IL29336A - 5-substituted-amino benzimidazoles - Google Patents

Description

{ 29336/2 tnpaa -Substituted-amiiio benzimidazoles HEBGfc & CO., INC, C. 27764 29336/2 2 The present invention pertains to benzimidazoles having a heteroaryl radical at the 2-position and a substituted amino radical at the 5-position. The 5-substituent is of the carbamate, thionocarbamate, carbonylamino or thiocarbonylaraino type. The invention also relates to processes for making such compounds as well as to anthelmintic compositions containing them as the essential active ingredients.

Benzimidazoles having a heteroaryl radical in the 2-position have been described in the prior art as anthelmintic agents . For example, French Patent Specification No. 4,234 M discloses such compounds which, in addition to Hie 2-substituents , may also bear halogen or amino, (lower alkyl)amino or di(lower alkyl)amino groups in t e 5 and/or 6 positions of the benzimidazole nucleus Although these known materials are active anthelmintic agents, the search has continued for substances which are more potent and which are effective against helminths that are non-responsive or weakly responsive to the prior art compounds. 29336/2 In accordance with the present invention, there are provided a group of highly active and broad spectrum anthelmint having the following structural formula: In the above formula , X is oxygen or sulphur, R^ represents a five-membered monocyclic heteroaromatic 'ring containing from 1 to 3 oxygen, sulfur or nitrogen hetero atoms selected from the group consisting of furyl, thienyl, pyrazolyl, imidazolyl, pyrryl, thiazolyl, thiadiazol l, isothiazolyl and oxa- xolyl; Rg is hydrogen, hydroxy, loweralkoxy, loweralkyl, aralkyl, carboxylic acyl, carboxyalkoxy, carbamoyl, alkyl- carbamoyl or alkoxycarbonyl; .^ is hydrogen or a straight or branched loweralkyl of 1 to 8 carbon atoms; and R. is 29336/2 hydrogen or optionally halo-substituted loweralkyl, lower-alkoxy or lower alkylthio; an alkenyl, alkynyl, alkenyloxy, alkenylthio, alkynyloxy or alkynylthio group of 1 to 8 carbon atoms, cycloalkyl, adamantyl; aryl, aryloxy or arylthio optionally substituted by halogen, amino, alkyl or alkoxy; aralkyl optionally substituted by halogen; pyridyl, thienyl, furyl, thiazolyl and the corresponding heteroaryloxy and heteroarylthio radicals; a straight or branched chain mono- or dilower alk lamino radical having 1 to 8 carbon atoms .in the alkyl moiety, or a cycloalkylamino radical; · " · . . . ' ..; and nonr-toxic acid addition salts and metal complexes thereof when R2 is hydrogen.

Also included within the scope of this invention are the non-toxic acid addition salts and the heavy metal complexes of the above-defined benzimidazoles which form or are obtainable when represents hydrogen.

Preferred substituents are the nitrogen and sulfur containing heterocycles with '-thiazolyl and 2*-thiazolyl being particularly desirable.

Examples of R^ substituents are methyl, ethyl, propyl, isopropyl, amyl, hexyl, n-octyl and the like.

The symbol R^ preferably represents a loweralkoxy, loweralkylthio, aryloxy, arylthio, heteroaryloxy, or a hetero- where the heteroaryl is as defined above, arylthio radical/, where the 5-substituent on the benz- imidazole. is of the carbamate or thionocarbamate type depending upon the nature of the X substituent, and is hydrogen, 1 i an optionally halogen-substituted loweralkyl, cyeloalkyl, aryl, aralkyl, heteroaryl (as defined abov )5 Εΐοηοΐουβι»-alleylamino„ diiowerallcylamino or cycloalkylamino, in which event the substituent at the 5-position of the bensimidazole is of the carbonylariino or thiocsrbonylamino type depending upon the nature of the 7 substituent.

It has been found according to this invention that the substituted amino substituent at the 5-position of the benzimidazole nucleus imparts, in many cases „ a surprisingly high degree of anthelmintic activity as compered with the corresponding 5~unsubstituted amino, and the corresponding sono-and di(loweralkyl)amino compounds, which was not predictable or anticipated from the teachings of the prior art. 2ms, e.g. as eoapared to the data given in Exaa le 94 herein, the corresponding M-unsubstituted 2~(4'-thiazolyl)~5(6 )-aminobenssiniidazole compound, while active at the 200 ng/kg. level, showed only variable activity at 50 mg/kgj, whereas all the compounds, according to this invention, tested in Example 94, were fully active at 50 rag/kg or below that level.

The compounds of formula I above according to this invention are used to treat helminthiasis in the form of orally admini3trable drenches, boluses9 capsules, or in anm feeds, ihey may also be administered to the infected host via intramuscular, intraruainal or intratracheal injection. In addition to their high degree of anthelmintic activity, the novel bens-imidazoles of this invention also possess significant antifungal activity. 29336/3 6 - The substitucnt present at the 5-position of 6 the. benzimidazole is important and represents the focal 7 point of the present invention. Specific examples of ■8 suitable substituents include those wherein R^ is a '9 straight or branched chain, saturated or unsaturated, loweralkoxy or halo loweralkoxy radical having from 1 · 11 to 8 carbon atoms such as methoxy, ethoxy, isopropoxy, 12 allyloxy, propenyloxy, 2 , 2 , 2-trifluoroethoxy , amyloxy, 13 n-octyloxy and the like; those wherein R^ is a straight 14 or branched chain, saturated or unsaturated", loweralkyl- 15 thio or halo lowe'ralkylthio radical having from 1 to 8 16 carbon atoms such as methyl thio, ethylthio, 2-chloro- 17 ethylthio, isopropylthio , all thio, n-hexylthio and 18 the like; those wherein is aryloxy such as phenoxy, 19 halophenoxy, aminophenoxy , tolyloxy, naphthyloxy and the like; those wherein R^ is arylthio such as phenylthio, 21 halophenylthio, arainophen lthio, tolylthio, naphthylthio 22 and the like; those wherein R, is heteroaryloxy such 23 as. furyloxy, thiazolylox , thienyloxy, pyrazinyloxy and 24 the like; and those wherein R^ is heteroarylthio such as furylthio, thiazolyl 'nio, thienylthio, pyrazinylthio 26 and the like. As noted above, substituents of the 27 foregoing type will afford carbamates or thionocarbamate . 28 at the 5-position.

Further specific illustrations of suitable sub- stituents at the 5-position include those wherein R^ is a straight or branched chain, saturated or unsaturated, loweralkyl or haloloweralkyl radical having from 1 to 8 carbon atoms such as methyl, dichloromethyl , ethyl, isopropyl, allyl, t-butyl, amyl, octyl and the like; those wherein R^ is cycloalkyl such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl and the like; those wherein R^ is aryl such as phenyl, halophenyl, amino-phenyl, tolyl, naphthyl and the like; those wherein R^ is aralkyl such as benzyl, halobenzyl, phenethyl and the like; heteroaryl such as furyl, thiazolyl, thienyl, pyridyl, and the like; those wherein R^ is a straight or branched chain mono- or diloweralkylamino radical having from 1 to 8 carbon atoms in the alkyl moiety such as methylamino, diethylamino, isopropylamino, methylethyl-amino, n-hexylamino and the like; and those wherein ^ is cycloalkylamino such as piper zino, piperidino, morpholino, pyrrolidino and the like. These substituents , as noted above, will afford carbonylamino or thiocarbonyl-amino groups at the 5-position.

In the preferred embodiments of the invention, R2 represents hydrogen. However, the 1-position of the benzimidazole may be acylated as with a loweralkanoyl or loweralkanoyloxy radical, or it may be substituted with a loweralkyl radical such as methyl, ethyl or propyl, or with an aralkyl group such as benzyl. In addition, the N-l-nitrogen may be substituted with a hydroxy group or with a loweralkoxy group such as methoxy, cLhoxy or n-propoxy. Also, the N-l-nitrogen may be substituted with a carboxyloworalkoxy group such as carboxymethoxy , carboxyethoxy or carboxypropaxy with a carbamoyl group such as N-methylcarbamoyl , N-ethyl-carbamoyl or N-butylcarbamoyl ; or with an alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl or iso-propoxycarbonyl.

In those cases where is hydrogen, there may be formed acid addition salts with acids such as hydro-chloric, sulfuric, nitric, phosphoric and hypophosphorous acid; with organic acids such as acetic, tertiarybuty1-acetic, dialkylphosphoric , citric, benzoic, lactic and oxalic acid. Certain of these salts are more soluble than the parent base and for this reason are preferred when a soluble form of product is desired for anthelmintic or antifungal use. This invention also contemplates the heavy metal complexes of the disclosed benzimidazoles which ara obtained by reacting the benzimidazole (where is hydrogen) with a salt of a heavy metal such as copper, lead, iron and mercury.

While all of the compounds embraced within the scope of the instant invention display potent anthelmintic activity, the preferred compounds are of the carbamate and carbonylamino type (i.e. those compounds wherein X is oxygen) . Most preferred are the compounds wherein X is oxygen, is thiazolyl, 2 an(* R3 are hydrogen and Rj is methoxy, ethoxy, iso-propoxy, benzoyl and p-fluorobenzoyl . These preferred compounds have been found to be especially potent The novel bcnzimidazoles of this invention wherein the substitucnt at the 5-position is of the carbamate type are readily prepared by reacting a ¾mino-2-R^-benzimidazole with an R-haloformate or halothio- ^ formate where R is the hydrocarbon moiety derived from ^ as defined above. When an R-haloformate is employed as a reactant, the resultant substituent at the 5-position of the benzimidazole will have the characteristic structure, R-0-CO-NH-. For convenience, such substituents may be referred to generically as hydrocarbonoxy-carbonylamino radicals. When an R-halothioformate is employed as a reactant, the resultant substituent at the 5-position will have the charaqteristic structure, R-S-CO-NH-. For con-venience, these substituents may be referred to generically as hydrocarbonthiol-carbonylamino radicals.

