for treating seed may include an agent for assisting the adhesion of the composition to the seed (for example a mineral oil).
Wetting agents, dispersing agents and emulsifying agents may be of the cationic, anionic, amphoteric or non-ionic type.
* Suitable agents of the cationic type include quaternary ammonium compounds (for example cetyltrimethyl ammonium bromide), imidazolines and amine salts.
Suitable anionic agents include alkali metals salts of fatty acids, salts of aliphatic monoesters of sulphuric acid (for example sodium lauryl sulphate), salts of sulphonated aromatic compounds (for example sodium dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures of sodium di-isopropyl- and tri-isopropyl-naphthalene sulphonates), ether sulphates, alcohol ether sulphates (for example sodium laureth-3-sulphate), ether carboxylates (for example sodium laureth-3-carboxylate), phosphate esters (products from the reaction between one or more fatty alcohols and phosphoric acid (predominately monoesters) or phosphorus pentoxide (predominately di-esters), for example the reaction between lauryl alcohol and tetraphosphoric acid, additionally these products may be ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates, taurates and lignosulphonates.
Suitable agents of tie amphoteric type include betaines, propionates and glycinates.
Suitable agents of the non-ionic type include condensation products of ethylene oxide with fatty alcohols (such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such as octylphenol, nonylphenol or octylcresol); partial esters derived from long chain fatty acids or hexitol anhydrides; condensation products of said partial esters with ethylene oxide; block polymers (comprising ethylene oxide and propylene oxide); alkanolamides; simple esters (for example fatty acid polyethylene glycol esters) or their ethoxylated derivatives; amine oxides (for example lauryl dimethyl amine oxide); and lecithins.
Suitable suspending agents include hydrophilic colloids (such as polysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose) and swelling clays (such as bentonite or attapulgite).
A compound of formula (I) can be applied by any of the known means of applying pesticidal compounds. For example, it can be applied, formulated or unformulated, to any part of the plant, including the foliage, stems, branches or roots, to the seed before it is planted or to other media in which plants are growing or are to be planted (such as soil surrounding the roots, the soil generally, paddy water or hydroponic culture systems), directly or it can be sprayed on, dusted on, applied as a cream or paste formulation, applied as a vapour or applied through distribution or incorporation of a composition (such as a granular composition or a composition packed in a water-soluble bag) in soil or an aqueous environment.
A compound of formula (I) may also be injected into plants or sprayed onto vegetation using electrodynamic spraying techniques or other low volume methods, or applied by land or aerial irrigation systems.
Compositions for use as aqueous preparations (aqueous solutions or dispersions) are generally supplied in the form of a concentrate containing a high proportion of the active ingredient, the concentrate being added to water before use. These concentrates, which may include SLs, SCs, ECs, EWs, SGs, SPs, WPs, WGs and CSs, are often required to withstand storage for prolonged periods and, after such storage, to be capable of addition to water to form aqueous preparations which remain homogeneous for a sufficient time to enable them to be applied by conventional spray equipment. Such aqueous preparations may contain varying amounts of a compound of formula (I) (for example 0.0001 to 10%, by weight) depending upon the purpose for which they are to be used.
A compound of formula (I) can be used in mixtures with fertilisers (for example nitrogen-, potassium- or phosphorus-containing fertilisers). Suitable formulation types include granules of fertiliser. The mixtures suitably contain up to 25% by weight of the compound of formula (I).
The invention therefore also provides a fertiliser composition comprising a fertiliser and a compound of formula (I).
The compositions of this invention may contain other compounds having biological activity, for example micronutrients or compounds having similar or complementary fungicidal activity or which possess plant growth regulating, herbicidal, insecticidal, nematicidal or acaricidal activity.
By including another fungicide, the resulting composition can have a broader spectrum of activity or a greater level of intrinsic activity than the compound of formula (I) alone. Further the other fungicide can have a synergistic effect on the fungicidal activity of the compound of formula (I).
The compound of formula (I) may be the sole active ingredient of the composition or it may be admixed with one or more additional active ingredients such as an insecticide, synergist, herbicide, fungicide or plant growth regulator where appropriate. An additional active ingredient may: provide a composition having a broader spectrum of activity or increased persistence at a locus; synergise the activity or complement the activity (for example by increasing the speed of effect or overcoming repellency) of the compound of formula (I); or help to overcome or prevent the development of resistance to individual components. The particular additional active ingredient will depend upon the intended utility of the composition.
Examples of fungicidal compounds which may be included in the composition of the invention are (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide, (E)-N-methyl- 2-[2-(2,5 -dimethyiphenoxymethyl)phenyl] -2-methoxy-iminoacetamide, (RS)-1-sminopropyl- phosphonic acid, (RS)-4-(4-chlorophenyl)-2-phenyl-2-(1H-1,2,4-triazol-1-ylmethyl)butyronitrile, (Z)-N-but-2-enyloxymethyl-2-chloro-2',6'-diethylacetanilide, 1-(2-cyano-2 -methoxyiminoacetyl)-3-ethyl urea, 4-(2,2-difluoro-1,3-benzodioxol-4-yl)pyrrole-3-carbonitrile, 4-bromo-2-cyano-N,N-dimethyl-6-trifluoromethylbenzimidazole-1-sulphonamide, 5-ethyl-5,8-dihydro-8-oxo(1,3)-dioxol (4,5-g)quinoline-7-carboxylic acid, a-[N-(3-chloro-2,6-xylyl)-2-methoxy- acetamido]-y-butyrolactone, N-(2-methoxy- 5-pyridyl)-cyclopropane carboxamide, acibenzolar (CGA245704), alanycarb, aldimorph, ampropylfos, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl, biloxazol, binapacryl, bitertanol, blasticidin S, bromuconazole, bupirimate, butenachlor, buthiobate, captafol, captan, carbendazim, carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396, CGA41397, chinomethionate, chloroneb, chlorothalonil, chlorozolinate, clozylacon, copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate, and Bordeaux mixture, cycloheximide, cymoxanil, cyproconazole, cyprodinyl, cyprofuram, debacarb, di-2-pyridyl disulphide l,l'-dioxide, dichlofluanid, dichlone, diclobutrazol, diclomezine, dicloran, didecyl dimethyl ammonium chloride, diethofencarb, difenoconazole, difenzoquat, diflumetorim, O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole, dimethomorph, dimethirimol, diniconazole, dinocap, dipyrithione, ditalimfos, dithianon, dodemorph, dodine, doguadine, edifenphos, epoxiconazole, etaconazole, ethirimol, ethoxyquin, ethyl (Z)-N-benzyl-N-( [methyl(methyl-thioethylideneamino- oxycarbonyl)amino]thio)-p-alaninate, etridiazole, famoxadone, fenaminosulph, fenapanil, fenarimol, fenbuconazole, fenfliram, fenhexamid (KBR 2738), fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentin hydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover, fluoroimide, fluquinconazole, flusilazole, flutolanil, flutriafol, folpet, fuberidazole, furalaxyl, furametpyr, furconazole-cis, guazatine, hexaconazole, hydroxyisoxazole, hymexazole, imazalil, imibenconazole, ipconazole, iprobenfos, iprodione, isopropanyl butyl carbamate, isoprothiolane, kasugamycin, kresoxim-methyl, LY186054, LY211795, LY248908, mancozeb, maneb, mefenoxam, mepanipyrim, mepronil, metalaxyl, metconazole, methfuroxam, metiram, metiram-zinc, metominostrobin, metsulfovax, myclobutanil, neoasozin, nickel dimethyldithiocarbamate, nitrothal-isopropyl, nuarimol, ofurace, organomercury compounds, oxadixyl, oxasulfuron, oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole, pencycuron, phenazin oxide, phosetyl-Al, phosphorus acids, phthalide, picoxystrobin (ZA1963), polyoxin D, polyram, probenazole, prochloraz, procymidone, propamocarb, propiconazole, propineb, propionic acid, prothiocarb, pyracarbolid, pyrazophos, pyrifenox, pyrimethanil, pyroquilon, pyroxyfur, pyrrolnitrin, quaternary ammonium compounds, quinconazole, quinomethionate, quinoxyfen, quintozene, rabenazole, sodium pentachlorophenate, spiroxamine, streptomycin, sulphur, tebuconazole, tecloftalam, tecnazene, tetraconazole, thiabendazole, thicyofen, thifluzamide, 2-(thiocyanomethylthio)benzothiazole, thiophanatemethyl, thiram, timibenconazole, tolclofos-methyl, tolylfluanid, triacetate salt of 1,1 '-iminodi(octamethylene)diguanidine, triadimefon, triadimenol, triazbutyl, triazoxide, tricyclazole, tridemorph, trifloxystrobin, triforine, triflumizole, triticonazole, validamycin A, vapam, vinclozolin, XRD-563, zineb and ziram. The compounds of formula (I) can be mixed with soil, peat or other rooting media for the protection of plants against seed-borne, soil-borne or foliar fungal diseases.
