USRE28403E - Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles - Google Patents

Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles Download PDF

Info

Publication number
USRE28403E
USRE28403E US38193773A USRE28403E US RE28403 E USRE28403 E US RE28403E US 38193773 A US38193773 A US 38193773A US RE28403 E USRE28403 E US RE28403E
Authority
US
United States
Prior art keywords
water
added
ethanol
mixture
benzimidazolyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed filed Critical
Priority to US38193773 priority Critical patent/USRE28403E/en
Application granted granted Critical
Publication of USRE28403E publication Critical patent/USRE28403E/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
Expired legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C07D235/32—Benzimidazole-2-carbamic acids, unsubstituted or substituted; Esters thereof; Thio-analogues thereof

Definitions

  • ABSTRACT OF THE DISCLOSURE 5 (6) -n-butyl 0r n-propoxy 2 carbomethoxyaminobenzimidazoles having anthelmintic activity are prepared by reacting methylcyanocarbamate with n-butyl or npropoxy-o-phenylenediamin'e in a suitable organic solvent.
  • This invention relates to anthelmintic compositions containing esters of benzimidazolyl carbamic acids, and their 'thio analogs, benzene ring substituted esters, and to meth- Formula I wherein R is a lower alkyl group containing from one to five carbon atoms, or preferably hydrogen;
  • R is lower alkyl containing from one to six carbon 7 atoms, cycloalkyl including alkyl cycloalky containing from three to ten carbon atoms; akenyl straight or branched chain containing from two to ten carbon atoms; phenyl; or naphthyl;
  • X and X are oxygen or sulfur, with at least one of them being oxygen;
  • Y and Z are hydrogen, alkyl containing from one to fifteen carbon atoms; lower alkoxy containing from one to fifteen carbon atoms, trifiuoromethyl; amino; halogen; preferably chloro or bromo; hydroxy; nitro; lower alkyl thio; alkylamino; dialkylamino; cyano; acylamino containing from two to seven carbon atoms; carboxy; carbalkoxy containing from two to seven atoms; N-alkylcarboxamido; or N,N-dialkylcarboxamido; with the alkyl substituents not specifically defined having from one to eight carbon atoms.
  • R is lower alkyl containing from one to three carbon atoms; and Y and Z are hydrogen, lower alkyl containing from one to eight carbon atoms; lower alkoxy containing from one to eight carbon atoms; amino; alkylamino or dialkylamino, each alkyl group containing from one to four carbon atoms; halogen, preferably chloro; or nitro.
  • Preferred members of Formula II which are wholly novel compounds are those where R is cycloalkyl from three to six carbon atoms, phenyl or naphthyl.
  • the most advantageous compounds are those of Formula II in which one of Y and Z is lower alkyl containing from one to six carbons, or lower alkoxy containing from one to six carbons, and the other is hydrogen; and R is methyl.
  • a novel compound within Formula II of exceptional eflicacy is 5(6) n butyl 2 carbomethoxyaminobenzimidazole, which demonstrates excellent activity against the mouse pinworm at 10 mg./kg.; against important sheep nematodes at 5 mg./kg.; and against the migratory stages of Ascaris suum in mice at 0.1% of the diet.
  • the isomers may be separated for individual use by resolution methods known to the art, such as fractional crystallization of the l-tartrate salts of the carbamates.
  • a synthesis starting with an optically active side chain may yield the desired optical isomer.
  • the compounds of Formula I being weak bases will normally form salts with inorganic and organic acids. Accordingly, the nontoxic salts formed with pharmaceutically acceptable strong inorganic and organic acids may be alternatively employed in the compositions of the invention.
  • Other nontoxic molecular complexes known to exist that can be derived from compounds of Formula I may also be used in this invention, since the anthelr'nintic acivity rests in the benzimidazolyl carbamic acid structure itself.
  • the compounds of Formula I in which R is hydrogen, X is sulfur, and X is oxygen, are prepared by reacting appropriately substituted Z-aminobenzimidazoles with carbon disulfide and an appropriate alcohol to give the corresponding ester of benzimidazolyl thionocarbamic acid by refluxing the reaction mixture on a steam bath.
  • the compound of Formula I in which R is hydrogen R is lower alkyl, X is oxygen, and X is sulfur, are prepared from the corresponding appropriately strongly substituted lower alkyl N-benzimidazolyl thionocarbamate by treatment thereof with an alkyl halide in a suitable solvent.
  • the compounds of Formula I in which R is hydrogen and both X and X are oxygen are prepared by reacting cyanamide in a suitable organic solvent, such as pyridine, with the appropriate R substituted haloformate to form a cyanocarbamate, followed by the addition of an ophenylenediamine to give the corresponding ester of a benzimidazolyl carbamic acid.
  • a suitable organic solvent such as pyridine
  • the haloformate reactant can be a chloroformate or a bromoformate, the chloroformate being preferred for reasons of availability and cost.
  • the choice of the R substituted haloformate is of course dependent upon the particular ester product desired.
  • one to two molar equivalents of an o-phenylenediamine are added slowly to a solution of the cyanocarbamate and the reaction mixture either heated at steam bath temperature for 1-4 hours or allowed to stand at room temperature for a longer period of time, up to 24 hours. Heating for about 3 hours, following reaction at room temperature for an equal period of time is preferred.
  • the o-phenylenediamine reactant can have substituents on the benzene ring which correspond to Y and Z as defined in Formula I.
  • the resulting benzimidazoles hear these substituents at the corresponding position of the benzene ring.
  • the nature of the condensation reaction is such that it is generally applicable to o-phenylenediamines, regardless of the substituents which may appear on the benzene ring.
  • An alternative process for making the anthelmintio compounds of this invention starts with an S-lower alkyl pseudothiourea sulfate.
  • This sulfate is treated with one benzene.
  • This intermediate is reduced with tin chloride to give the corresponding p-aminoalkylbenzene, followed by nitration in mineral acid medium with amyl nitrate to give an o-nitro-p-alkylaniline.
  • This latter intermediate is again reduced with tin chloride to yield a lower alkyl substituted o-phenylenediamine.
  • the diamine intermediate is converted by the afore-discussed thiourea sulfate process to the appropriate lower alkyl substituted benzimidazole- Z-carbamic acid, alkyl ester.
  • the compounds of Formula II in which R is alkyl and Y is dialkylamino and Z is hydrogen, can be prepared starting with a dialkylaminobenzene, and following the above-described sequence of steps to yield the dialkylamino substituted benzimidazole-2-carbamic acid, alkyl ester.
  • the compounds of Formula II wherein R is lower alkyl, Y is alkylamino and Z is hydrogen, are prepared starting with 3,4-dinitroaniline.
  • the dinitro compound is treated with, for example, butyryl chloride to yield 1- butyramido-3,4-dinitrobenzene, which is reduced with lithium aluminum hydride to yield 1-butylamino-3,4-diaminobenzene.
  • This triaminobenzene is converted to the corresponding benzimidazole-Z-carbamic acid, alkyl ester, by the afore-discussed thiourea method.
  • the compounds of Formula II wherein R' is lower alkyl, Y is alkoxy, and Z is hydrogen, are prepared starting with 4-hydroxyacetanilide.
  • the anilide is treated with the appropriate alkyl bromide and an alkali metal hydroxide, to yield the corresponding p-alkoxylacetanilide, according to the procedure of Buu-Hoi et al., J. Chem. Soc., 1955, 1573.
  • the substituted compound is nitrated with red fuming nitric acid, while suspended in glacial acetic acid and acetic anhydride at about 0 C.
  • the resulting o-nitro-p-alkoxyacetanilide is collected, and is recrystallized from methanol.
  • This disubstituted acetanilide is then deacylated by refluxing with an alkali metal hydroxide in ethanol, with the disubstituted aniline being recovered from acidified Water.
  • the disubstituted aniline is then hydrogenated at 50-80 p.s.i. in benzene, with removal of the solvent by distillation, yielding the corresponding diamine.
  • This diamine intermediate is converted by either of the afore discussed cyanamide or thiourea sulfate processes to the appropriate lower alkoxy substituted benzimidazole-Z-carbamic acid, alkyl ester.
  • R is lower alkyl
  • Y and Z are alkoxy
  • R is lower alkyl
  • Y and Z are alkoxy
  • the compounds of Formula II werein R is lower alkyl, and Y and Z are alkoxy, are prepared starting with o-dihydroxybenzene.
  • the benzene is treated with the appropriate alkyl bromide, and an alkali metal hydroxide in ethanol, to yield the corresponding o-dialkoxybenzene.
  • the substituted compound is nitrated with nitric acid while suspended in acetic acid, to yield 1,2-dialkoxy-4,5- dinitro benzene (J. Proc. Roy. Soc., N. S. Wales, 71, 103-11 (1938)), followed by hydrogenation to give the corresponding substituted diamine.
  • the diamine is converted, as previously described, to a 5,6-dialkoxybenzimidazole-Z-carbamic acid, alkyl ester.
  • the benzimidazolyl carbamates of Formula I have been found to possess useful anthelmintic properties, that is, broad spectrum activity against parasites of warm blooded animals, including both mature and immature parasitic forms. In particular, these compounds have been found to exhibit high activity against various helmintic infections of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
  • the disclosed compounds are generally effective in clearing mice of worm infections for laboratory purposes, among others: Syphacia obvelata and Aspicularis tetraptera (mouse pinworm), Nematospiroides dubius (mouse hookworm), and the migratory stages of Ascaris suum.
  • Toxocara canis found in naturally infested dogs.
  • parasitic to this host are Ancylostoma canium, Trichuris vulpis (whipworm), and Physalaptera spp.
  • Compounds of Formula I have also been demonstrated as eflicacious against parasitic gastroenteritis in sheep, such as Haemonchus contortus, Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Trichuris ovis, Cooperia spp., and Strongyloides papillosus. Bunostomum trigonocephalum and Oesophagostornum spp., are other important parasites of sheep.
  • Animals of low weight are treated with unit doses ranging no higher than a few milligrams; whereas animals of high body weight, such as ruminants, require proportionately larger unit doses ranging up to several grams.
  • a single dose is administered daily for each animal species based on the weight of that species.
  • the amount of ingredient administered will depend on the weight of the host, but will usually be between about 1 mg./kg. and 500 mg./kg. of body weight daily.
  • Typical daily dosage in dogs will run from about 25- 200 mg./kg. (preferably 100 25 mg), given orally.
  • ethyl 2-benzimidazolyl carbamate was particularly effective against Trichuris vulpis.
  • the test compound caused a percent reduction ranging from zero up to 100%, in five dogs, with an average of 41% as determined by the number of helminths expelled in voided feces, as compared to the number of T. vulpis surviving an autopsy.
  • a pharmacologically active compound of structural Formula I is usually formulated with a nontoxic carrier therefore to give anthelmintic compositions of this invention.
  • the carrier may be an orally ingestible container for the active ingredient, for example, a hard or soft gelatin capsule; or it may be a pharmaceutically acceptable diluent or excipient of the kind normally used in the production of medicaments, ready for use, for example maize starch, terra alba, lactose, sucrose, calcium phosphate, gelatin, talcum, stearic acid, magnesium stearate, dextrin, agar, pectin or acacia.
  • liquid carriers are peanut oil, olive oil, sesame oil, and water.
  • the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a Wax.
  • the preparation can be tableted, placed in a hard gelatin capsule, or compounded in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 3 gm.
  • the preparation may be in the form of a soft gelatin capsule, placed in an ampule or in liquid suspension.
  • compositions are most often made up in a form suitable for internal administration and may therefore take the form of a liquid, for example, an emulsion or a sterile solution or suspension in Water, oil, such as arachis oil, or other liquid.
  • a liquid for example, an emulsion or a sterile solution or suspension in Water, oil, such as arachis oil, or other liquid.
  • compositions are advantageously made up in a dosage unit form adapted for the desired mode of administration.
  • the dosage unit may take the form of a suspension, tablet, packaged powder, bolus, or encapsulated powder.
  • the quantity of active ingredient in each dosage unit Will be such that one or more units are required for each therapeutic administration.
