GB1593721A - Parenteral administration of anthelmintic derivatives of benzimidazoles - Google Patents

Description

(54) PARENTERAL ADMINISTRATION OF ANTHELMINTIC DERIVATIVES OF BENZIMIDAZOLES (71) We, E.R. SQUIBB & SONS INC., a Corporation organised and existing under the laws of the State of Delaware, United States of America, of Lawrenceville-Princeton Road, Princeton, New Jersey, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to the parenteral administration of anthelmintic derivatives of benzimidazoles.

Various benzimidazole compounds are known for their use as anthelmintic agents. For example, U.S. Patent No. 3,574,845 to Actor et al and assigned to Smith Kline discloses 5(6)-benzene ring substituted benzimidazole-2-carbamate derivatives including 5(6) - methylthio - 2 - carboethoxyaminobenzimidazole and various 5(6) - alkyl - 2 - carbomethoxyaminobenzimidazoles.

U.S. Patents Nos. 3,929,821 and 4,002,640 to Beard et al and assigned to Syntex disclose various 5(6)-benzene ring substituted benzimidazole-2-carbamate derivatives including 5(6) - alkylsulfinyl - 2 carbomethoxyaminobenzimidazoles, as well as 5(6) - benzylsulfinyl - 2 carbomethoxyaminobenzimidazole, 5(6) - phenylsulfinyl - 2 carbomethoxyaminobenzimidazole, 5(6) - cycloalkylsulfinyl - 2 carbomethoxyaminobenzimidazoles and 5(6) - cyclopropylmethylsulfinyl - 2 carbomethoxyaminobenzimidazole.

The benzimidazoles mentioned above are said to be active orally.

Other benzimidazoles useful as anthelmintic agents are disclosed in U.S.

Patents Nos. 3,929,822, 3,929,823, 3,929,824, 3,935,209, 3,965,113 and 4,005,202 all to Beard et al and assigned to Syntex; U.S. Patents Nos. 3,682,952 to Actor et al, 3,578,676 and 3,694,455 to Dunn, 3,915,986 and 3,969,526 to Gyurik, all assigned to Smith Kline; and U.S. Patent No. 3,738,993 to Haugwitz et al assigned to Squibb.

The aforementioned patents teach that the benzimidazole compounds disclosed therein are useful orally in treating helminthiasis.

U.S. Patents Nos. 3,954,791 to Loewe et al and 3,928,375 to Duwel et al, both assigned to Hoechst disclose 2 - carbalkoxy - amino - benzimidazole - 5(6) phenyl and phenylthio ethers which are said to be active perorally and subcutaneously.

In accordance with the present invention, it is indeed surprising that sulfoxide derivatives of benzimidazoles herein described may be effectively administered parenterally in the treatment or prevention of helminthiasis inasmuch as most benzimidazole compounds are active only upon oral administration.

The present invention provides a method for treating or inhibiting helminthiasis by parenterally administering to a non-human mammalian host a sulfoxide derivative of a benzimidazole having the structure

or such a compound in physiologically acceptable salt form, wherein R1 is lower alkyl or phenyl-lower alkyl, and R2 is lower alkyl or a group of formula

where R is hydrogen, lower alkyl, halogen, lower alkoxy or nitro, R4 and R5 are the same or different and are hydrogen or lower alkyl. R6 is cycloalkyl m is 0 to 3. and n is 0 to 3, m+n being not more than 5.

The term "lower alkyl" as used herein means straight or branched chain aliphatic hydrocarbon radicals having up to and including seven carbon atoms, preferably one to five carbons, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, amyl, hexyl and heptyl.

The term "lower alkoxy" as used herein refers to lower alkyl groups as defined above attached to an oxygen atom.

The term "halogen" as employed herein refers to chlorine, bromone, iodine, or fluorine with chlorine and bromine being preferred.

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

The term "cycloaklyl" includes cyclic hydrocarbon groups containing 3 to 12 carbons. Examples of suitable cycloalkyl groups including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl.

(CH2)m and (H2)n represent a single bond or straight or branched chain alkylene radicals containing 3 or less carbons in the longest normal chain.

Preferred are those compounds wherein R is methyl, ethyl, propyl or benzyl and R is n-propyl, i-propyl, n-butyl- or (2-methylpropyl), or a group of the aforesaid formulae wherein m is 0, n is 0 or 1, R4 is hydrogen or methyl, R5 is hydrogen and R6 is cyclopropyl, cyclopentyl, cyclohexyl or cyclooctyl.

Examples of compounds which may be employed in the method of the present invention include the following.

A Rl R2 I. CH3 CH3 2. CH3 C2H5 3. C2H5 n-C3H7 4. C3H7 i- C3H7 5. CH3 n-C4H9 6. C6H5CH2 s- C4H9 7. C6H5CH2 t-C4H9 8. CH3 n-C3H7 9. CH3 i-C4H9 10. C2H5 n-C5H11 11. CH3 n-C6H13 12. CH3 n C71113

B R' R3 1. CH3 H 2. CH3 H 3. C2H5 CH3(4) 4. C3H7 H 5. CH3 NO2(3) 6. C6H5CH2 H 7. C6H5CH2 H 8. CH3 C2H5O(2) 9. CH3 Cl(4) 10. C2H5 H

(CH2)m (CH2)n R R4 R5 R6 1. CH3 H H 2. CH3 H H 3. C2H5 CH3 H 4. C3H7 H H 5. CH3 H H 6. C6H5CH2 H H 7. C6H5CH2 H H

R1 R4 R5 R6 (CH2)m (CH2)n

8. CH3 H H C - 9. CH3 H C2H5 0 CH2 Cil 10. C2H5 H H t The benzimidazole derivatives of structures A and B may be prepared as described in U.S. Patents Nos. 3,929,821 and 4,002,640 to Beard et al.

