CA1057197A - Control of animal parasites with benzimidazoles - Google Patents

Abstract

Abstract of the Disclosure A class of substituted benzimidazoles are useful parasiticides for the systemic control of insects and acarina which feed on living tissues of animals. The compounds, which control both bloodsucking parasites and flesh-eating para-sites, are characterized by a 2-fluoroalkyl substituent, a single nitro substituent on the benzene ring, and a single fluoroalkyl or chloro substituent on the benzene ring.

Description

~OS7197 CONTROL OF ANIMAL PARASITES
WITH BENZIMIDAZOLES
The control of animal parasites is one of the oldest and ~ost important problems of the animal husbandry industry.
Many types of parasites afflict virtually all species of anl~al~. Most animals are afflicted by free-flying parasites such as flies, crawling ectoparasites such as lice and mites, burrowing parasites such as bots and grubs, and by microscopic endopar~sites such as coccidia, as well as by larger endo-parasites such as worms. Thus, the control of parasites evenin a single host species is a complex and many-sided problem.
The insect and acarina parasites which consume living tissues of a host animal are particularly harmful. The group includes parasites of all the economic animals, including ruminant and monogastric mammals and poultry, and of companion animalQ such as dogs as well.
Many methods of control of such parasites have been tried. The screwworm has been practically eradicated in Florida by the release of great numbers of sterile male blowflies. The method obviously is applicable only to an easily lsolated area.
The free-flying insects are usually controlled by routine methods such as air-dispersed and contact insecticides and fly traps. The skin-inhabiting, crawling parasites are usually controlled by dipping, drenching, or spraying the animal~
with appropriate parasiticides.
Some progress has been made in the systemic control of some parasites, particularly those which burrow in or migrate through the host animal. Systemic control of animal parasites is accomplished by absorbing a parasiticide in the bloodstream or other tissues of the h~st animal. Parasites which eat or come into contact with the parasiticide-containing tissue are killed, either by ingestion or contact. A few phosphate, phos-phoramidate, and phosphorothioate insecticides and acaricides have been found to be sufficiently nontoxic to be used systemically in animals.
Recently, the field of benzimidazole chemistry has beon extremely active. A great many patents and publications have appeared disclosing a variety of substituted benzimida-zoles, some of which have insecticidal and acaricidal activity.
For example, Belgian Patent 766,870 teaches a group of acaricidal benzimidazoles characterized by l-carboxylate and 2-chlorofluoroalkyl substituents and a variety of sub-stituents, including halo, nitro, and trifluoromethyl, on the benzene ring.
Newbold et al., U. S. Patent 3,542,923, discloses an insecticidal method making use of benzimidazoles having no l-substituent or a l-carboxylate substituent, a 2-perfluoro-alkyl substituent, and as many as four benzene ring substituents chosen from among a large group of substituents including nitro, halo, alkyl, carboxy, and so forth.
British Patent 1,122,988 teaches insecticidal and acaricidal benzimidazoles of structures notable for the ex-tremely w~e ~J~r;ety of the henzene r; ng substituents, of which the compounds can have as many as four. The 2-substituents of the compounds are perfluoroalkyl, and the l-substituent, if present, is alkyl or aryl.
British Patents, 1,087,561 and 1,144,620 provide further disclosure of insecticidal 2-perfluoroalkyl ben-zimidazoles.
French Patent 1,430,139 adds another group of in-lOS7197 secticidal, acaricidal, and nematocidal benzimidazoles bearing as many as four benzene ring substituents chosen from the group including nitro, chloro, and cyano, among others, and a 2-halo-alkyl substituent.
British patent 1,113,999 discloses a group of l-thio-carbamoylbenzimidazoles which are insecticides active against pests such as mustard beetles, aphids, and mosquitoes.
South African Patent 69.02813 teaches the biological activity of a family of benzimidazoles including compounds with l-caxboxylate and l-sulfonyl substituents. The compounds are insecticides and acaricides.
Holan et al., U. S. Patent 3,448,115 discloses a family of substituted benzimidazoles characterized by a 2-dichlorofluoromethyl or chlorodifluoromethyl substituent. The compounds of the patent are stated to be anthelmintics and her-bicides.
Hannah et al., U. S. Patent 3,749,734, disclose a group of l-cyanobenzimidazoles having chlorine atoms on the phenyl ring which are said to be anthelminticq and ectopara-siticides.
This invention provides a new means of killing byingestion insect and acarine parasites which consume living tissues of a host animal. It comprises an orally or per-cutaneously administerable composition comprising an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a parasiticidally-effective amount of a compound of the formula ~ ,.

lOS7197 OzN \ R1 R / ~ R~ (I) wherein R is chloro, trifluoromethyl, difluoromethyl, chloro-difluoromethyl;

Ol Ol O
Rl is hydrogen, -C-o-R3, -C-R4, -~-R5, ~ o 'i1 -C-NtCl-C3 alkyl)2, -O-(Cl-C3 alkyl), or -O-C-R ;
R2 is chlorodifluoromethyl, trifluoromethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, heptafluoro-propyl, or heptafluoroisopropyl;
R3 is Cl-C6 alkyl, C2-C3 alkenyl, phenyl, or benzyl;
R4 is Cl-C5 alkyl, phenyl, chlorophenyl, anisyl, or tolyl;
R5 is Cl-C3 alkyl, or phenyl;
or the ammonium, alkali metal, or alkaline earth metal salts of the compounds of formula (I) wherein Rl is hydrogen.
A preferred group of compounds which are particularly useful in the invention have the formula ~ / ~ CF2R~ (II) wherein R6 is chloro, fluoro, difluoromethyl, or trifluoro-methyl; R7 is hydrogen, phenylsulfonyl, phenoxycarbonyl, Cl-C4 alkoxycarbonyl, Cl-C3 alkoxy, or - C - N(Cl-C3 alkyl)2;
R is chloro or trifluoromethyl; or the ammonium, alkali metal, or alkaline earth metal salts of the compounds of formula (II) wherein R7 is hydrogen.
The general chemical terms in the above generic formulae are used in the sense in which they are usually under-stood in organic chemistry. The following specific examples of sub tituents referred to by the general chemical terms are presented to assure clarity.
Alkali metal refers to atoms such as sodium, potassium, and lithium.
Alkaline earth metal refers to atoms such as calcium, magnesium, and strontium.
Cl-C3 alkyl, Cl-C6 alkyl, Cl-C4 alkyl, C2-C3 alkenyl, Cl-C3 alkoxy, and Cl-C5 alkyl refer to substituents such as methyl, ethyl, isopropyl, isobutyl, hexyl, 2-pentyl, vinyl, allyl, t-butyl, methoxy, propoxy, and 3-hexyl.
The following specific compounds are presented to assure that those skilled in the organic chemlcal and para-sitological arts understand the scope of the invention.

