IE48281B1 - Acaricidal,larvicidal and ovicidal tetrazine derivatives and compositions,processes for their preparation and methods of using them - Google Patents

Description

This invention concerns certain tetrazines which are active against acarid eggs and larvae, processes for their preparation, compositions containing them and methods of using them.

Very many tetrazine derivatives are known compounds.

For example, United States Patent No. 3863010 discloses various phenyl and substituted phenyl tetrazines which are useful to relieve inflammation in warm-blooded animals. The Journal of Agriculture and Food Chemistry, vol 25, No 4, 1977, pages 888-892, provides further examples of substituted tetrazines derivatives. These have herbicidal activity. However, despite the large number of known tetrazine derivatives, there appears to be no mention of any of them possessing activity against animate pests such as insects or acarids.

We have now found that a particular group of tetrazine derivatives possesses surprisingly good activity against acarids, their eggs and their larvae.

In one aspect, this invention provides a method of 20 combating acarids, their eggs or their larvae, which comprises applying to a site either infested or liable to infestation with them- an effective amount of one or more substituted tetrazines of the formula: Ν—Ν or of the formula: R —R6 (II) Ν—N A1 4 wherein, R , R and R , which may be the same or different, each represent hydrogen, phenyl, alkyl of 1 to 6 carbon atoms, or alkenyl or alkynyl of 3 to 6 carbon atoms, each of which may be unsubstituted or substituted by one or more halogen atoms, hydroxy groups, cyano groups, carboxy groups, alkoxycarbonyl groups of 2 to 5 carbon atoms or alkoxy groups of 1 to 4 1 2 carbon atoms; or R and R together represent a single bond; R represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, or phenyialkyl of 7 to 10 carbon atoms, each of which may be unsubstituted or substituted by one or more halogen atoms, alkyl or alkoxy groups of 1 to 6 carbon atoms, nitro groups, cyano groups, mercapto groups or alkyluercapto groups of 1 to 4 carbon stems; and R represents a phenyl group substituted in at least the 2-position by fluorine, chlorine, bromine or iodine.

In another aspect, this invention provides an acaricida], larvicidal or ovicidal eanposition whicti canprises from 0.5 to 99% by weight of one or more ccnpounds of formula I or formula II as defined hereinbefore in association with a suitable carrier and/or surface active agent.

In a further aspect, tliis invention provides per se the compounds of formulae I and II with the proviso that, in the compounds of formula 1 12’ 1° wherein R° represents 2- fluorophenyl, When R and R represent a single bond R3 does not represent methyl, trifluoromethyl or 2-fluorophenyl, and when R1 2 3 and R both represent hydrogen, R does not represent trifluoromethyl. 4 R , F! and R independently preferably represent hydrogen or alkyl of 1 to 6, especially 1 to 4, carbon atoms, which is preferably unsubstituted, for example methyl, ethyl, n-propyl, isopropyl or t-butyl. In the compounds of formula I, hydrogen is especially 1 2 preferred for one of R and R , the other preferably representing alkyl, especially methyl or ethyl. hi the compounds of formula II, R1 and R4 each preferably represent alkyl, especially methyl or ethyl.

When R1 and/or RZ and/or R4 represents a substituted alkyl Rtoup, however, it is preferably substituted by hydroxy (e.g. 2-hydroxyethyl), but each may represent, for example, 2-chloroethyl, chloromethyl, cyanomethyl, carboxymethyl, methoxycarbonyl-methyl or 2-methoxyethyl if desired. 8 2 81 Preferred alkenyl and alkynyl groins which R3, R2 may represent are allyl and propargyl, which are preferably unsubstituted.

When R1 and/or R2 and/or R4 represents phenyl, it is preferably unsnbstituteil.

Wien R represents alkyl of 1 to 6 carbon atoms, it may, for example, be methyl, ethyl, n-propyl, isopropyl or, especially, t-butyl. Preferred cycloalkyl groups which R my represent include cyclopentyl and cyclohexyl. When R represents alkyl or cycloalkyl it is preferably unsubstituted. When substituted, however, it is preferably substituted by one or more halogen atoms, cyano groups or hydroxy groups, specific preferred substituted groups being trifluoromethyl, chloromethyl, cyanomethyl, trichloromethyl and 2-hydroxyethyl.

When R represents phenyl, as is preferred, it is desirably substituted by one or more halogen atoms, C 1 to 4 alkyl or alkoxy groups or nitro groups. The group is preferably mono-substituted, specific preferred groups being 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 3-nethylphenyl and 4-methylphenyl.

When P' represents a phenylalkyl group, it is preferably benzyl which is desirably unsubstituted or mono-substituted by halogen, e.g, 4-chlorobenzyl. p/’ preferably represents 2-chlorophenyl or 2-bromophenyl, especially 2-chlorophenyl, or a further substituted derivative thereof, for example 2,4-dichlorophenyl or 2-chloro-4-methylphenyl.

R2 and are preferably identical.

Where R^ in formula II represents hydrogen, the compounds are of 4828 1 course also compounds of formula I (where R represents hydrogen). i , 2 In a preferred group of compounds of Formula I, R anu R both represent hydrogen, or together represent a single bond, or one represents hydrogen while the other represents methyl, represents 2-chlorophenyl or 2-fluorophenyl, and R represents t-butyl, phenyl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 3-methylphenyl or 4-methylphenyl.

Specific preferred compounds of this invention are those of the Examples provided hereinafter. Particular mention may be made however of the most preferred compounds 3,6-bis(2-chlorophenyl)-1,2dihydro-l-nethyl-1,2,4,5-tetrazine and 3,6-bis(2-chlorophenyl)-1,2,4,5tetrazine.

In another aspect, this invention provides a process for the •preparation of tho compounds of formula I wherein R and R' represent IS other than a single bond, ir. which process a substituted azine of the formula: R3-C=N-N=C-R6 (TII) X X (wherein R3 and R^ are as defined hereinbefore and each X represents a leaving group) i-= reacted with a hydrazine of the formula: (TV) 2 (wherein R and R are as defined hereinbefore but do not together represent a bond) to give the desired compound.

The reaction is conveniently carried out at an elevated temperature, e.g. from 30° to 100°C, especially 50° to 80°C, in an 4828 1 appropriate solvent medium, e.g. an alkanol, e.g. ethanol, an ether, e.g. tetrahydrofuran, or a hydrocarbon.

