BE621596A - - Google Patents

Description

       

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 EMI1.1
 The present invention relates to compounds useful for combating helminthiasis. It relates, more particularly, to new bsnzimidazols. More particularly still, the invention relates to 1-acyl bonzimidazoles containing in the 2 position of the ring an o-halophenyl radical, as well as to processes for the preparation of these compounds *] The invention also relates to anti-helminthi-
 EMI1.2
 quea containing a 2- (o-hal.ophenyl) benxirnidazol as an active ingredient.



   The infection known under the name "helminthiasis" is an infection of the body of animals, and in particular of the
 EMI1.3
 gastrointestinal tract by various species of parasitic worms. It is a serious and widespread disease. The methods available so far for the treatment of this disease and for its prevention have not been entirely satisfactory. The pre-
 EMI1.4
 The present invention relates to a class of substituted benzimidazola which can be used effectively for combating helminthiasis, these compounds being devoid of many of the drawbacks of a-
 EMI1.5
 known anthelmintic agents.



  The Applicant has discovered - and the invention is based on this discovery - that bonzimidazole comprising, in position 2 of the bonzimidazoliquop nucleus, an o-halophenyl radical in which the halogen has an atomic weight of between 19 and Inclusive, possess significant antiheluinthic activity and can be effectively used for the treatment and / or prevention of helminthiasis.

   The present invention has
 EMI1.6
 the subject of anthelmithic compositions containing such compounds. It also relates to a process for combating

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   helminthiasis using these substances, The invention * also
 EMI2.1
 the subject of new 1-acyl benzimidazola substituted in position 2 by an o-fluorophenyl or o-chlorophenyl radical as well as processes for the synthesis of these compounds. Other subjects of the invention will emerge from the following description,
The compounds which have proved to be effective as anthelmintic agents, within the scope of the present invention, can be represented by the following structural formula:

   
 EMI2.2
 in which R1 denotes hydrogen, an alkyl radical
 EMI2.3
 lower or an interior alkenyl radical. R2 and R3 denote hydrogen or a lower alkyl or alkoxy radical and X is a halogen having a high temperature ... ".. and inclusive, such as fluorine or chlorine. also embraced the addition salts with acids of these benzillldazoles, when R 1 denotes hydrogen.



  The N..1 position of ben, 3.idazoip (Ri in formula I) can, as mentioned above, be substituted by hydrogen, by a lower alkyl radical, such as methyl,
 EMI2.4
 ethyl, propyl or isopropyl, or by a later alceryl radical, such as allyl and d1éthallyl. We . preferred that the alkyl and alkenyl radicals contain less than 6 carbon atoms.

   If desired, the 6 member ring of benz11liclazol can also be substituted with interior alkyl groups or
 EMI2.5
 lower alkoxy groups in the 5 and /, or 6 positions. Where substituents are present in the 6 member ring of the benzimidazole ring, the preferred substituents are
 EMI2.6
 methyl or methoxy radicals, although methyl, ethyl, propyl, methoxy, ethoxy and lower alkyl radicals

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 and similar lower alkoxy can of course be employed.
 EMI3.1
 bent. However, in preferred compost, R 2 and R3 denote hydrogen in formula I.



  Conrao example of benzimidazo11ques components substituted in position 2 and which constitute active antihelminthic agents falling within the scope of the present invention, there may be mentioned 2-to-fluorophenyl) betzimidazols 2- (o-chlorophenyl) benzimidazol , N-methyl 2- (o fluorophenyl} benziraidazol, li-methyl-2- (o-chlorophenyl) .5.methoxy benzimidazol, N- allyl -Iofluorophnyl-5-5thoxy benziraidazol, N-propyl 2-a -t "luorophn3l benzimidazolp, N-allyl 2- (o-chlorophenyl) benzimidazol, 2-io-, fluorophenyl-5-aethyl benzimidazol, 2- (o-crùorophenyl) -5-ethoxy benzimidazol etc.

   fi "/ '"
The 2-substituted benzimidazols described herein are isolated under free bases by the methods
 EMI3.2
 Synthetic compounds normally employed are readily available as addition salts by treatment with acids.

