US3192226A - Certain l-axyl-z-(z -naphthyl)-benzim- i idazqle compounds - Google Patents

Certain l-axyl-z-(z -naphthyl)-benzim- i idazqle compounds Download PDF

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US3192226A
US3192226A US3192226DA US3192226A US 3192226 A US3192226 A US 3192226A US 3192226D A US3192226D A US 3192226DA US 3192226 A US3192226 A US 3192226A
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms

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  • the infection known as helminthiasis involves infest-ation of the animal body, and particularly the gastrointes- It is a very widespread and serious disease, and the methods tinal tract, with various species of parasitic worms.
  • R is hydrogen, a lower alkyl or a lower alkenyl radical, or an acyl group, and R and R represent hydrogen, lower alkyl or lower alkoxy groups.
  • the invention also includes within its scope acid addition salts of these benzimidazoles.
  • the N-l position of the 2-(2'-naphthyl)-.benzimidazoles (R in Formula I) may be substituted with hydrogen, a lower alkyl group such as methyl, ethyl, propyl or isopropyl, or a lower .alkenyl radical of the type represented by allyl and methallyl.
  • the alkyl 'and alkenyl radicals preferably contain less than six carbon atoms.
  • the N-l position may be acylated, preferably with an :aralkanoyl, 'a lower alkanoyl or aroyl radical such as acetyl, propionyl, butyryl, benzoyl and the like.
  • -the six-mem- 'bered ring of the tbenzimidaz-ole nucleus may also be substituted, as with a lower alkyl or lower alkoXy group at the 5- 'or 6-position.
  • Methyl groups are :the preferred lower alkyl substituents although ethyl, propyl and similar lower alkyl radicals may, of course, be employed.
  • Fluorinated alkyl groups, such as a trifiuoromethyl substituent may also be present at the 5- or 6-position of the benzimidazole ring nucleus.
  • the 5- or 6-.alkoxy group which may be present is preferably a lower alkoxy radical such as methoxy, ethoxy, isopropoxy and the like. It will be appreciated that when R in these compounds is hydrogen, the 5- and 6-positions of the nucleus are equivalent, and substitution at those positions is often described as 5(6)-substitution. This equivalence or symmetry is, of course, lost when R is other than hydrogen.
  • the new 2-(2'-naphthyl)-benzim-idazoles are isolated as the free bases by the synthetic processes normally employed, and may be converted to acid addition salts by treatment or intimate contactwith an appropriate acid.
  • Typical salts which may be formed in this manner are mineral acid salts such as the hydrohalides, e.g. hydrochloride, hydrohromide, hydroiod-ide, sulfates, nitrates, phosphates, and the like, aliphatic acid salts such as the acetate, trimethylacet-a-te, t-butyl acetate, or propionate,
  • salts of polycarboxylic acids such as the citrate, oxalate, succinate and the like and salts of other insoluble organic acids such as the embonate and hydroxyn-aph-thoate salts. Certain of these salts are much more Water soluble than the free bases. This is true of the hydrohalides. Since the solubility may also be decreased by formation of an appropriate salt, it will be seen that the solubility properties of a particular compound may be generally adjusted by judicious selection of a salt. When the acid addition salts are used to treat helminthiasis, it is of course, desirable that the particularacid employed be an edible, non-toxic one.
  • the 2-(2'-naphthyl)-benzimidazoles are synthesized by a method which comprises broadly the reaction of Z-naphthoic acid or a derivative thereof, such as an ester, amide, nitrile, acid halideor aldehyde, with a compound of the general formula wherein Y is N0 NH or NHR, R is lower alkyl or lower alkenyl, and R and R are hydrogen, lower alkyl or lower alkoXy. At'least one of the R and R substitutents is hydrogen.
  • the 2(2'-naphthyl)-benzimidazoles are prepared by intimately contacting ophenylenediamine and 2-naphthoic acid (or a derivative thereof) in polyphosphoric acid.
  • Z-naphthoic acid itself is notemployed, it is preferred to use the amide or a lower alkyl ester derivative thereof.
  • the process is carried out at elevated temperatures, and preferably at temperatures of about 150300 C. The optimum reaction time and temperature will depend to some extent on the particular reactants being employed, but in general good yields are obtained by conducting the process at temperatures of about 175 to about 275 C. for from 2 to 6 hours. It may be helpful in some cases to preheat the reaction mixture at about 100150 C.
  • benzimidazoles do not crystallize readily under these conditions, they are precipitated by neutralizing the quenched mixture with a base such as ammonium hydroxide, an alkali metal hydroxide or an alkali metal carbonate.
  • the 2-(2-naphthyl)-benzimidazole may be synthesized by reacting together o-phenylenediamine and Z-naphthaldehyde in a reaction medium comprising nitrobenzene. Good results are, obtained by heating the reaction mixture slowly to the reflux temperature (ca. 210 C.), and maintaining that temperature for a short time.
  • a solvent such as a lower alkanol may be used to promote the solubility of the reactants at lower temperatures. Such solvents are allowed to distil off during the heating period.
  • the 2-(2-napthyl)-benzimidazoles are readily recovered. In many cases they crystallize directly on cooling the nitrobenzene solution.
  • the benzimidazoles described herein are prepared by condensing Z-naphthaldehyde with a compound of Formula II above.
  • the reaction is preferably brought about by contacting the reactants in a suitable solvent such as a lower .alkanol, e.g. methanol, ethanol, isopropanol or t-butanol.
  • a suitable solvent such as a lower .alkanol, e.g. methanol, ethanol, isopropanol or t-butanol.
  • the first product formed is the Schiff base of the aldehyde and the primary amine. In normal practice this is not isolated but rather converted directly to the benzimidazole.
  • the ring closure of the Schiif base to the desired benzimidazole is effected with a suitable oxidizing agent such as 'cuprie acetate, lead tetracetate, mercuric acetate, air and the like.
  • an ester-or an acid halide derivative of Z-naphthoic acid is employed as the other reactant.
  • An intermediate anilide is formed initially.
  • the nitro group is then reduced and benzimidazole formation effected by treatment of the intermediate antilide with a metal-acid reducing system such as zinc-hydrochloric acid, zinc-acetic'acid, iron-hydrohalic acid or tinhydrohalic acid.
  • a heavy metal reagent is used to bring about benzimidazole formation in either of the two last-menis readily converted to the free benzimidazole by red moval of the heavy metal with reagents suitable for this purpose, such as hydrogen sulfide, ammonium polysulfide, ammonium hydroxide and the like.