2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-benzimidazole 6-nitro-2,4-bis(trifluoromethyl)benzimidazole l-benzoyloxy-4-nitro-2,6-bis(trifluoromethyl)benzimi-dazole 5-nitro-2,6-bis(trifluoromethyl)benzimidazole 4-nitro-2-pentafluoroethyl-6-trifluoromethylbenzimi-dazole -` ~057197 l-ethoxy-4-nitro-2,6-bis(trifluoromethyl)benzimida-zole 4-nitro-2,6-bis(trifluoromethyl)benzimidazole 6-difluoromethyl-4-nitro-2-trifluoromethylbenzimi-dazole allyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate 4-nitro-N,N-dipropyl-2,6-bis(trifluoromethyl)thio-1-benzimidazolecarboxamide 7-nitro-N,N-dipropyl~2,5-bis(trifluoromethyl)thio-1-benzimidazolecarboxamide ethyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate phenyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate N,N-diethyl-4-nitro-2,6-bis(trifluoromethyl)thio-1-benzimidazolecarboxamide l-acetyl-7-nitxo-2,5-bis(trifluoromethyl)benzimi-dazole 2,6-bis(trifluoromethyl)-4-nitro-1-phenylsulfonyl-benzimidazole ~ anisoyl)-4-nitro-2,6-bis(trifluoromethyl)ben-zimidazole l-methoxy-4-nitro-2,6-bis(trifluoromethyl)benzimi-dazole 2,6-bis(trifluoromethyl)-4-nitrobenzimidazole, sodium salt n-hexyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate isopropyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate l-benzoyl-4-nitro-2,6-bis(trifluoromethyl)benzimi-dazole 1-(4-chlorobenzoyl)-4-nitro-2,6-bis(trifluoromethyl) benzimidazole N,N-dimethyl-4-nitro-2,6-bis(trifluoromethyl)thio-1-benzimidazolecarboxamide N,N-dimethyl-7-nitro-2,5-bis(trifluoromethyl)thio-1-benzimidazolecarboxamide benzyl 2,6-bis(trifluoromethyl)-4-nitro-1-benzimi-dazolecarboxylate benzyl 2,5-bis(trifluoromethyl)-7-nitro-1-benzimi-dazolecarboxylate methyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate methyl 7-nitro-2,5-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate isopropyl 2-chlorodifluoromethyl-4-nitro-6-trifluoro-methyl-l-benzimidazolecarboxylate l-acetyl-4-nitro-2,6-bis(trifluoromethyl)benzimidazole l-hexanoyl-7-nitro-2,5-bis(trifluoromethyl)benzimi-dazole l-hexanoyl-4-nitro-2,6-bis(trifluoromethyl)benzimi-dazole 7-nitro-2-(1,1,2,2-tetrafluoroethyl)-5-trifluoro-methylbenzimidazole l-ethoxy-4-nitro-2-pentafluoroethyl-6-trifluoromethyl-benzimidazole phenyl 2-chlorodifluoromethyl-4-nitro-6-trifluoro-methyl-l-benzimidazolecarboxylate 5-chloro-6-nitro-2-trifluoromethylbenzimidazole 6-chloro-2-trifluoromethyl-4-nitrobenzimidazole 4-chloro-5-nitro-2-trifluoromethylbenzimidazole 4-chloro-7-nitro-2-trifluoromethylbenzimidazole 4-chloro-6-nitro-2-trifluoromethylbenzimidazole 5-chloro-4-nitro-2-trifluoromethylbenzimidazole 5-chloro-2-heptafluoropropyl-7-nitrobenzimidazole 1~ 4-chlorodifluoromethyl-6-nitro-2-trifluoromethyl-benzimidazole 5-nitro-2,6-bis(trifluoromethyl)benzimidazole, potassium salt 7-nitro-2,5-bis(trifluoromethyl)benzimidazole, calcium salt 6-difluoromethyl-4-nitro-1-propoxy-2-trifluoro-methylbenzimidazole 4-chloro-6-nitro-2-trifluoromethyl-1-(~-xyloyl)ben-zimidazole 1-acetoxy-4-nitro-2,6-bis(trifluoromethyl)benzimi-dazole 6-chloro-2-heptafluoroisopropyl-1-butyryloxybenzimi-dazole l-methylsulfonyl-4-nitro-2,6-bis(trifluoromethyl)ben-zimidazole l~propylsulfonyl-7-nitro-2,5-bis(trifluoromethyl)ben-zimidazole l-butyryl-7-nitro-2,5-bis(trifluoromethyl)benzimi-dazole The preferred compounds of this invention are the following.
phenyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimi-dazolecarboxylate isopropyl 4-nitro-2,6-bis(trifluoromethyl)-1-ben-zimidazolecarboxylate 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-benzimidazole l-ethoxy-4-nitro-2-pentafluoroethyl-6-trlfluoro-methylbenzimidazole phenyl 2-chlorodifluoromethyl-4-nitro-6-trifluoro-methyl-l-benzimidazolecarboxylate ethyl 2-chlorodifluoromethyl-4-nitro-6-trifluoro-methyl-l-benzimidazolecarboxylate isopropyl 4-nitro-2-(1,1,2,2-tetrafluoroethyl)-6-trifluoromethyl-l-benzimidazolecarboxylate Organic chemists are now aware of the synthetic methods which are used to make the benzimidazoles of this method.
Some explanation of the synthetic methods and a few specific examples will be given, however, to assure that all may obtain the compounds.
The method of synthesis depends on the l-substituent of the benzimidazole to be made. The synthesis of all the benzimidazoles except the l-alkoxy and l-acyloxy-substituted compounds begins with the reaction of an appropriately sub-stituted o-phenylenediamine with a fluoroalkanoic acid. The reaction can be done in 5N acid, such as HCl, at reflux temp-erature. The 2-substituent of the benzimidazole to be synthesized comes from the substituents of the alkanoic acid.
For example, if a 2-trifluoromethylbenzimidazole is to be made, the phenylenediam~ne is reacted with trifluoroacetic acid. If the benzimidazole is to have a 2-heptafluoropropyl substituent, the reactant is heptafluorobutyric acid.
Higher yields of the benzimidazoles are obtained by reacting the o-phenylenediamine with the 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 perform the synthesis in the presence of an acid chloride formed in situ in the reaction mixture. The . _ reaction goes quickly at reflux temperature.
The benzene ring substituents of the benzimidazole are the ring substituents of the o-phenylenediamine. For example, if the benzimidazole is to have a 4-chloro-6-nitro substitution, the reactant is 3-chloro-5-nitro-o-phenylenedia-mine. If the benzimidazole is to be a 7-nitro-5-chlorodifluoro-methyl compound, the reactant is 6-nitro-4-chlorodifluoro-methyl-_-phenylenediamine.
The l-substituents of the benzimidazoles, other than l-alkoxy and l-acyloxy, are conveniently made by the direct attachment of the desired l-substituent to the benzimidazole.
The sulfonyl, carboxylate, thiocarbamoyl, and acyl substituents are attached to the l-position of the benzimidazole ring system by direct reaction of the benzimidazole with a halide derivative of the desired substituent. For example, an ethylsulfonyl i9 provided by reaction with ethylsulfonyl chloride; a propyl-carboxylate, by reaction with propyl chloroformate; an anisoyl substituent, by reaction with anisoyl chloride; and an N,N-diethylthiocarbamoyl substituent, by reaction with N,N-diethyl-thiocarbamoyl bromide. The reaction goes easily at room temp-erature in solvents such as acetonitrile, tetrahydrofuran, and ~057~97 benzene. Either the benzimidazole itself or an alkali metal salt of it may be used as the starting compound for the reaction. Examples 2-4 below illustrate the synthesis.
The benzimidazoles with l-alkoxy and l-acyloxy sub-stituents are prepared through a l-hydroxybenzimidazole inter-mediate, which is prepared by reductive ring closure of an appropriate substituted acetanilide, which is prepared in turn from an o-nitroaniline.
A l-alkoxy-substituted benzimidazole is easily made by reacting the l-hydroxybenzimidazole intermediate with an alkyl halide in the presence of an alkali metal alkoxide, hydroxide, or carbonate at ambient or elevated temperature.
A l-acyloxybenzimidazole is synthesized at room temperature by reaction of a l-hydroxybenzimidazole with an acyl chloride.
For example, a l-benzoyloxybenzimidazole is made with benzoyl chloride as the reactant, carrying out the reaction at room temperature in pyridine.
Alkali metal, alkaline earth metal, and ammonium salts of the l-unsubstituted benzimidazoles are easily made by the common methods. For example, alkali metal and alkaline earth metal salts are made by reaction of a benzimidazole with a methoxide of the metal in methanol at room temperature. Such salts are also conveniently prepared from hydroxides of the alkali and alkaline earth metals by dissolving the hydroxide in an appropriate solvent such as water, aqueous alcohol, or aqueous acetone, and adding the benzimidazole compound to the solution at room temperature. Ammonium salts are prepared by contacting a benzimidazole with ammonium hydroxide or by bub-bling ammonia gas through a solution of the benzimidazole.