The benzimidazole derivatives of structure C may be prepared by thiocyanation of o-nitroaniline to yield 4-thiocyano-2-nitroaniline (1). This product is then subjected to a sodium borohydride reduction to yield the corresponding 4-mercapto-2-nitroaniline (II). The mercapto derivative may be isolated or used directly for the next step. Thus, to the reaction mixture there is added the haloalkyl cycloalkane III to furnish the sulfide IV which preferably is converted to its acetyl derivative.

C SCN%rt . < OC and NH2 NH2 jYS Oso I Na aH4 * NH2 R4 fP6 in -5 A/ ? 2+ RS-KcA)m-c-(cN?)n-Y R'5 R5 NH (wherein X is Cl or Br) Br The sulfides of structure IV (preferably their acetyl derivatives) are converted to the corresponding sulfoxides by oxidizing agents such as hydrogen peroxide, peracids (e.g., peracetic acid, m-chloroperbenzoic acid), manganese dioxide or sodium metaperiodate as outlined by Sandler and Caro (Organic Functional Group Preparations, 1968, p. 493).

The resulting sulfoxides V may be purified by crystallization and then reduced to the corresponding o-phenylene diamine VI. 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 C, namely ring closure of VI to furnish C, can be achieved in various ways. Whereas refluxing of VI with the isolated thiourea derivative VII in alcohols such as methanol or ethanol will furnish C, the preferred method of preparing C is by forming VII in situ and then without isolating it adding VI and refluxing it for 30 minutes to 5 hours to yield the desired product.

An alternative route toward the intermediate VI offers the reaction of VIII with the requisite mercaptoalkyl cycloalkane IX to yield X. Here, in contrast to the alkylation step described above, (i.e. II ,IV) the reaction temperature has to be higher and the reaction periods have to be longer. Oxidation of X yields the sulfoxide XI which on reduction furnishes the diamine VI.

Compounds of structure C may also be synthesized bv converting intermediate IV into the o-phenylenediamine XII as outlined above which is then cyclized to the benzimidazole XIII. The final step, i.e., oxidation of XIII, yields C.

Examples of suitable haloalkyl cycloalkanes of formula III suitable for use herein include the following.

Cycloprane Cyclobutanes Cyclopentanes Cyclohexanes

Cycloheptanes Cyclooctanes Cyclononanes Cyclodecane Cycloundecanes

A great variety of haloalkyl cycloalkanes III are commercially available. In some cases the requisite haloalkyl cycloalkane has to be synthesized. for example, from the corresponding alcohols by standard reactions.

In certain instances, the compounds of formula A, B and C 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 be 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, and toluensulfonate.

In accordance with the method of the present invention, the compounds of formula A, B and C are administered parenterally, such as subcutaneously, intravenously, intramuscularly or interperitoneally to a non-human mammalian host in the treatment and/or prevention of helminthiasis. Helminthiasis is a parasitic disease which causes widespread and often serious infection in domesticated animals such as swine, horses, cattle, dogs, cats and sheep. The compounds administered parenterally are useful in treating infections caused by haemonchus, Ostertagia, Trichostrongylus, Cooperia, Dictyocaulus, Nematodirus, Bunostomum, Stronglyoides, Oesophagostomum, Trichuris, Moniezia and liver flukes. In preparing injectable compositions for use in treating or inhibiting helminthiasis in mammalian species according to the invention, the compounds are mixed with a non-toxic, physiologically acceptable non-pyrogenic injectable carrier selected from sterile water (e.g. in the form of sterile saline solution), benzyl benzoate, 1,3-butylene glycol, ethyl oleate, caster oil, glyceryl triacetate, sesame oil, mixtures thereof, and sesame oil: benzyl benzoate (e.g. 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 formula A, B or C.

The above injectable compositions may also include a non-toxic physiologically acceptable non-pyrogenic suspending agent. Thus, where a nonoily carrier is employed such as water, suspending agents such as carboxymethyl 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 100 g).

A non-toxic, non-pyrogenic wetting agent may also be included in the injectable compositions in amounts ranging from about 0.005 to about 0.2% 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) Trade Mark) 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, Volum 19, page 507 et seq.

The compounds of Formula A may also be administered percutaneously i.e. by absorption through the skin for systemic transmission.

In preparing such percutaneous compositions according to the invention, the anthelmintic compounds are mixed with a non-toxic physiologically acceptable carrier which is 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 systemic absorbance via 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 13-250"C, e.g., 18-220"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 alkyl-benzene 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 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 parenteral or percutanoeus composition described above will be administered to animals in a single dose to provide from about 1 to about 100 mg active compound per kilogram of animal body weight. It is preferred to employ it in the range of 2.525 mg per kilogram of body weight. The compounds may be divided into a plurality of smaller doses given over one or more days, for example, up to 14 days.

The following examples are provided for illustrative purposes and may include particular features of the invention. All temperatures are in degrees centigrade.

Example 1 Parenteral Composition Containing [5-[(n-propyl)sulfinyl] lH-benzimidazol-2-yl]carbamic acid, methyl ester A. [5 - [(n - Propyl)sulfinyl] - I H - benzimidazol - 2 - yl] - carbamic acid, methyl ester (I) Preparation of n-Propyl Methanesulfonate To an ice cooled solution of 30 g (37.3 ml, 0.5 mol) of n-propanol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methansulfonyl chloride over 30 minutes.

The reaction mixture is stirred with continued cooling for 0.5 hour. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% HCI, saturated KHCO3, saturated NaCI and dried (MgSO4). Solvent is removed in vacuo to yield 65.3 g (95%) of n-propyl methanesulfonate as an oil.