  • the benzimidazoles are prepared by heating a mixture of an o-phenylenediamine or an N-alkyl-o-phenylenediamine and a lower alkyl Z-naphthoate with an aqueous mineral acid such as aqueous sulfuric or phosphoric acid in a closed system, i.e. an autoclave or bomb. The process is conducted at temperatures of from about C. for 3-10 hours, and the benzimidazole recovered from the acid reaction mixture by application of the isolation and purification techniques described above.
  • aqueous mineral acid such as aqueous sulfuric or phosphoric acid
  • 1-substituted-2-'(2 naphthyl)-benzimidazoles where R in Formula I above is alkyl or alkenyl, may further be synthesized by alkylation or alkenyllation of the 2-(2- naphthyl)-benzimidazole itself.
  • an alkali metal salt of the benzimidazole such as the sodium or potassium salt
  • an ester of a strong acid and a lower alkanol or lower alkenol suchas methyl bromide,-methyl iodide, allyl bromide and the like, or with an alkyl sulfate such as dimethyl sulfate.
  • the 1-acyl-2-(2-naphthyl)rbenzimidazoles described herein are prepared by acylation of an alkali metal salt of a 2-(2'-naphthyl)-benzimidazole as illustrated by the flow diagram:
  • R is a hydrocarbonyl radical
  • M is an alkali metal
  • X is a halogen such as chlorine or bromine.
  • the process is carried out by first converting the 2-(2'- naphthyl)-benzimidazole to an alkali metal salt. It is preferred to form the sodium salt by reactting or initimately. contacting the benzimidazole with sodium hydride in a suitable solvent medium. Satisfactory results are obtained when a slight molar excess of sodium hydride is employed, although equimolar quantities of benzimidazole and sodium hydride may be used if desired. The reaction is conveniently brought about by warming the reactants at slightly elevated temperatures, but this is not essen tial and room temperature is satisfactory.
  • novel 1-acryl-2-(2'-naphthyl)rbenzimidazoles are obtained by intimately contacting the benzimidazole alkali metal salt with an acyl halide, and preferably one having less than nine carbon atoms, such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, valeroyl bromide, benzoyl chloride, phenylacetyl chloride and the like.
  • the acyl halide is added directly to a solution or suspension of the benzimidazole salt in an Inert solvent, and the acylation reaction allowed to proceed at temperatures of room temperature up to about 100 C. Reaction temperatures in the range of 5075 C.
  • the solvent employed as the reaction medium is preferably a hydrocarbon solvent such as benzene, toluene, xylene,.petroleurn ether and the like either alone or mixed with other solvents miscible therewith, such as dimethylformamide.
  • the 1-acyl-2-(2.'-naphthyl)-benzirnidazoles thus formed are recovered fromthe reaction .mixture .by techniques 8 such as removal of the organic solvent and crystallization of the residual solid from solvents such as other or mixtures of ether with other solvents.
  • the 2-(2'-naphthyl)-benzimidazoles described above are active against blood sucking nematodes such as those commonly referred to as whipworrns and hookworms and for this purpose are administered to the worm-infested animal, such as sheep, cattle or dogs, orally in admixture with a suitable carrier vehicle.
  • nematodes such as those commonly referred to as whipworrns and hookworms
  • a suitable carrier vehicle for treating these and similar nematodes, they are administered at daily dose levels in the range of about 150-600 mg. per kilogram of animal body weight, the preferred level depending on the particular 2-(2'-naphthyl)-benzimidazole being used, the
  • the compounds may be administered in a single dose or divided into a plurality of smaller doses. Highly satisfactory results are achieved by administering the compounds for only a single day at the desired dose levels. If desired, however, the course of treatment may be extended over aperiod of days in which case the optimum daily dose level is reduced.
  • a group of dogs was fed a single oral dose of 150 mg. of 2-(2'- naphthyl)-benzimidazole per kilogram of body weight, the animals expelled hookworms and whipworms, and the fecal egg count was significantly reduced. Similar results were obtained when worm-infested dogs were fed 2-(2'-naphthyl)-benzimidazole in four equal doses of 50 mg. per kilogram of body weight over a two-day period.
  • the 2-(2-naphthyl)-benzimidazoles described herein are highly effective in controlling the development of worms in that they prevent the larvae from hatching. This is a preferred and highly important use of the compounds. This property of preventing larval development was demonstrated by feeding 2-(2'-naphthyl)-benzimidazole orally to mice infected with N ematospiroides dubius and measuring larval development. The compound was efiective in preventing such development when administered at levels of 500, 250, 125 and 62.5 mg. per kilogram of body weight, and moderately active at a 31.25 mg. per kilogram of body weight dose level.
  • anthelmin-tic compositions wherein -the 2-(2'-naphthyl)-benzimidazole is dispersed in a suitable carrier vehicle.
  • these substances are employed therapeutically to treat an established infection, they are conveniently administered in a unit dosage form such as me capsule, bolus, tablet or as a liquid drench. It will be noted that all of these methods contemplate oral administration since this is the most effective route.
  • the '2-(2'-naphthyl)-benzimidazoles are to be administered in dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable H vehicle or a vehicle acceptable for veterinary use are usually employed. These are prepared by intimately and uniformly mixing. the active ingredient with suitable finely divided diluents, .fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, dicalcium phosphate, vegetable gums and the like.
  • unit dosage formulations may be widely varied with respect-to their total weight and content of anthelmintic agent, depending on factors such as the type of host animal to be treated, the dose level desired, and the severity and type of parasitic infestation.
  • boluses weighing up to 15 grams may be used although it is preferred to employ boluses weighing from 5-10 grams and containing from 2-8 grams of the benzimidazole;
  • These boluses as well as smaller size tablets contain binders and lubricants, and are compounded by techniques known in this art.
  • Capsules are readily prepared by mixing the active ingredient with a diluent such as starch or lactose and filling into the capsule. In general, tablets, boluses and drenches containing from about 570% by weight of active ingredient are used to supply the desired dosage of anthelmintic.
  • the 2-(2'-naphthyl)-benzimidazoles may be mixed with a suspending agent such as bentonite and the solid mixture added to water just prior to administration.
  • a suspending agent such as bentonite
  • ready-to-use drench formulations such as those disclosed in US. Patent No. 2,918,403, may be utilized.
  • the preferred drenches in accordance with this invention contain from about 5-50% by Weight of anthelmintic.