The above reaction is preferably carried out using the appropriate chloroformate or chlorothioformate . It is conveniently conducted at temperatures of from about 20-50°C. in an organic solvent and in the presence of an acid binding agent. It has been found very convenient to conduct the reaction in a solvent such as pyridine which also serves as acid binding agent, although other basic solvents such as the picolines and lutidines could be vised equally well. Neutral solvents, however, can be employed in which ca?e the product is isolated as the acid addition salt. The resulting carbamate is wat r insoluble and is conveniently precipitated by diluting the reaction mixture with a relatively large volume of water. The solid is then recovered by standard methods and purified by rccrystallization from solvents such as methanol, ethanol, acetonitrile or mixtures thereof. When a loweralkanol is used as the recrystal- lization solvent, there is a tendency on the part of some of our compounds, especially those wherein the radical R^ is of lower molecular weight, to crystallize as an alcohol solvate. When this occurs, the free compound may be obtained by drying the solvate under vacuum at temperatures of from about 60-90 °C.

Representative of the compounds within the scope of our invention and prepared by the above-described procedure are 5-methoxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole, 5-ethoxycarbonylamino-2- (2 ' -thiazolyl) benzimidazole , 5-methylthiolcarbonylamino-2- (2 ' -furyl) benzimidazole , 5-ethylthiolcarbonylamino-2- (3 '-thienyl) benzimidazole, 5-p-fluorophenoxycarbonyl-amino-2- (4 '-thiazolyl) benzimidazole, .'5-benzyloxycarbonyl-amino-2- (4 ' -thiazolyl) benzimidazole , 5-cyclopropyloxy-carbonylamino-2- (4 ' -thiazolyl) benzimidazole , 5-thiazolyl-oxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole, 5-phenyl-thiocarbonylamino-2- (2 ' -oxazolyl) benzimidazole , and 5-phenoxycarbonylamino-2- ( 4 ' -pyrryl) benzimidazole .

It has carbonylamxno emb ed directly from the ments by treating the latter in the presence of a weakly basic catalyst such as dibutyltinoxide and aluminum isopropoxide with the alcohol corresponding to the desired /j function. Through this ester exchange technique, for example, 5-cyclopropoxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole may be prepared by treating the corresponding 5-ethylthiolcarbonylamino compound with cyclopropanol in the presence of dibutyltinoxide; -phonoxyccirbonylamino-2- (4 ' -thiazolyl) bunzimidazole may be prepared by treating the corresponding 5-methyl- thiolcarbonylamino compound with phenol in the presence of aluminum isopropoxide ; and 5-benzylcarbonylamino-2- (41 -thiazolyl) benzimidazole may be prepared by treating the corresponding 5-pher.ylthiolcarbonylamino compound with benzyl alcohol in the presence of dibutyltinoxide. While any of the 5-hydrocarbonthio-carbonylamino em-bodiments of this invention may be employed as starting material for the ester exchange, it is preferred to employ a loweralkylthiol-carbonylamino compound such as 5-meth l-l- (or ethyl) thiolcarbonylamino-2- (4 * -thiazolyl) benzimidazole.

The reaction is carried out by refluxing the 5-hydrocarbonthiol-carbonylamino benzimidazole in the selected alcohol in the presence of a catalytic quantity of the weak base. Reaction is usually complete in about 10 to about 24 hours after which the 5-hydrocarbonoxy-carbonylamino benzimidazole is recovered by evaporation of the solvent. The residue is purified by conventional recrystallization techniques.

The compounds of this invention having a carbonylamino radical at the 5-position are also obtained froma 5-amino-2-R, -benzimidazole by reacting the I benzimidazole with the appropriate acyl halide or an acid anhydride. It has been found convenient to employ an acyl chloride as the reactant arid carry out the process in an organic solvent such as pyridine, a picoline or a lutidine, which will then also serve as an acid binding agent. The resulting 5-carbonylamino benzimidazoles are only slightly soluble in water and are conveniently recovered by the same method described above for re-covering the carbamates. Representative examples of novel benzimidazoles obtained in this fashion are 5-acetylamino-2- (4 ' -thiazolyl) benzimidazole , 5~ {p-fluoro-benzoyl) amino-2- (2 ' -thiazolyl) benzimidazole, 5-formyl-amino-2- (3 '-thienyl) benzimidazole, 5-phenylacetylamino-2- (2 ' -oxazolyl) benzimidazole, 5-benzoylamino-2-- (4 ' -thiazolyl) benzimidazole and 5-propionoylamino-2- (41 -thiazolyl) benzimidazole.

The novel benzimidazoles of this invention wherein the substituent at the 5-position is of the thionocarbamate type may be prepared by a variety of methods from starting materials either well known or readily obtainable by the techniques hereinafter de-scribed. The thionocarbamate substituent at the 5-position will have the characteristic structure R-O-CS-NH-or R-S-CS-NH- where R is the hydrocarbon moiety derived from R^ as defined above. For convenience, thiono-carbamates of the structure R-O-CS-NH- may be referred yl -to generically as hydrocarbewioxy-thiocarbonylamino compounds and thionocarbamates having the structure R-S-CS-NH- may be referred to generically as hydro- 1196 The 5-hydrocarbo»oxy-thiocarbonylamino benzimida- zoles of this invention are readily prepared by treating a 5-amino-2-R^-benzimidazo.le with the appropriate alkoxy, aryloxy, or heteroaryloxy thiocarbonyl halide, preferably the thiocarbonyl chloride. The reaction conveniently is carried out by adding the thiocarbonyl halide at room temperature to a stirred suspension of the amino benzimidazole in a suitable organic solvent such as pyridine. Reaction is usually complete in from 1 to 3 hours after which the product may be precipitated from the reaction mixture by the addition of water. The product is recovered by filtration and purified by conventional recrystallization techniques.

Applicants have found that the 5-hydrocarb^¾oxy-thiocarbonylamino benzimidazoles of this invention, (and particularly a 5-phenoxythiocarbonylamino benzimidazole) when dissolved in pyridine and heated at about 100 °C. for 1 to 4 hours, are converted into the corresponding -isothiocyanato benzimidazole which compound is a valuable intermediate in the preparation of many of the novel benzimidazoles of this invention. It has been found, for example., that the 5-hydroca¾<$noxy-thiocarbonylamino benzimidazoles themselves are readily prepared by reacting a 5-isothiocyanato benzimidazole with an alcohol. Thus, 5-methoxythiocarbonylamino-2- (41 -thiazolyl) benzimidazole may be prepared by treating 5-isothiocyanato-2- (4 ' -thiazolyl) benzimidazole with methanol. Other 5-hydrocarbe*iyloxy-thiocarbonyl- 119-60 J benzimidazoles of this invention may be prepared by reacting a 5-isothiocyanato benzimidazole with a mercaptan.

The reaction is carried out by reacting the 5-isothio-cyanato benzimidazole in a suitable organic solvent at room temperature with the mercaptan. Reaction is usually complete in from about 10 to about 24 hours after which the product is precipitated from the reaction mixture by the addition of water. The product is recovered by filtration, purified by conventional recrystallization o -a? techniques. Thus, for example, 5-methylthio.Jthiocarbonyl" amino-2- (4 '-thiazolyl) benzimidazole is prepared by treating 5-isocyanato-2- (41 -thiazolyDbenzimidazole yl with methyl mercaptan. To prepare the other 5-hydrocarbeφirv o thiol thiocarbonylamino benzimidazoles of this invention, it is merely necessary to select the appropriate mercaptan.

The 5-thiocarbonylamino benzimidazoles of this invention are readily prepared from the corresponding -carbonylamino ben¾imida.zoles by treating the 5-carbonylamino benzimidazole at reflux in a suitable organic solvent such as pyridine with phosphorous pentasulfide . Upon completion of the reaction, which usually requires about 20 to about 40 minutes, the reaction mixture is poured onto ice and the product i which separates is recovered by filtration and purified by conventional techniques.

The 5-carbonylamino benzimidazoles of this invention wherein is a monoloweralkylamino radical 1196 may be prepared by treating a 5-amino-2-R^ benzimidazole at room temperature in a suitable organic solvent such as pyridine with a lower alkyl isocyanate. Reaction is usually complete in about 2 to 4 hours after which the product is precipitated from the reaction mixture by the addition of water and is recovered by filtration.

Purification is achieved by conventional recrystallizatiori techniques.

-DiloweralkyIamino-carbonylamino benzimidazoles can be prepared by reacting a 5-amino-2-R^ benzimidazole at room temperature in an organic solvent such as pyridine with a diloweralkylcarbamoyl halide, preferably the carbamoyl chloride. The reaction is usually complete in about 1 to 3 hours after which the product is re-covered and purified by the techniques previously described.

Alternatively, 5-diloweralkylamino-carbonyl-amino benzimidazoles can be prepared from a corresponding -alkyithiolcarbonylamino benzimidazole by refluxing a mixture of the 5-alkylthiolcarbonylamino benzimidazole and a dilpweralkylamine , After refluxing for about 1 to 2 hours, the reaction mixture is evaporated and water is added to precipitate the product which is recovered and purified by conventional techniques. This reaction also may be used to prepare 5-cycloalkylamino-carbonylamino benzimidazoles in which case a cyclo-alkylamine is used instead of the diloweralkyl amine.

The 5-thiocarbohylamino benzimidazoles of this invention wherein is a monoloweralkylamino radical may be prepared by reacting a 5-amino-2~R^ benzimidazole at room temperature in an organic solvent such as pyridine with ,a loweralkyl isothiocyanate. The reaction usually requires about 1 to 3 hours for completion. The product is precipitated from the reaction mixture by adding water and is recovered by filtration and purified by conventional recrystallization techniques.

-Diloweralkylamino-thiocarbonylamino and cycloalkylamino-thiocarbonyl amino benzimidazoles may be prepared by reacting a 5-isothiocyanato benzimidazole with a diloweralkylamine or a cycloalkylamine. The reaction may be carried out in the presence of water or an alcoholic solvent.. Although the reaction will proceed at room temperature, it may also be carried out at reflux temperatures. The reaction is usually complete in about 1 to 6 hours after which the solid product, if not already separated from the reaction mixture, may be precipitated by the addition of water. The crude product is recovered and purified by conventional techniques.

