DK146232B - APPLICATION OF O, O, O ', O'-TETRAMETHYL-O, O'-THIODI-P-PHENYLENTHIOPHOSPHATE IN EXTERNAL CONTROLS FOR CATS AND DOGS OF CATS AND DOGS - Google Patents

Description

- 'Λ * ,.

(19) DENMARK j | j | (a PUBLICATION <<, 146232 B "

DIRECTORATE OF

THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No. 6399/74 (51) Int.CI.3: A 01 N 57/14 (22) Filing Date: 10 Dec 1974 (41) Aim. available: 11 Jun 1975 (44) Submitted: 08 Aug 1983 (86) International Application No: - (30) Priority: 10 Dec 1973 US 423623 (71) Applicant: «AMERICAN CYANAMID COMPANY; Wayne, US.

(72) Inventor: Michael Stanley 'Schrider; US, Gordon Paul «Poeschel; US, Anthony Morris' Annand; AU.

(74) Plenipotentiary: Budde, Schou & Co (54) The use of 0,0,0 ', 0-tetramethyl-0,0-thi · odi-p-phenylphenothiophosphate in topical anti-flea and blood mites in cats and dogs

The present invention relates to the use of Ο, Ο, Ο ', Ο' - tetramethyl-0,0'-thiodi-p-phenylenethiophosphate and a physiologically acceptable diluent in agents for topical control of mites and fleas in cats and dogs in an amount of 0.7 to 400 mg of active compound or. kg body weight.

The active component used in accordance with the present invention can be illustrated by the following structure: 4 i- -i

Ϊ S

4 π

3 (CH30) 2P-O - ^^ .—- S

in 3 2 H6232

This compound is known from DK Patent No. 115,293 in which it is stated to be useful as an insecticide in general, while there is no mention of a possible effect against fleas and mites.

The control of fleas and mites in dogs and cats presents special problems that are not encountered in the control of pests in general. Dogs and cats are often pets for children, who often have the habit of sticking their fingers in their mouths after they pet the animals without first washing their hands. A means to control fleas and mites on such animals must therefore be as little toxic as possible, which is also of importance to the animals themselves because they often lick.

It is therefore of great importance that the active compound used according to the invention in experiments has been found to be far less toxic (LD50 = 8600 mg / kg in rats) than known compounds, namely 1-naphthyl-N-methylcarbamate. 2,2 - Dichlorovinyl-0,0-dimethyl phosphate, 0,0-dimethyl-S- (1,2-dicarbethoxyethyl ·) - phosphorus dithionate and pyrethrins which are from 5 to 140 times as toxic and which are compounds recommended for the control of fleas in dogs and cats. Furthermore, the compound used according to the invention is characterized by an action which lasts longer than the action of the known compounds.

Furthermore, it is known that 0,0,0 ', 0'-tetramethyl-0,0' - dithio-p-phenylene thiophosphate is effective against lice, while flea tests have been unsuccessful. It is therefore surprising that the compound has nevertheless proved effective in combating fleas and mites in dogs and cats, and the long duration of action in comparison with known flea and mite control agents is surprising.

The compound 0,0,0 ', 0'-tetramethyl-0,0-dithio-p-phenylene-thiophosphate can be prepared by reacting the diphenol h ° .O-s-O-0h with at least 2 moles of O, O-dimethnylthiophosphoryl halide of the formula

CH-0 S

j \ II

pp-x ch 3 wherein X is halogen, preferably chlorine.

The reaction between the diphenol and the 0.0-dimethylthiophosphoryl halide is carried out on a relative molar basis with 1 mol of diphenol to at least 2 mol of thiophosphoryl halide, although up to 4 mol of thiophosphoryl halide is advantageously used, under alkaline conditions and in the presence of a polar solvent such as water and methyl ethyl ketone, at a temperature of between 0 and 100 ° C. This compound can also be prepared in solvents with a wide range of polarity using a variety of methods to prevent the accumulation of hydrogen halide by-product. The preparation of the above compound is described in United States Patent Nos. 3,317,636, 3,390,209 and 3,459,856.

It has now been found that the compound 0,0,0 ', 0', - tetramethyl - 0.01-thiodi-p-phenylethiophosphate is highly effective in topically controlling fleas and blood mites.

The use of 0,0,0 ', Ο'-tetramethyl1-0,0'-thiodi-p-phenylene-thiophosphate for the control of infestation or gene attack in dogs and cats by fleas and blood mites is a novel use of this material.