  • novel feed compositions are provided in which compounds of Formula I above are present as an active anthelmintic ingredient.
  • Such compositions comprise the benzimidazoles intimately dispersed in or admixed with an inert carrier or diluent.
  • an inert carrier is meant one that is nonreactive with respect to the 2-(2'-naphthyl)-benzirnidazole and that may be administered with safety to the animals.
  • the carrier or diluent is preferably one that is or may be an ingredient of the animal ration.
  • compositions include feed supplements in which the active ingredient is present in relatively large amounts and which are suitable for addition to the feed either directly or after an intermediate dilution or blending step.
  • carriers or diluents suitable for such compositions are solid orally ingestible carriers-such as distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and the like.
  • the anthelmintic agents are intimately dispersed or admixed throughout the solid inertcarrier by methods such as grinding, stirring, milling or tumbling.
  • compositions of any desired concentrationr may be prepared.
  • Formulations containing from about 5% to about 50% by weight, and preferably from about 1030% by weight, of active ingredient are particularly suitable for addition to feeds.
  • the active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorhed on the carrier.
  • feed supplements are prepared by uniformly mixing the active ingredient with the carrier or carriers.
  • 2-(2-naphthyl)-benzimidazole is readily incorporated in nutritionally adequate alfalfa pellets (during the pelleting operation) at levels of 1-5 grams per pound of pellets for therapeutic use, and at lower levels for prophylactic use, and such pellets fed to the worm-infested animals.
  • it may be incorporated in salt licks or salt blocks atany desired concentration (concentrations of 525% by weight are conveniently employed) whereby large. animals such as sheep, cattle and swine would be enabled to receive the anthelmintics with their salt.
  • the compounds of Formula 1 above may be administered to domesticated animals such as sheep and cattle by admixing them with the protein-vitamin supplements employed as top dressings in the feed of such animals.
  • this route of administration is to be used, good results are obtained by adding from 515 grams of anthelrnintic to a pound of protein supplement.
  • Example 1 off, washed with water and with 100 ml. of 1:1 ethanolwater.
  • the green salt is then suspended with stirring in 400 ml. of 1:1 ethanol-water and a stream of hydrogen sulfide passed into the suspension to saturation.
  • the precipitated copper sulfide is filtered and washed with boiling ethanol to remove any occluded 2-(2'-naphthyl)-benzimidazole.
  • the filtrate and washings are combined and concentrated to dryness in vacuo. 13.5 g. of crude 2-(2'-naphthyl)-benzimidazole are obtained.
  • the solid is dissolved in the minimal amount of warm ethanol-water and the solution treated with a small amount of decolorizing charcoal.
  • Example 2 17.2. g. of ethyl Z-naphthoate and 11.5 g. of o-phenylenediamine are mixed and added slowly to 270 g. of polyphosphoric acid. The mixture is heated slowly with stirring to 245 C. and maintained at this temperature for 2 /2 hours. The hot solution is then poured onto about 200 g. of ice and the mixture stirred. It is filtered and the filtrate neutralized slowly with 30% sodium hydroxide until the 2-(2'-naphthyl)-benzimidazole precipitates. It is filtered, Washed with water, and dried in air. This product is extracted with hot ethanol, benzene is added to the extract and the solution boiled to remove traces of water. On'concentration of the solution to a small volume and cooling, substantially pure 2.-(2-naphthyl)-benzimidazole crystallizes.
  • Example 3 A. 9 g. of 2-naphthaldehyde in 12 ml. of ethanol is added with stirring to a suspension of 11 g. of o-phenylenediamine in 40 ml. of nitrobenzene. The mixture is stirred at room temperature for 15 minutes and then beated slowly to 210 C. During the heating period, the ethanol is removed by distillation. As soon as the temperature of the reaction mixture reaches 210 C., it is cooled with stirring to about 10 C. -2-(2'-naphthyl)- benzirnidazole crystallizes, is recovered by filtration and washed with ether. If desired, the product may be purified by recrystallization from ethanol.
  • Example 4 A. 7 g. of 2-naphthoyl acid chloride and 7 g. of o-nitroaniline are stirred together in 20 m1. of pyridine at room temperature for about 10 hours. The mixture is then poured into ice water and the solid nitroanilide recovered by filtration. It is washed with dilute aqueous sodium carbonate solution, and added to 70 ml. of glacial acetic acid. 40 ml. of 6 N-hydrochloric acid is added slowly to the acetic acid mixture followed by-30 g. of zinc dust. The zinc is added slowly in small portions. After the zinc addition is completed, and the reaction is essentially finished (by visual observation), the mixture is filtered and the filtrate neutralized with concentrated ammonium hydroxide. 2 (2' naphthyl)- benzimidazole precipitates on. neutralization. It is isolated by filtration, washed with ice water, and purified by recrystallization from ethyl acetate.
  • the mixture is extracted with three 10-ml. portions of ethyl ether, the ether extracts combined, washed with water, dried over sodium sulfate, filtered and the ether removed in vacuo.
  • the residual solid is 1methyl-2-(2'-naphthyl)-benzimidazole, which is purified by crystallization fromethyl acetate.
  • the hydrochloride salt is obtained by dissolving the product in hot alcoholic hydrogen chloride, treating the hot solution with activated charcoal, removing the charcoal by filtration, and adding about 3 volumes of ether to the alcoholic solution.
  • the acid salt crystallizes on cooling.
  • Example 6 13.0 g. of 4-methyl-1,2-diaminobenzene and 19 g. of
  • methyl 2-naphthoate are added to 325 g. of polyphosphoric acid which has been preheated to about 80 C. in a nitrogen atmosphere. The mixture is stirred for 50 minutes at 125 C., and the temperature then raised to 220 C. for 90 minutes. The solution is cooled to about 100 C. and poured slowly with stirring into 400 ml. of ice water. An amorphous solid is filtered otf and the filtrate neutralized to a pH of about 7 with 30% sodium hydroxide solution. The crystalline solid which precipitates is filtered, Washed with water and dried. This solid is extracted with 3 x 100-ml. portions of acetone. The combined acetone extracts are treated with decolorizing charcoal. The charcoal -is filtered olf and the filtrate concentrated to dryness to give substantially pure 5-methyl-2-(2-napl1thyl)-benzimidazole.
  • Example 7 A bolus of 2-(2'-naphthyl)-benzimidazole and having is prepared in the following manner:
  • the dicalcium phosphate is thoroughly mixed with the 2-(2'-naphthyl)-benzimidazole and the mixture reduced to a particle size finer than 60 mesh.