The 1-substituted benzimidazoles of this invention where R~ is hydroxy, loweralkoxy, carboxyalkoxy , the parent benzimidazoles by techniqeus well known in the art (see, for example, U.S. Patents 3,017,415; 3,080,282; 3,183,239; 3,265,706 and Belgian Patent 674,202). Alternatively, however, the 1-substituent ma be added 2- , -b z i techniques and the resulting l-substituted-2-R^ benzimidazole may then be converted into the corresponding l-substituted-5-amino-2-R^ benzimidazole by techniques hereinafter described. The 1-substi tubed-5-amino-2-P.^ benzimidazoles, of course, may be employed as inter- mediates in the various preparations described above in the same way as were the 5-amino-2-R^ benzimidazoles . 1-Carbamoyl benzimidazoles of this invention are also prepared from the parent benzimidazole by treating the parent benzimidazole with an isocyanate in a suitable organic solvent such as acetonitrile .

Thus, l-n-butylcarbamoyl-5-isopropylcarbonylamino-2- (4 ' -thiazolyl) benzimidazole is prepared by treating -isopropoxycarbonylamino-2- ( 1 -thiazolyl) benzimidazole with n-butylisocyanate . The reaction is carried out at reflux temperature and is usually complete in about 2 to 6 hours. The product is recovered by extracting the reaction mixture with chloroform and is isolated chromatography of the chloroform extract through silica gel. the parent benzimidazole with an alkyl haloformate, preferably a chloroformate . This reaction is carried out in substantially the same manner as heretofore described for preparation of the 5-carbamate species (see; pages 9 and 10 above) . Because of the tautomeric nature of the benzimidazole nucleus, there will be formed also some 1 , 6-disubstituted benzimidazole in the foregoing preparations. - n^^cor-daic^--w^fcfr~ay=^¾a^ b 1 at the 5-position an alkyl or aryl sulfonylamino sub- as =A-S 2 stituent, .ojcamploe of such -compounds hpirftg- those wherein 3 the 5-substituent is methylsulfonylamino, ethylsulfonyl- 4 amino, phenylsulfonylamino, and tolylsulfonylamino. Thoca nnv l i-rrmp nnflp- are obtained by reaction of the appropriate 6 2-Rj5-amino benzimidazole with an alkyl or aryl sulfonyl 7 halide, and preferably an alkyl or aryl sulfonyl chloride.

T 8 -J¾—ΆΑΑΪ t-ΐ niLtn hgying anthclmintio aotivity per ser~ hese 9 compounds serve as valuable intermediates in the preparation of the benzimidazoles of this invention wherein the 11 substituent is a lower alkyl radical. 12 It has been found that 5-alkyl or aryl sulfonylr- 13 amino benzimidazoles are readily converted into the 14 corresponding 5-N-alkyl alkyl or aryl sulfonylamino benzimidazole /treating the 5-alkyl or aryl sulfonylamino Ί 16 benzimidazole with an alkyl halide in an organic solvent 17 such as methanol. The reaction is carried out in the 18 presence of an alkali metal alkoxide such as sodium 19 methoxide which serves as an acid binding agent. The 5-N-alkyl alkyl or aryl sulfonylamino benzimidazoles 21 so produced then may be converted into the corresponding 22 5-alkylamino benzimidazoles by refluxing in a concentrated 23 mineral acid such as concentrated hydrochloric acid. i ,24 These 5-alkylamino benzimidazoles, then are employed as intermediates in the various preparations described 26 above in the same way as were the 5-amino benzimidazoles. 27 As stated previously, the compounds of Formula £8 I hereinabove have significant activity as anthelmintics. 2 The is s s helminthiasis is due to infestation of the animal body with parasitic worms known as helminths. Helminthiasis is a prevalent and serious economical problem in domesticated animals such as swine, sheep, cattle, goats, dogs and poultry. Among the helminths, the group of worms described as nematodes causes widespread and oftentimes serious infection in various species of animals. The most common genera of nematodes infecting the animals referred to above are Haemonchus , Trichostrongylus , Ostertagia, Nematodirus , Cooperia, Bunos.tomum, Oesophagostomum, Chabertia, Trichuris (whipworm) , Ascaris , Capillaria, Heterakis and A cylostoma. Certain of these, such its Trichostrongylus , Nematodirus and Cooperia, attack primarily the intestinal tract while others, such as Haemonchus and Ostertagia, are mofle prevalent in the stomach. The parasitic infections known as helminthiasis lead to anemia, malnutrition, weakness, weight loss, .-evere damage to the walls of the intestinal tract and, if left untreated, often result in death of the infected animals. The benzimidazoles of our invention have unexpectedly high activity against these helminths. When used as anthelmintic agents they may be administered orally in a unit dosage form such as a capsule, bolus, tablet or as a liquid drench. The drench is normally an aqueous suspension or dispersion of the active ingredient together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally, the drenches also contain an antifoaming agent. The ca sules and boluses comprise the active ingredient admixed with a carrier vehicle such as starch, talc, magnesium stearate, or dicalcium phosphate. When the anthelmintic is to be administered via the animal feed-stuff, it is intimately dispersed in the feed or else used as a top dressing or in the form of pellets which are then added to the finished feed. Alternatively, the anthelmintics of our invention may be administered to animals by intraruminal ( intramuscular and intratracheal injection, in which event the benzimidazole is dissolved or dispersed in a liquid carrier vehicle.

Although the anthelmintic agents of this invention find their primary use in the treatment and/or prevention of helminthiasis in domesticated animals, such as sheep, cattle, horses, dogs, swine and goats, they are also effective in treatment of helminthiasis that occurs in other living animals. The optimum amount to be employed for best results will, of course, depend upon the particular benzimidazole employed, the species of animal tc be treated and the type and; severity of helminth infection. Generally, good results are obtained with our novel compounds by the oral administration of from about 5 to 125 mg. per kg. of animal body weight, such total dose being given at one time or in divided doses over a relatively short period of time such as 1-2 days. With the preferred compounds of the invention, excellent control of helminthiasis is obtained in domesticated animals by administering from about 10 to 70 mg. per kg. of body weight in a single dose. , 11960 Certain of the 2-R^~5-amino benzimidazoles employed as starting materials in the processes of our invention have been reported in the literature. These, as well as those which have not been specifically described, may be prepared from the 2-R^-benzimidazole unsubstituted at the 5-position (wherein R^ is as previously defined) by reaction of such 5-unsubstituted compound with nitric acid in the presence of sulfuric acid which gives essentially selective nitration at the -position and thus affords the corresponding 2-R^-5-nitrobenzimidazole. This latter substance is then conveniently reduced to the 5-amino pompound by catalytic hydrogenation in the presence of palladium-on-charcoal catalyst. Details of these procedures, as well as' alternative procedures, are set forth below.

Preparation of 5-Nitro Benzimidazoles A.) 5-Nitro-2- (41 -thiazolyl) Benzimidazole ; G. of 2- (4 '-thiazolyl) benzimidazole is dissolved with cooling in 20 ml. of concentrated sulfuric acid. To this solution is added dropwise with cooling and stirring a mixture of 4 ml. of concentrated nitric acid and 6 ml. o^ concentrated sulfuric acid, maintaining the temperature between 20° and 30 °C. The reaction mixture is allowed to stir for a further five minutes at room temperature then poured Onto ice and made just basic with ammonium hydroxide. The solid -nitro-2- (41 -thiazolyl) benzimidazole is filtered off and washed with water. It is recrystallized from 1196 . By employing equivalent molar quantities of benzimidazoles such as, for example, 2- [3'- (1' ,2 ' ,5 '-thiadiazolyl) ] benzimidazole , 2- [4 ' - (1 ' ,2 ' , 3 * -thiadiazolyl) ] ■ benzimidazole, 2- [2 ' - (11 , 31 , 4 '-thiadiazolyl) ] enzimidazole , 2- (1 ' -pyrazolyl) enzimidazole, 2- (2 * -methyl- ' -thiazolyl) -benzimidazole, 2- (2 ' -oxazolyl) benzimidazole , 2-(2'-thiazolyl) benzimidazole, or 2- (2 ' -imidazolyl) benzimidazole in the above procedure in place of the 2- (4 ' -thiazolyl) -benzimidazole, there is obtained the corresponding -nitro derivative.

The foregoing nitration procedure is highly satisfactory for those compounds iri which the heteroaryl substituent at the 2-position is not readily nitrated.

In cases where the 2-substituent may be nitrated along with the 5-position of the benzimidazole ring, an alternate synthesis of the 2-R^-5-amino benzimidazoles is utilized which comprisies the reaction of o-amino-p-nitroaniline with a heteroaryl aldehyde in the presence of nitrobenzene or cupric diacetate. This method is illustrated below.

B.) 5-Nitro-2- (2 ' -furyl) Benzimidazole 2.2 G. of 2-furfuryl aldehyde in 3 ml. of ethanol is added to a suspension of 3 g. of o-amino-p-nitroaniline in 10 ml. of nitrobenzene. The resulting mixture is stirred for L0 minutes at room temperature and then heated slowly jto 210°C. for one minute. The methanol is allowed to distil during this heating.

The mixture is then cooled to about 5°C. to crystallize h 5-nit o-2- 21 -fur l benzimidazole which is recovered 11960 C. ) 5-Nitro-2- (2 ' -pyrryl) Benzimidazole 43.2 G. of pyrrole-2-aldehyde in methanol is added to a suspension of 54.0 g. of o-amino-p-nitroaniline and 160 g. of cupric diacetate in methanol (total of 1 liter) and this mixture is then heated at reflux temperature for 2 hours. The mixture is cooled to room temperature and the copper complex of the product is removed b filtration and suspended in ethanol and then treated with gaseous hydrogen sulfide to give 5-nitro-2- (2' -pyrryl) benzimidazole, m.p. 259-260°C.

By employing an equivalent molar quantity of thiophene-2-aldehyde in the above reaction in place of the pyrrole-2-aldehyde, there is obtained 5-nitro-2- (2 ' -thienyl) benzimidazole .

