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United States Patent Office Patented Aug 3,524,000 United States Patent Office Patented Aug. 11, 1970 2 3,524,000 pounds with the substantial absence of significant toxic ANTHELMINTC COMPOSITIONS AND effects. Still another object is to provide a method for METHOD OF USING SAME treating helminthiasis with tricyclic compounds together John R. Egerton, Neshanic Station, and Joseph Di Netta, With anthelmintically active 2-substituted benzimidazoles Watchung, N.J., assignors to Merck & Co., Inc., Rah wherein the tricyclic compounds enhance the activity of way, N.J., a corporation of New Jersey the benzimidazoles. These and other objects will appear No Drawing. Continuation-in-part of application Ser. No. from the detailed description which follows. 439,926, Mar. 15, 1965. This application Oct. 20, 1967, According to the present invention, it has been sur Ser. No. 676,697 Int, C.A01n 9/22 A61d 7/00 A61k27/00 prisingly discovered that the anthelmintic activity of 2-sub O stituted benzimidazoles can be greatly enhanced when the U.S. C. 424-267 13 Claims benzimidazole is administered to the host animal in the presence of certain classes of tricyclic compounds. Thus, in one of its preferred aspects, the invention provides ABSTRACT OF THE DISCLOSURE novel 2-component compositions wherein one component The anthelmintic activity of 2-substituted benzimida is at least one of certain tricyclic compounds and the zoles is greatly enhanced when the benzimidazole is ad other component is at least one anthelmintically active ministered to the host animal in the presence of a tricyclic 2-substituted benzimidazole. The 2-substituted benzimida compound selected from the group consisting of dibenzo - Zoles contemplated for use in the present invention have cycloheptenes and thioxanthenes. Preferably, the 2-sub the following structural formula: stituted benzimidazoles and the tricyclic compounds are administered together in a single formulation. Enhance 20 ment of activity, however, is also obtained when each component is administered as a separate formulation. This application is a continuation-in-part of copending:25 application, Ser. No. 439,926, filed Mar. 15, 1965, now abandoned. - This invention relates to compositions and methods useful in the treatment of parasitic diseases in animals. 30 where R is thiazolyl, isothiazolyl, thiadiazolyl, pyrryl, More particularly, the invention relates to compositions furyl, halofuryl, thienyl, naphthyl, halonaphthyl such as containing anthelmintically active tricyclic compounds, 2-naphthyl-3-fluoro, pyrdyl, pyrazinyl, coumarinyl, thia compositions containing both anthelmintically active coumarinyl, phenyl, or halophenyl, R is hydrogen, hy 2-substituted benzimidazoles and tricyclic compound droxy, alkoxy, lower alkyl, alkenyl or acyl such as al which enhance the anthelmintic action of the 2-substituted 35 kanoyl and aroyl exemplified by acetyl, propionyl, buty benzimidazoles, and methods for using the tricyclic com royl, benzoyl and the like, R2 and Rs are hydrogen, lower pounds either alone or together with the 2-substituted alkyl, lower alkoxy, halogen, phenyl, halophenyl, phe benzimidazoles. Specifically, it relates to the methods and noxy, thienyl or trifluoromethyl. Also contemplated for compositions above mentioned wherein the tricyclic com use are the nontoxic acid addition salts of the foregoing pounds are dibenzocycloheptenes or thioxanthenes. 40 compounds. Helminthiasis is a widely occurring disease affecting Typical of the 2-substituted benzimidazoles, which may animals including humans and causes large economic be employed are losses in the domesticated animal industry. Particularly susceptible to the disease are ruminants such as sheep, 2-(4-thiazolyl)-benzimidazole, cattle, and goats and equines such as horses and mules. 45 2-(2'-thiazolyl)benzimidazole, A wide variety of anthelmintic agents have been discov 2-(4-thiazolyl)-5-methyl benzimidazole, ered and have varying degrees of efficacy on the particular 2-(2'-thiazolyl)-5,6-dimethyl benzimidazole, helminths causing the infections. Among such classes of 2-(4'-thiazolyl)-5-trifluoromethyl benzimidazole, materials is a family of 2-substituted benzimidazoles. In 2-(3'-thienyl)benzimidazole, view of the large economic interest in the prevention and 50 2-phenyl benzimidazole, control of helminthiasis, modern-day research is directed 2-(2-chlorophenyl)benzimidazole, toward providing new classes of anthelmintically active 1-methyl-2-phenyl benzimidazole, materials and finding ways for improving the efficacy of 2-phenyl-5,6-dimethyl benzimidazole, the currently known anthelmintic agents. 2-phenyl-5-ethoxybenzimidazole, It is accordingly an object of the present invention to 55 2-(2-thienyl)benzimidazole, provide compositions possessing a high degree of anthel 1-methyl-2-(2'-thienyl)benzimidazole, mintic activity. Another object is to provide compositions 1,5-dimethyl-2-(2-thienyl)benzimidazole, containing anthelmintically active tricyclic compounds. 