X preferably represents halogen (especially chlorine or bromine), cyano, or C 1 to 4 alkoxy (especially methoxy).

The reaction of compounds of formulae III and IV appears to give 6 1 2 rise (when R° is not the same as R° and R1 is not the same as R ) to a mixture of isomeric products. The present invention extends of course to cover the isomeric structures which may be produced.

The substituted azines of formula III enployed as starting materials in the above process may themselves be prepared by a process in which a conpound of the formula: R3-A-R6 (V) «7 £ (wherein R and R are as defined hereinbefore, and A represents -CQNH-JHCO-, -CQNH-N-CH-, -CH=N-NHCO- or -CH=N-N=CH-) is halogenated to give the desired conpound of formula III wherein X represents halogen, and the product is, if desired, reacted with an anion forming conpound to give the corresponding conpound where X represents a different leaving group.

When A represents -C0NH-MIC0-, the halogenating agent is preferably a phosphorus pentahalide, especially phosphorus pentachloride or phosphorus pentabromide, and is preferably enployed in a suitable solvent medium, for example a hydrocarbon or halogenated hydrocarbon, e.g. carbon tetrachloride or o-dichlorobenzene. The reaction is conveniently effected at elevated tenperature, e.g. ¢828 1 from 70-150°C, especially from 90-110°C.

When A represents -G0NH-N=CH- or -CH-N-XHGO-, the halogenation is desirably achieved in two stages by reaction of the compound of formula V with a thionyl halide, especially thionyl chloride, and with the halogen itself, especially chlorine.

When A represents -CH=N-N=CH-, the halogenation is conveniently achieved in a single step reaction with the desired halogen in an appropriate solvent medium, for example acetic acid.

The compounds of formula V where A represents -CONH-NHCO- may be prepared by a process in which a hydrazide of the formula R3CQNHNH2 is reacted with a compound of the formula R^COY, where R3 and R® are as defined hereinbefore and Y represents halogen (especially chlorine or bromine), hydroxy, C 1 to 6 alkoxy or a group R6COO-, to give the desired compound.

The reaction is preferably carried out in the presence of a base, e.g. an alkali-metal hydroxide or carbonate, e.g. sodium hydroxide or carbonate, or an amine, e.g, triethylamine.

The reaction is conveniently effected at a temperature of from 5 to 50°C. Λ Where A represents -CONH-NHGQ- and RJ is the same as R , the conpounds of formula V may be prepared directly by reaction of a halide of formula P. CCHal where Hal represents halogen, especially chlorine or bromine, with hydrazine.

This reaction is desirably effected in a suitable solvent for the product, e.g. water, and in the presence of a base, e.g. an 4-8 28 f alkali-metal base, e.g. sodium hydroxide, lhe temperature enployed is preferably 5-3O°C.

The ccmpounds of formula V where A represents -CH=N-N=CH- and R3 and R6 are identical may be prepared by a process in which an 3 3 aldehyde of the formula R CHO where R is as defined hereinbefore is reacted with hydrazine in a suitable solvent medium to give the desired compound.

The solvent is preferably water and/or an alkanol, e.g. aqueous ethanol, and the reaction is preferably carried out at a tenperature of from 5 to 30°C, especially 10 to 20°C.

The conpounds of formula V where A represents -CONH-N=CH- or -CH=N-NHCO-may be prepared by reaction of a hydrazide of the formula R3COMfflHg or R^CONHNHg with an aldehyde respectively of the formula R6CHO or R3CH0.

The hydrazides of formula R3CONHNH2 enployed as starting materials may be prepared by conventional processes, for example by reaction of hydrazine with one molar proportion of the appropriate ester R3C00R where R represents alkyl, especially of 1 to 4 carbon atoms.

The compounds of formula I wherein R1 and R2 together represent a single bond may be prepared from the corresponding 1 2 conpounds of formula I wherein R and R both represent hydrogen by reaction thereof with a suitable oxidising agent.

The preferred oxidising agent is an alkali-metal nitrite, e.g. sodium nitrite, employed in the presence of an acid, and the reaction 4828 1 is desirably carried out in an appropriate solvent medium which is inert under the reaction conditions employed, e.g. glacial acetic acid. However, many other oxidising agents may be appropriate, for example nitric acid, hydrogen peroxide, bromine or isoamyl nitrite, each desirably employed in a suitable solvent medium, e.g. acetic acid, an alkanol for example ethanol, or an optionally halogenated hydrocarbon, e.g. carbon tetrachloride or chloroform.

The reaction is conveniently carried out at a tenperature of from 5 to 3O°C, preferably 10 to 20°C.

In another aspect, this invention provides a process for the preparation of the conpounds of formula II wherein a thiadiazolium salt of the formula: τ R N-4—N (wherein R1, R3 and R^ are as defined hereinbefore) and X” represents an anion, is reacted with a hydrazine of formula R^NHN^ (wherein R^ is as defined hereinbefore) to give the desired conpound.

The reaction is desirably effected in the presence of a solvent, e.g. an alkanol such as ethanol, and is preferably carried out at a tenperature of from 20°C to the reflux tenperature, e.g. 100°C.

X may represent any suitable anion, but is preferably halogen, 25 especially chlorine, sulphate or p-toluensulphonate. 46281 The thiadiazolium salts of formula VI may themselves be prepared by a process in which a corresponding thiadiazole of the formula: CVII) ' t ft (wherein RJ and R are as defined hereinbefore) is reacted 10 with the appropriate compound of formula R^X to give the desired compound.

The reaction is preferably effected in an appropriate solvent medium, e.g. an alkanol such as ethanol, and at a temperature of from 60°C to the reflux temperature, e.g. 180°C.

The thiadiazoles of formula VII may themselves be prepared either by reaction of a compound of formula V wherein A represents -CQNH-MiCO- with phosphorous pentasulphide, or by reaction of a conpound of formula III with a sulphide (especially phosphorous pentasulphide) or hydrosulphide to give the desired conpound.

The reactions involving phosphorous pentasulphide are desirably effected in an appropriate solvent medium, and desirably also in the presence of a tertiary organic base. Hie base may act as the solvent medium, and may for example be pyridine, triethylamine or dimethylaniline, and the reaction is desirably effected at a temperature of from 80°C 8 281 to the reflux tenperature, e.g. 120°C.

