GB2052264A - Ectoparasiticidal agents containing substituted phenoxy-benzyloxycarbonyl derivatives and (thio) phoshphoric acid esters, a process for the preparation and their use as estoparasiticides - Google Patents

Abstract

A composition containing a synergistic combination of the active ingredients (1) a phenoxybenzyloxycarbonyl derivative of the general formula <IMAGE> in which R, R<1> and R<2> are selected independently and each represent hydrogen or halogen, R<3> represents phenyl or substituted phenyl, Y represents hydrogen or cyano, n represents an integer from 1 to 5 and m represents an integer from 1 to 4, and (2) a (thio)phosphoric acid ester, alone or in admixture with a solid of liquid or liquefied gaseous diluent or carrier, has a powerful ectoparasiticidal action, especially against ticks.

Description

SPECIFICATION Ectoparasiticidal agents containing substituted phenoxybenzyloxycarbonyl derivatives and (thio)phosphoric acid esters, a process for the preparation and their use as ectoparasiticides The present invention relates to new ectoparasiticidal synergistic comb.inations of certain substituted phenoxybenzyloxycarbonyl derivatives and (thio)phosphoric acid esters; It is already known that certain substituted phenoxybenzyloxywarbonyl derivatives, for example 4'-fluoro3'-phenoxy- a-cyano-benzyl 2,2-dimethyl-3-(2-chloro- 2-(4-chlorophenyl)-vinyl)- cyclopropane-1 -carboxylate, have insecticidal and acaricidal properties and are suitable for combating ticks (see DE-OS (German Published Specification) 2,730,515).

It is also known that certain O-alkyl O-quinolyl alkyl or aryl-phosphonothioates, for example O-ethyl 0-(8-quinolyl) phenyl-phosphonothioate (quintiofos, oxinothiophos) can be used for combating ectoparasites (see U.S. Patent Specification 3,284,455).

However, over the years, ticks have become increasingly resistant to the preparations, employed as combating agents, based on organic phosphorus compounds, so that the success of the combating operation is jeopardised to an increasing extent.

Synergistic mixture of pyrethroids, for example 3'-phenoxy-benzyl 2,2-dimethy- 3-(2,2-dichlorovinyl)cyclopropane-1 -carboxylate (Permethrin) and pesticidal organic phosphorus compounds, for example O-ethyl O-(8-quinolyl) phenyl-phosphonothioate (quintiofos, oxinothiophos), have been disclosed as agents for combating pests (see DE-OS's (German Published Specifications)-2,757,768 and 2,757,769).

However, the action of these known active-compound combinations is notatways satisfactory, especially in the case of low concentrations of active compound and when small amounts are applied.

The present invention now provides an ectoparasiticidal composition containing as active ingredients (1) a substituted phenoxybenzyloxycarbonyl derivative of the general formula

in which R, R' and R2 are selected independently and each represent hydrogen or halogen, R3 represents phenyl or substituted phenyl, Y represents hydrogen or cyano, n reoresents an integer from 1 to 5 and m represents an integer from 1 to 4, and (2) a (thio)phosphoric acid ester, alone or in admixture with a solid or liquid or liquefied gaseous diluent or carrier.

The active-compound combinations of the present invention have a particularly powerful ectoparasticidal action, especially against ticks.

Surprisingly, the ectoparasiticidal action of the active-compound combinations according to the invention is considerably more powerful than the action of the individual components or the sum of the actions of the individual components. Furthermore, it is considerably more powerful than the action of the activecompound combination of Permethrin and oxinothiophos which is already known.

Formula (I) provides a definition of the components, to be used for the active compound combinations according to the invention, from the series of phenoxybenzyloxycarbonyl derivatives. Preferably, in this formula, R and R1 each represent hydrogen or fluorine, with the proviso that R and or R' represent at most 2 fluorine atoms, R2 represents hydrogen, chlorine or bromine, R3 represents phenyl or phenyl which is substituted by fluorine, chlorine, bromine, C,-C4--alkyl, methoxy, methylenedioxy, trifluoromethoxy or trifluoromethylthio, Y represents hydrogen or cyano, n represents an integer from 1 to 5 and m represents an integer from 1 to 4.

