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WO2003002115A2 - Benzimidazoles substitues destines a lutter contre les endoparasites - Google Patents

Benzimidazoles substitues destines a lutter contre les endoparasites Download PDF

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Publication number
WO2003002115A2
WO2003002115A2 PCT/EP2002/007049 EP0207049W WO03002115A2 WO 2003002115 A2 WO2003002115 A2 WO 2003002115A2 EP 0207049 W EP0207049 W EP 0207049W WO 03002115 A2 WO03002115 A2 WO 03002115A2
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formula
acid
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compounds
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German (de)
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WO2003002115A3 (fr
Inventor
Achim Harder
Gisela Greif
Folker Lieb
Albrecht Marhold
Georg Von Samson-Himmelstjerna
Bernd Baasner
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Bayer AG
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Bayer AG
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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents

Definitions

  • the present invention relates to the use of substituted benzimidazoles for controlling endoparasites, in particular endoparasitic worms (helminths).
  • Halogenated benzimidazoles and their effects as anthelmintics, coccidiostatics and pesticides have become known (DE-OS 2 047 369, DE-OS 4 237 617). Mixtures of nitro-substituted benzimidazoles and polyether antibiotics have become known as coccidiosis agents (US Pat. No. 5,331,003).
  • WO 00/68225 describes substituted benzimidazoles which can be used as agents against parasitic protozoa, in particular against coccidiosis and toxoplasmosis.
  • the invention therefore relates to the use of compounds of the formula (I)
  • R 1 represents fluoroalkyl
  • R 2 represents hydrogen or alkyl
  • R 3 represents alkyl
  • X 1 , X 2 , X 3 and X 4 independently of one another represent hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulfonyl,
  • X 2 and X 3 or X 3 and X 4 together represent dioxyhaloalkylene
  • R 1 , R 2 , R 3 , X 1 to X 4 have the meanings given above,
  • R 1 and X 1 to X 4 have the meaning given above,
  • A stands for a suitable leaving group
  • R 2 and R 3 have the meaning given above
  • the compounds of formula (I) may optionally, depending on the
  • Formula (I) provides a general definition of the substituted benzimidazoles used in accordance with the invention. Compounds of are preferably used
  • R 1 represents C 1 -C 4 fluoroalkyl
  • R 2 represents hydrogen or C r C 4 alkyl
  • R 3 represents C r C 4 alkyl
  • X 1 , X 2 , X 3 and X 4 independently of one another are hydrogen, F, CI, Br, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -haloalkylthio, ⁇ -haloalkylsulfonyl, or
  • X 2 and X 3 or X 3 and X 4 together represent a dioxyhalo -CC-C4 alkylene radical.
  • R 1 stands for CF 3 , CHF 2 , CHF,
  • R 2 represents hydrogen, methyl, ethyl, n-propyl or isopropyl
  • R 3 represents methyl, ethyl, n-propyl or isopropyl
  • X 1 , X 2 , X 3 and X 4 independently of one another for hydrogen, F, CI, Br, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCH 2 F, OCHF 2 , SCF 3 , SCHF 2 , SCH 2 F, SO 2 CF 3 , SO 2 CHF 2 ,
  • SO 2 CH 2 F stands, whereby X 2 and X 3 or X 3 and X 4 also together for a radical -O-CF 2 -O-, -O-CF 2 -CF 2 -O-, -O-CF 2 -CF 2 -CF 2 -O -, -O-CF 2 -CHF-O-, -O-CC1F-CC1F-O-, -O-CHF-O-, -O-CHF-CHF-O- or -O-CC1F-O- ,
  • R 1 very particularly preferably represents -CF 3 or -CHF 2 ,
  • R 2 very particularly preferably represents hydrogen
  • R 3 very particularly preferably represents methyl
  • X 1 very particularly preferably represents hydrogen, -CF 3 , CI, Br, F or -SCF 3 ,
  • X 2 very particularly preferably represents hydrogen, -OCF 3 , F, Br, CI or CF 3 ,
  • X 3 very particularly preferably represents F, Br, CI, -OCF 3 , -CF 3 or -SO 2 CF 3 ,
  • X 4 very particularly preferably represents hydrogen.
  • X 2 and X 3 or X 3 and X 4 can also very particularly preferably be used for -OCF 2 -CFHO-, -O-CC1F-CC1F-O-, -OCF 2 -CF 2 -O- or -O-CF 2 -O- stand.