The sulphide or hydrosulphide enployed in the reaction with the conpound of formula III may alternatively be an alkali-metal sulphide or hydrosulphide, e.g. sodium sulphide or potassium hydrosulphide, and the reaction is desirably effected in an appropriate solvent medium, e.g. an alkanol, e.g. ethanol, or a polar solvent, e.g. dimethylformamide, and at a tenperature of from S°C to the reflux tenperature, e.g. 80°C.

In a further aspect, this invention provides a process for the 3 6 preparation of the compounds of formula II in which R-3 and R° are 1 4 identical and R and R are identical, wherein a conpound of the formula: R6CH=N.NHR4 (VIII) (where R4 and R& are as defined hereinbefore) is subjected to the action of an oxidising agent to give the desired conpound.

The oxidising agent is conveniently a halogen, e.g. iodine, or an alkali-metal hypochlorite or ferricyanide, especially sodium hypochlorite or ferricyanide, and the reaction is conveniently effected in a suitable solvent, e.g. pyridine, and at a tenperature of from 60 to 120°C.

The compounds of formula II in which R3 and R^ are identical and r1 and R4 are identical may alternatively be prepared by a process in which a conpound of the formula: A828 1 S R6-C-tfl-NHR4 (IX) (wherein R4 and are as defined hereinbefore) is subjected to 5 the action of an alkylating agent in the presence of an alkali-metal base, e.g. sodium hydroxide or sodium carbonate.

The alkylating agent is conveniently a haloacetic acid, e.g. iodoacetic acid, or a dialkyl sulphate, e.g. dimethyl sulphate, and the reaction is desirably effected in a suitable solvent, e.g. an alkanol such as ethanol. The temperature employed is desirably from 5 to 80°C.

The compounds of formula II wherein RI * 3 and R4 are other than hydrogen, R3 and R^ are identical and R3 and R4 are identical, may be prepared by a process in which a compound of the formula: Α Λ R -C=N-N-R4 (X) I I Hal H (wherein R4 and R6 are as defined hereinbefore and Hal represents halogen) is dimerised in the presence of a base in an appropriate solvent medium to give the desired compound.

The reaction is desirably effected in a suitable solvent, especially a polar aprotic solvent such as acetonitrile or dimethylformamide, and at elevated temperature, e.g. 50°C to reflux.

Hal preferably represents chlorine.

Tlie base is conveniently a tertiary amine, e.g. triethylamine, and the solvent is preferably a polar solvent, e.g. acetonitrile.

The tetrazines of formula I and formula II are of particular use against the eggs and larvae of acarids, particularly the eggs of the red spider mite, 5 Tetranychus clnnabarinus, but also against the eggs and larvae of other nite species, e.g.

Tetranychus urticae, Panonychus ulmi, Phyllocontrata oleivora, Eutetranychus banksi, p. citri and T. medanieli. They are norrally employed in the form of compositions. 1° The coirpositions of the invention will normally be produced initially as cormulations containing from 0.5 to 99s, preferably from 0.5 to SS’· by weight, more usually from 10 to 50¾ by weight, of the active compounds, which are diluted if necessary before a-plication to the locus to he treated such that tlie concentration j of active ingredient in the formulation applied is from 0.05 to 5', by weight.

The substituted tetrazines of formula T and formula II are generally water insoluble and may be formulated in any of the ways commonly aJo-ted for insoluble compounds. 2' For example, they may be dissolved in a water immiscible solvent, for example a high boiling hydrocarbon, as carrier, suitably containing dissolved emulsifying agents so that the composition acts· as a self-erulsifiable oil on addition to water.

The substituted tetrazines may alternatively be admixed with a wetting agent with or without a solid carrier to form a wettable powder which is soluble or dispersible in water, or may be mixed with just a solid carrier to form a solid product.

An aqueous suspension concentrate may alternatively be prepared by grinding the conpounds with water, a wetting agent and a suspending agent.

Solid carriers with which the substituted tetrazines may be incorporated include clays, sands, talc, mica or solid fertilizers, such products either comprising dust or larger particle size materials. The surface active agents used may comprise anionic surface active agents, for example mono- or di-esters of phosphoric acid with fatty alcohol ethoxylates or salts of such esters, fatty alcohol sulphates such as sodium dodecyl sulphate, ethoxylated fatty alcohol sulphates, ethoxylated alkylphenol sulphates, lignin sulphonates, pezroleum sulphonates, alkylaryl sulphonates such as alkyl-benzene sulphonates or lower alkyl-naphthalene sulphonates, salts of sulphonated naphthalene-formaldehyde condensates, salts of sulphonated phenol-formaldehyde condensates, or more complex sulphonates such as the amide sulphonates, e.g. the sulphonated condensation product of oleic acid and N-methyl taurine or the dialkyl sulphosuccinates e.g. the sodium sulphonate of dioctyl succinate.

Hie surface active agents may also comprise non-ionic agents, for example condensation products of fatty acid esters, 8 2 8 1 Tatty alcohols, Fatty acid amides or alkyl-substituted phenols with ethylene oxide, fatty esters of polyhydric alcohol ethers e.g. sorhitan 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-decyn4,7-diol, or ethoxylated acetylenic glycols.

The surface active agents may also comprise cationic agents, for example alkyl- and/or aryl-substituted quarternary ammonium compounds such as cetyl trimethylammonium bromide, or ethoxylated tertiary fatty amines.

Preferred surface active agents include ethoxylated fatty alcohol sulphates, lignin sulphonates, alkyl-aryl sulphonates, salts of sulphonated naphthalene-formaldehyde condensates, salts of sulphonated phenol-formaldehyde condensates, sodium oleoyl N-methyltauride, dialkyl sulphosuccinates, allyl phenol ethoxylates, and fatty alkyl ethoxylates.

The composition may alternatively be in the form of an aercsol composition, suitably using a cosolvent and a wotting agent, in addition to the propellant, which is suitably a polyhalogenated alkane such as dichlorodifluoronethane.

The compositions according to the nresent invention may contain in addition to the substituted tetrazines other active insecticides, acaricides, ovicides, bactericides and fungicides. it lias been found that particular advantages are obtained with mixtures with other acaricides, especially those which combat the motile stages, e.g. amitraz, dicofol, cyhexatin or nropargite, and particularly where the compound of formula I or TI is one of those exemplified herein, especially 3,6-bis(2-chlorop!ienyl)-l,2-dihydro-l5 methyl-1,2,4,5-tetrazine or 3,6-bis(2-chlorophenyl)-1,2,4,5-tetrazine.

