CS203978B2 - Means for exterminating the non-patogenous parazites living on the surface of animal body - Google Patents

Abstract

1505846 Parasiticidal Formulation ELI LILLY & CO 10 March 1975 [11 March 1974 2 Dec 1974] 10 March 1975 9843/75 Heading A5E A parasiticidal formulation for oral or porcutaneous administration to an infected host animal is a capsule, implant injectable sterile suspension or matrix formulation, and includes a compound of formula I wherein R is chloro trifluoromethyl, difluoromethyl or chlorofluoromethyl; R' is H, R<SP>2</SP> is chlorodifluoromethyl 1, trifluoromethyl, 1, 1, 2, 2 - tetrafluoroethyl, pentafluoroethyl, pentafluoroethyl, heptafluoropropyl, or beptafluoroisopropyl; R<SP>3</SP> to C 1-6 alkyl, C 2-3 alkenyl, phenyl or benzyl; R<SP>4</SP> is C 1-5 alkyl, phenyl, chlorophenyl, anisyl or tolyl; R<SP>5</SP> is C 1-3 alkyl or phenyl; or an ammonium, alkali metal or alkaline earth metal salt of a compound of formula I wherein R<SP>1</SP> is H associated with a suitable veterinarally acceptable carrier therefor.

Description

The invention relates to compositions for combating non-pathogenic parasites living on the surface of an animal body.

Combating animal parasites is one of the oldest and most important problems of the animal husbandry industry. Most animals are attacked by free-flying parasites such as flies, thistles and horseflies, crawling ectoparasites such as lice and mites, drilling parasites such as various larvae, such as throat and worm larvae, by microscopic endoparasites such as coccidia as well as larger endoparasites such as helminths. Therefore, combating parasites even on a single host species is a complex and multifaceted problem. »

Insect and mite parasites that feed on living tissues of the animal host are particularly dangerous and harmful. This group includes parasites of all livestock, including ruminants and non-ruminant mammals and poultry, as well as companion animals such as dogs.

A number of methods have been tested for combating such parasites. In Florida, Phormia regina larvae were virtually completely exterminated by the release of a large number of sterile males.

Of course, this method can only be applied to easily insulable surfaces. Free-flying insect species are usually combated by conventional methods such as dispersing contact insecticides in the air or using Venus flytrap. Skin-crawling parasites are usually controlled by painting, soaking or spraying animals with appropriate parasiticidal agents.

Some progress has been made in the systematic killing of some parasites, especially those burying or passing through a swirl host. Systemic killing of animal parasites is achieved by absorbing the parasiticidal agent in the bloodstream or other tissues of the animal host. Parasites that feed or come into contact with tissues containing the parasiticidally active agent are killed by either ingestion or contact. Several phosphate, phosphoramidate and phosphorothioate insecticides and acaricides have been shown to be non-toxic for systemic administration in animals.

Recently there has been great activity in the field of benzimidazole chemistry. A large number of patents and publications have been disclosed describing various substituted benzimidazoles, some of which exhibit insecticidal and acaricidal activity.

For example, Belgian patent no.

766,870 discloses a group of acaricidally active berizimidazoles bearing a carboxylate203978 substituent at position 1, a chlorofluoroalkyl substituent at position. 2 and a variety of other substituents, including halogen atoms, nitro and trifluoromethyl, on the benzene ring.

Newbold et al. In U.S. Patent 3,542,923 disclose a method for controlling insects using benzimidazoles having no 1-position substituent or a 1-carboxylate substituent, a 2-perfluoroalkyl substituent, and up to 4 benzene ring substituents selected from the group consisting of: including a plurality of substituents including nitro, halogen, alkyl, carboxyl, and the like.

British Patent No. 1,122,988 discloses insecticidally and acaricidally active benzimidazoles whose structures are characterized by an unusually wide variety of possible substituents on the benzene ring, of which said compounds may contain up to four. The substituent at position 2 of these compounds is a perfluoroalkyl group and the substituent at position 1, if present, is an alkyl or aryl group.

British Patent Specifications Nos. 1,087,561 and 1,144,620 disclose additional insecticidally active 2-perfluoroalkylbenzimidazoles.

French Patent No. 1430139 discloses another class of insecticidally, acaricidally and nematocidally active benzimldazoles bearing on the benzene ring up to four substituents selected from, inter alia, nitro, chloro and cyano, and the haloalkyl substituent at the 2-position.

British Patent Specification No. 1,113,999 describes a group of 1-thiocarbamoylbenzimidazoles which are insecticidally active against various pests such as the leaf beetle, aphid and mosquito.

In South African Patent No. 69.02813. describes the biological activity of a group of benzimidazoles, including compounds bearing 1-carboxylate and 1-sulfonyl substituents. These compounds are insecticidally and acaricidally active.

Holan et al. in U.S. Pat. No. 3,448,115 discloses a group of substituted benzimidazoles characterized by the presence of a dichlorofluoromethyl or chlorodifluoromethyl substituent at the 2-position. The compounds of this patent disclose anthelmintic and herbicidal activity.

Hannah et al. U.S. Pat. No. 3,749,734 discloses a group of 1-cyanobenzimidazoles bearing chloro atoms on the phenyl ring, which compounds are said to be anthelmintically and ectoparasiticidally active.

SUMMARY OF THE INVENTION The present invention provides a composition for controlling non-pathogenic parasites living on the body surface of an animal, which comprises as an active ingredient a benzimidazole derivative of the formula I

in which

R represents a chlorine atom or a trifluoromethyl group,

R 1 represents hydrogen, C 1 -C 3 alkoxy, C 1 -C 4 alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl or dimethylthiocarbamoyl; and

R ² represents a trifluoromethyl group, a difluorochloromethyl group, a pentafluoroethyl group or a 1,1,2,2-tetrafluoroethyl group, or an ammonium salt, a salt with alkalickým- metal. or - a metal salt. alkaline earths any of the compounds of formula I wherein R 1 is hydrogen.