  • the compounds of Formula I have general anthelmintic activity and accordingly a further and most important aspect of this invention provides a method of treating hehnintic infections in an animal which comp-rises administering, usually orally, to the animal in a sufficient nontoxic, but effective dose, an anthelmintic compound falling within the definition of Formula I, generally in the form of a pharmaceutical or veterinary composition as hereinbefore described.
  • the daily dose range commonly used is from about 1 mg./kg. to about 500 mg./ kg. depending on the species of host and regimen used.
  • One dose per day administration is preferred but up to five of the dosage units described above may be used if desired.
  • the resulting tablets are then coated with methyl methacrylate to form an enteric coating, i.e. a coating which is substantially insoluble in gastric secretion but substantially soluble in intestinal fluids.
  • the active ingredient used in the formulation of the tablets described above may be replaced with other compounds of Formula I having the necessary anthelmintic activity.
  • other materials may be used to form the enteric coating, for example other synthetic plastic materials such as methyl acrylate, cellulose derivatives, hydrogenated caster oil or phthalates.
  • compositions thusly prepared are administered, usually orally, to an infected host from 1-5 times daily for anthelmintic activity.
  • EXAMPLE 1 Preparation of ethyl 2-benzimidazolyl thionocarbamate A mixture of 13.3 g. of Z-aminobenzimidazole, 50 ml. of carbon disulfide, and 30 ml. of absolute ethanol is refluxed for 50 hours. The product is separated by filtration and purified by recrystallization from absolute ethanol.
  • O-Phenylenediamine (10.8 g.) was added and the mixture was allowed to stand at room temperature for three hours,- then heated three hours on the steam-bath. The mixture was cooled to about 0 C., with the solid that formed being collected, washed with cold pyridine, dissolved in aqueous-ethanolic alkali, filtered, and the product precipitated by adding acetic acid. The material had m.p. 33033l C. (dec.). Similarly, the melting points in Examples 4 to 7 are assumed to be of the decomposition products.
  • EXAMPLE 4 Preparation of methyl 2-benzimidazolyl carbamate Using the procedure detailed in Example 3, 3.98 g. of cyanamide, 8193 g. of methylchloroformate, and 20.52 g. of o-phenylenediamine, are reacted to give 2.44 g. of crude product, m.p.,-313-315 C. Two recrystallizations from 9 glacial acetic acid, yielded a purified product of 1.3 g., mp. 320-322 C., whose structure was confirmed by elemental analyses and spectral data.
  • EXAMPLE 5 Preparation of propyl 2-benzimidazolyl carbamate Using the procedure described in Example 3, the desired product may be prepared from n-propyl chloroformate, Cyanamide, and o-phenylenediamine.
  • EXAMPLE 7 Preparation of isobutyl Z-benzimidazolyl carbamate Using the procedure of the foregoing examples, 6 g. of cyanarnide, 19.04 g. of isobutyl chloroformate, and 30.24 g. of o-phenylenediamine are reacted to give a crude product (2 g.) m.p. about 170 C.
  • EXAMPLE 8 Typical Cattle Bolus Containing an Anthelmintic Described Herein Grams Ethyl 2-benzimidazolyl thionocarbamate 2.0 Calcium phosphate 2.5 Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesium stearate 0.05
  • the calcium phosphate and the anthelmintic compound are thoroughly mixed, and the mixture reduced to a particle size finer than 60 mesh.
  • About one-half of the starch is added, as an aqueous paste, and the resulting mixture granulated.
  • the granules are passed through a #10 mesh screen and dried at 110-130 F. for about 8 hours.
  • the dried materials then passed through a #16 mesh screen.
  • the guar gum and the balance of the starch are added and the mixture thoroughly blended. Finally, the remainder of the ingredients are added and the entire mass thoroughly mixed and compressed into a bolus.
  • the magnesium stearate, talcum and gum acacia are of a particle size to pass a #10 mesh screen.
  • EXAMPLE 9 Typical Sheep Drench Containing an Ant-helmintic Described Herein Parts by Weight Ethyl Z-benzimidazolyl carbamate 60 Terra Alba English 35.5 Tragacanth, U.S.P. 3.0 Sodium Lauryl Sulfate 1.5 Water.
  • This powder can be directly admixed with water in concentrations on the order of 5 g. of powder to 5 cc. of water.
  • EXAMPLE 12 Novel Sheep Drench Containing an Anthelmintio' Carbamate Ethyl 2-benzimidazolyl carbamate, l0 grants. 0.1 N HCl solution, quantum sufiicient to make 1 liter.
  • O-Phenylenediamine (20.56 g.) is added with stirring and the mixture is allowed to stand at room temperature for one hour, then is heated two hours on the steam bath, followed by the addition of 240 ml. of H 0.
  • the mixture is cooled to about 0 C., with the solid that formed being collected by suction filtration, and air dried.
  • the material had a ma). (fast heat) about 300 C. It is recrystallized once from 225ml. ethanol, then twice from cold absolute ethanol, which will not raise the melting point of the sample.
  • the purity and structure of the product are confirmed by thin layer chromatography, elemental analyses and spectral data.
  • the pyridine is evaporated with stirring at 50. C., and the resultant slurry of black oil and solid is mixed with 300 ml. ethanol, warmed slightly, and stirred until. all of the black oily liquid dissolves. Only crystalline material is left undissolved. Water (100 ml.) is added and the pyridine is filtered off, washed with ethanol and dried overnight on a porous plate. Crude yield is 13.3 -g. (.059 moles). The product is suspended in 400 ml. of ethanol:water, then ml. of 2.5 NaOH is added. The solution turns black, and almost all of the solid will dissolve. The insoluble material is filtered off and the pH of the solution is adjusted to 7.5 using glacial acetic acid. A light grey solid appears. It is collected, washed (Yield: 10.2 g.)
  • the product is further purified by dissolving in dimethylsulfoxide at 100 C., filtering the dark solution and add- 12 is light tan colored and decomposes with melting at 295- 300 C.
  • the solid product is stirred with boiling Water twice, and then filtered off. It is dried at 25 C. in vacuo over P 0
  • the structure is confirmed by elemental analyses and spectral data.
  • EXAMPLE 17 Typical Cattle Bolus Containing an Anthelmintie Described Herein Grams 2-Carboallyloxyaminobenzimidazole 2.0 Calcium phosphate 2.5 Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesium stearate 0.05
  • the calcium phosphate and the anthelmintic compound are thoroughly mixed, and the mixture reduced to a particle size finer than 60 mesh.
  • About one-half of the starch is added, as an aqueous paste, and the resulting mixture granulated.
  • the granules are passed through a #10 mesh screen and dried at 130 F. for about 8 hours.
  • the dried materials then pass through a #16 mesh screen.
  • the guar gum and the balance of the starch are added and the mixture thoroughly blended. Finally, the remainder of the ingredients are added and the entire mass throughly mixed and compressed into a bolus.
  • the magnesium stearate, talcum and gum acacia are of a particle size to pass a #10 mesh screen.
  • EXAMPLE 18 The above solid components are thoroughly mixed, giving a water dispersable powder. This powder can be directly admixed with water in concentrations on the order of 5 g. of'powder to 5 cc. of water.
  • EXAMPLE 20 70. with 50% aqueous ethanol, and dried on porous plate.
  • DMSO dimethylsulfoxide
  • thermometer 13.9 g. (0.05 moles) of 2-m'ethyl-2-thiopseudoureasulfate in about ml. of water is stirred in an ice bath. Methylchloroformate (9.45 g.0.1 moles) is added at one time. The; mixture is stirred at 0 C., for ten minutes, then a total of 19 ml. of sodium hydroxide is added over ten minutes while maintaining the temperature-below 20 C. j e
  • the addition funnel is replaced by a condenser, attached to three traps for methyl .mercaptan, one empty and two with 10% aqueous NaOI-I. Heat is applied very slowly to the stirred mixture, with gas evolving constantly.” As the temperature rises slowly, ethanol is added, to con-" trol foaming. The total'reflux time is about of an hour. to room temperature and left over" The reaction is cooled the week-end.
  • a light tan solid is suspended in 50% aqueous ethanol, and recollectedl solid is dried on a porous plate in an oven.
  • Ihe product is recrystallized from 1200 to 1400 ml.
  • the structure is confirmed by elemental analysis and spectral data.
  • EXAMPLE 23 Preparation of 5,6-dimethyl-2-carbornethoxyaminobenzimidazole Using a 1-liter B-necked, round-bottomed flask, equipped with mechanical stirrer, addition funnel, and thermometer, 20.4 g. (0.0735 moles) of 2-methyl-2-thiopseudourea sulfate in 10 ml. of water, is stirred and maintained at 0 C. Methylchloroformate (13.9 g..147 moles) is added all at once, followed by the addition of about 40 ml. of 25 aqueous sodium hydroxide, which is added dropwise keeping the temperature about 15 C. and the pH about 6.
  • a condenser replaces the funnel, and the gas outlet on the condenser is attached to a series of three traps. Two traps containing about 10% sodium hydroxide. Heat is applied very slowly, and as the temperature rises gas evolves. Ethanol is added to maintain stirrability. After one-half hour at 95 C., the reaction mixture is further diluted with water and cooled. The pasty mixture is filtered, washed with water, followed by washing with an ethanohwater mixture, and then stirred into an ethanol: Water mixture. It is recollected, and dried overnight on a porous plate.
  • the product (13.3 g.) is recrystallized from 350 ml. DMSO plus 320 ml. of ethanol, and left in a refrigerator overnight. Crystals are collected, Washed with cold ethanol, and air-dried. The solid product is boiled twice with 250 ml. of water, collected, air-dried, and dried at 25 C. in vacuo over P 0 to give pure product, having a mp. of 295-305 C. (d.).
  • the structure is confirmed by elemental analysis and spectral data.
  • EXAMPLE 24 Preparation of 5-methoxy-Z-carbomethoxyamidobenzimidazole In a 500 ml. 3-necked round-bottomed flask, equipped with a thermometer, mechanical stirrer, and dropping funnel, 19.8 g. (0.1 moles) of 2-methyl-2-thiopseudourea sulfate is stirred into 9 ml. of water. It is cooled to about 5 C., and methylchloroformate is added in one portion. The mixture is stirred at 10-15 C., then 21.4 ml. of 25 aqueous sodium hydroxide is added drop-wise over about v. tion mixture.
  • the resulting salmoncolored mixture is cooled, stoppered, and left at room temperature overnight.
  • the product is recrystallized from 1300 m1. 30-ethanol plus 200 ml. of water. Following filtering, recrystallization occurs spontaneously, and it is left in the refrigerator overnight. Y
  • the crystals are collected, washed in 1:1 mixture of ethanol-water, giving a product, which is dried at 25 C. in vacuo over P
  • the product is again recrystallized, from 1500 ml. of ethanol plus 100 ml. of water, collected, and washed with 60-40 mixture of ethanol-water and dried at 25 C.'in vacuo over P 0 yielding the pure product, having an M.P. of 235 C. (d.).
  • EXAMPLE 25 Preparation of S-nitro-2-carbomethoxyaminobenzimidazole To 12.4 g. (0.163 mole of thiourea in 6.2 ml. of water, is added, dropwise, 14 g. (0.11 mole) of dimethyl sulfate with stirring. The mixture becomes warm and colorless, and is refluxed gently for 30 minutes, during which time a white crystalline solid appears. The reaction mixture is then cooled at 2 C., yielding 2-methyl-2-thiopseudourea sulfate.
  • Methylchloroformate (30.8 g.0.326 moles) is added in one portion to the sulfate. To this mixture is added about 75 ml. of 25% aqueous sodium hydroxide, at a rate which maintains the temperature no higher than l5-- C., with the resulting pH of about 7. To this mixture is slowly added 17 ml. of glacial acetic acid.
  • This solid is suspended in 350ccyof 1:1 ethanolwater, and treated with 10% aqueous sodium hydroxide until .a solution, dark brown in color, forms. This is then treated with decolorizing Norit. A, filtered through a Su-' 7 per-Cel mat, and the dark filtrate is neutralized with glacial-acetic acid, togiveaalavender solid. 'This is collected, washed with 1:1 ethanol-water, anddriedl on a porous plate in a steam oven,giving a solid, m.p. 270- 276 C. (d.). i
  • This compound i-s; suspended in 1151 ethanol-water, and
  • the solution is de- .colorized with 'Norit'A and "Darcot ogether.
  • the mixture is filteredgthrough a Super-Celmat, and the filtrate is once again decolorized, again filtered througha Super Cel that,
  • the reaction mixture is put on a Parr shaker. for one" hour, during which time 5 pounds of hydrogen are taken
  • the final-filtrate is, neutralized'with 10% aqueous sodium hydroxide giving-a white solid, whichis filtered'oifiwashed with water, and dried overnight.
  • the compound is suspended in 50%. aqueous ethanol; then.sufficient. 10% aqueous sodium hydroxide isi-added to Y give a solution which is again filtered through asuper-Cel mat. The resulting clear light yellow filtrate is-neutralized to., give awhite. solid, which is filtered off, washed w-ith 1 50% aqueous ethanol, and-dried. ina dessicatorover P 0 in vacuo, giving .the pureproduct, 2336-2375 C.
  • the structure is confirmed by elemental analysis and spectral data.