Preparation of 5-Amino Benzimidazole -Amino-2- (4 ' -thiazolyl) Benzimidazole : A suspension of 141 g. of 5-nitro-2- (41 -thiazolyl) benzimidazole in 4 liters of dry ethanol is reduced with 22 g. of 5% palladium on carbon catalyst and hydrogen at 24 °C. and 45 psi. The theoretical amount of hydrogen is absorbed in approximately 5-1/2 hours. The catalyst is then filtered off and the*, solvent evaporated to near dryness. The solid is recovered by filtration and washed with ether to afford 5-amino-2- (4 ' -thiazolyl) benzimidazole as a yellow solid. It is dissolved in absolute ethanol and crystallized by addition of hexane to give sub-stantially pure material, m.p. 232-233°C.

By employing equivalent molar quantities of the 5-nitro-2-R^ benzimidazoles prepared as described in the foregoing section in the above procedure instead of the 5-nitro-2- (41 -thiazolyl)benzimidazole, corresponding 5-amino-2-R^-benzimidazoles are obtained.

The foregoing methods for making 2-R^-5-amino benzimidazoles are not a part of the present invention/ although the selective nitration of a 2-Rj-benzimidazole to a 2-Rj-5-nitrobenzimidazole and reduction of the latter compound to 2-R 5-aminobenzimidazole is a separate invention and will be claimed elsewhere.

Most of the haloforma.te , halothioformates and acylhalides used as the second reactant in the process of our invention are known; those not specifically reported in the literature are prepared by known methods .

The following examples are given for the purpose of illustration and not be way of limitation. 1196 EXAMPLE 1 -Methoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole To a suspension of 2.16 g. of 5-amino-2- (41 -thiazolyl) benzimidazole in 7.5 ml. of pyridine there is added dropwise with stirring 1 g. (.815 ml.) of methyl chloroformate. The mixture is allowed to stir for a further two hours at room temperature and then several volumes of ice and water are added to precipitate the product. The solid thus obtained is collected by filtration and washed with water to give 5-methoxy-carbonylamino-2- (4 '-thiazolyl) benzimidazole, m.p. 225-226 °C. It is dissolved in methanol, the solution treated with decolorizing charcoal and then evaporated to near dryness. 5-Methoxycarbonylamino-2- (41 -thiazolyl) -benzimidazole crystallizes and is recovered by filtration and dried in vacuo for two hours at 65 °C. to afford pure material, m.p. 237-239°C.

EXAMPLE 2 -Methoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 3.86 G. of methyl chloroformate in 100 ml. of acetone are added at room temperature to a stirred solution of 10.2 g. of 5-amino-2- (4 ' -thiazolyl) -benzimidazole in 300 ml. of acetone, and the resulting mixture stirred for one hour at room temperature. At the end of this time the solid product is collected by filtration, washed with acetone and dissolved in water.

The aqueous solution is made basic with sodium bicarbonate and the resulting precipitate filtered off and washed decolorizing charcoal, filtered and the methanol filtrate evaporated to a small volume. 5-Kethoxycarbonylamino-2- (41 -thiazolyl) benzimidazole crystallizes and is recovered by filtration, m.p. 220-222°C. The product is recrystal-lized from methanol and then dried for two hours in vacuo at 65 °C. to give substantially pure 5-methoxycarbonyl-amino-2- ( ' -thiazolyl)benzimidazole, m.p. 234-235°C.

EXAMPLE 3 -Ethoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 2.27 G. of ethyl chloroformate are added drop-wise over a 10 minute period to a stirred solution of 4.32 g. of 5-amino-2- (4 ' -thiazolyl) benzimidazole in ml. of pyridine. The resulting mixture is stirred for two hours at room temperature, then poured onto ice and diluted with water to a volume of about 300 ml. The resulting solid product is removed by filtration and washed with water. It is crystallized from a mixture of methanol-ether-petroleum ether, with a decolorizing charcoal treatment of the solution, to give the methanol solvate of 5-ethoxycarbonylamino-2- (4 ' -thiazolyl) -benzimidazole, m.p. 94-105°C.

When the above reaction is repeated and the solid product that is recovered from the aqueous solution is recrystallized from acetonitrile-ether, there is obtained substantially pure 5-ethoxycarbonyl-amino-2- (4 ' -thiazolyl) benzimidazole , m.p. 203-205 °C. 11960 EXAMPLE 4 -Propoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 2.60 G. of n-propyl chloroformate are added at room temperature to a stirred solution of 4.32 g. of -amino-2- (4 ' -thiazolyl) benzimidazole in 15 ml. of pyridine. The resulting mixture is stirred at room temperature for 2 hours then poured onto ice and the mixture diluted with water to a volume of about 300 ml.

A dark oil separates and is recovered by decanting the mother liquors. The oil is washed with water and then dissolved in methanol. The methanolic solution is filtered, evaporated to near dryness iri vacuo and the residue dried by adding benzene and removing the benzene by distillation. The residue is then crystallized from methanol-ether-petroleum ether, the crystals separated and air dried to give 5-propoxycarbonylamino-2- (4 ' -thiazolyl) -benzimidazole, m.p. 214-215°C.

EXAMPLE 5 -n-Butoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 4.32 G. of 5-amino-2- (4 ' -thiazolyl) benzimidazole are added to 15 ml. of pyridine, and to the resulting mixture there is added with stirring over a 10 minute period 2.9 g. of n-butyl chloroformate . The mixture is stirred for two hours at room temperature, then poured onto ice and diluted to 300 ml. with water. The resulting solid product is collected by filtration, washed with ice water and recrystallized from methanol to give substan-tially pure 5-n-butoxycarbonylamino-2- (4 ' -thiazolyl) -benzi -2 2° EXAMPLE 6 -Amyloxycarbonylamino-2- (41 -Thiazolyl) Benzimidazole When the procedure of Example 5 is repeated employing 3.2 g. of n-amyl chloroformate instead of butyl chloroformate, there is obtained 5-amylo ycarbonylamino-2- ( 4' -thiazolyl) benzimidazole, m.p. 178-179°C.

EXAMPLE 7 -n-Hexyloxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole The procedure of Example 5 is repeated using 3.5 g. of n-hexyl chloroformate instead of butyl chloro-formate. The 5-n-hexyloxycarbonylamino-2- (4 ' -thiazolyl) -benzimidazole thus obtained melts at 150-152 °C.

EXAMPLE 8 -n-Octyloxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole When the procedure of Example 5 is carried out replacing the butyl chloroformate of that example with 4.05 g. of n-octyl chloroformate, there is obtained -n-octyloxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole , m.p. 66-67°C.

EXAMPLE 9 -Phenoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 3.5 G. of phenyl chloroformate are added dropwise over 10 minutes to a mixture of 4.32 g. of 5-amino-2- (4 ' -thiazolyl) benzimidazole in 18 ml. of dry pyridine. There is an exothermic reaction and the temperature rises to about 60 °C. The mixture is cooled to about room temperature and stirred for about two hours then diluted with water to a volume of 500 ml. The container is scratched to ind ce crystallization and the resulting crystals collected, washed with cold water and dried to give 5-phenoxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole; This material is dissolved in a minimum volume of methanol, the solution treated with decolorizing charcoal and concentrated to a small volume. About 1/10 volume of ether is added and the resulting solid product collected by filtration and dried in vacuo to afford 5-phenoxycarbonylamino-2- (4 ' -thiazolyl) -benzimidazole, m.p. 115-1^.6°C.

EXAMPLE 10 -p-Fluorophenoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole Employing the process of Example 9 using 4.63 g.: of p-fluorophenylchloroformate instead of the phenyl chlo oformate, there is obtained 5-p-fluorophenoxycarbonyl-amino-2-( 4' -thiazolyl) benzimidazole, m.p. 275-280°C.

EXAMPLE 11 -o-Fluorophenoxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 4.63 G. of o-fluorophenyl chloroformate were 4.32 G of added dropwise to a mixture of 5-amino-2- (41 -thiazolyl) -benzimidazole in 35 ml. of dimethyl formamide. After 2 1/2 hours, 500 ml. of ether is added and the powder which separates is collected and treated with aqueous ammonia yielding 5-o-fluorophenoxycarbonylarnino-2- (4 ' -thiazolyl) benzimidazole, m.p. 135-140 °C. ' 1 EXAMPLE 12 -Isobuty^bxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole 2.9 G. of isobutyl chloroformate is added drop-wise to a mixture of 4.32 g. of 5-amino-2- (4 * -thiazolyl) -benzimidazole in 20 ml. of dry pyridine, the addition being carried out at room temperature. The mixture is stirred at room temperature for 90 minutes and then about 200 ml. of ice water are: added. The resulting solid is collected by filtration and washed with water. It is dissolved in a minimum volume of methanol, and the methanol i solution treated with decolorizing charcoal. The charcoal is filtered off and the clear solution evaporated to a small volume and a small amount of water added to induce crystallization. 5-Isobutyoxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole crystallizes and is separated and dried, m.p. 231-232 ''C.

EXAMPLE 13 -Isopropyloxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole The procedure of Example 12 is repeated employing 2.6 g. of isopropyl chloroformate . There is obtained 2- isopropyloxycarbonylamino-2- (4 ' -thiazolyl) benzimidazole , m.p. 212-214°C.

EXAMPLE 14 -Allyloxycarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole The procedure of Example 12 is repeated using 3.12 g. of allylchloroformate in place of isobutyl chloroformate to afford 5-allyloxycarbonylamino-2- ( '-thiazolyl) benzimidazole, m.p. 210-212°C.

EXAMPLE 15 - (2-Propynyl) -oxycarbonylamino-2- ( ' -Thiazolyl) Benzimidazole When the procedure of Example 12 is repeated using 2.61 g. of 2-propynyl chloroformate in place of isobutyl chloroformate there is obtained 5- (2-propynyl) -oxycarbonylamino-2- ( 4' -thiazolyl) benzimidazole/ m.p. 200-202°C.

EXAMPLE 16 -Ethylthio^carbonylamino-2- (4 ' -Thiazolyl) Benzimidazole .3 G. of ethyl chlorothioformate is added dropwise to a stirred suspension of 40 g. of 5-amino-2-( ' -thiazolyl) benzimidazole in 150 ml. of pyridine.