(2) Preparation of 4-(1-Propyl sulfenyl)-2-nitroaniline To a solution of 19.5 g (0.1 mol) 4 - thiocyano - 2 - nitroaniline dissolved in 200 ml ethane nitrile is added 3.78 g (0.1 mol) sodium borohydride portionwise, over I hour. To the resulting mixture is added 14.49 g n-propyl methanesulfonate, dropwise. The reaction mixture is heated to reflux for 30 minutes. then stirred at 20 for 2 hours. The resulting paste is partitioned between water and ether, the layers separated, and the aqueous phase reextracted with ether. The organic phases are combined, washed with aqueous K2CO3 and aqueous NaCI, dried, filtered and stripped in vacuo to yield 21 g of red oil which is taken up in CH2CI2, filtered through a silica pad, stripped in vacuo and crystallized from ether/petroleum ether to yield 14.35 g of4 - (I - propyl sulfenyl) - 2 - nitroaniline in the form of a red solid, m.p. 40410, 68% yield.

(3) Preparation of 4-(1-Propylsulfinyl)-2-nitroaniline To an ice-cold solution of 8.48 g (40 mMol) 4 - (1 - propylsulfenyl) - 2 nitroaniline in 150 ml methanol is added 8.98 g (42 mMol) NaIO4 in 150 ml H2O.

The resulting suspension is stirred at 5 C for 16 hours, and then partitioned between water and CH2Cl2. The aqueous is reextracted with CH2Cl2, the organics combined, washed with saturated NaCI, dried, filtered and stripped in vacuo to yield 8.5 g yellow solid which is recrystallized from acetonitrile to yield 7.15 g of 4 - (1 - propylsulfinyl) - 2 - nitroaniline in the form of an orange solid, m.p. 109112 , 78% yield.

(4) Preparation of 4-( 1 -Propylsulfinyl)- I ,2-diaminobenzene To a solution of 6.84 g (0.03 mol) of 4 - (1 - propylsulfinyl) - 2 - nitroaniline in 100 ml ethanol is added 18.02 g (0.103 mol) sodium hydrosulfite in 100 ml water and 22 mg concentrated aqueous NH3. The resulting solution is heated to reflux for 1 hour, cooled, alcohol stripped and the aqueous layer extracted with CH2CI2.

The organics are combined, dried, filtered and evaporated in vacuo to yield 3.56 g of 4 -(1 - propylsulfinyl) - 1,2 - diaminobenzene in the form of an oil, 60% yield.

(5) Preparation of 1,3-Bistmethoxycarbonyl)-S-methyl isothiourea To a mixture of 73.8 g (0.3 mol) 2-methyl 2-thio pseudouronium sulfate in 300 ml H2O at 5 C is added, dropwise, through separate addition funnels, methyl chloroformate and 50% aqueous NaOH to maintain pH at 7-8 (monitored with a pH meter). After 1 hour, 185 ml (1.2 mol) methyl chloroformate and 200 ml aqueous NaOH have been added. The resulting mixture is extracted with dichloromethane, the extracts combined, washed with water, dried, filtered and stripped to yield 41 g of white solid which is recrystallized from 30 ml methanol to yield 25.95 g of 1,3 - bis(methoxycarbonyl) - S - methyl isothiourea in the form of white crystals, m.p. 9498%, yield 45%.

(6) Preparation of [5 - (Propylsulfinyl) - 1H - benzimidazol - 2 - yllcarbamic acid, methyl ester To 3.56 g (18 mMol) 4 (I - propylsulfinyl) - 1,2 - diaminobenzene in 45 ml methanol is added 1.03 ml acetic acid and 3.84 g (19.8 mMol) 1,3 bis(methoxycarbonyl) - S - methyl isothiourea. The resulting solution is heated to reflux for 2-1/2 hours, cooled and the solvent stripped. The white solid is digested with water, filtered, washed with ether and dried to yield 4.1 g of the title compound in the form of a white solid, m.p. 215--216", yield 81%.

B. Parenteral Formulation of [5 - [(n - propyl)sulfinyl] - IH - benzimidazol - 2 yllcarbamic acid, methyl ester A suspension suitable for subcutaneous administration is prepared by dispesing 150 mg of [5 - [(n - propyl)sulfinyl] - I H - benzimidazol - 2 yl]carbamic acid, methyl ester in about 10 ml of water for injection, USP. The resulting suspension contains 1.5% by weight of the benzimidazole compound.

Example 2 Testing of Parenteral Formulation of [5-[(n-propyl) sulfinyl]-1H-benzimidazol-2-yl]carbamic acid, methyl ester The following test is carried out to determine the effectiveness of treating sheep infected with gastrointestinal nematodes by subcutaneously administering a single dose of an aqueous suspension of [5 - [(n - propyl)sulfinyl] - I H benzimidazol - 2 - ylicarbamic acid, methyl ester prepared in Example 1 so as to inject 10 mg of the above benzimidazole compound per kg of body weight of the test animal.

Egg per gram of feces (EPG) counts are conducted 2--4 days (avg. 3) prior to subcutaneously administering the above benzimidazole compound in order to determine the degree of parasitism of the test animal. Generally, animals are used which have at least 10,000 eggs per gram of feces although, on occasion, lambs with 8-9,000 eggs per gram can be used. An average pretreatment EPG is calculated for the test animal and medication is given according to individual body weight (10 mg/kg).

EPG's are conducted daily during the week the animal is on test and the final three (3) EPG's are used to calculated an average post-treatment EPG. The percent reduction in the EPG count for a given compound is calculated by taking the average pretreatment EPG and dividing this figure into the average posttreatment EPG and subtracting the quotient from 100.

The [5 - [(n - propyl)sulfinyl] - 1H - benzimidazol - 2 - yl]carbamic acid, methyl ester in the form of an aqueous suspension reduces the fecal egg count (EPG) by 70%, when administered subcutaneously at 10 mg/kg.

