SI20002A - Insecticidal compositions and methods - Google Patents

Abstract

An insecticidal composition comprising a first insecticidally active ingredient, to which insect pests have developed a degree of resistance, an insecticidally inert carrier or diluent and, optionally, one or more surface active agents, characterised in that the composition further contains a sufficient amount of a compound of formula (I), wherein A represents a bidentate group of formula -CH2CH2- or CH=CH; Ar is phenyl, pyridinyl, pyridazinyl or pyrazinyl, all being optionally substituted with halogen, C1-4 alkyl, C1-4 alkoxy, C2-4 alkenyl, C2-4 alkynyl or cyano; R is hydrogen, C1-4 alkyl (optionally substituted with cyano, CO2(C1-4 alkyl) or phenyl (itself optionally substituted with halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl or C1-4 haloalkoxy)), C2-4 haloalkyl (the 'alpha'-carbon being unsubstituted), C3-4 alkenyl or C3-4 alkynyl; provided that when R is alkenyl or alkynyl said group does not have an unsaturated carbon atom bonding directly to the ring nitrogen of formula (I); or an acid addition salt, quaternary ammonium salt or N-oxide derived therefrom; to boost the activity of the composition to overcome the resistance of the insect pests; and a method of using such a composition to combat insect pests.

Description

ZENECA LIMITED

Insecticidal compositions and processes

The present invention relates to insecticidal compositions useful for controlling resistant insect pests and to a process for controlling resistant insect pests.

The present invention provides an insecticidal composition comprising the first insecticidal active ingredient against which harmful insects have developed a degree of resistance, an insecticidal inert carrier or diluent and optionally one or more surfactants, characterized in that it further contains a sufficient amount of the compound with the formula (I):

wherein A represents a bidentate group of the formula -CH ₂ CH ₂ - or CH = CH; Ar is phenyl, pyridinyl, pyridazinyl or pyrazinyl, all of which are optionally substituted by halogen (especially fluorine, chlorine or bromine), C 1-4 alkyl (especially methyl), C 1-4 alkoxy (especially methoxy), C ₂ m alkenyl, C? M alkynyl or cyano; R is hydrogen, alkyl (optionally substituted by cyano, CO ₂ (C 1-6 alkyl) or phenyl (optionally substituted by halogen, C _1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl or C 1-4 haloalkoxy), C ₂ m haloalkyl (at the α-carbon being unsubstituted), C3M alkenyl or C3M alkynyl; with the proviso that when R is alkenyl or alkynyl, said group does not have an unsaturated carbon atom bonded directly to the ring nitrogen of formula (I); or an acid addition salt, a quaternary ammonium salt or an N-oxide derived therefrom; to amplify the activity of the composition to overcome the resistance of harmful insects. Preferably, the ratio of the first insecticidal active ingredient to the compound of formula (I) is in the range of 1: 100 to 100: 1 (e.g., 1:10 to 10: 1) w / w.

It is to be appreciated that the compounds of formula (I) are capable of being in more than one isomeric form, since the groups may be located in either an exo or endo bond and the present invention encompasses both exo and endo forms and mixtures thereof in all ratios, as well as any subsequent isomeric variants resulting from cis and trans substitution patterns or chiral centers.

Halogen includes fluorine, chlorine, bromine and iodine.

The alkyl moieties may be in the form of straight or branched chains, e.g. methyl, ethyl, n- or isopropyl, or n-, sec-, iso- or tert-butyl.

Haloalkyl is especially fluoroalkyl (e.g. trifluoromethyl, 2,2,2-trifluoroethyl or 2,2difluoroethyl) or chloroalkyl. For R is haloalkyl e.g. 2,2,2-trifluoroethyl or 2,2-difluoroethyl.

The alkenyl and alkynyl moieties may be in the form of straight or branched chains, and where appropriate, the alkenyl moieties may be in either the (E) - or (Z) configuration. Examples are vinyl, allyl and propargyl.

Suitable acid addition salts include those with inorganic acid, such as e.g. hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid or organic carboxylic acid, such as e.g. oxalic, tartaric, lactic, butyric, toluic, hexanoic and phytic acids, or sulfonic acids such as methane, benzene, and toluenesulfonic acids. Other examples of organic carboxylic acids include halo acids, such as e.g. trifluoroacetic acid.