It is known that 0.0-diethyl-O- (2-isopropyl-6-methyl-4-pyrimidinyl) thiophosphate (Diazinone) and 0,0-dimethyl-S- (1,2-dicarbethoxyethyl) -dithiophosphate (Ilalathion) is among the insecticidal agents that are constantly used as sprays to control lice in cattle, but it is usually recommended to apply two of these materials within a few weeks. It is stated by Buchanan et al. in New Zealand Vet. Journal 19 (9): 197-202 (1971) that the use of 0.0-diethyl-O- (3,5,6-trichloro-2-pyridyl) -thiophosphate (Dursban, chloropyrifos) provides effective control of lice in cattle by a single spray treatment.

It is highly desirable to combat flea and blood mite attacks or re-infestations due to the losses caused by these pests. The undeveloped stages as well as the fully developed stages of the acaridae are financially devastating.

Typically, such insects include fleas (Siphonaptera) such as Ctenocephalides felis in dogs and cats.

The ectoparasites include acaridae, such as Boophilus, Amblyomma, Anocentor, Dermacentor, Ixodes, Haemaphysalis, Hyalomma, Rhipicentor, Morgaropus, Rhipicephalus, Argas, Otobius and Ornithodoros in the larval and new stage, and the fully developed stage and its application important in combating dog fleas (Ctenocephalides canis) and cat fleas (Ctenocephalides felis).

The use of 0,0,0 ', 0', tetramethyl 1-0,0'-thiodi-β-phenylene-thiophosphate for controlling flea infestation in dogs and cats would be particularly advantageous because it is practically non-toxic in concentrations that are many times the concentration of the quantities actually used. The active ingredient, 0.0.0 ', C-tetramethyl 1-0.0'-thiodi-p-phenylthiophosphate, may conveniently be formulated as powders, powder concentrates, wettable powders, emulsifiable concentrates and as solutions with conventional solid or liquid auxiliaries. . Wettable powders and emulsifiable concentrates are particularly useful because they can be diluted with water and applied topically as diluted liquid sprays to the animals to be protected from attack. In the latter case, the diluted liquid compositions can also be used both as immersion agents and as sprays.

Powders or powder concentrates can be prepared by grinding the inert solid diluent such as attapulgite, kaolin, walnut shell flour, diatomaceous earth, ground corn cob grits or ground coconut shells, together with the active ingredient when in solid form. When the active ingredient is liquid, it can be sprayed onto the support and mixed thoroughly with it, or it can be dissolved in a solvent such as acetone or xylene and the solution sprayed onto the solid support. Powders usually contain from ca. 1 to 15% by weight of active ingredient, while concentrates may contain from ca. 16 to approx. 85% by weight of the active material.

5 146232

Solutions in organic solvents such as various ketones, lower monovalent aliphatic alcohols, ketoalcohols such as diacetone alcohol, various esters, aromatic and aliphatic hydrocarbons may be applied as a spray or may be poured.

Wettable powders are prepared in the same way as powder concentrates, with the exception that approx. 5% to 10% by weight of a surfactant and from 5% to 10% of a dispersant.

The present active component can also be prepared as emulsifiable concentrates by dissolving or dispersing from ca. 10% to 75% by weight of the active compound in a suitable solvent or carrier, such as a petroleum distillate having a minimum content of aromatic compounds of 85%, and mixing this or that with approx. 10% by weight of an emulsifier such as polyoxyethylene derivatives and mixtures with alkylarylsulfonates. These concentrates are also generally dispersed in water or other suitable solvent for application.

The application is preferably carried out at a dose concentration that is lethal to fully developed insects and acaridae and provides final control of the harmful organisms by ovicidal or larvicidal activity.

The active ingredient may be applied either directly, e.g. by powdering, dipping and spraying, or by pouring, or from pressure spray containers.

Application to dogs and cats to control fleas can be done 3 by spraying each animal with 20 cm aqueous solutions containing from 0.0375 to 0.355% (w / v) [0.355% (w / v) contains 0.355 g of active ingredient per day. 100 g of solution] to provide from 1.25 mg to 10 mg of active material per ml. kg body weight.

Application to dogs and cats to control fleas can also be done by treating each animal with a powder containing approx. 2% active ingredient to provide from 10 mg to 120 mg of active ingredient per day. kg body weight.

As an ovicidal agent, an application of from ca. 0 ', 7 to 140 mg / kg of active ingredient effective in preventing embryogenesis of insect and acaridae eggs. Preferably, the application rate should be from 1 to 100 mg / kg.