Some mixtures may comprise active ingredients which have significantly different physical, chemical or biological properties such that they do not easily lend themselves to the same conventional formulation type. In these circumstances other formulation types may be prepared. For example, where one active ingredient is a water insoluble solid and the other a water insoluble liquid, it may nevertheless be possible to disperse each active ingredient in the same continuous aqueous phase by dispersing the solid active ingredient as a suspension (using a preparation analogous to that of an SC) but dispersing the liquid active ingredient as an emulsion (using a preparation analogous to that of an EW). The resultant composition is a suspoemulsion (SE) formulation.
The invention is illustrated by the following Examples, in which the ingredients below are referred to by their Registered Trade Marks and have the following compositions.
Registered Trade Mark Composition SYNPERONIC NP8 } SYNPERONIC NP13 } NonylphenolOylene oxide condensate SYNPERONIC A7 Synthetic primary alcohol-ethylene oxide condensate AROMASOL H Alkylbenzene solvent SOLVES SO 200 Inert organic diluent KELTROL Polysaccharide PROXEL Bactericide EXAMPLE 1 This Example illustrates the preparation of 4-methyl-2-methylthio- 1 -phenylamino4- (O-phenylaldoximino)-2-imidazolin-5-one (Compound No. 17 in Table Ia ).
Methyl3 -nhenvldithiocarb'azate.
A solution of potassium hydroxide (2.80g, 0.05M) in water (7.5ml) was added simultaneously with carbon disulphide (5.70g, 0.075M, 4.50ml), dropwise, to a mechanically stirred solution of phenyihydrazine (5.40g, 0.05M) in ethanol (130ml), with ice-water cooling to maintain the reaction mixture temperature at 20-250C. The initial orange solution became a thick, buff-coloured suspension. The mixture was stirred at room temperature for ninety minutes, then methyl iodide (7.10g, 0.05M, 3.1 lml) was added in one portion. There was an exothermic reaction, the reaction mixture temperature rising to 280C and all solids went back into solution. After stirring for a further two hours at room temperature the solvent was removed by evaporation under reduced pressure (at 40"C) to give a yellowish-green solid. This was triturated with water, filtered off, washed copiously with water and then air dried to give a sand coloured solid. The crude product was stirred in dichloromethane (100ml) and the mixture heated to reflux. Hexane was slowly added and the dichloromethane allowed to boil away until the boiling point of the mixture was 55"C and a lot of solid had precipitated out. The mixture was cooled and filtered, leaving a solid, which was washed with hexane (4x75ml) and air-dried to yield the title compound as an offwhite solid (8.22g; 83%). lH NMR (CDCl3): 6 8.58(1H,s), 7.29(2H,t), 7.00(1H,t), 6.84(2H,d), 6.02(1H,s), 2.60(3H,s)ppm.
4-Methyl-1-phenylamino-2-thionoimidazolidin-5-one.
Alanine methyl ester hydrochloride (2.79g, 0.02M) and methyl-3phenyldithiocarbazate (1.98g, 0.01M) were stirred in dimethylformamide (DMF) (40ml) under a nitrogen atmosphere. Triethylamine (2.02g, 0.02M, 2.79ml) was added in one portion and the resultant thick green suspension heated to 1 100C for five hours. The reaction mixture was allowed to cool to room temperature and left to stand overnight The bulk of the DMF solvent was removed by evaporation under reduced pressure with a water bath at 70 80"C, using an in-line bleach trap to scrub out methanethiol. The oily residue was diluted with water (20ml) and extracted with diethyl ether (3xl 50ml). The organic extracts were combined, washed with saturated brine solution (2x100ml) then dried over MgSO4 and filtered. Removal of the solvent by evaporation under reduced pressure (at 40"C) gave a pale yellow gummy solid. This crude solid was triturated with 10% by volume diethyl ether in hexane, filtered off, washed with 10% by volume diethyl ether in hexane, then further washed with a small amount of diethyl ether, and finally dried under suction to give an offwhite powdery solid (1.572g; 71%). Recrystallisation of a 0.46g sample of this solid from ethyl acetate (using decolourising charcoal) gave 0.233g of the title compound as a white, powdery solid (mp 190.6-192.2 C). lH NMR (CDCl3): 6 7.35(1H,s), 7.27(2H,m), 7.00(1H,t), 6.81(2H,d), 6.48(1H,s), 4.30(1H,q), 1 .60(3H,d)ppm.
4-Methyl-2-methvlthio- 1 -phenvlamino-2-imidazolin-5-one.
To a stirred solution of 4-methyl-1-phenylamino-2-thionoimidazolidin-5-one (1 .105g, 0.005M) in acetone (25ml) under a nitrogen atmosphere was added potassium carbonate (0.68g, 0.0049M) and iodomethane (0.70g, 0.0049M, 0.31ml). The mixture was heated to reflux with stirring for four hours, then allowed to cool to room temperature. The mixture was filtered and the filter-cake washed through with further portions of acetone. The solvent was removed from the combined filtrate and washings, by evaporation under reduced pressure, to give a gritty orange-brown oil. The crude product was partitioned between diethy lether (30ml) and water (20ml), the organic layer being separated and the aqueous layer being further extracted with diethyl ether (2x20ml). The organic extracts were combined, washed with water (2xl5ml), dried over MgSO4 and filtered, the solvent being removed by evaporation under reduced pressure to give a yellowish gum that crystallised.
The solid was triturated with hexane containing 10% by volume diethyl ether and filtered off, washed twice with hexane containing 10% by volume diethyl ether and then dried at the pump to yield the title compound as a cream powdery solid (0.883g; 75%). lH NMR (CDCl3): # 7.26(2H,t), 6.99(1H,t), 6.77(2H,d), 6.12(1H,s), 4.22(1H,q), 2.51 (3H,s), 1 .50(3H,d)ppm.
4-(Hydroxymethyl)-4-methyl-2-methylthio-1-phenylamino-2-imidazolidin-5-one.