The mixture is stirred for 4 hours and a mixture of ice and water is added to precipitate 5-ethylthio__carbonyl-amino-2- ( '-thiazolyl) benzimidazole, m.p. 215°C. 1196 EXAMPLE 17 -Cyclopropoxycarbonylamino-2- ( '-Thiazolyl) Benzimidazole A mixture of 1.1 g. of 5-ethylthiolcarbonylaiuino-2- (4 ' -thiazolyl) benzimidazole and 0.15 g. of dibutyltin-oxide in 1.5 g. of cyclopropanol is refluxed for 20 hours.

The solvent is evaporated and the residue is crystallized from a mixture of ethyl acetate and hexane to give 5-cyclopropoxycarbonylamino-2- ( 4 * -thiazolyl) benzimidazole , m.p. 190-195°C. (hydrate), 207-208°C. (anhydrous).

EXAMPLE 18 -Acetylamino-2- ( ' -Thiazolyl) Benzimidazole To a suspension of 6.48 g. of 5-amino-2- (4 ' -thiazolyl) benzimidazole in 23 ml. of pyridine there is added dcopwise at room temperature over a 5-7 minute period 2.4 ml. of acetyl chloride. The resulting mixture is stirred for two hours at room temperature, and ice water then added to a volume qf about 200 ml.

The solid product is recovered by filtration, washed with water and dried iri vacuo for 18 hours to give crude -acetylamino-2- (4 '-thiazolyl) benzimidazole/ m.p. 240-250 °C. This product was dissolved in methanol, the solution treated with decolorizing charcoal, filtered and then concentrated to the point of crystallization.

It is chilled and the crystals collected, washed with methanol and dried in vacuo to afford substantially pure product, m.p. 260°C. 1196 EXAMPLE 19 -Phcnylacetylamino-2- (4 ' -Thiazolyl) Benz.i mida To a mixture of 4.32 g. of 5-amino-2- (4 ' -thiazolyl) benzimidazole in 18 ml. of dry pyridine there is added slowly over a 10 minute period at room temperature 3 ml. of phenylacetyl chloride. The mixture is stirred at room temperature for two hours and then the product recovered as in Example 18 to afford 5-phenylacetyl-amino-2- ( 4' -thiazolyl) benzimidazole, m.p. 210-211°C.

EXAMPLE 20 -For ylamino-2- (4 ' -Thiazolyl) Benzimidazole 4 G. of 5-amino-2~ (4 ' -thiazolyDbenzimidazole is mixed with 300 ml. of 99% formic acid, and the resulting mixture stirred at room temperature for 20 hours. At the end of this time about 300 ml. of ice water are added and the mixture brought to pH 8 with concentrated aqueous ammonium hydroxide. The resulting solid precipitate is separated by filtration and dried to give crude 5-formylamino-2- (4 ' -thiazolyDbenzimidazole, m.p. 242-244°C. This material is purified by dissolving it in methanol, treating with decolorizing charcoal and filtering, and concentrating until crystallization begins.

The resulting pure material melts at 247-248°C. , 1196 EXAMPLE 21 -Propionylamino-2- ( ' -Thiazolyl) Benzimidazole To a mixture of 4.32 g. of 5-araino-2- (4 ' - thiazolyl) benzimidazole and 20 ml. of pyridine there is added dropwise 1.95 g. of propionyl chloride. The reaction mixture is stirred for one hour at room temperature and water is then added to the point of cloudiness. The mixture' is chilled and the solid product recovered. The solid crystallizes by dissolving in methanol and then evaporating the methanol solution to a small volume. 5-Propionylamino-2- (4 ' -thiazolyl) -benzimidazole crystallizes and is recovered by filtration, m.p. 255-256°C.

E?1AMPLE 22 -Benzoylamino-2- (4 ' -Thiazolyl) Benzimidazole When the procedure of Example 21 is repeated using 2.81 g. of benzoyl chloride in place of propionyl chloride, there is obtained 5-benzoylamino-2- (4 ' -thiazolyl) -benzimidazole, m.p. 118-120°C.

EXAMPLE 23 -Nicotinylamino-2- (4 ' -Thiazolyl) Benzimidazole 4.56 G. of nicotinic anhydride is added slowly to 4.32 g. of 5-amino-2- ( ' -thiazolyl) benzimidazole in 20 ml. of pyridine. The resulting mixture is stirred until the solids are dissolved and then allowed to stand at room temperature for 20 hours. An equal volume of water is then added and the resulting solid product collected by filtration and washed with water. It melts at 282-284°C. This material is dissolved in dimethyl formamide " 1196 and water added to induce crystallization. The resulting crystals are collected, washed with methanol and ether and dried to afford substantially pure 5-nicotinylamino-2- (4 '-thiazolyl)benzimidazole, m.p. 284-285°C.

EXAMPLE 24 -o-Fluorobenzoylamino-2- (4-1Thiazolyl) Benzimidazole When the procedure of Example 23 is repeated using 5.24 g. of o-fluorobenzoic anhydride in place of nicotinic anhydride, the resulting crude product crystallized from aqueous methanol, there is obtained substantially pure 5-o-fluorobenzoylamino-2- (4 '-thiazolyl) -benzimidazole, m.p. 132-133°C.

. EXAMPLE 25 - (1-Adamantanyl) Carbonylamino-2- (4 ' -Thiazolyl) Benzimidazole When the procedure of Example 22 is carried out riusing 2.97 g. of adamantatee-l-carbonyl chloride in place of benzoyl chloride, 5- (1-adamantanyl) carbonylamino-2-(4 '-thiazolyl) benzimidazole is produced, m.p. 246-247°C.

EXAMPLE 26 - (2-Nciphthoylamino) -2- (4 ' -Thiazolyl) Benzimidazole The procedure of Example 22 is repeated using 4 g. of 2-naphthoyl chloride in place of benzoyl, there is obtained in this manner 5- (2-naphthoylamir.o) -2-(41 -thiazolyl) benzimidazole , m.p. 154-156 °C.

EXAMPLE 27 -Cyclopropylcarbonylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 2.3 g. of cyclopropylcarbonyl chloride there is obtained 5-cyclopropylcarbonylaiuino-2- (4 ' -thiazolyl) benzimidazole, m.p. 245°C.

EXAMPLE 28 -Isobutrylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 2.34 g. of iso chloride for the propionyl chloride, there is obtained 5-isobutrylamino-2- (4' -thiazolyl) benzimidazole, m.p. 203-205°C.

„ EXAMPLE 29 - (3-Thieny^o¾rbonylaminoj '-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.21 g. of thiophene-3-carbonyl chloride for the propionyl chloride, there is obtained 5- (3- (41 -thiazolyl) benzimidazole , m.p. 276-278°C.

EXAMPLE 30 -m-Fluorobenzoylamino-2- (4 '-Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.4 g. of n-fluorobenzoyl 'chloride for the propionyl chloride, there is obtained 5-m-fluoro-benzoyiamino-2- (4 ' -thia olyl) benzimidazole , m.p. 232-233°C. 1196 EXAMPLE 31 -p_-Fluorobenzoylamino-2- ( ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.4 g. of p-fluorobenzoyl chloride for the propionyl chloride, there is obtained 5-p_-fluoro-benzoylamino-2- (41 -thiazolyl) benzimidazole , m.p. 151-152°C.

EXAMPLE 32 -o-Methoxybenzoylamino-2- (41 -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.6 g. of o-methoxybenzoyl chloride for the propionyl chloride, there is obtained 5-o-methoxy-benzoylamino-2- (4' -thiazolyl) benzimidazole, m.p. 113-114°C.

EXAMPLE 33 -m-Methoxybenzoylamino-2- (41 -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.75 g. of m-methoxybenzoyl chloride for the propionyl chloride, there is obtained 5-m-methoxy-benzoylaraino-2- (41 -thiazolyl) benzimidazole , m.p. 105-109°C EXAMPLE 34 -o-Phenoxybenzoylamino 2- (41 -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 4.87 g. of o-phenoxybenzoyl chloride for the propionyl chloride, there is obtained 5-o-phenoxy-benzoylamino-2- (4 '-thiazolyl) benzimidazole, m.p. 95-100°C.

EXAMPLE 35 -o_-Chlorobenzoylamino-2- (41 -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.68 g. of o-chlorobenzoyl chloride for the propionyl chloride, there is obtained 5-o-chloro-benzoylamino-2- (4 ' -thiazolyl) benzimidazole , m.p. 146-147°C.

EXAMPLE 36 -m.-Iodobenzoylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 7.2 g. of m-iodobenzoyl chloride for the propionyl chloride, there is obtained 5-m-iodobenzoyl-amino-2- (4' -thiazolyl) benzimidazole, m.p. 127-129°C.

EXAMPLE 37 -jQ-Trifluoromethylbenzoylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 4.22 g. of m-trifluoromethylbenzoyl chloride for the propionyl chloride, there is obtained 5-m-tri-fluoromethylbenzoylamino-.!- (4 * -thiazolyl) benzimidazole , m.p. 201-203°O. | EXAMPLE 38 -ja-Nitrobenzoylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 3.9 g. of m-:,iitrobenzoyl chloride for the propionyl chloride, there is obtained 5-m-nitrobenzoyl-amino-2- (4 ' -thiazolyl) benzimidazole , m.p. 163-164°C.

EXAMPLE 39 - (2 , 5-Difluorobenzoylamino) -2- ( 4_- hiazolyl) Benzimidazole Following the procedure of Example 21 and sub-stituting 3.9 g. of 2 , 5-difluorobenzoyl chloride, for the propionyl chloride, there is obtained 5- (2 , 5-difluoro-benzoy^amino/'-2- (4 '-thiazolyl) benzimidazole, m.p. 113-114°C.

EXAMPLE 40 -Picolinylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and substituting 4.2 g. of picolinyl chloride hydrochloride for the propionyl chloride, there is obtained 5-picolinyl-amino-2- ( 1 -thiazolyl) benzimidazole , m.p. 240-241°C.

EXAMPLE 41 -Isonico/-tinylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 21 and t + substituting 5 g. of isonico^inyl chloride hydrochloride for the propionyl chloride, there is obtained 5-iso- t + nicOJinylamino-2- (41 -thiazolyl) benzimidazole , m.p. 150-153°C.