1057~97 The examples immediately below show the synthesis of typical ex~mplary compounds. Organic chemists, guided by the above general teaching as well as the common skill of the chemical art, can use the methods of the examples below to prepare all the benzimidazoles useful in this method.
The first example illustrates the synthesis of an intermediate o-phenylenediamine, as well as the synthesis of a typical benzimidazole.
Example 1 4-nitro-2-pentafluoroethyl-6-trifluoromethylbenzimidazole A solution of 40.5 g. of 2,6-dinitro-4-trifluoro-methyl-l-chlorobenzene in 300 ml. of benzene was mixed with 250 ml. of 14N ammonium hydroxide. The mixture was stirred at room temperature for about 1-1/2 hours, when another 100 ml. of 14N ammonium hydroxide was added. The mixture was stirred for 2 hours more. The mixture was allowed to separate in layers, and the organic layer was separated, washed with water, and dried. Evaporation of the solvents under vacuum gave 2,6-dinitro-4-trifluoromethylaniline, m.p. 142-144C. after re-crystallization from hexane-benzene.
A 24 g. portion of the above product was dissolved in 300 ml. of ethanol. The solution was heated to about 35C. and 110 ml. of 20 percent aqueous ammonium polysulfide, containing 5 percent free sulfur, was added. The temperature of the mix-ture rose spontaneously to about 60C., at which temperature it was maintained for about 10 minutes. The reaction mixture was then cooled to about 40C. and poured into water. The re-sulting mixture was filtered. Acetone was added to the pre-cipitate to remove residual product from the sulfur, and the resulting suspension was filtered also. Excess benzene was ~L057197 added to the combined filtrates, and the liquid mixture was then evaporated to dryness. Recrystallization of the dry solid produced 3-nitro-5-trifluoromethyl-o-phenylenediamine, m.p.
121-123C.
A 44 g. portion of the above intermediate product was mixed with 100 ml. of pyridine and 35 g. of pentafluoropropionic acid. The mixture was stirred while 65 g. of phosphorus oxy-chloride was added dropwise. The mixture was then heated at reflux temperature for 5 minutes and cooled. When the temp-erature of the mixture had decreased to about 70C., 300 ml. of water was added, and the mixture was vigorously stirred while it was cooled to room temperature. A light brown solid pre-cipitated which was separated by filtration and air-dried. The product was 59 g. of 4-nitro-2-pentafluoroethyl-6-trifluoro-methylbenzimidazole, m.p. 124-125C.
The following synthetic examples illustrate the synthesis of l-substituted benzimidazoles.
Example 2 4-nitro-1-PhenYlsu onyl-2,6-bis(trifluoromethyl)benzimidazole A solution of 3.5 g. of phenylsulfonyl chloride in 20 ml. of anhydrous acetonitrile was added to a solution of 6.4 g. of 4-nitro-2,6-bis(trifluoromethyl)benzimidazole, sodium salt in 50 ml. of anhydrous acetonitrile. The mixture was stirred at room temperature for 2 hours, and the reaction mix-ture was filtered. The filtrate was evaporated to dryness under vacuum, and the residue was recrystallized from benzene-pentane to yield 4-nitro-1-phenylsulfonyl-2,6-bis(trifluoromethyl)ben-zimidazole, m.p. 183-185C.