The reaction apparatus was dried by heating under vacuum then purging with dry nitrogen prior to use. A solution of lithium bis(trimethylsilyl)amide (0.0049M; 4.9ml of 1 .0M in hexane stock solution) and dry tetramethylethylenedianiine (0.82g, 0.00705M, 1.05ml) in dry tetrahydrofliran (10ml), was added dropwise with stirring under a nitrogen atmosphere, to a solution of 4-methyl-2-methylthio- 1 -phenylamino-2-imidazolin-5-one (1.18g, 0.005M) in dry tetrahydrofuran (65ml), previously cooled to -700C in an acetone/solid carbon dioxide bath, at such a rate as to maintain a reaction temperature of less than - 65 C. The reaction mixture turned from apale yellow solution through a pale salmon pink to a very deep salmonvpink suspension. After one and a half hours, formaldehyde gas was bubbled through the reaction mixture, with vigorous stirring, for approximately five minutes. The reaction mixture was then allowed to warm to #15 C, the deep salmon pink colour changing to deep cherry-red at approximately -40 C to 30CC, and paling to a light orange at OOC to +100C. Saturated aqueous ammonium chloride solution (15ml) was added and the two phase mixture stirred for one hour. Dilute aqueous hydrochloric acid (5ml) was added and stirring continued for ten minutes. The organic phase was then separated. The aqueous phase was further extracted with dichloromethane (2xSOml). All the organic extracts were then combined, washed with brine (2x70mi), dried over MgSO4 and filtered.
The solvent was removed from the filtrate by evaporation under reduced pressure to give a yellow oil, 2.10g. Column chromatography (silica, ethyl acetate as eluent) furnished the product as a pale yellow oil that crystallised. The solid was triturated with hexane containing 5% by volume diethyl ether, filtered off, washed with hexane containing 5% by volume diethyl ether and dried at the pump to yield the title compound as a pale yellow powdery solid (0.849g; 64%).
'H NMR (CDCl3): 6 7.25(2H,m), 6.97(1H,m), 6.79(2H,d), 6.19(1H,s), 3.93 3 .76(2H,m), 2.52(3H,s), 2.03(1H,s), 1.37(3H,s)ppm.
4-Methyl-2-methylthio- 1 -phenYlamino4(0-phenelaldoxirnino!-2-imidazolin-5-one.
To a stirred solution of oxalyl chloride (0.88g, 0.00692M, 0.6ml) in dry dichloromethane (25ml) at -70 C (acetone/solid carbon dioxide bath) under a nitrogen atmosphere, was added dropwise a solution of dry dimethylsuphoxide (0.96g, 0.0122M, 0.88ml) in dry dichloromethane (lOml) at such a rate as to maintain the internal reaction temperature below -65 C. After twenty minutes, a solution of 4-(hydroxymethyl)-4-methyl- 2-methylthio-1-phenylamnio-2-imidauolidin-5-one (1.06g, 0.004M) in dry dichloromethane (25ml) was added, again at such a rate as to maintain the internal reaction temperature below -65 C, to give a fine white suspension. After stirring for thirty minutes, triethylamine (1.64g, 0.0162M, 2.28ml) was added to a give a pale yellow solution. The solution was allowed to warm to -50 C, at which point solid O-phenylhydroxylamine hydrochloride (0.64g, 0.0044M) was added in one portion. The stirred mixture was allowed to warm to ambient temperature, stirring then being maintained for a further one hour. The mixture was washed with water (2x50ml), dried over MgSO4 and filtered, the solvent being removed by evaporation under reduced pressure to give a red brown oil. The crude material crystallised with scratching, the solid treing triturated with the minimum volume of diethyl ether, filtered off, washed with 10% by volume diethyl ether in hexane, then with diethyl ether, and dried under suction to yield the desired compound as a pale, pinkish-brown powdery solid (0.719g; 50.8%).
Alternative aminooxy compounds can also be prepared: Preparation of O-(2-Bromophenyl)hydroxylamine.
Under a stream of dry nitrogen, sodium hydride (0.652g of an 80% suspension in oil washed with hexane) was suspended in dry dimethylformamide (30ml) with stirring. At 100C, a solution of 2-bromophenol (3.74g) in dry dimethylformamide (8ml) was added over fifteen minutes, keeping the temperature below 100C. The effervescing mixture was stirred for one hour and allowed to reach ambient temperature. To the resulting grey solution was added a solution of O-(2,4-dinitrophenyl)hydroxylamine (2.151 g) in dry dimethylformamide (1 Omi) over one hour. The mixture was stirred for one hour and then left to stand for 16hours at ambient temperature. The dark solution was poured into aqueous sodium hydroxide solution (250ml, 1M) and extracted with diethyl ether (3x100ml). The organic fractions were combined, washed with aqueous sodium hydroxide solution (100ml, 1M), water and then brine, dried over Mg 504 and filtered. Concentration under reduced pressure gave a solid.
Trituration with pentane and a few drops of diethyl ether, followed by filtration and drying, gave the title compound as a pale tan solid (0.989g; 49%).
'H NMR (CDCl3): # 7.54(1H,dd), 7 .48(1H,dd), 7.28(1H,dt), 6.84(1H,dt), 6.03 (2H,s)ppm.
Ref. J. Org. Chem. 49 1348, (1984).
Preparation of O-(6-Fluoropyrid-2-yl)hydroxylamine.
N-t-Butvloxycarbonvl-0-(6-fluoropvrid-2-vl)hydroxvlamine.
Solid t-butyl-N-hydroxycarbamate (2.66g, 0.02M) was added in a single portion to a solution of potassium hydroxide (1.22g, 0.022M) in ethanol (40ml) at 40C (ice water bath) to give a colourless solution. 2,6-difluoropyridine (2.3g, 0.02M) was then added with stirring over one minute (no visible exotherm) to give an orange solution. The cooling bath was removed and the solution was allowed to stand at ambient temperature for 24hours, during which time it became pale yellow. The reaction was quenched by pouring into water (200ml) and extracting with diethyl ether (3x80ml). The ether solution was combined, washed with water (2x50ml), brine (100ml), dried over MgSO4 and evaporated under reduced pressure to give a pale yellow liquid (2.89g) which was purified by chromatography on silica gel, eluting with a 4:1 (by volume) mixture of hexane and ethyl acetate to give the title compound as a pale yellow, viscous liquid (2.35g; 51.5%).
'H NMR (CDCl3): # 7.99(1H,s), 7.77(1H,q), 6.87(1H,dd), 6.63(1H,dd), 1.50(9H,s)ppm.
O-(6-Fluoroovrid-2-vIlhvdroxvlamine.
Trifluoroacetic acid (semi) was added to N-t-butyloxycarbonyl-O-(6-fluoropyrid-2yl)hydroxylamine and the pale yellow solution was stirred at ambient temperature for approximately ten minutes, until effervescence had ceased. Ice water (50ml) was then added to give a clourless solution to which sodium hydroxide solution (1M) was added to pH 12.
The pale yellow solution was extracted with diethyl ether (3x80ml) and the combined organic solution was washed with water (2x20ml), brine (SOml), dried over MgSO4 and evaporated under reduced pressure to give a yellow liquid (0.2g; 71.25%).
1H NMR (CDCl3): 8 7.71(1H,q), 6.83(1H,dd), 6.54(1H,dd), 6.31(2H,s)ppm.
EXAMPLE 2 This Example illustrates the preparation of 4-Methyl4-(O-methylacetatealdoximino)- 2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 10 in Table Ia).
4-MethvlA-(O-methvlacetatealdoximino)-2-methvlthio- 1 -nhenylamino-2-imidazolin-5-one (Methoxycarbonylmethyl)hydroxylamine was reacted with 4-hydroxymethyl)-4- methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (prepared as described in Example 6) under the conditions described in Example 1. The initial product was an aminol, which was treated with a trace of trifluoroacetic acid in dimethyl sulphoxide. Work up in the normal manner then gave the desired product.