The method of combatting acarids, their eggs or their larvae provided hy the present invention may be employed at any site where infestations of such pests are present or are liable to occur. Taus, it may be employed for example on plants or the soil.

Plants which may be treated include food crops, for example, fruit trees and cereals, e.g. anples, nears, apricots, citrus fruits, maize, wheat or barley, beans, sugar beet, potatoes, carrots, or greenhouse crons, e.g. peppers, tomatoes, cucumbers, melons or strawberries.

In their various applications the compounds of formula I and formula II may be used at various rates; thus for example for the treatment of plants for the control of pests on plants tiie compounds are suitably applied at a rate or about ^,25-16 ounces per acre 4828 1 (17-1120g per hectare) or at a concentration of 1 to 2000 ppm as appropriate, e.g. 100 to 1000 ppm, and preferably 0,5-4 ounces per acre (35-280g per hectare). Normally the compounds will be applied to the foliage of plants, but systemic activity has also been observed when applied to the soil around the base of the plants.

The following Examples are given merely to illustrate the present invention. The tenperatures given therein are in °C, and parts and percentages are by weight.

Example 1 3,6-bis(2-Chlorophenyl)-1,2-dihydro-l-methyl-l,2,4,5-tetrazine (a) Ν,Ν'-bis(2-chlorobenzoyl)hydrazine A stirred solution of hydrazine hydrate (25g) in water (500 ml) was treated dropwise and simultaneously with sodium hydroxide (43,6g) in water (150 ml) and 2-chlorobenzoyl chloride (180.25g). The addition over the mixture was stirred at room tenperature for 2 hours. The solid was filtered off, washed with acetone/water 1:1 and recrystallised from acetic acid.

Yield 97.5g, m.p. 217-219°. (b) bis (ot.: 2-Dichlorobenzylidene)hydrazine Phosphorus pentachloride (443.5g) in 1,2-dichlorobenzene (850 ml) was heated to 110°. Ν,Ν'-bis(2-chlorobenzoyl) hydrazine (164.7g) was added in portions to the stirred solution. The addition over the mixture was stirred and heated at 110° for 1 hour. At the end of this time the excess phosphorus pentachloride and 1,2-dichlorobenzene were distilled off under 48881 reduced pressure to leave a viscous oil which solidified. The crude solid was recrystallised from methanol (2x) to give 58.Og of bis(ex:2-dichlorobenzylidene)hydrazine as a white crystalline solid, m.p. 105-107°. (c) 3,6-bis(2-Chlorophenyl)-1,2-dihydro-l-methyl-l,2,4,5-tetrazine Methyl hydrazine (31.Og) in ethanol (550 ml) was heated to reflux and treated portionwise with bis(c<:2-dichlorobenzylidene) hydrazine (58.Og). The addition over the mixture was refluxed for I hour.

The ethanol was evaporated in vacuo and the residue washed with water. Recrystallisation from an ethanol/water mixture yielded 37.Og, m.p. 116-118°.

Examples 2-5 Tlie following compounds were prepared by the method of Example 1 but employing the appropriate o-halobenzoyl chloride in stage (a) and the appropriate hydrazine or substituted hydrazine in stage (c). 2. 5,6-bis(2-Chlorophenyl)-1,2-dihydro-l,2,4,5-tetrazine, mp 168-169°C. 3. 3,6-bis(2-Fluorophenyl)-1,2-dihydro-l-methyl-1,2,4,5-tetrazine, up 93-94°C. 4. 3,6-bis(2-Fluorophenyl)-l,2-dihydro-l,2,4,S-tetrazine, mp 14S-148°C. . 3,6-bis(2-Chlorophenyl)-1,2-dihydro-l-(2-hydroxyethyl)-1,2,4,5tetrazine, np 5O~55°C. 8 2 8 1 Example 6 3- (4-Methy lphenyl) -6- (2-chlorophenyl) -1,2-dihydro-1-methyl-l ,2,4,5tetrazine (a) N-(2-chlorobenzoyl) -Ν' - (4-methylbenzoyl)hydrazine 2-Chlorobenzhydrazide (38.8g) was dissolved in sodium hydroxide solution (9.18g in 125 ml water). Ihe solution was stirred and 4- methylbenzoyl chloride (35.2g) added dropwise. The mixture was then stirred for 2 hours and the solid which precipitated was filtered off, washed with water and reerystallised from ethanol to give 30.0g of the desired product, mp 204-206°C. (b) 3- (4-tethy lphenyl) -6- (2-chlorophenyl) -1,2-dih.ydro-l-methyl1,2,4,5-tetrazine By the method of Example 1 stages (b) and (c) , the above compound was prepared from the product of stage (a) of this Example.

IS Mp 152-1S4°C.

Examples 7-13 By methods analogous to that of Example 6, the following compounds were prepared: 7. 3- (4-f fethy lphenyl) -6- (2-chlorophenyl) -1,2-dihydro-l ,2,4,520 tetrazine, nip 1S4-197°C. 8. 3-t-Buty 1-6- (2-chlorophenyl) -1,2-dihydro-l, 2,4,5-tetrazine, mp 172-174°C. 9. 3-t-Butyl-6-(2-chlorophenyl)-1,2-dihydro-l(or 2)-methy1-1,2,4,5tetrazine, mp 10S-120°C. . 3-Phenyl-6-(2-chlorophenyl)-l,2-dihydro-l,2,4,5-tetrazine, 4-828 1 mp 2O6-21O°C. 11. 3-(2-Fluorophenyl)-6-(2-chlorophenyl)-1,2-dihydro-l(or 2) -methyl1, 2,4,5-tetrazine, mp 95-97°C. 12. 3-(3-Methylphenyl)-6-(2-chlorophenyl)-1,2-dihydro-l(or 2)-methyl1,2,4,5-tetrazine, mp 163-165°C. 13. 3-(2-Bromophenyl)-6-(2-chlorophenyl)-1,2-dihydro-l(or 2)-methyl1,2,4,5-tetrazine, mp 1O2-1O4°C.