Abstract

1. 5(6)-N-BUTYL-2-CARBOMETHOXYAMINOBENZIMIDAZOLE.

Description

United States Parent Reissued Apr. 29, 1975 28,403 (6)-N-BUTYL AND N-PROPOXY-Z-CARBO- METHOXYAMINOBENZIMIDAZOLES Philip Paul Actor, Phoenixville, and Joseph Frank Pagano,
Paoli, Pa., assignors to Smithkline Corporation, Philadelphia, Pa.
No Drawing. Original No. 3,682,952, dated Aug. 8, 1972, Ser. No. 48,669, May 19, 1970, which is a division of application Ser. No. 562,117, July 1, 1966, now Patent No. 3,574,845, which is a continuation-in-part of abandoned applications Ser. No. 387,524, Aug. 14, 1964, and Ser. No. 516,120, Dec. 23, 1965. Application for reissue July 25, 1973, Ser. No. 381,937
Int. Cl. C07d 49/38 US. Cl. 260309.2 2 Claims Matter enclosed in heavy brackets II] appears in the original patent but forms no part of this reissue specification; matter printed in italics indicates the additions made by reissue.
ABSTRACT OF THE DISCLOSURE 5 (6) -n-butyl 0r n-propoxy 2 carbomethoxyaminobenzimidazoles having anthelmintic activity are prepared by reacting methylcyanocarbamate with n-butyl or npropoxy-o-phenylenediamin'e in a suitable organic solvent.
[Anthelmintic compositions comprising esters of benzimidazolyl carbamic acids, and their trio analogs, both of which may be optionally substituted on the benzene ring, are disclosed. A process for their preparation involves reacting cyanamide in a suitable organic solvent with the appropriate alkyl substituted haloformate to form a cyanocarbamate, followed by the addition of an o-phenylenediamine to yield the described anthelmintic agents] This application is a reissue of US. Pat. No. 3,682,952 issued Aug. 8, 1972 from Ser. No. 48,669 filed May 19, 1970, which is a divisional application of Ser. No. 562,117 filed July I, 1966 now U.S. Pat. No. 3,574,845 issued April I 3, 1971, which is a continuation-in-part of Ser. No. 516,120 filed Dec. 23, 1965, now abandoned, and Ser. No. 387,524 filed Aug. 4, 1964, now abandoned.
[This application is a division of our copending application, Ser. No. 562,117, filed July 1, 1966, now US. Pat. No. 3,574,845 which application is a continuationin-part of our copending applications. Ser. No. 387,524, filed Aug. 4, 1964 now abandoned, and Ser. No. 516,120, filed Dec. 23, 1965 now abandoned] This invention relates to anthelmintic compositions containing esters of benzimidazolyl carbamic acids, and their 'thio analogs, benzene ring substituted esters, and to meth- Formula I wherein R is a lower alkyl group containing from one to five carbon atoms, or preferably hydrogen;
R is lower alkyl containing from one to six carbon 7 atoms, cycloalkyl including alkyl cycloalky containing from three to ten carbon atoms; akenyl straight or branched chain containing from two to ten carbon atoms; phenyl; or naphthyl;
X and X are oxygen or sulfur, with at least one of them being oxygen; Y and Z are hydrogen, alkyl containing from one to fifteen carbon atoms; lower alkoxy containing from one to fifteen carbon atoms, trifiuoromethyl; amino; halogen; preferably chloro or bromo; hydroxy; nitro; lower alkyl thio; alkylamino; dialkylamino; cyano; acylamino containing from two to seven carbon atoms; carboxy; carbalkoxy containing from two to seven atoms; N-alkylcarboxamido; or N,N-dialkylcarboxamido; with the alkyl substituents not specifically defined having from one to eight carbon atoms.
It is preferred to use as the active ingredient of the 5 novel compositions of this invention, compounds as shown in Formula 11 below:
Formula II wherein R is lower alkyl containing from one to three carbon atoms; and Y and Z are hydrogen, lower alkyl containing from one to eight carbon atoms; lower alkoxy containing from one to eight carbon atoms; amino; alkylamino or dialkylamino, each alkyl group containing from one to four carbon atoms; halogen, preferably chloro; or nitro.
Preferred members of Formula II which are wholly novel compounds are those where R is cycloalkyl from three to six carbon atoms, phenyl or naphthyl.
The most advantageous compounds are those of Formula II in which one of Y and Z is lower alkyl containing from one to six carbons, or lower alkoxy containing from one to six carbons, and the other is hydrogen; and R is methyl.
A novel compound within Formula II of exceptional eflicacy is 5(6) n butyl 2 carbomethoxyaminobenzimidazole, which demonstrates excellent activity against the mouse pinworm at 10 mg./kg.; against important sheep nematodes at 5 mg./kg.; and against the migratory stages of Ascaris suum in mice at 0.1% of the diet.
An accidental synthesis of one of the thio compounds of Formula I has been mentioned in the literature but no 'particular pharmacological activity was attributed to it.
Specifically, the synthesis of the compound ethyl N- benzimidazolyl thionocarbamate has been reported by Wang et al., I. Am. Chem. Soc., 79, 5706 (1957). Similarly, certain compounds of Formula I wherein the R is hydrogen and the Xs are both oxygen are known, but no anthelmintic activity has been suggested for them (US. Pat. Nos. 2,933,502 and 3,010,968).
Examples of specific compounds falling within Formula I are:
Methyl 2-benzimidazolyl carbamate Methyl Z-benzimadazolyl thionocarbamate Ethyl Z-benzimidazolyl carbamate Ethyl 2-benzimidazolyl thionocarbamate 2-Benzimidazolylthiocarbamic acid, S-ethyl ester Propyl Z-benzimidazolyl carbamate Propyl Z-benzimidazolyl thionocarbamate Isopropyl 2-benzimidazolyl thionocarbamate Butyl 2-benzimidazolyl carbamate Butyl 2-benzimidazclyl thionocarbamate Isobutyl 2-benzimidazolyl carbamate sec-Butyl Z-benzimidazolyl carbamate Pentyl 2-benzimidazolyl carbamate Isopentyl Z-benzimidazolyl carbamate Hexyl Z-benzimidazolyl carbamate 4(7)-Methyl-2-carbomethoxyaminobenzimidazole 6-)-Methoxy-Z-carbomethoxyaminobenzifiiidaiole' 4 (7 -Trifluoromethyl-2-carbomethoxyaminobenzimidazole 5 (6) -Amino-2-carboethoxyaminobenzimidazole 4( 7 -Chloro-2-carboethoxyaminobenzimidazole 5 (6 -Hy'clroxy-2-carboethyoxyaminobenzimidazole 4(7) -Nitro-2 carboethoxyaminobenzimidazole 5 6) -Methylthio-Z-carboethoxyaminobenzimidazole 2-Carbovinyloxyaminobenzimidazole 2-Carboethynyloxyaminobenzimidazole 2-Carboallyloxyaminobenzimidazole 2-Carbomethallyloxyaminobenzimidazole 2-Carbodimethallyloxyaminobenzimidazole Z-Carbopropargyloxyaminobenzimidazole 2-Carbopheny1oxyaminobenzimidazole 2-Carbonaphthyloxyaminobenzimidazole Z-Carbocyclopropyloxyaminobenzimidazole Z-Carbo-l-methylcyelopropyloxyaminobenzimidazole 2-Carbocyclobutyloxyaminobenzimidazole 2-Carbocyclopentyloxyaminobenzimidazole 2-Carbocyclohexyloxyaminobenzimidazole 4 (7)-Methyl-2carbovinyloxyaminobenzimidazole 5 6 -Methoxy-2-carboallyloxyaminobenzimidazole 4(7)-Trifluoromethyl-2-carbomethallyloxyaminobenzimidazole 4 6) -Amino-Z-carbodimethylallyloxyaminobenimidazole 4 (7 -Chloro-2-carbopropargyloxyaminobenzimidazole' 5 (6 -Hydroxy-2-carbobutynoxyaminobenzimidazole '4 (7 -Nitro-2-carbopentynoxyaminobenzimidazole 5 (6) -Methylthio-2,2-carbohexynoxyaminobenzimidazole 4 (7 -Bromo-2-carbo allyloxyaminobenzimidazole 5 6) -Chloro-2-carboallyloxyannnobenzimidazole 4( 7 -Ethoxy-2-carboallyloxyaminobenzimidazole 5 6)-Methoxy-2-carboallyloxyaminobenzimidazole 4 (7 -Nitro-2-carboallyloxyaminobenzimidazole 5 (6 -Methyl-2-carboallyloxyaminobenzimidazole 4(7 )-Trifluoromethyl-2-carboallyloxyaminobenzimidazole 5 (6 -Amino-2-carboallyloxyaminobenzimidazole 4.( 7 -Hydroxy-2-carboallyloxyaminobenzimidazole 5 6) -Chloro-2-carbornethoxyaminobenzimidazole 5 (6 )-Amino-2-carbomethoxyaminobenzimidazole 5 (6) -Dirnethylamino-Z-carbomethoxyaminobenzimidazole 5 6) -Methyl-2-carbomethoxyaminobenzimidazole 4(7) -Ethyl-2-carbomethoxyaminobenzimidazole 5 6) -n-Propyl-2-carbomethoxyaminobenzimidazole 5 (6 )-n-B utyl-Z-c arbomethoxyaminobenzimid azole 5 (6 -Methoxy-2-carbomethoxyaminobenzimidazole 4 (7) -Ethoxy-2-carb omethoxyarninobenzimidazole 5 (6 -n-Prop oxy-2-carb omethoxyaminobenzirnid azole 4 (7 -n-Butoxy-2-carbomethoxyaminobenzimidazole 5 (6 -n-Pentyl-2-carb omethoxyaminobenzimidazole 5,6-Dimethyl-2-carbomethoxyaminobenzimidazole 5 (6 -Nitro-2-carbomethoxyaminobenzimidazole 5 6 -n-Pentyl-2-carbometh oxyaminobenzimidazole' 5 6) -Isopentyl-Z-carbomethoxyaminobenzimidazole 5 (6 )-sec-Butyl-2-carbomethoxyaminobenzimidazole 5 6) -Isobutyl-2-carbomethoxyaminobenzimidazole 5(6) -n-Hexyl-2-carbomethoxyaminobenzimidazole 5 6) -n-Heptyl-2-carbomethoxyaminobenzimidazole 5 (6 -n-Octyl-2-carbomethoxyaminobenzimidazole or l-optical isomers, as well as racemic mixtures of these isomers.
If desired, the isomers may be separated for individual use by resolution methods known to the art, such as fractional crystallization of the l-tartrate salts of the carbamates. Alternatively, a synthesis starting with an optically active side chain may yield the desired optical isomer.
The compounds of Formula I being weak bases will normally form salts with inorganic and organic acids. Accordingly, the nontoxic salts formed with pharmaceutically acceptable strong inorganic and organic acids may be alternatively employed in the compositions of the invention. Other nontoxic molecular complexes known to exist that can be derived from compounds of Formula I may also be used in this invention, since the anthelr'nintic acivity rests in the benzimidazolyl carbamic acid structure itself.
