IE47530B1 - Derivatives of benzimidazoles - Google Patents

Abstract

Benzimidazoles are provided having the structure wherein R is lower alkyl or phenyl- lower alkyl and A is wherein R1 is lower alkyl, R2 is hydrogen or lower alkyl, or R1 and R2 may be taken together with the carbons to which they are attached to form a cycloalkenyl ring, R3 is hydrogen or lower alkyl, and y is 0 or 1; wherein R4 and R5 are the same or different and are hydrogen or lower alkyl, R6 is lower alkyl or phenyl, and R7 and R8 are the same or different and are chlorine, bromine, fluorine or iodine, m is 0 to 3, n is 0 to 3, and m+n is wherein R9, R10 and R11 may be the same or different and may be lower alkyl or lower alkoxy, z is 0, 1 or 2 and p is 1 to 5, with the proviso that when A is R is lower alkyl. These compounds have anthelmintic properties.

Description

The present invention relates to derivatives of benzimidazoles having the structure nhco2r H wherein R is lower alkyl or phenyl-lower alkyl and A is wherein R^ is lower alkyl, R2 is hydrogen or lower alkyl, or and R2 may be taken together with the carbons to which they are attached to give a cycloalkenyl ring containing 3 to 10 carbons, preferably 4 to 8 carbons, optimally 5 to 7 carbons, Rg is hydrogen or lower alkyl, and n is 0 or li Rr R R R wherein R^ and Rg are the same or different and are hydrogen or lower alkyl, Rg occupies the 1- or 3-position and is lower alkyl or phenyl, and Ry and Rg are the same or different and are chlorine, bromine, fluorine or iodine, m is 0 to 3, n is 0 to 3, and m + n is ί 5 or lc 47530 R.

R R wherein Rg, ί^θ and R^ may be the same or different and may be lower alkyl or lower alkoxy, z is 0, 1 or 2 and (CH2)p represents an alkylene group having 1 to 5 carbons, with the proviso that when A is rni R is lower alkyl.

The term lower alkyl as used herein includes straight or branched chain aliphatic hydrocarbon radicals having up to and including 7 carbon atoms, preferably 1 to 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, heptyl and the like. However, in the case of Rg, R^g and R^^, only one or two lower alkyls of same may contain more than one branch.

The term lower alkoxy includes any of the above lower alkyl groups linked to an oxygen atom.

The term phenyl lower alkyl as used herein refers to lower alkyl groups as discussed above having a phenyl substituent, such as benzyl.

The term cycloalkenyl includes cyclic hydrocarbon groups containing 3 to 10 carbons. Examples of suitable cycloalkenyl groups include cyclopropenyl, cyclobutenyl, cyclohexenyl, cycloheptenyl, cyclononenyl and cyclodecenyl. In the above cycloalkenyl rings, the 4*7530 double bond is at-the alpha position in the ring.

(CH2)m and (CH2)n represent a single bond or straight or branched chain alkylene radicals containing 3 or less carbons in the longest normal chain.

A method is also provided for treating or preventing whipworm, tapeworm and other helminth infestation by orally, parenterally or topically administering to a mammalian or poultry host a benzimidazole as described above.

The preferred compounds of structure 1 are those wherein R is -methyl, ethyl, propyl or benzyl, y is 0 or 1, R1 and ®2 are taken together to form a cyclohexen-1yl ring or a cyclopenten-l-yl ring, or R^ is methyl, ethyl or n-propyl and R2 is hydrogen, methyl or ethyl, and Rg is hydrogen.

Examples of preferred compounds falling within the present invention include the following.

R Rl (Rl + Rp) r2 R.3 x 1. ch3 CH3 H H 0 2.C2H5C2H5 ch3 H 0 3.C2H4C6H5C4H8 H 0 4. ch3C3H6 H 0 5. ch3C3H7C2H5 H 0 6.C2H5 C3Hg H 1 7. ch3C3H6 H 1 8.C2H5c2h5 ch3 H 1 9. CH3C3H7C2H5 H 1 10. ch3C2H4 ch3 1 11. CH3C6H12 H 0 12. ch3C8H16 H 1 13.c2H5C5H11 HC2H5 0 14. ch2c6h5C2H5 ch3 ch3 1 The preferred compounds of structure 2 are those benzimidazoles wherein R? and Rg are chlorine and/or bromine, Rg is methyl or ethyl in the 1-position, - (CH2)m-C-(CHjJjj- is methylene or ethylene, and R is *5 methyl or benzyl.

H The preferred compounds of structure 3 are those wherein 2 is methyl, ethyl or propyl, p is 1, z is 0 or 1 and Rg, R^q and R-q are each methyl, or two thereof are ethoxy and the other methyl, or each are ethoxy.

The compounds of structure 1 may be prepared as follows.

The vinyl thiol II is prepared by using the methods published by Mayer [J. Praktische Chemie 34, 116 (1966); Chem. Ber. 96, 3096 (1963)? 99, 1771 (1966); Agnew.

Chemie Internat. Ed. 1, 217 (1962)]. The alkali salt of II is then reacted with 5-chIoro-2-nitroaniline III to furnish IV. The reaction can be carried out in solvents such as alcohols, acetonitrile or glyme at temperatures ranging from about 25° to about 100° for periods of about 30 minutes to 10 hours.

R„ R.

' CH-C=S I R1 + + 'C-SH έ, XI 1. MOH 2. Cl NH„ III M=K, Na The compounds of structure IV where Rj and Rg form a cycloalkene may be prepared as reported by Seebach et al. [Chem. Ber. 107, 847 (1964)]. Reaction of the lithilated vinyl derivative V with a disulfide VI yields IV.

,Br Li (CH3)3-C Li -78° Bl - 7 R12 = N02 or NH2 R13 = NH2 °r N°2 Mykaiyama [Chem. Letters 479 (1973)] describes an additional route toward TV by reacting a carbonyl compound VII with a thiol VIII in the presence of TiCl^.

HS R12 TlC14 C=O I Ri *13 n(c2h5)3 VII VIII Vinyl sulfides IV are conveniently reduced to the requisite o-phenylenediamines IX by using aqueous Na-^O^.

Na2S2O4 R, C-S^^-ν,ΝΗ. 3 ι 7Γ 2 i2rx kA™'’ IV IX The final step in the synthesis of 1 where n = 0, namely ring-closure of IX to furnish la, can be achieved in various ways. Refluxing IX with the isolated thiourea derivative X will yield la. The preferred method of preparing la is by forming X in situ and then without isolating it, adding IX and refluxing it for 30 minutes to 5 hours, to yield the desired product.

CHjS-C .N-CO-R IX NHCOgR NHCOgR Compound III can be prepared by the sequence depicted J36low: Cl / . \ /ΪΗ, Cl.^,/NHCOCH, Cl y^'^/NHCOCHg AC2O NOOH -> Cl X /NH2 Gr.

HS III npour G' G XI IO] ·> Compound XI is prepared by the route outlined below: NO.

NCS NH.

SCN h Br. ,θ NO.

NH.

NaBH, HS x NO.