In particular, the present invention provides novel insecticidal compositions comprising an insecticidal active ingredient against which harmful insects have developed a degree of resistance, together with an insecticidal inert diluent and optionally one or more surfactants, characterized in that they contain sufficient the amount of the compound of formula (Ia):

R

wherein X is hydrogen or halogen, more particularly chloro or bromo, and R is lower alkyl or lower haloalkyl having up to 4 carbon atoms, or benzyl or halobenzyl, to enhance the activity of the composition to overcome resistance.

In another aspect, the present invention provides a compound of formula (I) wherein Ar is pyridin-3-yl optionally substituted at the 5-position by chlorine or bromine.

In a further aspect, the present invention provides a process for improving insecticide activity against insect pests that have developed a degree of resistance to such insecticides, comprising administering an insecticide composition comprising the insecticide together with a compound of formula (I) to pests or to a pest locus.

Examples of insecticides that may develop resistance and for which the compositions of the invention and method are useful include:

pyrethroids: lambdacihalotrin, cyhalothrin, deltamethrin, fenvalerate, esfenvalerate, cyfluthrin, betaciflutrin, deltamethrin, etofenprox. A further example is teflutrin.

organophosphates: chlorpyrifos, profenofos, acephate, dimethoate, parathion-methyl, terbufos, monocrotophos, sulprophos, prothiophos.

carbamates: aldicarb, carbofuran, carbaryl, methomyl, phenobacarb, pyrimicarb.

benzoyl urea: diflubenzuron, chlorofluazuron, teflubenzuron, hexaflumuron, flufenoxuron, lufenuron, flucycloxuron.

others: amitraz, clofentezine, phenpyroximate, hexythiazox, propargite, tebufenpirad, phenazquin, pyridaben, spinosad, triazamate, buprofezin, abamectin, fipronil, tebufenozide, diophenolane, imidacloprid. A further example is chlorfenapyr.

Among the insect pests that have become more difficult to control due to the development of resistance to one or more of the above insecticides are:

Homoptera: lice (e.g. Myzus persicae, Myzus nicotianae, Aphis fabae,

Aphis gossypii, Rhopalosiphum padi, Aphis nasturtii, Macrosiphum euphorbiae)

White fly (e.g. Bemisia tabaci, Bemisia argeniifolii, Trialeurodes vaporariorum) Grasshoppers (e.g. Nephotettix cincticeps, Nilaparvata lugens)

Heteroptera (e.g. Lygus lineolaris, Lygus hesperus)

Lepidoptera (e.g., Plutella xylostella, Heliothis virescens, Spodoptera exigua,

Laspeyresia pomonella)

Diptera (e.g. Liriomyza trifolii)

Coleoptera (eg Phaedon cochlearae, Anthonomus grandis)

The present invention also provides a composition comprising spinosad and a compound of formula (I):

Ar CN where A represents a bidentate group of formula -CH ₂ CH ₂ -; Ar is phenyl, pyridinyl, pyridazinyl or pyrazinyl, all being optionally substituted with halogen (especially fluorine, chlorine or bromine), C _w alkyl (especially methyl), C _M alkoxy (especially methoxy), _C2 -4 alkenyl, C ₂ _4 alkynyl or cyano; R is hydrogen, C _M alkyl (optionally substituted with cyano, _CO2 (C _M alkyl) or phenyl (itself optionally substituted by halogen, C 1.4 alkyl, CM alkoxy, C _w haloalkyl or Cm haloalkoxy)), C ₂ -4 haloalkyl (where the α-carbon being unsubstituted), C ₃ _4 alkenyl or C ₃ _4 alkynyl; with the proviso that when R is alkenyl or alkynyl, said group does not have an unsaturated carbon atom bonded directly to the ring nitrogen of formula (I); or an acid addition salt, the ammonium salts or N-oxide derived therefrom are quatted. Preferably, the ratio of spinosad to the compound of formula (I) is in the range of 1: 100 to 100: 1 (e.g. 1:10 to 10: 1) w / w. [Spinosad, see, e.g. EP-0375316 or 1997 abstracts of the Beltvvide Cotton Insect Research and Control Conference, p. 1082-1086.]