   As an example of salts obtainable in this way, there may be mentioned
 EMI3.3
 lacto-mineral salts, such as hydrohalides, such as hydrochlorides, hydrosides, hydroiods, sulfates, nitrates and phosphates; salts of aliphatic acids, such as acetates,
 EMI3.4
 trimethylacetateea # t-butylacetates or propionates, salts of polycarboxylic acids, such as citrates, oxalates, succinates and the like; as well as the salts of other insoluble organic acids such as embonat and hydroxynaphthoatene. Some of these salts are much more soluble in water than the free bases. This is true for halohydrates.

   Since the solubility can also decrease by formation of an appropriate salt, it will be seen that the solubility properties of a particular compound can be adjusted, generally.
 EMI3.5
 generally, by a judicious choice of a salt, when the compounds according to the present invention are used in the form of salts,
 EMI3.6
 as anthelmic agents, it is of course desirable that the particular acid employed be a non-toxic, edible acid.

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 EMI4.1
 2- (o-fluorûphenyl) benzimidasol and -o-.ch3, oro. phenyl) benzimidazol are the preferred compounds according to the invention.

   The preparation of these and other substances 2- (o-
 EMI4.2
 t3Tuoroptdnylibenzimidxzal of formula 1 not made by producing leo-fluorobenzalddhyde or o-fluorobonzoic acid or an o-fluorobonzolque acid derivative, such as o-fluorobenzamide or an o-fluoro-benzoate lower alkyl with a compound of the general formula:
 EMI4.3
 
 EMI4.4
 wherein R1 denotes hydrogen or a lower alkyl inner alkenyl radical and R2 and R3 denote hydrogen or a lower alkyl or alkoxy radical.



   Or, N-alkyl- and N-alkenyl 2- (o-halophenyl)
 EMI4.5
 benziraidazols can be obtained by alkylation or alkenylation of a 2-o-halophny,) benzni3, oL. If removed, the 6-membered ring of the benzimidazole ring can also be substituted, in particular lower alkyl or lower alkoxy radicals in the 5 and 6 positions.
 EMI4.6
 an alkali metal salt of 2- (o-halopéhyl) benzimidazol. This can be done by putting an alkali metal hydride such as sodium hydride, lithium hydride or potassium hydride.
 EMI4.7
 sium intimately in contact with 2- (ōhaloplenyl) benzimidazol.



  To form the N-alkylated or N-alkenylated3 derivatives, one carries out
 EMI4.8
 There is the alkali metal salt of 2-to-fluorophenyl) benzimidazol or 2- (o-chlorophenyl) benzimidazol with an alkylating agent, such as methyl chloride, ethyl bromide, chloro-
 EMI4.9
 rule of allyl or cinnanyl chloride, in a suitable solvent, such as benzene and / or dimethyl roraaaraide.



  The 2- (o-fluorophenyl) benzimidazole and 2- (o-chlorophenyl} benzimidazols described herein have

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 EMI5.1
 a degree of antlbel.nth1qu1 "activity and are useful for the treatment and / or prevention of helminthiasis, which is a very widespread and often serious parasitic disease in domestic animals such as pigs, cattle hair, sheep and goats * For treatment of animals
 EMI5.2
 domestic components can be mixed with an edible, non-toxic vehicle. so as to form a feed supplement, which is then incorporated into the animal feed! in desired concentration.

   The compounds can also be ad-
 EMI5.3
 ministers in the form of dosage dosesa which, in the case of} large domestic animals, are presented in the form of bowls or in the form of a liquid drink, or alternatively, salts
 EMI5.4
 soluble in water or a wettable and diaperaable powder! von W containing the anthelmintic agent can be added to the drinking water of the animals.



   The preferred dose for the treatment of helminth infection depends, in a large house, on compound 2 (-o-
 EMI5.5
 The particular haiaphenyibeziaidaaliqua used as well as the severity of the infection and the particular animal space to be treated. In general, 2-to-chloro-phenyl) and 2- {o fluoro-piënyl. jbenicaidazole have anthelmintic activity,. when administered to animals at a daily dose; from about 50 to 300 mg / kg of animal body weight. It is preferred to use 100 to 200 mg of compound per kg of animal body weight. The compounds can be administered in a single dose or in several smaller doses.