XI The sulfides of structure IV are converted to the corresponding sulfoxides by oxidizing agents such as hydrogen peroxide, peracids (e.g., peracetic acid, mchloroperbenzoic acid), manganese dioxide, sodium metaperiodate as outlined by Sandler and Caro (Organic Functional Group Preparations, 1968, p. 493).

IV [0] ‘13 XII wherein one of R12 and R13 is no2 The resulting sulfoxides XII may be purified by crystallization and then reduced to the corresponding o-phenyl15 enediamine XIII. Chemical reduction may be used. For the chemical reduction, the procedure outlined by Sandler and Caro (Organic Functional Group Preparations, 1968, pp. 339-340) is preferred. The final step in the synthesis of sulfoxides of formula 1 (n=l), namely ring closure of XIII to furnish lb, can be achieved in various ways. Whereas refluxing of XIII with the isolated thiourea derivative XIV in alcohols such as methanol or ethanol will furnish lb, the preferred method of preparing 1 is by forming XIV in situ and then without isolating it adding XIII and refluxing it for 30 minutes to 5 hours to yield the desired product.

XIII ο ( ROC-N=CSCH, -NHC-OR Alternatively, sulfoxides of structure lb may be prepared directly from the sulfides la by oxidizing the sulfides with NalO^.

The benzimidazole derivatives of structure 2 may be prepared hy thiocyanation of O-nitroaniline to yield 4-thiocyano-2-nitroaniline. This product is then subjected to a sodium borohydride reduction to yield the corresponding 4-mercapto-2-nitroaniline XI. The mercapto derivative may be isolated or used directly for the next step. Thus, to the reaction mixture there is added the haloalkyl cycloalkane XV to furnish the sulfide XVI.

XI XI V A .(ra2)m-€-(di2)n-X -\ *6 (wherein X is Cl or Br) Examples of haloalkyl cycloalkanes of formula XV suitable for use herein include the following: The resulting sulfides XVI may be purified by crystallization and then reduced to the corresponding o-phenylene diamine XVII.

Either chemical or catalytic reduction may be used. For the chemical reduction the procedure outlined by Sandler and Caro (Organic Functional Group Preparations, 1968, pp. 339-340) is preferred. The final step in the synthesis of 2, namely ring closure of XVII to furnish 2, can be achieved in various ways. Whereas refluxing of XVII with the isolated thiourea derivative XVIII in alcohols such as methanol or ethanol will furnish 2, the preferred method of preparing 2 is by forming XVIII in situ and then without isolating it adding XVII and refluxing it for desired product. minutes to 5 hours to yield the or Fe/Ha ί fCH3|) R0C-N=C-NHC-0R XVIII An alternative route toward the intermediate XVII offers the reaction of III with the requisite mercaptoalkyl cycloalkane XIX, to yield XX. Here, in contrast to the alkylation step described above, (i.e., XV ·> XVI) the reaction temperature has to be higher and the reaction periods have to be longer. Reduction of XX yields the desired diamine XVII.

XX A great variety of haloalkyl cycloalkanes XV are commercially available. In some cases the requisite haloalkyl cycloalkane has to be synthesized. For example, reaction of the appropriate alkene with the requisite halocarbene will yield the desired starting material.

The requisite haloalkyl cycloalkanes may also be prepared from the corresponding alcohols by standard reactions.

The compounds of structure 3 may be prepared according to the following reaction sequences.

NaBH4 non-reacting solvent e.g. DMF or acetonitrile under N2 NH, •ΐ/ •NH.

XXVI ,[H] SMs Oq I R'S NO.

NH.

XXV XXIII SMs ro2c»=c-nhco2r BD2CN=C^ XXtV 03 [0] VF XXIV R'S Λ N NH002R <-S5=r^cBng· N seven H 3d 3a q= 1 or 2 R' = R^Si(CH2,? B, The compounds of structure 3 wherein m is 0, that is ,N H may be prepared by reacting 4-thiocyanate-2-nitroaniline with sodium borohydride in the presence of a non-reacting solvent, such as dimethyl formamide or acetonitrile under nitrogen for a period ranging from about 0.5 to about 4 hours. Thereafter, a silane derivative XXI is admixed with the mixture with heating to form a silylalkylenethio-2-nitroaniline derivative XXII.

The silylalkylenethio-2-nitroaniline derivative XXII is then reduced employing conventional reduction techniques, for example, catalytically with hydrogen and platinum or chemically with dithionite, or zinc and acetic acid, to form the corresponding o-phenylenediamine XXIII which is then reacted with an isothiourea of the structure XXIV in the presence of an alcohol solvent (ROH) or other non-reacting solvent, and optionally, an acid catalyst, such as acetic acid at temperatures ranging from about 50 to about 200°C, and preferably from about 80 to about 130°C, for one minute to 3 days, preferably for 1 to 24 hours, to form the formula 3a compounds.

The formula 3a compound may be oxidized to the corresponding sulfoxide 3b employing one equivalent of an oxidizing agent such as hydrogen peroxide in acetic acid, sodium meta periodate or m-chloroperbenzoic acid. may be prepared by reacting the thio compound 3a with two or more equivalents of any of the above oxidizing agents; alternatively, the sulfone 3c may be prepared by reacting the sulfoxide 3b with one equivalent of any of the above oxidizing agents.

Compounds of structures 3b and 3c may also be prepared by oxidizing the formula XXII silylalkylenethio20 2-nitroaniline derivative with one or two or more equivalents of oxidizing agent to form a silylalkylenesulfinyl(or sulfonyl)-2-nitroaniline XXV which is then reduced to the o-phenylenediamine XXVI. The o-phenylenediamine XXVI is then reacted with the thiourea XXIV in the presence of an alcohol solvent (ROH) or other non-reacting solvent to form the compound of structure 3d (that is, 3b or 3c).

The starting materials employed in the above reactions are either known in the art or easily prepared according to conventional techniques.

In certain instances, the compounds of formulae 1, and 3 form physiologically acceptable acid-addition salts with inorganic and organic acids. These salts frequently provide useful means for isolating the products from reaction mixtures by forming the salt in a medium in which it is insoluble. The free base may then by obtained by neutralization. Then any other salt may again be formed from the free base and the appropriate inorganic acid. Illustrative are the hydrohalides, especially the hydrochloride and hydrobromide which are preferred, sulfate, nitrate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like.

The compounds of formulae 1, 2 and 3 have anthelmintic activity and are useful in the treatment and/or prevention of helminthiasis, a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine, cattle, horses, dogs, cats and sheep. The compounds are useful in treating infections caused by Haemonchus, Ostertagia, Trichostrongylus, Cooperia, Dictyocaulus, Nematodirus, Bunostomum, Strongyloides, Oesophagostomum, Trichuris, Moniezia, and liver flukes (for example in sheep). In treating domesticated animals, the compounds are given orally? however, other routes such as parenterally, for example, subcutaneously, intravenously, interperitoneally and intramuscularly may be employed. The compounds of formula 2 can also be applied topically (cutaneously), preferably directly on to exposed skin surface.

When the compounds are to be administered in unit dosage form, capsules, boluses or drenches containing the desired amount of anthelmintic distributed in a pharmaceutically acceptable vehicle are usually employed. These are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, suspending agents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium, stearate, vegetable gums and the like and are compounded by techniques generally known in the art.

