WO1998004532A1

WO1998004532A1 - Fungicidal aryl-substituted five-membered heterocylic compounds

Info

Publication number: WO1998004532A1
Application number: PCT/GB1997/002014
Authority: WO
Inventors: Peter John West; Clive Leonard Cornell
Original assignee: Agrevo Uk Limited
Priority date: 1996-07-27
Filing date: 1997-07-28
Publication date: 1998-02-05
Also published as: GB9615832D0; ZA976694B; AU3700497A

Abstract

The invention provides compounds of general formula (I) wherein A is O, N or S; B is CR?1R2, CR1¿ or O; D is CR?3R4, CR3, NR3¿ or N; E is CR?5R6 or CR5¿; F is C or N; where the dotted line signifies that a single or a double bond can be present as appropriate; K is -O-, -S(O)¿n?-, -CHR?13-, -CHR13CHR14-, -CR13=CR14¿-, -C=C-, CHR13O-, -OCHR?13-, -CHR13S(O)¿n-, -S(O)nCHR13-, -CH(R13)O-N=C(R15)-, -C(R15)=N-OCH(R13)-, -C(R15)=N-O-, -O-N=C(R15)-, -CHR13OC(=O)N(R20)-, -CH(R?13)N(R21)N=C(R15¿)-, -C(=O)NR?15-, -CHR13SC(R15¿)=N-, CHR?13SC(R15)=N-NR15-, -CHR13SC(R15¿)=N-N=CR?15-, -CHR13OC(R15¿)=N-N=CR15-, or a direct bond; where the moiety depicted on the right side of the linkage is attached to L; L is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted phenyl, or Si(R22)3; or R9, K, and L taken together with the phenyl ring M, can form an optionally substituted fused aromatic ring system.

Description

FUNGTCIDAL ARYL-SUBSTITUTED FIVE-MEMBERED HETEROCYLIC COMPOUNDS

This invention relates to compounds having pesticidal, especially fungicidal, insecticidal and acaπcidal, activity.

The invention provides compounds of general formula I

wherein

A is O, N or S; B is CR 1 R2, CR¹ or 0, where R ^ and R2, which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted alkoxy, or optionally substituted alkylthio; D is CR³R⁴, CR³, NR³ or N, where R³ and R⁴, which may be the same or different, are hydrogen or optionally substituted alkyl;

E is CR5R6 or CR^, where R^ and R^, which may be the same or different, are hydrogen, halogen, -OR' or -S(0)_mR^; wherein R is optionally substituted alkyl, optionally substituted alkynyl, optionally substituted haloalkyl, halogen, amino or optionally substituted heterocyclyl; and m is 0, 1 or 2;

F is C or N; where the dotted line signifies that a single or a double bond can be present as appropriate; R9 to R1 2, which may be the same or different, are hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted alkoxy, or any two of R^ to

R^ 2 together with the phenyl ring M form an optionally substituted fused ring system; K is -0-, -S(0)_n -, -CHR^{1 3}-, -CHRl SCHR^{1 4}-, -CR^{1 3} = CR^{1 4}-, -C=C-, CHR1³0-, -OCHR^{1 3}-, -CHR^{1 3}S(0)_n-, -S{0)_nCHR^{1 3}-, -CH(R¹ )0-N = C(R15_K -C(R^{1 5}) = N-OCH(R^{1 3})-, -C(R^{1 5}) = N-0-, -0-N = C(R^{1 5})-, -CHR^{1 3}OC( = 0)N(R²⁰)-, -CH(R^{1 3})N(R²¹ )N = C(R^{1 5})-, -COO)NR^{1 5}-, -CHR^{1 3}SC(R^{1 5}) = N-, -CHR^{1 3}SC(R^{1 5}) = N-NR^{1 5}-,

-CHR^{1 3}SC(R^{1 5}) = N-N = CR^{1 5}-, -CHR^{1 3}OC(R^{1 5}) = N-N = CR^{1 5}-, or a direct bond; where the moiety depicted on the right side of the linkage is attached to L; R^{1 3} and R^ ⁴, which may be the same or different, are hydrogen or optionally substituted alkyl; R¹ ^ j_s hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted acyl or cyano, or R15 _and the carbon to which it is attached form a ring, which ring is optionally substituted; R ^ is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted cycloalkyl; R²^ is acyl; and n is 0, 1 or 2; L is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted phenyl, or Si(R²²)3, where R²² is optionally substituted alkyl; or R^, K, and

L taken together with the phenyl ring M, can form an optionally substituted fused aromatic ring system.

The term heterocyclyl includes both aromatic and non-aromatic heterocyclyl groups. Heterocyclyl groups are generally 5, 6 or 7-membered rings containing up to 4 hetero atoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, thiazolinyl, benzimidazolyl, tetrazolyl, benzoxazolyl, imidazopyridinyl, 1 ,3-benzoxazinyl, 1 ,3-beπzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, sulfolanyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, azepinyl, oxazepinyl, thiazepinyl, diazepinyl and benzodiazepinyl. Heterocyclyl groups may themselves be substituted.

Alkyl groups are preferably of 1 to 6 carbon atoms. Alkenyl and alkynyl groups are generally of 3 to 6 carbon atoms. Cycloalkyl or cycloalkenyl groups are preferably of 3 to 8 carbon atoms.

Substituents, when present on any alkyl, cycloalkyl, cycloalkenyl, alkenyl or alkynyl moiety include halogen, cyano, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted haloalkyl, hydroxy, nitro, optionally substituted amino, acyl, acyloxy, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted phenoxy and optionally substituted heterocyclyloxy. Preferred substituents are halogen.

Cycloalkyl or cycloalkenyl groups may also be substituted by alkyl.

Amino groups may be substituted for example by one or two optionally substituted alkyl or acyl groups, or two substituents can form a ring, preferably a 5 to 7- membered ring, which may be substituted and may contain other hetero atoms, for example morphoiine, or piperidine.

The term acyl includes the residue of sulfur and phosphorus-containing acids as well as carboxylic acids. Examples of acyl groups are thus -C( = 0)R^, -C( = 0)OR^{1 6}, -C( = X)NR^{1 6}R^{1 7}, -C( = 0)N(Rl 6)ORl 7_r -C( = 0)ONR^{1 6}R^{1 7}, -C( -= 0)N{R1 6)_NR1 7R1 8₍ -C( = 0)SR^{1 6}, -C( = S)SR^{1 6}, -S(0)_pR^{1 6}, -S(0)₂0R16₍

-S(0)_pNR^{1 6}R^{1 7}, -P( = X)(OR^{1 6})(OR^{1 7}), -C( = 0)-C( ^*= 0)OR^{1 6}, where R^{1 6}, R 1 7 _and R18 which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted phenyl or optionally substituted heterocyclyl or R^{1 7} and R¹ ** together with the atom(s) to which they are attached can form a ring; p is 1 or 2; and X is 0 or S.

Any fused ring system, when present, may be carbocyclic or heterocyclic, containing up to 3 heteroatoms; and include aromatic or non-aromatic 5, 6, or 7 membered rings. Preferred fused ring systems include naphthalene and quinoline. Substituents when present on any heterocyclyl group may for example be halogen, CN, NO2, acyl, O-acyl or a group T, OT or S(0)_nT, where n is 0, 1 or 2 and T is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted phenyl, optionally substituted heterocyclyl or optionally substituted amino or two adjacent groups on the ring together with the atoms to which they are attached form a carbocyclic or heterocyclic ring, which may be similarly substituted.

Substituents when present on any phenyl group are preferably as defined above for the substituents on the heterocyclyl group.

We have found that a particularly efficacious group of compounds are those of general formula I where A and F are both N. Preferably B is CR¹ and/or D is N and/or E is CR⁵.

The group R^ is preferably optionally substituted alkyl and/or R⁵ is preferably -OR⁷, -SR⁷, halogen, amino or optionally substituted heterocyclyl. When R⁵ is -SR⁷ or -OR⁷, R⁷ is preferably alkyl or haloalkyl.

Preferably K is -CHR^{1 3'}, -CHR^{1 3}0-, -CHR^{1 3}S(0)_n., -CH(R^{1 3})0-N = C(R^{1 5})-,

-CHR^{1 3}SC(R^{1 5}) = N-, -C( = 0)NR^{1 5}\ -C(R^{1 5}) = N-0CH(R^{1 3})-, -CHR^{1 3}SC(R^{1 5}) = N-N = CR^{1 5}-, -0-N = C(R^{1 5})-, -CHR^{1 3}0C(R^{1 5}) = N-N = CR¹5-, -CH(R^{1 3})N(R²¹ )N = C(R^{1 5})-, -CHR^{1 3}SC(R^{1 5}) = N-NR^{1 5}\ or a direct bond.

Particularly preferred linkages K are -CHR^{1 3}0- or -CH(R^{1 3})0-N = C(R^{1 5})-. R^ ³ is preferably hydrogen or optionally substituted alkyl. R^{1 5} j_s preferably hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted alkylthio or cyano, especially hydrogen or optionally substituted alkyl; and R^{2 1} is -C( = 0)Me.

Further, the group L is preferably an optionally substituted phenyl group, especially a substituted phenyl group, which is substituted by one or more of the following groups: C -\ -CQ alkyl, C-| -C6 haloalkyl, C -\ -CQ alkoxy, C-| -C6 alkylthio, C-i -Cβ haloalkoxy, halophenoxy, halogen, Cβ-Cg cycloalkyl, piperidino or pyrimidinyl.

Preferably R^ to R^ ² are each hydrogen or halogen.

In cases where the compounds of the invention exist as the E and Z isomers, the invention includes individual isomers as well as mixtures thereof.

The compounds of the invention have activity as fungicides, especially against fungal diseases of plants, e.g. mildews and particularly barley powdery mildew (Erysiphe graminis) and vine downy mildew (P/asmopara viticola), rice blast (Pyricularia oryzae), cereal eyespot (Pseudocercosporella herpotrichoides), rice sheath blight (Pellicularia sasakii), grey mould (Botrytis cinerea), damping off (Rhizoctonia sofani), wheat brown rust (Pυccin/a recondita), late tomato or potato blight (Phytophthora infestans), apple scab ( Venturia inaequalis), glume blotch (Leptosphaeria πodorum). Other fungi against which the compounds may be active include other powdery mildews, other rusts, and general pathogens of Deuteromycete, Ascomycete, Phycomycete and Basidomycete origin.

The invention also provides an agricultural composition comprising a compound of formula I in admixture with an agriculturally acceptable diluent or carrier.

The composition of the invention may of course include more than one compound of the invention.

In addition the composition can comprise one or more additional active ingredients, for example compounds known to possess plant-growth regulant, herbicidal, fungicidal, insecticidal or acaricidal properties. Alternatively the compound of the invention can be used in sequence with the other active ingredient.

The diluent or carrier in the composition of the invention can be a solid or a liquid optionally in association with a surface-active agent, for example a dispersing agent, emulsifying agent or wetting agent. Suitable surface-active agents include anionic compounds such as a carboxylate, for example a metal carboxylate of a long chain fatty acid; an N-acylsarcosinate; mono- or di-esters of phosphoric acid with fatty alcohol ethoxylates or salts of such esters; fatty alcohol sulfates such as sodium dodecyl sulfate, sodium octadecyl sulfate or sodium cetyl sulfate; ethoxylated fatty alcohol sulfates; ethoxylated alkylphenol sulfates; lignin sulfonates; petroleum sulfonates; alkyl-aryl sulfonates such as alkyl-benzene sulfonates or lower alkylnaphthalene sulfonates, e.g. butyl-naphthalene sulfonate; salts of sulfonated naphthalene-formaldehyde condensates; salts of sulfonated phenol-formaldehyde condensates; or more complex sulfonates such as the amide sulfonates, e.g. the sulfonated condensation product of oleic acid and N-methyl taurine or the dialkyl sulfosuccinates, e.g. the sodium sulfonate of dioctyl succinate. Nonionic agents include condensation products of fatty acid esters, fatty alcohols, fatty acid amides or fatty-alkyl- or alkenyl-substituted phenols with ethylene oxide, fatty esters of polyhydric alcohol ethers, e.g. sorbitan fatty acid esters, condensation products of such esters with ethylene oxide, e.g. polyoxyethylene sorbitan fatty acid esters, block copolymers of ethylene oxide and propylene oxide, acetylenic glycols such as 2,4,7, 9-tetramethyl-5-decyne-4,7-diol, or ethoxylated acetylenic glycols.