  • reaction sequence of the preparation process can be represented by the following formula:
  • Formula (II) provides a general definition of the 1H-benzimidazoles required as starting materials for carrying out the production process.
  • R to R 3 and X 1 to X 4 preferably represent those radicals which are already in the
  • Formula (III) provides a general definition of the alkylating agents which are furthermore required as starting products for carrying out the production process.
  • R ⁇ and R ⁇ preferably represent those radicals which have already been mentioned as preferred for these substituents in connection with the description of the substances of the formula (I) according to the invention.
  • A represents a leaving radical customary in the case of alkylating agents, preferably halogen, in particular chlorine, bromine or iodine, or in each case optionally sub- substituted alkylsulfonyloxy, alkoxysulfonyloxy or arylsulfonyloxy, such as in particular methanesulfonyloxy, trifluoromethanesulfonyloxy, methoxysulfonyloxy, ethoxysulfonyloxy or p-toluenesulfonyloxy.
  • alkylating agents preferably halogen, in particular chlorine, bromine or iodine, or in each case optionally sub- substituted alkylsulfonyloxy, alkoxysulfonyloxy or arylsulfonyloxy, such as in particular methanesulfonyloxy, trifluoromethanesulfonyloxy, methoxysulfony
  • the compounds of the formula (III) are generally known or can be obtained in analogy to known processes (see, for example, JP 58152879 [CA 100: 121042]; US 4,434,173; US 4,448,732).
  • Inert organic solvents are suitable as diluents for carrying out the production process.
  • These include in particular aliphatic, alicyclic or aromatic, optionally halogenated hydrocarbons, such as, for example, gasoline, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform or carbon tetrachloride; Ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethyl or diethyl ether; Ketones, such as acetone, butanone or methyl isobutyl ketone; Nitriles such as acetonitrile, propionitrile or benzonitrile; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylformanilide
  • the production process is preferably carried out in the presence of a suitable reaction auxiliary.
  • a suitable reaction auxiliary All conventional inorganic or organic bases are suitable as such. These include, for example, alkaline earth metal or alkali metal hydrides, hydroxides, amides, alcoholates, acetates, carbonates or hydrogen carbonates, such as sodium hydride, sodium amide, lithium diethylamide, sodium methylate, sodium ethylate, potassium tert.
  • lithium-organic compounds such as n-butyllithium and tertiary amines such as trimethylamine, triethylamine, tributyl - amine, di-isopropyl-ethylamine, tetramethylguanidine, N, N-dimethylaniline, pyridine, piperidine, N-methylpiperidine, N, N-dimethylaminopyridine, diazabicyclooctane (DABCO), diazabicyclonones (DBN) or diazabicycloundecen (DBU).
  • DABCO diazabicyclooctane
  • DBN diazabicyclonones
  • DBU diazabicycloundecen
  • the production process can optionally also be carried out in a two-phase system, such as water / toluene or water / dichloromethane, if appropriate in the presence of a suitable phase transfer catalyst.
  • suitable phase transfer catalysts are: tetrabutylammonium iodide, tetra-butylammonium bromide, tetrabutylammonium chloride, tributyl-methylphosphonium bromide, trimethyl-C ⁇ / Ci 5-alkylammonium chloride, trimethyl-Ci ß / Ci ⁇ -alkylam-monium bromide, dibenzylethyl-dimethyl -C ⁇ 2 / C ⁇ 4-alkyl-benzylammonium chloride, dimethyl-C 2 / C 14-alkyl-benzylammonium bromide, tetrabutylammonium hydroxide, triethylbenzylammonium chloride, methyltrio
  • reaction temperatures can be varied within a wide range when the manufacturing process is carried out. In general, temperatures between -70 ° C and + 200 ° C, preferably at temperatures between 0 ° C and 130 ° C.
  • the manufacturing process is usually carried out under normal pressure. However, it is also possible to work under increased or reduced pressure.
  • 1.0 to 5.0 mol, preferably 1.0 to 2.5 mol, of alkylating agent of the formula (III) and, if appropriate, 0, are generally employed per mol of 1H-benzimizazole of the formula (II), 01 to 5.0 mol, preferably 1.0 to 3.0 mol, of reaction auxiliary.
  • reaction is carried out, worked up and isolated by known processes (see also the preparation examples).
  • end products of the formula (I) are purified using customary methods, for example by column chromatography or by recrystallization.
  • the characterization takes place with the help of the melting point or with non-crystallizing compounds - in particular with regioisomer mixtures - with the help of proton nuclear magnetic resonance spectroscopy (1 H-NMR).