In a further aspect, the present invention provides a method of controlling and controlling harmful insects, mites or nematodes at a locus comprising treating pests or a pest locus with an effective amount of a composition comprising a spinosad and a compound of formula (I):

R

I

N,

Ar CN where A represents a bidentate group of formula -CH ₂ CH ₂ -; Ar is phenyl, pyridinyl, pyridazinyl or pyrazinyl, all of which are optionally substituted by halogen (especially fluorine, chlorine or bromine), C 1-4 alkyl (especially methyl), C 1-4 alkoxy (especially methoxy), C ₂ m alkenyl, C? M alkynyl or cyano; R is hydrogen, C _M alkyl (optionally substituted with cyano, _CO2 (Ci_4 alkyl) or phenyl (itself optionally substituted by halogen, Cm alkyl, Cm alkoxy, C _w haloalkyl or Cm haloalkoxy)), C ₂ _4 haloalkyl (wherein the α-carbon is unsubstituted), C _3-4 alkenyl or C ₃ m alkynyl; with the proviso that when R is alkenyl or alkynyl, said group does not have an unsaturated carbon atom bonded directly to the ring nitrogen of formula (I); or an acid addition salt, the ammonium salt or the N-oxide derived therefrom. Insects, mites or nematodes include harmful insects such as: Lepidoptera, Diptera, Homoptera and Coleoptera (including Diabrotica), pests related to agriculture (the term includes cultivation of food and fiber products), horticulture and animal husbandry, forestry and by storing products of plant origin, such as e.g. fruits, grains and wood, as well as pests related to the transmission of human and animal diseases. Examples of harmful insect and mite species include: Mvzus persicae, Aphis gossvpii, Aphis fabae, Aedes aegvpti, Anopheles spp., Culex spp., Dvsdercus fasciatus, Musca domestica, Pieris brassicae, Plutella xylostonella, Phaedepoides spp. , Bemisica tabaci, Blattella germanica, Periplaneta americana, Blatta orientalis, Spodoptera littoralis, Heliothis virescens, Chortiocetes terminifera, Diabrotica spp., Agrotis spp., Chilo partellus, Nilaparvata lugens, Nephotettchcinctchuset, Panhoti cvitchuset, Panhoti , Tetranvchus cinnabarinus, Phvllcoptruta oleivora, Polvphagotarsonemus latus and Brevipalpus spp.

Preferred compounds of formula (I) in the compositions of the invention are compounds of formula (Ia) wherein X is chloro or bromo and R is 2,2-difluoroethyl or 2,2,2-trifluoroethyl, including e.g. 3 (5-chloropyrid-3-yl) -3-cyano-8- (2,2,2-trifluoroethyl) -8-azabicyclo [3.2.loctane (compound A) and 3- (5-chloropyrid-3-yl) -3-cyano-8- (2,2-difluoroethyl) -8-azabicyclo [3.2. lactane (compound

B).

A further preferred compound of formula (I) in the compositions of the invention is 3- (5chloropyrid-3-yl) -3-cyano-8-azabicyclo [3.2. lactane (Compound C).

The compounds of formula (I) can be prepared by adapting the procedures described in the literature (such as J. Med. Chem. (1975) 18 (5) 496-501) using one or more of the following synthetic techniques described below. or by combining literature procedures with those described below. Throughout the following description, R ^{5 is} alkyl or phenylalkyl (especially benzyl).

Compounds of formula (I) can be prepared by treating compounds of formula (II) with a compound of formula RL, wherein L is a suitable leaving group such as halide or triflate, optionally in the presence of a suitable base such as potassium carbonate.

Compounds of formula (II) (which are compounds of formula (I) wherein R is hydrogen) can be prepared by deprotection of compounds of formula (III), e.g. by either: (i) treating them with chloroformate ester (such as vinyl chloroformate) and the carbamate thus formed is subjected to acid hydrolysis (eg hydrochloric acid); or (ii) treated with azodicarboxylate (eg diethylazodicarboxylate) at elevated temperatures.

The compound of formula (I) can be prepared by reacting a compound of formula (III) with a compound RHal (where Hal is halogen) under suitable conditions (e.g., in the presence of alkali metal base and iodide) in a suitable solvent (e.g., N, N-dimethylformamide ).

Alternatively, compounds of formula (I) may be prepared from compounds of formula (II) by reductive amination with an aldehyde (R ⁶ CHO; wherein R ⁶ CH ₂ = R) in the presence of a suitable reducing agent, such as e.g. formic acids.

Compounds of formula (III) can be prepared by treating compounds of formula (IV) first with a suitable base such as lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide, and then by reacting the product thus formed with the compound ArHal, wherein Hal halogen.