  • To the mixture is added 0.330 gm. of starch in the form of an aqueous starch paste and the resulting mixture is granulated :in the usual manner.
  • the granules are then passed through a #10 mesh screen and dried at 110130 F. for about 8 hours.
  • the dried material is then passed through a #16 mesh screen.
  • the guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.
  • a bolus providing 4.0 gm. of l-benzoyl-2-(2-naphthyl)-benzimidazole is prepared as above using twice the amount of ingredients.
  • the dicalcium phosphate is thoroughly mixed with the l-methyl-Z-(2-naphthyl)-benzimidazole and the mixture reduced to a particle size finer than 60 mesh.
  • To the mixture is added 0.430 gm. of starch in the form of an aqueous starch paste and the resulting mixture is granulated in the usual manner.
  • the granules are then passed through a #10 mesh screen and dried at 110130 F. for about 8 hours.
  • the dried material is then passed through a #16 mesh screen.
  • the guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.
  • Example 9 Drenches having the following composition are prepared by standard formulating methods:
  • the compounds of Formula I above are added to the velhicles in concentrations in the range of 6-25 gm./
  • the benzallconium chloride used in the drench vehicles isda mixture of C -C dimethylbenzylammonium chlorr es.
  • R is selected from the class consisting of lower alkanoyl and benzoyl, and R and R are selected from the class consisting of hydrogen, lower alkyl and lower alkoxy groups, at least one of R and R being hydrogen.

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Description

v United States Patent 3,192,226 CERTARN 1-AYL-2-(2'-NAPHTHYL)-BENZIM- HDAZOLE COMPOUNDS Lewis H. Sarett, Princeton, and Horace D. Brown, Plainfield, Ni, assignors to Merck & (30., Inc, Railway, N.J., a corporation'of New Jersey No Drawing. Filed May 25, 1961, Ser. No. 112,545 3 Claims. (Cl. 260-3092) This invention rel-ates to compounds useful against helminthiasis. More par-t-icularly,'it relates generally to new benzimidazoles and to benzimidazole compositions. Still more particularly, it is concerned with 2-'(2-naph-thyl)- benzirnidazoles and with derivatives thereof. It is concerned further with methods of making such compounds and using them in the treatment of helminthiasis.
This application is a continuation-in-part of our copending application Serial No. 22,100, filed April 14, 1960, and now abandoned.
The infection known as helminthiasis involves infest-ation of the animal body, and particularly the gastrointes- It is a very widespread and serious disease, and the methods tinal tract, with various species of parasitic worms.
heretofore available for its treatment and prevention have not been entirely satisfactory. It is a purpose of this invention to provide a group of benzimidazloes which are effective in controlling helminthiasis, and which lack many of the objectionable features of the known anthelmintics.
According to this invention, it has been found that 2-(2- naphthyl)-benzimid-azoles possess a significant degree of formula I RF it.
wherein R is hydrogen, a lower alkyl or a lower alkenyl radical, or an acyl group, and R and R represent hydrogen, lower alkyl or lower alkoxy groups. The invention also includes within its scope acid addition salts of these benzimidazoles.
The N-l position of the 2-(2'-naphthyl)-.benzimidazoles (R in Formula I) may be substituted with hydrogen, a lower alkyl group such as methyl, ethyl, propyl or isopropyl, or a lower .alkenyl radical of the type represented by allyl and methallyl. The alkyl 'and alkenyl radicals preferably contain less than six carbon atoms. The N-l position may be acylated, preferably with an :aralkanoyl, 'a lower alkanoyl or aroyl radical such as acetyl, propionyl, butyryl, benzoyl and the like. If desired, -the six-mem- 'bered ring of the tbenzimidaz-ole nucleus may also be substituted, as with a lower alkyl or lower alkoXy group at the 5- 'or 6-position. Methyl groups are :the preferred lower alkyl substituents although ethyl, propyl and similar lower alkyl radicals may, of course, be employed. Fluorinated alkyl groups, such as a trifiuoromethyl substituent, may also be present at the 5- or 6-position of the benzimidazole ring nucleus. The 5- or 6-.alkoxy group which may be present is preferably a lower alkoxy radical such as methoxy, ethoxy, isopropoxy and the like. It will be appreciated that when R in these compounds is hydrogen, the 5- and 6-positions of the nucleus are equivalent, and substitution at those positions is often described as 5(6)-substitution. This equivalence or symmetry is, of course, lost when R is other than hydrogen.
Typical examples of compounds'which are within the purview of this invention and which may be prepared as described below are 2-(2'-naphthyl)-benzimidazole, 1-methyla2=(2-naphthyl)-benzimidazole, 1-propyl-2-(2'-naphthyD-benzimidazole, l a1lyl-2-G2'-naphthyl)benzimidazole, 1-.acetyl-2-(2-naphthyl)-benzimidazole, "1-propionyl-2-(2-naphthyD-benzimidazole,
1-butyryl-2-(2'-naphthyD-benzimidazole, 5(6)-methoXy-2-(2-naphthyl)-benzimidazole, 5(6)-methyl-2-(2'-naphthyl)-benzimidazole, 1,5-diethyl-2-(2-naphthyn benzimidazole, 1-benzoyl-'2 (2'-naphthylybenzimidazole, and the like.
The new =2-(2'-naphthyl)-benzim-idazoles are isolated as the free bases by the synthetic processes normally employed, and may be converted to acid addition salts by treatment or intimate contactwith an appropriate acid. Typical salts which may be formed in this manner are mineral acid salts such as the hydrohalides, e.g. hydrochloride, hydrohromide, hydroiod-ide, sulfates, nitrates, phosphates, and the like, aliphatic acid salts such as the acetate, trimethylacet-a-te, t-butyl acetate, or propionate,
salts of polycarboxylic acids such as the citrate, oxalate, succinate and the like and salts of other insoluble organic acids such as the embonate and hydroxyn-aph-thoate salts. Certain of these salts are much more Water soluble than the free bases. This is true of the hydrohalides. Since the solubility may also be decreased by formation of an appropriate salt, it will be seen that the solubility properties of a particular compound may be generally adjusted by judicious selection of a salt. When the acid addition salts are used to treat helminthiasis, it is of course, desirable that the particularacid employed be an edible, non-toxic one.