   With the compounds of the present invention, it is possible, in / administered
 EMI5.6
 trant the compounds only for 1 day at the above doses. quées, rid the animal of helminths. If desired, the duration of treatment can be extended, in which case the optimal daily dose can be decreased.

   When the compounds are to be used primarily as prophylactic agents for the prevention of helminthic infections, the daily dose

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 favorite link is obviously inside,. the therapeutic dose and her * and preferably * between about 10 and
 EMI6.1
 70 a1g / kg of animal body weight.

   2- (o-chlorophenyl) beni # idazo18 can be incorporated into animal feed and this mode of administration is the preferred one, when the * compounds are to be used prophylactically, in which case they are incorporated into the food in doses such that the animal consumes about 10 to
 EMI6.2
 70 mg of 2- (o.chZoraphdnyljben3.midasa .. per k:

  The means used to administer this benliaidaso18 to animals are not critical and which of the methods currently in use or available for the treatment of infected or susceptible animals can be applied. '' be infected with parasites, to treat helminthiasis, using * 2-
 EMI6.3
 phenyl benz1midaola described in advance. When these substances are used therapeutically to treat an * established / infection, they are advantageously administered in unit dosage form * in a capsule, pill, tablet or in the form of a liquid drink.

   It should be noted that all of these methods are for oral administration, as this is the most effective way to treat stomach and intestinal infections *.
 EMI6.4
 



  When 2- (o-chlorophenyl) or 2- (o-fluorophenyl) benzimidazols are to be administered in the form of oral doses in solid and dry state # of wood capsules, pills or tablets containing the desired amount of An anthelmintic agent distributed in a pharmaceutically acceptable carrier is ordinarily used. These compounds are prepared by thoroughly and uniformly mixing the active ingredient with diluents, charges, disintegrants.
 EMI6.5
 tion and / or binders in a finely divided state, such as starch, lactose, talc. magnesium stearate, vegetable gums, etc.

   These figures under polologic dose can vary greatly. With regard to the total weight and

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 the content of anthelmintic agent, depending on the type of animal 4 treated. depending on the desired dose, depending on the severity and type of parasitic infection, etc., When it comes to treating large animals, such as sheep, pigs or cattle, bowls weighing up to 15 g can be used, although it is preferred to use bowls weighing 5-10 grams and containing 2-8 grams of 2-phenylbenzimidazol.

   These bowls, as well as smaller sized tablets contain binders and lubricants and are made by well known techniques.
Mixing the active ingredient with a diluent, such as starch or lactose, and putting the mixture into capsules.



   To treat infected animals with a drink, 2- (o-halopéhyl) benzimidaelos are mixed with a suspending agent, such as bentonite, and the solid product is added to water just before administration. Preferred beverages according to the present invention contain about 5-50% by weight of 2- (o-halophenyl) benzimidazole.



   The 2- (o-halophenyl) benéimidezols described in the present specification can also be administered as a constituent of animal feed or in solution or suspension in drinking water. The present invention also relates to novel food and food supplements, in which compounds of formula I given above are present as the active anthelmintic ingredient. In such compositions, the benzimidazols are intimately dispersed or mixed with an inert vehicle or diluent, i.e. a vehicle not reactive with 2- (o-halophenyl) benzimidazol and which can be administered from animal style.

   The carrier or diluent is preferably a product which constitutes or may constitute an ingredient of the feed supplied to the animals.

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   In food supplement, the active ingredient is. present in relatively large quantities. These supplements * are suitable to be added to food either directly or after mixing or intermediate dilution. As examples.

   vehicles or diluent suitable for such * compositions, there may be mentioned the solid vehicles which can be absorbed by the mouth, such as dried seeds. distiller, corn flour, citrus fruit flour, fermentation residues, ground oyster shells,
 EMI8.1
 attapulgus type, wheat middlings, soluble molasses products, corn bark flour, edible vegetable substances, decosaee soybean flour, crushed soybean * flour, mycelia used for production of antibiotics, crushed limestone and other products
 EMI8.2
 analogues.