Alkali metals in this case are, in particular, sodium, potassium and lithium.

Alkaline earth metals are in particular calcium, magnesium and strontium.

As examples. The compounds used for the purposes of the invention are:

2-chlorodifluoromethyl-4-nitro-6-trifluoromethylbenzimidazole,

6-nitro-2,4-bis (trifluoromethyl) benzimidazole,

5-nitr2-6,6-bis (trifluoromethyl) benzimidazole, 4-nitro-2-penfafluoroethyl-6-irifluoromethylbenzimidazole, 1-ethoxy-4-nitro-0,6-bis (trifluoromethylbenzimidazole),

4-nitro-6, b-bis (trifluoromethyl) benzimidazole, ethyl 4-nitro-0,6-6ls (trifluoromethyl) -1-benzimidazolecarboxylate, phenyl-4-nitro-0,6-6ib (trifluoromethyl) -1-benzimidazolecarboxylate

2,6-bis (trifluoromethyl) -4-nitro-1-phenylsulphonylbenzimidazole, 1-methoxy-4-nitro-0,6-6is (trifluoromethyl-4-carboxylic acid) benzimidazole, sodium 2,6-bis (trifluoromethyl) -4-nitrobenzimidazole, isopropyl-4-nitix) -4,6-bis (trifluoromethyl) -1-benzimidazolecarboxylate,

N, N-dimethyl-4-nitro-2,6-bis (trifluoromethyl) -1-benzimidazolthiocarboxamide,

N, N-dimethyl-7-methyl-2,5-bis (trifluoromethyl) -1-benzimidazolthiocarboxamide, benzyl 2,6-bis (trifluoromethyl) 4-nitro-1-benzimidazolecarboxylate, benzyl 2,5- bis (trifluoromethyl) -4-nitro-1-benzimidazolecarboxylate, methyl 4-nitro-2,6-bis (trifluoromethyl) -1-benzimidazolecarboxylate, methyl 7-nitro-2,5-bis (trifluoromethyl) -1-benzimidazolecarboxylate, isopropyl- 2-chloro-4-trifluoromethyl-4-nitro-64-trifluoromethyl-1-benzimidazolecarboxylate;

7-nitro-2- (1,1,2,2-tetrafluoroethyl) -5-trifluoromethylbenzimidazole,

1-ethoxy-4-nitro-2-phenylfluocethyl-16-trifluoromethylbenzimidazole, phenyl-2-chlorodifluoromethyl) 4-nitro-6-trifluoromethyl-1-benzimidazolecarboxylate,

5-chloro-6-nitro) 2-trifluoromethylbenzimidazole,

(6) Chloro (2) trifluoromethyl-4-nitrobenzimidazole,

4-chloro-5-nitro) 12-trifluoromethylbiszimidazole,

4-chloro-7-nitro) 12-chloromethylbenzimidazole,

4-Chloro-6-nitro-12-trifluoromethyl- (enzimidazole),

5-chloro-4-nitro) 2-trifluoromethylbenzimidazole, potassium salt of 5-nitro-2,6-bis (trifluoromethyl) benzimidazole, 7-mtrO) 2,5-lis (trifluoromethyl) benzimidazole calcium salt.

Preferred compounds used in the compositions of the present invention are: phenyl-4-nitro-2,6-bis ((1R, 4R, 4R)) -1-benzimidazolecarboxylate, isopropyl-4-nitro-2,6-bis (tri- (1-methyl) -1-benzimidazolecarboxylate

2-Chlorodifluoromethyl-4-nitro-6-trifluoromethylbenzimidazole, 1-ethoxy-4-nitro-2-piperitluoroethyl-6-difluoromethylbenzimidazole, phenyl) 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-1-benzimidazolecarboxylate, ethyl 2-chlorodifluoromethyl) 4-nitro-6-difluoromethyl-1-benzimidazolecarboxylate, isopropyl-4-methyl-2- (1,1,2,2-tetrafluoroethyl) -6-trifluoromethyl-11-benzimidazolecarboxylate.

The benzimidazoles used in the present invention can be prepared by methods known per se. To illustrate, some of these methods will be explained in more detail below and some examples will be given.

The process for preparing the above compounds depends on the nature of the substituent at the 1-position of the resulting benzimidazole. The synthesis of all the benzimidazoles of the invention, with the exception of the 1-alkoxy-substituted compounds, begins with the reaction of an appropriately substituted o-phenylenediamine with a fluoroalkanoic acid. The reaction can be carried out in 5N acid, such as hydrochloric acid, at reflux. The substituent at the 2-position is transferred to the resulting benzimidazole from a substituted alkanoic acid. For example, to prepare 2-trifluoromethylbenzimidazole, the phenylenediamine is reacted with trifluoroacetic acid.

Higher yields of benzimidazoles are obtained by reacting o-phenylenediamine with a fluoroalkanoic acid in the presence of a halide such as phosphorus oxychloride or phosphorus pentachloride in a solvent such as pyridine. It is also possible to carry out the reaction in the presence of an acid chloride prepared in situ in the reaction mixture. The reaction proceeds rapidly under reflux.

The substituents on the benzene ring of the benzimidazole correspond to the substituents on the benzene ring of the starting o-phenylenediamine. For example, if the resulting benzimidazole is to be substituted at the 4-position by chlorine and at the 6-position by a nitro group, 3-chloro-5-nitro-o-phenylenediamine is used as the starting material. If the resulting benzimidazole is to be substituted at the 7-position with a nitro group and the 5-position with a chlorodifluoromethyl group, 6-nitro-4-chlorodifluoromethyl-o-phenylenediamine is used as the starting material.