Example 14 3,6-Bis(2-chlorophenyl)-1,2,4,5-tetrazine The dihydrotetrazine from Example 2 (8.0g) was dissolved in glacial acetic acid (50 ml) and treated dropwise with stirring with a solution of sodium nitrite (2.0g) in water (10 ml). The addition over the mixture was poured into water and the solid filtered off. Recrystallisation from ethyl acetate yielded the product, mp 179-182°C.

Examples 15-1S By the method of Example 14, the following conpounds were prepared by oxidation cf the corresponding 1,2-dihydrotetrazines: . 3-t-Butyl-6-(2-chlorophenyl)-1,2,4,5-tetrazine, mp 86-90°C. 16. 3-Phenyl-6-(2-chlorophenyl)-1,2,4,5-tetrazine, np 12O-122°C. 17. 3-(2-Bromophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine, np 166-168°C. 18. 3-(4-Nfethylphenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine, up 129-132°C.

Example 19 Bis (ex.: 2-dichlorobenzylidene) hydrazine (alternative method) (a) Bis(2-chlorobenzylidene)hydrazine Hydrazine hydrate (l,000g) in water (12 1) and ethanol (2.4 1) was stirred at room tenperature. 2-Chlorobenzoldehyde (5,620g) in ethanol (2 1) was added dropwise over 3 hours at below 30°C. The mixture was then stirred for 2 hours at room temperature. Water (10 1) was added and the product was filtered off, washed with water and dried to give 5,4O2g of the desired product. (b) Bis(<χ :2-dichlorobenzylidene)hydrazine The azine product of stage (a) (300g) was suspended in acetic acid (1,350 ml) and acetic anhydride (150 ml). The stirred suspension was then cooled and chlorine was passed in, whilst maintaining the tenperature at under 20°C. The azine dissolved and was replaced by a precipitate of the monochloroazine. At this stage cooling was stopped and the chlorination continued at Toom tenperature until all the solid had dissolved. The mixture was then left at room tenperature overnight. The crystalline precipitate was filtered off, washed with methanol and dried in vacuo to give 257.Sg of desired product, mp 1O3-1O5°C.

Example 20 N- (ot: 2-dichlorobenzylidene) -N1- (o<: 2:4-trichlorob enzylidene) hydrazine (a) N- ( c*:2-dichlorobenzylidene)-N1-(2,4-dichlorob enzylidene) hydrazine Ν' -(2,4-dic’nlorobenzylidene) -N-2-chlorobenzoylhydrazine (21.2g) was suspended in dichloroethane (160 ml) and the mixture was refluxed with stirring. Thionyl chloride (8.4g) was added dropwise and the mixture was stirred and refluxed overnight. Half the solvent was evaporated off in vacuo and the remainder was left to crystallise. 14.4g Of desired product, up 86-91, were obtained. (b) N- (o<:2-dichlorobenzylidene)-N1-(o<:2:4-trichlorobenzylidene)hydrazine The product of stage (a) (18.5g) was suspended in acetic acid (115 ml) and acetic anhydride (11.5 ml), and the mixture was heated to 50°C. A stream of chlorine gas was passed through the mixture to saturation. The mixture was then left overnight at room tenperature, then the acetic acid and acetic anhydride were evaporated off in vacuo. The residue was dissolved in diethyl ether, and the ether solution was extracted with sodium bicarbonate, washed with water, and dried over magnesium sulphate. Evaporation of the ether gave an oil which solidified to give 7.6g of the desired product, np 45-5O°C.

Example 21 ,6-bis (2-Chlorophenyl) -1,2-dihydro-l-meth.yl-l, 2,4,5-tetrazine (a) 2,5-bis(2-Chlorophenyl)thiadiazole bis(2-Chlorophenyl)hydrazine (30.9g) in pyridine (250 ml) was treated with phosphorous pentasulphide (22.2g) in portions. The mixture was refluxed for 12 hours, cooled and poured into ice/water (1 litre). Tne solid obtained was filtered off, washed with water and dried in vacuo, and was recrystallised from isopropanol to give 18.3g of the desired product as colourless needles, np 111-113°C. 4828 1 (a1) 2,5-bis(2-Chlorophenyl) thiadiazole - alternative route The dichloroazine product of Example 1(b) (103.8g) in ethanol (500 ml) was treated with sodium sulphide aonahydrate (90.0g), and the mixture was refluxed for 2 hours. It was then poured whilst still hot into ice/water (2 litres). The solid which formed was filtered off, washed with water and dried in vacuo to give 90.2g of the desired product, mp 110-112°C. (b) l,S-bis(2-Chlorophenyl)-3(or 4)-methylthiadiazolium sulphate The product of stage (a) (16.Og) and dimethyl sulphate (6.56g) were heated together on a steam bath for 30 minutes and then cooled.

The solid obtained was triturated with acetone, filtered off, washed with acetone, then with diethyl ether, and was then dried in vacuo to give 16.8g of the desired product, iro 146-148°C. (c) 3,6-bis(2-Chlorophenyl)-1,2-dihydro-l-methyl-l,2,4,5-tetrazine The product of stage (b) (6.0g) was suspended in ethanol (30 ml) and hydrazine hydrate (l.Sg) was added. The mixture was refluxed, for 50 minutes, cooled and filtered. The filtrates were evaporated, to low volume and diluted witn water to give a semi-solid which solidified on trituration. The solid was filtered off and dried in vacuo to give 3.1g of desired product, up 115-116°C, identical to the product of Example 1.

Example 22 3,6-bis(2-Chlorophenyl)-1,4-dihydro-l,4-dimethyl-l,2,4,5-tetrazine The product of Example 21 stage (b) (6.0g) was suspended in ethanol (30 ml) and methyl hydrazine (1.40g) was added. The mixture 8 281 was refluxed for 30 minutes, cooled and filtered. Hie filtrate was then evaporated to low volume and diluted with water. The solid which formed was filtered off, washed with water and dried in vacuo to give, on recrystallisation from petroleum ether (80-100°C), 3.40g of desired product, mp 148-149°C.