EXAMPLE 42 -Pivaloylamino-2- (4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 23 and substituting 4.10 g. of pivalic anhydride for the nicotinic anhydride, there is obtained 5-pivaloylamino-2- ( '-thiazolyl) benzimidazole, m.p. 241-242°C.

Following the procedure of Example 23 and substituting 4.4 g. of 2-furoic anhydride for the \ nicotinic anhydride, there is obtained 5- (2-furoy)laraino/ -2-(4'-thiazolyl)benzimidazole, m.p. 139-140°C.

EXAMPLE 44 -(4'-'Thiazolyl)Carbonylamino-2-(4l-Thiazolyl)Benzimidazole The procedure of Example 21 is repeated using 3.1 g. of thiazole-4-carboxylic acid chloride in place of propionyl chloride to afford 5- (4' -thiazolyl)-carbonylamino-2- 8 (4,-thiazolyl)benzimidazolei m.p. 3 7-388°C.

EXAMPLE 45 - (2-Thienyl)-Carbonylamino-2- (41 -Thiazolyl)Benzimidazole When the procedure of Example 21 is repeated using g. of t.henoic acid anhydride in place of propionyl chloride there is obtained 5- (2-thienyl)carbonylamino-2- (4' -thiazolyl)-benzimidazole, m.p. 288°C. (d).

EXAMPLE 46 -Methoxyacetylamino-2-(4l -Thiazolyl)Benzimidazole Following the procedure of Example 21 and sub-stituting 2.3 g. of methoxya.eetyl chloride for the propionyl chloride, there is obtained 5-methoxyacetylamino-2- (4' -thiazolyl) benzimidazole, m.p. 238-239°C.

EXAMPLE 47 -Dich1.oroaceLylamino-2-(4l -Thiazolyl)Benzimidazole Following the procedure of Example 21 and sub-stituting 3.68 g. of dichloroacetyl chloride for the propionyl chloride, there is obtained 5-dichloroacetylamino-2-(4'-thiazolyl)benzimidazole, m.p. 220°C.

EXAMPLE 48 Following the procedure of Example 21 and substituting 3.55 g. of 3, 3-dimethylacryloyl chloride for the propionyl chloride, there is obtained 5- (3, 3-dimethyl- acryloyl)aminoy-2-(4l-thiazolyl)benziniidazole, m.p. 270-272°C.

EXAMPLE 49 - (2, 2, 2-Trif luoroethoxy)-Carbonylamino-2-(4'-Thiazolyl)- Benzimidazole A mixture of 5 g. of 5-ethylthiolcarbonylamino-2- (4'-thiazolyl)benzimidazole and 0.5 g. of dibutyltinoxide in 50 ml. of 2.,2, 2-trif luoroethmol is refluxed for 20 hours.

The solvent is evaporated and the residue is crystallized from a mixture of ethyl acetate and hexane to give the title compound, m.p. 231-232°C.

EXAMPLE 50 -(2-Propyxfyloxy)-Carbonylamino-2-(4'-Thiazolyl)Benzimidazole When the procedure of Example 49 is repeated employing 4 g. of the 5-ethylthiolcarbonylamino-2- (4' -thiazolyl)- . benzimidazole, 0.4 g. of the dibutyltinoxide and substituting 25 ml. of 2-propyn-l-ol for the 2, 2, 2- trif luoroethanol, there is · EXAMPLE 51 -Phenoxythiocarbonylar.ino-2 - ( 1 -Thiazoly1) -Ben,zimidazo e^ 3.62 G. of pheno;ythiocarbonyl chloride is added dropwise to a stirred suspension of 4.32 g. of 5-amino-2- ( ' -thiazolyl) -benzimidazole in 25 ml. of pyridine. After stirring for 1.5 hours, water is added, and the solid which separates is collected and crystallized from methanol to give the title compound, ra.p. 155-157°C.

EXAMPLE 52 -© p0-5-Isothiocyanatgr-2" (4 '-Thiazolyl) -Eenzimidazole 7.2 G. of 5-phenoxythiocarbonylairino-2- (4 ' -thiazolyl) -benzimidazole is dissolved in 50 ml. of pyridine and heated for one hour at 100°C. Addition of water to the solution EXAMPLE 53 -Methoxythiocarbony1amino-2 -_(4 ' -Thiazoly1) -Eenzimidazole A solution of 2.5 g. of 5-isothiocyanat^r-2~ (4 * -thiazolyl) -benzimidazole and 25 mg. of sodium methoxide in 300 ml. of methanol is refluxed for 20 hours. Evaporation of the solvent followed by recrystallization of the residue from methanol gives 5-methoxythiocarbonylamino-2- (4 '-thiazolyl) -benzimidazole, m,p. 224°C.

EXAMPLE 54 -Ethoxythiocarbonylamino-2- (4 ' -Thiazol 1) -Benzimidazole When the procedure of Example 53 is repeated using ethanol in place of methanol, the title compound is obtained, m.p. 218°C.

EXAMPLE 55 -Methy11hio^hioca b3_ny_lam A slow stream of methyl raercaptan is passed into a solution of 4 g. of 5-isothiocyanato-2- ( ' -thiazolyl) -benzimidazole in 25 ml. of dimethylformamide for 15 minutes. The solution is allowed to stand at room temperature for twenty hours and then water is added to precipitate 5-methylthic^thiocarbonylainino-2- (41 -thiazolyl) -benzimidazole, m.p. 202-205°C.

EXAMPLE__5_6 -T iobenzoy1amino-2- ( 4 ' ~Thiazoly1) -Benzimidazole A mixture of 1 g. of 5-benzoylamino-2- (41 -thiazolyl) -benzimidazole, 2 g. of phosphorus pentasulfide and 20 xil. of pyridine is refluxed for 25 minutes. The solution, is poured onto ice and the product which separates is purified by column chromatography through silica using chloroform as the elu nt. Crystallization from methanol gives the title compound, m.p. 140--143°C. ; E ^A LL - ( 3-Methylureido) - 2- (41 -Thiazolyl) -Benzimidazole 1.2 G. of methyl isocyanate is added dropwise with stirring to a suspension of 5-amino-2- (4 '-thiazolyl) -benzimidazole in 25 ml. of pyridine. After stirring for 2.5 hours, water is added ½nd the solid which separates is filtered off and crystallized from methanol to give 5- (3-methylureido) -2- ( '-thiazolyl) -benzimidazole, m.p. 160°C.

EXAMPLE 58 - (3, 3-Dimethylureido) -2- ( ' -Thiazolyl) -Benzimidazole dropwisc with stirring to a suspension of 4.32 g. of 5-amino-2- (4 * -thiazolyl) -benziiuidazole in 25 nil. of pyridine. Afbcr stirrincj for 1.5 hours, water is added, and the solid which separates is collected and crystallised froi.i methanol to give the title compound* m.p. 260-262°C.

EXAMPLE 59 - ( 3 , 3-Diethylureido) -2-·» (4.' -Thiazolyl) -Benzimidazole A mixture of 5 g. of 5~ethylthiolcarbonylamino-2- (4 '-thiazolyl) -benzimidazole and 25 ml. of diethylamine is refluxed for one hour. Evaporation to an oil followed by addition of water precipitates a solid which is crystallized from chloroform to give 5·- (3 , 3-diethylureido) -2- (4 ' -thiazoly^) -benzimidazole, m.p. 234-235°C.

EXAMPLE 60 - (1-Pyrrolidinyl) -Carbonylamino-2- (4 ' -Thiazolyl) -Benzimidazole When the procedure of Example 59 is repeated using 25 ml. of pyrrolidine in place of diethylamine, the title compound is obtained, m.p. 296-298°C.

EXAMPLE 61 - (1-Piperidiny1) -Carbon lamino-2- ( 41 -Thiazolyl) -Benzimidazole When the procedure of Exaiaple 59 is repeated using 25 ml. of piperidine in place of diethylamine, the title compound is obtained.

EXAMPLE 62 - (3-Methylthioureido) -2- (4 '-Thiazolyl) -Benzimidazole 1.6 G. of methyl isothiocyanate is added dropwise with stirring to a suspension of 4.32 g. of 5-amino-2-(4 ' -thiazol l) -benzimidazole in 25 ml. of ridine. After stirring for two hours, water is added to precipitate a solid which is collected and crystallized from a mixture of dimethylforr.iamide and water to give 5-- ( 3 -meth lthio-ureido) -2- (4 '-thiazolyl) -benzi idazole, m.p. 235-237°C.

EXAMPLE 63 - (3-Phen lthioureido) -2- (41 -Thiazoly1) -_Benzimidazole When the procedure of Example 62 is repeated using 2.9 g. of phenyl sothiocyanate in place of methyl isothiocyanate, the title compound is obtained, m.p. 244-246°C.

^ -^JIAI - (3 , 3~Diitteth lthioureido) -2~ (4 ' -Thiazoly1) -Be ziiojldazo1e A mixture of 3 g. of 5-isothiocyanato-2- (4 ' -thiazolyl) -benzimidazole and 100 ml. of 40% aqueous di-methylamine is stirred at room temperature for five hours.

The solid portion is collected and recrystallized from methanol to give the title compound, m.p. 156-159 °C.

EX¾MPLE 65 - (3,3-Diethylthioureido) -2- (4 '-Thiazolyl) -Benzimidazole A solution of 4 g, of 5-isothiocyanato-2- (4 '-thiazolyl) -benzimidazole and 30 ml. of diethylamine in 50 ml. of ethanol is refluxed for one hour. Evaporation and addition of water gives a solid which is recrystallized from a mixture of methanol, ether and petroleum benzin to give - (3 , 3-dicthylthioureido) -2- { '-thiazolyl) -benzimidazole , m.p. 130-135°C.

EXAMPLE 66 - (3-Cyclopentylene-2-thioureido) -2- ( '-Thiazolyl) -Benzimidazole ml. of piporidino in place of the diethyl ir.iine (re-crystallization of crude from a mixture of dimethylformamide and water)., the title product is obtained, m.p. 225-226°C.