The compounds may also be administered as a component of the feed of the animals or suspended in the drinking water. Thus, novel feed and feed supplement compositions may be prepared in which the compounds of this invention are present as an active anthelmintic ingredient. A typical feed supplement comprises the anthelmintic agent intimately dispersed in or admixed with an inert carrier or diluent, i.e., one that is nonreactive with respect to the anthelmintic agent 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 an animal ration. This composition may be mixed with the feed to give any useful desired concentration, preferably about 0.1-2%. Lastly, feeds containing the active ingredient may he made directly by mixing said active ingredient in a feed which is inert to said anthelmintic compounds so as to give feeds having concentrations of anthelmintic agent of from 0.1-2%.

In preparing injectable compositions, the compounds are mixed with a non-toxic, physiologically acceptable non-pyrogenic carrier such as sterile water, sterile saline solution, benzyl benzoate, 1,3-butylene glycol, ethyl oleate, castor oil, glyceryl triacetate, sesame oil, and sesame oilsbenzyl benzoate (1:1). The parenteral product will usually take the form of a suspension containing from about 1 to about 10% by weight of the compound of formulae 1, 2 or 3.

The above injectable compositions may also include a non-toxic physiologically acceptable non-pyrogenic suspending agent. Thus, where a non-oily carrier is employed such as water, suspending agents such as carboxy5 methyl cellulose, methyl cellulose, polyvinyl pyrrolidone or non-antigenic gelatin may be employed. Where the carrier employed is an oil, aluminum monostearate may be employed as a suspending agent. The suspending agent may be employed in amounts ranging from about 0.05 to about 2%, and preferably from about 0.1 to about 1% by volume of carrier (the above % may be based on the weight of the carrier where the carrier is qs to lOOg).

A non-toxic, non-pyrogenic wetting agent may also be included in the injectable compositions in amounts ranging from about 0.005 to about 2% and preferably from about 0.01 to about 0.1% by weight of the carrier. Examples of suitable wetting agents include non-ionic surfactants such as polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate [e.g.. Tweens] and fatty acid monoglycerides or diglycerides. Other surfactants suitable for use herein are disclosed in the published literature, for example, Kirk-Othmer, Encyclopedia of Chemical Technology, Second Edition, Volume 19, page 507 et seq.

In preparing topical or cutaneous compositions, the anthelmintic compounds are mixed with carriers which are effective in penetrating the skin, whereby the compounds are absorbed by the animal through the skin and transmitted systemically within the animal. A wide range of appropriate carriers may be employed to pass the compound through the skin. The composition employed may be a cream. A liquid composition, however, is particularly convenient to use, e.g., facilitating measuring out doses, and facilitating absorbance through the skin. Thus, a solution or suspension of the compound in a liquid carrier is preferred. Solutions are especially good for transmitting the compound through the skin and are therefore most preferred. The liquid carrier preferably comprises one or more liquids selected from hydrocarbons (e.g., aromatic hydrocarbons, such as an aromatic hydrocarbon fraction of boiling point 130-250°C, e.g., 180-220°C, xylene, benzene or toluene, or paraffins, such as those of 6-20 carbon atoms), halogenated aliphatic hydrocarbons (e.g., carbon tetrachloride), ketones (e.g., cyclohexanone or 2-butanone), esters (e.g., ethyl acetate, ethyl benzoate or triacetin), ethers (e.g., diisopropyl ether or tetrahydrofuran), alcohols (e.g., alkanols of 2-8 carbon atoms, such as butyl alcohol, amyl alcohol or isopropyl alcohol, or glycols, such as monopropylene glycol), amides (e.g., dimethylformamide), sulphones (e.g., dimethyl sulphone or sulpholane), and sulphoxides (e.g., dimethyl sulphoxide).

In many cases a mixture of liquids is desirable. Preferably the liquid carrier comprises one or more liquids selected from hydrocarbons (e.g., aromatic hydrocarbons especially xylene), alcohols (e.g., isopropyl alcohol or amyl alcohol and sulphoxides (e.g., dimethyl sulphoxide). Water tends to be ineffective as a liquid carrier for passing the compound through the skin of the animal. Accordingly, the carrier in the liquid compositions preferably comprises an organic liquid.

The viscosity of liquid compositions may be increased over what it would otherwise be by including thickeners which increase the viscosity. This may be desirable in order to retard or prevent the composition from running off the animal.

The additives may include, for example, a surface active agent, an animal fat or wax, e.g., lanolin, a mineral oil, e.g., liquid paraffin, a vegetable oil, e.g., peanut oil, olive oil, corn oil or castor oil, or a polymer, e.g., a hydrocarbon polymer such as polyisobutene.

The surface active agents may comprise anionic compounds, for example, soaps, fatty sulphate esters, such as dodecyl sodium sulphate, fatty aromatic sulphonates, such as alkylbenzene sulphonates or butyl-naphthalene sulphonates, more complex fatty sulphonates, such as the amide condensation product of oleic acid and N-methyl taurine or the sodium sulphonate of dioctyl succinate.

The surface active agents may also comprise non-ionic surface active agents such as, for example, condensation products of fatty acids, fatty alcohols or fatty polyhydric alcohols, or the products obtained from the latter by condensation with, ethylene oxide, or the products known as block copolymers of ethylene oxide and propylene oxide.

The surface active agents may also comprise cationic agents such as, for example, cetyl trimethylammonium bromide.

The term surface active agent is used in the broad sense to cover materials variously called wetting agents, emulsifying agents and dispersing agents.

The composition may contain substances whose taste deters other animals from licking the composition off the animal treated. An example of such a substance is bitter aloes.

Generally, additives facilitating the use in pour-on 5 formulations of other materials, e.g., systemic insecticides, active on animal physiology may be of use also in the present composition.

In general, in carrying out the method of the invention, the oral, parenteral or topical compositions IQ described above may be administered to animals in a single dose or divided into a plurality of smaller doses given over one or more days, for example, up to 14 days, to provide from 1 to about 200 mg active compound per kilogram of animal body weight. It is preferred to employ in the range of 2.5-75 mg per kilogram of body weight.

The compounds of formula 2 are especially useful against whipworm (Trichuris vulpis), and when so employed, it is preferred that such compounds be administered over a 5 to 9 day period in amounts ranging from about 4 to 2Q about 10 mg per kilogram of animal body weight per day, and more preferably over a 6 to about 8 day period in amounts ranging from about 4 to about 6 mg per kilogram of animal body weight per day.

If the compounds of the invention are to be employed against tapeworm, for example, Taenia pisiformis and Dipylidium caninum, it is preferred that such compounds be administered over a 2 to 10 day period, in amounts ranging from about 7 to about 20 mg per kilogram of animal body weight to provide from about 75 to about 400 mg per day and more preferably from about 8 to about 15 mg per kilogram of animal body weight to provide from about 100 to about 300 mg per day.

The following examples are provided for illustrative purposes and may include particular features of the invention, however the examples should not Be construed as limiting the invention, many variations of which are possible without departing from the spirit or scope thereof. All temperatures are in degrees centigrade.