Suitably, the substituents at the 1-position of the resulting benzimidazoles other than the 1-alkoxy groups are conveniently introduced at the 1-position of the corresponding benzimidazole directly. Sulfonyl, carboxylate and thiocarbamoyl substituents are introduced into the 1-position of the benzimidazole ring system by direct reaction of benzimidazole with the halide derivative of the respective substituent. Thus, for example, the phenylsulfone group is introduced by reaction with phenylsulfonyl chloride, the propoxycarbonyl group is reacted with propyl) Chlorofloamate, and the N, N-dimethylthiocarbamoyl substituent is reacted with Ν, Ν-dimethylcarbamoyl bromide. The above reaction proceeds smoothly at room temperature in solvents such as acetonitrile, tetrahydrofuran or benzene. As a starting material for this. the benzimidazole or the alkali metal salt thereof may be used in the reaction. The above procedures are illustrated by Examples 2 and 3 below.

The benzimidazoles substituted at the 1-position with alkoxy groups are obtained via the 18-hydroxybenzimidazoles intermediate, which are prepared by reductive cyclization of an appropriately substituted acetanilide, which is prepared from o-nitroaniline.

The 1-alkoxy-substituted benzimidazole is readily prepared by reacting the intermediate 1-hydroxybenzimidazole with an alkyl halide in the presence of an alkali metal alkoxide, hydroxide or carbonate, at room temperature. or at elevated temperature.

The alkali metal, alkaline earth metal or ammonium salts of the benzimidazoles, unsubstituted in the 1-position, are readily prepared by conventional methods. For example, alkali metal or alkaline earth metal salts are prepared by reacting benzimidazole with the metal methoxide in methanol at room temperature. The salts are also conveniently prepared from alkali metal or alkaline earth metal hydroxides by dissolving the hydroxide in a suitable solvent such as water, aqueous alcohol or aqueous acetone and adding the appropriate benzimidazole at room temperature. The ammonium salts are prepared by reacting benzimidazole with ammonium hydroxide or by introducing ammonia gas into a benzinjidazole solution.

The following examples illustrate the synthesis of some typical compounds used within the meaning of the invention but do not limit the scope of the invention in any way.

The first example illustrates the synthesis of the intermediate o-phenylenediamine as well as the synthesis of typical benzimidazoles.

Example 1

4-Nitro-2-pentafluoroethyl-6-trifluoromethylbenzimidazole

A solution of 40.5 g of 2,6-dinitro-4-trifluoromethyl-1-chlorobenzene in 300 ml of benzene was treated with 250 ml of 14N ammonium hydroxide. The mixture was stirred at room temperature for about 1.5 hours. An additional 100 mL of 14N ammonium hydroxide was added thereto, and the resulting mixture was stirred for a further 2 hours. The reaction mixture was allowed to separate into layers, the organic layer was separated, washed with water, dried and the solvent was evaporated in vacuo. There was obtained 2,6-dinitro-4-trifluoromethylaniline, melting after recrystallization from hexane-benzene at 142-144 ° C.

g of the product prepared above is. Dissolve in 300 ml of ethanol, heat to about 35 ° C and add 110 ml

20% aqueous ammonium polysulfide containing 5% free sulfur. The temperature of the mixture spontaneously rises to about 60 ° C and is maintained at this level for about 10 minutes. The reaction mixture was cooled to about 40 ° C, poured into water, and the resulting mixture was filtered. To separate the product from the sulfur, a precipitate was filtered off; acetone was added and the resulting suspension was filtered again. The filtrates were combined, excess benzene was added and the liquid mixture was evaporated to dryness. Recrystallization of the dry solid gave 3-nitro-5-trifluoromethyl-o-phenylenediamine, m.p. 121-123 ° C.

g of the intermediate obtained above are mixed with 100 ml of pyridine and 35 g of pentafluoropropionic acid and 65 g of phosphorus oxychloride are added dropwise with stirring. The resulting mixture was then heated at reflux for 5 minutes and then cooled. When the temperature of the mixture had dropped to about 70 ° C, 300 mL of water was added and the resulting mixture was cooled to room temperature with vigorous stirring. The precipitated brownish solid product is filtered off and air-dried. There were obtained 59 g of 4-nitro-2-pentafluoroethyl-6-trifluoromethylbenzimidazole, m.p. 124-125 ° C.

The following examples illustrate the synthesis. 1-substituted benzimidazoles.

Example 2

4-Nitro-1-phenylsulfonyl-2,6-bis (trifluoromethyl) benzimidazole

To a solution of 6.4 g of 4-nitro-2,6-bis (trifluoromethyl) benzimidazole sodium salt in 50 ml of anhydrous acetonitrile was added a solution of 3.5 g of phenylsulfonyl chloride in 20 ml of anhydrous acetonitrile, followed by stirring at room temperature for 2 hours. The filtrate was evaporated to dryness in vacuo and the residue was recrystallized from benzene-pentane to give 4-nitro-1-phenylsulfonyl-2,6-bis (trifluoromethyl) benzimidazole, m.p. 183-185 ° C.

Example 3

Phenyl-4-nitro-2,6-bis (trifluoromethyl) -1-benzimidazolecarboxylate

The procedure described in Example 2 was repeated except that phenyl chloroformate was used in place of the phenylsulfonyl chloride. The product was isolated as described in Example 2 and recrystallized from pentane. There was obtained phenyl 4-nitro-2,6-bis (trifluoromethyl) -1-benzimidazolecarboxylate, m.p. 100-103 ° C.

The procedure described in Example 2 can also be used to prepare 1-N, N-dimethylthiocarbamoyl substituted compounds, using N, N-dimethylthiocarbamoyl chloride instead of phenylsulfonyl chloride.