Examples of the phenoxybenzyloxycarbonyl derivatives of the formula (I) which may be mentioned are: 3'-phenoxy-benzyl, 3'-(4-fluoro-phenoxy)-benzyl, 4'-fluoro-3'- phenoxy-benzyl, 4'-fluoro-3'-(4- fluoro- phenoxy)-benzyl, 3'-phenoxy-o-cyano- benzyl, 3'-(4-fluoro-phenoxy)-cc- cyano-benzyl, 4'-fluoro-3'- phenoxy -a-cyano-benzyl and 4'-fluoro-3'-(4-fluoro -phenoxy)-a-cyano-benzyl 2,2-dimethyl-3-(2- chloro-2-phenyl vinyl)-cyclopropane- 1 -carboxylate, 2,2-dimethyi-3- (2-chloro-2-(4-chloro-phenyl )-vinyl)-cyclopropane- 1carboxylate and 2,2-dimethyl- 3-(2-chloro-2-(4-fluoro-phenyl )-vinyl-cyclopropane -1 -carboxylate.

4'-Fl uoro-3'- phenoxy-a-cyano -benzyi 2,2-dimethyl-3- (2-c-hloro-2-(4-chloro-phenyl)-vinyl) -cyclopropane 1-carboxylate is particularly preferred as the active compound component from the series of phenoxybenzy loxycarbonyl derivatives (I).

Virtually any of the (thio)phosphoric acid esters having an ectoparasiticidal action, especially a tickicidal action, can be used as the (thio)phosphoric acid esters. Examples which may be mentioned are: O,O-diethyl O-(3-chloro-4-methyl -7-coumarinyl) phosphorothioate (coumaphos), O,O-diethyl 0-(2,5- dichloro-S bromophenyl) phosphorothioate (bromophos-ethyl), O,O-diethyl O-(2-isopropyl -6-methyl- pyrimidin-4-yl) phosphorothioate (diau'non), 2,3-p-dioxanedithio-S,S-bis-O,O- diethyl phosphorodithioate (dioxathion), O,O-diethyl 0-(3,5,6-trichloro-2- pyridyl) phosphorothioate (chiorpyrifos), O,O,O',O'4etraethyl- S,S'methylene diphosphorodithioate (ethion), 3-(dimethoxyphosphinyloxy)-N-dimethyl-cis-crotonamide (dicrotophos), S-(1,2-dicarbethoxyethyl) 0,0- dimethyl phosphorodithioate (malathion), cis-1-methyl-2- (1phenylethoxycarbonyl)- vinyl phosphate (crotoxyphos), O-ethyl-O- (quinol-8-yl) phenylphosphorothioate (oxinothiophos), (S-45,7-dichlorobenzoxazol-2-yl- methyl} O,O-diethyl phosphorodithioate) (benoxaphos), S-[((4-chlornphenyl)-thio}-methyl] O,O-diethyl phosphorodithioate (carbophenothion), S((1,3-dihydro-1,3- dioxo- 2H-isoindol-2-yl) -methyl} O,O-dimethylphosphorodithioate (phosmet) or 2-chloro-1-(2,4dichlorophenyl)-vinyl diethyl phosphate (chlorfenvinphos).

Oxinothiophos (= quintiofos) and coumaphos are particularly suitable.

The individual components of the synergistic active compound combinations (phenoxybenzyloxycarbonyl derivatives of the formula (1) and the above-mentioned (thio)phosphoric acid esters) are known (see, for example, DE-OS (German Published Specification 2,730,515 and U.S. Patent Specification 3,284,455).

The active compound combinations according to the invention, whilst having a low toxicity to warm-blooded animals, exhibit an insecticidal and a powerful acaricidal action which rapidly sets in, especially against acarids which, as animal ectoparasites, infest domesticated animals, such as cattle, sheep and rabbits. They are thus very particularly suitable for combating animal ectoparasites from the class of acarids and insects.

However, owing to their insecticidal and acaricidal activity, the active compound combinations could, in principle, be used in the plant protection sector.