Examples of a cationic surface-active agent include, for instance, an aliphatic mono-, di-, or polyamine as an acetate, naphthenate or oleate; an oxygen-containing amine such as an amine oxide or polyoxyethylene alkylamine; an amide-linked amine prepared by the condensation of a carboxylic acid with a di- or polyamine; or a quaternary ammonium salt.

The compositions of the invention can take any form known in the art for the formulation of agrochemicals, for example, a solution, a dispersion, an aqueous emulsion, a dusting powder, a seed dressing, a fumigant, a smoke, a dispersible powder, an emulsifiable concentrate or granules. Moreover it can be in a suitable form for direct application or as a concentrate or primary composition which requires dilution with a suitable quantity of water or other diluent before application.

An emulsifiable concentrate comprises a compound of the invention dissolved in a water-immiscible solvent which is formed into an emulsion with water in the presence of an emulsifying agent.

A dusting powder comprises a compound of the invention intimately mixed and ground with a solid pulverulent diluent, for example, kaolin. A granular solid comprises a compound of the invention associated with similar diluents to those which may be employed in dusting powders, but the mixture is granulated by known methods. Alternatively it comprises the active ingredient absorbed or adsorbed on a pre-granular diluent, for example, Fuller's earth, attapulgite or limestone grit. Wettable powders, granules or grains usually comprise the active ingredient in admixture with a suitable surfactant and an inert powder diluent such as china clay.

Another suitable concentrate is a flowable suspension concentrate which is formed by grinding the compound with water or other liquid, a wetting agent and a suspending agent.

The concentration of the active ingredient in the composition of the present invention, as applied to plants is preferably within the range of 0.0001 to 1 .0 per cent by weight, especially 0.0001 to 0.01 per cent by weight. In a primary composition, the amount of active ingredient can vary widely and can be, for example, from 5 to 95 per cent by weight of the composition.

In the method of the invention the compound is generally applied to seeds, plants or their habitat. Thus, the compound can be applied directly to the soil before, at or after drilling so that the presence of active compound in the soil can control the growth of fungi which may attack seeds. When the soil is treated directly the active compound can be applied in any manner which allows it to be intimately mixed with the soil such as by spraying, by broadcasting a solid form of granules, or by applying the active ingredient at the same time as drilling by inserting it in the same drill as the seeds. A suitable application rate is within the range of from 5 to 1000 g per hectare, more preferably from 10 to 500 g per hectare.

Alternatively the active compound can be applied directly to the plant by, for example, spraying or dusting either at the time when the fungus has begun to appear on the plant or before the appearance of fungus as a protective measure. In both such cases the preferred mode of application is by foliar spraying. It is generally important to obtain good control of fungi in the early stages of plant growth as this is the time when the plant can be most severely damaged. The spray or dust can conveniently contain a pre- or post-emergence herbicide if this is thought necessary. Sometimes, it is practicable to treat the roots of a plant before or during planting, for example, by dipping the roots in a suitable liquid or solid composition. When the active compound is applied directly to the plant a suitable rate of application is from 0.025 to 5 kg per hectare, preferably from 0.05 to 1 kg per hectare.

Compounds of the invention may be prepared, in known manner, in a variety of ways.

Compounds of formula la; i.e. compounds of general formula I where A is N; B is

CR¹ ; D is CR³, where R³ is hydrogen; E is CR⁵, where R⁵ is -OR⁷; and F is N; can be prepared in two steps, according to the following reaction scheme. Firstly, compounds of formula II are reacted with R^ C( = 0}CH2C( = 0)Y (where Y is a leaving group, e.g. alkoxy) preferably in acetic acid solution to give compounds of formula III. Compounds of formula III are then treated with base followed by reaction with compounds of formula R⁷Q to give 1 a, where Q is a leaving group, e.g. halogen.

(la) Compounds of formula lb; i.e. compounds of general formula I where A is N; B is

CR¹ ; D is N; E is CR⁵, where R⁵ is OR⁷; and F is N; can be prepared by reacting compounds of formula IV with R⁷Q under basic conditions, where Q is a good leaving group. In the instance where R⁷ is methyl then (trimethylsilyl)diazomethane in methanolic toluene solution is a preferred reagent. In the instance when R⁷ is - CHF2 then it is preferred to use sodium hydride in conjunction with chlorodifluouromethane.

Alternatively, compounds of formula lb can be prepared via the halogenated compound Ic, where X is a halogen. Preferred reaction conditions comprise reaction with sodium methoxide in methanol. In addition, halogenated compounds of formula Ic, can be used to prepare a number of other compounds of general formula I. For example: i) compounds of formula Id, where R⁵ is -SR⁷ can be prepared using the corresponding sodium thioalkoxide; ii) compounds of formula le, i.e. where R⁵ is amino, can be prepared by reacting Ic with a primary or secondary amine.

(lb)

Compounds of formula IV can be prepared in two steps, according to the following reaction scheme, by firstly reacting compounds of formula II with α-keto acids of formula V, followed by cyclisation of the resulting hydrazones of formula VI, preferably using diphenylphosphoryl azide.

(ID (V) (VI)

(IV)

Alternatively compound of formula IV can be prepared according to the following reaction scheme.

Construction of the group -K-L can be performed using a number of strategies either before or after construction of the 5-membered heterocyclyl group. For example, compounds of formula If, i.e. compounds of general formula I where

-K-L is -C≡C-Si(R )3, can be prepared, according to the following reaction scheme, by coupling compounds of formula VII, where Q is preferably a halogen, with a silylacetylene VIII. Preferred reaction conditions comprise reacting compound VII with VIII in dimethylformamide solution in the presence of bis(triphenylphosphine)palladium (II) chloride, triethylamine and cuprous iodide.

(VII) (If)

Compounds of formula Ig; i.e. compounds of general formula I where K is

-(R^{1 5})C = N-OCH(R^{1 3})- wherein R^{1 5} is hydrogen; can be prepared according to the following reaction scheme by reacting aryl aldehydes of formula IX with alkoxyamines of formula X, where L is preferably optionally substituted phenyl. Preferred reaction conditions comprise refluxing IX and X in toluene solvent.

Compounds of formula Ih; i.e. compounds of general formula I where K-L contains the group -CHR^{1 3}0-, -CHR^{1 3}S- or -CHR^{1 3}NR2 wherein the carbon is attached to the benzene ring M, can be prepared by reacting compounds of formula XI where Q is a leaving group, preferably a halogen, with compounds of formula M-OR, M- SR or M-NR2 respectively, where M is a metallic element. Preferred reaction conditions comprise reacting compounds ROH, RSH or NHR2 with sodium hydride followed by addition of XI in tetrahydrofuran solution. Examples ROH include alcohols, oximes; examples of RSH include mercapto, dithiocarbamate or thiobenzamide compounds. Examples of NHR2 include primary or secondary amines or hydrazides.

(Ih)

We have discovered that many compounds of general formula I can be prepared following the above-mentioned chemistry using the key di-halogenated intermediate XII, where X is preferably chlorine. Intermediate XII can be prepared according to the following reaction scheme. In the case when X is chlorine, preferred halogenation conditions are POCI3 in DMF.

(XII)

Compounds of formula li, i.e. compounds of general formula I where K is a direct bond and L is an aryl group, can be prepared by palladium assisted coupling of aryl halide XIII with and aryl boronic acid according to the following reaction scheme.

(XIII)

(li) Other methods will be apparent to the chemist skilled in the art as will be the methods for preparing starting materials and intermediates.

The following Examples also make apparent various methods of preparing compounds of the invention as well as starting materials and intermediates of the invention. Structures of isolated novel compounds were confirmed by elemental and/or other appropriate analyses. Where ^"Η N.M.R. spectra were used to confirm chemical structure, these were performed in CDCI3.

Example 1 5-Chloro-3-methvl-1 -{α-f 1 -(3-trifluoromethvlDhenvl)ethvlideneaminn- oxy1-o-tolyl}-1 .2.4-triazole (Compound 1 )

Potassium tert-butoxide (5.1 g) was added portionwise with stirring to 3'- trifluoromethyl acetophenone oxime (9.0 g) in dry dimethylformamide ( 100 ml) at between 5 and 10 °C and stirring was continued for 10 minutes. The product from stage c) (10.1 g) was then added followed by dry dimethylformamide (20 ml). The solution was stirred for a further 1 5 minutes at approx. 5 °C and then allowed to warm to room temperature over 5 hours. The solution was then added to ice water and extracted with diethyl ether. The ether phases were combined and washed with water, dried (MgSO,--.), filtered and evaporated to give the title compound as an oil, ¹ H N.M.R. δ(ppm) 2.20 (3H, s, CH₃), 2.45 (3H, s, CH3), 5.10 (2H, s, CH₂), 7.25-7.70 (6H, m, ArH), 7.75 (1 H, d, ArH), and 7.85 (1 H, s, ArH).

Preparation of starting materials a) 3-Methvl-1 -phenyl-1 ,2.4-triazolin-5-one Phenyl hydrazine (43.2 g) was added to acetone (400 ml) at 0 °C.

Anhydrous sodium sulfate was added, followed by 4A molecular sieves. The solution was allowed to stand at room temperature overnight under nitrogen. The solution was filtered and the solvent removed to give the corresponding hydrazone.

Oxalyl chloride (81 .3 g) was added with stirring to acetamide (35.4 g) in dry toluene (600 ml) and the solution was heated gradually to 60 °C (N.B. copious gas evolution). The solution was maintained at 60 °C for 45 minutes and then heated slowly to reflux at 130 °C and refluxed for 1 .5 hours. The solution was cooled to room temperature and filtered. This solution was then added dropwise with stirring to the hydrazone in dry toluene (1 50 ml) cooled in ice. The minimum quantity of triethylamine (approx. 5 ml) was added to the solution to basify it. The solution was stirred at room temperature for 20 mins and then heated at reflux for 1 hour. The solution was extracted with water, dried (MgS04) and the solvent removed. Dilute hydrochloric acid [a solution containing concentrated hydrochloric acid (1 20 ml) in water (480 ml)] was then added to the resulting oil and the solution was heated at reflux for 30 minutes.

The solution was cooled in ice, filtered, and the resulting solid was washed with water, extracted with ether and then dried to give the title product.

b) 1 -(2-Hvdroxvmethvl^phRnvl⁾-3-methvl-1 .2.4-tnazolιn-5-one n-Butyllithium (87 ml, 2.5 ml in hexane) was added dropwise to the product from stage a) (20 g) in dry tetrahydrofuran (350 ml) at -78 °C over a 1 5 minute period and stirred at -78 °C for a further 2 hours. The solution was allowed to warm to -30 °C and stirring continued for 30 minutes. Paraformaldehyde ( 1 1 g) was then added and the solution was allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride solution (300 ml) was added followed by diethyl ether (200 ml) and the layers were separated. The organic phase was washed with saturated aqueous ammonium chloride solution, dried (MgSO.4), filtered, and the solvent removed. The resulting semi-solid was recrystallised from acetone to give the title product as a solid. A second crop of product was isolated by extracting the combined aqueous extracts with tetrahydrofuran. Drying of the organic phase (MgSO.4), filtration and evaporation gave a solid which was recrystallised from acetone to give the title compound. Both crops were combined and used as starting material for stage c) below.

c) 1 -(2-Chlorormethvlphenvl)-3-methyl-5-chloro- 1 .2.4-trιazole

A solution of the product from stage b) ( 10.5 g) phosphorus oxychloride ( 1 70 ml) and /,Λ/-dιmethylanιlιne ( 1 1 ml) was refluxed with stirring for 1 6 hours. The excess phosphorus oxychloride was distilled off in vacuo and the residue added to ice water. The aqueous solution was extracted with diethyl ether (x3), and the combined ether phases were washed with water, dried (MgSθ4), and filtered through a pad of silica gel. The filtrate was evaporated to give the title product. The following compounds (see Table 1 ) of general formula I, where A is N, B is CR¹ , D is N, E is CCI and R⁹, R¹⁰, R^{1 1} and R^{1 2} are hydrogen were prepared by methods analogous to those of Example 1 , wherein 3'-trifluoromethyl acetophenone oxime was replaced by the corresponding oxime, and acetone was replaced by the corresponding ketone to form the hydrazone.