Example 3 Parenteral Composition Containing [5-[(2-methyl propyl)-sulfinyl]- I H-benzimidazol-2-yl] carbamic acid, methyl ester A. [5 - [(2 - Methylpropyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester (1) Preparation of isobutyl methanesulfonate To an ice cooled solution of 37 g (46.1 ml, 0.5 mol) of isobutyl alcohol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methanesulfonyl chloride. The temperature of the reaction mixture during the addition is ca. 10 . The reaction mixture is then stirred for 1.5 hours at 100. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% MCI, saturated KHCO3, saturated NaCI and dried (MgSO4). Solvent is removed in vacuo to yield 68 g (90%) of the isobutyl methanesulfonate as an oil.

(2) Preparation of 4-(2 - methylpropyl)sulfonyl - 2 - nitroaniline To a solution of 19.5 g (0.1 mol) 4 - thiocyano - 2 - nitroaniline in 130 ml dimethylformamide is added 3.78 g (0.1 mol) sodium borohydride, all at once. The mixture is stirred for 1/2 hour, then 15.2 g (0.1 mol) 2-methylpropyl methanesulfonate in 70 ml dimethylformamide is added. The solution is-stirred at 30 for 3 hours, cooled and partitioned between water and dichloromethane. The layers are separated and the aqueous phase reextracted with dichloromethane.

The organic phases are combined, washed with aqueous K2CO3, water and saturated NaCI, dried, filtered and stripped to yield a red solid which is crystallised from ether/petroleum ether to yield 14.4 g of solid which is recrystallized from cyclohexane to yield 13.1 g of 4 - (2 - methylpropyl)sulfenyl - 2 - nitroaniline in the form of brilliant red crystals, m.p. 56.5--58.5", 58%.

(3) Preparation of 4 - (2 - methylpropyl)sulfinyl - 2 - nitroaniline To an ice-cold solution of 9.04 (40 mMol) 4 - (2 - methylpropyl)sulfenyl - 2 nitroaniline in 150 ml methanol is added 8.98 g (42 mMol) sodium meta-periodate in 150 ml water. The resulting suspension is stirred at 50C for 42 hours, then partitioned between water and dichloromethane. The layers are separated and the aqueous layer reextracted. The organic layers are combined and washed with saturated NaCI, dried, filtered and stripped to yield 9.5 g yellow-green solid which Is crystallized three times from acetonitrile to yield 6.47 g of 4-(2methylpropyl)sulfinyl-2-nitroaniline in the form of a yellow crystalline solid, m.p.

111.118.50, yield 67%.

(4) Preparation of 4-(2-methylpropyl)sulfinyl-1,2-diaminobenzene To a solution of 6.29 g (26 mMol) 4 - (2 - methylpropyl) - sulfinyl - 2 nitroaniline in 100 ml ethanol is added 15.39 g (88 mMol) sodium hydrosulfite in 100 ml H2O and 20 ml concentrated aqueous NH3. The resulting solution is heated to reflux for I hour, cooled, alcohol stripped and the aqueous mixture extracted with dichloromethane to yield 3.09 g of 4 - (2 - methylpropyl)sulfinyl - 1,2 diaminobenzene in the form of an orange oil, yield, 56%.

(5) Preparation of [5 - [(2 - methylpropyl)sulfinyll - I H - benzimidazol - 2 yl]carbamic acid, methyl ester To 3.09 g (14.5 mMol) of 4 - (2 - methylpropyl)sulfinyl - 1,2 diaminobenzene in 35 ml methanol and 0.84 ml acetic acid is added 3.11 g (16 mMol) 1,3 - bis(methoxycarbonyl) - S - methyl isothiourea, prepared as described in Example 1A(5), and the resulting solution heated to reflux for 3 hours. The solvent is removed in vacuo, the solid digested with water and filtered and washed with ether. The resulting orange solid is recrystallized from 35 ml ethanol to yield 3.0 g of the title compound, m.p. 198201 , yield, 70%.

B. Parenteral Formulation of [5 - (2 - methylpropyl)sulfinyll - lH benzimidazol - 2 - yl]carbamic acid, methyl ester A suspension suitable for subcutaneous administration is prepared by dispersing 150 mg of[5 - [(2 - methylpropyl) - sulfinyll - IH - benzimidazol - 2 yl]carbamic acid, methyl ester in about 10 ml of water for injection, USP. The resulting suspension contains 1.5% by weight of the benzimidazole compound.

Example 4 Testing of Parenteral Formulations of [5-[(2-methyl propyl)-sulfinyl]- I H-benzimidazol-2-yl] carbamic acid, methyl ester In a manner similar to that described in Example 2, the compound of Example 3 is tested to determine the effectiveness of treating sheep infected with gastrointestinal nematodes by subcutaneously administering a single dose of an aqueous suspension of [5 - [(2 - methylpropyl) - sulfinyll - 1H - benzimidazole 2 - yl]carbamic acid, methyl ester (prepared in Example 3) so as to inject 10 mg of the above benzimidazole compound per kg of body weight of the test animal: The [5 - [(2 - methylpropyl)sulfinyll - IH - benzimidazol - 2 - yllcarbamic acid, methyl ester in the form of an aqueous suspension reduces the fecal egg coun so as to provide 10 mg of the above benzimidazole compound per kg of body weight of the test animal.

The Example 6A formulation is found to be extremely effective in reducing the fecal egg count (EPG), when administered cutaneously at 10 mg/kg.