As a larvicidal agent, it has been found that from ca. 0.001% of the compound 0,0,0 ', 0'-tetramethyl-0,0'-thiodi-p-phenylene-thiophosphate is generally effective in controlling Boophilus acarina larvae. The amount of application to larvae is preferably in the range of from ca. 0.001 to 0.04%.

6 146232

The present invention is illustrated by Examples 2-8 below, while Example 1 describes the preparation of the compound used. All parts and percentages are parts by weight and percentages unless otherwise specified.

Example 1.

Preparation of 0,0,0 ', 0, -tetramethyl-0,0'-thiodo-p-phenyl-enthiophosphate.

This compound is prepared by reacting 11 g (0.05 mole) of 4,4'-thiodiphenol and 5.5 g (0.1 mole) of sodium methoxide suspended in 400 ml of methyl ethyl ketone and refluxing for 15 minutes, distilling to remove of methanol, dilution with 100 ml of methyl ethyl ketone and addition of 16.2 g (0.11 mol) of 0.0-dimethylthiophosphoryl chloride dissolved in 50 ml of methyl ethyl ketone over 5 minutes under reflux. The mixture is then refluxed for 1.5 hours.

The solids are filtered off and the solvent is removed under reduced pressure. The residue is dissolved in chloroform and the solution is washed with 5% sodium hydroxide, 5% hydrochloric acid, water and saturated sodium chloride solution. The washed solution is then dried and concentrated under reduced pressure to give 18.3 g of oil. Purification by washing with hexane and chromatography on acid washed alumina yields pure material with ηβ = 1.5880.

Example 2.

Effective control of Siphonaptera is demonstrated by the use of bastard dogs experimentally infected with 100 fully developed Ctenocephalides felis. The dogs used in the experiment are placed in raised cages with steel grating floors. Three days before treatment, 100 fleas are applied to each dog. On the day of treatment, each cage is lined with absorbent brown paper. The dogs are treated with various dosage amounts (1-40 mgAg) applied topically using a powder composition with 2% active ingredient and a dilute aqueous dispersion applied as a spray. The activity is determined by the number of dead fleas that appear on the brown paper and by a systematic study of the test animal in relation to infected, untreated control dogs.

7 148232

The residual activity of the initial application of the test compound is assessed by experimentally re-infecting each dog at 7 day intervals with an additional 100 fully developed Ctenocephalides felis. The activity is determined as described above. The results obtained are described in Table I.

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Example 3

An experiment is carried out using Ο, Ο, Ο ', Ο' - tetramethyl-0,0'-thiodi-p-phenylene thiophosphate prepared from a 25% talc diluted concentrate, thus that the final powder is a 2% drug. Prior to the start of the experiment, 23 cats are classified by gender, age, coat length and color and are divided into 5 groups. One of these groups is then arbitrarily selected to be the control group and the other groups are selected for treatment in random order. The amount of the 2% drug powder applied to each cat is calculated prior to treatment to give a dose amount of 60 mg of drug per day. kg. Weigh the breath before treating each cat and at intervals during the pudding to get as close to the desired dose as possible. The following Table II shows the weight of the cats used in the experiment, together with the amount of drug used. Table III summarizes the results obtained up to 48 days after treatment.

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The above results show that excellent residual mating against C. felis in cats is achieved for 4 weeks. Usage * 1 of 60 mg of OjOfO'O'-tetramethyl-O ^ '- thiodi-p-phenylethiophosphate per ml. kg in the form of a 2% powder produces 100% control in 3 weeks, 90% in the fourth week, 64% in the fifth week and 40% in the sixth week.

Example 4

An experiment is carried out using 2% s, Ο, Ο ', Ο' - tetramethyl-0,0 '' thiodi-p-phenylenthiopho3phatTspray, which has been added. pressure and having the following composition:

Percent 0.0.0 ', 0'-Tetramethyl-1.0.0' - thiodi-p-phenylthiophosphate 2.2 PEG 2.5