Table 1

Cmp R¹ -K- L m.pJ°C

2 Et -CH₂-0-N = C(Me)- 3-CF3-phenyl 77-8

3 Pr' -CH₂-0-N = C(Me)- 3-CF3-phenyl 43-5

4 Me -CH₂-0-N = C(Me)- 4-iodopheπyl 105-10

5 Me -CH₂-0-N = C(Me)- 3-CI-phenyl oil

6 Me -CH₂-0-N = C(Me)- 4-Pr'-phenyl 93-4

7 Me -CH₂-0-N = C(Me}- 3,4,5-tri-MeO-phenyl oil

8 Me -CH₂-0-N = C(Me)- 4-Me-phenyl 61 -2

9 Me -CH₂-0-N = C(Me)- 4-Bu^t-phenyl oil

10 Me -CH₂-0-N = C(Me)- 4-Br-phenyl 84-5

1 1 Me -CH₂-0-N = C(Me)- 3,4-diMe-phenyl oil

12 Me -CH -0-N = C(Me)- 4-CHF2θ-phenyl oil

1 3 Me -CH₂-0-N = C(Me)- 3,5-diCF3-phenyl 82-5

The H N.M.R. data of those compounds in Table 1 which did not possess discrete melting points at room temperature are presented below. Compound 5

¹H N.M.R. δ(ppm) 2.12 (3H, s, CH₃), 5.15 (2H, s, CH₂, 7.2-7.35 (3H, m, 3xArH) and 7.4-7.66 (5H, m, 5xArH).

Compound 7

¹H N.M.R. δ(ppm) 2.15 (3H, s, CH₃), 2.40 (3H, s, CH₃), 3.84 (3H, s, OCH₃), 3.89 (6H, s, 2xOCH₃), 5.14 (2H, s, CH₂), 6.80 (2H, s, 2xArH), 7.30 (1H, dd, ArH)), 7.43 (1H, t, ArH), 7.52, (1H, t, ArH) and 7.61 (1H, d, ArH).

Compound 9

¹H N.M.R. δ(ppm) 1.31 (9H, s, 3xCH₃), 2.17 (3H, s, CH3), 2.42 (3H, s, CH3), 5.14 (2H, s,CH₂), 7.31 (3H, m, 3xArH), 7.49 (4H, m, 4xArH) and 7.62 (1H, d, ArH).

Compound 11

¹H N.M.R. δ(ppm) 2.17 (3H, s, CH3), 2.24 (6H, d, 2xCH₃), 2.42 (3H, s, CH3), 5.16 (2H, s, CH₂), 7.08 (1H, d, ArH), 7.32 (3H, m, 3xArH), 7.43 (1H, t, ArH), 7.53 (1H, t, ArH) and 7.62 (1H, d, ArH).

Compound 12

¹H N.M.R. δ(ppm) 2,17 (3H, s, CH3), 2.42 (3H, s, CH3), 5.17 (2H, s, CH₂), 6.50 (1H, t, CHF₂), 7.08 (2H, d, 2xArH), 7.32 (1H, d, ArH), 7.44 (IH, t, ArH) and 7.58 (4H, m, 4xArH).

Compound 15

¹H N.M.R. δ(ppm) 2.15 (3H, s, Me), 2.36 (3H, s, Me), 2.42 (3H, s, Me), 5.15 (2H, s, CH₂), 7.27-7.36 (3H, m, 3xArH) and 7.4-7.63 (4H, m, 4xArH).

Compound 16 ¹H N.M.R. δ(ppm) 2.11 (3H, s, Me), 2.43 (3H, s, Me), 5.12 (2H, s, CH₂) 7.33 (1H, d, ArH), 7.45-763 (5H, m, 5xArH) and 7.66 (1H, s, ArH). Compound 17

!H N.M.R. δ(ppm) 1.4 (9H, s, t-butyl), 2.15 (3H, s, CH₃), 5.2 (2H, s, OCH₂), 7.5

(6H, m, ArH), 7.75 (1H, d, ArH), and 7.8 (1H, s, ArH).

Compound 18

¹H N.M.R. δ(ppm) 1.40 (4H, m, 2xCH₂), 1.80 (6H, m, 3xCH₂), 2.16 (3H, s, CH₃), 2.42 (3H, s, CH₃), 2.50 (1H, m, CH), 5.12 (2H, s, CH₂), 7.19 (2H, d, 2xArH), 7.31 (1H, d, ArH), 7.49 (4H, m, 4xArH) and 7.62 (1H, d, ArH).

Compound 19

¹H N.M.R. δ(ppm) 1.63 (6H, m, 3xCH₂), 2.12 (3H, s, CH₃), 2.42 (3H, s, CH₃), 3.20 (4H, m, 2xCH₂), 5.10 (2H, s, CH₂), 6.83 (2H, d, 2xArH), 7.30 (1H, d, ArH), 7.48 (3H, m, 3xArH), 7.55 (1H, d, ArH) and 7.62 (1H, d, ArH).

Compound 21

¹H N.M.R. δ(ppm) 2.42 (3H, s, CH₃), 5.38 (2H, s, CH₂), 7.11 (1H, dd, ArH), 7.34 (1H, d, ArH), 7.50 (1H, t, ArH), 7.60 (3H, m, 3xArH) and 7.68 (1H, d, ArH).

Compound 22 ¹H N.M.R. δ(ppm) 2.17 (3H, s, CH₃), 2.43 (3H, s, CH₃), 3.20 (2H, t, CH₂), 4.58 (2H, t, CH₂), 5.13 (2H, s, CH₂), 6.72 (1H, d, ArH), 7.31 (2H, d, 2xArH), 7.45 (2H, m, 2xArH), 7.52 (1H, t, ArH) and 7.62 (1H, d, ArH).

Compound 26 ¹H N.M.R. δ(ppm) 2.12 (3H, s, Me), 2.27 (3H, s, Me), 2.4 (3H, s, Me), 2.45 (3H, s, Me), 5.2 (2H, s, CH₂), 7.2 (1H, d, ArH), 7.27 (1H, m, ArH), 7.39 (1H, dd, ArH) and 7.45-7.69 (5H, m, 5xArH).

Compound 27 Compound 27 of general formula I, where A is N; B is CMe; D is N; E is CCI; R⁹, R¹⁰ and R¹² are hydrogen; R¹¹ is Cl; K is -CH₂-0-N = C(Me)-; and L is 3- CF3-phenyl was prepared by methods analogous to those of Example 1 using ortho-chlorophenyl hydrazine to give an oil, ^"Η N.M.R. δ(ppm) 2.2 (3H, s, Me), 2.4 (3H, s, Me), 5.1 2 (2H, s, CH₂), 7.27 ( 1 H, d, ArH), 7.4-7.48 (2H, m, ArH), 7.6 (2H, m, ArH), 7.75 ( 1 H, d, ArH) and 7.82 (1 H, s, ArH).

Example 2

5-Methoxv-3-mRthvl-1 -{α-f 1 -(3-trifluoromethvlphenvnfithylideneamino- nxyl-o-tolvl}-1 .2.4-triazole (Compound 28)

To a solution of sodium methoxide (4.6 g) in methanol (100 ml) was added compound 1 (16.4 g) in dry 1 ,2-dimethoxyethane (100 ml), and the solution heated under reflux for 1 8 hours. Ethyl acetate (300 ml) was added and the solution washed with water. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with dilute brine (x2), dried (MgSU4), filtered and evaporated. Purification by silica gel chromatography gave the title product as a solid, m.p. 98-101 °C, ^"Η NMR δ(ppm) 2.22 (3H, s, Me), 2.35 (3H, s, Me), 4.1 7 (3H, s, Me), 5.27 (2H, s, -CH₂-) and 7.30-7.85 (8H, m, Ar-H).

The following compounds (see Table 2) of general formula I, where A is N, B is CR¹ , D is N, E is C(OR⁷) and R⁹, R^{1 0}, R ^{1 1} and R^{1 2} are hydrogen were prepared by methods analogous to those of Examples 1 and 2, wherein 3'-trifluoromethyl acetophenone oxime of Example 1 was replaced by the corresponding oxime, and in Example 2 sodium methoxide was replaced by the sodium alkoxide corresponding to R⁷.

Table 2

Cmp R1 R7 -K- L m.p./°C

29 Me Me -CH2-0-N = C(Me)- 2-pyridyl oil

30 Me Me -CH₂-0-N = C(Me)- N-Me-pyrrol-2-yl oil

31 Me Me -CH2-0-N = C(Me)- oil

32 Me Me -CH2-0-N = C(Me)- 3-pyridyl oil

33 Me Me -CH₂-0-N =C(Me)- 3-CF3-phenyl oil

34 Me Me -CH₂-0-N = C(Me)- oil

35 Me Me -CH2-0-N = C(Me)- 2-CF3-phenyl oil

36 Me Me -CH2-0-N =C(Me)- 2,4-diCI-phenyl 134-6

37 Me Me -CH₂-0-N = C(Me)- 2-Me-phenyl oil

38 Me Me -CH2-0-N = C(Me)- 3-nitrophenyl 1 13-4

39 Me Me -CH₂-0-N = C(Me)- 3-MeO-phenyl oil Cmp R1 R7 -K- L m.pJ°C

40 Me Me -CH₂-0-N = C(Me)- 3-Br-phenyl oil

41 Me Me -CH₂-0-N = C(Me)- 3-Me-phenyl oil

42 Me Me -CH₂-0-N = C(Me)- 2,4-diMe-phenyl oil

43 Me Me -CH₂-0-N = C(Me)- 3-(2,4-diCI-phenoxy)phenyl oil

44 Me Me -CH₂-0-N = CH- 4-pyridyl oil

5 Me Me -CH₂-0-N = C(Me)- 3,4-methylenedioxyphenyl oil

6 Me Me -CH₂-0-N = C(Bu^t)- 2-pyridyl oil

7 Me Me -CH₂-0-N = CH- 2-pyridyl oil

8 Me Me -CH₂-0-N = C(Me)- 4-biphenylyl oil

9 Me Me -CH₂-0-N = CH- 2-quinolinyl 1 14-6

50 Me Me -CH₂-0-N = C(2- 2-pyridyl 132-3 pyridyl)-

51 Me Me -CH₂-0-N = C(Me)- 2-pyrazinyl 94-5

52 Me Me -CH₂-0-N = C(Me)- 1 -naphthyl oil

53 Me Me -CH₂-0-N = C(Me)- 2-naphthyl 1 12-4

4 Me Me -CH₂-0-N = C(Me)- 4-CF3-phenyl 1 12-3

55 Me Et -CH₂-0-N =C(Me)- 3-CF3-phenyl 86-8

6 Me Bu -CH -0-N = C(Me)- 3-CF3-pheπyl 45-7 Cmp R1 R7 -K- L m.pJ°C

57 Me Pr' -CH₂-0-N = C(Me)- 3-CF3-phenyl oil

58 Et Me -CH₂-0-N = C(Me)- 3-CF3-phenyl 89-91

59 Pr' Me -CH -0-N = C(Me)- 3-CF3-phenyl 59-62

60 Me Me -CH₂-0-N = C(Me)- 4-Bu'-phenyl oil

61 Me Me -CH₂-0-N = C(Me)- 3-CF₃0-phenyl oil

62 Me Me -CH₂-0-N = C(Me)- 4-iodophenyl oil

63 Me Me -CH₂-0-N = C(Me)- 3-CI-phenyl 1 10-1 2

64 Me Ph -CH₂-0-N = C(Me)- 3-CF3-phenyl oil

65 Me Cyclo- -CH₂-0-N = C(Me)- 3-CF3-phenyl oil hexyl-

66 Me Me -CH₂-0-N = C(Me)- 4-Pr'-phenyl oil

67 Me Me -CH₂-0-N = C(Me)- 4-MeO-phenyl oil

68 Ph Me -CH₂-0-N = C(Me)- 3-CF3-phenyl oil

69 Me ailγl -CH₂-0-N = C(Me)- 3-CF3-phenyl oil

70 Me Me -CH₂-0-N = C(Me)- 4-Me-phenyl oil

71 Me Me -CH₂-0-N = C(Me)- 3,4,5-triMeO-phenyl oil

72 Me Me -CH₂-0-N = C(Me)- 3,5-diCF3-phenyl 109-1 1

73 Me Me -CH₂-0-N = C(Me)- 4-Br-phenyl 95-7

The ^H N.M.R. data of those compounds in Table 2 which did not possess discrete melting points at room temperature are presented below.