Example 1 [5- (1-Cyclohexen-l-ylthioJ-lH-benzijnidazol-2-yl]carbamic acid, methyl ester A. 5-(1-Cyclohexen-l-ylthio)-2-nitrobenzene-amine To a solution of 6.9 g (0.04 mole) of 5-chloro-2nitroaniline in 50 ml of absolute ethanol there is added 6.0 g of the potassium salt of 1-cyclohexene-l-thiol IJ. Praktische Chemie 34, 116 (1966)]. The mixture is heated on the steam bath for 0.5 hour, filtered and the filtrate is reduced in volume in vacuo. The resulting solid is filtered off and crystallized from absolute ethanol to yield 5.3 g, m.p. 100-102®.

B. 5-(1-Cyclohexen-l-ylthio)-o-phenylenediamine To a suspension of 3.5 g (0.014 mole) of 5-(115 cyclohexen-l-ylthio,-2-nitrobenzene-amine in 125 ml of absolute ethanol under Ng there is added a solution of 8.4 g of NagSgO^, 8.4 ml of concentrated aqueous ammonia and 52.5 ml of water. The mixture is refluxed for 15 minutes and an additional 0.8 g of NagSgO^ is added.

After an additional 15 minutes reflux period TLC (silica, EtgO] shows no starting material present. The ethanol is removed in vacuo; the aqueous residue is taken to pH 12 with 50% aqueous NaOH and then extracted with CHgClg.

The organic extracts are combined, dried (MgSO^) and evaporated to give an oil which is used immediately in the following reaction.

C. 15-(l-Cyclohexen-l-ylthio-lH-benzimidazol-2-yl]fearbamic acid, methyl ester To a solution of the above diamine in 50 ml of methanol there is added 1 ml of acetic acid and 2.8 g (0.014 mole) of 1,3-bis(methoxycarbonyl)-5-methylisothiourea and the resulting mixture is refluxed for 2 hours. The methanol is removed in vacuo and water is added. The resulting solid is filtered off, dried and crystallized from glyme-aeetonitrile (1:1)to yield 2.9 g of the title compound, m.p. 224-226*C (dec.).

Example 2 - CL-cyclopenten-l-ylthio]-lK-6enzimidazol-2-yl]carbamic acid, methyl ester Following the procedure of Example 1, but substituting for cyclohexanone, cyclopentanone, the title compound is outlined.

Example 3 -Cl-Cyclohepten-l-ylthio)-lH-benzimidazol-2-yl]carbamic acid, methyl ester Following the procedure of Example 1 but substituting for cyclohexanone, cycloheptanone, the title compound is obtained.

Example 4 - (.4-Hepten-l-ylthio) -IH-benziroidazol-2-yl] carbamic acid, methyl ester Following the procedure of Mayer (Ber. 99, 1771 (1966)] for preparing heptan-4-thione and substituting it for the 1-cyclohexene-l-thiol used in Example 1, the title compound is obtained.

Example 5 [5-(l-Cyclohexen-l-ylsulfinyl)-lH-benzimidazol-2-yl]carbamic acid, methyl ester A. 4-(1-Cyclohexen-l-ylthio)-2-nitrobenzene-alnine To 500 ml of dry tetrahydrofuran under N2 there is added 5.0 g of cyclohexanone and then 5.5 ml of TiCl^.

Then there is added a mixture of 11.0 ml of triethylamine and 8.5 g of 3-amino-4-nitrobenzenethiol in 105 ml of dry tetrahydrofuran and the mixture is stirred overnight at room temperature. Then there is added 300 ml of H20 and the mixture is extracted with dichloromethane. The organic layers are combined, dried (MgSO4) and evaporated in vacuo. The residue is chromatographed on silica gel. Elution with 1:1 PE-Et2O yields 2.8 g of 4-(l-cyclohexen-l-ylthio)-215 nitrobenzene-amine, m.p. 93-95<>C.

B. 4-(1-Cyclohexen-l-ylsulfinyl)-2-nitrobenzene-amine To a solution of 2.5 g (0.01 mole) of the benzeneamine obtained from part A in 50 ml of methanol under N2 there is added a solution of 2.2 g NaIO4 in 20 ml of H2O at 0°-5°C for 30 hours. The mixture is then extracted with dichloromethane. The orgainc layers are combined, dried and evaporated. The residue is crystallized from acetonitrile to give 2.2 g, m.p. 139-140°C of the sulfoxide.

C. 15-(1-Cyclohexen-l-ylsulfinyl)-o-phenylenediamine To a suspension of 2.0 g (0.0075 mole) of 4-(1cyclohex-l-ylsulfinylJ-2-nitrobenzeneamine in 75 ml of absolute ethanol under N2 there is added a solution of 4.9 g of Na2s2o4, 4.9 ml of concentrated ammonia and 30 ml of H20. The mixture is refluxed for 15 minutes and an additional 0.4 g of Na2S2O4 is added. After an additional 15 minutes reflux period the ethanol is removed in vacuo. The aqueous residue is taken to pH 12 with 50% aqueous NaOH and then extracted with diehloromethane. The organic extracts are dried (MgSO4) and evaporated to give an oil which is used immediately in the following reaction.

D. 15-(1-Cyclohexen-l-ylsulfinyl)-IH-benzimidazol2-yl]carbamic acid, methyl ester To a solution of the above diamine in 25 ml of 10 methanol there is added 0.5 ml of acetic acid and 1.5 g of 1,3-bis (methoxy carbonyl)-5-methylisothiourea and the resulting mixture is refluxed for 3 hours. The methanol is removed in vacuo and water is added. The resulting solid is filtered off and crystallized from acetonitrile to yield 1.05 g of the title compound, m.p. 228-230°C (dec.).

Example 6 -(1-Cyclopenten-l-ylsulfinyl)-lH-benzimidazol-2-yl]carbamic acid, methyl ester 2Q Following the procedure of Example 5, but substituting for cyclohexanone, cyclopentanone, the title compound is obtained.

Example 7 - (1-Cycloh.epten-l-ylsulf inyl) -lH-benzifflidazol-2-yl]carbamic acid, methyl ester Following the procedure of Example 5, but substituting for cyclohexanone, cycloheptanone, the title compound is obtained.

Example 8 - (4-Hepten-l-ylsulfinyl)-lH-benzimidazol-2-yl]carbamic acid, methyl ester The sulfide of Example 4 is oxidized with NalO^ to give the title sulfoxide.

Example 9 - (3-Penten“l-ylthio)-lH-benzimidazol-2-yl.]carbamic acid, methyl ester Following the procedure set out in Example 5A, C 10 and D except substituting 3-pentanone for cyclohexanone, the title compound is obtained.

Example 10 -(5-Nonen-l-ylthio)-lH-benzimidazol-2-yl]carbamic acid, methyl ester Following the procedure set out in Example 5A, C and D except substituting 5-nonanone for cyclohexanone, the title compound is obtained.

Examples 11 to 21 Following the procedure of Example 1 but substituting for 1-cyclohexene-l-thiol the compound shown in Column I of Table I below, and substituting for 1,3-bis(methoxycarbonyl) -5-methylisothiourea the compound shown in Col25 umn II, the sulfide derivatives of benzimidazoles as shown in Column III are obtained. κ CM Ο Ci CM o ϋ ω a co co a o in » io a a >d in v in m in ϋ σι a B ma a nK σι co cm a cm cm a cm cm a cm a a a υυουυυαουοο pTI in J1® a cm in co co B a a cm co a BBCJCJteOUUlSUJS CM & I cn S3 S3 O CM U 1 m 4° w S3 cm u υ ι i a ω • r* □—a II o /V « « in ω ® S3 cm υ a ι t Γ* a cn U l , tn , r.