The compounds of Formula I in which R is hydrogen, X is sulfur, and X is oxygen, are prepared by reacting appropriately substituted Z-aminobenzimidazoles with carbon disulfide and an appropriate alcohol to give the corresponding ester of benzimidazolyl thionocarbamic acid by refluxing the reaction mixture on a steam bath.
In the case of the compounds of Formula I'in which R is lower alkyl, X is sulfur, and X is oxygen, these may advantageously be prepared by the same general procedure, starting with an appropriately substituted 2-aminobenzimidazole having a lower alkyl grouping on the 1- position.
The compound of Formula I in which R is hydrogen R is lower alkyl, X is oxygen, and X is sulfur, are prepared from the corresponding appropriately strongly substituted lower alkyl N-benzimidazolyl thionocarbamate by treatment thereof with an alkyl halide in a suitable solvent.
The compounds of Formula I in which R is hydrogen and both X and X are oxygen, are prepared by reacting cyanamide in a suitable organic solvent, such as pyridine, with the appropriate R substituted haloformate to form a cyanocarbamate, followed by the addition of an ophenylenediamine to give the corresponding ester of a benzimidazolyl carbamic acid. Thus, these compounds are readily synthesized by prior art methods.
The haloformate reactant can be a chloroformate or a bromoformate, the chloroformate being preferred for reasons of availability and cost. The choice of the R substituted haloformate is of course dependent upon the particular ester product desired.
More specifically, one to two molar equivalents of an o-phenylenediamine are added slowly to a solution of the cyanocarbamate and the reaction mixture either heated at steam bath temperature for 1-4 hours or allowed to stand at room temperature for a longer period of time, up to 24 hours. Heating for about 3 hours, following reaction at room temperature for an equal period of time is preferred.
The o-phenylenediamine reactant can have substituents on the benzene ring which correspond to Y and Z as defined in Formula I. The resulting benzimidazoles hear these substituents at the corresponding position of the benzene ring. The nature of the condensation reaction is such that it is generally applicable to o-phenylenediamines, regardless of the substituents which may appear on the benzene ring. I
An alternative process for making the anthelmintio compounds of this invention starts with an S-lower alkyl pseudothiourea sulfate. This sulfate is treated with one benzene. This intermediate is reduced with tin chloride to give the corresponding p-aminoalkylbenzene, followed by nitration in mineral acid medium with amyl nitrate to give an o-nitro-p-alkylaniline. This latter intermediate is again reduced with tin chloride to yield a lower alkyl substituted o-phenylenediamine. The diamine intermediate is converted by the afore-discussed thiourea sulfate process to the appropriate lower alkyl substituted benzimidazole- Z-carbamic acid, alkyl ester.
The compounds of Formula II in which R is alkyl and Y is dialkylamino and Z is hydrogen, can be prepared starting with a dialkylaminobenzene, and following the above-described sequence of steps to yield the dialkylamino substituted benzimidazole-2-carbamic acid, alkyl ester.
The compounds of Formula II wherein R is lower alkyl, Y is alkylamino and Z is hydrogen, are prepared starting with 3,4-dinitroaniline. The dinitro compound is treated with, for example, butyryl chloride to yield 1- butyramido-3,4-dinitrobenzene, which is reduced with lithium aluminum hydride to yield 1-butylamino-3,4-diaminobenzene. This triaminobenzene is converted to the corresponding benzimidazole-Z-carbamic acid, alkyl ester, by the afore-discussed thiourea method.
The compounds of Formula II wherein R' is lower alkyl, Y is alkoxy, and Z is hydrogen, are prepared starting with 4-hydroxyacetanilide. The anilide is treated with the appropriate alkyl bromide and an alkali metal hydroxide, to yield the corresponding p-alkoxylacetanilide, according to the procedure of Buu-Hoi et al., J. Chem. Soc., 1955, 1573. The substituted compound is nitrated with red fuming nitric acid, while suspended in glacial acetic acid and acetic anhydride at about 0 C. The resulting o-nitro-p-alkoxyacetanilide is collected, and is recrystallized from methanol. This disubstituted acetanilide is then deacylated by refluxing with an alkali metal hydroxide in ethanol, with the disubstituted aniline being recovered from acidified Water. The disubstituted aniline is then hydrogenated at 50-80 p.s.i. in benzene, with removal of the solvent by distillation, yielding the corresponding diamine. This diamine intermediate is converted by either of the afore discussed cyanamide or thiourea sulfate processes to the appropriate lower alkoxy substituted benzimidazole-Z-carbamic acid, alkyl ester.
The compounds of Formula II werein R is lower alkyl, and Y and Z are alkoxy, are prepared starting with o-dihydroxybenzene. The benzene is treated with the appropriate alkyl bromide, and an alkali metal hydroxide in ethanol, to yield the corresponding o-dialkoxybenzene. The substituted compound is nitrated with nitric acid while suspended in acetic acid, to yield 1,2-dialkoxy-4,5- dinitro benzene (J. Proc. Roy. Soc., N. S. Wales, 71, 103-11 (1938)), followed by hydrogenation to give the corresponding substituted diamine. The diamine is converted, as previously described, to a 5,6-dialkoxybenzimidazole-Z-carbamic acid, alkyl ester.
The benzimidazolyl carbamates of Formula I have been found to possess useful anthelmintic properties, that is, broad spectrum activity against parasites of warm blooded animals, including both mature and immature parasitic forms. In particular, these compounds have been found to exhibit high activity against various helmintic infections of the intestinal tract of economically important animals, coupled with low systemic toxicity to the host animal.
For example, the disclosed compounds are generally effective in clearing mice of worm infections for laboratory purposes, among others: Syphacia obvelata and Aspicularis tetraptera (mouse pinworm), Nematospiroides dubius (mouse hookworm), and the migratory stages of Ascaris suum.
Other susceptible helminths include Toxocara canis, found in naturally infested dogs. Also, parasitic to this host are Ancylostoma canium, Trichuris vulpis (whipworm), and Physalaptera spp.
Compounds of Formula II have been demonstrated as efficacious against parasites of pigs, such as the migratory 6 stages of Ascaris suum, thus preventing the development of verminous pneumonia.
Compounds of Formula I have also been demonstrated as eflicacious against parasitic gastroenteritis in sheep, such as Haemonchus contortus, Ostertagia spp., Trichostrongylus spp., Nematodirus spp., Trichuris ovis, Cooperia spp., and Strongyloides papillosus. Bunostomum trigonocephalum and Oesophagostornum spp., are other important parasites of sheep.
Animals of low weight are treated with unit doses ranging no higher than a few milligrams; whereas animals of high body weight, such as ruminants, require proportionately larger unit doses ranging up to several grams. Preferably, a single dose is administered daily for each animal species based on the weight of that species.
The amount of ingredient administered will depend on the weight of the host, but will usually be between about 1 mg./kg. and 500 mg./kg. of body weight daily.
For example, ethyl-N-benzirnidazolyl thionocarbamate at an oral daily dose of 25 mg./kg. tested in clearing mice of natural pinworm infection, following generally the method of McCowen et al., reported in the American Journal of Tropical Medicine, 6, 894 (1957), gave a 45% result in terms of worms cleared; while a 400 mg./kg. dose gave 98%. Its LD in mice is in excess of 1 g./kg.
Ethyl 2-benzimidazolyl carbamate at an oral daily dose of 50 and 250 mg./ kg. for three days, tested in clearing mice of natural pinworm infection, gave 73% and 100% clearance, respectively. Additionally, this same compound, given at a daily dosage of 0.05% and 0.20% of diet for 5 days, against mouse hookworm infection (0.2% of diet approximates 100 mg./kg. of body weight, based on 20 gram mouse) gave a 65% and 100% reduction in the worm burden, respectively.
2-Carboallyloxyaminobenzimidazole at an oral daily dose of 10 mg./kg. tested in clearing mice of natural pinworm infection, following generally the method of McCowen et al., gave a 69.7% 1 result in terms of worms cleared; while at a dose of 50 and 250 mg./kg. for three days, tested in clearing mice of natural pinworm infection, it gave 74.9% and 100% clearance, respectively.
In the same procedure against pinworm 5-chloro-2- carbomethoxyaminobenzimidazole, at an oral daily dose of 10 and 50 mg./kg. gave 55% 1 and 59% clearance, respectively.
Typical daily dosage in dogs will run from about 25- 200 mg./kg. (preferably 100 25 mg), given orally.
In dogs, naturally infested with various gastrointestinal helminths, ethyl 2-benzimidazolyl carbamate was particularly effective against Trichuris vulpis. At 100 mg./kg. of body weight the test compound caused a percent reduction ranging from zero up to 100%, in five dogs, with an average of 41% as determined by the number of helminths expelled in voided feces, as compared to the number of T. vulpis surviving an autopsy.
In lambs, naturally infested with various gastrointestinal nematodes, three of the compounds of Formula I were each tested at 100 mg./kg. of body weight (B.W.), in a single dose of 10% concentration in city water, with the impressive results given in the tabulation below:
In lambs, naturally infested with various gastrointestinal nematodes, three of the compounds of Formula I, (formulated per Example 16) were each tested at the indicated dosages in mg./kg. of body weight (B.W.), in
1 Figure is average of two experiments.
a single dose of 1% concentration in city water, with the striking results given in the tabulation below:
5(6)-methoxy-Z-carbomethoxyarninobenzirnidazole (15 mg. 'g.).
Identification of helminths by examination of the feces of the lambs, both preand post-treatment, in terms of eggs per gram, and also at autopsy, verified that the tabulated compounds were highly active against almost all the sheep helminths enumerated previously. The named methyl compound was also active against Trichuris at 100 mg./kg. B.W. The named allyl compound was quite active against Haemonchus, Strongyloides and Trichuris at 12.5 mg./kg. B.W.
In practice, a pharmacologically active compound of structural Formula I is usually formulated with a nontoxic carrier therefore to give anthelmintic compositions of this invention. The carrier may be an orally ingestible container for the active ingredient, for example, a hard or soft gelatin capsule; or it may be a pharmaceutically acceptable diluent or excipient of the kind normally used in the production of medicaments, ready for use, for example maize starch, terra alba, lactose, sucrose, calcium phosphate, gelatin, talcum, stearic acid, magnesium stearate, dextrin, agar, pectin or acacia.
Exemplary of liquid carriers are peanut oil, olive oil, sesame oil, and water. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a Wax.
A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used, the preparation can be tableted, placed in a hard gelatin capsule, or compounded in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 3 gm. If a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, placed in an ampule or in liquid suspension.
The compositions are most often made up in a form suitable for internal administration and may therefore take the form of a liquid, for example, an emulsion or a sterile solution or suspension in Water, oil, such as arachis oil, or other liquid.
The compositions are advantageously made up in a dosage unit form adapted for the desired mode of administration. Thus, for the preferred oral administration, the dosage unit may take the form of a suspension, tablet, packaged powder, bolus, or encapsulated powder. The quantity of active ingredient in each dosage unit Will be such that one or more units are required for each therapeutic administration.
As previously mentioned, the compounds of Formula I have general anthelmintic activity and accordingly a further and most important aspect of this invention provides a method of treating hehnintic infections in an animal which comp-rises administering, usually orally, to the animal in a sufficient nontoxic, but effective dose, an anthelmintic compound falling within the definition of Formula I, generally in the form of a pharmaceutical or veterinary composition as hereinbefore described. The daily dose range commonly used is from about 1 mg./kg. to about 500 mg./ kg. depending on the species of host and regimen used. One dose per day administration is preferred but up to five of the dosage units described above may be used if desired.
Where tableting is used, the resulting tablets are then coated with methyl methacrylate to form an enteric coating, i.e. a coating which is substantially insoluble in gastric secretion but substantially soluble in intestinal fluids.
It will be appreciated that the active ingredient used in the formulation of the tablets described above may be replaced with other compounds of Formula I having the necessary anthelmintic activity. Furthermore, other materials may be used to form the enteric coating, for example other synthetic plastic materials such as methyl acrylate, cellulose derivatives, hydrogenated caster oil or phthalates.
The compositions thusly prepared are administered, usually orally, to an infected host from 1-5 times daily for anthelmintic activity.
The following examples illustrate syntheses which may be employed in formulating the compositions of the invention but are not considered limiting the invention described herebefore.
EXAMPLE 1 Preparation of ethyl 2-benzimidazolyl thionocarbamate A mixture of 13.3 g. of Z-aminobenzimidazole, 50 ml. of carbon disulfide, and 30 ml. of absolute ethanol is refluxed for 50 hours. The product is separated by filtration and purified by recrystallization from absolute ethanol.
EXAMPLE 2 Preparation of 2-benzimidazolyl-thionocarbamic acid, S-ethyl ester Three g. of ethyl 2-benzimidazolyl thionocarbamate, 4.5 ml. of ethyl iodide, and 9 ml. of dimethylformamide were mixed and stirred for 3.5 hours, at the end of which time a clear, yellow solution was present. Acetone (25 ml.) was added and evaporated at room temperature, the acetone addition and evaporation steps Were repeated. Water (20 ml.) was added, which precipitated a white solid. The solid was collected (1.1 g.), washed with water, and dried in vacuo, over P 0 The entire product was recrystallized twice by dissolution in a minimum amount of cold glacial acetic acid, followed by Water addition to initiate recrystallization. A slight opalescent appearance required charcoaling and filtration.
The crude product was again dissolved in minimal glacial acetic acid, and water added, while being maintained at 0 C. A white solid formed, which was collected, washed with water, and dried overnight, in vacuo, over P 0 yielding a purified sample 320-323" C. (dec.).
The structure was confirmed based on the analytical data' and spectra.
EXAMPLE 3 Preparation of ethyl 2-benzimidazolyl carbamate Cyanamide (2.1 g.) was added to 40 ml. of pyridine. Ethyl chloroformate (4.78 ml.) was then added dropwise, while the temperature was maintained at about 0 C. The reaction mixture was stirred for 10 minutes at this temperature, and then at room temperature for an additional 20 minutes.
O-Phenylenediamine (10.8 g.) was added and the mixture was allowed to stand at room temperature for three hours,- then heated three hours on the steam-bath. The mixture was cooled to about 0 C., with the solid that formed being collected, washed with cold pyridine, dissolved in aqueous-ethanolic alkali, filtered, and the product precipitated by adding acetic acid. The material had m.p. 33033l C. (dec.). Similarly, the melting points in Examples 4 to 7 are assumed to be of the decomposition products.
EXAMPLE 4 Preparation of methyl 2-benzimidazolyl carbamate Using the procedure detailed in Example 3, 3.98 g. of cyanamide, 8193 g. of methylchloroformate, and 20.52 g. of o-phenylenediamine, are reacted to give 2.44 g. of crude product, m.p.,-313-315 C. Two recrystallizations from 9 glacial acetic acid, yielded a purified product of 1.3 g., mp. 320-322 C., whose structure was confirmed by elemental analyses and spectral data.
EXAMPLE 5 Preparation of propyl 2-benzimidazolyl carbamate Using the procedure described in Example 3, the desired product may be prepared from n-propyl chloroformate, Cyanamide, and o-phenylenediamine.
EXAMPLE 6 Preparation of butyl 2-benzimidazolyl carbamate Using the procedure of the foregoing examples, 6 g. of cyanamide, 19.04 g. of n-butyl chloroformate, and 30.24 g. of o-phenylenediamine, are reacted to give crude product (7.93 g.) m.p. 266268 C. Two recrystallizations from ethanol gave 3.68 g. of solids which were dried in vacuo over P yielded a dried product, whose structure was confirmed by elemental analyses and spectral data.
EXAMPLE 7 Preparation of isobutyl Z-benzimidazolyl carbamate Using the procedure of the foregoing examples, 6 g. of cyanarnide, 19.04 g. of isobutyl chloroformate, and 30.24 g. of o-phenylenediamine are reacted to give a crude product (2 g.) m.p. about 170 C.
Two recrystallizations from methanol, give 0.341 g. of a solid, which was dried, in vacuo, over P 0 yielding dried product, whose structure was confirmed by elemental analyses and spectral data.
EXAMPLE 8 Typical Cattle Bolus Containing an Anthelmintic Described Herein Grams Ethyl 2-benzimidazolyl thionocarbamate 2.0 Calcium phosphate 2.5 Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesium stearate 0.05
The calcium phosphate and the anthelmintic compound are thoroughly mixed, and the mixture reduced to a particle size finer than 60 mesh. About one-half of the starch is added, as an aqueous paste, and the resulting mixture granulated. The granules are passed through a #10 mesh screen and dried at 110-130 F. for about 8 hours. The dried materials then passed through a #16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. Finally, the remainder of the ingredients are added and the entire mass thoroughly mixed and compressed into a bolus. The magnesium stearate, talcum and gum acacia are of a particle size to pass a #10 mesh screen.
EXAMPLE 9 Typical Sheep Drench Containing an Ant-helmintic Described Herein Parts by Weight Ethyl Z-benzimidazolyl carbamate 60 Terra Alba English 35.5 Tragacanth, U.S.P. 3.0 Sodium Lauryl Sulfate 1.5 Water.
The above solid components are thoroughly mixed, giving a water dispersable power. This powder can be directly admixed with water in concentrations on the order of 5 g. of powder to 5 cc. of water.