The weight ratios of the groups of active compounds in the active compound combinations can vary within relatively wide limits. in general, 0.5 to 10,000 moles of (thio)phosphoric acid ester, preferably 1.0 to 3,000 moles, of (thio)phosphoric acid ester, are employed per mole of active compound of the formula (l).

The synergistic combination of4'4luoro-3'-phenoxy-a-cyanobenzyl 2,2-dimethyl-3-(2-chloro-2- (4chlorophenyl )-vinyl) cyclopropane-1-carboxylate and O,O-diethyl O-(3-chloro- 4-methyl- 7-coumarinyl) phosphorothioate (coumaphos), especially in the ratio 1:1 to 1:1,000, and the synergistic combination of the above-mentioned phenoxybenzyloxycarbonyl derivative and O-ethyl-O- (8-quinolyl) phenylphosphonothioate {quintiofos, oxinothiophos), especially in the ratio 1:1 to 1:5,000, are particularly preferred.

The sy.7ergistic active compound combinations according to the invention can be converted into ihe customaryformulations,such as solutions, emulsions, suspensions, powders, dusting agents, foams, pastes, soluble powders, granules, aerosols, suspension-emulsion concentrates, seed-treatment powders, natural and synthetic materials impregnated with active compound, very fine capsules in polymeric substances, coating compositions for use on seed, and formulations used with burning equipment, such as fumigating cartridges, fumigating cans and fumigating coils, as well as ULV cold mist and warm mist formulations.

These formulations may be produced in known manner, for example by mixing the active compounds with extenders, that is to say liquid or liquefied gaseous or solid diluents or carriers, optionally with the use of surface-active agents, that is to say emulsifying agents andlor dispersing agents and/orfoam-forming agents. In the case of the use of water as an extender, organic solvents can, for example, also be used as auxiliary solvents.

As liquid diluents or carriers, especially solvents, there are suitable in the main, aromatic hydrocarbons, such as xylene, toluene or alkyl naphthalenes, chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzenes, chloroethylenes or methylene chloride, aliphatic or alicyclic hydrocarbons, such as cyclohexane or paraffins, for example mineral oil fractions, alcohols, such as butanol or glycol as well as their ethers and esters, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, or strongly polar solvents, such as dimethylformamide and dimethylsulphoxide, as well as water.

By liquefied gaseous diluents or carriers are meant liquids which would be gaseous at normal temperature and under normal pressure, for example aerosol propellants, such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide.

As solid carriers there may be used ground natural minerals, such as kaolins, clays, talc, chalk, quartz, attapulgite, montmoriilonite or diatomaceous earth, and ground synthetic minerals, such as highlydispersed silicic acid, alumina and silicates. As solid carriers for granules there may be used crushed and fractionated natural rocks such as calcite, marble, pumice, sepiolite and dolomite, as well as synthetic granules of inorganic and organic meals, and granules of organic material such as sawdust, coconut shells, maize cobs and tobacco stalks.

As emulsifying and/or foam-forming agentsthere may be used non-ionic and anionicemulsifiers, such as polyoxyethylene-fatty acid esters, polyoxy.ethylene-fatty alcohol ethers, for example alkylaryl polyglycol ethers, alkyl sulphonates, alkyl sulphates, aryl sulphonates as well as albumin hydrolysis products.

Dispersing agents include, for example, lignin sulphite waste liquors and methylcellulose.

Adhesives such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or latices, such as gum arabic, polyvinyl alcohol and polyvinyl acetate, can be used in the formulations.

It is possible to use colorants such as inorganic pigments, for example iron oxide, titanium oxide and Prussian Blue, and organic dyestuffs such as alizarin dyestuffs, azo dyestuffs or metal phthalocyanine dyestuffs, and trace nutrients, such as salts of iron, manganese, boron, copper, cobalt, molybdenum and zinc.

The formulations in general contain from 0.1 to 95 per cent by weight of active compound, preferably from 0.5 to 90 per cent by weight.