  • the agents according to the invention are suitable for controlling pathogenic endoparasites which occur in humans and in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals. They are effective against all or individual stages of development of the pests and against resistant and normally sensitive species. By fighting the pathogenic endoparasites, illness, deaths and reduced performance (e.g. in the production of meat, milk, wool, hides, eggs,
  • Pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephals in particular:
  • Schistocephalus spp. Ligula spp., Bothridium spp., Diphlogonoporus spp.
  • Cyclophyllidea for example: Mesocestoides spp., Anoplocephala spp., Paranoplocephala spp., Moniezia spp., Thysanosomsa spp., Thysaniezia spp., Avitelellina spp., Stilesia spp., Cittotaenia spp., Andyella spp., Bertella spp spp., Taenia spp., Echinococcus spp., Hydatigera spp., Davainea spp., Raillietina spp., Hymenolepis spp., Echinolepis spp., Echinocotyle spp., Diorchis spp., Dipylidium spp., Joyeuxiella spp., Diplop.
  • Stronylus spp. Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp.
  • Globocephalus spp. Syngamus spp., Cyathostoma spp., Metastrongylus spp.,
  • Dictyocaulus spp. Muellerius spp., Protostrongylus spp., Neostrongylus spp., Cystocaulus spp., Pneumostrongylus spp., Spicocaulus spp., Elaphostrongylus spp.
  • Parelaphostrongylus spp. Crenosoma spp., Paracrenosoma spp., Angiostrongylus spp., Aelurostrongylus spp., Filaroides spp., Parafilaroides spp., Trichostrongylus spp., Haemonchus spp., Ostertagia spp., Cooper, Nematodirus spp., Hyostrongylus spp., Obeliscoides spp., Amidostomum spp., Ollulanus spp.
  • Oxyuris spp. Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.
  • Ascaridia From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.
  • the active compounds of the formula (I) are also suitable for combating parasitic protozoa which occur in animal husbandry and animal breeding in farm animals, breeding, zoo, laboratory, experimental and hobby animals.
  • the parasitic protozoa include:
  • Mastigophora such as Trypanosomatidae such as Trypanosoma b. brucei, Tb gambiense, Tb rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica such as Trichomonadidae, for example Giardia lamblia, G. canis.
  • Sarcomastigophora Roscomastigophora (Rhizopoda) such as Entamoebidae e.g. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.
  • Apicomplexa such as Eimeridae e.g. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum , E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciforrnis, E. faurei, E. flavescens, E.
  • Eimeridae e.g. Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburn
  • Toxoplasma gondii such as Sarcocystidae e.g. Sarcocystis bovicanis, S. bovihominis,
  • S. neurona S. ovicanis, S. ovifelis, S. spec, S. suihominis such as Leucozoidae e.g.
  • Leucozytozoon simondi such as Plasmodiidae e.g. Plasmodium berghei, P. falciparum,
  • P. malariae P. ovale
  • P. vivax P. spec, such as Piroplasmea e.g. Babesia argentina, B. bovis, B. canis, B. spec, Theileria parva, Theileria spec, such as Adeleina e.g.
  • Ichthiophthirius spec Trichodina spec, Epistylis spec.
  • the compounds according to the invention are also active against protozoa which occur as parasites in insects.
  • Parasites of the Microsporida strain in particular of the genus Nosema, may be mentioned as such.
  • Nosema apis is particularly worth mentioning for the honeybee.
  • the present invention therefore furthermore relates to the combined control of parasitic protozoa and endoparasitic helminths, in particular the combined control of worm infections and coccidiosis or toxoplasmosis.
  • Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon, birds such as Chickens, geese, turkeys, ducks, pigeons, ostriches, bird species for home and zoo keeping. It also includes
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
  • the pets include dogs and cats.
  • the fish include utility, breeding, aquarium and ornamental fish of all ages that live in fresh and salt water.
  • Useful and farmed fish include e.g. Carp, eel, trout, white fish, salmon, bream, roach, rudd, chub, sole,
  • the agents according to the invention are particularly suitable for the treatment of fish fry, e.g. Carp of
  • the agents are also very suitable for eel fattening.
  • the application can be prophylactic as well as therapeutic.
  • the active ingredients are used directly or in the form of suitable preparations enterally, parenterally, dermally, nasally.
  • the enteral application of the active ingredients takes place, for example, orally in the form of powder, suppositories, tablets, capsules, pastes, drinkers, granules, drenches, boluses, medicated feed or drinking water.