Examples 23-25 By methods analogous to those of Examples 21 and 22 the following compounds were prepared: 23. 3,6-bis(2-Chlorophenyl)-1,2-dihydro-l-ethyl-l,2,4,5-tetrazine, mp 106-108°C. 24. 3,6-bis(Z-Chlorophenyl)-l,4-dihydro-l-ethyl-4-methyl-l,2,4,5tetrazine, mp 92-94°C. . 3,6-bis (2-Chlorophenyl)-1,4-dihydro-l-(2-hydroxyethyl)-4-ethy ΙΙ, 2,4,5-tetrazine, mp 149-152°C.

Example 26 A 501 wettable powder formulation of the compound of Example 1 was prepared from the following: t w/w Compound of Example 1 50 Reax 45L (Lignin based wetting and dispersing agent) 5 Polyfon H (sodium salt of sulphonated Kraft lignin, by Westvaco Corporation) 2 10 Neosyl (precipitated silica) China Clay 4828 1 Example 27 A 50¾ wettable powder formulation of the compound of Example 14 was prepared from the following: % w/w Compound of Example 14 50 Reax 45L 5 China clay 45 Example A Aqueous acetone solutions containing 1,000, 300, 100, 10 and 3 ppm respectively of each of the compounds listed below together with 500 ppm of the wetting agent Lissapol NX (a nonylphenol/ethylene oxide condensate) were applied to 2 cm diameter discs cut from the leaves of french bean plants, Phaseolus vulgaris, each infested with 50-100 eggs of the greenhouse red spider mite, Tetranychus telarius. The treated leaf discs and mite eggs, together with controls treated with wetting agent alone were held at 25°C for 5 days on moist filter paper. The percentage mortality of the mite eggs was then recorded, and tlie LCS0 was determined and scored according to the following scale: 4-8 281 Ι£50 (ΡΡΦ) Score >1000 0 300-1000 1 100-299 2 -99 3 -29 4 3-9.9 5 1-2.9 6 The results obtained were as follows: Compound Example No Score 6 S 1 3 2 2 2 1 3 4 1 6 6 3 Compound Example No Score Control leaf discs treated with water and wetting agent alone gave less than 5¾ mortality over the same period.

Example B French bean plants with two fully expanded cotyledonary leaves 10 were sprayed with aqueous acetone solutions respectively of the conpounds of Examples 1 and 14 containing 1,000 ppm wt/vol active ingredient and SCO ppm of Lissapol NX. After 24 hours and at 7 day intervals up to 35 days, 2 cm discs were cut from the treated leaves, placed on a moist filter paper and each infested with 10 adult female mites, Tetranychus cinnabarinus. After 24 hours the mites were removed, by which time they had deposited about 103 eggs on each disc. Tlie mortality of these eggs was measured after 5 days when it was observed tnat greater than 95¾ mortality occurred on each disc.

Example C Adjacent rows of young Top Red apple trees were managed until the European red mite (Panonychus ulmi) numbers started to increase. The trees were then sprayed with aqueous suspensions of a wettable powder containing, as active ingredient, the compound of Example 1.

Different trees were then sprayed at a rate of 1.5 litres/tree with suspensions containing 250, 500 and 1,000 ppm respectively of active ingredient. Other trees were left untreated as controls. Counts were taken pre-treatment and at roughly 7-day intervals of the numbers of mites present, a 60-leaf sample being counted each time without removal from the tree.

Results obtained, expressed as mean number of mites per leaf, were as follcws: Days after Treatment Treatment (Pre- count) +7 +14 +21 +28 +35 +42 +49 +55 +62 250 ppm 0.43 0.65 0.36 0.S1 0.50 0.85 1.01 0.97 0.55 0.35 500 ppm 0.73 1.35 1.01 0.96 1.08 1.25 1.20 1.43 0.93 0.78 1,000 ppm 0.61 0.45 0.36 0.51 0.46 0.53 0.4S 0.20 0.16 0.13 0 ppm (control) 0.26 1.70 2.11 4.88 6.70 8.50 9.91 16.93 13.76 S.6

Claims (3)