   The anthelmintic agents are intimately disposed of or mixed with the solid inert vehicle by methods such as grinding, agitation, sewing, or kneading. By choosing suitable diluents and varying the ratio of vehicle or carrier to active ingredient, compositions can be prepared having any desired concentration.

   Compositions containing about 5 to 50% by weight and preferably about 10 to 30% by weight of active ingredient are particularly suitable for addition to foods: The active compound is normally dispersed or mixed uniformly in the diluent. , but in some cases it can be adsorbed or absorbed on the vehicle.



   Examples of food supplements countering 2- (o-halophenyl) benzimidazol dispersed in a solid vehicle are brominated below:
 EMI8.3
 luxeµ A. 2- (o-chlorohenyl) bensimidazol 20.0 Dried still corn kernels, 80.0 Bo 2.o-tluorophenyl hydrochloride
 EMI8.4
 
<tb> bonzimidazol <SEP> 5.0
<tb>
 
 EMI8.5
 From standard 95 wheat, rt C. 2- (o-chlorophenyl) -5-fflethoxy benztmi4azol zaza Wheat middlings 65.0 13.

   N-methyl-2 '- (o-fluoï' <! Phenyl) beMimidMOl 50.0
 EMI8.6
 
<tb> Graina <SEP> from <SEP> but <SEP> from <SEP> still <SEP> 50.0
<tb>
 

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These supplements or supplements as well as supplements * or similar supplements are prepared by mixing 2-phenyl benéimidazol evenly with the diluent or diluents.



   These supplements are added to the finished animal feed in an adequate amount so that the standard contains the desired concentration to combat or treat helminthiasis. Although the preferred dose of anthelmintic agent in the food will depend on the particular compound used, the anthelmintic compounds according to the present invention are normally administered in doses of 0.10 to 2.0%.



   An advantageous mode of administration of the compounds according to the present invention for animals, dent the food is advantageously in the form of pellets, in particular sheep, consists in directly incorporating the compounds in question in! lozenges. Thus, 2- (o-chlorophenyl) benzimidazol that easily incorporated into nutritionally adequate alfalfa pellets (during the manufacture of these pellets) doses of 0.5 to 5 g per 0.45 kg lozenges for therapeutic purposes and in lower doses for prophylactic purposes *, the lozenges being administered to animals infested with worms.

   The 2- (o-halophenyl) benzimidazols can also be incorporated into salt blocks to be licked by animals, in the desired concentration (concentrations of S at 25% by weight are advantageously used). Large animals, such as sheep, cattle and goats, then receive the anti-helminthic agents with their salt; It has also been found, within the scope of the present invention, that the new N-acyl-2- (o-halophenyl) benzimidazols, in which the halogen has an atomic weight = prie between 19 and 35.5 inclusive, also constitute strongly active anthelmintic agents.

   These compounds can be represented by the formula:

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 EMI10.1
 wherein X is halogen having an atomic weight of
 EMI10.2
 between 19 and 35.5 inclusive (for example, fluorine, and chlorine), R2 and R 3 denote hydrogen or an alkyl radical, the lower alkoxy or and R denote an acyl radical.



   These new N-acyl benzimidazola are getting ready to go '
 EMI10.3
 starting 2- (o -halophenyl) benziraidazol, forming an alkali metal salt of this compound / reacting this salt with a
 EMI10.4
 acyl halide The salt is obtained by reacting benzimidazol with an alkali metal hydride, such as dekodiura or potassium hydride. This compound is then treated without isolation, with an aroyl halide or a lower alkylene halide, such as acetylchloride, acetyl bromide, propionyl chloride, butyroyl bromide or chloride. benzoyl, to form the corresponding N-scyl 2Io-hsophenym benzimidazol.

   In this way, new acyl benziraidazols, such as N-acttyl 2ochlorophenylbesziatida zol, N-benzoyl 2- (o-fluorophenyl) benzidasol, N-propionyl 2-o-fluarophenyl-5-aethoxy benzimidazol and N-acetyl 2-tao-chlorophenyl) -5-methyl are produced. These compounds are very active anthelmintic agents. When used for the treatment or prevention of this disease, they are prepared and administered in the form of bowls, capsules,
 EMI10.5
 beverages or in food, as described above in detail for ber.z.midazo.s of formula I.