The 2-(2'-naphthyl)-benzimidazoles are synthesized by a method which comprises broadly the reaction of Z-naphthoic acid or a derivative thereof, such as an ester, amide, nitrile, acid halideor aldehyde, with a compound of the general formula wherein Y is N0 NH or NHR, R is lower alkyl or lower alkenyl, and R and R are hydrogen, lower alkyl or lower alkoXy. At'least one of the R and R substitutents is hydrogen.
According to one process, the 2(2'-naphthyl)-benzimidazoles are prepared by intimately contacting ophenylenediamine and 2-naphthoic acid (or a derivative thereof) in polyphosphoric acid. When Z-naphthoic acid itself is notemployed, it is preferred to use the amide or a lower alkyl ester derivative thereof. The process is carried out at elevated temperatures, and preferably at temperatures of about 150300 C. The optimum reaction time and temperature will depend to some extent on the particular reactants being employed, but in general good yields are obtained by conducting the process at temperatures of about 175 to about 275 C. for from 2 to 6 hours. It may be helpful in some cases to preheat the reaction mixture at about 100150 C. for a short period of time, and then to complete the process at the higher temperatures referred to above. It is preferred to employ substantially equimolar amounts of the Z-naphthoic acid compound and the diamine, and from about -20 parts by Weight of polyphosphoric acid per part of naphthoic acid, although it will be appreciated by those skilled in this art that the relative amount of reactants is not a critical feature of the invention.
The desired 2- (2' -naphthyl)-benzimidazoles are re-.
covered by cooling the reaction mixture and diluting with water. Where the benzimidazoles do not crystallize readily under these conditions, they are precipitated by neutralizing the quenched mixture with a base such as ammonium hydroxide, an alkali metal hydroxide or an alkali metal carbonate.
Alternatively, the 2-(2-naphthyl)-benzimidazole may be synthesized by reacting together o-phenylenediamine and Z-naphthaldehyde in a reaction medium comprising nitrobenzene. Good results are, obtained by heating the reaction mixture slowly to the reflux temperature (ca. 210 C.), and maintaining that temperature for a short time. If desired, a solvent such as a lower alkanol may be used to promote the solubility of the reactants at lower temperatures. Such solvents are allowed to distil off during the heating period. The 2-(2-napthyl)-benzimidazoles are readily recovered. In many cases they crystallize directly on cooling the nitrobenzene solution. Alternatively, they may be crystallized by addition of ether or petroleum ether to the nitrobenzene solution. This process is particularly useful for the direct preparation of 1-lower-alkyl-2 (2' naphthyl) benzimidazoles from an N-lower alkyl-o-phenylenediamine and Z-naphthaldehyde.
Accordingv to a further embodiment of the invention, the benzimidazoles described herein are prepared by condensing Z-naphthaldehyde with a compound of Formula II above. The reaction is preferably brought about by contacting the reactants in a suitable solvent such as a lower .alkanol, e.g. methanol, ethanol, isopropanol or t-butanol. The first product formed is the Schiff base of the aldehyde and the primary amine. In normal practice this is not isolated but rather converted directly to the benzimidazole. When an o-phenylenediamine or an N-substituted-o-phenylenediamine is used, the ring closure of the Schiif base to the desired benzimidazole is effected with a suitable oxidizing agent such as 'cuprie acetate, lead tetracetate, mercuric acetate, air and the like.
Alternatively, in those cases where an o-nitroaniline is one of the starting materials, an ester-or an acid halide derivative of Z-naphthoic acid is employed as the other reactant. An intermediate anilide is formed initially. The nitro group is then reduced and benzimidazole formation effected by treatment of the intermediate antilide with a metal-acid reducing system such as zinc-hydrochloric acid, zinc-acetic'acid, iron-hydrohalic acid or tinhydrohalic acid.
Where a heavy metal reagent is used to bring about benzimidazole formation in either of the two last-menis readily converted to the free benzimidazole by red moval of the heavy metal with reagents suitable for this purpose, such as hydrogen sulfide, ammonium polysulfide, ammonium hydroxide and the like.
In an additional embodiment of the invention, the benzimidazoles are prepared by heating a mixture of an o-phenylenediamine or an N-alkyl-o-phenylenediamine and a lower alkyl Z-naphthoate with an aqueous mineral acid such as aqueous sulfuric or phosphoric acid in a closed system, i.e. an autoclave or bomb. The process is conducted at temperatures of from about C. for 3-10 hours, and the benzimidazole recovered from the acid reaction mixture by application of the isolation and purification techniques described above.
1-substituted-2-'(2 naphthyl)-benzimidazoles, where R in Formula I above is alkyl or alkenyl, may further be synthesized by alkylation or alkenyllation of the 2-(2- naphthyl)-benzimidazole itself. According to this method, an alkali metal salt of the benzimidazole, such as the sodium or potassium salt, is treated or contacted with an ester of a strong acid and a lower alkanol or lower alkenol, suchas methyl bromide,-methyl iodide, allyl bromide and the like, or with an alkyl sulfate such as dimethyl sulfate.
The 1-acyl-2-(2-naphthyl)rbenzimidazoles described herein are prepared by acylation of an alkali metal salt of a 2-(2'-naphthyl)-benzimidazole as illustrated by the flow diagram:
Rar-
where R and R have the same meaning as above, R is a hydrocarbonyl radical, M is an alkali metal and X is a halogen such as chlorine or bromine.
The process is carried out by first converting the 2-(2'- naphthyl)-benzimidazole to an alkali metal salt. It is preferred to form the sodium salt by reactting or initimately. contacting the benzimidazole with sodium hydride in a suitable solvent medium. Satisfactory results are obtained when a slight molar excess of sodium hydride is employed, although equimolar quantities of benzimidazole and sodium hydride may be used if desired. The reaction is conveniently brought about by warming the reactants at slightly elevated temperatures, but this is not essen tial and room temperature is satisfactory.
The novel 1-acryl-2-(2'-naphthyl)rbenzimidazoles are obtained by intimately contacting the benzimidazole alkali metal salt with an acyl halide, and preferably one having less than nine carbon atoms, such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, valeroyl bromide, benzoyl chloride, phenylacetyl chloride and the like. Normally, the acyl halide is added directly to a solution or suspension of the benzimidazole salt in an Inert solvent, and the acylation reaction allowed to proceed at temperatures of room temperature up to about 100 C. Reaction temperatures in the range of 5075 C. are preferred. The solvent employed as the reaction medium is preferably a hydrocarbon solvent such as benzene, toluene, xylene,.petroleurn ether and the like either alone or mixed with other solvents miscible therewith, such as dimethylformamide.