I EXAMPLE 10 Preparation of substituted 2-carbalkoxyaminobenzimidazoles When the following substituted o-phenyleuediamines are substituted for the o-phenylen'ediaminedn the procedure of Example 4, the corresponding listed products are obtained:
Starting material Product 3-brorno-o-phenylenediamine- 4(7)-bromo-2-carbomethoxyamlno benzimidaz e. 3-ethoxy-o-phenylenediamine- 4(7)-ethoxy2earbomethoxyamiuo= benzimidazole. 3-nitro-o-phenylenediamine 4(7)-nitro-2-earbomethoxyaminobenzimidazo S-trifluoromethyl-o-phenylenedi- 4(7)-trifluoromethyl-2-earbomethoxy amine. aminobenzimidazole. i-amino-o-phenyleuediamine 5(6)-amino-2-earbomethoxyaminobenzimidazole. j 3-hydroxy-o-phenylenediamine 4(7)-hydroxy-2earbomethoxyaminobenzirnidazole.
EXAMPLE ll Novel Sheep Drench Containing an Anthelmintic Carbamate Parts by Weight Methyl 2-benzimidazolyl carbamate 60 Terra Alba English 16 Methyl cellulose l Polethylene glycol (Methocel 4000) 20 Antifoam AF 3 Silicone emulsion supplied by Dow Chemical Co. The above ingredients are suspended, one part powdered mixture to four parts water, and spray dried as is well known in the art.
EXAMPLE 12 Novel Sheep Drench Containing an Anthelmintio' Carbamate Ethyl 2-benzimidazolyl carbamate, l0 grants. 0.1 N HCl solution, quantum sufiicient to make 1 liter.
' chloroformate 2 (11.47 g.) is then added dropwise, while the temperature is maintained at about 0 C. The reaction mixture is stirred for 10 minutes at this temperature, and then at room temperature for an additional 20 minutes.
O-Phenylenediamine (20.56 g.) is added with stirring and the mixture is allowed to stand at room temperature for one hour, then is heated two hours on the steam bath, followed by the addition of 240 ml. of H 0. The mixture is cooled to about 0 C., with the solid that formed being collected by suction filtration, and air dried. The material had a ma). (fast heat) about 300 C. It is recrystallized once from 225ml. ethanol, then twice from cold absolute ethanol, which will not raise the melting point of the sample. The purity and structure of the product are confirmed by thin layer chromatography, elemental analyses and spectral data.
EXAMPLE 14 Preparation of substituted Z-carballyloxyamino- I benzimidazoles When the following substituted o-phenylenediamines are substituted for the o-phenylenediamine in the proce- Available from Ohemetron Corp., Chicago, 111.
fl-tiifluoromethyl-o-phenyleneallyloxyaminobenzimidazole.
diarnine.
4-amino-o-phenylenedlamine 5(6)-amino-2-carboallyloxyaminobenzimidazole. 3-hydroxy-ophenylenediamine 4(7)-hydroxy-2-carboallyloxyaminobenzimidazole.
EXAMPLE 15 When the following haloformates are substituted for the allyl chloroformate in the procedure of Example 13, the corresponding listed products are obtained:
Starting material Product Z-Methallylchloroi'ormate 2-carbometha1lyloxyamino- (C.A. 46'8417, g benzimidazole VinylchloroiormateTuS. Patent 2-carblovinyloxyaminobenzimidazo e Cyanamide (18.6 g.0.444 moles), dried in vacuo over P is dissolved in 225 ml. dry pyridine and is chilled in an ice bath. The solution is stirred continuously as 34.2 ml. (42 g.==0.444 moles) of methylchloroformate is added fairly slowly, keeping the temperature below 26". C. The solution is stirred in an ice bath for minutesafter the addition is completed, and then at room temperature for 1 hour. 4-Chloro-o-phenylenediamine (63.6 g.0. 444. moles) is added. The dark red solution is stirred at room temperature for /2 hour, and is heated on the steam bath for 5 hours.
The pyridine is evaporated with stirring at 50. C., and the resultant slurry of black oil and solid is mixed with 300 ml. ethanol, warmed slightly, and stirred until. all of the black oily liquid dissolves. Only crystalline material is left undissolved. Water (100 ml.) is added and the pyridine is filtered off, washed with ethanol and dried overnight on a porous plate. Crude yield is 13.3 -g. (.059 moles). The product is suspended in 400 ml. of ethanol:water, then ml. of 2.5 NaOH is added. The solution turns black, and almost all of the solid will dissolve. The insoluble material is filtered off and the pH of the solution is adjusted to 7.5 using glacial acetic acid. A light grey solid appears. It is collected, washed (Yield: 10.2 g.)
The product is further purified by dissolving in dimethylsulfoxide at 100 C., filtering the dark solution and add- 12 is light tan colored and decomposes with melting at 295- 300 C. In order to get rid of residual dimethylsulfoxide, the solid product is stirred with boiling Water twice, and then filtered off. It is dried at 25 C. in vacuo over P 0 The structure is confirmed by elemental analyses and spectral data.
EXAMPLE 17 Typical Cattle Bolus Containing an Anthelmintie Described Herein Grams 2-Carboallyloxyaminobenzimidazole 2.0 Calcium phosphate 2.5 Maize starch 0.54 Talcum 0.14 Gum arabic 0.15 Magnesium stearate 0.05
The calcium phosphate and the anthelmintic compound are thoroughly mixed, and the mixture reduced to a particle size finer than 60 mesh. About one-half of the starch is added, as an aqueous paste, and the resulting mixture granulated. The granules are passed through a #10 mesh screen and dried at 130 F. for about 8 hours. The dried materials then pass through a #16 mesh screen. The guar gum and the balance of the starch are added and the mixture thoroughly blended. Finally, the remainder of the ingredients are added and the entire mass throughly mixed and compressed into a bolus. The magnesium stearate, talcum and gum acacia are of a particle size to pass a #10 mesh screen.
EXAMPLE 18 The above solid components are thoroughly mixed, giving a water dispersable powder. This powder can be directly admixed with water in concentrations on the order of 5 g. of'powder to 5 cc. of water.
EXAMPLE l9 Novel Sheep Drench Containing an Anthelmintic Carhamate Parts by Weight 5(6)-n-Butyl-2-carbomethoxyaminobenzimidazole 80.0 Atmos 300 5.0 Starch, U.S.P. 12.0 Tragacanth, U.S.P. 3.0 Water Q.s.
Mono and diglycerides of fatformin fatt acids su lied by Atlas Chemical. g y pp The above solid components are thoroughly mixed, giving a water'dispersable powder. This powder can be directly admixed with water in concentrations on the order of 5 g. of powder to 5 cc. of water.
EXAMPLE 20 70. with 50% aqueous ethanol, and dried on porous plate.
ing an equal volume of hot methanol. The final precipitate 75 Novel Sheep Drench Containing an Anthelmintic Carbamate 2-Carboallyloxyaminobenzimidazole, 10 grams. 0.1 N HCl solution, quantum sufiicit to make 1 liter.
Preparation of 5-methyl-2-carbomethoxyamino benzimidazole Dry cyanamide (20.6 g.0.488' moles) is dissolved in 250 ml. of dry pyridine and is chilled in an ice bath. Methyl chloroformate (46.1 g.) is added over a 20-minute period, stirred for. 10 minutes in an ice bath, then at room temperature for 1.5 hours. 3,4-Toluene diarnine (59.8 g. 0.488 mole) is added in one portion forming a deepwine red solution. The solution-is stirred at room temperature for 40 minutes, and heated on a steam bath for 2 /z hours,-then is left at room temperature overnight. v Almost all ofthe pyridine is evaporated in vacuo and the orange residue is suspended in 700ml. of 50% aqueous ethanol,- to which is added 250 ml. of 2.5 N sodium hydroxide. Any undissolved solid is filtered 01f. The very dark filtrate is adjusted to a pH of about 7.5 using glacial acetic acid, and the precipitated crude product is collected, washed, and dried overnight on porous plates in a steam oven. t
. Twelve g. of crude product are dissolved in 170 ml. of dimethylsulfoxide (DMSO) at 100-l05 C., forming a dark solution, which is filtered, diluted with 190 ml. of 28 ethanol. A precipitate forms, which is chilled quickly, and is put in a freezer.
it Another 15.9 g. of crude product is dissolved in 200 ml. of DMSO of 100-105 C., which is filtered, and diluted with 180 ml. of hot ethanol. The solution is cooled quickly, stored in a freezer.
The products are collected, combined and washed with 2B ethanol, yielding 13.0 g. of a slightly off-white product, which is resuspended in 500 ml. of boiling hot water and with stirring, filter, resuspended in fresh water. The procedure is repeated yielding a product which is then dried in vacuo over P having a m.p. 297-303 C. (d.).
The structure is confirmed by elemental analyses and spectral data. 1 r
EXAMPLE 22 5n-butyl-2-carbomethoxyamino-' 7 Preparation of benzimidazole equipped with a mechanical stirrer; addition funnel, and
thermometer, 13.9 g. (0.05 moles) of 2-m'ethyl-2-thiopseudoureasulfate in about ml. of water is stirred in an ice bath. Methylchloroformate (9.45 g.0.1 moles) is added at one time. The; mixture is stirred at 0 C., for ten minutes, then a total of 19 ml. of sodium hydroxide is added over ten minutes while maintaining the temperature-below 20 C. j e
At this point the pH is about 8 and remains there after 5 minutes of stirring. Ten ml. of acetic acid is added, making the pH about 5 and keeping the temperature about 20 C. t
- A solution of 4-n-butyl-o-phenylenediamine ethanol, the hydrochloride, is
prepared-from 11.9 g. (0.05 mole) of added to the reaction mixture. 1
The addition funnel is replaced by a condenser, attached to three traps for methyl .mercaptan, one empty and two with 10% aqueous NaOI-I. Heat is applied very slowly to the stirred mixture, with gas evolving constantly." As the temperature rises slowly, ethanol is added, to con-" trol foaming. The total'reflux time is about of an hour. to room temperature and left over" The reaction is cooled the week-end.