Alternatively, compounds of formula (I) can be prepared by treating compounds of formula (VI) with a suitable base such as lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide, and by reacting the product thus formed with the compound ArHal, wherein Hal is halogen .

Compounds of formula (VI) can be prepared by treating compounds of formula (VII) with a suitable base such as potassium carbonate in the presence of a compound of formula RHal, wherein Hal is halogen.

Alternatively, compounds of formula (VI) can be prepared by treating compounds of formula (VIII) with tosylmethyl isocyanide in the presence of a suitable base such as potassium ethoxide.

The compounds of formula (VIII) can be prepared by a process analogous to Robinson's synthesis for tropinone, e.g. from 2-ethoxy-3,4-dihydropyran. (See, for example, Organic Synthesis (summary volume 4), p. 816).

Compounds of formula (I) wherein A is CH = CH can be prepared by heating a compound of formula (I) wherein A is CH ₂ CHZ (where Z is a suitable group, such as a thio-4-tolyloxy group), in to a suitable solvent (such as xylene) at a suitable temperature (such as reflux).

Compounds of formula (I) wherein A is CH ₂ CHZ (where Z is a suitable group, such as a thio-4-tolyloxy group) can be prepared by treating compounds of formula (I) wherein A is CH ₂ CH (OH). with a suitable chloroformate (such as 4-tolyl chlorothioneformate) in the presence of a suitable base (such as Ν, Ν-dimethylaminopyridine).

Compounds of formula (I) wherein A is CH ₂ CH (OH) can be prepared by acid hydrolysis of compounds of formula (I) wherein A is CH ₂ CH (OZ ') wherein Z' is a hydrolyzable group (such as tert-butyldimethylsilyl).

A compound of formula (I) wherein A is CH ₂ CH (OZ ') wherein Z' is hydrogen or a hydrolysable group (such as tert-butyldimethylsilyl) can be prepared by reaction of the corresponding compound of formula (VI ) with a suitable base such as lithium diisopropylamide (LDA) or lithium bis (trimethylsilyl) amide, and the reaction of the product thus formed with the compound ArHal, wherein Hal is halogen.

A compound of formula (VI) wherein A is CH ₂ CH (OZ ') wherein Z' is hydrogen or a hydrolysable group (such as tert-butyldimethylsilyl) can be prepared by treating the corresponding compound of formula (V) with tosylmethyl isocyanide (also known as (4-tolylsulfonyl) methylisocyanide) in the presence of a suitable base such as e.g. of potassium tert.-butoxide.

A compound of formula (V) wherein A is CH ₂ CH (OZ ') wherein Z' is a hydrolysable group (such as tert-butyldimethylsilyl) can be prepared by reaction of a compound of formula (V) wherein A is CH ₂ CH (OH), with compound Z'L, where L is a leaving group.

Alternatively, a compound of formula (I) may be prepared where A is CH = CH by dehydration of a compound of formula (I) wherein A is CH ₂ CH (OH) with a suitable dehydrating agent such as e.g. diethylamino sulfotrifluoride.

A compound of formula (I) wherein A is CH = CH can be prepared by reaction of a compound of formula (I) wherein A is CH ₂ CH (OZ ') wherein Z' is a suitable group (such as SO ₂ CH ₃ ), with a suitable amine (such as 1,8-diazabicyclo [5.4.0] undec-7-ene).

A compound of formula (I) wherein A is CH ₂ CH (OZ ') wherein Z' is a suitable group (such as SO ₂ CH ₃ ) can be prepared by reaction of a compound of formula (I) wherein A is CH ₂ CH (OH) with a suitable acid chloride (such as mesyl chloride).

The amount of the composition of the present invention, which is generally administered for controlling insect pests, provides an active ingredient ratio of 0.01 to 10 kg per hectare, preferably 0.1 to 6 kg per hectare.

The compositions of the invention may be administered to the soil, plant or seed, to the locus of pests or to the place of pest in the form of dusting powders, wettable powders, granules (slow or fast release), emulsion or suspension concentrates, liquid solutions, emulsions, seed disinfectants, blurring / smoking formulations or controlled release compositions, such as e.g. microencapsulated granules or suspensions.

Dust powders are formulated by mixing the active ingredient with one or more finely divided solid carriers and / or diluents, such as e.g. natural clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite, oxygen, chalk, diatomaceous earth, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flour, talc and other organic and inorganic solid carriers.