Example 7 Parenteral Composition Containing [5 (Phenylsulfinyl)- I H-benzimidazol-2-yl] carbamic acid, methyl ester A. [5 - (Phenylsulfinyl) - 1H - benzimidazol - 2 - yl] - carbamic acid, methyl ester To a solution of 4.0 g of [5 - (phenylthio) - I H - benzimidazol - 2 yl]carbamic acid, (prepared as described in U.S. Patent No. 3,965,113) in 120 ml of chloroform acid and 120 ml of acetic acid, there is added a solution of 2.8 g of mchloroperoxybenzoic acid (85%) in 20 ml of chloroform at OOC. The reaction mixture is stirred for 3 hours allowing it to warm to room temperature. The solvent is removed in vacuo and the residue is neutralized with aqueous NaMCO3.

The resulting solid is filtered off and crystallized from glyme to yield 2.4 g of product, m.p. N250", resolidifies, remelts 285--286"C. Lit m.p. N250"C, resolidifies, remelts 275--278"C. J. Med Chem 18, 1164 (1975).

B. Parenteral Formulation of [5 - (phenylsulfinyl) - IH - benzimidazol - 2 yl]carbamic acid, methyl ester A suspension suitable for subcutaneous administration is prepared by dispersing 150 mg of [5 - (phenylsulfinyl) - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester in about 10 ml of water for injection, USP. The resulting suspension contains 1.5% by weight of the benzimidazole compound.

Example 8 Testing of Parenteral Formulation of [5 (Phenylsulfinyl)- 1 H-benzimidazol-2-yl] carbamic acid, methyl ester The test as outlined in Example 2 is carried out to determine the effectiveness of treating sheep infected with gastrointestinal nematodes by subcutaneously administering a single dose of an aqueous suspension of [5 - (phenylsulfinyl) I H - benzimidazol - 2 - yl)carbamic acid, methyl ester (hereinafter referred to as "benzimidazole compound") prepared in Example 7 so as to inject 10 mg of the "benzimidazole compound" per kg of body weight of the test animal.

The "benzimidazole compound" in the form of an aqueous suspension reduces the fecal egg count (EPG) by 87% in one sheep and by 57% in a second sheep when administered subcutaneously at 10 mg/kg.

Example 9 Parenteral Composition. Containing [5-[(Cyclo propylmethyl)sulfinyl]- I H-benzimidazol- 2-yl]carbamic acid, methyl ester A. 4 - (Cyclopropylmethyl)thio - 2 - nitroaniline To a stirred mixture of 11.7 g (0.06 mole) of 2 - nitro - 4 - thiocyanoaniline in 500 ml of absolute ethanol under nitrogen there is added 2.5 g (0.06 mole) of sodium borohydride in portions. The mixture is stirred at room temperature for 15 minute and then refluxed for 15 minutes. The heating mantle is removed and 3.9 g (0.06 mole) of KOH in 25 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 4.8 g (0.06 mole) of (chloromethyl)cyclopropane in 10 ml of absolute ethanol is added and the mixture is stirred at room temperature for 15 minutes then refluxed for 2 hours. Equal amounts of water and CMCl3 are added until 2 layers are formed. The organic layer is separated, dried (MgSO4), and the solvent removed in vacuo to give 9.1 g of an orange-red solid, m.p.

45--47".

B. 4 - (Cyclopropylmethyl)thio - 0 - phenylenediamine A mixture of 6.75 g (0.03 mole) of 4 - (cyclopropylmethyl)thio - 2 nitroaniline and 0.5 g of PtO2 in 200 ml of absolute ethanol is reduced on the Parr hydrogenator at 50 psi. The mixture is filtered and the solvent is removed in vacuo to yield the solid diamine, m.p. 57--60"C.

C. [5 - [(Cyclopropylmethyl)thiol - 1H - benzimidazol - 2 - yllcarbamic acid, methyl ester To a mixture of 9 g of 2 - methyl - 2 - thiopseudourea sulfate in 6 ml of water there is added 5.7 ml of methyl chloroformate at OOC and the mixture is stirred for 15 minutes. Then there is added 12 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. The total amount of 4 (cyclopropylmethyl)thio - o - phenylenediamine from above in 50 ml of methanol is then added and the mixture is refluxed for 2 hours. The alcohol is removed in vacuo and water is added. The resulting solid is filtered off and crystallized from glyme-acetonitrile to yield 3.9 g, m.p. 228231 .

D. [5 - [(Cyclopropylmethyl)sulfinyll - 1H - benzimidazol - 2 - yllcarbamic acid, methyl ester To a solution of 2.77 g of [5 - l(cyclopropylmethyl)thiol - lH benzimidazol - 2 - yllcarbamiac acid, methyl ester in 120 ml of chloroform and 120 ml of acetic acid at 20a, there is added at once a solution of 2.1 g of mchloroperbenzoic acid in 20 ml of chloroform. The stirred mixture is allowed to react slowly at room temperature after 4 hours of stirring. The chloroform is evaporated in vacuo. The remaining mixture is neutralized with aqueous sodium bicarbonate. The resulting solid is filtered off and crystallized from glyme to yield 1.2 g, m.p. 223224 of the title compound.

E. Parenteral Formulation of [5 - [(Cyclopropylmethyl)sulfinyl] - 1H benzimidazol - 2 - yllcarbamic acid, methyl ester A suspension suitable for subcutaneous administration is prepared by dispersing 150 mg of [5 - [(cyclopropylmethyl)sulfinyl] - 1H - benzimidazol - 2 yl]carbamic acid, methyl ester in about 10 ml of water for injection, USP. The resulting suspension contains 1.5% by weight of the benzimidazole compound.

Example 10 Testing of Parenteral Formulation of [5-[(Cyclo propylmethyl)sulfinyl]- 1 H-benzimidazol-2-yl] carbamic acid, methyl ester The test as outlined in Example 2 is carried out to determine the effectiveness of treating sheep infected with adult and immature lung worm and tapeworm by subcutaneously administering a single dose of an aqueous suspension of [5 [(cyclopropylmethyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester (hereinafter referred to as "benzimidazole compound" prepared in Example 9 so as to inject 20 mg of the "benzimidazole compound" per kg of body weight of the test animal.