  The following examples are given for illustrative purposes and are not limiting.

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    EXAMPLE
 EMI11.1
 2- (o-chlorophenyl) benxiaidazols N-acyls are obtained by reacting an alkali metal salt of 2..o..ch.ch.arophenyl benzimidazol and an appropriate acyl halide. Thus, N-acôtyl 2- (Q¯chlorophenyl} benzimidazol is prepared as follows: A. A 2.1 g sample of 2¯Io-chlorophényllbsnziarida. Zol is added to a mixture of 50 ml of toluene and 15 ml daaâthy3forlaamide in a round-bottomed flask The suspension is then distilled by azeotropic distillation of a small quantity of toluene and a suspension of 0.7 g of a 52% solution of sodium hydride in 5 ml. toluene is then added,
The mixture is heated to 60 ° C. (evolution of hydrogen) and stirred at 60 ° C. for 1 hour.

   Then add a fraction of 1
 EMI11.2
 gram of acetyl chloride drop by drop. The yellow coloration of the sodium salt disappears quickly. After further stirring for 1 hour, the solution is cooled, after which a small volume of water is added and the organic phase is separated, washed with water, dried over sodium sulfate and concentrated in vacuo, in so that we get a
 EMI11.3
 1-acetyl 2- (o-chlorophenyl) benzimidazol residue. This product is further purified by recrystallization from a small volume of ethyl acetate or from a mixture of ether and petroleum ether.
 EMI11.4
 B.

   1-Benzoyl 2- (o-chlorophenyl) benzimidazol is prepared by reacting a 0.05 M solution of benzoyl chloride
 EMI11.5
 and a 0.5 µl solution of the sodium salt of 2- (o-chlorophenyl) benzimidazol by the procedure described in A above.



  C. By bringing the sodium salt of 2- (o-chlorophenyl) benzimidazol intimately into contact with propionyl chloride,
 EMI11.6
 benzoyl bromide, p-chlorobertzbyl chloride and dliaobutyroyl chloride according to the process described for preparing 1-acetyl 2- (a-chldrophenyl) benzimidazol, the ti-prop3, ony1, benzoyl ', p -chlorobenzoyl and iso-

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 EMI12.1
 butyr07, ll; \ 2- (oochlorophenyl) benzimidazol In some cases, a recrietallization does not allow to obtain a so pure cat flap. These compounds are further purified by chro-
 EMI12.2
 matography on neutral alumina and eluting the desired N.-acyl 2- (o-chlorophenyl) banzimidazol with ether or ethyl acetate.



     EXAMPLE 2
 EMI12.3
 1-Propionyl 2- (o-chlorophenyl) -5-fflethoxy bonzinidatol, 2.1 g of 2 o.chlorophgnyl -.5-ntho benz1.ddazo1 are added to a mixture of 50 ml of toluene and 15 ml of diaethyltormamide in a balloon. The suspension is then dried * by azeotropic distillation of a small amount of the toluene.
 EMI12.4
 A suspension of 0.7 g of 52% sodium hydride in 5 at, toluene is then added to the aforementioned solution. The mixture is stirred at 60 ° C for 1 hour, then 1 gram of propionyl chloride is stirred. added dropwise. The yellow coloration of the sodium salt disappears quickly.

   After further stirring for an hour, the solution is cooled and added with a small volume of water. The organic phase is separated, washed with water, dried over sodium sulfate and concentrated in vacuo,
 EMI12.5
 so that 1-propionyl 2-io-chl, orophdnfl-5 methoxy benzimidazol is obtained. This product is further purified by crystallization in a small amount of ethyl acetate. EXAMPLE 3 N-acyl 2- (o-fluorophenyl) benzimidazols are obtained by reacting an alkali metal salt of 2-b -fiuorDphenyl} benzimidazol and an appropriate acyl halide.