1-Alkoxy-substituted benzimidazoles are prepared via the intermediate 1-hydroxybenz203978 imidazoles. The following example illustrates the synthesis of 1-hydroxybenzimidazoles.

Example 4 1-Hydroxy-4-nitro-2,3-bis (trifluoromethyl) benzimidazole

To a solution of 25.1 g of 2,6-dinitro-4-trifluoromethylaniline in 100 ml of pyridine is added trifluoroacetyl chloride prepared from 10 ml of thifluoroacetic acid. Ethanol was added to the resulting mixture until homogeneity, then the reaction mixture was evaporated in vacuo. The residue is washed with water, dried, dissolved in acetone and filtered. The product precipitates from the filtrate by the addition of chloroform, which is filtered off and dried. The purified intermediate 2 ', 6'-dinitro-4'-trifluoromethyl-2,2,2-brifluoroacetanilide is obtained.

1.75 g of the above intermediate are dissolved in 100 ml of ethyl acetate, 100 mg of 5% palladium on carbon are added and the mixture is hydrogenated at room temperature under an initial pressure of 91 kPa until up to 0.01 mol of hydrogen is taken up. The reaction mixture is filtered, the filtrate is evaporated to dryness, the solid residue is taken up in 300 ml of ether, the solution is extracted with 5% sodium carbonate and acidified. The desired 1-hydroxy-4-nitro-2,6-bis (trifluoromethylbenzimidazole) precipitates and is filtered off, the product is taken up in ether, the solution is dried over magnesium sulphate and the ether is evaporated. 222 DEG-224 DEG C. 4-nitro-2,6-bis (trifluoromethyl) benzimidazole.

The corresponding 1-alkoxy compounds are prepared from the intermediate 1-hydroxy derivative as illustrated in the following example.

EXAMPLE 5 1-Ethoxy-4-nitro-2,6-bis (trifluoromethyl) benzimidazole 1-hydroxy-4-nitro-4-bis-trifluoromethyl-4-nitro-imidazole is mixed with 50 ml of methanol, 10 ml of ethyl iodide. and 2.5 g of sodium ethoxide, the mixture is heated to reflux with stirring overnight, then cooled and evaporated to dryness. The residue is taken up in ether, the ether solution is washed with water, evaporated to dryness and the residue is recrystallized from petroleum ether. The desired 1-ethoxy-4-nitro-2,6-bis (trifluoromethyl) benzimidazole is obtained, m.p. 94-96 ° C.

The following example illustrates the preparation of the benzimidazole salts of the invention.

Example 6

Sodium 4-nitгo 2 ₁ 6-bis (trifluoromethyl] benzimidazole g of 4-nitro-2,6-bisttrifluormethy benzini--carbonyldiimidazole and 1.1 g of sodium methoxide were combined in 100 ml of methanol, indole carboxylic mixture was shaken for several minutes Evaporation of the residue in vacuo to dryness afforded the sodium salt of 4-ηΜ-2,6-Μ8 (trifluoromethyl) benzimidazoles, melting at 200 ° C.

The method of killing parasites using the compositions of the invention is of the systemic type. The benzimidazole compounds of the invention have the ability to penetrate into the living tissues of an animal host to which some of these compounds have been administered. Insect and mite parasites that feed on blood or other living tissues of the host ingest the compound through which the tissue is permeated, thereby killing them. It is likely that blood is a mediator of dispersing the active ingredient in the body of an animal host, but parasites that do not carry blood, such as Phormia regina larvae, are also killed in this way, indicating that the compounds described penetrate into others weaving.

Some parasites, like most ticks, feed on living host tissues throughout most of their lives. Other parasites, such as larvae of Phormia regina, feed on the host only at the larval stage. A third group of parasites, such as blood-sucking flies, only feed on animal hosts in adulthood. Application of the benzimidazoles according to the invention kills parasites which feed on the living tissues of animals, regardless of the developmental stage of the parasites.

All insect and acarid parasites that feed on living animal tissues are killed using the compositions of the invention. Animal-sucking parasites, drilling and feeding on animal tissues, and those that penetrate the host's natural apertures, adhere to the mucous membranes and from there feed on, like the throat larvae, are killed equally effectively.

For purposes of illustration, a number of specific parasites of various animal hosts that can be combated using the compositions of the invention are set forth below. For each parasite, the developmental stage and the way it feeds on the animal host are also given.

Horse parasites

Tabanus sulcifrons (horsefly) - adult - - sucking blood

Stomoxys calcitrans - adult - sucking blood

Tabanus atratus (Prosimulium pecuarum) —mature - sucking blood

Haematopinus asini - adults and juveniles - sucking blood

Sarcoptes scabiei (nymph), adult - nesting in skin

Psoroptes equi - adult - skin-eating

Gastrophilus intestinalis - larva migrating to the digestive tract

Gastrophilus nasalis (larvae) migrating to the digestive tract

Gastrophilus haemorrhoi-dalis - - larva migrating to the digestive tract

Beef cattle parasites

Haematobia irritans. (adult thistle) - adult - sucking blood

Bovicola bovis, (all lice) - adult - - skin-eating

Haematopinus eurysternus (cow louse) - - nymph, adult - sucking blood

Demodex bovis - adult - nesting in the skin

Boophílus annulatus (tick) - larva, nymph, adult - blood. sucking

Otobius megnini - nymph - blood sucking

Amblyomma maculatum (drinker) - adult - blood sucking

Dermacentor andersoni (adult) - sucking blood

Amblyomma americanum (drinker) - adult - blood sucking

Hypoderma lineatum. (larva) - a larva migrating through the host

Hypoderma bovis. (larvae) - larva migrating through the host

Phormia regina - larva infecting wounds

Pig parasites

Haematopinus suis (porcine louse). - nymph, adult - blood sucking

Tunga penetrans (adult flea) - adult - blood sucking

Sheep parasites

Haematopinus ovillus - adult - - sucking blood

Linognathus pedalis (adult louse) - - sucking blood

Melophagus. ovinus. (sheep's horse) - adult - sucking blood

Psoroptes equi ovis - nymph, adult - skin devouring

Oestrus ovis (larva migrating to the nasal cavities)