  • the dermal application takes place, for example, in the form of diving (dipping), spraying (spraying), bathing, washing, pouring on
  • Parenteral use happens e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.
  • Suitable preparations are:
  • Solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, pour-on formulations, gels;
  • Emulsions and suspensions for oral or dermal use and for injection Semi-solid preparations
  • Solid preparations such as powders, premixes or concentrates, granules, pelleis, tablets, boluses, capsules; Aerosols and inhalants, molded articles containing active ingredients.
  • Injection solutions are administered intravenously, intramuscularly and subcutaneously.
  • Injection solutions are prepared by dissolving the active ingredient in a suitable solvent and possibly adding additives such as solubilizers, acids, bases, buffer salts, antioxidants, preservatives.
  • the solutions are sterile filtered and filled.
  • solvents physiologically compatible solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.
  • the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.
  • solubilizers solvents which promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. examples are
  • Polyvinyl pyrrolidone polyoxyethylated castor oil, polyoxyethylated sorbitan esters.
  • Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.
  • Oral solutions are applied directly. Concentrates are used orally after previous dilution to the application concentration. Oral solutions and concentrates are prepared as described above for the injection solutions, and sterile work can be dispensed with.
  • Solutions for use on the skin are dripped on, spread on, rubbed in, sprayed on, sprayed on or applied by dipping (dipping), bathing or washing. These solutions are prepared as described above for the injection solutions.
  • Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and metacrylates. Gels are applied to or spread on or placed in body cavities. Gels are produced by adding enough thickening agent to solutions that have been prepared as described for the injection solutions to form a clear mass with an ointment-like consistency. The thickeners specified above are used as thickeners.
  • Pour-on formulations are poured onto or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed over the surface of the body.
  • pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. If necessary, other auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers and adhesives are added.
  • solvents water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerin, aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol, esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as alkylene glycol alkyl ethers such as dipropylene glycol monomethyl ether, diethylene glycol, mono-butyl glycol, mono Acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethyl acetamide, N-methyl pyrrolidone, 2-dimethyl-4-oxy-methylene-1, 3-dioxolane.
  • aromatic alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol
  • esters such as ethyl acetate, butyl acetate
  • benzyl benzoate ether
  • Dyes are all dyes approved for use on animals, which can be dissolved or suspended.
  • Absorbing substances are e.g. DMSO, spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
  • spreading oils such as isopropyl myristate, dipropylene glycol pelargonate, silicone oils, fatty acid esters, triglycerides, fatty alcohols.
  • Antioxidants are sulfites or metabisulfites such as potassium metabisulfite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol.
  • Light stabilizers are, for example, substances from the class of benzophenones or novantisolic acid.
  • Adhesives are e.g. Cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.
  • Emulsions can be used orally, dermally or as injections.
  • Emulsions are either water-in-oil or oil-in-water.
  • hydrophobic phase paraffin oils, silicone oils, natural vegetable oils such as sesame oil, almond oil, castor oil, synthetic triglycerides such as caprylic capric acid biglyceride, triglyceride mixture with vegetable fatty acids
  • Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, lauric acid hexyl ester, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length Cig-C ⁇ g, isopropyl myristate, isopropyl palmitate, caprylic / capric alcohol ester of the saturated fatty acid Chain length Ci ⁇ -C ⁇ g, isopropyl stearate, oleic acid oleyl ester, oleic acid decyl ester, ethyl oleate, lactic acid ethyl ester, waxy fatty acid esters such as dibutyl phthalate, adipic acid diisopropyl ester, ester mixtures related to the latter, inter alia, fatty alcohols such as isotridecyl alcohol, 2-octyld
  • Fatty acids such as Oleic acid and its mixtures.
  • hydrophilic phase The following can be mentioned as the hydrophilic phase:
  • Alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.
  • nonionic surfactants e.g. polyoxyethylated castor oil, polyoxyethylated
  • ampholytic surfactants such as di-Na-N-lauryl- ⁇ -iminodipropionate or lecithin;
  • anionic surfactants such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt; cationic surfactants such as cetyltrimethylammonium chloride.
  • Viscosity-increasing and emulsion-stabilizing substances such as carboxymethyl cellulose, methyl cellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, or colloidal silica Mixtures of the listed substances.
  • Suspensions can be used orally, dermally or as an injection. They are produced by suspending the active ingredient in a carrier liquid, optionally with the addition of other auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers. All homogeneous solvents and solvent mixtures may be mentioned as carrier liquids.