lOS7~97 ExamPle 3 phe_yl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimidazole-carboxYlate The procedure of Example 2 was repeated, using phenylchloroformate in place of phenylsulfonyl chloride. The product was isolated by the procedure of Example 2 and re-crystallized from pentane to yield phenyl 4-nitro-2,6-bis-(trifluoromethyl)-l-benzimidazolecarboxylate, m.p. 100-103C.
The method of Example 2 is also used, substituting an N,N-dialkylthiocarbamoyl chloride for the sulfonyl chloride, in the synthesis of the l-thiocarbamoyl-substituted compounds.
The l-acylbenzimidazoles are easily synthesized by a method exemplified by the following.
Exam~le 4 -l-acetyl-2,6(2,5)-bis(trifluoromethyl)-4(7)-nitrobenzimidazole A 9 g. portion of 4-nitro-2,6-bis(trifluoromethyl)-benzimidazole was dissolved in about 600 ml. of dry benzene, and 3.3 g. of triethylamine was added. To the solution was added dropwise 2.5 g. of acetyl chloride dissolved in 75 ml. of benzene. The addition was over a period of about 2.5 hours.
The mixture was then stlrred overnight at room temperature. In the morning, the reaction mixture was filtered, and the filtrate was evaporated under vacuum to give a yellow-orange solid residue, m.p. 100-114C. Recrystallization of the residue from benzene gave a product in the form of gummy platelets, m.p.
115-125C. Nuclear magnetic resonance analysis of the product indicated a 50-50 mixture of the two acetyl isomers, 1-acetyl-2, 5-bis(trifluoromethyl)-7-nitrobenzimidazole and 1-acetyl-2,6-bis(trifluoromethyl)-4-nitrobenzimidazole, which were separated by column chromatography.

--` 1057197 Benzimidazoles which have l-alkoxy and l-acyloxy sub-stituents are prepared through a l-hydroxybenzimidazole inter-mediate. The example below illustrates the synthesis of 1-hydroxybenzimidazoles.
ExamPle 5 l-hydroxy-4-nitro-2,6-bis(trifluoromethyl)benzimidazole A solution of 25.1 g. of 2,6-dinitro-4-trifluoro-methylaniline in 100 ml. of pyridine was treated with trifluoro-acetyl chloride, which had been prepared from 10 ml. of tri-fluoroacetic acid. Ethanol was added to the resulting mixtureuntil it was homogeneous, and the reaction mixture was then evaporated under vacuum. The residue after evaporation was washed with water, dried, dissolved in acetone, and filtered.
Chloroform was added to the filtrate until the product pre-cipitated. The precipitate was separated by filtration and dried to obtain the purified intermediate, 2',6'-dinitro-4'-trifluoromethyl-2,2,2-trifluoroacetanilide.
A 1.75 g. portion of the above intermediate was dis-solved in 100 ml. of ethyl acetate. One hundred mg. of 5 percent palladium on carbon was added, and the mixture was hydrogenated at an initial pressure of 13 psig. and room temperature until 0.01 mole of hydrogen had been taken up. The reaction mixture was then filtered and evaporated to dryness. The solid residue was taken up in about 300 ml. of ether, extracted into 5 percent Na2CO3, and acidified. The desired l-hydroxy-4-nitro-2,6-bis-(trifluoromethyl)benzimidazole precipitated and was separated by filtration. The product was then taken up in ether and dried over MgSO4, and the ether was evaporated. The product was crystallized from chloroform to produce 900 mg. of 1-hydroxy-4-nitro-2,6-bis(trifluoromethyl)benzimidazole, m.p. 222-224C.