   Thus, N .. acetyl 2- (o (fluorophenyl) bensimidazol is prepared as follows: To 9,? G of 2-to-fluorophenyl) benzimidazol in 100 garlic of dimethyltormamido # one adds 2.3 g of a solution to z4 sodium hydride in mineral oil. The mixture is stirred at room temperature for about 20 minutes, then carefully heats up to about 50 ° C. for 10 minutes.

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  It is cooled to room temperature, then 1.6 g of
 EMI13.1
 Acetyl chloride in 10 ml of dethy3.fornarida is slowly added to the cooled solution. The reaction mixture is then heated at about 80 ° C. for 20 minutes, cooled, diluted with 200 ml of water and extracted with three 100 ml fractions of ether. The ethereal extracts are combined, washed with water,
 EMI13.2
 dried over sodium sulfate and filtered. The ether is expelled in a vacuum, in aorta which is obtained 1-acetyl 2- (o-flgorophdnyl) ba r imid azctl.



  By bringing the sodium salt of 2- (o <-f3uorophenyl) benzimidazol in intimate contact with acetyl bromide, propionyl chloride, hexanoyl chloride and benzoyl chloride, according to the procedure described above to form
 EMI13.3
 From N-acetyl 2- (o-fluorophenyl) benzi11l.idazol, N-acetyl, N-propionyl-, M-hexanoyl- and N-benzoyl 2- (o-fluorophenyl) benzimidazola are obtained respectively. The compounds are purified by; recrystallization or by chromatography under neutral alumina.



  EXAMPLE 4
 EMI13.4
 2- (o-fluorophenyl) b9nziraidazol, administered by mouth to mice infected with Nemao5Diode dubiu, prevented the development of nematode larvae at doses of 310 62, 125, 250 and 500 mg / kg. 2- (o-chlorophenyl) benzimidazol effectively inhibited the development of nematode larvae at doses of 62, 250 and 500 mg / kg.



    EXAMPLE 5
 EMI13.5
 Bowls of 2- (o-fluorophenyl) benximidazol or 2- (o-chlorophenyl) bensimidazol suitable for administration by mouth to domestic animals are prepared. These bowls have the following composition:
 EMI13.6
 
<tb> (A) <SEP> (B)
<tb>
 
 EMI13.7
 2- (o-halophdnyl) benzimidazol 1.0 2.0
 EMI13.8
 
<tb> Dicalcium <SEP> Phosphate <SEP> 3.0 <SEP> 1.0
<tb> Starch <SEP> Ce-535 <SEP> 0.702
<tb> Like <SEP> of <SEP> guar <SEP> 0.15 <SEP> 0.16
<tb> Talc <SEP>. <SEP> 0.14 <SEP> 0.11
<tb> Magnesium <SEP> stearate <SEP> <SEP> 0.04 <SEP> 0.028
<tb>
 

 <Desc / Clms Page number 14>

 
 EMI14.1
 To prepare the composition (joz, phosphate cU, cc1. '", Which is intimately mixed with 2- (o-halophenyl) beeiz.imidazol and the mixture is reduced to particles of less than 60 mesh.

   To the mixture, 0.330 g of starch is added in the form of an aqueous paste, of starch and the mixture obtained is granulated in the usual manner.



    The granules are then passed through 10 mesh tanis, whereupon they are dried at 110-130 ° P for about 8 hours.



  After passing the dried material through a 16 mesh sieve, the guar gum and the rest of the starch are added, after which the mixture is kneaded vigorously. The remaining ingredients are then subjected to mixing, after which the tablets are formed by compression.



  B. Composition (B) is prepared by thoroughly mixing
 EMI14.2
 2.-o-halophdnrl.bensicaida; .ol dicalcium phosphate; .ol and reducing the mixture to particles of less than 60 me-aht At nd .. mixture, 0.430 g of starch is added in the form of an aqueous paste of 'starch. The mixture obtained is then granulated in the usual manner. Granules are passed through a sieve of 10
 EMI14.3
 mesh and dried at 110-130 ° F for about 8 hours.



  The dried material is then passed through a 16 mesh screen. The guar gum and the rest of the starch are then added, after which the mixture is kneaded well. The remaining ingredients are then added and the mixture is kneaded further, which is finally compressed.