Compound 28 ¹H N.M.R. δ(ppm) 2.25 (3H, s, N = C(C±t₂)Py), ²-30 (3H, s, HetAr CH₃), 4.00 (3H, s, OMe), 5.20 (2H, s, PhCH₂), 7.15 (1H, m, ArH), 7.25-7.40 (3H, m, ArH), 7.50- 7.60 (2H, m, ArH), 7.751H, d, ArH) and 8.55 (1H, d, ArH).

Compound 3Q ¹H N.M.R. δ(ppm) 2.18 (3H, s, CH₃), 2.40 (3H, s, CH₃), 2.60 (3H, x, CH₃), 3.81 (3H, s, OMe), 3.87 (6H, s, 2xOCH₃), 5.17 (2H, s, CH₂), 6.80 (2H, s, 2xArH), 7.30 (1H, d, ArH), 7.40 (IH, t, ArH), 7.48 (1H, t, ArH) and 7.61 (1H, d, ArH).

Compound 31 ¹H N.M.R. δ(ppm) 0.64 (3H, t, CH₃), 1.20 (2H, m, CH₂), 2.15 (3H, s, CH₃), 2.40 (3H, s, CH₃), 2.40 (3H, s, CH₃), 3.20 (2H, m, CH₂), 4.10 (3H, s, OCH₃), 5.20 (2H, s, CH₂), 7.3-7.7 (6H, m, ArH), 7.75 (1H, d, ArH), 7.90 (1H, d, ArH) and 11.30 (1H, s, OH).

Compound 32

¹H N.M.R. δ(ppm) 2.25 (2H, CH3), 2.35 (3H, s, CH3), 4.05 (3H, s, OCH3), 5.25 (s, 2H, CH₂), 7.2-7.5 (4H, m, ArH), 7.60 (1H, d, ArH), 7.85 (1H, d, ArH), 6.60 (1H, m, ArH) and 8.80 (1H, s, ArH).

Compound 33

¹H N.M.R. δ(ppm) 2.20 (3H, s, N = C (CH3)), 2.35 (3H, s, HetAr CH3), 4.05 (3H, s, OMe), 5.15 (2H, s, PhCH₂), 7.25-7.70 (7H, m, ArH) and 7.80 (1H, s, ArH).

Compound 34 ¹H N.M.R. δ(ppm) 0.65 (3H, t, CH3), 1.25 (2H, m, CH₂), ²-30 (3H, s, CH3), 2.35 (3H, s, CH3), 3.00-3.40 (2H, m, CH₂), 4.1 (3H, s, OCH3), 5.20 (2H, m, CH₂), 7.3-7.7 (6H, m, ArH), 7.80 (1H, d, ArH), 8.05 (1H, d, ArH) and 13.60 (1H, s, OH).

Compound 35 (Mixture of rotamers) ¹H N.M.R. δ(ppm) 2.15 + 2.10 (3H, s, CH₃), 2.35 + 2.40 (3H, s, CH₃), 4.05 + 4.15 (3H, s, OCH₃), 5.20 (2H, s, CH₂), 7.25-7.65 (7H, m, ArH) and 7.70 (1H, d, ArH).

Comppund 37 ¹H N.M.R. δ(ppm) 2.15 (3H, s, CH3), 2.25 (3H, s, CH3), 2.40 (3H, s, CH3), 4.05 (3H, s, OCH3), 5.20 (2H, s, CH₂), 7.1-7.5 (7H, m, ArH) and 7.6 (H_r d, ArH).

Compound 39

¹H N.M.R. δ(ppm) 2.20 (3H, s, CH3), 2.40 (3H, s, CH3), 3.80 (3H, s, OCH3), 4.10 (3H, s, OCH3), 5.20 (2H, s, CH₂), 6.90 (IH, d, ArH), 7.15-7.50 (6H, m, ArH) and 7.60 (1H, d, ArH).

Compound 40

^'■ N.M.R. δ(ppm) 2.20 (3H, s, CH3), 2.35 (3H, s, CH3), (4.10 (3H, s, OCH3), 5.25 (2H, s, CH₂), 7.20-7.60 (7H, m, ArH) and 7.75 (1H, s, ArH).

Compound 41

^"•H N.M.R. δ(ppm) 2.20 (3H, s, CH3), 2.35 (6H, s, 2xCH₃), 4.05 (3H, s, OCH₃),

5.25 (2H, s, CH₂), 7.1-7.5 (7H, m, ArH) and 7.6 (1H, d, ArH).

Compound 42

¹H N.M.R. δ(ppm) 2.15 (3H, s, CH3), 2.20 (3H, s, CH3), 2.30 (3H, s, CH3), 2.35 (3H, s, CH3), 4.05 (3H, s, OCH3), 5.20 (2H, s, CH₂), 6.95-7.15 (3H, m, ArH), 7.35-7.50 (3H, m, ArH) and 7.6 (1H, d, ArH). Compound 43

¹H N.M.R. δ(ppm) 2.20 (3H, s, CH₃), 2.35 (3H, s, CH₃), 4.05 (3H, s, OCH₃), 5.2 (2H, s, CH₂), 6.9-7.0 (2H, m, ArH), 7.35-7.50 (7H, m, ArH), 7.60 (1H, d, ArH) and 7.75 (1H, s, ArH).

Compound 44 (mixture of rotamers)

¹H N.M.R. δ(ppm) 2.35 + 2.40 (3H, s, CH3), 4.05 (3H, s, OCH3), 5.25 + 5.45 (2H, s, CH₂), 7.2-7.6 (5H, m, ArH), 8.00 + 8.10 (1H, s, = CH), and 8.60 + 8.70 (2H, d, ArH).

Compound 45

¹H N.M.R. δ(ppm) 2.15 (3H, s, CH3), 2.35 (3H, s, CH3), 4.05 (3H, s, OCH3), 5.20 (2H, s, CH₂), 5.95 (2H, s, CH ), 6.80 (1H, d, ArH), 7.05 (1H, d, ArH), 7.20 (1H, s, ArH), 7.3-7.5 (3H, m, ArH) and 7.6 (1H, t, ArH).

Compound 46

¹H N.M.R. δ(ppm) 1.20 (9H, s, 3xCH₃), 2.35 (3H, s, CH3), 4.00 (3H, s, OCH3), 5.00 (2H, s, CH₂), 7.05 (1H, d, ArH), 7.2-7.4 (5H, m, ArH), 7.70 (1H, t, ArH), and 8.65 (1H, d, ArH).

Compound 47

¹H N.M.R. δ(ppm) 2.40 (3H, s, CH3), 4.10 (3H, s, OCH3), 5.25 (2H, s, CH₂), 7.2-

7.5 (4H, m, ArH), 7.6-7.8 (3H, m, ArH), 8.20 (1H, s, =CH) and 8.60 (1H, d, ArH).

Compound 48

¹H N.M.R. δ(ppm) 2.25 (3H, s, CH3), 2.40 (3H, s, CH3), 4.15 (3H, s, OCH3),

5.25 (2H, s, CH₂) and 7.30-7.75 (13H, m, ArH). Compound 52

¹ H N.M.R. δ(ppm) 2.35 (3H, s, CH₃), 2.40 (3H, s, CH₃), 4.05 (3H, s, OCH₃), 5.30 (2H, s, CH₂), 7.30-7.50 (5H, m, ArH), 7.65 ( 1 H, d, ArH) and 7.80-7.95 (4H, m, ArH).

Compound 57

¹ H N.M.R. δ(ppm) 1 .35 (6H, d, CH(Cϋ₃)₂), 2.2 (3H, s, CH3), 2.35 (3H, s, CH3), 5.1 5 ( 1 H, m, OCH(CH₃)₂), 5.3 (2H, s, OCH₂), 7.4 (4H, m, ArH), 7.6 (2H, dd, ArH), 7.8 (1 H, d, ArH) and 7.85 ( 1 H, s, ArH).

Compound 60

1 H N.M.R. δ(ppm) 0.87 (6H, d, 2CH₃), 1 .84 (1 H, m, CH), 2.2 (3H. s. CH3), 2.36 (3H, s, CH₃), 2.48 (2H, d, CH₂), 4.06 (3H, s, OMe), 5.2 (2H, s, CH₂), 7.09 (2H, d 2xArH), 7.3-7.48 (2H, m, 2xArH), 7.5 (2H, d, 2xArH) and 7.6 (1 H, d, ArH).

Compound 61

^"Η N.M.R. δ(ppm) 2.2 (3H, s, Me), 2.33 (3H, s, Me), 4.09 (3H, s, OMe), 5.24 (2H, s, CH₂), 7.3-7.6 (7H, m, 7xArH) and 7.2 (1 H, d, ArH).

Compound 62

¹ H N.M.R. δ(ppm) 2.18 (3H, s, Me), 2.35 (3H, s, Me), 4.06 (3H, s, OMe), 5.21 (2H, s, CH₂), 7.21 -7.48 (6H, m, 6xArH) and 7.57 (2H, m, 2xArH).

Compound 64

¹ H N.M.R. δ(ppm) 2.2 (3H, s, CH3), 2.35 (3H, s, CH3), 5.35 (2H, s, OCH₂), 7.3 (3H, m, ArH), 7.4 (2H, m, ArH), 7.5 (4H, m, ArH), 7.6 (2H, dd, ArH), 7.9 (1 H, d, ArH) and 7.85 (1 H, s, ArH).

Compound 65

¹ H N.M.R. δ(ppm) 1 .2 (2H, m cyclohexyl), 1 .4 (2H, m, cyclohexyl), 1 .5 (2H, m, cyclohexyl), 1 .7 (2H, m, cyclohexyl), 2.0 (2H, m, cyclohexyl), 2.25 (3H, s, CH3), 2.35 (3H, s, CH₃), 4.9 (1H, m, cyclohexyf-OCH), 5.3 (2H, s, 0CH₂), 7.4 (4H, m, ArH), 7.6 (2H, dd, ArH), 7.8 (1H, d, ArH) and 7.85 (1H, s, ArH).

Compound 66 ¹H N.M.R. δ(ppm) 1.22 (6H, d, 2xCH₃), 2.20 (3H, s, CH₃), 2.36 (3H, s, CH₃), 4.07 (3H, s, 0CH₃), 5.20 (2H, s, CH₂), 7.19 (2H, d, 2xArH), 7.30 (1H, m, ArH), 7.41 (2H, m, 2xArH), 7.51 (2H, d, 2xArH) and 7.59 (1H, d, ArH).

Compound 67 ¹H N.M.R. δ(ppm) 2.19 (3H, s, CH3), 2.35 (3H, s, CH3), 3.79 (3H, s, OCH3), 4.07 (3H, s, OCH3), 5.20 (2H, s, CH₂), 6.85 (2H, d, 2xArH), 7.32 (1H, t, ArH), 7.41 (2H, m, 2xArH), 7.53 (2H, d, 2xArH) and 7.58 (IH, t, ArH).

Compound 68 ¹H N.M.R. δ(ppm) 2.15 (3H, s, CH3), 4.1 (3H, s, OCH3), 5.3 (2H, s, OCH₂), 7.4

(7H, m, ArH), 7.6 (2H, m, ArH), 7.7 (IH, d, ArH), 7.8 (1H, s, ArH) and 8.1 (2H, d, ArH).