Results of EPG Determination using Sheep Following Subcutaneous Treatment with "Benzimidazole Compound" Pretreatment EPG Unmedicated Control Benzimidazole Compound 10,800 14,200 25,600 16,200 29,800 11100 66,200+3 41,500t3 Avg. 22,067 13,833 Post-treatment EPG Unmedicated Control Benzimidazole Compound 41,400 0 34,600 200 21,600 200 97,600+3 400t3 Avg. 32,533 133 0% reduction 99.99% reduction in EPG in EPG The "benzimidazole compound" in the form of an aqueous suspension reduces the fecal egg count (EPG) by 100% when administered subcutaneously at 20 mg/kg.

Similar tests are carried out using different dosages of the aqueous suspension of the "benzimidazole compound," namely, 10 mg/kg, 5 mg/kg, and 2.5 mg/kg, administered subcutaneously. The results of these tests show that fecal egg count (EPG) is reduced by 100% at 10 mg/kg, 100% at 5 mg/kg and 94% at 2.5 mg/kg.

Example 11 Parenteral Composition Containing [5-[(Cyclo hexylmethyl)sulfinyl]-l H-benzimidazol-2 yl]carbamic acid, methyl ester A. 2-Nitro-4-thiocyanoaniline To a well-stirred mixture of 108 g of o-nitroaniline and 128 g of ammonium thiocyanate in 400 ml of acetic acid there is added dropwise a solution of 128 g of bromine in 160 ml of acetic acid below 20"C. The mixture is stirred for 4 hours at room temperature and then poured into 4 liters of water. The resulting solid is filtered off and crystallized from ethanol to yield 86.7 g, m.p. 11 1-I 140C.

B. 4 . (Cyclohexylmethyl)thio - 2 - nitroaniline To a stirred mixture of 9.75 g (0.05 mole) of 2 - nitro - 4 - thiocyanoaniline in 500 ml of absolute ethanol under nitrogen there is added 2.04 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 3.25 g (0.05 mole) of KOH in 15 ml of absolute ethanol is added. The mixture is stirred for 1 minute. A solution of 8.85 g (0.05 mole) of cyclohexyl methyl bromide in 15 ml of absolute ethanol is added and the mixture is stirred at room temperature for 15 minutes then refluxed for I hour. Equal amounts of water and CMCl3 are added until 2 layers are formed. The organic layer is separated, dried (MgSO4) and the solvent removed in vacuo. The residue is crystallized from ethyl ether to yield 8.3 g, m.p. 8082 .

C. 4 - (Cyclohexylmethyl)thio - 0 - phenylenediamine A mixture of 8.0 g (0.03 mole) of 4 - (cyclohexylmethyl)thio - 2 - nitroaniline and 0.5 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 yield the solid diamine, m.p.

76--79"C.

D. [5 - [(Cyclohexylmethyl)thio] - 1H - benzimidazol - 2 - yl]carbamic acid, methyl ester To a mixture of 9 g of 2 - methyl - 2 - thiopseudourea sulfate in 6 ml of water there is added 5.7 ml of methyl chloroformate at 0 C and the mixture is stirred for 15 minutes. Then there is added 12 ml of 25% NaOH dropwise and the mixture is stirred for 15 minutes. Then the total amount of 4 - (cyclohexylmethyl)thio - o phenylenediamine from the above reaction in 50 ml of methanol is added and the mixture is refluxed for 2 hours. The alcohol is removed in vacuo and water is added. The resulting solid is filtered off and crystallized from CH3CN to yield 2.5 g, m.p. 200204 C.

E. [5 - [(Cyclohexylmethyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester To a mixture of 3.2 g of [5 - [(cyclohexylmethyl)thio] - IH - benzimidazol 2 - yl]carbamic acid, methyl ester in 120 ml CMCl3 and 120 ml HOAc at -200C there is added a solution of 2.1 g of m-chloroperbenzoic acid. The resulting mixture is stirred and allowed to warm to room temperature. Stirring is continued for 5 hours and then CMCl3 is removed in vacua. Water is added and the solution is neutralized with NaMCO3. The resulting solid is filtered off and crystallized from acetonitrile (1.5 g) to give the title compound, m.p. 272--274"C.

F. Parenteral Formulation of [5 - [(Cyclohexylmethyl)sulfinyl] - lM benzimidazol - 2 - yl]carbamic acid, methyl ester A suspension suitable for subcutaneous administration is prepared by dispersing 300 mg of [5 - [(cyclohexylmethyl)sulfinyl] - 1H - benzimidazol - 2 yl]carbamic acid, methyl ester and 100 mg carboxymethyl cellulose in about 10 ml of water for injection, USP. The resulting suspension contains 3% by weight of the benzimidazole compound.

Example 12 Parenteral Composition Containing [5-[(Cyclo- butylmethyl)sulfinyll- I H-benzimidazol-2 yl]carbamic acid, methyl ester A. 15 - [(Cyclobutylmethyl)thioi - 1H - benzimidazol - 2 - yll - carbamic acid, methyl ester To a solution of 15 g (0.174 mole) cyclobutanemethanol and 26.4 triethylamine (0.192 mole, 1.5 equivalent) in 800 ml methylene chloride at 0 C is added 14.8 ml (1.1 equivalent) methanesulfonyl chloride in 25 ml methylene chloride over 1 hour. The solution is stirred for an additional 0.5 hour, then washed successively with cold 10% HCI, ice-water, concentrated aqueous NaMCO3, and aqueous NaCI. The organic layer is dried, filtered and stripped to yield 27.8 g of cyclobutanemethyl mesylate as a water-white liquid.