The active compounds according to the invention may be used in the form of their formulations of the types that are commercially available or in the use forms prepared from these formulations.

The active compound content of the use forms prepared from the formulations of the types that are commercially available can vary within wide ranges. The active compound concentration of the use forms can be from 0.0000001 to 100% by weight of active compound, preferably from 0.0001 to 10% by weight.

The compounds may be employed in a customary manner appropriate for the particular use forms.

The formulations of the active compound combinations according to the invention are produced in a manner which is in itseif known, by mixing together the individual components in the specifically required proportions, the sequence of the addition of active compounds andaddkives and formulation auxiliaries in general being of no great significance. The use of inert, non-toxic, pharmaceutically suitable excipients is preferred.

In the veterinary field, the active compounds according to the invention may be used in a known manner, such as orally in the form of, for example, tablets, capsules, drenches and granules; dermally by means of, for example, dipping, spraying, pouring-on, spotting-on and powdering; and parenterally, for example by means of injections. They may also be used by the so-called "feed-through" process.

The present invention also provides a method of combating insects or acarids, which comprises applying to the insects or acarids or to a habitat thereof, a composition according to the present invention.

The invention also provides a method of freeing or protecting domesticated animals from ectoparasitical insects or acarids which comprises applying to said animals a composition according to the present invention.

The invention also provides domesticated animals whenever freed or protected from ectoparasitical insects or acarids by the application to said animals of a composition according to the present invention.

The ectoparasiticidal activity of the compositions of the present invention is illustrated in the following biotest Examples.

Example 1.. Tick tes Fully engorged female Boophilus microplus (Biarra strain) adults were divided into groups of 20 ticks each and were dipped, in each case for 1 minute, into dilution series of the individual active compounds to be tested. The dilution series of these individual active compounds were prepared by diluting emulsion concentrates of these individual active compounds with tap water to the appropriate desired use concentration. After being dipped into these active compound preparations, the ticks were transferred to Petri dishes, the bottom of each of which was covered with a filter paper disc of corresponding size.

After 21 days, the activity of the active compound preparations was determined by examining the inhibition of the laying of eggs, as compared to untreated control ticks. The action was expressed as a percentage, 100% denoting that eggs were no longer laid and 0% denoting that the ticks laid normal amounts of eggs.

The ED50 values of the two individual active compounds were now determined with the aid of probit analysis.

In this method, the relative actions of the two individual active compounds were determined by equating the sum of the two ED50 values with 100 and calculating the relative action of the individual components as a percentage.

The action to be expected for the mixture of the two individual active compounds, according to their relative action in per cent, was calculated as Y from the following formula 1 Y = relative action of A in %, relative action of B in % +relativeactionofBin% ED50ofAx 100 ED50ofB x 100 Thereafter, a mixture of the two individual components in the ratio of the relative actions of the two components was prepared. The ED50 value of this mixture was then determined by means of probit analysis.

F was now calculated from the following formula: F= expected action (= action of A + action of B) action found (= action of A + B) If the dose determined was lower than the expected dose, that is to say if F was greater than 1, this proved that the mixture had a synergistic action, since less active compound was required in the mixture to achieve the same action than in the case of separate application of the individual components.

ED50 value of O,O-diethyl O-(3-chloro-4-methyl-7-coumarinyl) phosphorothioate (coumaphos) = 505.9 ppm (as substance A) ED50 value of 3'-phenoxy-4'-fluoro- a-cyanobenzyl 2,2-dimethyl-3-(2"-p-chloro-phenyl -2"-chlorovinyl)- cyclopropanecarboxylate = 1.4 ppm (as substance B).

ppm = parts per million.

y 1 relative action of substance A 99.7 + 0.3 in % 505.9 x 100 1.4 x 100 505.9 x 100 = 99.7% 505.9 + 1.4 1 1 relative action of substance B 0.0019707 + 0.0021428 in % 1 1 1.4 x 100 = 0.3% 0.0041135 505.9+1.4 Y = 243.3 ppm = expected action.