A light tan solid is suspended in 50% aqueous ethanol, and recollectedl solid is dried on a porous plate in an oven.
Ihe product is recrystallized from 1200 to 1400 ml.
collected, washed with water, then The '14 of 30-ethanol plus '150 ml. of water, and is left in a refrigerator overnight. The product is collected and washed twice with 20% aqueous ethanol.
The product is then recrystallized again from 20% aqueous ethanol. It is dried in vacuo over P 0 to give pure product, m.p. 2257 C. (d.).
The structure is confirmed by elemental analysis and spectral data.
EXAMPLE 23 Preparation of 5,6-dimethyl-2-carbornethoxyaminobenzimidazole Using a 1-liter B-necked, round-bottomed flask, equipped with mechanical stirrer, addition funnel, and thermometer, 20.4 g. (0.0735 moles) of 2-methyl-2-thiopseudourea sulfate in 10 ml. of water, is stirred and maintained at 0 C. Methylchloroformate (13.9 g..147 moles) is added all at once, followed by the addition of about 40 ml. of 25 aqueous sodium hydroxide, which is added dropwise keeping the temperature about 15 C. and the pH about 6.
At 15 C., 18 ml. glacial acetic acid is added dropwise over about 5 minutes reducing the pH to between 5 and 6.
Ten g. (.0735 mole) of comminuted 4,5-dimethyl-ophenylene-diamine is added all at once to the reaction mixture, followed by 20 ml. of water.
A condenser replaces the funnel, and the gas outlet on the condenser is attached to a series of three traps. Two traps containing about 10% sodium hydroxide. Heat is applied very slowly, and as the temperature rises gas evolves. Ethanol is added to maintain stirrability. After one-half hour at 95 C., the reaction mixture is further diluted with water and cooled. The pasty mixture is filtered, washed with water, followed by washing with an ethanohwater mixture, and then stirred into an ethanol: Water mixture. It is recollected, and dried overnight on a porous plate.
The product (13.3 g.) is recrystallized from 350 ml. DMSO plus 320 ml. of ethanol, and left in a refrigerator overnight. Crystals are collected, Washed with cold ethanol, and air-dried. The solid product is boiled twice with 250 ml. of water, collected, air-dried, and dried at 25 C. in vacuo over P 0 to give pure product, having a mp. of 295-305 C. (d.).
The structure is confirmed by elemental analysis and spectral data.
EXAMPLE 24 Preparation of 5-methoxy-Z-carbomethoxyamidobenzimidazole In a 500 ml. 3-necked round-bottomed flask, equipped with a thermometer, mechanical stirrer, and dropping funnel, 19.8 g. (0.1 moles) of 2-methyl-2-thiopseudourea sulfate is stirred into 9 ml. of water. It is cooled to about 5 C., and methylchloroformate is added in one portion. The mixture is stirred at 10-15 C., then 21.4 ml. of 25 aqueous sodium hydroxide is added drop-wise over about v. tion mixture.
' until it is heated to about 102 C.
After one-half hour at -102 C., the resulting salmoncolored mixture is cooled, stoppered, and left at room temperature overnight.
When water is added to the reaction mixture, a pinkishwhite solid forms which is collected, washed with water, and then 60% ethanol in water mixture, to yield a'white solid product. The product is again slurried in 200 ml. of ethanol-water (60:40), collected, and is dried on a porous plate.
The product is recrystallized from 1300 m1. 30-ethanol plus 200 ml. of water. Following filtering, recrystallization occurs spontaneously, and it is left in the refrigerator overnight. Y
The crystals are collected, washed in 1:1 mixture of ethanol-water, giving a product, which is dried at 25 C. in vacuo over P The product is again recrystallized, from 1500 ml. of ethanol plus 100 ml. of water, collected, and washed with 60-40 mixture of ethanol-water and dried at 25 C.'in vacuo over P 0 yielding the pure product, having an M.P. of 235 C. (d.).
EXAMPLE 25 Preparation of S-nitro-2-carbomethoxyaminobenzimidazole To 12.4 g. (0.163 mole of thiourea in 6.2 ml. of water, is added, dropwise, 14 g. (0.11 mole) of dimethyl sulfate with stirring. The mixture becomes warm and colorless, and is refluxed gently for 30 minutes, during which time a white crystalline solid appears. The reaction mixture is then cooled at 2 C., yielding 2-methyl-2-thiopseudourea sulfate.
Methylchloroformate (30.8 g.0.326 moles) is added in one portion to the sulfate. To this mixture is added about 75 ml. of 25% aqueous sodium hydroxide, at a rate which maintains the temperature no higher than l5-- C., with the resulting pH of about 7. To this mixture is slowly added 17 ml. of glacial acetic acid.
4-Nitro-o-phenylenediamine (25.0 g.0.163 mole) added in one portion, followed by 60 ml. of 30% aqueous ethanol.
Three mercaptan traps are connected to the condenser on the reaction flask, one empty, and two with aqueous sodium hydroxide. The reaction mixture is heated slowly, being brought to reflux at 91 C., for one hour,
after which time the mixture is cooled and filtered. The
precipitate is washed with water and 30% cold aqueous" The structure is confirmed by elemental analysisand spectral data. Y it EXAMPLE 26 Preparation of 5-amino-2-carbomethoxyarninobenzimidazole To 30 ml. of formic acid is cautiously added 0.5 g. of palladium catalyst (5% by weight on charcoal). Five grams of 5 nitro-Z-carbomethoxyaminobenzimidazole" (Example 25) are dissolved in 250 ml. of formic acid, which is then added cautiously to the catalyst suspension.
Preparation of 5-N,N-dimethylamino-Z-carbomethoxy benzimidazole 2-Methyl-24hiopseudourea' sulfate (8.15 as previously described in Example'25. v
To the sulfate suspension isadded 9.34 g.' ((10986 moles) of methylchloroformate in one portion. To this mixture is added dropwise ('17.55"cc.) of 25% aqueous sodium hydroxide, while maintaining the temperature be low 20 C. When the NaOH" addition is completed, the pH of the mixture is about 7. The mixture is maintained below"20 C., and 7.15 cc. of glacial acetic acid are added at a fairly rapid rate.
4- N,N-Dimethylamino -o-phenylenediamine "dihydro chloride (13.0 g.) is added in one portion, and theresulting deep-purple mixture is then gradually heated'to is prepared 100 C. During the heating process, methyl merca'ptan' evolves which is routed through a series of three traps, as-
until the-pH is 8.0. A lavender solid forms, which is filtered olf, washed liberally with water, and is dried on a porous plate overnight in the air, yielding 9.0 g. of crude solid.
This solid is suspended in 350ccyof 1:1 ethanolwater, and treated with 10% aqueous sodium hydroxide until .a solution, dark brown in color, forms. This is then treated with decolorizing Norit. A, filtered through a Su-' 7 per-Cel mat, and the dark filtrate is neutralized with glacial-acetic acid, togiveaalavender solid. 'This is collected, washed with 1:1 ethanol-water, anddriedl on a porous plate in a steam oven,,giving a solid, m.p. 270- 276 C. (d.). i
This compound i-s; suspended in 1151 ethanol-water, and
sufiicient 10% sodium hydroxideadded tocause solution thereof. The dark solution is decolorized with Norit A,
filtered through a Super-Ce] mat, and the filtrate isneutralized to pH 6.5 with glacial acetic acid giving a pinkish '2 solid, m.p. 250-275 "C. ('d.)
This product is-suspended in 400cc. of 'ab out 20% aqueous ethanol. Sufficient glacial acetic acid is "added-to givethe solution a deep violet 'co'lor. The solution is'decolorized with Norit fi 'and Darco together; Th'e'mi'xt'ure I is filtered through a 'Su'per-Cel mat,'*an'd the filtrate is neu tralized to pH 6.5 with glacial acetic acid-'giving'a pinkish' solid, M.P. 250-275 C. (d.).
This product is :suspended in 400cc. of about 20% aqueous ethanol.'='Sufiic-ient glacial acetic acid is added to give the solution a deep violet color. The solution is de- .colorized with 'Norit'A and "Darcot ogether. The mixture is filteredgthrough a Super-Celmat, and the filtrate is once again decolorized, again filtered througha Super Cel that,
and thenwthrough a Whatman'No. l"'gravity-'flutdpaper (torremovm any traces of finely divided' charcoal):
The reaction mixture is put on a Parr shaker. for one" hour, during which time 5 pounds of hydrogen are taken The final-filtrate is, neutralized'with 10% aqueous sodium hydroxide giving-a white solid, whichis filtered'oifiwashed with water, and dried overnight.
The compound; is suspended in 50%. aqueous ethanol; then.sufficient. 10% aqueous sodium hydroxide isi-added to Y give a solution which is again filtered through asuper-Cel mat. The resulting clear light yellow filtrate is-neutralized to., give awhite. solid, which is filtered off, washed w-ith 1 50% aqueous ethanol, and-dried. ina dessicatorover P 0 in vacuo, giving .the pureproduct, 2336-2375 C.
The structure is confirmed by elemental analysis and spectral data.
28,403 17 18 We claim:
3,480,642 11/ 1969 Stedman 260-3092 1. 5(6)-n-butyl-2-carbomethoxyaminobenzimidazole. 3,541,213 11/1970 Klopping 260309.2 azZie5(6)-n-pr0p0xy 2 carbomethoxyaminobenzimid- OTHER REFERENCES References 5 Blor nquist et 3.1., V01. 56, pp. The following references, cited by the Examiner, are Rldl et 4658.9 (1955) oitieliord in the patented file of this patent or the original HENRY LES, Primary Examiner p UNITED STATES PATENTS C. M. S. JAISLE, Assistant Examiner 2,933,502 4/1960 Klopping 260-3092 10 2,933,504 4/1960 Klopping 260-309.2 424 273 CL 3,010,968 11/1961 Loux 260309.2 2,920,994 1/ 1960 Epperly et a1 424300