The 1-acyl-2-(2.'-naphthyl)-benzirnidazoles thus formed are recovered fromthe reaction .mixture .by techniques 8 such as removal of the organic solvent and crystallization of the residual solid from solvents such as other or mixtures of ether with other solvents.
The 2-(2'-naphthyl)-benzimidazoles described above are active against blood sucking nematodes such as those commonly referred to as whipworrns and hookworms and for this purpose are administered to the worm-infested animal, such as sheep, cattle or dogs, orally in admixture with a suitable carrier vehicle. For treating these and similar nematodes, they are administered at daily dose levels in the range of about 150-600 mg. per kilogram of animal body weight, the preferred level depending on the particular 2-(2'-naphthyl)-benzimidazole being used, the
species of animal being treated, and the type and severity of infection. The compounds may be administered in a single dose or divided into a plurality of smaller doses. Highly satisfactory results are achieved by administering the compounds for only a single day at the desired dose levels. If desired, however, the course of treatment may be extended over aperiod of days in which case the optimum daily dose level is reduced. Thus, when a group of dogs was fed a single oral dose of 150 mg. of 2-(2'- naphthyl)-benzimidazole per kilogram of body weight, the animals expelled hookworms and whipworms, and the fecal egg count was significantly reduced. Similar results were obtained when worm-infested dogs were fed 2-(2'-naphthyl)-benzimidazole in four equal doses of 50 mg. per kilogram of body weight over a two-day period.
The 2-(2-naphthyl)-benzimidazoles described herein are highly effective in controlling the development of worms in that they prevent the larvae from hatching. This is a preferred and highly important use of the compounds. This property of preventing larval development was demonstrated by feeding 2-(2'-naphthyl)-benzimidazole orally to mice infected with N ematospiroides dubius and measuring larval development. The compound was efiective in preventing such development when administered at levels of 500, 250, 125 and 62.5 mg. per kilogram of body weight, and moderately active at a 31.25 mg. per kilogram of body weight dose level.
The methods for employing our 2-(2'-naphthyl)- benzimidazoles in treating helminthiasis are not critical and any of the methods now used or available for treating animals infected with or susceptible to parasitic infections are satisfactory. In accordance with one aspect of the invention, there are provided anthelmin-tic compositions wherein -the 2-(2'-naphthyl)-benzimidazole is dispersed in a suitable carrier vehicle. When these substances are employed therapeutically to treat an established infection, they are conveniently administered in a unit dosage form such as me capsule, bolus, tablet or as a liquid drench. It will be noted that all of these methods contemplate oral administration since this is the most effective route.
When the '2-(2'-naphthyl)-benzimidazoles are to be administered in dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable H vehicle or a vehicle acceptable for veterinary use are usually employed. These are prepared by intimately and uniformly mixing. the active ingredient with suitable finely divided diluents, .fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, dicalcium phosphate, vegetable gums and the like. These unit dosage formulations may be widely varied with respect-to their total weight and content of anthelmintic agent, depending on factors such as the type of host animal to be treated, the dose level desired, and the severity and type of parasitic infestation. For large animals such as sheep, swine or cattle, boluses weighing up to 15 grams may be used although it is preferred to employ boluses weighing from 5-10 grams and containing from 2-8 grams of the benzimidazole; These boluses as well as smaller size tablets contain binders and lubricants, and are compounded by techniques known in this art. Capsules are readily prepared by mixing the active ingredient with a diluent such as starch or lactose and filling into the capsule. In general, tablets, boluses and drenches containing from about 570% by weight of active ingredient are used to supply the desired dosage of anthelmintic.
In order to treat infected animals by means of a drench, the 2-(2'-naphthyl)-benzimidazoles may be mixed with a suspending agent such as bentonite and the solid mixture added to water just prior to administration. Alternatively, ready-to-use drench formulations, such as those disclosed in US. Patent No. 2,918,403, may be utilized. The preferred drenches in accordance with this invention contain from about 5-50% by Weight of anthelmintic.
In addition, the benzimidazoles described herein may be administered as a component of the feed of the animals or dissolved or suspended in the drinking water. According to the invention, novel feed compositions are provided in which compounds of Formula I above are present as an active anthelmintic ingredient. Such compositions comprise the benzimidazoles intimately dispersed in or admixed with an inert carrier or diluent. By an inert carrier is meant one that is nonreactive with respect to the 2-(2'-naphthyl)-benzirnidazole and that may be administered with safety to the animals. The carrier or diluent is preferably one that is or may be an ingredient of the animal ration.
These compositions include feed supplements in which the active ingredient is present in relatively large amounts and which are suitable for addition to the feed either directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable for such compositions are solid orally ingestible carriers-such as distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and the like. The anthelmintic agents are intimately dispersed or admixed throughout the solid inertcarrier by methods such as grinding, stirring, milling or tumbling. By select ing proper diluents and by altering the ratio of carrier to active ingredient, compositions of any desired concentrationrmay be prepared. Formulations containing from about 5% to about 50% by weight, and preferably from about 1030% by weight, of active ingredient are particularly suitable for addition to feeds. The active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorhed on the carrier.
Examples of typical feed supplements containing a 2-(2-naphthyl)-benzimidazole dispersed in a solid carrie are:
, Lbs. 2-(2'-naphthyl)-benzimidazole 20.0 Corn 'distillers dried grains 80.0
2-(2-naphthyl)-benzirnidazole hydrochloride 5.0 Wheat standard middling 95.0
l-acetyl-2- 2'-naphthyl -benzimidazole 25 .0 SOybeanmill feed 75.0
1-methyl-2 (2-naphthyl)-benzimidazole 30.0 Wheat shorts 70.0
2- (2'-naphthyl) -5 (6 -methylbenzimidazole 25 .0 Corn distillers dried grains 75.0
These and similar feed supplements are prepared by uniformly mixing the active ingredient with the carrier or carriers.
These supplements are added to the finished animal feed in an amount adequate to give the final concentration desired for controlling or treating helminthiasis by Way of the animal ration. Although the preferred level in feeds will depend on the particular compound being employed and the species of animals to be treated, the 2-(2- naphthyl)-benzimidazoles of this invention are normally fed at levels of 0.5-2.0% in the feed. One advantageous method of administering the compounds of this invention 'to animals'whose feeds are conveniently pelleted, such as sheep, is toincorporate them directly in the pellets. For instance, 2-(2-naphthyl)-benzimidazole is readily incorporated in nutritionally adequate alfalfa pellets (during the pelleting operation) at levels of 1-5 grams per pound of pellets for therapeutic use, and at lower levels for prophylactic use, and such pellets fed to the worm-infested animals. Alternatively, it may be incorporated in salt licks or salt blocks atany desired concentration (concentrations of 525% by weight are conveniently employed) whereby large. animals such as sheep, cattle and swine would be enabled to receive the anthelmintics with their salt.