'H NMR (CDCl3): 6 4.66(2H,s)ppm.
EXAMPLE 3 This Example illustrates the preparation of 2-methoxy-4-methyl4-(O- phenylaldoximino)-1-phenylamino-2-imidazolin-5-one (Compound No. 17 in Table IIIa).
2-Methoxv4-methvl4-(O-Dhenvlaldoximino)- 1 -phenvlamino-2-imidazolin-5-one A solution of sodium methoxide (96mg, 1.78mmol) in dry methanol (2.7ml) was added to a stirred suspension of 4-methyl-2-methylthio-4-(O-phenylaldoximino)- 1 phenylamino-2-imidazolinv5-one (630mg, 1.78mmol, prepared as described in Example 1) in dry methanol (lSml). The resulting mixture was stirred at ambient temperature for 16 hours, and the solvent removed under reduced pressure. The brown residue was dissolved in ethyl acetate (SOml), and the resulting solution washed with water (2 x 25ml), dried over MgSO4, filtered and evaporated to provide an orange oil. This was purified by column chromatography, first on silica, with ethyl acetate:hexane (3:7) as eluant, then on basic alumina, with ethyl acetate:hexane (first 1:4, then 3:7) as eluant, to provide the desired compound as a colourless gum (3mg, 0.6%).
'H NMR (CDCl3): 8 1.71(3H,s); 4.05(3H,s); 6.09(1H,s); 6.80(2H,d); 6.99(1H,t); 7.01(1H,t); 7.13(2H,dd); 7.19-7.33(4H,m); 7.75(1H,s)ppm.
EXAMPLE 4 This Example illustrates the preparation of 4-methyl-2-methylthio-4-(O phenylacetoximino)-1-phenylamino-2-imidazolin-5-one (Compound No. 238 in Table Ia).
4-(1-Hydroxyethyl)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one.
To a stirred solution of 4-methyl-2-methylthio- 1 -phenylamino-2-imidazolin-5-one (2.5g, 0.01064M, prepared as described in Example 1) in dry tetrahydrofuran (80ml) under a nitrogen atmosphere was added potassium carbonate (1.47g, 0.01064M) and acetaldehyde (9.37g, 0.213M, 11.9ml). The mixture was warmed to reflux for two and a half hours, cooled to ambient temperature and left to stand for sixteen hours. The mixture was filtered, washing the filter-cake with further portions of tetrahydrofuran, the filtrate being concentrated to approximately 15% by volume by evaporation under reduced pressure. The liquid residue was dissolved in ethyl acetate (100ml), washed with water (3x50ml), dried over MgSO4 and filtered, the solvent being removed by evaporation under reduced pressure to give a yellow oil. Chromatography on silica, using gradient elution with 1:9, 1:1 and 1:0, ethyl acetate: hexane mixtures yielded the title compound as a yellow solid (2.48g; 83.5%) (as a 1:1 mixture of diastereoisomers). lH NMR (CDCl3): 8 7.24(2H,m), 6.96(1H,t), 6.78(2H,d), 6.27 and 6.25(1H,2s), 3.96(1H,m), 2.52(3H,s), 2.45 and 2.19(1H,2d), 1.44 and 1.38(3H,2s),1.35 and 1.29(3H,2d)ppm.
4-Acetvl-4-methrl-2-methvlthio- 1 -phenylamino-2-imidazolin-Sene.
To stirred solution of oxalyl chloride (2.22g, 0.01747M,1.52ml) in dry dichloromethane (130ml) at -70 C (acetone/solid carbon dioxide bath) under a nitrogen atmosphere, was added dropwise a solution of dry dimethylsulphoxide (2.41g, 0.03081M, 2.19ml) in dry dichloromethane (20ml) at such a rate as to maintain the internal reaction temperature below -65 C. After twenty minutes a solution of 4-(1-hydroxyethyl)-4-methyl-2 methylthio-l -phenylamino-2-imidazolin-5-one (2.81g, 0.0101M) in dry dichloromethane (50ml) was added, again at such a rate as to maintain the internal reaction temperature below -65 C, to give a fine white suspension. After one and a quarter hours triethylamine (4.14g, 0.0409M, 5.7ml) was added to give a pale orange solution, which was then allowed to warm to ambient temperature over one and a half hours. The solution was washed with water (2xlOOml), dried over MgSO4 and filtered, the solvent being removed by evaporation under reduced pressure to give a light brown solid. This was triturated with 10% by volume diethyl ether in hexane, filtered off, washed with 10% by volume diethyl ether in hexane and dried at the pump to yield the title compound as a pale pinkish-fawn powdery solid (2.14g; 77%).
'H NMR (CDCl3): 6 7.27(2H,t), 7.00(1H,t), 6.78(2H,d), 6.17(1H,s), 2.56(3H,s), 2.24(3H,s), 1.63(3H,s)ppm.
4-Methvl-2-methvlthio-4-(0-phenslacetoximino)- 1 -Dhenvlamino-2-imidazolin-5-one.
To a stirred solution of 4-acetyl9-methyl-2-methylthio- 1 -phenylamino-2-imidazolin5-one (0.14g, 0.000505M) in glacial acetic acid (lOml) was added O-phenylhydroxylamine hydrochloride (0.088g, 0.000606M) to give a purplish solution. After three hours the mixture was diluted with ethyl acetate (30ml), washed with water (3x30ml), dried over MgSO4, filtered and the solvent removed by evaporation under reduced pressure to give a pale red-brown oil which crystallised. Trituration with 5% by volume diethyl ether in hexane, filtration, washing with 5% by volume diethyl ether in hexane and drying at the pump yielded the desired compound as a pale pink solid (0.088g; 47%).
EXAMPLE 5 This Example illustrates the preparation of 4-acetyl4-methyl-2-methylthio-1- phenylamino-2-imidazolin-5 -one phenyl hydrazone (Compound No. 238 in Table Ill).
4-Acetvl-4-methvl-2-methvlthio- 1 -ohenvlamino-2-imidazolin-5-one vhenvl hydrazone.
To a stirred solution of 4-acetyl4-methyl-2-methylthio- 1 -phenylaniino-2-imidazolin- 5-one (0.14g, 0.000505M, prepared as described in Example 4) in glacial acetic acid (5ml) was added phenylhydrazine (0.066g, 0.000606M, 0.06ml) to give a thick mustard coloured suspension. A further 2ml glacial acetic acid was added, giving a deep yellow solution.
After three hours the mixture was diluted with ethyl acetate (50ml), washed with water (3x50rnl), dried over MgSO4 filtered and the solvent removed by evaporation under reduced pressure to give a dark green oil. Chromatography on silica using 1:1 ethyl acetate:hexane as eluent gave a light brown oil which crystallised. Trituration with 5% by volume diethyl ether in hexane, filtration, washing with 5% by volume diethyl ether in hexane and drying at the pump yielded the desired compound as a fawn solid (0.078g; 42%).
EXAMPLE 6 This Example illustrates an alternative preparation of the intermediate 4 (hydroxymethyl)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one. a-Methyl-DL-serine methvl ester hydrochloride salt.
Methanol (125ml) was stirred at an internal temperature of-20 C in an acetone/dry ice bath as thionyl chloride (32.4ml) was added over 15minutes (exotherm). The mixture was allowed to warm to -100C and was then cooled to below -40 C. Solid a-methyl-DLserine (14.82g) was added in portions, maintaining the temperature below -40 C. When all had been added, the mixture was allowed to warm to the ambient temperature and stirred for 18hours. The resulting solution was concentrated by evaporation under reduced pressure.