S3 tf cm cn ο υ ι ι CM tf rd tf CO CD w a ’tf cn t u u JP S3 tf cn cn ί Ο Ο ί «Μ* to a tf cm cn ϋ ϋ MO Hcjr)tfiniDr>comoH W J2J J HHrHHHHHHf-iCMCM Examples 22 to 32 Following the procedure of Example 8, the sulfides of Examples 11 to 21 shown in Column I of Table II below are oxidized to give the corresponding sulfoxides. 47S30 Column I I Column II Β « 'λ CM w I J-1 U—B II u z\p Ci pi rn Β I CM pi I CM Pi in tC Ko U in in to in co EC in EC U fO CO CM [ij B O O B U in cn cn B a B CN rt u u a cn B , U I co EC ϋ in EC CM U in co tC tC Γ* tc co ι υ in t** tc tc CM CO ο υ co KO tc W co υ □ KO KO tc tc co co υ υ vo tc tc CM CO ο υ Example 33 -1 [(2,2-Dichloro-l-methylcyclopropyl)methyl]thioj-1Hbenzimidazol-2-yl]carbamic acid, methyl eater A. 1,l-Dichloro-2-chloromethyl-2-methylcyclopropane (Makosza and Fedorynski Synthesis, 1974, p.2 Robinson, J. Org. Chem. 34, 2518 (1969)) To a vigorously stirred mixture of 45.3 g (0.5 mole) of 3-chloro-2-methylpropene, 120 g of chloroform (precursor of dichlorocarbene, and 1.5 g of benzyltriethylammonium chloride (TEBA) there is added dropwise 120 ml of 50% NaOH not allowing the temperature to rise above 40°C. The mixture is kept at 35 to 40eC for 3 hours then diluted with 250 ml of HgO and extracted with chloroform. The organic layer is dried (MgSO^) and the CHClg removed in vacuo. Distillation of the residue under house vacuum yields a fraction, b.p. 89-90°C, 45.7 g.

B. [5-[[(2,2-Dichloro-l-methylcyclopropyl)methyl]thio-lH-benzimidazol-2-yl]carbamic acid, methyl ester To a stirred mixture of 9.75 g (0.05 mole) of 2nitro-4-thiocyanoaniline in 500 ml of absolute ethanol under Ng, there is added 2.1 g of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3.25 g (0.05 mole) of KOH in 30 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 8.7 g (0.05 mole) of 1,1dichloro-2-chloromethyl-2-methyloyclopropane in 15 ml of absolute ethanol is added and the mixture is refluxed for 3 hours. Egual amounts of HgO and CHClg are added until two layers are formed. The organic layer is separated, dried (MgSO4), and the solvent removed in vacuo to give a red oil which is triturated with 10 ml of absolute ethanol to yield 9.6 g of solid, m.p. 76-78eC.

A mixture of 9.Q g (0.03 mole) of 2-nitro-4-J (2,2dichloro-l-methylcyclopropyl)methyl]thioaniline and 0.9 g of PtO2 in 200 ml of absolute ethanol is reduced on the Parr hydrogenator at 50 psi until the theoretical amount of H2 is absorbed. The mixture is filtered and the solvent is removed in vacuo to give a dark oil which is used immediately in the following reaction.

To a mixture of 6 g of 2-methy1-2-thiopseudourea sulfate in 6 ml of H2Q, there is added 5.7 ml of methylchloroformate at 0°C and the mixture is stirred for 15 minutes. Then there is added 14 ml of 25% NaOH dropwise and the mixture is stirred for 15 minutes. Then there is added 6 ml of acetic acid dropwise and the mixture is stirred for 15 minutes. Then the entire amount of the phenylenediamine from the preceding reaction in 20 ml of MeOH is added and the mixture is refluxed for 3 hours. The alcohol is removed in vacuo and H20 is added. The resulting solid is filtered off and crystallized from MeCN to yield 4.9 g, m.p. 175-178®.

Examples 34 to 40 Following the procedure of Example 33A except substituting for 3-chloro-2-methylpropene, the compound shown in Column I of Table I Below, and substituting for chloroform, the compound shown in Column II, the cyclopropane starting material shown in Column III is obtained.

TABLE ,ζΗ U' Μ <η ω W Η υ ο (Μ ι Κ Κ υ—u ι m . ca u-u u CN W cn L ffl CN I U-UK cn I ffl u—u II υ CJ a * 2 a ai nun a ι a u—v—u m a cj U-U δ CJ a Column I I Column II 1 Column III x I c N co U /·· p* ft κ o w si ca 1 rq M a I CQ B p* CM cq XJ B » B 1 cn u a u— II_a 0« in B UB u ll cq cq ύ— U o— B m B r*· cn co cn cs X Μ 0 w ζι Following the procedure of Example 33B except substituting for l,l-dichloro-2-chloromethyl-2-raethylcyclopropane the compound shown in Column HI of Table I (Column I of Table II) below and substituting for methyl chloroformate the compound shown in Column II, the product shown in Column III is obtained.

TABLE II Column I Column II Column III CH-C TABLE II (continued) Column I _ Column II Example 41 -1((2,2-Dichloro-3-methylcyclopropyl)methyl]thio]-1Hbenzimidazol-2-yl3carbamic acid, methyl ester A mixture of 21.6 g (0.3 mole) of crotyl alcohol, 600 ml of 50% aqueous sodium hydroxide and 1.2 g of triethylbenzylammonium chloride (TEBA) is stirred vigorously at 40°C to emulsify. Then 480 ml of chloroform is added dropwise over 2 hours and the mixture is stirred for a further 2 hours. The mixture is poured into water and extracted with chloroform. The organic layers are combined, dried (MgSO^), and the solvent is removed in vacuo. Distillation of the residue yields 18.3 g of l-chloromethyl-2,2-dichloro-3-methylcyclopropane.

To a stirred mixture of 9.75 g (0.05 mole) of 2-nitro-4-thiocyanoaniline in 200 ml of dry acetonitrile under nitrogen there is added 2.1 g (0.05 mole) of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minutes and then refluxed for 15 minutes. The heating mantle is removed and 3.5 g (0.05 mole) of KOH is added. The mixture is stirred for 15 minutes. Then a solution of 8.7 g (0.05 mole) of 1-chloromethyl-2,2-dichloro-3-methylcyolopropane in 10 ml of acetonitrile is added and the mixture is refluxed for 2 hours. The reaction mixture is cooled, filtered, and the solvent is removed in vacuo. Water and chloroform are added to the residue. The organic layer is separated, dried (MgSO^), and the solvent is removed in vacuo to give 12.4 g of red orange oil.

A mixture of 12 g (0.04 mole) of the above nitroaniline and 1.2 g PtO2 in 200 ml of absolute ethanol is reduced on the Parr hydrogenator at 50 psi. The mixture is filtered and the solution is used immediately in the following reaction.