Phaenicia. sericata - wound infecting larva Phormia regina —- wound infecting larva

Callitroga macellaria - larva infecting wounds Parasites of poultry

Cimex lectularius (adult bug) - adult - sucking blood

Echidnophaga gallinacea - adult - blood sucking

Argas persicus (nymph), adult - sucking blood

Dermanyssus gallinae - Nymph,. adult - blood sucking

Knemidokoptes mutans - adult - nesting in the skin

Knemidokoptes gallinae - adult - nesting in the skin

Dog parasites

Tabanus sulcifrons (Tabanus atratus) - adult - sucking blood

Stomoxys calcitrans - adult - sucking blood

Sarcoptes scabiei (nymph, adult - nesting in skin)

Demodex canis - adult - - nesting in hair follicles

Ctenocephalides felis (Pulex irritans - Adult Flea) - Adult - Sucking Blood

It should be emphasized that the parasites mentioned above are not limited to the one host animal in respect of which they have been introduced. Most parasites live on different hosts, although each parasite has a host it prefers. For example, Sarcoptes scabiei attacks at least horses, pigs, mules, humans, dogs, cats, foxes, rabbits, sheep and. cattle. Horseflies freely attack horses, mules, cattle, pigs, dogs and most other animals. Using the compositions of the invention, parasites of the above-described species living on the above-mentioned animal hosts as well as on other animal hosts are effectively killed. The compositions of the invention can also be used effectively in cats, for example

203'978 goats, camels and animals in zoos, gardens.

The animal hosts in which the compositions of the invention are preferably used are dogs, cattle, sheep or horses. Said compositions are preferably used to kill ticks, fleas, flies, horse thistles and middlings or larvae of Phormia regina.

The time, method and dosages at which the compounds are effectively administered in accordance with the invention may vary within wide limits. A detailed explanation of the methods by which the compositions of the invention are applied is given below.

The compounds of the invention are administered to animals at doses of about 1 to 100 mg / kg, a parasiticidally effective dose. The best dose for eradicating the parasite infecting the animal in question must be determined individually, but it has been found that in most cases the optimal dose is in the preferred range of about 2.5 to 50 mg / kg. The optimum dose for each case depends on such factors as the health of the animal being treated, the sensitivity of the parasite to the composition used, the expense that can be incurred on the animal, and the degree of effect desired. Lower doses are safer for the animal host, are less expensive and often easier to administer, but can lead to incomplete or minimal parasite extermination, so that new infestations can occur. On the other hand, at higher doses, parasites are more completely eradicated, but these higher doses are more expensive and can cause stress in the treated animals.

The compounds of the invention are effective when administered at any time of the year to animals of any age. In accordance with the invention, the disclosed compounds may be administered continuously to the animals, for example by continuously feeding a food containing any of the compounds of the invention, thereby ensuring that all parasites in contact with the treated animal are killed. However, such an application is by no means economical, and it usually proves to be preferable to administer the active ingredients at a time when the best economic return on costs of the compounds used is guaranteed by effective parasite control. Certain parasites, such as the larvae of Hypoderma lineatum and bovine hypoderma (Hypoderma bovis), have a known active seasons when they attack animals. If such parasites are of primary importance, the compositions of the invention may be applied only during this period to provide year-round parasite control. Other parasites, such as ticks, ticks and drinkers, infest and bite the animals practically all year round. However, it is still possible to control such parasites in relatively short application periods by administering the active ingredient to all animals on the farm or in the area in question for a short period of time, such as for several weeks. In this way, all parasites of one generation will be exterminated and it can be expected that the animals will remain free of parasites for a considerable period of time unless the parasites coming with the imported animals and the like are reinfested.

The compounds of the invention may be administered by any conventional route orally or percutaneously. It should be noted that many of the compounds of the invention change chemically as they pass through the rumen of ruminants. Thus, oral administration to ruminants is suitable only if the active substances are protected from the rumen environment by special treatment of the composition. Such means will be discussed below.

The adaptation of biologically active compounds to the respective compositions and their application to animals is very old and sophisticated. Some explanations on the preparation and composition, the different compositions and the method of application will be given below.

The percutaneous administration of the benzimidazole derivatives according to the invention is carried out by methods customary in veterinary medicine. If water-insoluble benzimidazole is to be used, it is practical to dissolve such a compound in a physiologically acceptable solvent, for example in one of the polyethylene glycols. It is equally practical to formulate such a compound into an injectable suspension consisting of finely divided benzimidazole suspended in a formulation consisting of physiologically acceptable non-solvents, surfactants and suspending agents.

For example, the non-solvent may be a vegetable oil such as peanut oil, corn oil or sesame oil, or a glycol such as polyethylene glycol, depending on the benzimidazole selected.

The compounds used according to the invention are applied in the form of compositions in which the excipient is other than water or a common organic solvent. The presence of suitable physiologically acceptable substances is necessary to keep the benzimidazole in suspension. The excipients may be selected from the group consisting of emulsifiers such as dodecylbenzenesulfuric acid and toluenesulfonic acid salts, ethylene oxide adducts of alkylphenols, oleic acid esters and lauric esters, and dispersants such as naphthalenesulfonic acid salts, lignin sulfonates and sulfated fatty alcohols. Thickening agents such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates can also be used as auxiliary agents for the preparation of injectable suspensions. Many types of surfactants, as well as those mentioned above, serve to suspend benzimidazoles. Useful surfactants are, for example, lecithin and polyoxyethylene sorbitan esters.