To a stirred solution of 12.3 g (0.063 mole) 2 - nitro - 4 - thiacyanoaniline in 600 ml EtOH, is added 2.84 g Nabs4, all at once. The mixture is stirred for 45 minutes and 4.95 g KOH pellets and 10.35 g (0.063 mol) cyclobutanemethyl mesylate are added. The resulting mixture is heated to reflux for 10 minutes, and stirred at room temperature overnight. The mixture is partitioned between water and methylene chloride; the organic layer is separated, dried, filtered and stripped to yield 15 g, red crystalline solid which is recrystallized from ether-petroleum ether to yield 11.6 g of 4 - (cyclobutylmethylthio) - 2 - nitroaniline as a red crystalline solid, m.p. 4953 .

II g of the above nitroaniline is reduced under pressure in 200 ml absolute ethanol with 1.1 g PtO2. The solution is filtered and stripped to yield 9.7 g of 4 (cyclobutylmethylthio) - o - phenylenediamine as a dark solid.

9.2 g 2 - methyl - 2 - thiopseudo-urea is added to 9.09 ml water at 0 C. To this is added 8.63 ml methyl chloroformate; the resulting paste is stirred 15 minutes. 18.18 ml of 25% aqueous NaOH is added dropwise and then stirred for 15 minutes. 9.09 ml glacial acetic acid is added dropwise and stirred for 15 minutes.

To this mixture is added 9.45 g (0.045 mole) of the above phenylene diamine in 25 ml methanol, and the resulting mixture heated to reflux for 3 hours, cooled, and the product filtered. The resulting solid is washed with ether and acetonitrile and dried to yield 9.4 g of a purple solid. The above solid is recrystallized from glyme to yield 5.6 g of [5 - [(cyclobutylmethyl)thio - I H - benzimidazol - 2 yl]carbamic acid, methyl ester as a tan powder, m.p. 216218".

B. [5 - [(Cyclobutylmethyl)sulfinyl] - 1H - benzimidazol - 2 - yl]carbamic acid, methyl ester 2.5 g (0.0086 mole) of the [5 - [(cyclobutylmethyl) - thio - IH benzimidazol - 2 - yl]carbamic acid, methyl ester is dissolved in 60 ml acetic acid and 60 ml chloroform. To this is added 1.5 g (1 equivalent at 100%) mchloroperbenzoic acid at -100C over 0.5 hour. The mixture is stirred while temperature rises to room temperature.

The chloroform is stripped, and acetic acid azeotroped with heptane yielding an amber oil, which is digested with aqueous NaHCO3; the resulting solids are filtered, washed with H2O, dried overnight and recrystallized from glyme to yield 1.1 g of the title compound, m.p. 198--206".

C. Parenteral Formulation of [5 - [(Cyclobutylmethyl)sulfinyll - 1H benzimidazol - 2 - yl]carbamic acid, methyl ester A suspension suitable for subcutaneous administration is prepared by dispersing 300 mg of [5 - [(cyclobutylmethyl)sulfinyl] - IH - benzimidazol - 2 yl]carbamic acid, methyl ester in about 10 ml of water for injection, USP. The resulting suspension contains 3% by weight of the benzimidazole compound.

Example 13 Parenteral Composition Containing [5-[(Cyclo propylmethyl)sulfinyll- I H-benzimidazol-2 yl]carbamic acid, benzyl ester A. Following the procedure of Example 9 and substituting benzyl chloroformate for methyl chloroformate, the above benzimidazole compound is obtained.

B. Parenteral Formulation of 15 - [(Cyclopropylmethyl)sulfinyll - 1H benzimidazol - 2 - yllcarbamic acid, benzyl ester A suspension suitable for subcutaneous administration is prepared by dispersing 300 mg of [5 - [(cyclopropylmethyl)sulfinyl] - IH - benzimidazol - 2 yl]carbamic acid, benzyl ester and 100 mg of carboxymethyl cellulose in about 10 ml of water for injection, USP. The resulting suspension contains 3% by weight of the benzimidazole compound.

Examples 14 to 21 A. Following the procedure of Example 11 except substituting for cyclohexylmethyl bromide the compound shown in column I of Table I below and substituting for methyl chloroformate the compound shown in column II, the product shown in column III is obtained.

TABLE I Column I Column II Column III

rtlU R4 H R4 Z :1 zj E b (CH2)-C; (CH2)nX Uq " R U Urdu O + ell ru cu N SC 1: t) H Ex. -Clt2m2n x m G No. R6 fi C CH2CH3 E A N o 14. -CH- Cl n-C3H7 as in Column I as in 3: o c Column II I vo en W X 4 16. 0' -C- Cl CR3 CR3 r1 O H O re 0 U E C U U U U C2H5 X I rd rd u al u aw az X I I U) U E Y N ~ E Pr N N :1: N c ~ w UC) UU ~ I vol l O O O (g l X O v U) W b 71 z ri rl rd TABLE I Column I Column II Column III

rl 8 6 6 g rq r t c61 O + uz nr rJ ~ es ~ FS Ex. 6 1 s 1 15 1 No. R R x R R R oiU -- I I E r E O -(CR2)2- Cl ~ rl V I E, vl rq rq ] e: p: o o 21. u -CR2- u CR3 xl rq r I ) x U u m I vc a F,2: 1N = X I N WA 0 C3 X I x l j rd B. Parenteral Formulations of Benzimidazole Compounds of Examples 14 to 21 Suspensions suitable for subcutaneous administration are prepared by dispersing 300 mg of a benzimidazole compound of Examples 14 to 21 in about 10 ml of water for injection, USP. The resulting suspensions contain 3"" by weight of the benzimidazole compounds.