1. Claims: 1. A method of combatting acarids, their eggs or their larvae, which comprises applying to a site either infested or liable to infestation with them an effective amount of one or more substituted 5 tetrazines of the formula: or of the formula: (I) (Π) wherein R 2 ar.d r\ which may be the same or different, each represent hydrogen, phenyl, alkyl of 1 to 6 carbon atoms or alkenyl or alkynyl of 3 to 6 carbon atoms, each of which phenyl, alkyl, 20 alkenyl or alkynyl groups may be unsubstituted or substituted by one or more halogen atoms, hydroxy groups, cyano groups, carboxy groups, alkoxycarbonyl groups of 2 to 5 carbon atoms, or alkoxy 1 2 groups of 1 to 4 carbon atoms; or R and R together represent a X single bond. ; R represents allyl of 1 to 6 carbon atoms, cycloalkyl 25 of 3 to 7 carbon atoms, phenyl, or phenylalkyl of 7 to 10 carbon -4-8 2 Si atoms, each of which may be unsubstituted or substituted by one or more halogen atoms, alkyl or alkoxy groups of 1 to 6 carbon atoms, nitro groups, cyano groups, mercapto groups or alkylmercapto groups of 1 to 4 carbon atoms; and R® represents a phenyl group substituted 5 in at least the 2-position by fluorine, chlorine, bromine or iodine.
2. 2. A method according to claim 1 wherein the compounds are applied at a rate of from 17 to 1120 grams per hectare.
3. 3. A method according to claim 2 wherein the compounds are applied at a rate of from 35 to 280 grams per hectare. Ιθ 4. A method according to any of claims 1 to 3 wherein the site to which the compounds are applied conprises plants or the soil. 5. A method according to claim 4 wherein the site to which the conpounds are applied is a food crop selected from apples, pears, apricots, citrus fruits, maize, wheat, barley, beans, sugar beet, 15 potatoes, carrots, peppers, tomatoes, cucumbers, melons and strawberries. 6. An acaricidal, larvicidal or ovicidal composition which cctiprises frcm 0.5 t o 99% by weight of cne or more substituted tetrazines of formula I or formula II -as defined in claim 1 in association with a 20 suitable carrier and/or surface active agent. 7. A composition according to claim 6 which contains from 0.5 to 85% by weight of the substituted tetrazines. 8. A composition according to claim 7 which contains from 10 to 18 2 8 1 50¾ by weight of the substituted tetrazines. 9. A substituted tetrazine of the formula: (I) or of the formula: N — N (Π) wherein R 1 , R 2 and R 4 , which may be the same or different, each 15 represent hydrogen, phenyl, alkyl of 1 to 6 carbon atoms or alkenyl or alkynyl of 3 to 6 carbon atoms, each of which phenyl, alkyl, alkenyl or alkynyl groups may be unsubstituted or substituted by one or more halogen atoms, hydroxy groups, cyano groups, carboxy groups, alkoxycarbonyl groups of 2 to 5 carbon atoms, or alkoxy 1 2 20 groups of 1 to 4 carbon atoms; or R and R together represent a single bond; R 3 represents alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, or phenylalkyl of 7 to 10 carbon atoms, each of which may be unsubstituted or substituted by one or more halogen atoms, alkyl or alkoxy groups 25 of 1 to 6 carbon atoms, nitro groups, cyano groups, mercapto groups 48381 or alkylmercapto groups of 1 to 4 carbon atoms; and represents a phenyl group substituted in at least the 2-position by fluorine, chlorine, bromine or iodine; , with the proviso that, in the compounds of formula I wherein R° represents 2 12 3 fluorophenyl, when R and R represent a single bond, R does not represent 1 2 methyl, trifluorcmethyl or 2-f luorophenyl, and when R and R both represent hydrogen, R does not represent trifluoromethyl. 10. A conpound according to claim 9 ldierein R 1 represents hydrogen or alkyl of 1 to 6 carbon atcms. 11. A conpound according to claim 10 wherein R 3 represents hydrogen, 10 methyl or ethyl. 12. A conpound according to any of claims 9 to ll wherein R represents hydrogen or alkyl of 1 to 6 carbon atoms. 13. A conpound according to claim 12 wherein R represents hydrogen, methyl or ethyl. 15 14. A conpound according to any of claims 9 to 13 wherein R^ represents alkyl of 1 to 5 carbon atoms. 15. A conpound according to any of claims 9 to 14 wherein R represents unsubstituted alkyl of 1 to 6 carbon atoms. •t 16. A conpound according to claim 15 wherein R represents t-butyl. 20 17. A conpound according to any of claims 9 to 14 wherein R represents phenyl which is unsubstituted or substituted by one or more halogen atoms, alkyl or alkoxy groups of 1 to 4 carbon atoms or nitro groups. τ 18. A conpound according to claim 17 wherein R represents a 25 mono-substituted phenyl group. 4828 1 19. A compound according to claim 18 wherein R 3 represents 2-chlorophenyl, 2-fluorophenyl, 2-broitiophenyl, 3-methylphenyl or 4-methylphenyl. 20. A compound according to any of claims 9 to 19 wherein R^ 5 represents 2-fluorophenyl, 2-chlorophenyl or 2-bromophenyl. 3 6 21. A compound according to any of claims 9 to 20 wherein R and R are identical. 22. A compound according to any of claims 9 to 21 wherein and 2 R together represent a single bond, or one represents hydrogen 10 while the other represents hydrogen, methyl or ethyl, R 6 represents 3 2-chlorophenyl or 2-fluorophenyl, and R represents t-butyl, pheryl, 2-chlorophenyl, 2-fluorophenyl, 2-bromophenyl, 3-methylphenyl or 4. -methylphenyl. 23. 3,6-bis (2-Chlorophenyl) -1,2-dihydro-l-ro.ethyl-l,2,4,5-tetrazine. 15 24. 3,6-bis(2-Chlorophenyl)-1,2,4,5-tetrazine. 25. 3,6-bis (2-Fluorophenyl)-l,2-dihydro-l-raethyl-l, 2,4,5-tetrazine. 26. 3,6-bis (2-Fluorophenyl) -1,2-dihydro-l,2,4,5-tetrazine. 27. 3,6-bis (2-Chlorophenyl) -1,2-dihydro-l- (2-hydroxyethyl) -1,2,4,5tetrazine. 20 23. 3,6-bis(2-Chlorophenyl)-1-(2-hydroxyethyl)-1,2,4 ,5-tetrazine. 29. 3-t-Butyl-6- (2-chlorophenyl) -1,2-dihydro-l, 2,4,5-tetrazine. 30- 3-t-Butyl-6-(2-chlorophenyl)-1,2-dihydro-l(or 2)-methyl-l,2,4,5tetrazine. 31. 3-Phenyl-6-(2-chlorophenyl)-1,2-dihydro-l, 2,4,5-tetrazine. 25 32. 3-(2-Fluorophenyl)-6-(2-chlorophsnyl)-l,2-dihydro-l(or 2)-methyl· 48381 1,2,4,5-tetrazine. 33. 3-(2-Bromophenyl)-6-(2-chlorophenyl)-1,2-dihydro-l(or 2)-methyl1, 2,4,5-tetrazine. 34. 3-(3-Methylphenyl)-6-(2-chlorophenyl)-1,2-dihydro-l(or 2) -methyl3 1,2,4,5-tetrazine. 35. 3- (4-Methylphenyl) -6- (2-chlorophenyl) -1,2-dihydro-l, 2,4,5-tetrazine. 36. 3-(4-Methylphenyl)-6-(2-chlorophenyl)-1,2-dihydro-l(or 2)-methyl1,2,4, 5-tetrazine. 37. 3,6-Bis(2-chlorophenyl)-l,2-dihydro-l,2,4,5-tetrazine. 10 38. 3-J:-Butyl-6-(2-chlorophenyl)-1,2,4,5-tetrazine. 39. 3-Phenyl-6-(2-chlorophenyl)-1,2,4,5-tetrazine. 40. 3-(2-Bronophenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine. 41. 3-(4-Methylphenyl)-6-(2-chlorophenyl)-1,2,4,5-tetrazine. 42. 3,6-bis(2-Chlorophenyl)-1,4-dihydro-l,4-dimethyl-l,2,4,5-tetra15 sine. 43. 3,6-bis(2-Chlorophenyl)-1,4-dihydro-l-(2-hydroxyethyl)-4-ethyl1,2,4,5-tetrazine. 44. 3,6-bis(2-Chlorophenyl)-1,4-dihydro-l-ethyl-4-methyl-l,2,4,5tetrazine. 