Action found for a mixture of 99.7% of substance A + 0.3% of substance B ED50 = 210 ppm F = expected action ~ 243.3 ~ 1.15 action found 210.0 Thus, instead of the expected 243 ppm of the mixture, only 210 ppm were required, and the same action was hence achieved merely with a 1.15 times lower amount of active compound.

ED50 value of O-ethyl O-(quinol-8-yl) phenylphosphorothioate (oxinothiophos) = 5,810.84 ppm (as substance A) ED50 value of 3'-phenoxy-4'-fluoro-a-cyanobenzyl 2,2-dimethyl- 3-(2"-p-chloro-phenyl-2"-ch lorovinyl)- cyclo- propanecarboxylate = 2.966 ppm (as substance B).

1 = 1 relative action of 99.95 0.05 substance A in % 5807.84 x 100 2.96 x 100 5807.84 x 100 = 99.95 5807.84 + 2.96 Y = 1 relative action of substance 0.0001719 + 0.0001689 B in % = 1 2.96 0.0003408 5807.84 + 2.96 x 100 = 0.05 Action found for a mixture of 9.95% of substance A + 0.05% of substance B.

ED50 = 206.0 ppm expected action 2934.3 action found 206 =14.24 Thus, instead of the expected 2934.3 ppm of the mixture, only 206.0 ppm were required, and the same action was thus achieved with a 14.24 times lower concentration of active compound.

Example2: In vivo tick test on Boophllus microplus for the development of the synergistic action The active compound combination was prepared immediately before the start of the test by mixing the two constituents, which were formulated as emulsion concentrates. The mixture thus obtained was diluted with water to the particular desired use concentration. Cattle which had been infested several times (12 infestations at intervals of 2 days) with tick larvae of the species Boophilus microplus resistant, Biarra strain, were sprayed with the active compound preparation thus obtained.The action of the active compound preparation was measured by determining the number of adult female ticks which developed onthe treated cattle This number was compared with the. number of adult female ticks which developed on untreated cattle.

A compound was the more active, the fewer female ticks developed after the treatment.

The number of adult female ticks which, in treated and untreated animals, developed in the last three days before thetime of treatmentwas used as a measure of the severity of the infestation.

The results are shown in the following Table.

TABLE 1 Boophilus microplus (Biarra strain, res.) / all stages of development (cattle) Active compound Number of ticks with fertile eggs concentration Days in ppm a.i. before Days after treatement Action treat- in % ment Substance Substance A1 B1 -2#0 +1-3 4-6 7-9 10-12 13-15 16-18 19-21 +1-21 - 6 1432 5 19 1 19 3 0 0 57 95 - 3 1074 819 580 849 336 103 14 28 2729 35.9 200 - 1263 550 332 337 106 49 31 1969 21.6 200 + 20 1664 0 0 0 0 0 0 0 0 100 100 + 10 971 0 0 0 0 0 0 0 0 100 50 + 5 951 3 4 2 0 0 0 0 9 99.67 1766 968 338 396 230 99 73 06 2210 0 Control 1583 967 560 528 255 84 135 39 2668 0 1230 849 892 933 499 52 17 0 3242 0 Substance A1 = oxinothiophos Substance B1 = 3'-phenoxy-4'-fluoro-&alpha;;-cyanobenzyl 2,2-dimethyl-3-(2"-p-chlorophenyl-2"-chlorvinyl)cyclopropanecarboxylate TABLE 1 Boophilus microplus (Biarra strain, res.) /all stages of development (cattle) Active compound Number of thicks with fertile eggs concentration Days in ppm a.i. before days after treatement Action treat- in % ment Substance Substance A1 B1 -2#0 +1-3 4-6 7-9 10-12 13-15 16-18 19-21 +1-21 - 30 1318 0 0 0 0 0 0 0 0 100 - 10 1802 0 0 0 0 0 0 0 0 100 - 6 1275 55 3 1 2 4 0 0 65 98.6 3 1074 819 580 849 336 103 14 28 2799 35.9 500 - 1035 83 51 27 21 34 6 5 227 93.3 400 + 20 2033 0 0 0 1 0 0 0 1 99.9 300 + 15 245 0 0 0 0 0 0 0 0 100 200 + 10 1566 0 0 0 0 0 0 0 0 100 100 + 5 1062 1 0 0 0 0 0 0 0 99.99 Control 1052 2040 1486 703 273 75 94 10 4681 0 1008 2249 1407 720 399 451 393 177 5796 0 1150 1129 550 941 294 450 409 39 3812 0 1613 2460 1494 981 307 422 346 286 696 0 Substance A2 = coumaphos Substance B2 = 3'-phenoxy-4'-fluoro-&alpha;-cyanobenzyl 2,2-dimethyl-3-(2"-p-chlorophenyl-2"-chlorovinyl)cyclopropanecarboxylate