Claims (33)

WHAT WE CLAIM IS:

1. A method of treating or inhibiting helminthiasis, which comprises parenterally administering to a non-human mammalian host a compound of the structure

or such a compound in physiologically acceptable salt form, wherein R' is lower alkyl or phenyl-lower alkyl, R2 is lower alkyl containing I to 7 carbons, or a group of the formula

where R3 is hydrogen, lower alkyl, lower alkoxy, halogen or nitro, R4 and R5 are the same or different and are hydrogen or lower alkyl, R6 is cycloalkyl and m is 0 to 3, n is 0 to 3 and m+n is not more than 5, dispersed in a non-toxic, nonpyrogenic physiologically acceptable injectable carrier.

2. The method as defined in claim 1 wherein, in said compound, R' is lower alkyl or benzyl.

3. The method as defined in claim 1 or 2 wherein, in said compound, R2 is lower alkyl containing 1 to 5 carbons.

4. The method as defined in any preceding claim wherein in said compound, R3 is hydrogen.

5. The method as defined in any preceding claim wherein, in said compound, R6 contains 3 to 12 carbons.

6. The method as defined in any preceding claim wherein, in said compound, R4 and RS are each independently hydrogen or methyl.

7. The method as defined in any preceding claim wherein, in said compound, m is 0 and n is 0, and R4 and RS are both hydrogen.

8. The method as defined in claim I wherein said compound has the name [5 - [(n - propyl)sulfinyl] - 1H - benzimidazol - 2 - yl]carbamic acid, methyl ester.

9. The method as defined in claim I wherein said compound has the name 15 [(2 - methylpropyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester.

10. The method as defined in claim I wherein said compound has the name [5 - (phenylsulfinyl) - 1H - benzimidazol - 2 - yl]carbamic acid, methyl ester.

11. The method as defined in claim I wherein said compound has the name 15 - [(cyclohexylmethyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester.

12. The method as defined in claim 1 wherein said compound has the name [5 - [(cyclopropylmethyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester.

13. The method as defined in claim 1 wherein said compound has the name [5 - [(cyclobutylmethyl)sulfinyl] - I H - benzimidazol - 2 - yl]carbamic acid, methyl ester.

14. The method as defined in any preceding claim wherein said compound is administered by subcutaneous injection.

15. The method as defined in any one of claims 1 to 13 wherein said compound is administered by intravenous injection.

16. An injectable composition for use in treating or inhibiting helminthiasis in mammalian species comprising a compound as defined in any one of claims I to 7, and a non-toxic, non-pyrogenic physicologically acceptable carrier therefor selected from sterile water (e.g. in the form of sterile saline solution), benzyl benzoate 1,3-butylene glycol, ethyl oleate, glyceryl triacetate, mixtures thereof, and a mixture of benzyl benzoate and sesame oil.

17. The composition as defined in claim 16 wherein said compound is as defined in claim 1 and has the name [5 - [(n - propyl)sulfinyl] - lH benzimidazol - 2 - yl]carbamic acid, methyl ester.

18. The composition as defined in claim 16 wherein said compound is as defined in claim 1 and has the name [5 - [(2 - methylpropyl)sulfinyl] - IH benzimidazol - 2 - yl]carbamic acid, methyl ester.

19. The composition as defined in claim 16 wherein said compound is as defined in claim 1 and has the name [5 - (phenylsulfinyl) - IH - benzimidazol 2 - yl]carbamic acid, methyl ester.

20. The composition as defined in claim 16 wherein said compound is as defined in claim 1 and has the name [5 - [(cyclopropylmethyl)sulfinyl] - IH benzimidazol - 2 - yl]carbamic acid, methyl ester.

21. An injectable composition for use in treating or inhibiting helminthiasis in mammalian species comprising a compound of the structure

wherein R' is lower alkyl or phenyl-lower alkyl, R4 and R5 are the same or different and are hydrogen or lower alkyl, and R is cycloalkyl, m is 0 to 3, n is 0 to 3 and m+n is not more than 5, or a physiologically acceptable salt thereof, and sterile water for injection USP as a carrier therefor.

22. The composition as defined in claim 21 wherein said compound has the name [5 - [(cyclopropylmethyl)sulfinyl] - 1H - benzimidazol - 2 - ylicarbamic acid, methyl ester.

23. The composition as defined in claim 21 further including a non-toxic physiologically acceptable non-pyrogenic suspending agent.

24. The composition as defined in claim 23 wherein said suspending agent is carboxymethyl cellulose.

25. A method of treating or inhibiting helminthiasis, which comprises percutaneously administering to a non-human mammalian host a compound of the structure

wherein R' is lower alkyl or phenyl-lower alkyl and R2 is lower alkyl containing 1 to 7 carbons, dispersed in a non-toxic physiologically acceptable carrier which is effective in penetrating the skin whereby the compound is absorbed by the host animal through its skin and transmitted systemically within the animal.

26. The method as defined in claim 25 wherein said compound has the name [5 - [(n - propyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester.

27. The method as defined in claim 25 wherein said compound has the name [5 - [(2 - methylpropyl)sulfinyl] - IH - benzimidazol - 2 - yl]carbamic acid, methyl ester.

28. A method as defined in claim 1, wherein, in said compound, R2 is

where R4, R5, R6, m and n are as defined in Claim 1.

29. A method as defined in Claim 1, wherein, in said compound, R2 is

where R3 is as defined in Claim 1.

30. A method as defined in Claim 1, wherein, in said compound, R2 is lower alkyl containing 1 to 7 carbons.

31. A composition as defined in claim 16, wherein said compound is as defined in claim 1 and R2 is

32. A method as defined in Claim 1, wherein said compound is as named or shown in any of the Examples.

33. A composition as defined in Claim 16, wherein said compound is as named or shown in any of the Examples.