Alternatively, the compounds of Formula 1 above may be administered to domesticated animals such as sheep and cattle by admixing them with the protein-vitamin supplements employed as top dressings in the feed of such animals. When this route of administration is to be used, good results are obtained by adding from 515 grams of anthelrnintic to a pound of protein supplement.
The following examples are given for the purpose of illustration and not by way of limitation:
Example 1 off, washed with water and with 100 ml. of 1:1 ethanolwater. The green salt is then suspended with stirring in 400 ml. of 1:1 ethanol-water and a stream of hydrogen sulfide passed into the suspension to saturation. After about 45 minutes the precipitated copper sulfide is filtered and washed with boiling ethanol to remove any occluded 2-(2'-naphthyl)-benzimidazole. The filtrate and washings are combined and concentrated to dryness in vacuo. 13.5 g. of crude 2-(2'-naphthyl)-benzimidazole are obtained. The solid is dissolved in the minimal amount of warm ethanol-water and the solution treated with a small amount of decolorizing charcoal. The charcoal is filtered off and the 2-(2'-naphthyl),-benzimidazole crystallized by chilling the solution. 9 g. are obtained,,M.P. 2102l6 C. On recrystallization from ethyl acetate, the product melts at 215-216 C.
Example 2 17.2. g. of ethyl Z-naphthoate and 11.5 g. of o-phenylenediamine are mixed and added slowly to 270 g. of polyphosphoric acid. The mixture is heated slowly with stirring to 245 C. and maintained at this temperature for 2 /2 hours. The hot solution is then poured onto about 200 g. of ice and the mixture stirred. It is filtered and the filtrate neutralized slowly with 30% sodium hydroxide until the 2-(2'-naphthyl)-benzimidazole precipitates. It is filtered, Washed with water, and dried in air. This product is extracted with hot ethanol, benzene is added to the extract and the solution boiled to remove traces of water. On'concentration of the solution to a small volume and cooling, substantially pure 2.-(2-naphthyl)-benzimidazole crystallizes.
3 g. of this material is added slowly with stirring to S 150 ml. of ethanolic hydrogen chloride. The solution is treated hot with 2 g. of activated charcoal, the charcoal removed by filtration and the solution cooled. Three volumes of ethyl ether are added and the mixture chilled, whereupon, 2-(2-naphthyl) -benzimidazole hydrochloride crystallizes. It is recovered by filtration, washed with ether and air dried.
Example 3 A. 9 g. of 2-naphthaldehyde in 12 ml. of ethanol is added with stirring to a suspension of 11 g. of o-phenylenediamine in 40 ml. of nitrobenzene. The mixture is stirred at room temperature for 15 minutes and then beated slowly to 210 C. During the heating period, the ethanol is removed by distillation. As soon as the temperature of the reaction mixture reaches 210 C., it is cooled with stirring to about 10 C. -2-(2'-naphthyl)- benzirnidazole crystallizes, is recovered by filtration and washed with ether. If desired, the product may be purified by recrystallization from ethanol.
B. 1.8 g. of 2-(2-naphthyl)-benzimidazole in a-mixture of 40 ml. of benzene and 17 ml. of dimethylformamide is treated at 60 C. with 0.4 g. of sodium hydride. The sodium hydride isadded as a 50% emulsion in oil mixed with 2 ml. of benzene. The addition is carried outslowly and the mixture heated withstirring at 60 C. for 45 minutes after completion of the sodium hydride addition. At the end of this time, 1.5 g. of benzoyl chloride is added slowly at a temperature of 50 C. and the mixture heated for 35 minutes at that temperature with stirring. It is then cooled to about 10 C., 2.0 ml. of water added and the entire mixture washed with 5% sodium bicarbonate solution. The organic solvent solution is filtered to remove any solid material and the benzene solution concentrated to dryness in vacuo. The residue is crystallized from ethyl ether to give l-benzoyl-2-(2-naphthyl)- benzimidazole.
When an equivalent molar amount of acetyl chloride is employed instead of benzoyl chloride in the above procedure, there is obtained 1 -acetyl-2 (2' naphthyl)- benzimidazole.
Example 4 A. 7 g. of 2-naphthoyl acid chloride and 7 g. of o-nitroaniline are stirred together in 20 m1. of pyridine at room temperature for about 10 hours. The mixture is then poured into ice water and the solid nitroanilide recovered by filtration. It is washed with dilute aqueous sodium carbonate solution, and added to 70 ml. of glacial acetic acid. 40 ml. of 6 N-hydrochloric acid is added slowly to the acetic acid mixture followed by-30 g. of zinc dust. The zinc is added slowly in small portions. After the zinc addition is completed, and the reaction is essentially finished (by visual observation), the mixture is filtered and the filtrate neutralized with concentrated ammonium hydroxide. 2 (2' naphthyl)- benzimidazole precipitates on. neutralization. It is isolated by filtration, washed with ice water, and purified by recrystallization from ethyl acetate.
B. To 2.4 g. of 2-(2'-naphthyl) -benzimidazole in 20 ml. of dry dimethylformamide is added 0.5 g. of a 52% sodium hydride emulsion-in mineral oil. The mixture is stirred at room temperature for about 20 minutes and then heated to 50 C. for 5 minutes. It is cooled to room temperature and 1.5 g. of methyl iodide in 2 ml. of dimethylformamide added slowly to the cooled solution containing the sodium salt of 2-(2' -naphthyl)-benzimidazole. Thereaction mixture is heated to about C., for 20 minutes, cooled to room temperature, and 20 ml. of water added thereto. The mixture is extracted with three 10-ml. portions of ethyl ether, the ether extracts combined, washed with water, dried over sodium sulfate, filtered and the ether removed in vacuo. The residual solid is 1methyl-2-(2'-naphthyl)-benzimidazole, which is purified by crystallization fromethyl acetate.
When the above process is carried out employing allyl 9 bromide in place of methyl bromide, 1-allyl-2-(2' naphthy1)-benzimidazole is produced.