Isopropyl Alcohol 42.4 "Genetron 11" 33.8 "Genetron 12" 18.8

Masking agent ("BQTV 1480") 0.3

Bastard cats are sourced from a pet store that sells to labs. Upon arrival, the cats are caged separately and fed with a beaker "Purine" ® cat food daily and given drinking water to which "aureomycin" is added ad libitum. Four cats, Nos. 91, 93, 100 and 101, are from litters raised in the laboratories. The cats are kept for at least three weeks prior to the start of the experiment to ensure that they are in good health. Two separate rooms are used to house the cats and a suitable number of test and control cats are kept in each room during the two tests. Prior to the beginning of each sample, the cats are classified by gender, age, coat length and color and are divided into five identical groups with five cats in each. One of these groups is then randomly selected to be controls, and the other groups are selected for treatment in random order. The amount of 2% drug spray applied to each cat from a pressure can is calculated prior to treatment to give a dose amount of 60 mg / kg cat. The spray can is weighed before each cat is sprayed, and then weighed again at intervals during spraying to get as close to the desired dose as possible. During dosing, an attempt is made to distribute the spray evenly throughout the cat's surface area. The cats are removed from their cages and examined for live fleas on a stainless steel board by two technicians. As soon as a live flea is found, the investigation ends. All dead fleas found in the fur are removed and counted. Only fleas-free cats 34 days after treatment and controls are re-infected with fleas on day 35. Activity in both samples is based on the absence or presence of fleas and not on the percentage reduction in flea populations. The percentages of activity used in Table IV below are calculated using the formula below:

Number of cats free of fleas χ 10 ". prooent combat

Total number of tested cats

The following tables XV and V summarize the weight of the cats, grams of spray and actual doses of drug in samples 1 and 2. Table vi and will give the flea count the indicated number of days after treatment in the two samples.

Table IV

2% 0.0.0 ', 0'-tetramethyl 1-0.0'-thiodi-β-, phenylenthiophosphate pressure spray against Cteiiocephalides felis infestation in cats (Sample 1)

Gram Actual dose

Cat No. Weight applied to "Temefos" (kg) spray (mg / kg) 3 3, 15 11.0 0 0 3.9 8.0 0 2 2.2 7.0 0 8 3.35 10.0 0 0 - 2.75 8.0 0 128 3.3 10.0 60.6 91 3.15 8.5 53.96 151 1.9 7.0 73.68 117 3.45 11.0 63.76 83 3.5 11.5 65.71 161 3.1 10.0 64.51 159 2.4 7.5 62.5 154 2.2 6.5 59.09 140 3.4 11.0 64.7 157 2.0 7.5 75.0 93 1.35 4.0 59.25 119 5.55 17.0 61.26 155 2.25 7.0 62.22 146 3.0 9.5 63.33 150 1.75 6.0 68.57 73 2.9 8.5 58.62 101 3.75 12.0 64.0 147 1.75 6 * 0 68.57 124 3.5 11.0 62.85 153 2.3 7.0 60.86

Average for treated cats ^ 55 16 146232

Table V · 2% 0.0.0 ', 01-tetramethyl-0.0'-thiodi-p-phenylenthiophosphate spray against Ctenocephalides felis infestation in cats (Sample 2).

Actual dose

Cat No. Weight Gram "Temefos" (kg) applied _ _ spray (mg / kg) _ 188 2.5 8 "0 0 169 2.9 12.0 0 173 3.0 9.0 0 179 3.2 10 , 0 0 185 4.5 14.0 0 194 2.7 9.5 0 166 2.9 9.0 62.07 143 2.9 8.5 58.62 183 4.0 13.0 65.0 156 2.2 7.0 63.64 186 2.9 10.0 68.97 167 2.5 7.5 60.0 171 3.1 9.5 61.29 130 4.1 12 ^ 5 60.98 174 3.2 9.5 59.38 187 3.1 9.0 58.06 168 2.3 7.0 60.87 189 3.2 10.5 65.63 178 3.3 9.5 57.58 100 3.2 9.5 59.38 181 3.5 11.5 65.71 170 2.3 7.0 60.87 175 4.6 13.5 58.70 180 3.2 9.5 59.38 176 3.1 9.0 58.06 190 3.2 10.0 62.5

Mean for treated cats 61.33 146232 ίΜ Κ Η + I + 1 m Φ ^ μ c +> m η ο + + ι + 1 μ ΐί Ό ^ φ> ι c ο μ (β. · Η +1, β r - + II + 1 «μ <1) η β = Λ · Η Ο μ νο + I ++ + φ ιμ φ <η 0> Φ + ι i Μ-ι« <0 φ <ϋ & s'1 φ + + ++ Ι ++++ ++ φ

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146232 21

Example 5

An experiment is being conducted to determine the activity of 0,0,0 ', 0'-tetramethyl-0,0'-thiodi-p-phenylenthiophosphate ("Abate") ® as 2% powder to combat Ctenocephalides felis attack on dogs.