The resulting gum was redissolved in toluene (300ml) and again concentrated under reduced pressure. This procedure was repeated and the title compound was produced as a gum (21 g), which was used, without further purification, in the preparation of 4-(hydroxymethyl)4methyl- 1 -phenylamino-2-thionoimidazolidin-5-one.
4-(Hydroxymethyl)-4-methyl-1-phenylamino-2-thionoimidazolidin-5-one.
-Methyl-DL-serine methyl ester hydrochloride salt (16.1 g), methyl-3 phenyldithiocarbazate (20.7g, prepared as described in Example 1) and triethylamine (10.6g) were stirred together at 1 100C in dimethyl formamide (300ml) under a stream of dry nitrogen. Methane thiol was evolved and was trapped in chloros solution. After three hours the mixture was cooled and concentrated by evaporation under reduced pressure to give a dark oil which was redissolved in 4:1 (by volume) ethyl acetate : tetrahydrofuran (250ml) and washed with saturated brine (100ml). The organic layer was separated and the aqueous layer extracted twice with 4:1 (by volume) ethyl acetate : tetrahydrofuran (250ml). The combined organic phases were dried (MgSO4), filtered and evaporated under reduced pressure to give a dark oil (28g). This was dissolved in dichloromethane, seeded with a small quantity of product (obtained by scratching a small portion of the solution in a vial) and left to crystallise for ca. one hour. The product was recovered by filtration, washed with cold dichloromethane until white, and air dried to yield the title compound (10.08g; mp 185 186"C).
'H NMR (CDCl3): 6 9.38(1H,br s), 7.22(2H,t), 6.94(1H,t), 6.86(2H,d), 6.69(1H,s), 4.41(1 H,t), 3.87(1H,dd), 3.71(1H,dd), 1.44(3H,s)ppm.
4-(Hydroxymethyl)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one.
4-(Hydroxymethyl)4-methyl- 1 -phenylamino-2-thionoimidazolidin-5-one (10.08g) was dissolved in acetone (150ml) and cooled to 3 C. Potassium carbonate (5.83g) was added and then a solution of methyl iodide (6g) in acetone (SOml) was added dropwise over ten minutes at 30C. The mixture was allowed to warm to the ambient temperature and stirred under a nitrogen atmosphere for 65hours. The product solution was filtered and the inorganic material washed with dichloromethane. The combined filtrates were evaporated under reduced pressure to give a pale yellow foam which was dissolved in diethyl ether and scratched until crystallisation commenced. The mixture was left to stand for one hour and was then cooled to 0 C for 30minutes. The crystalline product was recovered by filtration, washed with cold diethyl ether and air dried to yield the desired compound (8.07g; mp 159 160"C). lH NMR (CDCl3): 8 9.38(1H,br s), 7.24(2H,dd), 6.96(1H,t), 6.77(2H,d), 6.31(1H,s), 3.84(2H,m), 2.52(3H,s), 2.31(1H,dd), 1.36(3H,s)ppm.
EXAMPLE 7 This Example illustrates the preparation of 4-methyl-2-methylthio-4-[0-(2- naphthylmethyl)aldoximino]-1-phenylamino-2-imidazolin-5-one (Compound No. 211 in Table Ia).
4-Aldoximino-4-methyl-2-methylthio- 1 -ohenvlamino-2-imidazolin-5-one (Compound No. 1 in Table Ia) A solution of dimethylsulphoxide (4.76g, 6lmmol) in dry dichloromethane (15ml) was added dropwise to a stirred solution of freshly distilled oxalyl chloride (4.39g, 34.6mmol) in dry dichloromethane under nitrogen at -700C at such a rate that the reaction temperature was maintained below -65 C. The reaction mixture was stirred at -700C for 20 minutes, then a solution of 4-(hydroxymethyl)-4.methyl-2-methylthio-1-phenylamino-2- imidazolin-5-one (5.30g, 20mmol; prepared as described in Example 6) in dry dichloromethane (100ml) was added rapidly, again maintaining the temperature below 65"C. The resulting white suspension was stirred at -700C for 30 minutes, then triethylamine (8.20g, 81mmol) was added and the resulting yellow solution stirred for a further 10 minutes at -70 C and then allowed to warm to -500C. Dry and finely powdered hydroxylamine hydrochloride (1.53g, 22mmol) was added portionwise over a few minutes and the reaction mixture allowed to warm to ambient temperature over 90 minutes, then stirred at this temperature for a further 3 hours.
The reaction mixture was then directly applied to a column of silica and purified by column chromatography, with ethyl acetate:hexane (1:1) as eluant, to give the crude product.
This was further purified by crystallisation from ether:hexane to provide the desired product as a pale yellow solid (2.31g, 41%). lH NMR (CDC13): 6 1.62(3H,s); 2.51(3H,s); 6.21(1H,s); 6.76(2H,d); 6.99(1H,t); 7.26(2H,t); 7.46(1H,s); 7.73(1H,s)ppm.
4-Methvl-2-methvlthio rO-(2-naohthvlmethvl)aidoximinol - 1 -phenvlamino-2-imidazolin- 5-one Aqueous sodium hydroxide solution (0.25M; 2.90 ml, 0. 73mmol) was added to a stirred solution of 2-(bromomethyl)naphthalene (0.243g, I immol) and 4-aldoximino4 methyl-2-methylthio- 1 -phenylamino-2-imidazolin-5-one (0.2g, 0.72mmol) in methanol (6ml). The reaction mixture was then stirred for 2 hours at ambient temperature.
The solvent was removed by evaporation under reduced pressure (450C) and the residue partitioned between ethyl acetate and water. The organic phase was separated, washed with water and brine and the solvent was again removed by evaporation under reduced pressure to give the crude product.
The crude product was purified by chromatography on silica gel with hexane: ethyl acetate (7:3) as eluant. lH NMR (CDCl3): 8 5.27(2H,s)ppm.
EXAMPLE 8 This Example illustrates the preparation of 4-methyl-2-methylthio-1-phenylamino-4- [O-(6-pyrimidinylmethyl)aldoximino] -2-imidazolin-5-one (Compound No. 706 in Table Ia ).
4-Methvl-2-methvlthio- I-ohenvlamino-4- rO-(6-Dvrimidinvlmethvl)aldoximinol-2- imidazolin-5-one A solution of 4-methylpyrimidine (0.5g, 5.3mmol) and N-bromosuccinimide (1.04g, 5.84mmol) in carbon tetrachloride (1 Oml) was heated at reflux in the presence of a bright light for 20 minutes. After cooling to ambient temperature, the reaction mixture was filtered and the residue washed with carbon tetrachloride. The filtrate was evaporated under reduced pressure, and the residual yellow oil was added to a solution of 4-methyl-2-methylthio-1phenylamino-4-aldoximino-2-imidazolin-5-one (250mg, 0.9mmol, prepared as described in Example 7) in methanol (10ml in total). Aqueous sodium hydroxide solution (0.25M; 3.8ml, 0.9lmmol) was added and the reaction mixture stirred at the ambient temperature for two days.
The reaction mixture was poured into water and extracted with ethyl acetate (x2).
The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure. The resulting dark orange oil was purified by extensive column chromatography on silica, with first dichloromethane, then ethyl acetate:hexane (1:1), as eluant, followed by trituration with diethyl ether: pentane, to give the desired product, mixed with 1-(4-bromophenyl)amino-4methyl-2-methylthio-4-[O-(6-pyrimidinylmethyl)aldoximino]-2-imidazolin-5-one, as a cream coloured solid (37mg).