Granules are formed either by absorbing the active ingredient in a porous granular material such as e.g. tufts, atapulgite clays, Fuller's soils, oxygenates, diatomaceous earths, ground corn cobs, etc., or hard core material such as sands, silicates, mineral carbonates, sulfates, phosphates, etc. Agents commonly used as auxiliaries for the impregnation, binding or coating of solid carriers include aliphatic and aromatic petroleum solvents, alcohols, polyvinyl acetates, polyvinyl alcohols, ethers, ketones, esters, dextrins, sugars and vegetable oils, with the active ingredient. Other additives such as e.g. emulsifying, wetting and dispersing agents.

Microencapsulated formulations, (CS capsule suspensions) or other controlled release formulations, especially for slow release over time and for seed treatment, may also be used.

Alternatively, the compositions of the invention may be in the form of liquid preparations to be used as baths, irrigation additives or sprays, which are generally aqueous dispersions or emulsions of the active ingredient with one or more known wetting, dispersing or emulsifying agents (surfactants ). The compositions to be used in the form of aqueous dispersions or emulsions are generally supplied in the form of an emulsifiable concentrate (EC) or suspension concentrate (SC) containing a high proportion of the active ingredient or ingredients. EC is a homogeneous liquid composition that usually contains an active ingredient dissolved in an organic solvent that is substantially non-volatile. SC is the dispersion of a solid active ingredient in the form of fine particles in water. In use, the concentrates are diluted with water and sprayed onto the surface to be treated.

Suitable liquid solvents for EC include methylketones, methylisobutyl ketone, cyclohexanone, xylenes, toluene, chlorobenzene, paraffins, kerosene, white oil, alcohols (eg butanol), methylnaphthalene, trimethylbenzene, trichlorethylene, N-methyl-tetrahydro-pyrrolidine (N-methyl-tetrahydro-pyrrolidine). ).

The wetting, dispersing and emulsifying agents may be cationic, anionic or nonionic. Suitable cationic type agents include e.g. quatememic ammonium compounds, e.g. cetyltrimethyl ammonium bromide. Suitable anion-type agents include e.g. soaps, salts of aliphatic sulfuric acid monoesters, e.g. sodium sulfate, salts of sulfonated aromatic compounds, e.g. sodium dodecyl benzene sulfonate, sodium, calcium or ammonium lignosulfonate or butylnaphthalene sulfonate and mixtures of the sodium salts of diisopropyl and triisopropylnaphthalene sulfonates. Suitable non-ionic type means include e.g. condensation products of ethylene oxide with fatty alcohols, such as e.g. oleyl alcohol or cetyl alcohol, or with alkyl phenols such as e.g. octylphenol, nonylphenol and octylcresol. Other non-ionic agents are long-chain fatty acid partial esters and hexitol anhydrides, the condensation products of said partial esters with ethylene oxide and lecithins.

These concentrates are often required to withstand storage for extended periods and, after such storage, can be diluted with water to form aqueous preparations that remain homogeneous for a sufficient amount of time to be applied with a conventional spray device. Concentrates may contain 10-85% by weight of the combination of active ingredients. Such preparations may contain, after being diluted to form aqueous preparations, varying amounts of the active ingredient, depending on the purpose for which they are to be used.

The compositions of the invention may be in the form of powders (dry seed treatment DS or water-dispersible powder WS) or liquids (concentrate capable of flowing FS, liquid seed treatment LS, or microcapsule suspension CS) for use in seed treatment.

In use, the compositions of the invention are administered to harmful insects, to the locus of the pest, to the pest's residence, or to growing plants subject to pest attack in any known manner for the application of pesticidal compositions, e.g. by dusting, spraying or mounting granules.

The compositions of the invention may be mixed with one or more additional active ingredients such as e.g. insecticides or synergists where appropriate. Suitable additional active ingredients for inclusion in the composition of the invention may be compounds that broaden the activity spectrum of the compositions of the invention or increase their duration of effect at the pest site. They can act synergistically with the activity of a compound of formula (I) or complement the activity, e.g. by increasing the speed of effect or overcoming defenses. The particular additional active ingredient that is included depends on the intended use of the mixture and the type of complementary action required. Examples of suitable insecticides include:

a) pyrethroids, such as e.g. permethrin, esfenvalerate, deltamethrin, cyhalothrin, in particular lambdacihalotrin, bifenthrin, fenpropatrin, cyfluthrin, teflutrin, for fish pyrethroids, e.g. ethofenprox, natural pyrethrin, tetramethrin, s-bioalletrin, phenflutrin, pralethrin and 5-benzyl 3-furylmethyl- (E) - (1 R, 3 S) -2,2-dimethyl-3- (2-oxothiolan-3-ylidene methylcyclopropane carboxylate ;

b) organophosphates, such as e.g. profenofos, sulprofos, methyl parathion, azinfos-methyl, demeton-s-methyl, heptenofos, thiomethon, phenamiphos, monocrotophos, profenofos, triazophos, metamidophos, dimethoate, phosphamidon, malathion, chloropirifos, fosalon, fulfroposimphos, phosalone, sulfulfbufos , pyrimiphos-methyl, pyrimiphos-ethyl, phenitrothion or diazinone;

c) carbamates (including aryl carbamates) such as e.g. pyrimicarb, chloethocarb, carbofuran, furatiocarb, ethiophenecarb, aldicarb, thiofurox, carbosulfan, bendiocarb, phenobacarb, propoxur or oxamyl;

d) benzoyl urea, such as e.g. triflumuron or chlorofluazuron;

e) organic tin compounds, such as e.g. cyhexatin, phenbutatin oxide, azocyclotin;

f) macrolides such as e.g. avermectin or milbemycin, such as abamectin, ivermectin and milbemycin;

g) hormones and pheromones;

h) organochlorine compounds, such as e.g. benzene hexachloride, DDT, chlordane or dieldrin;

i) amidines such as e.g. chlordimeform or amitraz;

j) smokers;

k) imidacloprid;

l) spinosad.

In addition to the major chemical classes of insecticides listed above, other special purpose insecticides may be used in the mixture, provided it is intended for the intended use of the mixture. We can use e.g. selective insecticides for special crops, e.g. stem-insecticides specific for use in rice, such as cartap or buprofezin. Alternative insecticides specific to specific insect species / stages may also be included in the compositions, e.g. ovolarvicides such as clofentezine, flubenzimine, hexythiazox and tetradifone, motilicides such as e.g. dicofol or propargite, acaricides such as e.g. bromopropylate, chlorobenzylate, or growth regulators such as hydramethylron, cyromazine, metoprene, chlorofluazuron and diflubenzuron.

Examples of suitable synergists for use in compositions include: piperonyl butoxide, sesamax, safroxan and dodecyl imidazole.

The following Examples illustrate the present invention.

EXAMPLE 1

The effect of attenuating the resistance to the compositions of the invention is shown in the following test using the resistant (R2) strain of the Mvzus persicae aphid, which is designated as highly resistant to organophosphorus compounds (OP), pyrethroids and carbamates due to the increased level of E4 esterase. The test compositions are as indicated below.

The procedure is as follows:

One day before processing:

Fill small pots of plastic to about one-third with a 1% agar solution and allow to settle. Slices of Chinese cabbage (tip tip variant), about 2.54 cm in diameter, are sliced and placed on top of the agar. A slice of leaf is populated with pests by placing on its surface a radish cotilidone populated with pests (from the main crop) and left overnight; the cotilidone is dried and the lice go to slice.

Working day:

Dried cotilidones are removed and pots are labeled as necessary - in this case 1 measurement x 10 replicates. Spray the solutions using a Burkhard Potter tower, approximately 300 l / ha. When air-dried, attach to the top of the lid with ventilation slots and maintain the test for 3 days at 20 ° C. In this process, lice are dosed by direct contact, and the residue is collected as they move across the leaf surface.

days after processing:

Dead and live lice are identified in each pot. The data is analyzed and the results are

listed in the table below. test composition % mortality 1. Pyrimicarb (20 ppm) 57,68% 2. Pyrimicarb (20 ppm) + Compound A (1 ppm) 98.97% 3. Pyrimicarb (20 ppm) + Compound B (1 ppm) 95,24% 4. chlorpyrifos (20 ppm) 2.28% 5. chlorpyrifos (20 ppm) + compound A (1 ppm) 95,33% 6. chlorpyrifos (20 ppm) + compound A (1 ppm) 96,37% 7. Lambdacihalotrin (0.5ppm) 5.6% 8. lambdacihalotrin (0.5ppm) + compound A (1 ppm) 100% 9. Lambdacihalotrin (0.5ppm) + Compound B (1 ppm) 94.19% A similar test against Tetranvchus is not obtained the following results: test composition % mortality 10. lambdacihalotrin (0.02ppm) 15% 11. Compound A (250 ppm) 44%

12. lambdacihalotrin (0.02ppm) + compound A (250 ppm) 85%.