   EXAMPLE 6
 EMI14.4
 Tablets not having the following compositioni
 EMI14.5
 N-Înethyl 2-i (o-fluorophenyl) beniàlmidazbl 125 P # osptia "te dicalcique 2 5 0 Starch 125 GdmnH: 1 of gdar (60 mesh! T 17
 EMI14.6
 
<tb> Talc <SEP> (60 <SEP> mesh) <SEP> 14
<tb>
<tb> Magnesium <SEP> stearate <SEP> <SEP> (60 <SEP> mesh) <SEP>
<tb>
   prepare as follows:
 EMI14.7
 The dicalcium phosphate, Ntaethyl 2- (o * fluorophenyl) benzimidasol and 50 mg of starch are mixed and the mixture c7rrr .. held is reduced to particles with a particle size of at least

 <Desc / Clms Page number 15>

 of 60 mesh. 45 mg of starch are added in the form of an aqueous paste to the mixture and the whole is granulated in the usual manner. The granules are then sieved through a No. 10 sieve and dried at 110-130 F for about 8 hours.

   The dried material is then passed through a 16 mesh sieve. After adding the guar gum and remaining starch, the mixture is kneaded vigorously, after which the remaining ingredients are added. The resulting mass is mixed and compressed.
 EMI15.1
 



  Tablets containing 2- (o-chlorophenyl) benzimidazol as the active antihelmeinthic agent are prepared in a similar manner.



   EXAMPLE 7
Beverages having the following composition are prepared by conventional methods:
 EMI15.2
 A. 2- (o-fl.uorophenyl) benzimidazol .......... 2.3 g AF defoamer emulsion ................ 0.06 g Hydroxyethyl cellulose ........., ..., <.. 0.3 g Sodium phosphate monobasic 0.6 ml Benzalkonium chloride isoln.x2i8j,., 0.6 mal Water .... ............................. ad 30.0 ml B. N-benzoyl 2- (o-chloropMnyl) benzimidaol 4.0 g rXi1t118.On AF defoamer ................ 0.06 Hydroxyethyl cellulose ................. 0.3
 EMI15.3
 
<tb> Monobasic <SEP> sodium <SEP> <SEP> <SEP> <SEP> 0.3 <SEP> g
<tb>
<tb>
<tb>
<tb>
<tb>
<tb> <SEP> benzalconium <SEP> chloride <SEP> (treatment <SEP> 12.8% <SEP> 0.6 <SEP> ml
<tb>
 
 EMI15.4
 water ................................ ad 30.0 ml C.

   Drinks can also be prepared in large quantities to be subdivided before administration. The following vehicles contain:
 EMI15.5
 
<tb> 1. <SEP> Chlèure <SEP> de <SEP> benzalconium <SEP> (<SEP> treatment <SEP> 12.8%) ... <SEP> 40 <SEP> ml
<tb>
<tb> Emulsion <SEP> AF <SEP> anti-foam <SEP> ................ <SEP> 4 <SEP> g
<tb>
<tb> Hydroxyethyl <SEP> cellulose <SEP> 20 <SEP> g
<tb>
 
 EMI15.6
 Distilled water* ,....,. ad 2000 mil
 EMI15.7
 
<tb> 2. <SEP> <SEP> benzalconium chloride <SEP> <SEP> (treatment <SEP> 12.8%) ... <SEP> 0.5 <SEP> ml
<tb>
<tb> Emulsion <SEP> AF <SEP> anti-foam <SEP> ................

   <SEP> 4 <SEP> g
<tb>
 
 EMI15.8
 riyWoxy6thyl cellulose 20 g
 EMI15.9
 
<tb> Distilled <SEP> water <SEP> ........................... ad <SEP> 2000 <SEP> ml
<tb>
 
The compounds of formula I given above are added to the vehicles in concentrations of 15 to 40 g per 100 ml.



   Benzalkonium chloride used in vehicles
 EMI15.10
 of the beverages is a mixture of chlorides of imethlbenzylaMnon1um CB.18.