EXAMPLE 67 - (3-Cyclobuty1ene-2-thioure.ido) -2- (4 ' -Thiazolyl) -Benzimidazole VJhen the procedure of Example 65 is repeated using 25 ml. of pyrrolidine in place of the dieth l mine , the title compound is obtained m.p. 257-258°C. ν ΨΑ^Α -Isopropoxycarbon lamino-1- ethy1-2- (_4_'j-Thiazolyl) -Denzimidazole To 8.5 g. of 5-Isopropoxycarbonylaraino-2-- (4 thiazolyl) -benzimidazole in 100 ml. of dry direthylformamide is added 2.3 g. of a 52% sodium hydroxide emilsion in mineral oil. The mixture is stirred at room temperature for about twenty minutes and then warmed carefully to about 50°C. for ten minutes. It is cooled to room temperature and 7.1 g. of methyl iodide in 10 ml. of dimethylformamide is added slowly to the cooled solution. The reaction mixture is then heated to about 80°C. for 20 minutes, cooled, diluted with 200 ml. of water and extracted with three 100 ml. portions of ether.

The ether extracts are combined, washed with water, dried over sodium sulfate, filtered, and the ether removed in vacuo to give the title compound which is purified by recrystallization from ethyl acetate.

By substituting equivalent quantities of propyl chloride, phenylethyl chloride, benzyl bromide, or isopropyl chloride for the methyl iodide in the above reaction, there are obtained, respectively, the corresponding 1-propyl, 1- hcnelhyl, 1-bcnzyl and l-iso ro yl benzimidazole.

EXAMPLE 69 5jj_o_r^30xyca bonylamino-l-Mothoxy-2- ( ' -Thiazolyl ) ■ Benzimidazole A. 5-Nitro--1-Methoxy-2 · ( ' -thiazolyl) -Benzimidazole A mixture of 1.30 ml. of concentrated nitric acid (sp.g. 1.41) in 2.80 ml. of concentrated sulfuric acid (sp*g. 1.84) is added dropwise to a cold solution of 3.80 g. of 1-methoxy-2- (41 -thiazolyl) -benzimidazole in 12.3 ml. of concentrated sulfuric acid. The reaction temperature is maintained at 12° ί 2° during addition by external cooling. The reaction mixture is stirred at room temperature for 30 minutes, then poured onto an ice water mixture. The pH of the suspension is adjusted to pH 8. The yellow solids are collected by filtration and washed with water and cold methanol. Recrystal-lization from methanol yields 1.5 g. of purified product, m.p. 220-221°C.

B . 5-Amino~l-Methoxy-2- ( 4 ' -Thiazolyl) -Benzimidazole ·Ιΐρΐ A suspension of 0.5 g. of l-methoxy-2- (4-thiazolyl) ~ 5-nitrobenzimidazole in 400 ml. of absolute ethanol is reduced using 1 g. of 10% palladium on carbon at room tempera-ture in a hydrogen atmosphere at 40 lbs. p.s.i. When uptake of hydrogen is complete, the; catalyst is removed by filtra-tion and the filtrate is treated with 2.0 ml. of a 2.5N methanolic hydrogen chloride solution. The solvent is removed in vacuo to yield 450 mg. of amorphus product which is carried into the next step.

C. 5-Isopropoxycarbonylamino"l-Methoxy-2- ( '-Thiazolyl) - Benzimidazole A solution of the above hydrochloride salt in 15 ml. of pyridine is treated dropvise with 0.24 ml. of isopropyl chloroformate at room temperature. After stirring for 16 hours, the reaction mixture is diluted with 150 ml. of water and extracted with chloroform. The chloroform extracts are washed with water, dried over magnesium sulfate, filtered, and evaporated in vacuo . The oily residue is dissolved in chloroform and passed over a column of silica gel. Elution with a 5% methanol-95% chloroform mixture yields purified product. Recrystallization from ether-hexane mixture yields pure product, m.p. 123-125°C.

EXAMPLE 70 -Isopropoxycarbonylamino-l-Carboxymethoxy--2-- (4 ' -Thiazolyl) -Benzimidazole ' When the procedure of Example 69 is repeated using l-carboxymethoxy-2- (4 '-thiazolyl) -benziraidazole in step A in place of l-methoxy-2- (4 '-thiazolyl) -benzimidazole, there is obtained the title compound. , EXAMPLE 71 -1sopropox carbony amino-1-Hydroxy-2- ( ' -Thi zolyl) -Benzimidazole When the process of Example 69 is repeated using l-hydroxy-2- (4 '-thiazolyl) -benzimidazole in place of 1-methoxy-2- ( '-thiazolyl) -benzimidazole in Step A and carrying out the reduction of Step B in glacial acetic acid instead of absolute ethanol, the title product is obtained.

EXAMPLE 72 1-Acetyl-5-Methoxycarbonylamino-2^ (_4_-Thiazoly1)_-Benzinvidazol .4 G. of 5-metho ycarbonylamino-2-(4'-tliazolyl)-benzimidazole is added to a mixture of 100 ml. of toluene and 30 ml. of dimethyl formamide. The mixture is distilled to remove 5 ml. of toluene and then 0.7 g. of sodium hydride in 2 ml. of toluene are added at about 65°C. The mixture is then stirred for one hour at this temperature and 2.5 g. of acetyl chloride added dropwise at 55°C. The resulting mixture is refluxed for 30 minutes, chilled and 2 ml. of water added to it. It is then washed with 5% aqueous sodium bicarbonate, filtered and evaporated to dryness in vacuo to afford a residue of l-acetyl-5-methoxycarbonyl-amino-2- ( 4 ' -thiazoly1) -benzimidazole .

Repeating this procedure with 3 g. of benzoyl chloride in place of the acetyl chloride affords 1-benzoyl-5-methoxycarbonylamino-2- ( 4 ' -thiazolyl) -benzimidazole .

EXAMPLE 73 -Isopropoxycarbonylamino-l-Butylcarbamoyl-2- (4 '-Thiazolyl) ~ Ben .zimida —zol —e— — . p A solution of 3.26 g. of 5-isopropylcarbonylamino-2- (4 '-thiazolyl) -benzimidazole and 1 g. of n-butyl isocyanate in 100 ml. of dry acetonitrile is refluxed for four hours. The solvent is evaporated and the residue is extracted with chloroform. The product is isolated by chromatography of the chloroform extract through silica gel.

Similarly, by using methyl isocyanate, ethyl iso-cyanate or propyl isocyanate in the above procedure in place of the butyl isocyanate, the corresponding methylcarbamoyl , ethylcarbamoyl and propylcarbamoyl analogs can be obtained.

EXAMPLE 74 -Isopropoxycarbonylamino-l-Isopropoxycarbonyl-2- (4 ' - Thiazolyl) Benzimidazole 2.6 G. of isopropyl chloroformate is added dropwise to a mixture of 4.5 g. of 5-isopropoxycarbonyl- amino-2- ( ' -thiazolyl) benzimidazole in 20 ml. of dry pyridine, the addition being carried out at room temperature. The mixture is stirred at room temperature for another 90 minutes and then about 200 ml. of ice water are added. The resulting solid is separated by filtration and washed with water. It is dissolved in a minimum volume of methanol and the methanol solution is treated with decolorizing charcoal. The charcoal is filtered off and the cloar solution is evaporated to a small volume. A small amount of water is added to induce crystallization. The product is separated and dried.

EXAMPLE ^ Methylaulfonylamino-2" (4 ' -Thia'aolyl) Dengimidazole · 225 22GgC.

When the procedure of above ie repeated usjj g- 75 EXAMPLE -N-Methylmethoxycarbonylamino-2- (4 ' -Thiazolyl) - Benzimidazole A. 5-N-Methylbenzenesulfonylamino-2- (4 ' -thiazolyl) - Benzimidazole" ~~ 0.625 Ml. of methyl iodide is added to a mixture of 3.5 g. of 5-benzenesulfonylamino-2- (4 ' -thiazolyl) - benzimidazole and 0.54 g. of sodium methoxide in 10 ml. of methanol. After 24 hours, water is added to precipitate a solid which is collected and crystallized from methanol to give 5-N-methylbenzenesulfonylamino-2- (4 ' -thiazolyl) -benzimidazole, m.p. 142-143°C.

B. 5-Methylamino-2- (4 ' -thiazolyl) Benzimidazole A solution of 4 g. of 5-N-methylbenzenesulfonyl- amino-2- (4 ' -thiazolyl) benzimidazole in 100 ml. of con- centrated hydrochloric acid is refluxed for 3 hours.

Evaporation of the excess of acid followed by basification gives a solid precipitate which is filtered off and crystallized from acetonitrile to give 5-methylamino-2- (4 '-thiazolyl) benzimidazole, m.p. 192-193°C.