Compound 69 ¹H N.M.R. δ(ppm) 2.2 (3H, s, CH3), 2.35 (3H, s, CH3), 4.85 (2H, d,

OCH2CH = CH₂), 5.25 (2H, s, OCH₂), 5.3 (2H, m, OCH₂CH = CH2)- 6-0 (1H, m, OCH₂CH, = CH2), 7.4 (4H, m, ArH), 7.6 (2H, dd, ArH), 7.8 (1H, d, ArH) and 7.85 (1H, s, ArH).

Compound 70

¹H N.M.R. δ(ppm) 2.20 (3H, s, CH3), 2.39 (6H, s, 2xCH₃), 4.07 (3H, s, OCH3), 5.22 (2H, s, CH₂), 7.17 (2H, d, 2xArH), 7.25-7.56 (5H, m, 5xArH) and 7.60 (1H, d, ArH). Compound 71

¹ H N.M.R. δ(ppm) 2.21 (3H, s, CH₃), 2.38 (3H, s, CH₃), 3.84 (3H, s, OCH₃), 3.90 (6H, s, 2xOCH₃), 4.09 (3H, s, OCH3), 5.23 (2H, s, CH₂), 6.82 (2H, s, 2xArH), 7.35 (1 H, t, ArH), 7.42 (2H, m, 2xArH) and 7.60 (1 H, d, ArH).

Compound 80

^"Η N.M.R. δ(ppm) 1 .32 (9H, s, 3xCH₃), 2.20 (3H, s, CH3), 2.37 (3H, s, CH3), 4.06 (3H, s, OCH3), 5.21 (2H, s, CH₂), 7.37 (5H, m, 5xArH), 7.54 (2H, d, 2xArH) and 7.60 ( 1 H, d, ArH).

Compound 84

^"Η N.M.R. δ(ppm) 1 .63 (6H, m, 3xCH₂), 2.1 7 (3H, m, 3xCH₂), 2.37 (3H, s, CH3), 3.20 (4H, m, 2xCH₂), 4.05 (4H, m, 2xOCH₃), 5.1 9 (2H, s, CH₂), 6.84 (2H, d, 2xArH), 7.29 ( 1 H, d, ArH), 7.35 (2H, m, 2xArH), 7.49 (2H, d, 2xArH) and 7.60 (1 H, d, ArH).

Compound 86

¹ H N.M.R. δ(ppm) 2.05 (3H, s, CH3), 2.30 (3H, s, SMe), 4.05 (3H, s, OMe), 5.25 (2H, s, PhCH2θ), 7.30-7.50 (7H, m, Ar-H) and 7.60 (1 H, d, Ar-H).

The following compounds (see Table 3) of general formula I, where A is N, B is

CMe, D is N, E is C(OMe), R^{1 0} and R^{1 2} are hydrogen, K is -CH₂-0-N = C(Me)-, and

L is 3-CF3-phenyl were also prepared by methods analogous to those of Examples 1 and 2, wherein in Example 1 , stage a) phenyl hydrazine was replaced by the corresponding halophenyl hydrazine.

Table 3

Cmp R9 RU m.p. C

87 F H oil

88 H Cl 120-2

The ¹ H N.M.R. data of compound 87 in Table 3 was isolated as an oil, ¹ H N.M.R. δ(ppm) 2.2 (3H, s, Me), 2.33 (3H, s, Me), 4.03 (3H, s, OMe), 5.23 (2H, s, CH₂), 7.12 (1 H, t, ArH), 7.3-7.45 (3H, m, 3xArH), 7.54 (1 H, d, ArH), 7.75 (1 H, d, ArH) and 7.83 (1 H, s, ArH).

The following compounds (see Table 4) of general formula I, where A is N, B is

CR¹ , D is N, E is C(SMe) and R⁹, R^{1 0}, R^{1 1} and R^{1 2} are hydrogen were prepared by methods analogous to those of Example 1 and 2, wherein in Example 2 sodium methoxide was replaced by sodium thiomethoxide.

Table 4

Cmp R 1 -K- L m.pJ°C

89 Et -CH2-0-N = C(Me)- 3-CF3-pheπyl 106-8

90 Pr' -CH2-0-N = C(Me)- 3-CF3-phenyl 93-5

91 Ph -CH₂-0-N = C(Me)- 3-CF3-phenyl oil

92 Me -CH₂-0-N = C(Me)- 4-iodophenyl 92-5

93 Me -CH₂-0-N = C(Me)- 3-CI-phenyl oil

94 Me -CH₂-0-N = C(Me)- 4-Pr'-phenyl 84-5

95 Me -CH₂-0-N = C(Me)- 4-CI-3-Me-phenyl 98-100

96 Me -CH₂-0-N = C(Me)- 3,4,5-triOMe-phenyl oil

97 Me -CH₂-0-N = C(Me)- 4-Me-phenyl oil

98 Me -CH₂-0-N = C(Me)- 4-cyclohexylphenyl 78-9

99 Bu^: -CH₂-0-N = C(Me)- 3-CF3-phenyl 78-9

100 Me -CH₂-0-N = C(CF₃)- 2-thienyl 82-3

101 Me -CH₂-0-N = C(Me)- 4-Br-phenyl 92-4

102 Me -CH₂-0-N = C(Me)- oil Q Cmp R¹ -K- L m.pJ°C

103 Me -CH₂-0-N = C(Me)- 5-indanyl oil

104 Me -CH₂-0-N = C(Me)- 4-CHF2θ-phenyl 87-8

105 Me -CH₂-0-N = C(Me)- 4-piperidinophenyl 102-3

106 Me -CH₂-0-N = CH- 5-pyrimidinyl oil

107 Me -CH₂-0-N = C(Me)- 4-Bu'-phenyl oil

108 Me -CH₂-0-N = C(CN)- phenyl 1 16-7

109 Me -CH₂-0-N = C(Me)- 3-CF₃-phenyl 1 18-21

1 10 Me -CH₂-0-N = C(Me)- 4-But-phenyl 67-8

1 1 1 Me -CH₂-0-N = C(Me)- 3,4-diMe-phenyl 65-6

The H N.M.R. data of those compounds in Table 4 which did not possess discrete melting points at room temperature are presented below.

Compound 91

¹ H N.M.R. δ(ppm) 2.15 (3H, s, CH₃), 2.7 (3H, s, SCH₃), 5.25 (2H, s, OCH₂), 7.4 (6H, m, ArH), 7.5 (2H, m, ArH), 7.6 (1 H, d, ArH), 7.7 (1 H, d, ArH), 7.8 (1 H, s, ArH) and 8.1 5 (2H, d, ArH).

Compound 93

¹ H N.M.R. δ(ppm) 2.1 2 (3H, s, Me), 2.42 (3H, s, Me), 2.57 (3H, s, SMe), 5.18 (2H, s, CH₂), 7.1 5-7.48 (6H, m, 6xArH) and 7.6 (2H, m, 2xArH). Compound 96

¹H N.M.R. δ(ppm) 2.15 (3H, s, CH₃), 2.4 (3H, s, CH₃), 3.6 (3H, s, NCH₃), 4.05 (3H, s, OCH₃), 5.15 (2H, s, CH₂), 6.15 (1H, m, ArH), 6.40 (1H, m, ArH), 6.60 (1H, m, ArH), 7.40 (3H, m, ArH) and 7.55 (1H, d, ArH).

Compound 97

¹H N.M.R. δ(ppm) 2.20 (3H, s, CH3), 2.36 (3H, s, CH3), 2.42 (3H, s, CH3), 2.62 (3H, s, CH3), 5.17 (2H, s, CH₂), 7.12 (2H, d, 2xArH), 7.31 (1H, d, ArH), 7.41 (1H, t, ArH), 7.47 (3H, m, 3xArH) and 7.62 (1H, d, ArH).

Compound 1Q2

¹H N.M.R. δ(ppm) 2.19 (3H, s, CH3), 2.42 (3H, s, CH3), 2.61 (3H, s, CH3), 3.20 (2H, t, CH₂), 4.58 (2H, t, CH₂), 5.12 (2H, s, CH₂), 6.72 (1H, d, ArH), 7.30 (2H, m, 2xArH), 7.40 (1H, t, ArH), 7.48 (2H, m, 2xArH) and 7.61 (1H, d, ArH).

Compound 1Q3

¹H N.M.R. δ(ppm) 2.06 (2H, m, CH₂), 2.2 (3H, s, Me), 2.4 (3H, s, Me), 2.63 (3H, s, SMe), 2.9 (4H, m.2xCH₂), 5.12 (2H, s, CH₂), 7.15 (1H, d, ArH), 7.27-7.51 (5H, m, 5xArH) and 7.63 (1H, d, ArH).

Compound 106

¹H N.M.R. δ(ppm) 2.33 (3H, s, CH3), 2.62 (3H, s, CH₃), 5.34 (2H, s, CH₂), 6.64

(1H, d, ArH), 7.30 (1H, dd, ArH), 7.43 (2H, m, 2xArH), 7.60 (1H, d, ArH), 8.37 (1H, d, ArH) and 8.68 (1H, s, ArH).

Compound 107

¹H N.M.R. δ(ppm) 0.87 (6H, d, 2xMe), 1.87 (1H, m, Cid(CH₃)₂), 2.2 (3H, s, Me), 2.4 (3H, s, Me), 2.45 (2H, d, CH.₂CH(CH₃)₂), ⁵-¹² <²H, s, CH₂), 7.12 (2H, d, ArH), 7.3 (1H, dd, ArH), 7.4 (1H, t, ArH), 7.48 (3H, m, ArH) and 7.63 (1H, d, ArH). The following compounds (see Table 5) of general formula I, where A is N, B is

CMe, D is N, E is CR⁵ and R⁹, R^{1 0}, R^{1 1} and R^{1 2} are hydrogen were also prepared by methods analogous to those of Examples 1 and 2, wherein 3'-trifluoromethyl acetophenone oxime of Example 1 was replaced by the corresponding hydroxy or mercapto derivative of the group L.

Table 5

The ¹ H N.M.R. data of those compounds in Table 5 which did not possess discrete melting points at room temperature are presented below. Compound 112

¹H N.M.R. δ(ppm) 0.92 (2H, m, CH₂), 0.96 (3H, t, CH₃), 1.40 (4H, m, 2xCH₂), 1.80 (1H, m, CHN (CH₂)(CH₂)), 2.40 (3H, s, CH₃), 3.0-3.45 (2H, dd, CH₂), 4.10 (3H, s, OCH₃), 4.40 (2H, s, CH₂), 7.35 (2H, m, ArH) and 7.60 (1H, d, ArH).

Compound 113

1H N.M.R. δ(ppm) 2.35 (3H, s, CH3), 3.80 (2H, t, CH₂), 4.10 (3H, s, OMe), 4.15 (2H, t, CH₂), 4.60 (2H, s, CH₂), 6.80 (1H, d, ArH), 7.20 (1H, d, ArH), 7.35 (4H, m, ArH) and 7.70 (H, d, ArH).

Compound 114

¹H N.M.R. δ(ppm) 1.95 (2H, pentet, CH₂CJd2CH₂), 2.25 (3H, s, HetAr CH3), 3.55 (2H, t, OC±i2CH2), 4.00 (3H, s, OMe), 4.00 (2H, m,

4.40 (2H, s, Ar CH₂), 6.80 (1H, d, ArH), 7.05 (1H, dd, ArH), 7.20-7.40 (4H, m, ArH) and 7.45 (1H, dd, ArH).

Compound 115

¹H N.M.R. δ(ppm) 2.00 (2H, pentet, CH₂CU2CH2>, -30 (3H, s, HetAr CH3), 3.55 (2H, t, OCU2CH₂), 4.05 (3H, s, OMe), 4.05 (2H, t, OCH.2CH₂), 4.45 (2H, s, Ar CH₂) and 7.00-7.60 (8H, m, ArH).