2-(2'-thienyl)-5,6-dimethyl benzimidazole, Another object is to provide compositions which contain 2-phenyl-5-ethoxybenzimidazole, effective anthelmintic and antifungal 2-substituted benz 60 1-ethyl-2-(3'-thienyl)benzimidazole, imidazoles and tricyclic compounds, in which the tricyclic 1-allyl-2-(2'-thienyl)benzimidazole, compounds enhance the potency and efficacy of the 2-sub 2-(3'-thienyl)-5,6-dimethoxybenzimidazole, stituted benzimidazole. Yet a further object is to provide 2-(2-furyl)benzimidazole, methods for treating helminthiasis with tricyclic com 2-(3'-furyl)benzimidazole, 3,523,999 3 4 Insect species powders, vapors, and dusts as best suited to the conditions ousefly ------------- Oncopeltus fasciatus (Dallas) of use. In many applications, the material may even be merican cockroach --- Periplaneta americana (Linn.) used in its pure, undiluted form. alt-marsh caterpillar --- Musca domestica (Linn.) When used herein the term "pest' is intended in the potted milkweed bug -- Estigmene acrea (Drury) restricted Sense generally recognized in the art as supplying to the lower forms of life customarily controlled by chemi Mite Species cal means and excluding the higher animals, the verte WO-spotted mite ------ Tetranychus tellarius (Linn.) brates, for example, rodents, birds, and larger forms ABLE. I.-MORTALITY OF REPRESENTATIVE SPECIES OF COMMON INSECT ORDERS AND MITES T. tellaritis ompound (Example M. P. E. O. Post Limber see supra) domestica, pg. americana. acred fasciatts embryonic Nymphs Eggs 88/10 50/0.1 50/0.1 10/0.1 95/0.01 100/0.1 50/0.1 68/10 100/0.1 50/0.01 100/0.05 100/0.01 98/0.1 100/0.1 50/10 20/0.1 50/0.03 20/0.1 90/0.01 100/0.1 50/0.1 50/30 50/0.1 10070.05 2010.1 100/0.1 100/0.1 -------- In the screening tests for the insect species of Table I, which are more commonly controlled by mechanical rom ten to twenty-five insects were caged in cardboard 20 means Such as traps. It will be apparent to one skilled in tailing tubes 3%' diameter and 25/8' tall. The cages the art that the toxic activity demonstrated hereinbefore ere Supplied with cellophane bottoms and screen tops. on various test species in indicative of activity with species ood and water were supplied to each cake. Dispersions of and orders not specifically shown. he test compounds were prepared by dissolving one half The foregoing description is given for clearness of am of the toxic material in 10 ml. of acetone. This 25 understanding only, and no unnecessary limitations should olution was then diluted with water containing 0.017.5% be understood therefrom, as modifications will be obvious /v. Sponto 221, an emulsifying agent, the amount of to those skilled in the art, ater being Sufficient to dilute the active ingredients to We claim: concentration of 0.1% or below. The test insects were 1. A method of controlling insect and mite pests which Len sprayed with this dispersion. After twenty-four and 30 comprises contacting the pests with a pesticidal amount of venty-two hours, counts were made to determine living at least one compound having the formula: nd dead insects. Some of the compounds which showed high mortality ClCH S in house flies in the screening test were bioassayed on M. Y-s1. -( >-och, Omestica. In this test, a known quantity of the toxicant 35 RO as placed in a confined area. The same cages were em wherein R is lower alkyl. loyed as for the fly screening test. A weighted amount of 2. A method of controlling insect and mite pests which le toxicant was placed in Pyrex petri dishes having a sur comprises contacting the pests with a pesticidal amount ce area of 18.8 sq. centimeters along with 1 ml. of of O-n-propyl - S - (p-anisyl) chloromethylphosphonodi retone. After the solvent was evaporated by air-drying, 40 3. A method of controlling insect and mite pests which cage containing groups of twenty-five female flies, three comprises contacting the pests with a pesticidal amount of ) five days old, was placed over the residue. Counts of O-isopropyl - S-(p-anisyl) chloromethylphosphonodithio ving and dead insects were made forty-eight hours ate. fter initiation of the test. 4. A method of controlling insect and mite pests which Compounds which had an LD50 value (i.e., 50% of test 45 comprises contacting the pests with a pesticidal amount ecies killed) per concentration of 50 ug. or less on of O-n-propyl-S-(p-anisyl) chloromethylphosphonodi ouse flies, were selected for contact stomach screening on thioate. Le Salt-marsh caterpillar. Dock leaves approximately five 5. A method of controlling insect and mite pests which ches long were dipped in aqueous suspensions of the comprises contacting the pests with a pesticidal amount st materials for ten seconds. The leaves were then placed 50 of O-isoamyl-S-(p-anisyl) chloromethylphosphonodithio one pint food containers with the stems projecting ate. rough small holes in the bottoms into vials containing References Cited ater. Five 8 to 10 day-old Salt-marsh larvae were intro lced and the containers were closed with a petri dish UNITED STATES PATENTS p.
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