C. 5-N-Methylmethoxycarbonylamino-2- (4 ' -thiazolyl) - Benzimidazole 0.41 Ml. of methyl chloroformate is added drop-wise with stirring to a suspension of 1.15 g. of 5-methyl-amino-2- ( 4' -thiazolyl) benzimidazole in 5 ml. of pyridine. After stirring for 1 hour at room temperature water is added to precipitate a Following the procedure of Example 1 and substi- tuting an equivalent molar quantity of 5-amino-2~ (1 '-pyrazolyl) - benzimidazole for the 5-aiaino~2- (4 '-thiazolyl) -benzimidazole, the title compound is obtained, m.p. 207-210°C. 84 %M- EXAMPLE -Hethoxycarbonylamino-2- (2 '-Methyl-4 ' -Thiazolyl) Benzimidazole Following the procedure of Example 1 and substi- tuting an equivalent molar qviantity of 5-amino-2~ (21 -methyl- 4 * -thiazolyl) -benzimidazole for the 5-amino-2- (4 '-thiazolyl) -, benzimidazole, the title compound is obtained, m.p. 135°C. 85 -%£· EXAMPLE J½- Bej^zimi ^ z lc Following the procedure of Example 1 and substi-tuting an equivalent molar quantity of 5-amino~2- [4 '- (1' , 2' , 3'-thiadiazolyl) ] -benzimidazole for the 5-amino-2- (4 '-thiazolyl) -benzimidazole, the title product is obtained, m.p. 218-220°C. 86 EXAMPLE % Following the procedure of Example 1 and substi-tuting an equivalent molar quantity of 5-a ino-2- [2 ' - (1' ,3' ,4 '-thiadiazolyl) ]-benzimidazole for the 5-amino-2- (4 '-thiazolyl) -benzimidazole, the title product is obtained, m.p. 258°C. 87 &h EXAMPLE ^ -Isopropoxycarbonylamino-2- (2 '-Oxazolyl) -Benziiaidazole Following the procedure of Example 1 and substi-tuting equivalent molar quantities of 5-amino-2- (2 ' -oxazolyl) -benziiaidazole for the 5-amino-2- (4 ' -thiazolyl) -benzimidazole , and of isopropyl chlorofonuate for the methyl chloroformate, there is produced the title compound, m.p. 206°C. 88 %q EXAMPLE T -Isopropoxycarbonylamino-2- (2 '-Thiazolyl) -Benzimidazole Following the procedure of Example 1 and substi-tuting equivalent molar quantities of 5-amino-2- (2 ' -thiazolyl) -benzimidazole for the 5-amino-2- (4 '-thiazolyl) -benzimidazole, -φ 40- EXAMPLE J3rf . « " Following the procedure of Example 1 and substi-tuting an equivalent molar quantity of 5-cimino-2-- (2 ' -imidazolyl) -benziiuidazole for the 5-ainino--2 · (4 · --thiazolyl) -benzimidazole, the title compound is obtained, m.p. 205-207°C. 90 § - EXAMPLE -p-FluorobenzQ^ylamino-2- (2 '-Furyl) -Benzimidazole Following the procedure of Example 21 and substi-tuting equivalent molar quantities of 5-aminp-2- (2 ' -furyl) -benzimidazole for the 5-amino~2- (4 '-thiazolyl) -benzimidazolej, and of p-fluorobenzoyl chloride for the propionyl chloride, the title compound is obtained, m.p. 264°C. 91 <$A EXAMPLE - (2-Furyl) -Carbonylamino-2- (2 ' -Furyl) -Benzimidazole Following the procedure of Example 21 and substi-tut;i.ng equivalent molar quantities of 5-amino-2- (2 '-furyl) -benzimidazole for the 5-amino~2- (4 '-thiazolyl) -benzimidazole, and of furyl-2-carbonyl chloride for the propionyl chloride, the title compound is obtained, m.p. 248°C. 92 ¾ EXAMPLE X -p-Fluorobenzo lamino-2- ( L ' -Pyrazolyl) -Benzimidazole Following the procedure of Example 21 and substi-tuting equivalent molar quantities of 5-amino-2- (1 '-pyrazolyl) -benzimidazole for the 5-am.ino-2- (4 ' -thiazolyl) -benzimidazole, and of p-fluorobenzoyl chloride for the propionyl chloride, the title compound is obtained, m.p. 230°C. 29336/2 EXAMPLE 93 -Benzoylamino-2- ( 2 ' -thiazolyl )-benzimidazole Following the procedure of Example 21 and substituting equivalent molar quantities of 5-amino-2-(21 -thiazolyl)-benz- imidazole for the 5-amino-2-( ' -thiazolyl )-benzimidazole, and of benzoyl chloride for the propionyl chloride,, the title compound is obtained, m.p. 135-140°C.

EXAMPLE 94 Employing standard pharmacological techniques , the anthelmintic activity of the benzimidazoles listed below was determinsi in animals infected with HaemoExchus contortus . the large stomach worm of sheep. The results summarized in the following Table are expressed in t erms of the minimum concentration of test compound, in milligrams/killogram of body weight, found to be. effective in inhibiting the growth of the helminth.

MINIMUM INHIBITORY COMPOUND CONCENTRATION (Mg/Kg) -Methoxycarbonylamino-2- ( ' -thiazolyl) - benzimidazole -Ethoxycarbonylamino-2- (4 ' -thiazolyl) - benzim dazole -n-Propoxycarbonylamino-2- ( 4 ' -thiazolyl) - benzimidazole -Isopropoxycarbonylami no-2- ( ' -thiazolyl) - benzimidazole -Cyclopropoxycarbonylamino-2- ( ' -thiazolyl) benzimidazole -Trifluoromethylmethoxycarbonylamino-2- (4 ' - thiazolyl) benzimidazole - (1 ' -Trifluoromethylethoxy) carbonylamino-2- ( ' -thiazolyl) benzimidazole -ni-Methoxybenzoylamino-2- ( 4 ' -thiazolyl) -benzimidazole - (3~Phenylthioureido)'~2- (4 ' -thiazolyl) -benzimidazole - (3, 3-Dimcthylthioureido) -2- (4 ' -thiazolyl) ben imidazole -Metbo>:ythiocarbonylaifiino-2- (4 '-thiazolyl) benzimidazole -Ethoxythioc'arbonylamino-2- (4 '-thiazolyl) -benzimidazole -Th.iobcnzoylaraino-2- (4 ' -thiazolyl ) -bcnz:i midazolc (G) -Metlio>:ycarbony].airiino-l-methyl-2- ( ' -thiazolyl) benzimidazole -Mc hoxycarbonylam:i no-2- (2 ' -JTuryl) -benzimidazole ■ ' -Ethoxycarbonylamino-2- (2 ' -/:uryl) -ben imida ole -Tr;opropo>:ycorbony.1 amino-?.- (2 ' -thiazolyl) -bc'iv/ iii i ".ulc

Claims (1)

1. CLAIMS benzimidazoles having the formula wherein X is oxygen or is a heteroaryl ring from the group of isothiazolyl and is carboxylic alkylcarbamoy or is hydrogen a straight or branched loweralkyl of 1 to 8 carbon and is hydrogen or optionally loweralkoxy or lower an alken alkynyloxy or alkynylthio group of 1 8 carbon aryloxy or arylthio optionally tuted by alkyl or aralkyl optionally substituted by thiazolyl and the corresponding heteroaryloxy and heteroarylthio a straight or branched chain or dilower alkylamino radical having 1 to 8 carbon atoms in the alkyl or a amino and acid addition salts and metal complexes thereof when is Compounds according to Claim wherein X is oxygen and is Compounds according to Claim wherein is is hydrogen is benzoyl or according to substantially as described herein with reference xamples A method of preparing compounds according to aving the wherein and have the same meanings as in Claim 1 and is heteroaryloxy or heteroarylthio inClaim which comprises treating a compound of the formula a compound of the formula 0 Y 8 wherein to are defined above and Y is A method of preparing compounds according to Claim 1 having the formula 0 H and the same meaning as in Claim which 1 4 comprises treating a compound of the formula in Claim in which is with a compound of the formula III in Claim The method of Claim 12 wherein is thiazolyl and is The method of preparing the compound of Claim 4 which comprises reacting with a loweralkyl The method of preparing the compound of Claim 5 which comprises reacting benzimidazole with methyl The method for preparing the compound of Claim 6 which comprises reacting with ethyl The method preparing the compound of Claim 7 which comprises reacting with isopropyl A method of pisparing compounds of formula in Claim wherein and have the same meanings as in Claim 1 and is monoloweralkylamino diloweralkylamino or defined in Claim which comprises treating a compound of the formula II in Claim with a compound of the formula 0 Y wherein is as previously defined and Y is A method of preparing a compound of formula in Claim 12 wherein is as defined in Claim and is as defined in Claim which comprises treating a compound of the formula II in Claim wherein is with a compound of the formula 0 C Y wherein and are as previously defined and Y is The method of Claim wherein is thiazolyl and is benzoyl or The method for preparing the compound of Claim 8 which comprises reacting with benzoyl The method for preparing the compound of Claim 9 which comprises reacting 4 with A method for preparing a compound of formula la in Claim wherein and have the same meanings as in Claim 1 and is a aryloxy or heteroaryloxy group as defined in Claim which comprises reacting a compound of the formula wherein and are as previously defined and is a arylthio or heteroarylthio with a compound of the formula wherein is aryl or in the presence of a basic catalyst selected from dibutyltinoxide and aluminum A method for preparing a compound according to Claim 1 of the formula wherein and are as defined in Claim and is aryloxy or heteroaryloxy as defined in Claim comprises reacting a compound of the II in Claim with a compound of the formula S Y 4 wherein is as defined above and Y is A method for preparing a compound of formula Ic in Claim in is which comprises reacting a compound of the formula wherein and are as defined in with a compound of the formula wherein is aryl or heteroaryl defined in Claim The method of preparing a compound of the formula in Claim wherein and as defined in Claim and is lo arylthio or heteroarylthio defined in Claim which comprises reacting a compound of the V in Claim 25 with a compound of the formula wherein is aryl or A method of preparing a compound of formula Ic in Claim wherein and are as defined in Claim and is diloweralkylamino and defined in Claim which comprises reacting a compound of the formula in Claim in which 2 and are as defined with phosphorous A method of preparing a compound of formula in Claim or Ic in Claim wherein and are as defined in Claim 1 and is which comprises reacting a compound of the formula in Claim wherein and are as defined with a loweralkyl isocyanate or method of preparing a compound of La in wherein and are rs d in Claim and dilower which comprises acting a compound of the formula in Claim wherein and ae with a method of preparing a compound of formula in wherein and are as in Claim and is or which prises reacting a corresponding compound of formula in which is with a or a A method of preparing a compound of formula in Claim wherein and are as defined in Claim and is or which reacting compound of the formula V in Claim with a or Λ method according to Claim 25 wherein the compound of ormula is prepared by heating a compound of the formula in Claim 24 wherein and as defined in is hydrogen or and is or heteroaryloxy defined in Claim with pyridine about method of preparing a compound of formula I in Claim are as therein defined and is aralkyl or carboxylic acyl which comprises treating an alkali metal salt of a compound having the formula wherein and and X are as defined with an alkyl aralkyl halide or carboxylic acyl A method of preparing a compound of formula I in Claim wherein and X are as defined therein and is which comprises reacting a compound of the formula Ie in Claim 33 with an alkyl Methods of preparing compounds of formula I in Claim substantially as described herein with reference to the Anthelmintic compositions comprising a carrier vehicle and having intimately dispersed therein an mintically effective amount of a compound according to Claim Compositions according to Claim wherein the carrier vehicle is in the form of a For the Applicants insufficientOCRQuality