Compound 116

^"Η N.M.R. δ(ppm) 2.15 (3H, s, ArCH₃), 2.30 (3H, s, HetAr CH3), 4.10 (3H, s, OMe), 4.45 (2H, s, Ar CH₂), 6.55 (1H, s, HetArH), 7.00 (1H, dd, ArH), 7.10-7.40 (6H, m, ArH), 7.60 (1H, m, ArH) and 8.55 (1H, s, HetArH).

Compound 117

¹H N.M.R. δ(ppm) 1.05 (3H, d, CHCH.3), 1.55 (1H, m, CH), 2.20 (IH, m, CH), 2.35 (3H, s, HetAr CH3), 2.80 (1H, m, CH), 3.65 (1H, m, CH), 3.80 (1H, m, CH), 4.05 (3H, s, OMe), 4.25 (2H, s, Ar CH₂), 7.25-7.40 (3H, m, ArH) and 7.55 (1H, m, ArH). Compound 118

¹H N.M.R. δ(ppm) 1.45-2.05 (8H, m, CH₂), 2.35 (3H, s, CH₂), 2.35 (3H, s, HetAr CH₃), 2.50 (1H, m, PhCJd(CH₂)2!< 3.60 (1H, m, OCtKCH₂)2), 4.05 (3H, s, OMe), 4.25 (2H, s, PhCH₂), 7.10-7.30 (6H, m, ArH), 7.35 (1H, dt, ArH), 7.45 (1H, dt, ArH) and 7.65 (1H, dd, ArH).

Compound 120

1H N.M.R. δ(ppm) 2.35 (3H, s, HetAr CH₃), 3.75 (2H, m, OCH₂), 4.05 (3H, s, OMe), 4.08 (2H, m, OCH₂), 4.60 (2H, s, PhCH₂), 6.90-7.00 (3H, m, ArH), 7.20- 7.45 (5H, m, ArH) and 7.60 (1H, dd, ArH).

Compound 121

¹H N.M.R. δ(ppm) 2.30 (3H, s, HetArCH₃), 3.30 (3H, s, CH₂ OMe), 3.45 (4H, m, 2xCH₂), 4.00 (3H, s, OMe), 4.45 (2H, s, PhCH₂), 7.25 (1H, m, ArH), 7.30 (1H, m, ArH), 7.40 (IH, m, ArH) and 7.60 (1H, m, ArH).

Compound 122

¹H N.M.R. δ(ppm) 1.60 (6H, m, = C(£ti₃)2), 1.65 (3H, s, =C(CJJ₃)CH₂), 2.05 (4H, m, 2xCH₂), 2.35 (3H, s, HetAr CH₃), 3.90 (2H, d, OCH₂), 4.00 (3H, s,OMe), 4.40 (2H, s, PhCH₂), 5.05 (1H, t, CH₂CH =C(CH₃)₂), 5.30 (1H, t, OCH₂CH = ), 7.25 (1H, dd, ArH), 7.35 (1H, t, ArH), 7.40 (1H, t, ArH) and 7.60 (1H, dd, ArH).

Compound 127 ¹H N.M.R. δ(ppm) 2.40 (3H, s, CH₃), 4.30 (2H, s, CH₂), 7.20 (1H, d, ArH), 7.35,

7.50 (4H, m, ArH), 7.65 (1H, d, ArH), 7.75 (1H, d, ArH), 8.20 (1H, d, ArH), 8.40 (2H, s, ArH), and 8.75 (1H, d, ArH). Compound 1 28

¹ H N.M.R. δ(ppm) 1 .40, (6H, s, 2xCH₃), 2.40 (3H, s, CH₃), 4.10 (3H, s, OMe),

4.40 (2H, s, = CH₂), 5.10 (2H, s, CH₂), 7.40 (3H, m, ArH) and 7.60 (1 H, m,

ArH).

Compound 1 30

¹ H N.M.R. δ(ppm) 2.35 (3H, s, CH₃), 4.05 (3H, s, OCH₃), 4.50 (2H, s, CH₂), 7.2-

7.6 (1 3H, m, ArH) and 7.75 (H, d, ArH).

The following compounds (see table 6) of general formula I, where A is N, B is

CMe, D is N, E is C(OMe) and R⁹, R^{1 0}, R^{1 1} and R^{1 2} are hydrogen were also prepared by methods analogous to those of Examples 1 and 2, wherein 3'- trifiuoromethyl acetophenone oxime of Example 1 was replaced by the dithiocarbamate derivative corresponding to -K-L in Table 6.

Table 6

Cmp -K- L m.p./°C

132 -CH₂S-C(SMe) = N- 4-CI-phenyl oil

133 -CH₂S-C(SMe) = N- 4-Me-phenyl oil

134 -CH₂S-C(SMe) = N-NH- 2,4-diCI-phenyl oil

135 -CH₂S-C(SMe) = N- 3-CF3-phenyl oil

136 -CH₂S-C(SMe) ^*= NN = CH- 3-CF3-phenyl oil

137 -CH₂S-C(SMe) = NN = CH- 2,4-diCI-phenyl oil The ^"Η N.M.R. data of the compounds in Table 6 are as follows:

Compound 132 ¹H N.M.R. δ(ppm) 2.30 (3H, s, CH₃), 2.40 (3H, s, SMe), 4.00 (3H, s, OMe), 4.35 (2H, s, PhCH.₂S), 6.70 (2H, d, Ar-H), 7.20-7.40 (5H, m, Ar-H) and 7.50 (1H, s, Ar-H).

Compound 133 ¹H N.M.R. δ(ppm) 2.30 (3H, s, PHCH3), 2.35 (3H, s, CH3), 2.45 (3H, s, SMe), 4.05 (3H, s, OMe), 4.35 (2H, s, PhCti^S), 6.70 (2H, d, Ar-H), 7.10 (2H, d, Ar-H), 7.25-7.40 (3H, m, Ar-H) and 7.55 (1H, s, Ar-H).

Compound 134 ¹H N.M.R. δ(ppm) 2.15 (3H, s, CH3), 2.30 (3H, s, SMe), 3.90 (3H, s, OMe), 4.10 (2H, s, PhCH2S), 6.55 (1H, m, Ar-H), 6.95 (1H, d, Ar-H), 7.10-7.20 (5H, m, Ar- H), 7.30 (1H, m, Ar-H) and 8.30 (1H, s, NH).

Compound 135 ¹H N.M.R. δ(ppm) 2.15 (3H, s, CH3), 2.25 (3H, s, SMe), 3.85 (3H, s, OMe), 4.20 (2H, s, PhCH_2S), 6.80 (1H, d, Ar-H), 6.90 (1H, s, Ar-H), 7.10-7.30 (5H, m, Ar-H) and 7.40 (1H, s, Ar-H).

Compound 136 (mixture of rotamers) ¹H N.M.R. δ(ppm) 2.35 (3H, s, CH3), 2.40 + 2.50 (3H, s, SMe), 4.05 (3H, d,

OMe), 4.25 + 4.40 (2H, s, PhCH^S), 7.20-7.65 (6H, m, Ar-H), 7.90-8.05 (2H, m, Ar-H) and 8.83 (1H, d, N = CH).

Compound 137 (mixture of rotamers) 2.35 (3H, s, CH3), 2.40 + 2.55 (3H, s, SMe), 4.05 (3H, d, OMe), 4.25 + 4.45 (2H, s, PhCH^S), 7.10-7.40 (6H, m, Ar-H), 7.55-7.65 (1H, m, Ar-H) and 8.65 (1H, d,

N = CH). Compound 138

Compound 138 of general formula I, where A is N, B is CMe, D is N, E is C(OMe) and R⁹, R¹⁰, R^{1 1} and R^{1 2} are hydrogen, K is -CH₂S-C(Pr') = N-, and L is 4-CF₃- phenyl was prepared by methods analogous to those of Examples 1 and 2, wherein 3 '-trifluoromethyl acetophenone oxime of Example 1 was replaced by (4- trifluoromethyl)-2,2-dimethylbenzthioamide to give an oil, ¹ H N.M.R. δ(ppm) 1.05 (6H, d, 2xCH(CU3)2>.- ²-35 (3H, s, HetAr CH₃), 2.80 (1 H, septet, CH(CH₃)₂), 3.95 (3H, s, OMe), 4.20 (2H, s, Ar(H₂), 6.65 (2H, d, ArH), 7.20-7.40 (3H, m, ArH) and 7.50 (3H, m, ArH).

The following compounds (see Table 7) of general formula I, where A is N, B is CMe, D is N, E is CR⁵ and R⁹, R^{1 0}, R^{1 1} and R^{1 2} are hydrogen, K is -CH₂- were also prepared by methods analogous to those of Examples 1 and 2, wherein 3'- trifluoromethyl acetophenone oxime of Example 1 was replaced by the secondary amine corresponding to the group L.

Table 7

The ^ H N.M.R. data of those compounds in Table 7 which did not possess discrete melting points at room temperature are presented below.

Compound 141 (Mixture of rotamers)

¹ H N.M.R. δ(ppm) 2.40 (3H, s, CH₃), 4.05 (3H, s, OCH₃), 5.35 (2H, s, CH₂), 6.55 (1 H, s, ArH), 7.20 ( 1 H, d, ArH), 7.24-7.50 (7H, m, ArH) and 7.80 (2H, d, ArH) .

Compound 142 (mixture of rotamers) H N.M.R. δ(ppm) 1 .05 + 1 .1 5 (3H, d, CHCH3), 1 .60 (2H, dd, CH₂), 2.35 (3H, s, CH3), 2.45 (2H, d, CH₂), 3.40 (2H, s, CH₂), 3.50 (2H, m, CHCH3), 4.05 (3H, s, OCH3), 7.40 (3H, m, ArH) and 7.50 (1 H, m, ArH).

Compound 144

¹ H N.M.R. δ(ppm) 2.35 (3H, s, CH3), 3.45 (2H, t, CH₂), 3.65 (2H, t, CH₂), 3..70- 33.80 (4H, m, 2xCH2), 4.55 (2H, s, CH₂), 7.00 (2H m, ArH), 7.10 (4H, m, ArH), 7.30 (1 H, t, ArH) and 7.5 ( 1 H, d, ArH). Compound 146 (mixture of rotamers)

¹ H N.M.R. δ(ppm) 1 .2-2.1 (10H, m, CH2), 2.35 + 2.40 (3H, s, 2xCH₃), 4.05 and 4.10 (3H, s, 2xOCH₃), 5.30 (2H, s, CH₂), 7.20-7.45 (4H, m, ArH) and 7.8 (1 H, s, ArH).

Compound 147

Compound 147 of general formula I, where A is N; B is CMe; D is N; E is C(OMe); K is -CH₂N(C = OMe)-N = C(Me)-; L is 4-CI-phenyl; R⁹, R¹ °, R^{1 1} and R^{1 2} are hydrogen; was also prepared by methods analogous to those of Examples 1 and 2, wherein 3'-trifluoromethyl acetophenone oxime of Example 1 was replaced by (MeC = 0)NH-N = C(Me)-(4-CI-Ph) . The product was isolated as a solid, m.p. 94-5 °C.

Example 3 5-Methoxv-3-methvl-1 -r2-(3-trifluoromethvlbenzvloximinomethyl)phenvn-1 .2.4- triaznle (Compound 148)

A solution containing the product from stage a) (650 mg) and 3- trifluoromethylbenzylhydroxylamine hydrochloride (638 mg) in dry pyridine (5 ml) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice cooled 0.5M hydrochloric acid ( 100 ml) and extracted with diethyl ether (x3). The combined organic extracts were washed with water, dried (MgSO. ), filtered and the solvent removed. The resulting gum was purified by silica gel chromatography to give the title compound as an oil, ^ H N.M.R. δ(ppm) 2.35 (3H, s, CH3), 4.05 (3H, s, OMe), 5.1 5 (2H, s, PhCH.20), 7.30 (1 H, m, Ar-H), 7.35 (3M, m, Ar-H), 7.55 (2H, m, Ar-H), 7.65 ( 1 H, s, Ar-H), 7.90 ( 1 H, s, Ar-H) and 8.05 ( 1 H, s, N = CH).