To the above solution there is added 8.1 g of 1,3-bis(methoxycarbonyl)-5-methylisothiourea and 0.5 ml of acetic acid and the mixture is refluxed for 3 hours.

The solvent is removed in vacuo and water is added.

The resulting solid is filtered off and crystallized from ethanol to yield 6.2 g of the title compound.

Example 42 Oral Formulation of [5-[f(2,2-Dichloro-l-methylcyclopropyl)methyl]thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester Medication suitable for oral administration is prepared by filling gelatin capsules with suitable amounts of [5-[[ (2,2-dichloro-l-methylcyclopropyl)methyl]thio-lH-benzimidazol-2-yl]carbamic acid, methyl ester.

Example 43 Testing of Oral Formulation of [5-[[(2,2-Dichloro-l-methylcyclopropyl)methyl]thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester The following test is carried out to determine the effectiveness of treating dogs naturally infected with whipworm (Trichuris vulpis) and tapeworms (Taenia pisiformis and Dipylidium caninum) by orally administering capsules containing [5-[[(2,2-dichloro-l-methyl-cyclopropy1)methyl]thio]-ΙΗ-benz imidazol-2-y1]carbamic aci d, methyl ester prepared in Example 33.

The dogs are fasted overnight and receive medication the following morning.

Total fecal collections are made from each dog daily for seven days following treatment. Daily fecal material is soaked in water and washed through a 40-mesh sieve using a water spray and all scolioes, strobilae, proglottids and nematodes, immatures and adults are recovered.

Seven days after medication, the dogs are euthanitized and intestines and cecum are removed and examined for tapeworms and whipworms. The intestinal contents and mucosal scrapings are washed through a 40mesh sieve prior to examination for tapeworms (scolices) and whipworm under the dissection microscope.

A first group of dogs receiving 5 mg/kg for 7 days of I5-H(2,2-dichloro-l-methylcyclopropyl)methyl] thio]-ΙΗ-benzimidazol-2-yl]carbamic acid, methyl ester is found to have a 93% reduction in whipworms.

In a Control A experiment, one group of dogs receiving 5 mg/kg for 7 days of [5-[[(2,2-dichlorocyclopropyl)methyl]-thio]-lH-benzimidazol-2-yl]carbamic acid., methyl ester is found to have a 16% reduction in whipworms.

A second group of dogs receiving 100 mg twice daily for 5 days of [5-[[(2,2-dichloro-l-methylcyclopropyl) methyl]-thio]-ΙΗ-benzimidazol-2-yl]carbamic acid, methyl ester is found to have a 100% reduction in Taenia pisiformis and a 50% reduction in Dipylidium caninum.

In a Control B experiment, one group of dogs receiving 100 mg twice daily for 5 days of [5-[I(2,2dichlorocyclopropyl)methyl]thio]-lH-benzimidazol-2-yl] carbamic acid, methyl ester is found to have a 0% reduction in the tapeworms Taenia pisiformis and Dipylidium caninum.

A third group of dogs receiving 25 mg/kg for 5 days of 15— II(2,2-dichloro-l-methylcyclopropyl)methyl]thioj-lHbenzimidazol-2-yl]carbamic acid, methyl ester is found to have a 100% reduction in whipworms, a 100% reduction in Taenia pisiformis and a 100% reduction in Dipylidium caninum.

In a Control C experiment, one group of dogs receiving 25 mg/kg for 5 days of 15-11(2,2-dichlorocyclopropyl)methyl]thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester is found to have only a 34% reduction in whipworms and a 0% reduction in the tapeworms Taenia pisiformis and Dipylidium caninum.

The above test results clearly show the suprising superiority of 15-11(2,2-dichloro-l-methylcyclopropyl)methyl]thio]-lH-benzimidazol-2-yl]carbamic aoid, methyl ester over 15-I[(2,2-dichlorocyclopropyl)methyl]thio]lH-benzimidazol-2-yl]carbamic acid, methyl ester in the treatment or prevention of whipworm and tapeworm.

Example 44 -{(Diethoxymethylsilylmethyl) thio]-lH-benzimidazol-2yl]carbamic acid, methyl ester A. 4-(Diethoxymethylsilylmethyl)thio-2-nitroaniline To a stirring solution of 25.3 g (0.13 mol) 4thio-cyanato-2-nitroaniline in 500 ml of acetonitrile under nitrogen is added 4.94 g (0.13 mol) of sodium borohydride in portions over 45 minutes at room temperature. The mixture is stirred for 2 hours and 25.0 g (0.137 mol) of chloromethylmethyldiethoxysilane is added and the mixture is refluxed overnight. The reaction mixture is cooled, filtered and the filtrate eyaporated to dryness. The residue is extracted repeatedly with hot hexane to yield, on evaporation, 31 g of the title compound as a red oil. This is used without further purification. Β. 1,3-Bis(methoxycarbonyl)-S-methylisothiourea To a solution of 11.2 g of 2-methyl-2-thiopseudourea sulfate in 200 ml of water at 0°C there is added concurrently 260 ml of 25% NaOH and 160 ml of methylchloroformate at such a rate that the pH remains between 7 and 8 as monitored by a pH meter. After the addition is complete the mixture is stirred for an additional 2 hours at room temperature. Then 400 ml of water is added and the mixture is extracted with diehloromethane. The organic layers are combined, dried over magnesium sulfate, and evaporated in vacuo to give a white solid. Crystallization from methanol yields 60.4 g of the title B compound, m.p. 99-101eC.

C. [5-[ (DiethoxymethylsilyImethyl)thio]-1Hbenzimidazol-2-yl]carbamic acid, methyl ester 7.9 g (0.028 mol) of the nitroaniline obtained in part A is hydrogenated at 60 psi in 225 ml of methanol with 0.8 g of platinum oxide catalyst. After 24 hours, the color is largely gone and thin layer chromatography shows the absence of starting material. The mixture is filtered and 5.7 g (0.028 mol) of 1,3-bis(methoxycarbonyl)-Smethylisothiourea (prepared in part B), and 0.1 ml of acetic acid added to the filtrate. The mixture is refluxed for 36 hours, cooled and allowed to stand in the freezer. The resulting crystals are filtered off and recrystaliized (hot filtration) from cyclohexane to give 4.0 g of the title compound.

Example 45 [5-[(DiethoxymethylsilyImethyl)sulfinyl]-lH-benzimidazol-2yl]carbamic acid, methyl ester To an ice-cold solution of 40 mmol of [5-[(diethoxymethylsily Imethyl) thio] -lH-benzimidazol-2-yl]carbamic acid, methyl ester prepared as described in Example 44, in 150 ml methanol is added 8.98 g (42 mmol) sodium metaperiodate in 150 ml water. The resulting suspension is stirred at 5°C for 42 hours, then partitioned between water and dichloromethane. The layers are separated and the aqueous layer re-extracted. The organic layers are combined and washed with saturated NaCl, dried, filtered and evaporated to yield a residue which is crystallized three times from acetonitrile to yield the title sulfinyl compound.