Claims (1)

1. 5(6)-N-BUTYL-2-CARBOMETHOXYAMINOBENZIMIDAZOLE.
US38193773 1964-08-04 1973-07-25 Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles Expired USRE28403E (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US38193773 USRE28403E (en) 1964-08-04 1973-07-25 Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US38752464A 1964-08-04 1964-08-04
US51612065A 1965-12-23 1965-12-23
US56211766A 1966-07-01 1966-07-01
US4866970A 1970-05-19 1970-05-19
US38193773 USRE28403E (en) 1964-08-04 1973-07-25 Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles

Publications (1)

Publication Number Publication Date
USRE28403E true USRE28403E (en) 1975-04-29

Family

ID=27535055

Family Applications (1)

Application Number Title Priority Date Filing Date
US38193773 Expired USRE28403E (en) 1964-08-04 1973-07-25 Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles

Country Status (1)

Country Link
US (1) USRE28403E (en)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4198422A (en) 1979-05-17 1980-04-15 E. R. Squibb & Sons, Inc. Substituted 2,3-naphthimidazole carbamates and method
US5459155A (en) * 1991-07-15 1995-10-17 Pfizer Inc. Benzimidazole anthelmintic agents
US5538990A (en) * 1991-07-15 1996-07-23 Pfizer Inc. Benzimidazole anthelmintics
US6407131B1 (en) 1997-05-16 2002-06-18 The Procter & Gamble Company Compounds and method for use thereof in the treatment of cancer or viral infections
US6479526B1 (en) 1995-04-12 2002-11-12 The Procter & Gamble Company Pharmaceutical composition for inhibiting the growth of viruses and cancers
US20020193609A1 (en) * 2000-09-26 2002-12-19 The Procter & Gamble Company Compounds and methods for use thereof in the treatment of cancer or viral infections
US20040029942A1 (en) * 2000-09-26 2004-02-12 University Of Arizona Foundation Compounds and methods for use thereof in the treatment of viral infections
US6906091B2 (en) 1999-08-13 2005-06-14 Uaf Technologies And Research, Llc Method of cancer treatment
US6930121B2 (en) 2000-09-26 2005-08-16 Uaf Technologies And Research, Llc Compounds and methods for use thereof in the treatment of viral infections

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2920994A (en) * 1957-08-16 1960-01-12 Spencer Chem Co Compositions and methods for controlling plant rust
US2933504A (en) * 1959-08-10 1960-04-19 Du Pont Derivatives of polyalkoxycarbonyl imine
US2933502A (en) * 1958-02-12 1960-04-19 Du Pont Benzimidazolone derivatives
US3010968A (en) * 1959-11-25 1961-11-28 Du Pont Process for manufacture of certain alkyl esters of benzimidazole carbamic acids
US3480642A (en) * 1967-03-22 1969-11-25 Smithkline Corp Process for producing 2-carbalkoxyaminobenzimidazoles
US3541213A (en) * 1966-05-06 1970-11-17 Du Pont Fungicidal and mite ovicidal substituted 2-aminobenzimidazoles

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2920994A (en) * 1957-08-16 1960-01-12 Spencer Chem Co Compositions and methods for controlling plant rust
US2933502A (en) * 1958-02-12 1960-04-19 Du Pont Benzimidazolone derivatives
US2933504A (en) * 1959-08-10 1960-04-19 Du Pont Derivatives of polyalkoxycarbonyl imine
US3010968A (en) * 1959-11-25 1961-11-28 Du Pont Process for manufacture of certain alkyl esters of benzimidazole carbamic acids
US3541213A (en) * 1966-05-06 1970-11-17 Du Pont Fungicidal and mite ovicidal substituted 2-aminobenzimidazoles
US3480642A (en) * 1967-03-22 1969-11-25 Smithkline Corp Process for producing 2-carbalkoxyaminobenzimidazoles

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Blomquist et al., J.A.C.S., Vol. 56, pp.144-6, (1934) *
Ridi et al., CA, Vol. 49, 4658-9, (1955) *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4198422A (en) 1979-05-17 1980-04-15 E. R. Squibb & Sons, Inc. Substituted 2,3-naphthimidazole carbamates and method
US5459155A (en) * 1991-07-15 1995-10-17 Pfizer Inc. Benzimidazole anthelmintic agents
US5521204A (en) * 1991-07-15 1996-05-28 Pfizer Inc. Benzimidazole anthelmintic agents
US5538990A (en) * 1991-07-15 1996-07-23 Pfizer Inc. Benzimidazole anthelmintics
US6653335B2 (en) 1995-04-12 2003-11-25 University Of Arizona Foundationa Pharmaceutical composition for inhibiting the growth of viruses and cancers
US6479526B1 (en) 1995-04-12 2002-11-12 The Procter & Gamble Company Pharmaceutical composition for inhibiting the growth of viruses and cancers
US6482843B1 (en) * 1997-05-16 2002-11-19 The Procter & Gamble Company Compounds and methods for use thereof in the treatment of cancer or viral infections
US6984654B2 (en) 1997-05-16 2006-01-10 Uaf Technologies And Research, Llc Cancer treatments and pharmaceutical compositions therefor
US6506783B1 (en) 1997-05-16 2003-01-14 The Procter & Gamble Company Cancer treatments and pharmaceutical compositions therefor
US20050192328A1 (en) * 1997-05-16 2005-09-01 Uaf Technologies And Research, Llc Compounds and methods for use thereof in the treatment of viral infections
US6407131B1 (en) 1997-05-16 2002-06-18 The Procter & Gamble Company Compounds and method for use thereof in the treatment of cancer or viral infections
US20050288349A1 (en) * 1997-05-16 2005-12-29 Uaf Technologies And Research, Llc Cancer treatments and pharmaceutical compositions therefor
US6900235B1 (en) 1997-05-16 2005-05-31 Uaf Technologies And Research, Llc Benzimidazole compounds, and pharmaceutical compositions and unit dosages thereof
US20050119236A1 (en) * 1997-05-16 2005-06-02 University Of Arizona Foundation Cancer treatments and pharmaceutical compositions therefor
US6906091B2 (en) 1999-08-13 2005-06-14 Uaf Technologies And Research, Llc Method of cancer treatment
US20040029942A1 (en) * 2000-09-26 2004-02-12 University Of Arizona Foundation Compounds and methods for use thereof in the treatment of viral infections
US6930121B2 (en) 2000-09-26 2005-08-16 Uaf Technologies And Research, Llc Compounds and methods for use thereof in the treatment of viral infections
US6916836B2 (en) 2000-09-26 2005-07-12 Uaf Technologies And Research, Llc Compounds and methods for use thereof in the treatment of viral infections
US6720349B2 (en) * 2000-09-26 2004-04-13 Uaf Technologies And Research, Llc Compounds for use in the treatment of cancer or viral infections
US20020193609A1 (en) * 2000-09-26 2002-12-19 The Procter & Gamble Company Compounds and methods for use thereof in the treatment of cancer or viral infections

Similar Documents

Publication Publication Date Title
US3574845A (en) Anthelmintic compositions and methods employing esters of benzimidazolyl carbamic acids and their thio analogs
US3956499A (en) Methods and compositions for producing polyphasic parasiticide activity using methyl 5-propylthio-2-benzimidazolecarbamate
US3657267A (en) Benzimidazole carbamates
US3682952A (en) 5(6)-n-butyl-2-carbomethoxy-benzimidazole
US3336191A (en) Anthelmintic 2-amidobenzimidazoles
US3929823A (en) 5(6)-Benzene ring substituted benzimidazole-2-carbamate derivatives having anthelmintic activity
USRE28403E (en) Butyl and n-propoxy-z-carbo- methoxyaminobenzimidazoles
US3401171A (en) 2-amidobenzimidazoles
US3694455A (en) Acyloxyalkyl amidobenzimidazoles
US4002640A (en) 5(6)-Benzene ring substituted benzimidazole-2-carbamate derivatives having anthelmintic activity
HU192972B (en) Process for producing substituted phenyl-/sulfonyl-oxy/-benzimidazole-carbamate derivatives and pharmaceutical compositions containing them
US3965113A (en) 5(6)-Benzene ring substituted benzimidazole-2-carbamate derivatives having anthelmintic activity
US4025638A (en) Methods and compositions using 5-cycloalkylthio- and oxy-2-carbalkoxy-aminobenzimidazole
CH647237A5 (en) 5-THIOBENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF IN ANTHELMINTIC PREPARATIONS.
CH629203A5 (en) Method for producing thiazolinylbenzimidazolen.
US3578676A (en) Benzimidazole-2-carbamates substituted on the benzene ring with an acyloxyalkyl group
US3996369A (en) Anthelmintically active 2-carbalkoxyamino benzimidazolyl-5(6)-sulfonic acid phenyl esters
US3590045A (en) Certain substituted imidazo (4,5-b)pyridines
US3996368A (en) Anthelmintically active 2-carbalkoxyamino-5(6)-phenyl sulfonyloxy benzimidazoles
US3934017A (en) Anthelmintic composition and method utilizing isothiocyanobenzazoles active ingredients
US3535321A (en) 2-carbalkoxyaminodihydroquinazolines
US4258198A (en) 5-Cycloalkyl thio- and oxy-2-carbalkoxyaminobenzimidazoles
US4076828A (en) Method of treating helminthiasis by parenteral administration of sulfoxide derivatives of benzimidazoles
US3536711A (en) 8-acylamino- and 8-carbalkoxyaminopurines
US3929822A (en) 1,5(6)-Disubstituted benzizimidazole-2-carbamate derivatives having anthelmintic activity

Legal Events

Date Code Title Description
AS Assignment

Owner name: SMITHKLINE BECKMAN CORPORATION

Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769

Effective date: 19820304