Preparation of starting materials a) 5-Methoxy-3-mfithvl-1 -(2-formvlphenvl)-1 .2.4-triazole A solution of the product of stage b) (200 mg) and calcium carbonate (5.5 g) in 1 ,4 dioxan (2 ml) and water (2 ml) was heated under reflux for 3.5 hours. The solution was cooled and the dioxan was evaporated. The remainder was partitioned between dilute hydrochloric acid and dichloromethane. The layers were separated and the organic phase was washed with brine, dried (MgSθ4), filtered and evaporated to give the title compound as a solid.

b) 5-Methoxv-3-methvl-1 -(2.2-dibromomethvlphenvl)-1 .2.4-tria7nlp

The title product was prepared using bromination procedures known to the skilled person, for example by using Λ/-bromosuccinamide in the presence of UV light.

The following compounds (see Table 8) of general formula I, where A is N, B is

CMe, D is N, E is C(OMe) and R⁹, R^{1 0}, R^{1 1} and R ¹ are hydrogen were also prepared by methods analogous to those of Example 3.

Table 8

Cmp -K- L m.pJ°C

149 -CH = N-OCH₂- 4-CI-phenyl 140-2

150 -CH = N-OCH(Me)- phenyl oil

151 -CH = N-0- 2-tetrahydropyranyl oil

The ^ H N.M.R. data of those compounds in Table 8 which did not possess discrete melting points at room temperature are presented below.

Compound 1 50

¹ H N.M.R. δ(ppm) 1.60 (3H, d, CH3), 2.35 (3H, s, CH3), 4.00 (3H, s, OMe), 5.30 (1 H, m, O-CM), 7.25-7.45 98H, m, Ar-H), 7.85 (1 H, m, Ar-H) and 8.00 (1 H, s, N = Ctl). Compound 1 51

¹ H N.M.R. δ(ppm) 1 .50-1 .90 (6H, m, 3xCH₂), 2.35 (3H, s, CH₃), 3.60-3.95 (2H, m, O-CH2). -⁰⁵ <^3H- ^s< ^0Me>< ⁵-³⁵ < ^{1 H}- ' OCtlO), 7.30-7.50 (3H, m, Ar-H), 8.05 ( 1 H, m, Ar-H) and 8.10 (1 H, s, N = CH).

Example 4

5-Mfithoxv-3-methvl-1 -f2-(3.5-dichlorophenvl)phenvl)-1 .2.4-triazole (Compound 1521 A mixture containing the product from stage c) (0.5 g), tetrakistriphenylphosphine palladium (0) (108 mg) and 3,5-dichlorophenylboronic acid (0.47 g) in toluene (5 ml), ethanol ( 1 .5 ml) and 2M sodium carbonate (2.5 ml) was heated at reflux for 1 2 hours. The solution was cooled to room temperature and washed with brine. The phases were separated and the organic phase was dried (MgSθ4>, filtered, and evaporated to an oil which was purified by silica gel chromatography to give the title product as a solid, m.p. 86-7 °C.

Preparation of starting materials a) 2-(2-Bromnphenvlhvdrazono)propionic acid To a suspension of o-bromophenylhydrazine hydrochloride (52.1 g) in water

(300 ml) was added concentrated hydrochloric acid (30 ml) with caution. The resulting suspension was dissolved by heating to 70 °C. A solution of pyruvic acid (26 ml) in water (50 ml) was then added over a 5 minute period to produce a yellow precipitate. The reaction mixture was stirred for 3.5 hours 70 °C. The precipitate was filtered, washed with water and dried to give the title compound as a solid.

b) 5-Hvdroxy-3-methyl-1 -(2-bromophRnvl)-1 .2.4-triazole

To a solution of the product from stage a) (45.48 g), triethylamine (24.58 ml) in dry toluene ( 1 .5 I) at 80 °C was added diphenylphosphoryl azide

(38.0 ml) dropwise (N.B. effervescence ! exothermic !). After addition and when the effervescence had ceased, the solution was heated under reflux for 1 hour. The solution was allowed to cool and stand at room temperature for 48 hours. The solvent was removed to give a crude oil which was purified by silica gel chromatography to give the title product as a solid.

5-Methoxv-3-methvl-1 -(2-bromophenvl)-1 .2.4-tr zole A solution of the product from stage b) (0.5 g), silver carbonate (0.61 g) and iodomethane (0.5 ml) in toluene (20 ml) was stirred at 60 °C overnight. Further iodomethane (0.5 ml) was added and stirring was continued at 60 °C for 24 hours. The reaction mixture was filtered through a pad of silica, washing through with toluene. The filtrate and washings were evaporated and the residue purified by silica gel chromatography (ethyl acetate : petrol) to give the title product as a solid.

The following compounds (see Table 9) of general formula I, where A is N, B is CMe, D is N, E is C(OMe) and R⁹, R^{1 0}, R^{1 1} and R^{1 2} are hydrogen and K is a direct bond were also prepared by methods analogous to those of Example 4, wherein 3,5-dichlorophenylboronic acid was replaced by the boronic derivative corresponding to the group L.

Table 9

Cmp L m.p./°C

153 4-biphenylyl 132-4

154 2-furyl 81-2

155 4-formylphenyl 144-5

1 56 1 -naphthyl 92-3

The ! H N.M.R. data of Compound 1 58 is as follows: ¹ H N.M.R. δ(ppm) 2.30 (3H, s, CH₃), 3.50 (3H, s, OMe), 7.1 5 (3H, m, Ar-H), 7.45 (4H, m, Ar-H), 7.70 (2H, d, Ar-H), 7.95 (2H, d, Ar-H), and 8.65 ( 1 .H, d, Ar-H).

Example 5

5-Methoxy-3-methyl-1 -{4'-r/\ -(2-methvlthioethvl)carbamovllbiphenvl-2- yl}-1 .2.4-triazole (Compound 1 62)

To a solution of compound 1 61 (600 mg), triethylamine (0.36 ml) and dimethylformamide (2 drops) in dichloromethane (30 ml) at 0 °C was added dropwise oxalyl chloride (0.1 8 ml) in dichloromethane (5 ml). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Triethylamine (0.36 ml) and then 2-methylthioethylamine (0.21 ml) in dichloromethane (5 ml) were added and the resulting dark red solution was stirred for 1 .5 hours. 2N hydrochloric acid was then added and the reaction mixture was extracted with dichloromethane. The combined organic extracts were washed with saturated sodium bicarbonate solution and then brine, dried (MgSθ4> and filtered, and the solvent removed. The resulting gum was purified by silica gel chromatography to give the title compound as an oil, ¹ H N.M.R. δ(ppm) 2.1 5 (3H, s, CH₃), 2.30 (3H, s, SMe), 2.55 (2H, t, CH₂SMe), 3.55 (3H, s, OMe), 3.65 (2H, q, HNCH₂), 6.65

(1 H, t, NH), 7.20 (2H, d, Ar-H), 7.40-7.55 (4H, m, Ar-H) and 7.75 (2H, d, Ar-H). The following compounds (see Table 10) of general formula I, where A is N, B is

CMe, D is N, E is C(OMe) and R⁹, R ⁰, R ^{1 1} and R ^{1 2} are hydrogen and K is a direct bond were also prepared by methods analogous to those of Examples 1 to 5, wherein 2-methylthioethylamine in Example 5 was replaced by the corresponding amine or hydrazine.

Table 10

The 1 H N.M.R. data of those compounds in Table 10 which did not possess discrete melting points at room temperature are presented below.

Compound 165

¹ H N.M.R. δ(ppm) 1 .05-1 .35 (6H, m, 2xCH₃), 2.30 (3H, s, CH₃), 3.60 (3H, s,

OMe), and 7.10-7.55 (8H, m, Ar-H).

Compound 166

¹ H N.M.R. δ(ppm) 0.90 (6H, m, 2xCH₃), 2.20 (1 H, m, CH), 2.25 (3H, s, CH₃), 3.50 (3H, s, OMe), 3.70 (3H, s, C0₂Me), 4.70 (1 H, m, CH-N), 6.55 (1 H, d, NH), 7.15 (2H, d, Ar-H), 7.45 (4H, m, Ar-H) and 7.70 (2H, d, Ar-H).

Compound 167

¹ H N.M.R. δ(ppm) 1 .30 (9H, s, C(CH₃)₃), 2.30 (3H, s, CH₃), 3.50 (3H, s, MeO), 7.15 (2H, d, Ar-H), 7.35-7.55 (4H, m, Ar-H), 7.70 (2H, d, Ar-H) and 8.55 (1 H, s, NH). Compound 168

¹ H N.M.R. δ(ppm) 1 .30 (9H, s, C(CH₃)₃), 2.30 (3H, s, CH₃), 3.55 (3H, s, MeO),

7.25 (2H, d, Ar-M), 7.40-7.55 (4H, m, Ar-H), 8.10 (2H, d, Ar-H) and 8.55 (1 H, s,

NH).

The following compounds (see Table 1 1 ) of general formula I, where A is N, B is CMe, D is N, E is C(OMe) and R⁹, R^{1 0}, R¹ 1 and R ² are hydrogen were prepared by methods analogous to those of Examples 5, starting from 5-methoxy-3-methyl- 1 -(2-carboxyphenyl)-1 ,2,4-triazole and replacing 2-methylthioethylamine with the amine corresponding to L. The 5-methoxy-3-methyl-1 -(2-carboxyphenyl)-1 ,2,4- triazole can be prepared from the product of Example 4, stage c), using one of a number of methods available to the skilled person.

Table 1 1

Cmp -K- L m.pJ°C

171 -C( = 0)NH- 3,4-diMeO-benzyl oil

172 -C( = 0)NH- phenyl oil

173 -C( = 0)NMe- phenyl oil

The 1 H N.M.R. data of the compounds in Table 1 1 are as follows:

Compound 171 ¹ H N.M.R. δ(ppm) 2.1 5 (3H, s, CH₃), 3.85 (6.H, d, 2xMeO), 3.95 (3H, s, MeO), 4.35 (2H, d, N-CH₂>' 6.55 ( I H, t, NH), 6.75 (3H, dd, Ar-H), 7.30 ( 1 H, m, Ar-H), 7.50 (2H, m, Ar-H), and 7.85 ( 1 H, m, Ar-H). Compound 172

¹ H N.M.R. δ(ppm) 2.35 (3H, s, CH₃), 4.00 (3.H, s, MeO), 7.10 ( 1 H, t, Ar-H), 7.25

- 7.60 (7H, m, Ar-H), 7.90 ( 1 H, d, Ar-H) and 8.30 ( 1 H, s, NH).

Compound 173

¹ H N.M.R. δ(ppm) 2.30 (3H, s, CH₃), 3.40 (3H, s, N-CH₃), 4.00 (3H, s, OMe),

6.80 (2H, d, Ar-H), 7.10 (2H, d, Ar-H), 7.20-7.35 (4H, m, Ar-H) and 7.45 ( 1 H, d, Ar-H).

Example 6

5-(Λ/.Λ/-Dimethvlamino⁾-3-methyl-1 -{α-f 1 -(3-trifluoromethylphenyl)ethylideneamino- oxvl-o-tolvl}-1 .2.4-triazole (Compound 174) and 5-niperidino-3-methyl-1 -{ -ri -(3- trifluoromethylphenvl)ethvlideneamino-oxyl-o-tolyl}-1 .2.4-triazole (Compound 175) A solution of compound 1 ( 1 .0 g) and piperidine (2.1 g) in dry dimethylformamide (1 5 ml) was stirred at 120 °C for 48 hours. The solution was cooled and ice water added. The mixture was extracted with diethyl ether (x3), dried ( gSθ4), filtered and the solvent removed. The residue was purified by silica gel chromatography to give the two title compounds. Compound 175 was isolated as a solid, m.p. 105-8 °C. Compound 176 was isolated as an oil, ¹ H N.M.R. δ(ppm) 1 .45 (6H, m, piperidino), 2.25 (3H, s, CH ), 2.3 (3H, s, Me), 3.1 (4H, m, piperidino), 5.3 (2H, s,

CH₂), 7.4 (4H, m, Ar-H), 7.6 (2H, d, Ar-H), 7.75 (1 H, d, Ar-H) and 7.85 (1 H, s, Ar-H).