Example 46 -I(DiethoxymethylsilyImethyl)sulfonyl]-lH-benzimidazol2-yl]carbamic acid, methyl ester 0.00625 mole of [5-[(diethoxymethylsilyImethyl)thio]-lH-benzimidazol-2-yl]carbamic acid, methyl ester prepared as described in Example 44, is dissolved in 40 ml acetic acid and 40 ml chloroform, and cooled to -10°C with an ice-methanol bath. To this is added 2 equivalents of m-chloroperbenzoic acid in 10 ml chloroform, all at once. Stirring is continued for three hours, allowing temperature to rise to room temperature. The solvent is removed in vacuo yielding an oil, which is digested with aqueous NaHCOg. Solids are collected, washed with water, dried and crystallized from 1,2-dimethoxyethane to give the title sulfone.

Exanple 47 N-15-11(Trimethylsilyl)methyl]thio]-2-benzimidazolyl)carbamic acid, methyl ester A. 4-I(Trimethylsilyl)methylthio]-2-nitroaniline To a stirred solution of 1,95 g of 4-thiocyanato-2nitroaniline in 40 ml of CHgCN blanketed by nitrogen there is added in portions 0.5 g of NaBH^. The stirring is continued for one hour. At this time the color of the reaction mixture changes from yellow to dark purple. 1.4 ml of chloromethyltrimethylsilane is added with a syringe and the mixture is refluxed overnight. The solvent is evaporated and the residue is exhaustively extracted with petroleum ether. Evaporation of the solvent yields 1.9 g of the title A compound as a red solid.

B. 4- [ (Trimethylsilyl) methylthio]-o-phenylenediamine A solution of 1.9 g of the above nitroaniline in 200ml of methanol is catalytically reduced (60 psi) using 0.4 g PtO2 as catalyst. Upon completion, the catalyst is filtered off and the filtrate is used at once for the next step.

C. N-[5-[[(Trimethylsilyl)methyl]thio]-2-benzimidazolyl]carbamic acid, methyl ester To the above filtrate (part B) there is added 2 g of 1,3-bisfmethoxycarbonylJ-S-methylisothiourea (prepared as described in Example 44, part Β), 7 drops of acetic acid and the mixture is refluxed for two hours. The solvent is evaporated and the residue extracted with ether. The ether insoluble part is crystallized from ethanol. The ether soluble material and the ethanol purified fraction are combined and recrystallized from ethanol to yield 0.7 g of the title compound, m.p. 189°-191°.

Example 48 N-£5-[[TrimethylsilyDmethyl]sulfinyl]-2-benzimidazolyl]carbamic acid, methyl ester To an ice-cold solution of 40 mmol of £5-[[(trimethylsilyl)methyl]thio]-2-benzimidazolyl]carbamic acid, methyl ester prepared as described in Example 47, in 150 ml methanol is added 8.98 g (42 mmol) sodium metaperiodate in 150 ml water. The resulting suspension is stirred at 5°C for 42 hours, then partitioned between water and dichloromethane. The layers are separated and the aqueous layer re-extracted. The organic layers are combined and washed with saturated NaCl, dried, filtered and evaporated to yield a residue which is crystallized three times from acetonitrile to yield the title sulfinyl compound.

Example 49 Ν-15-11(Trimethylsilyl)methyl]sulfonyl]-2-benzimidazolyl]carbamic acid, methyl ester 0.00625 mole of N-I5-11(trimethylsilyl)methyl]5 thio]-2-benzimidazolyl]carbamic acid, methyl ester prepared as described in Example 47, is dissolved in 40 ml acetic acid and 40 ml chloroform, and cooled to -10’C with an ice-methanol bath. To this is added 2 equivalents of m-chloroperbenzoic acid in 10 ml chloroform, all at once.

Stirring is continued for three hours, allowing temperature to rise to room temperature. The solvent is removed in vacuo yielding an oil, which is digested with aqueous NaHCOg. Solids are collected, washed with water, dried and crystallized from 1,2-dimethoxyethane to give the title sulfone.

Examples 50 to 59 Following the procedure of Example 44 except substituting for chloromethylmethyldiethoxysilane, the compound shown in Table I, Column I below, and substituting for 1,3-bis-(methoxycarbonyl)-S-methylisothiourea, the compound shown in Column II, the compound shown in Column III is obtained. tf CM Ο ϋ I s tf CM o □ a a in in m in in n a Β η Β B n a nn a cm cm a cm cm a cm a a ουυυουυυδδ □ I w ro a o o in id ο m m cn nan na η n na a n j·* .Γ1 F? P cq a a a cm cm a a ouuuouooocj o fi a o o in o m in o in in o w ™ ™ w a jo W co a co .pi a a cm cm a cm a OUUUOUUUUU H σι tf cu CM a o in O in r- in > o co a ro a a co ro a a co a CM CO CM O’ CM a03 a03 cT ?T ?T hT ™ ™ g g2S2g£2g a inminminiominmin Examples 60 to 69 Following the procedure of Example 45, the sulfides of Examples 50 to 59 shown in Column I of Table IX below are oxidized to give the corresponding sulfoxides.

( B CM Column I Column III O<-M u U4 /'X C*i W H Β Β B in in in in in Μ Β B nB US MB mm Β CM CN Ε CM CM B IN Β B OOOOOOOOOO oi B IN B O O in in ο in in o E M MB M M MB B M cm Β B cmBBB cm cm B oooooooooo O in O ui in O - in O B M MB B MB MB M CM E B CM CM B CM B CM B oooooooooo in Ul o o in Ul C o MB MBB MmBB cm B O O CM MB Ο Ο O CM M B ο υ o CM CM CM CM CM Β Β B Β Ε Ο Ο Ο B Ο O — — — O CM CM CM B E CM CM ο Ο Β B — — O O ΟΗίΜΜΜί'ΜΙΟΓ'ΟΟ Ol φφΐφφφψφφΐΰ KO Examples 70 to 79 Following the procedure of Example 46, the sulfides of Examples 50 to 59 shown in Column I of Table III below are oxidized to give the corresponding sulfones.

Column I Column III ftf CM O a as a oi in in tn in cn a Κ cn a a Κ Π N a CM CM cj u cj cj cj cj in ® cn cm a α cj o in O cn 83 cn a cm a CJ CJ CJ ar\ a as tn a cn cm a U CJ o O tn cn a a cm CJ CJ m ma mm as cm as a cj cj cj cj in cn a a cm υ cj in o a cn « „ o in o m r~ in r~ o cna in a a cn cn B a cn a Ma cMmaa CM Oi ω n •4* Ol r>» »*-» , oi Ol Oi 04 Oi 04 Οί SB SC SB CM SB SB Oi Ol SB SB a a U a ο o SB SB u u ·«-» *** CJ U U ,,Ι ··'··· , χ o oHwrtiwiflON» «η aal ι^Γ-Γ'ΐ-ι-'ί-'Γ'-ί',Γ'Γ.