The l-alkoxy compounds are made from a l-hydroxy intermediate as shown in the following example.
Example 6 l-ethox~-4-nitro-2,6-bis(trifluoromethyl)benzimidazole A 6 g. portion of 1-hydroxy-4-nitro-2,6-bis(tri-fluoromethyl)benzimidazole was mixed with 50 ml. of methanol, 10 ml. of ethyl iodide, and 2.5 g. of sodium ethoxide. The mix-ture was heated at reflux temperature overnight with stirring, and~was then cooled and evaporated to dryness. The residue was taken up in ether, and the ether solution was washed with water.
The ether layer was then evaporated to dryness, and the residue was recrystallized from petroleum ether to produce the desired l-ethoxy-4-nitro-2,6-bis(trifluoromethyl)benzimidazole, m.p.
94-96C.
Similarly, the l-acyloxy compounds are readily syn-thesized by reacting the appropriate l-hydroxybenzimidazole with an acyl chloride. For example, l-benzoyloxy-4-nitro-2,6-bis-(trifluoromethyl)benzimidazole is made by reacting l-hydroxy-4-nitro-2,6-bis(trifluoromethyl)benzimidazole with benzoyl chloride at room temperature in pyridine.
The example below illustrates the synthesis of benzlmldazole salts.
Exam~ 7 4-nitro-2,6-bis(trifluoromethyl)benzimidazole, sodium salt A mixture of 6 g. of 4-nitro-2,6-bis(trifluoromethyl)-benzimidazole and 1.1 g. of sodium methoxide in 100 ml. of methanol was prepared. The reaction mixture was shaken for a few minutes at room temperature and filtered. Evaporation of the filtrate to dryness under vacuum produced the sodium salt ~)57197 of 4-nitro-2,6-bis(trifluoromethyl)benzimidazole, m.p. about 200C.
The instant method of parasite control is of the systemic type. The benzimidazole compounds described above have the ability to permeate the living tissues of a host animal to which one of the compounds is administered. Insect and acarina parasites which consume blood or other living tissues of the host animal ingest the compounds with which the tissue is permeated, and are thereby killed. It is probable that the blood is the agency through which the compound is dis-persed through the host animal, but parasites such as screw-worms, which do not suck blood, are killed by this method, in-dicating that the compounds permeate other tissues as well as blood.
Some parasites, such as most ticks, feed on living tissues of the host animal during most of the parasite's life.
Other parasites, such as screwworms, feed on the host only in the larval stage. A third group of parasites, such as the bloodsucking flies, feed on animal hosts only in the adult stage. Administration of the benzimidazoles of this method to host animals kills parasites which feed on the llving tissues of the animals, no matter what the life stage of the feeding parasite.
All the species of insect and acarina parasites which feed on the living tissues of animals are killed by this method.
The parasites which suck the host animal's blood, those which burrow into and feed on the animal's tissue, and those, like the larvae of the bot flies, which enter a natural orifice of the host, attach to the mucous membranes, and feed therefrom are all equally effectively killed. For the sake of clarity, a number 1~57197 of specific parasites of various host animals which are con-trolled by this method will be mentioned. The parasitic life stage and the means by which it inests the host animal are given for each parasite.
Parasites of Horses horsefly, adult, bloodsucking stable fly, adult, bloodsucking black fly, adult, bloodsucking horse sucking louse, immature, adult, bloodsucking mange mite, nymph, adult, skin burrowing scab mite, adult, skin-eating common horse bot fly, larva, migrating in alimentary canal chin fly, larva, migrating in alimentary canal nose bot fly, larva, migrating in alimentary canal Parasites of Bovines horn fly, adult, bloodsucking cattle biting louse, adult, skin-eating cattle bloodsucking louse, nymph, adult, bloodsucking cattle follicle mite, adult, skin-burrowing cattle tick, larva, nymph, adult, bloodsucking ear tick, nymph, bloodsucking Gulf Coast tick, adult, bloodsucking Rocky Mountain spotted-fever tick, adult, bloodsucking lone-star tick, adult, bloodsucking heel fly, larva, migrating through the body bomb fly, larva, migrating through the body blowfly, larva, infesting wounds Parasites of Swine hog louse, nymph, adult, bloodsucking chigoe flea, adult, bloodsucking Parasites of Sheep bloodsucking body louse, adult, bloodsucking bloodsucking foot louse, adult, bloodsucking sheep ked, adult, bloodsucking sheep scab mite, nymph, adult, skin-eating nose fly, larva, migrating in the sinuses greenbottle fly, larva, infesting wounds black blowfly, larva, infesting wounds secondary screwworm, larva, infesting wounds Parasites of Poultry bed bug, nymph, adult, bloodsucking Southern chicken flea, adult, bloodsucking fowl tick, nymph, adult, bloodsucking chicken mite, nymph, adult, bloodsucking scaly-leg mite, adult, skin-burrowing depluming mite, adult, skin-burrowing 0 Parasites of Dogs horse fly, adult, bloodsucking stable fly, adult, bloodsucking mange mite, nymph, adult, skin-burrowing dog follicle mite, adult, burrowing in hair follicles flea, adult, bloodsucking It will be understood that the parasites mentioned above are not confined to the single host animal with which each is here identified. Most parasites inhabit various hosts, although each parasite has a favorite host. For example, the 0 mange mite attacks at least horses, hogs, mules, humans, dogs, 1057~97 cats, foxes, rabbits, sheep, and cattle. Horseflies freely attack horses, mules, cattle, hogs, dogs, and most other animals. This method effectively kills parasites of the types described above growing in the host animals mentioned above, and in other host animals as well. For example, this inven-tion is effective in cats, goats, camels, and zoo animals.
The host animals in which this method is preferably practiced are dogs, bovines, sheep, or horses. The method is preferably used for the control of ticks, fleas, flies, or screwworms.
The time, manner, and rates at which the compounds of this method are effectively administered may be varied over a wide range. Detailed explanation of the ways in which this method is practiced will be given.
The compounds are administered to the animals at rates from about 1 to about 100 mg./kg. which is a parasiti-cidally-effective amount. The best rate for killing a given parasite infesting a given animal must be determined in-dividually, but it will be found that in most cases the optimum rate is within the preferred range of from about 2.5 to about 50 mg./kg. The optimum rate for a given instance depends on such factors as the health of the animal to be treated, the susceptibility of the parasite of primary concern, the expense which can be borne by the animal, and the degree of control desired. Lower rates are safer for the host animal, less ex-pensive, and often easier to administer, but are likely to give incomplete or minimum control of the parasite so that re-infestation may occur. On the other hand, higher rates of administration give more complete control of the parasites, but are more expensive and may impose a stress on the treated animals .
The comp~unds of this method are effective when administered at any time of year to animals of any age. It is possible to administer the compounds of this method to the animals continuously, as by constant feeding of a diet which contains one of the compounds, and thus assure that all para-sites which contact the treated animals will be killed. Such administration is by no means economical, and it will usually be found best to administer the compounds at such times as to give the best return of parasite control for the compound ex-pended. Certain parasites, such as cattle grubs, which are the larvae of the heel fly and the bomb fly, have a known active season when they attack animals. If such a parasite is of primary importance, this method can be practiced only during that season with assurance of year-round control of the para-site. Other parasites, such as ticks, infest and bite animals essentially the year round. Control of such parasites can still be accomplished with relatively brief periods of admini-stration by administering the compound to all the animals on a farm or in an area for a short period o time, such as for a few weeks. All the parasites of a generation are thus killed, and the animals can be expected to remain parasite-free for a considerable length of time, until reinfested by parasites arriving with imported animals or the like.
The compounds of this method may be administered by any of the usual oral and percutaneous routes. It should be noted that many of the compounds of this method are chemically changed by passage through the rumen of a ruminant animal.
Oral administration to ruminant animals is therefore advisable only if the compounds are protected from the rumen environment 105719~