The following compounds (see Table 1 2) of general formula I, where A is N, B is CMe, D is N, E is CR⁵; K is -CH2θ-N = C(Me)-; L is 3-CF3-phenyl; and R^{1 0} and

R1 ² are hydrogen were also prepared by methods analogous to Example 6.

Table 12

The ^"Η N.M.R. data of those compounds in Table 12 which did not possess discrete melting points at room temperature are presented below.

Compound 177

¹H N.M.R. δ(ppm) 1.4 (6H, br.s, 3xCH₂), 2.18 (3H, s, Me), 2.24 (3H, s, Me), 3.0 (4H,br.s, CH2 CH2)' 5.2 (2H, s, CH₂), 7.24 (2H, s, 2xAr), 7.36 (1H, t, ArH), 7.47-7.51 (2H, m, ArH), 7.66 (1H, d, ArH) and 7.75 (1H, s, ArH).

Compound 178

¹H N.M.R. δ(ppm) 1.33-1.51 (12H, 2brs, 6xCH₂>, 2.2 (3H, s, Me), 2.3 (3H, s, Me), 2.63 (2H, m, CH ), 2.8 (2H, m, CH₂), 3.12 (4H, m, CU2NCH2), ⁵-² '^2H- ^s< CH₂), 6.96 (1H, d, ArH), 7.15 (1H, d, ArH), 7.3 (1H, m, ArH), 7.42 (1H, t, ArH), 7.57 (1H, d, ArH), 7.75 (1H, d, ArH), and 7.81 (1H, s, ArH). Compound 179

¹ H N.M.R. δ(ppm) 1 .42 (6H, brs, 3xCH₂), 2.24 (3H, s, Me), 2.33 (3H, s, Me), 3.12 (4H, m, £H2N£H₂h 5.2 (2H, q, CH₂), 7.15 (1 H, t, ArH), 7.3-7.48 (3H, m, 3xArH), 7.57 (1 H, d, ArH), 7.75 (1 H, d, ArH) and 7.83 (1 H, s, ArH).

The following compounds (see Table 13) of general formula I, where A is N, B is CMe, D is N, E is C(0CHF₂) and R⁹, R^{1 0}, R^{1 1} and R^{1 2} are hydrogen were prepared by methods analogous to those described above, replacing the benzyl chloride in Example 1 with the benzyl bromide, 5-chlorodifluoromethyl-3-methyl-1 - (2-bromomethylphenyl)-1 ,2,4-triazole (see stage b) below).

Compound 182 ¹ H N.M.R. δ(ppm) 0.95 (3H, t, CH₃), 1.4 (6H, m, 3xCH₂), 1.8 (1 H, m, CH), 2.5 (3H, s, CH₃), 3.0-3.50 (2H, dd, CH₂), 4.40 (1 H, m, CHF₂), 4.45 (2H, s, CH₂), 7.40 (3H, m, ArH) and 7.60 (1 H, m, ArH).

Preparation of starting materials for Compounds in Table 13 a) 5-Chlorodiflιmromethoxv-3-methvl-1 -(o-tolvl)-1 .2.4-triazole

To a solution of 3-methyl-1 -phenyl- 1 , 2, 4-triazolin-5-one (the product from Example 1 , stage a)) (5.0 g) was added sodium hydride (1 .59 g) in dimethylformamide at room temperature. The reaction mixture was cooled to -60 °C and a solution of chlorodifluoromethane in dimethylformamide was added. The reaction mixture was allowed to warm to room temperature and the reaction mixture was partitioned between diethyl ether/petrol (1 : 1 ) and saturated aqueous ammonium chloride. The layers were separated and the organic phase was dried (MgSθ4> filtered and concentrated. Purification by silica gel chromatography gave the title compound as an oil.

5-Chlorodifluoromethoxv-3-methvl-1 -⁽2-hmmomethylphenyl)-1 .2.4-triazolf-

The title product was prepared by treating the product from stage a) above with Λ/-bromosuccinamide in carbon tetrachloride solvent whilst irradiating with UV light.

Test Example

Compounds are assessed for activity against one or more of the following: Phytophthora infestans: late tomato blight Pfasmopara viticola: vine downy mildew

Erysiphe graminis f. sp. hordei: barley powdery mildew Erysiphe graminis f. sp. tritici: wheat powdery mildew Pyricularia oryzae: rice blast Pellicuia a sasakii: rice sheath blight Botrytis cinerea: grey mould

Venturia inaequalis: apple scab Leptosphaeria nodorum: glume blotch Aqueous solutions or dispersions of the compounds at the desired concentration, including a wetting agent, were applied by spray or by drenching the stem base of the test plants, as appropriate. Plants or plant parts were then inoculated with appropriate test pathogens and kept under controlled environment conditions suitable for maintaining plant growth and development of the disease. After an appropriate time, the degree of infection of the affected part of the plant was visually estimated. Compounds were considered active if they gave greater than 50% control of the disease at a concentration of 500 ppm (w/v) or less.

Compounds 23, 43, 44, 48, 52, 59, 80, 81 , 1 73 and 1 74 showed activity against

Phytophthora infestans;

Compounds 18, 21 , 28, 38, 40, 41 , 49, 51 , 66, 71 , 72, 75, 80, 81 , 84, 86, 91 , 100, 104, 107, 109, 1 1 9, 1 20, 1 21 , 1 27, 1 28, 1 32, 1 33, 134, 1 35, 137, 1 66,

167, 168, 171 , 174, 181 and 1 82 showed activity against Plasmopara viticola;

Compounds 8, 52, 53, 60, 61 , 70, 76, 80, 81 , 82, 84, 93, 100, 101 , 103, 104,

105, 106, 1 23, 127 and 148 showed activity against Pyricularia oryzae;

Compounds 28, 35 and 44 showed activity against Pellicularia sasakii; Compounds 39, 51 , 1 59 and 1 65 showed activity against Botrytis cinerea;

Compound 1 14 showed activity against Venturia inaequalis;

Compounds 33, 39, 40, 54, 70, 78, 80, 81 , 83, 86, 103, 104, 1 1 3, 1 30, 145,

147 and 1 52 showed activity against Leptosphaeria nodorum; and. Compounds 1, 28, 32, 34, 35, 39, 40, 54, 60, 61, 66, 72, 79, 80, 81, 90, 94, 95, 98, 101, 102, 103, 106, 111, 116, 119, 121, 138, 142, 147, 152 and 154 showed activity against Erysiphe graminis f. sp. tritici

Claims

Compounds of general formula I

wherein A is O, N or S;

B is CR¹ R², CR¹ or 0, where R¹ and R², which may be the same or different, are hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, optionally substituted alkoxy, or optionally substituted alkylthio;

D is CR³R⁴, CR³, NR³ or N, where R³ and R⁴, which may be the same or different, are hydrogen or optionally substituted alkyl;

E is CR⁵R6 or CR⁵, where R⁵ and R^, which may be the same or different, are hydrogen, halogen, -OR '' or -S(0)_mR^; wherein R? is optionally substituted alkyl, optionally substituted alkynyl, optionally substituted haloalkyl, halogen, amino or optionally substituted heterocyclyl; and m is 0, 1 or 2; F is C or N; where the dotted line signifies that a single or a double bond can be present as appropriate;

R⁹ to R^ , which may be the same or different, are hydrogen, halogen, cyano, nitro, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted alkoxy, or any two of R⁹ to R^ ² together with the phenyl ring M form an optionally substituted fused ring system; K is -0-, -S(0)_n -, -CHR^{1 3}-, -CHR1³CHR^{1 4}-, -CR^{1 3} = CR^{1 4}-, -C=C-, -CHR1 ³0-, -OCHR^{1 3}-, -CHR ³S(0)_n-, -S(0)_nCHR^{1 3}-, -CH(R^{1 3})0-N = C(R^{1 5})-, -C(R ⁵) = N-OCH(R^{1 3})-, -C(R^{1 5}) = N-0-,

-0-N = C(R ^{1 5})-, -CHR^{1 3}0C( = 0)N(R²⁰)-,

-CH(R^{1 3})N(R²¹ )N = C(R^{1 5})-, -C( = 0)NR^{1 5}-, -CHR^{1 3}SC(R^{1 5}) = N-,

-CHR^{1 3}SC(R^{1 5}) = N-NR¹ 5-, -CHR^{1 3}SC(R ^{1 5}) = N-N = CR^{1 5}-, -CHR^{1 3}0C(R^{1 5}) = N-N = CR^{1 5}-, or a direct bond; where the moiety depicted on the right side of the linkage is attached to L; R^{1 3} and

R^{1 4}, which may be the same or different, are hydrogen or optionally substituted alkyl; R^{1 5} is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted acyl or cyano, or R ⁵ and the carbon to which it is attached form a ring, which ring is optionally substituted; R²⁰ is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, optionally substituted alkenyl, optionally substituted alkynyl or optionally substituted cycloalkyl; R²¹ is acyl; and n is 0, 1 or 2; L is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocyclyl, optionally substituted phenyl, or Si(R² >3, where R²² is optionally substituted alkyl; or R⁹, K, and L taken together with the phenyl ring M, can form an optionally substituted fused aromatic ring system.

Compounds according to claim 1 wherein A and F are N.

Compounds according to claims 1 or 2 wherein B is CR¹ .

Compounds according to any preceding claim wherein D is N.

Compounds according to any preceding claim wherein E is CR⁵. 6 Compounds according to any preceding claim wherein R¹ is optionally substituted alkyl.

7 Compounds according to any preceding claim wherein R⁵ is -OR?, -SR , halogen, amino or optionally substituted heterocyclyl.

8 when R⁵ is -SR⁷ or -OR⁷, R⁷ is alkyl or haloalkyl.

9 Compounds according to any preceding claim wherein K is -CHR^{1 3}", -CHR^{1 3}0-, -CHR^{1 3}S(0)_n_, -CH(R^{1 3})0-N = C(R^{1 5})-, -CHR^{1 3}SC(R^{1 5}) = N-,

-C( = 0)NR^{1 5"}, -C(R^{1 5}) = N-OCH(R^{1 3})-, -CHR^{1 3}SC(R^{1 5}) = N-N = CR^{1 5"},

-O-N = C(R^{1 5})-, -CHR^{1 3}OC(R^{1 5}) = N-N = CR^{1 5"},

-CH(R^{1 3})N(R²¹ )N = C(R^{1 5})-, -CHR^{1 3}SC(R^{1 5}) = N-NR^{1 5}-, or a direct bond.

10 Compounds according to any preceding claim wherein K is -CHR^{1 3}0- or -CH(R^{1 3})0-N = C(R^{1 5})-.

1 1 Compounds according to any preceding claim wherein R^{1 3} is hydrogen or optionally substituted alkyl.

12 Compounds according to any preceding claim wherein, when present, R¹ is hydrogen, optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted alkylthio or cyano.

13 Compounds according to any preceding claim wherein, when present, R^{1 5} is hydrogen or optionally substituted alkyl.

14 Compounds according to any preceding claim wherein when present, R²¹ is -C( = 0)Me.

1 5 Compounds according to any preceding claim wherein L is an optionally substituted phenyl group. 16 Compounds according to any preceding claim wherein L is a substituted phenyl group.

17 Compounds according to any preceding claim wherein L is a phenyl group substituted by one or more of the following groups: C1 -C5 alkyl, C -\ -CQ haloalkyi, C - -CQ alkoxy, C-| -C6 alkylthio, C-j -Cs haloalkoxy, halophenoxy, halogen, C3-C8 cycloalkyl, piperidino or pyrimidinyl.

1 8 Compounds according to any preceding claim wherein R⁹ to R^{1 2} are each hydrogen or halogen.

1 9 Intermediates of general formula XII

(XII)

wherein X is a halogen, R is optionally substituted alkyl, and R⁹ to R^{1 2} are hydrogen.

0 Intermediates according to claim 19 wherein X is a halogen.

1 Intermediates according to claim 19 wherein X is chlorine.

2 A pesticidal composition comprising compounds as claimed in any preceding claim in admixture with an agriculturally acceptable diluent or carrier.