Claims (42)

What is claimed is:

1. A compound of the structure wherein R is lower alkyl of 1 to 7 carbons or phenyllower alkyl of 1 to 7 carbons and A is wherein R^ is lower alkyl of 1 to 7 carbons, Rg is hydrogen or lower alkyl of 1 to 7 carbons, or Rj^ and may be taken together with the carbons to which they attached to form a cycloalkene ring containing from to 10 carbons, Rg is hydrogen or lower alkyl of 1 to carbons, and y is 0 or 1; are wherein R. and R_ are the same or different and are 4 5 hydrogen or lower alkyl of 1 to 7 carbons, Rg is lower alkyl of 1 to 7 carbons or phenyl? Ry and Rg are the same or different and are chlorine, or iodine, m is 0 to 3? n is 0 to 3 bromine, fluroine and m + n is <5; or (0). Rl 0- S i—( C H 2 ) p —S'11 wherein R g , and R^ may be the same or different and are selected from the group consisting of lower alkyl of 1 to 7 carbons or lower alkoxy of 1 to 7 carbons, 2 is 0, 1 or 2 andp is 1 to 5, with the proviso that when A is \ . R io7 Sl R 11 <°> Z —s— R is lower alkyl of 1 to 7 carbons, and physiologically acceptable salts thereof.

2. A compound of the structure wherein R is lower alkyl or 1 to 7 carbons or phenyllower alkyl of 1 to 7 carbons in the alkyl group, Rj. is lower alkyl of 1 to 7 carbons, R2 is hydrogen or lower alkyl of 1 to 7 carbons, or and R 2 ma Y k® taken together with the carbons to which they are attached to form a cycloalkene ring containing from 3 to 10 carbons, and R 3 is hydrogen or lower alkyl of 1 to 7 carbons; y 5 is 0 or 1, and physiologically acceptable salts thereof.

3. The compound as defined in claim 2 having the structure

4. The compound as defined in claim 2 having the 10 structure

5. The compound as defined in claim 2 wherein R is lower alkyl or benzyl.

6. The compound as defined in claim 2 wherein Rj 10 is lower alkyl and R 2 is hydrogen or lower alkyl.

7. The compound as defined in claim 2 wherein R^ and R 2 are taken together with the carbons to which they are attached to form a cycloalkene ring.

8. The compound as defined in claim 2 having the 20 name [5-(l-cyclohexen-l-ylthio)-lH-benzimidazol-2-yl]carbamic acid, methyl ester.

9. The compound as defined in claim 2 having the name [5-(l-cyclohexen-l-ylsulfinyl)-lH-benzimidazol-2-yl] carbamic acid, methyl ester. 47S30

10. A compound of the structure wherein R is lower alkyl of 1 to 7 carbons, or phenyllower alkyl of 1 to 7 carbons in the alkyl group; R^ and Rg are the same or different and are hydrogen or lower alkyl of 1 to 7 carbons, Rg is lower alkyl of 1 to 7 carbons or phenyl, and Ry and Rg are the same or different and are chlorine, bromine, fluorine or iodine; m is 0 to 3; n is 0 to 3; and m + n is <5, and physiologically acceptable salts thereof.

11. The compound as defined in claim 10 wherein R is lower alkyl or benzyl.

12. The compound as defined in claim 10 wherein R^ and Rg are the same or different and are hydrogen or methyl.

13. The compound as defined in claim 10 wherein m is 0, n is 0 and R^ and Rg are hydrogen and R g is in the 1-position.

14. The compound as defined in claim 10 wherein Ry and R g are chlorine or bromine and Rg is lower alkyl in the 1-position.

15. The compound as defined in claim 10 having the name [5-[((2,2-dichloro-l-methylcyclopropyl)methyl]thiojlH-benzimidazol-2-yl]carbamic acid, methyl ester.

16. A compound of the structure 47330 wherein R is lower alkyl containing 1 to 7 carbons, Rg, R 10 and R^^ may be the same or different and are selected from the group consisting of lower alkyl of 1 to 7 carbons or lower alkoxy of 1 to 7 carbons; z is 5 0, 1 or 2 and P is 1 to 5.

17. The compound as defined in claim 16 having the structure Ιθ the structure the structure

18. 20. The compound as defined in claim 16 wherein Rg, R^g and R^^ are lower alkyl.

19. 21. The compound as defined in claim 16 wherein Rg and are lower alkyl and R^ is lower alkoxy.

20. 22. The compound as defined in claim 16 having the name (5-[(diethoxymethylsilylmethyl)thio]-1Hbenzimidazol-2-yl]carbamic acid, methyl ester.

21. 23. The compound as defined in claim 16 having the name (5-((diethoxymethylsilylmethyl)sulfinyl]-1Hbenzimidazol-2-yl]carbamic acid, methyl ester.

22. 24. The compound as defined in claim 16 having the name [5-[(diethoxymethylsilylmethyl)sulfonyl]-1Hbenzimidazol-2-yl]carbamic acid, methyl ester.

23. 25. The compound as defined in claim 16 having the name N-[5-[((trimethylsilyl)methyl]thio]-2-benzimidazolyl]-carbamic acid, methyl ester.

24. 26. The compound as defined in claim 16 having the name N-[5-([(trimethylsilyl)methyljsulfinyl]-2benzimidazolyl]carbamic acid, methyl ester.

25. 27. The compound as defined in claim 16 having the name N-[5-[[(trimethylsilyl)methyl]sulfonyl]-2benzimidazolyl]carbamic acid, methyl ester.

26. 28. An anthelmintic composition comprising an effective amount of a compound as defined in claim 1, and a pharmaceutically acceptable carrier therefor.

27. 29. A method for treating helminthiasis which comprises administering to a/mammafian host an effective amount of the composition as defined in claim 28.

28. 30. The method as defined in claim 29 wherein said composition is administered orally.

29. 31. The method as defined in claim 29 wherein said composition is administered parenterally.

30. 32. A pharmaceutical composition for use in treating or preventing tapeworm or whipworm comprising a therapeutically effective amount of a compound as defined in claim 10 and a pharmaceutically acceptable carrier therefor.

31. 33. A method for treating or preventing tapeworm or whipworm in a/mammalian or poultry host, which comprises administering to a host a therapeutically effective amount of the composition as defined in claim 32.

32. 34. The method as defined in claim 33 wherein the compound present in said composition has the name [5-(((2,2-dichloro-l-methylcyclopropyl)methyl]thio]-1Hbenzimidazol-2-yl]carbamic acid, methyl ester.

33. 35. The method as defined in claim 33 wherein said tapeworm is of the species Taenia pisiformis.

34. 36. The method as defined in claim 33 wherein said tapeworm is of the species Dipylidium caninum.

35. 37. The method as defined in claim 33 wherein said composition is administered over a 2 to 10 day period to provide compound in amounts ranging from about 7 to about 20 mg/kg/day to provide from about 25 to about 400 mg/day in the treatment of tapeworm.

36. 38. The method as defined in claim 33 wherein said composition is administered over a 5 to 9 day period to provide compound in amounts ranging from about 4 to about 10 mg/kg/day in the treatment of whipworm.

37. 39. The method as defined in claim 33 wherein said whipworm is of the species Trichuris vulpis.

38. 40. A method for treating or preventing helminthiasis, which comprises administering to a host a therapeutically effective amount of the composition as defined in claim 32.

39. 41. A process for preparing a benzimidazole derivative, substantially as herein described with reference to any of the Examples.

40. 42. A benzimidazole derivative, whenever 5 prepared by a process according to claim 41.

41. 43. An anthelmintic composition, substantially as herein described.

42. 44. A method of treating or preventing helminthiasis, substantially as herein described.