20 45. A process for the preparation of a substituted tetrazine of 1 2 formula I as defined in claim 9 wherein R and S represent other than a single bond, in which process a substituted azine of the formula: X X (ΙΠ) (wherein R 3 and R® are as defined in claim 9 and each X represents a leaving group) is reacted with a hydrazine of the formula: rW-NHR 2 (IV) (therein R 1 and R 2 are as defined in claim 9 but do not represent a bond) to give the desired catpound. 46. A process according to claim 45 wherein each X represents halogen 47. A process according to claim 46 wherein each X represents 10 chlorine or bromine. 48. A process according to any of claims 45 to 47 which is effected at a temperature of from 30 to 100°C and in an appropriate solvent medium. 49. A process according to any of claims 45 to 48 wherein the 15 substituted azine of formula III is itself prepared by a process in which a corpound of the formula: R 3 -A-R® (V) (wherein R 3 and R® are as defined in claim 9 and A represents 20 -CONH-NHCO-, -CONH-N=CH-, -CH=N-NHCO- or -CH=N-N=CH-) is halogenated to give the corresponding compound of formula III wherein each X represents halogen, and the product is, if desired, reacted with an anion-forming compound to give the corresponding compound where each X represents other than halogen. 25 50. A process according to claim 49 wherein A represents -CONH-NHCO37 4828 1 and the halogenating agent employed is a phosphorus pentahalide. 51. A process according to claim 49 wherein A represents -CONH-N=CHor -CH=N-NHCO-, and the halogenation is effected in two stages by reaction with a thionyl halide and with the desired halogen. 52. A process according to claim 49 wherein A represents -CH=N-N=CH-, and the halogenating agent employed is the desired halogen. 53. A process according to any of claims 49 to 52 wherein the conpound of formula V is one wherein A represents -CCffl-NHCO- and is itself prepared by a process in which a hydrazide of the formula is reacted with a conpound of the formula R°COY, where κ and R are as defined in claim 9 and Y represents halogen, hydroxy, C 1 to 6 alkoxy or a group R^COO- to give the desired conpound. 54. A process according to any of claims 44 to 47 wherein the conpound of formula V is one wherein A represents -CONH-NHCO- and R 3 is the sane as R 6 , and is itself prepared by reaction of a halide of formula R COHal where Hal represents chlorine or bromine with hydrazine to give the desired conpound. 55. A process according to any of claims 49 to 52 wherein the conpound of formula V is one wherein A represents -CH=N-N=CH- and R 3 and R 6 are identical, and is itself prepared by a process in which an aldehyde of the formula R 3 CIW or R 6 CHO is reacted with hydrazine in a suitable solvent medium. 56. A process according to any of claims 49 to 52 wherein the conpound of formula V is one wherein A represents -CONH-N=CH- or -CH=N~NHCO- and is itself prepared by a process in which a hydrazide 4823 1 of the formula R^CONHNHg or R^CONHNHg is reacted with an aldehyde ft % respectively of the formula RCHO or R°CHO. 57. A process for the preparation of a substituted tetrazine of 1 2 formula I as defined in claim 9 wherein R and R together represent 1 2 a single bond, in which a conpound of formula I wherein R and R both represent hydrogen is reacted with a suitable oxidising agent. 58. A process according to claim 57 wherein the oxidising agent enployed is an alkali-metal nitrite in the presence of an acid, hydrogen peroxide, nitric acid, bromine or isoamyl nitrite. 59. A process for the preparation of a substituted tetrazine of formula II as defined in claim 9, in which a thiadiazolium salt of the formula: pi (VI) IS R· (wherein p3, R 3 and R® are as defined in claim 9 and X~ represents an anion) is reacted with a hydrazine of formula R^NHNHg 20 (where R 4 is as defined in claim 9) to give the desired caipound. 60. A process according to claim 59 wherein the thiadiazolium salt of formula VI enployed as starting material is itself prepared by a process in which a thiadiazole of the formula: Ν-Ν evil) 5. (wherein R 3 and R® are as defined in claim 9 ) is reacted with the appropriate confound of formula R 3 X to give the desired compound. 61. A process for the preparation of a substituted tetrazine of formula II as defined in claim 9 in which R and R are identical and R 3 and R 4 are identical, in which a compound of the formula: 10 fi Λ R°CH=N.NHR 4 (VIII) (where R 4 and R& are as defined in claim 9 ) is subjected to the action of an oxidising agent to give the desired compound. 62. Λ process according to claim 61 wherein the oxidising agent 15 employed is a halogen or an alkali-metal hypochlorite or ferricyanide. 63. A process according to claim 62 wherein the oxidising agent employed is iodine. 64. A process for the preparation of a substituted tetrazine of 3 fi formula II as defined in claim 9 wherein R and R° are identical 20 and R 4 and R 4 are identical, in which a conpound of the formula: S fill 4 κ C-NH-NHR* (IX) (wherein R 4 and R® are as defined in claim 9 ) is subjected to the 25 action of an alkylating agent in the presence of an alkali-metal 4828 1 base to give the desired compound. 65. A process according to claim 64 wherein the alkylating agent employed is a haloacetic acid or a dialkyl sulphate. 66. A process for the preparation of a substituted tetrazine of 1 4 5 formula II as defined in claim 9, wherein R and R are both other than hydrogen, R 3 and R& are identical and R 2 and R 4 are identical, in which a compound of the formula: Hal H (X) (wherein R 4 and R® are as defined in claim 9 and Hal represents halogen) is dimerised in the presence of a base in an appropriate solvent medium to give the desired compound. 67. A process according to claim 66 wherein the base is an organic amine. 68. A process according to any of claims 45 to 67 and substantially as described hereinbefore with reference to any one of Examples 1 to 25. 69. A substituted tetrazine of foimula I or formula II as claimed 20 in claim 9, whenever prepared by a process as claimed in any of claims 45 to 68. 70. A composition according to any of claims 6 to 8, wherein the substituted tetrazine active ingredient is as claimed in any of claims 9 to 44. 2S 71. A composition according to any of claims 6 to 8 and 70, and substantially as described hereinbefore with reference to Example 26 or Example 27. 72. A method according to any of claims 1 to 5, wherein the substituted tetrazine employed is as claimed in any of claims 9 to 44. 73. A method according to any of claims 1 to 5 and 72, wherein the substituted tetrazine is employed in the form of a composition as claimed in any of claims 6 to 8,70 and 71. 74. A method according to any of claims 1 to 5, 72 and 73, and substantially as described hereinbefore with reference to any one of Examples A to C.