MW 370 and 449/451.
EXAMPLE 9 This Example illustrates the preparation of 4-[O-(4-fluorophenyl)acetoximino]-4- methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 353 in Table Ia).
4-Acetoximino-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No.
222 in Table Ia) To a stirred solution of 4-acetyl-4-methyl-2-methylthio- 1 -phenylamino-2-imidazolin- 5-one (1 .2g, 4.35mmol, prepared as described in Example 4) in dry dichloromethane (25ml) under a nitrogen atmosphere was added triethylamine (0.57g, 5.66mmol) over 2 minutes. A solution of hydroxylamine hydrochloride (0.363g, 5.22mmol) in dry dimethylsulphoxide (9ml) was added dropwise over 5 minutes, and the resulting solution stirred at ambient temperature for five hours. Saturated aqueous ammonium chloride (30ml) was added and the mixture was extracted with ethyl acetate (3x30ml). The combined organic extracts were dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow oil. This residue was dissolved in ethyl acetate (lOml), washed with water (2x6mi), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow solid.
Chromatography on silica, eluting with 5% methanol in dichloromethane, yielded the title compound as a yellow solid (0.5g; 40%).
'H NMR (CDC13): 1.60(3H,s); 1.94(3H,s); 2.49(3H,s); 6.76(1H,br s); 6.70(2H,d); 6.94(1H,t); 7.24(2H,t); 9.64(1H,br s)ppm.
4-[O-(4-Fluorophenyl)acetoximino]-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5one 4-Fluorobenzyl bromide (0.065ml, 0.34mmol)was added to a stirred solution of 4acetoximino-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (0.1 g, 0.34mmol) in methanol (5ml). After stirring at ambient temperature for 5 minutes aqueous sodium hydroxide (0.25M; 1.4ml, 0.34mmol) was added and stirring continued for 2.5 hours.
Further aqueous sodium hydroxide (0.25M; 0.7ml, 0.17mmol) was added and stirring continued for a further 2 hours. The solvent was then removed under reduced pressure, and the orange oily residue suspended in water (20ml). The mixture was extracted with ethyl acetate (2x30ml), and the combined organic layers washed with water (10ml) and brine (1 Sml), dried over MgSO4, filtered, and evaporated under reduced pressure to give an orange gum. Chromatography on silica, eluting with 1:1 ethyl acetate:hexane, yielded the title compound as an orange oil (45mg; 48%).
'H NMR (CDCl3): 6 1.58(3H,s); 1.88(3H,s); 2.51(3H,s); 5.06(2H, ABq); 6.15(1H,br s); 6.81(2H,d); 7.02(3H,m); 7.27(4H,m)ppm.
EXAMPLE 10 This Example illustrates the preparation of 4-(O-cinnamylaldoximino)4-methyl-2 methylthio-l -phenylamino-2-imidazolin-5-one (Compound No. 13 in Table Ia ).
4-(O-Allylaldoximino)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (Compound No. 11 in Table Ia).
This compound was prepared by the same method described for 4-methyl-2methylthio-4-[O-(2-naphthylmethyl)aldoximino]-1-phenylamino-2-imidazolin-5-one in Example 7, except that allyl bromide was used in place of 2-(bromomethyl)naphthalene.
'H NMR (CDCl3): 8 1.60(3H,s); 2.49(3H,s); 4.58(2H,m); 5.18-5.34(2H,m); 5.88- 6.05(1H,m); 6.32(1H,s); 6.77(2H,d); 6.97(1H,d); 7.23(2H,m); 7.40(1H,s)ppm.
4-(O-Cinnamylaldoximino)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one 4-(O-Allylaldoximino)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one (0.1g, 0.31 mmol), palladium diacetate (0.7mg, 0.0031mmol), tributyl phosphine (1.3mg, 0.0062mmol), potassium carbonate (89mg, 0.63mmol) and phenyl iodide (0.64g, 3.lmmol) were dissolved in dry dimethylformamide (2ml). The stirred reaction mixture was then heated to 700C for 5 hours and allowed to cool to ambient temperature. The crude reaction mixture was then poured into water and extracted with ethyl acetate (x2). The combined organic extracts were washed with water and brine, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a dark orange oil. This was purified by column chromatography on silica, using first dichloromethane then ethyl acetate:hexane (1:1) as eluant, followed by trituration with diethyl ether:pentane, to give the desired product as a cream coloured solid, 37mg. lH NMR (CDC13): 6 1.63(3H,s); 2.52(3H,s); 4.75(2H,d); 6.34(1H,dt); 6.63(1H,d); 6.80(2H,d); 6.97(1H,t): 7.18-7.44 (7H,m); 7.47(1H,s)ppm.
EXAMPLE 11 This Example illustrates the preparation of 4-methyl-2-methylthio- 1 -phenylamino-4- (O-[ 1 (5-pyrimidinyl)-3-allyl]aldoximino } -2-imidazolin-5-one (Compound No. 14 in Table Ia).
4-Methvl-2-methvlthio- 1 -phenvlamino4- 0- [1 -(5-pyrimidinyl)-3-allyl]aldoximino}-2- imidazolin-5 -one The compound was prepared using the method described in Example 10, using 4-(Oallyaldoximino)-4-methyl-2-methylthio-1-phenylamino-2-imidazolin-5-one and 5bromopyrimidine. The reaction mixture was heated to 110"C for a total of 13 hours, and additional palladium diacetate, tributyl phosphine and 5-bromopyrimidine were added part way through. The crude reaction product was purified by column chromatography to give the desired product as a pale yellow/orange crushable foam.
'H NMR (CDCl3): 6 1.62(3H,s); 2.52(3H,s); 4.78(2H,d); 6.18(1H,s); 6.476.53(2H,m); 6.79(2H,d); 6.99(1H,t); 7.25(2H,t); 7.45(1H,s); 8.73(2H,s); 9.09(1H,s)ppm.
EXAMPLE 12 This Example illustrates the preparation of 4-methyi-2-methylthio- l-phenylamino4- (5-phenylisoxazolin-3-yl)-2-imidazolin-5-one (Compound No. 1 in Table Ib).
4-Methyl-2-methylthio- l-ohenvlamino-4-(5 -Dhenvlisoxazolin-3 -vl)-2-imidazolin-5-one Pyridine (one drop) was added to a solution of 4-aldoximino-4-methyl-2-methylthio- 1 phenylamino-2-imidazolin-5-one (83mg, 0.30mmol, prepared as described in Example 7) in chloroform (20ml). N-Chlorosuccinamide (69mg, 0.52mmol) was added in one portion and the mixture was stirred at ambient temperature for 1 hour. Styrene (0.05 lml, 0.44mmol) was added to the mixture, followed by a solution of triethylamine (0.044ml, 0.33mmol) in chloroform (1 ml) portionwise over about 5 minutes. The reaction mixture was stirred at ambient temperature for 30 minutes, then partitioned between dichloromethane and water, and the aqueous layer extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash column chromatography followed by preparative HPLC, to yield the desired compound as a mixture of isomers (37mg, 33%).
'H NMR (CDC13): 6 1.71(3H,s); 2.50(3H,s); 2.88-3.10(1H,m); 3.31-3.56(1H,m); 5.53 5.64(1H,m); 6.26-6.35(1H,br m); 6.70-6.80(2H,m); 6.92-7.01(1H,m); 7.1 9-7.39(7H,m)ppm.