    

Claims (1)

CLAIMS. 1.- Composition for the prevention and treatment of helminthic infections in animals, characterized in that it comprises a compound of formula: EMI16.1 or an addition salt with an acid of such a compound, intimately dispersed in a vehicle administrable by the buccal route, the various symbols of the above-mentioned formula having the following meanings R1 denotes hydrogen, a lower alkyl radical or a lower alkenyl radical, R2 and R denote hydrogen or a lower alkyl or alkoxy radi cal and X is a halogen having an atomic weight of between 19 and 35.5 inclusive, 2.- Anthelmintic composition, characterized in that it contains, in the form of a dosage dose, a comesti vehicle. ble and non-toxic, intimately mixed with a 2- (o-halophznyl) benzimidazol, in which the halogen has an atomic weight of between 19 and 35.5 inclusive. 3.- Anthelmintic composition, characterized in that it consists of a liquid beverage, in which eet dispersed a chemotherapeutic amount of 2- (o-chloro-phenyl) benzimidazol. 4.- Anthelmintic composition, characterized in that it consists of a liquid drink, in which is dispersed a chemotherapeutic amount of 2- (o-fluorophenyl) benzimidasol. 5.- Animal feed in which is distributed, as active anthelmintic agent, a 2- (o-halophenyl) benéimidazol <Desc / Clms Page number 17> in a concentration sufficient to ensure a daily absorption of at least about 5 mg of benzimidazole compound per kg of the body weight of the animal, the halogen contained in it. the benzimidazole compound having an atomic weight of between 19 and 35.5 inclusive. 6.- Method for combating helminthic infections in animals. characterized in that it is administered by the oral route to an animal infected with helminths. a chemotherapeutic dose of a compound of formula: EMI17.1 in which R1 denotes hydrogen, a lower alkyl radical or a lower alkenyl radical, R2 and R denote hydrogen or a lower alkyl or alkoxy radical and X is a halogen having an atomic weight of between 19 and 35.5 inclusive, or an addition salt with an acid of the aforementioned compound, 7.- Composition for the prevention and treatment of infections due to helminths in animals, characterized in that it contains, in intimate dispersion in a vehicle which can be administered by the buccal route, a compound of the formula: in which EMI17.2 R2 and R3 denote hydrogen or an alkyl or lower alkoxy radical and R4 denote an acyl radical in which X is a halogen having an atomic weight of between 19 and 35.5 inclusive, for example fluorine and chlorine. 8.- Anthelmintic composition, characterized in that it consists of a liquid beverage containing 2- (o-fluoro-; phenyl) benzimidazol as an active anthelmintic ingredient. <Desc / Clms Page number 18> EMI18.1 1. "'" N-acylbentioldazol having in position 29 an o-halophenyl substituent, wherein the halogen has an atomic weight of between 19 and 35.5 inclusive. 10, - Compounds of formula: EMI18.2 EMI18.3 in which R2 and R3 denote hydrogen, a lower coyl radical or a lower alkoxy radical li diielgne an aroyl or lower alkanoyl radical and X denotes a halogen whose atomic weight is between 19 and 35.5 Anclusi ventent. EMI18.4 11.- N-acetyl 2- (o-chlorophenyl) benzimidazo: i. 12.- N-Benzoyl 2- (o-chlorophenyl) -5-methoxy benzinidaitol. 13.- N-acdtyl 2-.lo.f3.uorophnylbenzimi.dazo:., 14 é- N-benzoyl -o-l, uaroplxôrrylben: 3mïda;.,. A process for the preparation of a 2- (0-haiophenyl)! I .... cyl benziwidazol of the formula: EMI18.5 in which R2 and R3 denote 1 hydrogen or - a lower alkyl or lower alkoxy radical, R4 denotes an aroyl or lower alkanoyl radical and X denotes a halogen whose atomic weight is between 19 and 35.5 inclusive, characterized in that that an alkali metal salt of a compound of formula is reacted: EMI18.6 <Desc / Clms Page number 19> in which R2 R3 and X have the meaning indicated above, with an acylating agent chosen from halides EMI19.1 dtaroyl and lower dualcanoyl, 16.- Process for the production of t3-tertzayl o.fluaro phenyl) benzimidazol, characterized in that the sodium salt of 2- (o-flubrophenyl} benzimidazQl is reacted with benzoyl chloride.