by a special formulation. Such formulations will be dis-cussed below.
The formulation and administration to animals of biologically-effective comp~unds is a very old and developed art. Some explanation of the different formulations and methods of administration will be given to enable all to practice this method of parasite control.
Percutaneous administration of the benzimidazole com-pounds is carried out in the ways usual in the animal veteri-nary art. If a water-insoluble benzimidazole is desired, it is practical to dissolve the compound in a physiologically-acceptable solvent, such as the polyethylene glycols for ex-ample. It is likewise practical to formulate an injectable suspension of the benzimidazole as a fine powder, suspended in a formulation of physiologically-acceptable nonsolvents, sur-factants, and suspending agents.
The nonsolvent can be, for example, a vegetable oil such as peanut oil, corn oil or sesame oil, a glycol such as a polyethylene glycol, depending on the benzimidazole chosen.
The compounds used in this invention are admini-stered as compositions wherein the adjuvant employed is a sub-stance other than water or common organic solvents. Suitable physiologically-acceptable adjuvants are necessary to keep the benzimidazole suspended. The adjuvants can be chosen from among the emulsifiers, such as salts of dodecylbenzene sulfate and toluenesulfonate, ethylene oxide adducts of alkylphenol, and oleate and laurate esters, and from the dispersing agents such as salts of naphthalenesulfonate, lignin sulfonate, and fatty alcohol sulfates. Thickeners such as carboxymethyl cel-lulose, polyvinylpyrrolidone, gelatin and the alginates are also used as adjuvants for injectable suspensions. Many classes of surfactants, as well as those which have been dis-cussed above, serve to suspend the benzimidazoles. For example, lecithin and the polyoxyethylene sorbitan esters are useful surfactants.
Percutaneous administration is conveniently accom-plished by subcutaneous, intramuscular, and even intravenous injection of the injectable formulation. Conventional needle-type injection devices as well as needle-less air-blast in-jection devices are useful.
It is possible to delay or sustain the permeation ofthe benzimidazole compound through the animal's living tissues by proper formulation. For example, a very insoluble benzimi-dazole may be used. In that event, the slight solubility of the compound causes sustained action because the body fluids of the animal can dissolve only a small amount of the compound at any one time.
Sustained action of the benzimidazole can also be obtained by formulating the compound in a matrix which will physically inhibit dissolution. The formulated matrix i9 in-jected into the body where it remains as a depot from which the compound slowly dissolves. Matrix formulations, now well known in the art, are formulated in waxy semisolids such as vegetable waxes and high molecular weight polyethylene glycols.
Even more effective sustained action is obtained by introducing into the animal an implant containing one of the compounds. Such implants are now well known in veterinary medicine, and are usually made of a silicone-containing rubber.
The benzimidazole compound is dispersed through a solid rubber implant or is contained inside a hollow implant. Care must be 1057~97 taken to choose a benzimidazole compound which is soluble in the rubber from which the implant is made, since it is dispersed by first dissolving in the rubber, and then leaching out of the rubber into the body fluids of the treated animal.
The rate at which the compound is released from an implant, and hence the lenqth of time during which the implant remains effective, is controlled with good accuracy by the proper adjustment of the concentration of the compound in the implant, the external area of the implant, and the formulation of the polymer from which the implant is made.
Administration of benzimidazole compounds by means of an implant is a particularly preferred method of this invention.
Such administration is highly economical and efficacious, because a properly designed implant maintains a constant concen-tration of the compound in the tissues of the host animal. An implant can be designed to supply compound for several months, and is easily inserted in the animal. No further handling of the animal or concern over the benzimidazole dosage is neces-sary after the insertion of the implant.
Oral administration of a benzimidazole may be per-formed by mixing the compound in the animal's feed, or by administering oral pharmaceutical dosage forms such as drenches, tablets, or capsules.
When a compound of this method is to be administered orally to a ruminant animal, it is necessary to protect the compound from the deleterious effect of the rumen processes.
The veterinary pharmaceutical art is now aware of effective methods for coating and encapsulating drugs to protect them from the rumen. For example, coating materials and methods are dis-closed in Grant et al., U. S. Patent 3,697,640. Grant teaches a method of protecting substances from action of the rumen by coating the substances with a film of cellulose propionate

3-morpholinobutyrate. Such a film can be used to protect the benzimidazoles of this method. Conveniently, tablets, or cap-sules containing a benzimidazole are coated with the film in a coating pan or a fluidized bed spray apparatus. Pellets of the parasiticide may be made, coated with the film, and filled into capsules. Alternatively, a solid mixture of the benzimidazole and the film-forming agent may be made and broken or ground into small particles, each of which comprises the benzimidazole en-closed in a matrix of the film-forming agent. The particles may be filled into capsules for oral administration, or made into an oral suspension.
The formulation of veterinary drugs in animal feed is an extremely well-known art. It is usual to formulate the compound first as a premix in which the benzimidazole is dis-persed in a liquid or particulate solid carrier. The premix may conveniently contain from about 1 to about 400 g. of drug per pound, depending on the desired concentration in the feed.
The premix is in turn formulated into feed by dispersing it in the feed mixture in a conventional mixer. The correct amount of benzimidazole, and hence of premix, to mix in the feed is easily computed by taking into account the weight of the ani-mals, the approximate amount each animal eats per day, and the concentration of the benzimidazole in the premix.
The compounds can easily be formulated into tablets and capsules according to the conventional methods, about which no teaching is required here. Drench formulations comprise the benzimidazole compound dissolved or dispersed in an aqueous liquid mixture. Again, it is most convenient to make the drench -by dissolving a water-soluble benzimidazole salt. It is almost as convenient, however, and equally efficacious to use a dis-persion of the compound made in the same way that the drinking water formulations discussed above are made.
The examples immediately below show the great effectiveness of this method in controlling a number of parasites which normally affect economic animals when those parasites were fed on guinea pigs to which the compounds of this method had been administered. The compounds were tested against screwworms, which are larvae of the black blowfly, against the stable fly, and against nymphs of the lone star tick. The blowfly and stable fly are insects; the lone star tick is representative of the acarina.
The stable fly is a common free-flying, bloodsucking parasite; the lone star tick is a typical bloodsucking parasite which spends the nymphal and part of the adult periods of the life cycle attached to the host animal, usually cattle. Blow-fly larvae, or screwworms, hatch from eggs laid near a wound of the host animal by the free-flying insect. The larvae eat their way into the healthy flesh exposed by the wound and pass part of the life cycle therein, feeding one host's flesh and blood.
The stable fly is parasitic on horses, mules, cattle, hogs, dogs, cats, sheep, goats, rabbits, and humans.
The lone star tick is primarily a cattle parasite, but also attacks horses, mules, and sheep. Blowfly larvae attack any wounded animal, but are particularly harmful to cattle, hogs, horses, mules, sheep, and goats.
The test animals were male guinea pigs weighing 400-500 g. The test compounds were administered to the animals at the rate of 10 mg./kg. Each compound was administered orally ~05719~7 to one animal, and injected subcutaneously (SC) to another animal. The test compounds were administered as dispersions in sorbitan monolaurate. ~ach group of treated guinea pigs was tested along with two pigs to which a sorbitan monolaurate blank was administered.
Each guinea pig was infested with 25 nymphs of the lone star tick 48 hours before treatment. Twenty-four hours before treatment, each pig was wounded, and the wounds were infested with larvae of the black blowfly. At 4 hours, 24 hours, and in some cases at 48 hours, after treatment, stable flies were fed on the guinea pigs.
The animals and the parasites with which they were infested were observed. The stable flies were observed 24 hours after they fed on the pigs and the number of flies killed by the blood they ingested was counted. The blow fly larvae were removed from the wounds 24 hours after treatment, and the num-ber of dead larvae was counted. The ticks were observed during their engorgement period, and the number of them killed by the blood they sucked from the guinea pigs was counted also. The observations are reported below as the percent of each parasite which was killed.

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:~ ~057197 It is clear from the tests reported above that this method of animal parasite control is effective in controlling the dif~erent types of insect and acarina parasites which consume the host's living tissues. The tests, carried out in a standard laboratory animal, show the high potency of the benzimidazoles of this method in killing parasites which burrow into and consume the flesh of the host animal, which periodically suck blood of the animal, and which suck the host's blood while remaining affixed to the animal's skin. Both oral and percutaneous administration of the compounds to the animals controlled the parasites.
The examples below report tests of the parasiticidal method in dogs. The dogs used in the test were suffering from natural infestations of dog ticks and fleas. The compounds were administered intravenously or subcutaneously as aqueous dispersions.
It will be noted that, in most of the tests, the 48-and 72-hour data indicate that male ticks are killed more effectively than are females. It is believed that the dif-ference is due to the feeding habits of the sexes. Males feedmore or less continuously, while females feed in periodic large meals. It is to be expected that the kill of female ticks will increase with time after the injection of the compound, as the compound moves through the host's body.
Example _ Two dogs were treated with 2.7 mg./kg. of isopropyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimidazolecarboxylate as a single intravenous injection. Twenty-four hours after admin-istration of the compound, one of the dogs had died. The cause of death was not determined.