EXAMPLE 13 This Example illustrates an emulsifiable concentrate composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The emulsifiable concentrate has the following composition: % by weight Compound No. 1 25.0 SYNPERONIC NP 13 2.5 Calcium dodecylbenzenesulphonate 2.5 AROMASOL H 70.0 EXAMPLE 14 This Example illustrates a wettable powder composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The wettable powder has the following composition: % by weight Compound No. 1 25.0 Silica 25.0 Sodium lignosulphonate 5.0 Sodium lauryl sulphate 2.0 Kaolin 43.0 EXAMPLE 15 This Example illustrates a dustable powder which may be applied directly to plants or other surfaces. The dustable powder has the following composition: % by weight Compound No. 1 1.0 Talc 99.0.
EXAMPLE 16 This Example illustrates an oil miscible liquid formulation suitable for application by ultra low volume techniques after mixing with an organic diluent. The formulation has the following composition: % by weight Compound No. 1 10.0 SOLVESSO 200 90.0 EXAMPLE 17 This Example illustrates a capsule suspension concentrate which is readily convertible, by addition to water, into a preparation suitable for application as an aqueous spray. The capsule suspension concentrate has the following composition: % by weight Compound No. 1 10.0 AROMASOL H 10.0 Toluene di-isocyanate 3.0 SYNPERONIC A7 1.0 Polyvinyl alcohol 2.0 Bentonite 1.5 KELTROL 0.1 Water 72.4 EXAMPLE 18 This Example illustrates a ready for use granular formulation that is prepared from a preformed granular carrier. The granular formulation has the following composition: % by weight Compound No. 1 0.5 SOLVESSO 200 0.2 SYNPERONIC A7 0.1 Calcium carbonate granules (diameter 0.3-0.7mm) 99.2 EXAMPLE 19 This Example illustrates a ready for use granular formulation that is prepared by granulation of the powdered components. The granular formulation has the following composition: % by weight Compound No. 1 0.5 Sodium lignosulphonate 5.0 Kaolin 94.5 EXAMPLE 20 This Example illustrates an aqueous suspension concentrate composition which is readily convertible, by addition to water, into a preparation suitable for spraying purposes.
The suspension concentrate has the following composition: % by weight Compound No. 1 25.0 Sodium lignosulphonate 3.0 Propylene glycol 10.0 Bentonite 2.0 KELTROL 0.1 PROXEL 0.1 Water 59.8 EXAMPLE 21 This Example illustrates a water dispersible granule formulation which is readily convertible, by addition to water, into a preparation suitable for spraying purposes. The water dispersible granule has the following composition: % by weight Compound No. 1 25.0 Silica 5.0 Sodium lignosulphonate 10.0 Sodium lauryl sulphate 5.0 Sodium acetate 10.0 Montmorillonite powder 45.0 EXAMPLE 22 The compounds were tested against a variety of foliar fungal diseases of plants. The technique employed was as follows.
Plants were grown in John Innes Potting Compost (No. 1 or 2) in 4cm diameter, 3.5cm depth minipots. The test compounds were individually formulated as a solution either in acetone or acetone/ethanol (1:1 by volume) which was diluted in deionised water to a concentration of 100ppm (that is, lmg of compound in a final volume of 1 Oml) immediately before use. When foliar sprays were applied to monocotyledonous crops, Tween 20 (0.1% by volume) was added.
Individual compounds were applied as a foliar (Folr) application (where the chemical solution was applied to the foliage of the test plants by spraying the plant to maximum droplet retention); or as a systemic (Syst) application (where the chemical solution, 1 Oml, was applied as a root drench treatment).
These tests were carried out against Plasmopara viticola, on vines; Phytophthora infestans lycopersici, on tomatoes; Venturia inaeaualis, on apples; and Puccinia recondita, on wheat. Each treatment was applied to two or more replicate plants for Plasmopara viticola Phvtonhthora infestans lvcopersici and Venturia inaeaualis. In tests on Puccinia recondita two replicate pots each containing 6 tolO plants were used for each treatment. The plants were inoculated with a calibrated fungal spore suspension one or two days before (Erad) or one or two days after (Prot) chemical application.
After chemical application and inoculation, the plants were incubated under high humidity conditions and then put into an appropriate environment to allow infection to proceed, until the disease qas ready for assessment. For Plasmopara viticola. the plants were reincubated under high humidity conditions for 24hours prior to assessment. The time period between inoculation and assessment varied from four to fourteen days according to the disease and environment. However, each individual disease was assessed after the same time period for all compounds.
Assessments were performed on a single leaf of each of the two replicate plants for Plasmopara viticola and Venturia inaeaualis and on each of two leaves on each of the replicate plants for Phvtonhthora infestans lycopersici. For Puccinia recondita assessments were carried out collectively on the plants in each replicate pot.
The disease level present (that is, the percentage leaf area covered by actively sporulating disease) was assessed visually. For each treatment, the assessed value for each replicate was then meaned before being expressed as a percentage of the mean level of disease present on the untreated control plants. This calculated value is referred to as a POCO (Percentage of Control) value.
An example of a typical calculation is as follows: Mean disease level for treatment A = 25 Mean disease level on untreated controls = 90 POCO = Mean disease level for treatment A x 100 = 25 x 100 = 27.8 Mean disease level on untreated controls 90 This POCO value is then rounded to the nearest of the points in the 9-point b
TABLE VI
Compound No PLASVI PLASVI PHYTIN VENTIN PUCCRT PUCCRT ERYSGT (Table No) (Prot/Folr) (Prot/Sys) (Prot/Folr) (Prot/Folr) (Erad/Folr) (Prot/Folr) (Prot/Folr) 1 (Ia) 90 90 90 90 90 90 2 (Ia) 0 0 0 90 0 60 90 3 (Ia) 90 60 90 60 90 90 9 (Ia) 0 60 60 0 1 10 10 (Ia) 3 90 90 90 90 90 90 11 (Ia) E-isomer 20 60 90 90 0 10 90 11 (Ia) Z-isomer 60 90 90 13 (Ia) 0 90 0 3 1 1 30 14 (Ia) 60 90 90 90 90 90 90 15 (Ia) 0 0 1 90 60 90 90 17 (Ia) 0 60 30 5 0 1 60 17 (IIIa) 0 90 20 30 20 (Ia) 90 90 30 90 90 90 90 21 (Ia) 0 90 30 30 60 3 60 42 (Ia) 30 90 90 60 90 90 90 74 (Ia) 0 90 0 90 5 20 90 75 (Ia) 0 90 90 20 3 0 30