Percutaneous administration is conveniently performed by subcutaneous, intramuscular or even intravenous injection of the injectable agent. Conventional needle injection devices or air injection devices that do not have a needle may be used.

Appropriate conditioning of the composition may delay or delay the permeation of the benzimidazole compound of the invention through living animal tissue. For example, very insoluble benzimidazole may be used. In this case, the low solubility of the active ingredient results in a protracted effect, since the animal ' s body fluids are able to dissolve only a small amount of the active ingredient at any time.

The protracted action of the benzimidazole according to the invention can also be achieved by mixing the active ingredient with a matrix which physically inhibits dissolution. Such a composition is injected into the body as a depot from which the active ingredient slowly dissolves. The matrix compositions are now well known in the art and are made from waxy semi-solids such as vegetable waxes and high molecular weight polyethylene glycols.

An even more effective protracted effect is achieved by implanting animals with one of the compounds of the invention. Such implants are now well known in veterinary medicine and are usually made of silicone-containing rubber. The benzimidazole compound is dispersed in a solid rubber implant or embedded within a hollow implant. Care should be taken in this case to select the rubber-soluble benzimidazole compound from which the implant is made, since this substance enters the animal's body by first dissolving it in rubber and then releasing it from the rubber into the body fluids of the treated animal.

The rate at which the compound is released from the implant and thus the time during which the implant remains effective is controlled with sufficient accuracy by appropriately adjusting the concentration of the compound in the implant, adjusting the outer surface of the implant and the composition of the polymer from which the implant is made.

Application of the benzimidazole compounds by means of an implant is particularly preferred. Such application is highly economical and effective because a properly prepared implant maintains a constant concentration of the active agent in the tissues of the animal host. The implant can be designed to release the active ingredient over a period of several months and to be easily introduced into the animals. After the implant has been introduced, no further manipulation of the animal is necessary and there is no need to worry about dosing with benzimidazole.

The benzimidazoles of the invention may be orally administered by mixing the active ingredient with animal feed or water for drinking, or administering oral dosage forms such as medicated drinks, tablets, or capsules.

If the compound of the invention is to be orally administered to ruminants, it is necessary to protect the compound from the degradation effect of the rumen processes. Veterinary pharmaceuticals. the technique now knows effective methods of coating and encapsulating active substances to protect them from the rumen environment. Coating materials and methods are disclosed, for example, in U.S. Patent No. 3,697,640 to Grant et al. Grant describes a method of protecting the active substances from the rumen environment by coating these substances with cellulose propionate 3-morpholinobutyrate. Such a film can also be used to protect the benzimidazoles of the invention. The benzimidazole-containing tablets or capsules of the invention are usually coated with a film in a coating pan or in a fluidized bed spray apparatus. It is also possible to produce pellets of the parasiticidal substance, which are then covered with a film and filled with capsules. Alternatively, a solid mixture of benzimidazole and a film former can be prepared and then crushed or ground into small particles, each consisting of benzimidazole enclosed in a film former. These particles may be filled into capsules for oral administration or may be made into a suspension for oral administration.

The introduction of veterinary medicines into animal feed is well known. Typically, the active ingredient is first formulated into a premix in which the benzimidazole is dispersed in a liquid carrier or a solid carrier in particulate form. This premix may conveniently contain about 2 to 900 g of active ingredient per kilogram, depending on the desired concentration of active ingredient in the final feed. This premix is then dispersed in a compound feed in a suitable mixer. The exact amount of benzimidazole and hence the premix to be mixed with the feed is easily calculated taking into account the weight of the animals, the approximate amount of feed that each animal ate each day, and the benzimidazole concentration in the premix.

The compounds of the invention can be readily formulated as tablets and capsules using conventional methods without the need to spread them. Liquid topical formulations comprise a benzimidazole derivative dissolved or dispersed in an aqueous liquid mixture. Most preferably, these compositions are again prepared by dissolving the water-soluble benzimidazole salt. It is almost as convenient and effective to use a dispersion of the disclosed compounds, produced in the same manner as the aqueous feed means discussed above.

The following examples illustrate the activity of the compounds of the invention.

Example 7

Calves are administered in a single subcutaneous injection at a dose of 5 mg / kg of 4-nitro-2- (1,1,2,2-tetrafluoroethyl) -6-trifluoromethylbenzimldazole The active ingredient is administered in the form of a dispersion in sesame oil.

Trial insects, which are adult stabs (Stomoxys calcitrans), are kept in wire mesh cages. Twenty-four hours after administration of the test substance, two or more of these 60- to 100-point cages are contacted with the clipped back of the test animal. The thistles are kept on the calf for 24 hours, after which the cages are removed and replaced with another set of cages. After each of these twenty-four hour intervals, the number of live and dead spikes was determined for mortality. Fresh thistles are then placed on the back of the test calf every day as long as mortality occurs.

The results are summarized as follows:

days after thistle mortality treatment in% 1 100 ALIGN! 2  100 ALIGN! 3 100 ALIGN! 4 95

582

626

Examples 8 to 21

These examples demonstrate the high activity of the compounds of the invention in controlling a number of parasites normally attacking livestock. For the purpose of these tests, the above mentioned parasites were grown in guinea pigs to which test compounds were applied. The active substances were tested against Phormia regina larvae, Stomoxys calcitrans thistle and Amblyomma americanum nymphs. Phormia regina and Stomoxys calcitrans belong to the insect class, Amblyomma americanum belongs to the mite order.

Stable thistle (Stomoxys calcitrans) is a common free-flying, blood-sucking parasite. The Amblyomma americanum is a typical blood-sucking parasite that experiences nymphal and part of adult life on a host animal, usually on cattle. The larvae of Phormia regina hatch from eggs deposited by free flying insects nearby. wounds on the host animal. The larvae eat the paths into healthy flesh exposed and spend. here part of his life cycle, feeding on the meat and blood of the host animal.