EXAMPLE 2

Cells from the thoracic ganglia of the keel are prepared following a simplified version of the procedures described by: Beadle and Lees {Beadle DJ, Lees G. (1986), in Neuropharmacology & Pesticide Action (ed. MG Ford et al), p. 423-444, Chichester: Ellis Honvood} and Pinnock and Sattelle {Pinnock RD, Sattelle DB (1987), J. Neuroscience Methods 20, p. 195-202}. One animal is used for each experiment. The insect is killed and its thoracic ganglia removed under saline consisting of 214 mM Na ⁺ ; 3.1 mM K ⁺ ; 9mM Ca ²⁺ ; 221 mM Cf; 10 mM TES, pH adjusted to 7.0. All axonal outgrowths are cut from each ganglion and the sheath layer is removed using fine forceps. The ganglia were then cut into halves or quarters and transferred to 1 mg / ml (approx.) Collagenase (Sigma type III) solutions in a cockroach saline solution. After 30-50 minutes (room temperature), the tissue was washed in saline, which was enzyme-free, and triturated with flame-polished Pasteur pipettes. The resulting suspension is applied to 50 mm-Petri Falcon Tight-Seal containers containing just enough medium to cover the bottom of the containers.

These cells survive overnight in the medium described by Beadle and Hicks {Beadle D.J., Hicks D. (1985), Insect Nerve Culture, in Comprehensive Insect Physiology, Biochemistry & Pharmacology, vol. 5, Nervous System: Structure & Motor Function. (ed. G.A. Kerkut and E.I. Gilbert), p. 181-211, Oxford: Pergamon Press}, for the differentiation of embryonic cells in culture, mixtures from equal parts of Liebovvitz L15 medium and Graces Insect T.C. (Gibco BRL) supplemented with 50IE / ml penicillin / streptomycin and 50 pg / ml gentamicin. 1-2 hours before the experiment, the medium was replaced with the same saline solution used for dissecting. It is perfused through the cells continuously as we obtain results.

Membrane tension is determined using conventional intracellulame technique (with current terminals). The isolated cell bodies are punctured with a borosilicate micropipette containing a silver / silver chloride electrode in 3 M KCl (aqueous) electrolyte. Micropipettes are prepared using a horizontal Sutter P97 drawing device to obtain resistances of about 20 ΜΩ. The cells are stimulated electrically via an intracellular electrode with repetitive pulses of either negative current to detect membrane resistance or positive current to elicit action potentials (spikes).

Compound C (10 μΜ) and Compound A (100 μΜ) were applied (separately) to a membrane of a cell from another micropipette positioned very close. This micropipette is coupled to a pressure generator (MSC PLilOO picoinjector) and the ejection of the compounds is achieved with controlled pulses of nitrogen gas. Spinosad is administered with a saline perfusion solution.

Compound C (referred to in Fig. As compound C) provokes a depolarization of the cell coupled with a decrease in membrane resistance, as shown by the shortening of voltage responses for negative current steps (Fig. 1). The response for compound A (referred to in the figures as compound A) in the same cell is shown in FIG. 2. There is no depolarization but even slight hyperpolarization.

The effect of spinosad on the response for compound C is shown in FIG. 3 and 4, where responses for four 50 ms pulses of Compound C (Fig. 3) are shown, compared to one 50 ms pulse in the presence of 1 μΜ spinosad (Fig. 4). The effects are at least partially reversible, the normal response profile of compound C, recovered after approximately 30 minutes of rinsing

1.3 ml / min (Fig. 5). Spinosad is active in this experiment at the lowest tested concentration of 100 pM.