76 (Ia) 0 90 5 0 0 0 3 77 (Ia) 0 90 0 90 10 0 90 83 (Ia) 3 90 90 60 0 0 10 86 (Ia) 0 90 1 87 (Ia) 0 90 0 88 (Ia) 0 90 0 89 (Ia) 0 90 1 5 0 3 90 91 (Ia) 20 90 20 99 (Ia) 90 90 30 102 (Ia) 90 90 60 90 104 (Ia) 20 90 0 90 90 30 90 108 (Ia) 0 90 90 109 (Ia) 3 90 90 90 90 90 90 110 (Ia) 20 60 1 112 (Ia) 3 90 60 90 3 5 60 113 (Ia) 10 90 0 114 (Ia) 0 90 0 115 (Ia) 3 90 90 90 0 0 30 121 (Ia) 90 90 90 90 90 90 90
125 (Ia) 0 90 10 126 (Ia) 90 5 127 (Ia) 0 90 10 128 (Ia) 0 90 30 129 (Ia) 5 90 20 130 (Ia) 0 90 3 60 131 (Ia) 0 90 0 132 (Ia) 3 90 5 60 3 0 20 133 (Ia) 60 90 0 134 (Ia) 0 90 90 0 0 0 1 135 (Ia) 0 90 3 60 0 0 30 136 (Ia) 0 90 3 140 (Ia) 0 90 60 30 0 0 10 143 (Ia) 0 90 60 90 1 0 30 144 (Ia) 0 90 10 30 5 0 90 146 (Ia) 0 90 30 0 0 0 5 151 (Ia) 0 90 90 10 0 0 20 152 (Ia) 0 90 90 90 10 0 60 155 (Ia) 0 90 60 20 3 0 30
165 (Ia) 0 90 0 171 (Ia) 0 60 20 30 0 0 1 173 (Ia) 0 90 0 176 (Ia) 0 90 1 194 (Ia) 10 90 60 90 0 0 20 195 (Ia) 3 90 30 60 0 0 20 196 (Ia) 5 90 90 90 0 0 60 197 (Ia) 5 90 1 198 (Ia) 0 90 90 90 0 0 20 199 (Ia) 3 90 0 203 (Ia) 90 90 90 90 90 90 90 210 (Ia) 3 90 1 211 (Ia) 0 90 30 60 0 0 10 217 (Ia) 0 90 60 60 90 30 90 218 (Ia) 0 90 20 90 60 30 90 222 (Ia) 60 90 90 90 90 223 (Ia) 0 0 90 20 60 60 90 224 (Ia) 60 0 90 90 90 60 90 232 (Ia) 20 0 90 60 90 20 90
238 (Ia) 90 90 90 20 90 60 90 238 (IIa) 90 90 60 90 90 90 241 (Ia) 5 90 90 90 90 90 90 242 (Ia) 60 90 60 30 90 60 60 257 (Ia) 90 90 90 90 90 90 90 263 (Ia) 90 90 90 90 90 90 90 295 (Ia) 0 90 90 60 60 3 90 304 (Ia) 60 90 60 20 1 0 353 (Ia) 5 90 60 60 0 0 355 (Ia) 0 90 60 3 3 0 372 (Ia) 20 90 90 30 90 60 432 (Ia) 0 90 90 60 60 60 90 437 (Ia) 90 90 90 90 90 90 90 438 (Ia) 0 90 90 90 90 90 90 439 (Ia) 0 60 90 90 90 60 90 667 (Ia) 0 90 60 60 90 10 670 (Ia) 30 90 90 60 3 10 673 (Ia) 0 90 5 60 5 0 90 679 (Ia) 90 90 90 90 60 90 90
682 (Ia) 0 90 90 30 0 0 685 (Ia) 5 90 30 20 90 30 90 688 (Ia) 0 90 90 60 10 5 90 691 (Ia) 5 90 60 90 90 90 90 703 (Ia) 90 90 90 90 90 90 90 706 (Ia) 90 90 90 90 90 90 90 712 (Ia) 90 90 20 90 90 1 (Ib) 3 90 90 90 90 90 90 13 (Ib) 3 30 90 60 90 90 90 60 (Ib) 90 90 90 90 90 90 90 61 (Ib) 30 60 60 90 90 90 90 64 (Ib) 90 90 90 90 90 90 90 67 (Ib) 90 90 90 90 90 90 90 68 (Ib) 20 90 90 90 90 90 Key to Diseases: PLASVI Plasmopara viticola VENTIN Venturia inaequalis ERYSGT Erysiphe graminis tritici PUCCRT Puccinia recondita PHYTIN Phytophthora infestans lycopersici

Claims (5)

  1. CLAIMS 1. A compound of formula (I):
    wherein R' is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkenyl or optionally substituted alkynyl; R2 is R8ON=C(R7) or RSHNN=C(R7); R3 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, haloalkoxy, cyano, SOAlkyl or SO2Alkyl; R4 is NH, NR6 or NC(=O)R6; R5 and R6 are, independently, hydrogen, alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted arylalkyl; R7is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, haloalkoxy, cyano, NR9R'0, optionally substituted aryl or optionally substituted heteroaryl; R8, R9 and R'O are, independently, hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroaryl, acyl or haloacyl; or R7 and R8 join together to provide an optionally substituted 5- or 6-membered heterocyclic ring; and X is O, S or NH.
  2. 2. Processes for preparing a compound as claimed in claim 1 as herein described.
  3. 3. A fungicidal composition comprising a fungicidally effective amount of a compound according to claim 1 and a fungicidally acceptable carrier or diluent therefor.
  4. 4. A method of combating fungi which comprises applying to plants, to the seeds of plants or to the locus of the plants or seeds, a compound according to claim 1 or a composition according to claim 3.
  5. 5. A process for preparing a compound of formula (5):
    comprising reacting a compound of formula (1):
    with an intermediate:
    wherein R' and R7 are as defined in claim 1 and R is hydrogen or halogen, hydroxy, mercapto, C1-4 alkyl, C2A alkenyl, C2A alkynyl, C1-4 alkoxy, C2A alkenyloxy, C2A alkynyloxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, C1-4 alkylthio, halo(C1-4)alkylthio, hydroxy(C1-4)alkyl, C1-4 alkoxy(C1-4)alkyl, C3-6 cycloalkyl, C3-6 cycloalkyl(C1-4)alkyl, phenyl, phenoxy, acyl, SF5, cyano, thiocyanato, nitro, -NR'R", -NHCOR', -NHCONR'R", -CQNR'R", -COOR', -SOR', -SO2R', -SO2(C3-6)alkenyl, -OSO2R', -NHSO2R', -SO2NR'R", -COR', -CR'=NR", -CR'=NOR" or -N=CR'R"; two substituents, when they are in adjacent positions on the aryl or heteroaryl ring can join to form a fused aliphatic ring (especially to form a fused 6-membered carbon aliphatic ring); R' and R" are independently hydrogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C3-6 cycloalkyl, C3-6 cycloalkyl(C1-4)alkyl, phenyl or benzyl; the phenyl, phenoxy and benzyl groups being optionally substituted with halogen, C1-4 alkyl, halo(C1-4)alkyl, C1-4 alkoxy or C1-4 haloalkoxy; when R' and R" are in -NR'R", CONR'R", -NHCONR'R" or -SO2NR'R" they can together form a 5- or 6-membered heterocyclic ring.
GB9816117A 1997-07-25 1998-07-23 Imidazoline-5-one compounds as anti-fungal agents Withdrawn GB2327676A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006503848A (en) * 2002-09-26 2006-02-02 リブ−エックス ファーマシューティカルズ，インコーポレイテッド Bifunctional heterocyclic compounds and methods of making and using them

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024467A1 (en) * 1992-05-22 1993-12-09 E.I. Du Pont De Nemours And Company Fungicidal imidazolinones
WO1995034541A1 (en) * 1994-06-10 1995-12-21 Rhone Poulenc Agrochimie Fungicidal 5-imino-2-imidazoline derivatives
WO1996002538A1 (en) * 1994-07-13 1996-02-01 Rhone Poulenc Agrochimie Fungicidal 2-imidazoline-5-one derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993024467A1 (en) * 1992-05-22 1993-12-09 E.I. Du Pont De Nemours And Company Fungicidal imidazolinones
WO1995034541A1 (en) * 1994-06-10 1995-12-21 Rhone Poulenc Agrochimie Fungicidal 5-imino-2-imidazoline derivatives
WO1996002538A1 (en) * 1994-07-13 1996-02-01 Rhone Poulenc Agrochimie Fungicidal 2-imidazoline-5-one derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006503848A (en) * 2002-09-26 2006-02-02 リブ−エックス ファーマシューティカルズ，インコーポレイテッド Bifunctional heterocyclic compounds and methods of making and using them

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