Stable thistle parasites on horses, mule, cattle, pigs, dogs, cats, sheep, goats, rabbits and humans. . The drinker Amblyomma americanum is primarily a parasite of cattle, but it also attacks horses, mules and sheep. Larvae of Phormia regina. attack all injured animals, particularly harming cattle, pigs, horses, mules, sheep and goats.

Male guinea pigs weighing 400-500 g are used as test animals. Test compounds are administered to the test animals. at a dose of 10 mg / kg. Every . of . of test compounds with one animal. administered orally and administered to another animal by subcutaneous injection. Test substances are applied in the form of dispersions in sorbitan monolaurate. Each group of treated guinea pigs is compared to two control guinea pigs given only sorbitan monolaurate.

hours. prior to treatment, each guinea pig is infected with 25 nymphs of Amblyomma americanum. 24 hours before treatment. each guinea pig is injured and its wounds infested with larvae of Phormia regina. 4 hours, 24 hours and in some cases 48 hours after treatment. the guinea pigs feed themselves on guinea pigs.

Both the test animals and the parasites infesting the animals are observed during the test. Stable thistle status is determined 24 hours after feeding in guinea pigs and the number of blood thistles killed is recorded. Phormia regina larvae are removed from the wounds 24 hours after treatment and the number of dead larvae is recorded. The drinkers are observed during the period of aspiration and the number of drinkers killed by the blood sucked in guinea pigs is also recorded.

The results are summarized in the following table, where they are reported in percent of killed parasites.

test substance Method of application larvae of Phormia regina Percentage of parasite killing Stomoxys calcitrans in 4 hours Stomoxys calcitrans in 24 hours nymphs of Amblyomma: americanum Example 8 4-methyl-2-pentafluoroethyl-6-trifluoromethylbenz- per os 90 76 - 100 ALIGN! imidazole · subcutaneously 0 0 · 7 100 ALIGN! Example 9 7-nitBo-2,5-bis: (- trlfluoro- per os 100 ALIGN! 50 32 100 ALIGN! methyl) benzimidazole subcutaneously 0 0 20: 100 ALIGN! Example 10 ft ^»u phenyl 4-nitro-2,6-bis (trifluoromethyl-ethyl) -l-benzimi- per os 100 ALIGN! 65 21 100 ALIGN! dazolcarboxylate subcutaneously 100 ALIGN! 0 25 100 ALIGN! Example '11 2; 6-bis (trifluoromethyl) - -4-nitro-1-phenylsulfonyl- per OS 100 ALIGN! 10 25 100 ALIGN! benzimidazole subcutaneously ’ 0 0 0 0 Example 12 isopropyl-4-nitro-2,6-bis- (trifluoromethyl) -1-benzi- per os 100 ALIGN! 51 7 100 ALIGN! midazolcarboxylate subcutaneously 0 0 0 75 Example 13 М, №41теШу1-7-т1го-2,5-bis (trifluoromethyl) thio-1-benzimidazolecarbox- per os 0 0 20 May 100 ALIGN! amid subcutaneously 0 0 6 23; Example 14 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl- per os 100 ALIGN! 73 91 100 ALIGN! benzimidazole subcutaneously 100 ALIGN! 0 32 100 ALIGN! sorbitan monolaurate per os 0 10 8 0 (control) subcutaneously 0 5 0: 8 · PřílAad'15 6-chloro-2-trifluoromethyl-4-nitrobenz- per os 100 ALIGN! 100 ALIGN! 100 ALIGN! 80 imidazole subcutaneously 0 - - 0 Example 16 1-ethoxy-4-nitro-2-pentafluoroethyl-6-trifluoromethylbenz- per os 100 ALIGN! 94 60 100 ALIGN! imidazole subcutaneously 0 0 5 0

It is clear from the results of the above tests that this method of controlling parasites is effective against various species of insect and mite parasites which feed on living host tissues. Tests carried out on standard laboratory animals show the high efficiency of the benzimidazoles of this method in killing parasites that are drilled and nourished by the flesh of host animals that periodically suck animal blood or which suck animal blood while remaining trapped. on his skin. Both oral and subcutaneous administration of the compounds to animals resulted in the suppression of parasites.

The examples below report on tests of a parasitocidal method in dogs. The dogs used in the tests were naturally infested with dog ticks and fleas. The compounds were administered intravenously or subcutaneously as aqueous dispersions.

It should be noted that in most tests, 48 hour and 72 hour data show that male ticks are killed more effectively than female ticks. This distinction is believed to be due to different feeding behavior. Males feed more or less continuously while females consume large-scale food at periodic intervals. It is expected that the killing of female ticks will increase with time after compound injection as the compound - disperses in the host body.

Example 22

Two dogs received 2.7 mg / kg, isopropyl-4-nitro-2,6-bis [trifluoromethyl] -1-benzimidazolecarboxylate in a single intravenous injection. Twenty-four hours after compound administration, one dog died. The cause of death was not identified.

Both ticks and fleas on the surviving dog were clearly affected 24 hours after application. Forty-eight hours after application, 10% of female ticks, 20% of male ticks and 95% of fleas were found to be dead.

Example 23

Two additional dogs were injected with 10 mg / kg of ethyl 2-chlorodifluoromethyl-4-nitro-6-difluoromethyl-1-benzimidazolecarboxylate in a single intravenous administration. When animals were first observed 24 hours after compound administration there was no apparent effect on the tick population, while fleas were clearly damaged.

The parasite population · was 48 hours after application. At this time, 10% of female ticks, 40% of male ticks and 100% fleas on both dogs were killed.