Example To a solution of 13.8 g. of 4-methoxy-1,2-diaminobenzene in 150 ml. of ethanol is added 15.6 g. of 2-naphthaldehyde. The reaction mixture is stirred at room temperature for 2 hours, during which time the Schiff base forms from the aldehyde and primary amine.
20 g. of cupric acetate monohydrate in 190 ml. of water is added'in small portions to the solution of Schiif base. The resulting mixture is refluxed gently with stirring until precipitation of the copper salt of 2-(2-naphthyl) 5(6) methoxy benzimidazole is complete. The mixture is then cooled, filtered and the solid washed with water. The solid copper salt is suspended in about 240 ml. of ethanol and the mixture saturated with hydrogen sulfide. The precipitated copper sulfide is removed by filtration and the filtrate concentrated to dryness in vacuo. The resulting residual solid is substantially pure 2-(2' naphthyl)-5(6)-methoxy benzimidazole.
The hydrochloride salt is obtained by dissolving the product in hot alcoholic hydrogen chloride, treating the hot solution with activated charcoal, removing the charcoal by filtration, and adding about 3 volumes of ether to the alcoholic solution. The acid salt crystallizes on cooling.
Example 6 13.0 g. of 4-methyl-1,2-diaminobenzene and 19 g. of
methyl 2-naphthoate are added to 325 g. of polyphosphoric acid which has been preheated to about 80 C. in a nitrogen atmosphere. The mixture is stirred for 50 minutes at 125 C., and the temperature then raised to 220 C. for 90 minutes. The solution is cooled to about 100 C. and poured slowly with stirring into 400 ml. of ice water. An amorphous solid is filtered otf and the filtrate neutralized to a pH of about 7 with 30% sodium hydroxide solution. The crystalline solid which precipitates is filtered, Washed with water and dried. This solid is extracted with 3 x 100-ml. portions of acetone. The combined acetone extracts are treated with decolorizing charcoal. The charcoal -is filtered olf and the filtrate concentrated to dryness to give substantially pure 5-methyl-2-(2-napl1thyl)-benzimidazole.
Example 7 A bolus of 2-(2'-naphthyl)-benzimidazole and having is prepared in the following manner:
The dicalcium phosphate is thoroughly mixed with the 2-(2'-naphthyl)-benzimidazole and the mixture reduced to a particle size finer than 60 mesh. To the mixture is added 0.330 gm. of starch in the form of an aqueous starch paste and the resulting mixture is granulated :in the usual manner. The granules are then passed through a #10 mesh screen and dried at 110130 F. for about 8 hours. The dried material is then passed through a #16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.
A bolus providing 4.0 gm. of l-benzoyl-2-(2-naphthyl)-benzimidazole is prepared as above using twice the amount of ingredients.
Mg stearate (through 60 mesh screen) 0.028
is prepared in the following manner:
The dicalcium phosphate is thoroughly mixed with the l-methyl-Z-(2-naphthyl)-benzimidazole and the mixture reduced to a particle size finer than 60 mesh. To the mixture is added 0.430 gm. of starch in the form of an aqueous starch paste and the resulting mixture is granulated in the usual manner. The granules are then passed through a #10 mesh screen and dried at 110130 F. for about 8 hours. The dried material is then passed through a #16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. The remainder of the ingredients are then added and the whole thoroughly mixed and compressed.
Example 9 Drenches having the following composition are prepared by standard formulating methods:
sion prior to use. The following vehicles are suitable:
(1) Benzalkonium chloride (12.8% soln.) ml 40 Antifoam AF emulsion gm 4 Hydroxyethyl cellulose gm 20 Distilled Water, to 2000 ml.
(2) Benzalkonium chloride (12.8%soln.) ml 0.5 Antifoam AF emulsion gm 4 Hydroxyethyl cellulose gm 20 Distilled water, to 2000 ml.
The compounds of Formula I above are added to the velhicles in concentrations in the range of 6-25 gm./
The benzallconium chloride used in the drench vehicles isda mixture of C -C dimethylbenzylammonium chlorr es.
Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.
What is claimed is:
1. A compound of the formula wherein R is selected from the class consisting of lower alkanoyl and benzoyl, and R and R are selected from the class consisting of hydrogen, lower alkyl and lower alkoxy groups, at least one of R and R being hydrogen.
2. l-acetyl-Z- 2'-naphthyl -benzimidazole. 3. 1-benzoyl-2- (2'-naphthyl -benzimidazole.
(References on following page) References {lifted by the Examines t OTHER REFERENCES UNITED STATES PATENTS V Abramovitch: Chem. Abstracts, Vol.51, page 13840 2,027,967 1/36 Elmslie et a1. 167-53 (1957)- 7 2,033,495 3/36 Taylor et a1. 5 (gigs t m- Abstracts, P 5903 2,663,712 12/53 Tulagin 260309.2 2, 7 9/54 Schenck et a1 2603092 (15250;? et 2.1.. Che m. Abstracts, Vol. 50, page 2841 ,7 5/57 Spinks 260-4564 Rao 1 c Abstracts 51 v page 1149 (1957). 2,861,072 7 11/58 wfgston et a1 26O 268 Rgo et a1.: Chem. Abstracts, v01. 52, page 1146 (1958). 2,965,648 12/60 W1egan 260-309.2 10 T Loev et 1 Primary Examiner.
2,976,291 3/61 Jacob et a1. DUVAL T. MCCUTCHEN, Examiner.

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Cited By (1)

* Cited by examiner, † Cited by third party
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US4109093A (en) * 1975-01-14 1978-08-22 Produits Chimiques Ugine Kuhlmann Process for making 2-(4'-aminophenyl) 5-amino benzimidazole

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US2861072A (en) * 1952-07-19 1958-11-18 Abbott Lab Preparation of piperazine derivatives
US2965648A (en) * 1960-12-20 Certain i-alkenyl benzimidazoles
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US2976291A (en) * 1961-03-21 Ethers of z
US2033495A (en) * 1933-09-07 1936-03-10 Tobacco By Products And Chemic Anthelmintic
US2027967A (en) * 1934-12-15 1936-01-14 Moorman Mfg Company Anthelmintic
US2663712A (en) * 1949-11-22 1953-12-22 Gen Aniline & Film Corp Hydroxy-benzimidazoles and method for their preparation
US2861072A (en) * 1952-07-19 1958-11-18 Abbott Lab Preparation of piperazine derivatives
US2794018A (en) * 1953-08-07 1957-05-28 New quinazoline derivatives
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