-Both ticks and fleas on the surviving dog were visibly affected by the compound 24 hours after administration.
Forty-eight hours after administration, it was found that 10 percent of the female ticks, 20 percent of the male ticks, and 95 percent of the fleas were dead.
Example _ Two other dogs were injected with 10 mg./kg. of ethyl 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-1-benzimi-dazolecarboxylate as a single intravenous administration. When the animals were first observed, 24 hours after administration of the compound, there was no visible effect on the tick pop-ulation, but the fleas were visibly injured.
The parasite population of the dogs was counted 48 hours after administration. At that time, 10 percent of the fema~e ticks, 40 percent of the male ticks, and 100 percent of the fleas on both dogs were dead.
Example 24 Four dogs were treated with 25 mg./kg. of isopropyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimidazolecarboxylate as a single subcutaneous injection. At the 24-hour observation, there was in general no effect on the parasites of the dogs, although the fleas on one dog were visibly affected.
At 48 hours, the flea populations on all the dogs were visibly reduced, and the ticks on two dogs were visibly injured by the compound.

The parasites remaining on the dogs were counted after 72 hours, and the p`ercent killed was found to be as follows.

Female Male Dog Ticks Ticks Fleas l 20% 80% 100%

3 60 60 lO0 Example 25 Another group of four dogs was injected with 50 mg./kg. of ethyl 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-l-benzimidazolecarboxylate as a single subcut.aneous injection.
Neither the ticks nor the fleas were seen to be affected 24 hours after administration. The fleas on all the dogs were injured 48 hours after administration, as were the ticks on one dog.
The 72-hour parasite counts showed the following per-cent of kill.

Female Male Dog Ticks Ticks Fleas l 100% 100% 100%
2 lO 50 lO0 The examples above show the outstanding value of this method of parasite control. Single percutaneous injections of the compounds gave essentially complete control of fleas, 30 and worthwhile control of ticks. The data indicate that, as 1057~97 the compounds continue to permeate through the tissues of the host, the tick kill will continue to improve.

SUPPLEMENTARY DISCLOSURE
The principal disclosure provides a means of killing insect and acarina parasites which consume living tissues of a host animal which comprises an orally or pre-cutaneously administerable composition comprising an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a parasiticidally-effective amount of a compound of the formula 02N ~ I

~ ¦ ~ Ra (I~

wherein R is chloro, trifluoromethyl, difluoromethyl, or chlorodifluoromethyl;
o o o Rl is hydrogen, -C-o-R3~ -C-R4, -S-R5, S O
-C-N(Cl-C3 alkyl)2, -O-(Cl-C3 alkyl), or -O-C-R ;
R is chlorodifluoromethyl, trifluoromethyl, 1,1,2,2-tetra~luoroethyl, pentafluoroethyl, heptafluoropropyl, or heptafluoroisopropyl;
R is Cl-C6 alkyl, C2-C3 alkenyl, phenyl, or benzyl;
R is Cl-C5 alkyl, phenyl, chlorophenyl, anisyl, or tolyl;
R5 is Cl-C3 alkyl, or phenyl;
or the ammonium, alkali metal~ or alkaline earth metal salts of the compounds of the formula (I) wherein Rl is hYdrogen.
The present disclosure further develops the method of the principal disclosure in that the compounds of the above formula are modified in that R can also represent hydroxy.
These compounds are also useful as parasiticides.

J
l. .^ , Thus, this Supplementary Disclosure provides a further means of killing by ingestion insect and acarina parasites which consume living ~issues of a host animal which comprises an orally or percutaneously administerable composition comprising an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a parasiticidally-effective amount of a compound of the formula OH
OzN

1~ /~ ~ (I) wherein R is chloro, trifluoromethyl, difluoromethyl, or chlorodifuloromethyl; and R2 is chlorodifluoromethyl, trifluoromethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, heptafluoropropyl, or heptafluoroisopropyl.
A preferred group of compounds which are particu-larly useful in this invention have the formula OH
02N ~ \ ~

~ CFzR~ (II) herein R6 is chloro, fluoro, difluoromethyl, or trifluoromethyl; and ~05719'7 R8 is chloro or trifluoromethyl.
The following specific compounds are presented to assure that those skilled in the organic chemical and para-sitological arts understand the scope of this invention.

5-chloro-1-hydroxy-7-nitro-2-trifluoromethyl-benzimidazole 2-chlorodifluoromethyl-1-hydroxy-4-nitro-6-trifluoromethylbenzimidazole

6-chloro-1-hydroxy-4-nitro-2-(1,1,2,2-tetra-fluoroethyl)benzimidazole

7-difluoromethyl-1-hydroxy-5-nitro-2-pentafluoro-ethylbenzimidazole 6-chlorodifluoromethyl-2-heptafluoropropyl-1-hydroxy-4-nitrobenzimidazole 2-heptafluoroisopropyl-1-hydroxy-6-nitro-5-tri-fluoromethylbenzimidazole The preferred compound of this invention is l-hydroxy-4-nitro-2-(l,i,2,2-tetrafluoroethyl)-6-trifluoro-methylbenzimidazole.
Organic chemists are now aware of the synthetic methods which are used to make the benzimidazoles of this method. Some explanation of the synthetic methods and a few specific examples will be given, however, to assure that all may obtain the compounds.
The l-hydroxybenzimidazoles are prepared by reductive ring closure of an appropriately substituted acetanilide, which is prepared in turn from an _-nitro-aniline.
The example immediately below shows the synthesisof typical exemplary compounds. Organic chemists, guided by the above general teaching as well as the common skill of 105719'7 the chemical art, can use the methods of the example below to prepare all the benzimidazoles useful in this method.
Example 26 A solution of 25.1 g. of 2,6-dinitro-4-trifluoro-methylaniline in 100 ml. of pyridine was treated with tri-fluoroacetyl chloride, which had been prepared from 10 ml.
of trifluoroacetic acid. Ethanol was added to the resulting mixture until it was homogeneous, and the reaction mixture was then evaporated under vacuum. The residue after evaporation was washed with water, dried, dissolved in acetone, and filtered. Chloroform was added to the filtrate until the product precipitated. The precipitate was separated by filtration and dried to ob~ain the purified intermediate, 2',6'-dinitro-4'-trifluoromethyl-2,2,2-tri-fluoroacetanilide.
A 1.75 g. portion of the above intermediate was dissolved in 100 ml. of ethyl acetate. One hundred mg. of 5 percent palladium on carbon was added, and the mixture was hydrogenated at an initial pressure of 13 psig. and room temperature until 0.01 mole of hydrogen had been taken up.