Claims (14)

1. An ectoparasiticidal composition, characterised in that it contains as active ingredients (1) a phenoxybenzyloxycarbonyl derivative of the general formula

in which R, R' and R2 are selected independently and each represent hydrogen or halogen, R3 represents phenyl or substituted phenyl, Y represents hydrogen or cyano, n represents an integer from 1 to 5 and m represents an integer from 1 to 4, and (2) a (thio)phosphoric acid ester, alone or in admixture with a solid or liquid or liquefied gaseous diluent or carrier.

2. A composition according to claim 1, characterised in that the phenoxybenzyloxycarbonyl derivative of the formula (I) is one in which R and R1 each represent hydrogen or fluorine, with the proviso that R and/or R1 represent at most 2 fluorine atoms, R2 represents hydrogen, chlorine or bromine, R3 represents phenyl or phenyl which is substituted by fluorine, chlorine, bromine, C1-C4-alkyl, methoxy, methylenedioxy, trifluoromethoxy ortrifluoromethylthio, Y represents hydrogen or cyano, n represents an integer from 1 to 5 and m represents an integer from 1 to 4.

3. A composition according to claim 1 or 2, characterised in that the (thio)phosphoric acid ester is an active compound selected from oxinothiophos, bromophos-ethyl, coumaphos, diazinon, dioxathion, chlorpyrifos, ethion, dicrotophos, malathion, crotoxyphos, benoxaphos, carbophenthion, phosmet and chlorfenvinphos.

4. A composition according to claim 1, characterised in that it contains as active ingredients (1) 3'-phenoxy-4'-fluoro-a-cyanobenzyl 2,2-dimethyl-3- (2"-p-chlorophenyl- 2"-chlornvinyl)- cyclopropanecarboxylate and (2) oxinothiophos.

5. A composition according to claim 1, characterised in that it contains as active ingredients (1) 3'-phenoxy-4'-fluoro-a- cyanobenzyl 2,2-dimethyl-3-(2"-p-chlorophenyl- 2"-chlorovinyl)- cyclopropanecarboxylate and (2) coumaphos.

6. A composition according to any of claims 1 to 5, characterised in that the molar ratio of (1) phenoxybenzyloxycarbonyl derivative of the formula (I) and (2) (thio)-phosphoric acid ester is between 1:05 and 1:10,000.

7. A composition according to claim 6, characterised in that the molar ratio of (1) phenoxybenzyloxycarbonyl derivative of the formula (I) and (2) (thio)phosphoric acid ester is between 1:1 and 1 :3,000.

8. A composition according to any of claims 1 to 7, characterised in that it contains from 0.1 to 95% of total active compound, by weight.

9. A composition according to claim 1, substantially as described in Example A or B.

10. A method of combating insects or acarids, characterised in that there is applied to the insects or acarids, or to a habitat thereof, a composition according to any of claims 1 to 9.

11. A method of freeing or protecting domesticated animals from ectoparasitical insects or acarids, characterised in that there is applied to said animals a composition according to any of claims 1 to 9.

12. A method according to claim 10 or 11, characterised in that a composition is used containing from 0.0000001 to 100% of total active compound, by weight.

13. A method according to claim 12, characterised in that a composition is used containing from 0.0001 to 10% of total active compound, by weight.

14. Domesticated animals, characterised by being freed or protected from ectoparasitical insects or acarids by the application to said animals of a composition according to any of claims 1 to 9.