The effect of spinosad on the response for compound A is shown in Figures 6 to 11. Figures 6 to 8 show the superimposed voltage responses for sixty 90 ms positive current pulses (Ιλ). applied via an electrode at a level just enough to elicit a tip (0.4 nA), and at a rate of one-step events every 1.8 s. The 90 ms pulse of compound A was administered during the tenth step in each case. The perpendicular wave at the bottom of each diagram shows the duration of I η, which is also the duration of the compound A pulse during a ten-step event. The first example (Fig. 6) is a control in the absence of spinosad showing no response for compound A. Fig. 7 is recorded in the presence of 50 nM spinosad and shows changes in both the pre-I dormant potential and the tip profile. The separation of events in Figs. 7 shows that prior to administration of compound A (events 1 to 10 inclusive), the tip profile is stable (Fig. 7a), and after administration of compound A (Fig. 7b: events 10-13), depolarization results in a shortening of the stimulus time -the tip and eventual termination of the tip at the top of the response. As the cell recovers its dormant potential, the tip profile is restored (Fig. 7c: events 20, 30, 40, 50 and 60). This type of tip inhibition can be mimicked by slightly depolarizing the cell with a continuous positive current passing through the electrode, suggesting that termination of the tip due to a decrease in AV at the onset of the step event and is little more than a symptom of depolarization. FIG. 8 is for a shot taken in a rinse fluid 10-12 minutes after spinosad application. There is clearly some reverse effect: there is no abolition of the tip, but still some depolarization and shortening of the stimulus time, as shown in Figs. 8a (events 10 to 13).

FIG. 9 to 11 are graphical representations of changes in dormant potential induced by compound A in the absence (Fig. 9) and presence (Fig. 10) of the spinosad and after 10-12 minutes of rinsing (Fig. 9).

11). These diagrams are constructed by applying a casual voltage at 19 ms (just before Ifl) at each of the sixty events shown in Figs. 6 to 8. The scale area for each diagram is the same to facilitate comparison of responses for compound A. The response for compound A in the absence of spinosad (Fig. 9) does not increase beyond the background noise levels, while in the presence of spinosad (Fig. 10) it is clear depolarization of more than 14 mV. This decreases steadily when the spinosa is flushed sideways (Fig. 11).

Compound C is a potent insect neuronal depolarizer and spinosad reversibly enhances this action. Significant depolarization responses with compound A can be achieved in the presence of spinosad.

Claims (5)

PATENT APPLICATIONS An insecticidal composition comprising the first insecticidal active ingredient against which harmful insects have developed a resistance level, an insecticidal inert carrier or diluent and optionally one or more surfactants, characterized in that it further comprises a sufficient amount of a compound with formula (I): R A Ar CN where A represents a bidentate group of formula -CH ₂ CH ₂ - or CH-CH; Ar is phenyl, pyridinyl, pyridazinyl or pyrazinyl, all being optionally substituted with halogen, C _M alkyl, C _M alkoxy, C _{2nd 4} alkenyl, C ₂ m alkynyl or cyano; R is hydrogen, _{C! 4} alkyl (optionally substituted with cyano, _CO2 (C _M alkyl) or phenyl (itself optionally substituted by halogen, C _w alkyl, Cm alkoxy, Cm haloalkyl, or haloalkoxy)); C ₂ _4 haloalkyl (where the α-carbon being unsubstituted), C ₃ _4 alkenyl or C ₃ m alkynyl; with the proviso that when R is alkenyl or alkynyl, said group does not have an unsaturated carbon atom bonded directly to the ring nitrogen of formula (I); or an acid addition salt, a quaternary ammonium salt or an N-oxide derived therefrom; to enhance the activity of the composition to overcome the resistance of harmful insects. Composition according to claim 1, characterized in that the first insecticidal active ingredient is selected from the group consisting of: lambdacihalotrin, cyhalothrin, deltamethrin, fenvalerate, esfenvalerate, cyfluthrin, betaciflutrin, deltamethrin, etofenproxor, teflutrin, teflutrin , dimethoate, terbufos, monokrotofos, sulphoros, carbofuran, carbaryl, metomil, pheromobenzone, flufenzuron, flufuron , tebufenpirad, phenazquin, pyridaben, spinosad, triazamate, buprofezin, abamectin, fipronil tebufenozide, diophenolane, imidacloprid and chlorfenapyr. Composition according to claim 1, characterized in that the compound of formula (I): 3- (5-chloropyrid-3-yl) -3-cyano-8- (2,2,2-trifluoroethyl) -8-azabicyclo [3.2. ljoktan; 3- (5-chloropyrid-3-yl) -3-cyano-8- (2,2-difluoroethyl) -8-azabicyclo [3.2. but not 3- (5-Chloropyrid-3-yl) -3-cyano-8-azabicyclo [3.2.1] octane. A method of controlling or controlling harmful insects, mites or nematodes at a locus comprising treating pests or a pest locus with an effective amount of a composition according to claim 1. A method according to claim 4, characterized in that the pests are harmful insects of the growing plants.