Example 24

Four dogs received 25 mg / kg of isopropyl 4-methyl-2,6-bis (trifluoromethyl) -1-benzimidazole carboxylate in a single subcutaneous injection. When observed at 24 hours · there was no general effect on dog parasites, although fleas on one dog were visibly affected.

After 48 hours the flea population on all dogs was visibly reduced and the ticks of the two dogs were clearly damaged by the compound.

The parasites remaining on the dogs were counted after 72 hours and the percentage of killed was found as follows:

Dog no female tick male tick fleas

100% 100% 100%

40% 100 100%

60% (2 votes)

0% 0% 0%

Example 2 5

Another group of four dogs were injected with 50 mg / kg 2-tthyl chlordifhιormtthyl-4-nitro-6-třШ'U · chloromethylated ---- ^ι benzιmlidazolkarboxylátem single subcutaneous injection. Ani ticksPes no female ticks

100%

10 ·%

50%

10% of those or fleas did not appear to be clearly affected 24 hours after application. Fleas on all dogs were damaged 48 hours after injection as well as ticks on one dog.

Parasite readings at 72 hours post-application showed the following percentages killed.

male fleas ticks

100 '% 100%% 100%'% '100%% 100% total tick suppression. The data indicate that the compounds continue to permeate through host tissues as the number of killed ticks is continuously improving.

The above examples show the exceptional qualities of this parasite control method.

A single percutaneous injection of the compounds essentially results in complete flea suppression and almost

test substance Way Percentage of parasite killing application larvae of Phormia regina Stomoxys Stomoxys nymphs Calcitrans Calci-Trans Amblyomma in 4 hours in 24 hours americanum

Example 17

phenyl-2-chlorodifluoromethyl-4-nitto-6-trifluoromethyl-1-benzimidazolecarbooylate per os subcutaneously sotbitanmonolautát per os (control) subcutaneously Example 18 isopropyl-2-chlorodifluoromethyl-4-nitro-6-irifluoromethyl-1-benzimidazo- per os carbooylate subcutaneously Example 19 benzyl-4-nitro-2- (1,1,2,2-tetrafluoroethyl) -6-trifluoromethyl-1-benzimido per os dazolcarbooylate subcutaneously Example 20 isopropyl-4-nitro-2- - (1,1,2,2-tetrafluoro- ethyl) -6-trifluoromethyl- ethyl-1-benziolidazolocatbo- per os oylate subcutaneously Example 21 1-Methoxy-4-nitro-2- - (1,1,2,2-Tetrafluoroethyl) -6-trifluoro- per os methylbenzimidazole subcutaneously sorbitan monolaurate per os (control) subcutaneously

* fed 48 hours after application

100 ALIGN! 94 87 100 ALIGN! 100 ALIGN! ⁵³ . 83 88 0 0 0 0 0 0 6 0 100 ALIGN! 77 * 96 100 ALIGN! 100 ALIGN! 92 * 92 100 ALIGN! 100 ALIGN! 28 * 38 100 ALIGN! 0 4 * 25 100 ALIGN! 100 ALIGN! 12 * 56 100 ALIGN! 70 - - · 0 100 ALIGN! 25 * 46 100 ALIGN! 0 8 * 12 100 ALIGN! 0 12 * 0 0 0 5 * 5 0

OBJECT OF THE INVENTION

Claims (10)

A composition for controlling non-pathogenic parasites living on the body surface of an animal, characterized in that it comprises as an active ingredient a benzimidazole derivative of the general formula I in which: R represents a chlorine atom or a trifluoromethyl group, R ¹ is hydrogen, C 1 -C 3 alkoxy, C 1 -C 4 alkoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, phenylsulfonyl or dimethylthiocarbamoyl; and R ² represents a trifluoromethyl group, a difluorochloromethyl group, a pentafluoroethyl group or a 1,1,2,2-tetrafluoroethyl group, or an ammonium salt, an alkali metal salt or alkaline earth metal salt of any of the compounds of formula I wherein R ¹ represents hydrogen. 2. A composition according to claim 1, wherein the active ingredient is a compound of formula (A) in which: R 'represents a chlorine atom or a trifluoromethyl group, R * represents a chlorine atom, a fluorine atom, a difluoromethyl group or a trifluoromethyl group and R ¹ 'is hydrogen, phenylsulfonyl, phenoxycarbonyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 3 alkoxy or dimethylthiocarbamoyl, or an ammonium salt, an alkali metal salt or an alkaline earth metal salt any of the compounds of formula Г in which R ¹ 'is hydrogen. 3. A composition according to claim 1, wherein the active ingredient is phenyl 4-nitro-2,6-bis [trifluoromethyl] -1-benzimidazolecarboxylate. 4. A composition according to claim 1, wherein the active ingredient is isopropyl 4-nitro-2,6-bis (trifluoromethyl) -1-benzimidazolecarboxylate. 5. A composition according to claim 1, wherein the active ingredient is 2-chlorodifluoromethyl-4-nitro-6-trifluoromethylbenzimidazole. 6. A composition according to claim 1, wherein the active ingredient is 1-ethoxy-4-nitro-2-pentafluoroethyl-6-trifluoromethylbenzimidazole. 7. A composition according to claim 1, wherein the active ingredient is phenyl-2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-1-benzimidazolecarboxylate. 8. A composition according to claim 1, wherein the active ingredient is ethyl 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-1-benzimidazolecarboxylate. 9. A composition according to claim 1, wherein the active ingredient is isopropyl-4-nitro-2- (1,1,2,2-tetrafluoroethyl) -6-trifluoromethyl-1-benzimidazolecarboxylate. 10. A composition according to claim 1, wherein the active ingredient is 4-nitro-2- (1,1,2,2-tetrafluoroethyl) -6-trifluoromethylbenzimidazole.