The reaction mixture was then filtered and evaporated to dryness. The solid residue was taken up in about 300 ml. of ether, extracted into 5 percent Na2CO3, and acidified. The desired l-hydroxy-4-nitro-2,6-bis(trifluoromethyl)benzimi-dazole precipitated and was separated by filtration. The product was then taken up in ether and dried over MgSO4, and the ether was evaporated. The product was crystallized from chloroform to produce 900 mg. of 1-hydroxy-4-nitro-2,6-bis-(trifluoromethyl)benzimidazole, m.p. 222-224C.

All of the specific details set out in the principal disclosure as to methods of formulation, dosages, methods of application, etc. apply equally well to the additional compounds described herein.

The following example reports representative results of a bio-assay test.
Example 27 Larvae of the black blowfly were used as assay organisms in a bio-assay test system. The tests were carried out by administering a compound of formula I as a single subcutaneous injection to a calf. Samples of blood were withdrawn from the calf on successive days after the administration of the compound, and blowfly larvae were fed on the withdrawn whole blood. The end point of the test was recorded as the last day on which 90 percent or more of the blowfly larvae were killed.
Aqueous suspensions of l-hydroxy-4-nitro-2-(1,1,2,2-tetrafluoroethyl)-6-trifluoromethylbenzimidazole were administered at rates of 5, 10 and 15 mg./kg. The 15 mg./kg. rate killed 90 percent or more of the larvae for four successive days, and administration at 10 mg./kg.
killed the larvae for three days. The 5 mg./kg. rate was not effective.
In the tests of this example, the parasites were exposed to the treated animal's blood indirectly, instead of directly by feeding the parasites on the animal. The control obtained, however, is obviously as significant as if the parasites had sucked blood directly from the animal.
The value of the method in protecting animals from the very injurious parasite, the blowfly, is clearly demon-strated by the tests, since several days of parasite con-trol were obtained from a single administration of a com-pound of this invention.

Claims (16)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A parasiticidal composition for oral or per-cutaneous administration to an infected host animal which comprises an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a compound of the general formula (I) wherein R is chloro, trifluoromethyl, difluoromethyl, or chlorodifluoromethyl;

R1 is hydrogen, , , , -O-(C1-C3 alkyl), or ;
R2 is chlorodifluoromethyl, trifluoromethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, heptafluoro-propyl, or heptafluoroisopropyl;
R3 is C1-C6 alkyl, C2-C3 alkenyl, phenyl, or benzyl;
R4 is C1-C5 alkyl, phenyl, chlorophenyl, anisyl, or tolyl;
R5 is C1-C3 alkyl, or phenyl;
or the ammonium, alkali metal, or alkaline earth metal salts of the compounds of formula (I) wherein R1 is hydrogen.

2. A parasiticidal composition for oral or percutaneous administration to as infected host animal which comprises an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a compound of the general formula (II) wherein R6 is chloro, fluoro, difluoromethyl, or trifluoro-methyl;
R7 is hydrogen, phenylsulfonyl, phenoxycarbonyl, C1-C4 alkoxycarbonyl, C1-C3 alkoxy, or R8 is chloro or trifluoromethyl;
or the ammonium, alkali metal, or alkaline earth metal salts of the compounds of formula (II) wherein R7 is hydrogen.

3. The composition of Claim 1, wherein the active compound is dispersed through or contained inside an implant.

4. The composition of Claim 1 in the form of an injectable suspension in which the active compound is suspended in a formulation selected from physiologically-acceptable non-solvents, surfactants and suspending agents.

5. The composition of Claim 1, 3 or 4 in which the compound is phenyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimidazole-carboxylate.

6. The composition of Claim 1, 3 of 4 in which the compound is isopropyl 4-nitro-2,6-bis(trifluoromethyl)-1-benzimidazolecarboxylate.

7. The composition of Claim 1, 3 or 4 in which the compound is 2-chlorodifluoromethyl-4-nitro-6-trifluoro-methylbenzimidazole.

8. The composition of Claim 1, 3 or 4 in which the compound is 1-ethoxy-4-nitro-2-pentafluoroethyl-6-trifluoromethylbenzimidazole.

9. The composition of claim 1, 3 or 4 in which the compound is phenyl 2-chlorodifluoromethyl-4-nitro-6-trifluoromethylbenzimidazolecarboxylate.

10. The composition of Claim 1, 3 or 4 in which the compound is ethyl 2-chlorodifluoromethyl-4-nitro-6-trifluoromethyl-1-benzimidazolecarboxylate.

11. The composition of Claim 1, 3 or 4, in which the compound is isopropyl 4-nitro-2-(1,1,2,2-tetrafluoro-ethyl)-6-trifluoromethyl-1-benzimidazolecarboxylate.

CLAIMS SUPPORTED BY THE SUPPLEMENTARY
DISCLOSURE

12. A parasiticidal composition for oral or per-cutaneous administration to an infected host animal which comprises an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a compound of the formula wherein R is chloro, trifluoromethyl, difluoromethyl, or chlorodifluoromethyl; and R2 is chlorodifluoromethyl, trifluoromethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, heptafluoropropyl, or heptafluoroisopropyl.

13. A parasiticidal composition for oral or percutaneous administration to an infected host animal which comprises an adjuvant suitable for oral or percutaneous administration to an animal and as an active ingredient a compound of the formula II

wherein R6 is chloro, fluoro, difluoromethyl, or trifluoro-methyl; and R8 is chloro or trifluoromethyl.

14. The composition of Claim 12 wherein the active compound is dispersed through or contained inside an implant.

15. The composition of Claim 12 in the form of an injectable suspension in which the active compound is sus-pended in a formulation selected from physiologically-acceptable non-solvents, surfactants and suspending agents.

16. The composition of Claim 12, 14 or 15 in which the compound is 1-hydroxy-4-nitro-2-(1,1,2,2-tetrafluoroethyl)-6-trifluoromethylbenzimidazole.