A group of 40 mixed breed dogs is obtained from a pet dealer licensed to sell animals to laboratories and placed in individual cages. The 2% "Abate" powder is formulated from a 25% powder concentrate containing 26% "Abate" 24% "celite 209" and 50% acidic kaolin. Talc is used to dilute the concentrate to 2% "Abate" Each dog is infected with 100 1 day old fully developed Ctenocephalides felis 72 hours prior to treatment and re-infected weekly for 6 weeks beginning 7 days after treatment, each dog treated with 20 mg / kg of actual "Abate" ® formulated Five or more dogs are treated with a blind powder and used as infected controls. The following table VIII summarizes the results obtained in two separate experiments with 20 dogs in each. Table IX 0 <3 x summarizes dead fleas, obtained from papers placed under each dog cage Table χχ summarizes the average number of dead fleas on treated dogs relative to the average number of dead fleas on control dogs.

Table VIII J $)

Activity of 2% 's' Abate powder applied at 20 mg / kg in dogs.

Number of dogs where fleas are fought »Weeks after treatment

Attempt 0 1 2 3 4 5 6 1 * 20 20 20 20 17 14 5 20 20 20 20 20 20 20 2 * ^ 20 20 20 20 20 18 13 20 20 20 20 20 20 20 f 40 4 ° 4 ° 4 ° 37 32 18 trials 1 and 2 40 40 40 40 40 40 40 percent dogs with combat 100 100 i00 100 92.5 80 45 x All control dogs remain infected as long as the trials last; an exception is observed due to accidental exposure to "Temefos".

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27 146232

An experiment is being conducted on dogs obtained from a pet dealer licensed to sell animals to laboratories.

These dogs are of mixed woods and of different sizes and genders. The dogs are placed individually in cages with absorbent paper placed underneath each for counting dead fleas. A mixture containing 2% 0.0.0 '/ 0'-tetramethyl-OfO'-thiodi-p-phenylethiophosphate ("Abate") ® and with the composition below is used as a pressure spray.

Percent "Abate" ® 2.2 "PEG 200" 2.5

Isopropyl Alcohol 42.4 "Genetron 11" 33.8 "Genetron 12" 18.8

Masking agent ('BQTV n, 1480 ")

Two experiments are conducted, one with 22 dogs and the other with 21 dogs, each experiment using 5 control dogs. Each dog is treated with approx. 60 mg / kg actual "Abate" ® using the above preparation. Each dog is infected with 100 1 day old fully developed Ctenocephalides felis 72 hours prior to the spray treatment and re-infected weekly for 7 weeks beginning 7 days after treatment. Control dogs are treated with a blind spray containing everything except "Abate" ®. After treatment or each reinfection, daily examinations of each dog are performed up to 7 days after or until no live fleas can be found. Once a live flea is found , the dog is still considered infected, even though the flea population may have been low.The flea control expressed as number of dogs with control / number of treated dogs is summarized in Table XII.The number of dead fleas that appeared on the papers under the cages is expressed as average dead of treated / averaged died on controls and are summarized in Table XIII.

28 146232

Table XXX

Activity of 2% "Temefos" pressure spray applied in an amount of 60 mg.

"Temefos" / kg on dogs

Number of dogs on which fleas are fought

Trials Weeks after treatment 0 1 2 3 4 5 6 7 1 * 22 22 22 22 22 22 20 12 22 22 22 22 22 22 22 ** 21 2 * 21 21 21 20 19 18 14 12 21 21 21 20 ** 20 20 20 20

Combination of Experiments 1 and 2 43 43 43 42 41 40 34 24 43 43 43 42 42 42 41 41

Percentage of Fighting Dogs 100 100 100 97., 6 95., 2 82., 9 58? 5 x All control dogs remain infected for as long as the trials last.

XX A dog has died from a respiratory infection.

Table XIII

29 146232 Dead fleas that appeared on papers placed under the cages.

Average died on treated / average died on controls

Weeks after treatment Experiment 1 Experiment 2 Average of two trials.

0 34.6 38.0 36.3 3.8 0.2 2.0 1 38.2 44.5 41.4 10.4 0.8 5.6 2 42.1 40.3 41.2 3.4 2 , 6 3.0 3 41.6 40.7 41.2 4.6 5.0 4.8 4 37.8 43.6 40.7 5.4 5.0 5.2 5 34.1 37.9 36.0 5 , 0 6.2 5.6 6 34.1 26.0 30.0 6.2 3.5 4.8 7 30.8 21.8 26.3 6.6 3.0 4.8

Each trial represents 20-22 treated and 4-5 control dogs.

The above experiments show that a 2% spray spray is extremely active in the control of Ctenocephalides felis in dogs.