  • the surfactants specified above may be mentioned as wetting agents (dispersants).
  • Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.
  • the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
  • Inorganic substances are e.g. Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.
  • Organic substances are e.g. Sugar, cellulose, food and feed such as milk powder, animal meal, cereal flour and meal, starches.
  • Excipients are preservatives, antioxidants, dyes, which have already been listed above.
  • auxiliaries are lubricants and lubricants such as, for example, magnesium stearate, stearic acid, talc, bentonite, substances which promote decay, such as starch or crosslinked polyvinylpyrrolidone, binders, such as starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • lubricants and lubricants such as, for example, magnesium stearate, stearic acid, talc, bentonite, substances which promote decay, such as starch or crosslinked polyvinylpyrrolidone, binders, such as starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • the active substances can also be present in the preparations as a mixture with synergists or with other active substances.
  • Ready-to-use preparations contain the active ingredients in concentrations of 10 ppm to 20 percent by weight, preferably 0.1 to 10 percent by weight.
  • Preparations which are diluted before use contain the active ingredient in concentrations of 0.5 to 90 percent by weight, preferably 1 to 50 percent by weight.
  • mixtures according to the invention are in a mixture with others
  • Active ingredients in a ratio of 1 to 0.1-10 to 1 to 1-10.
  • the ratio 1 to 5 is preferred.
  • the active ingredients can also be administered together with the animal's feed or drinking water.
  • Feed and food contain 0.01 to 250 ppm, preferably 0.5 to 100 ppm of the active ingredient in combination with a suitable edible material. Such feed and food can be used for medicinal purposes as well as for prophylactic purposes.
  • Such feed or food is produced by mixing a concentrate or a premix which is 0.5 to 30%, preferably 1 to
  • Edible carriers are e.g. Corn meal or corn and soybean meal or mineral salts, which preferably contain a small amount of an edible dust control oil, e.g. Corn oil or soybean oil.
  • an edible dust control oil e.g. Corn oil or soybean oil.
  • Feed must be added to the animals before they are fed.
  • amounts of active compound of 0.5 to 100 mg / kg body weight are preferably administered daily in order to achieve the desired results. Nevertheless, it may be necessary at times to deviate from the amounts mentioned, in particular depending on the body weight of the test animal or the type of administration method, but also because of the
  • An active ingredient-containing feed is prepared in such a way that the required amount of active ingredient with a nutritionally balanced animal feed, e.g. is thoroughly mixed with the chick feed specified under.
  • a concentrate or a premix is to be prepared, which is ultimately to be diluted in the feed to the values mentioned in the experiment, generally about 1 to 30%, preferably about 10 to 20% by weight of active ingredient with an edible organic or inorganic carrier , e.g. Corn and soy flour or mineral salts containing a small amount of an edible defatting oil, e.g. Contain corn oil or soybean mixed.
  • an edible organic or inorganic carrier e.g. Corn and soy flour or mineral salts containing a small amount of an edible defatting oil, e.g. Contain corn oil or soybean mixed.
  • composition is an example of the use of the substances according to the invention in poultry feed.
  • feed grain meal namely: 40% corn, 12% wheat
  • Such feed contains 18% crude protein, 5% crude fiber, 1% Ca, 0.7% P as well as 1200 iE Vitamm A, 1200 iE vitamin D3, 10 mg vitamin E and 20 mg zinc bacitracin per kg.
  • Examples 2 to 28 were obtained analogously to Example 1 and in accordance with the general information on the preparation.
  • 1,400 g (6.7 mol) of 2,3-tetrafluoro-l, 4-benzodioxane and 7 g (0.08 mol) of FeS (powder) are initially introduced, dripped at 20 to 30 ° C. in about 4 h 1 190 g (7.4 mol) of bromine are added and the mixture is stirred for about 20 h until the evolution of gas has ended. It is washed with aqueous sodium sulfite solution and dried over sodium sulfate. The residue is distilled in vacuo.
  • the lumpy reaction residue is mixed with water, the organic portion is separated off, dried over sodium sulfate and evaporated.
  • Phase is separated from the mother liquor and dried over sodium sulfate. The evaporated residue and the isolated precipitate are combined.

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Abstract

La présente invention concerne l'utilisation de benzimidazoles substitués pour lutter contre des endoparasites, en particulier des vers endoparasitaires (Helminthes).
PCT/EP2002/007049 2001-06-28 2002-06-26 Benzimidazoles substitues destines a lutter contre les endoparasites Ceased WO2003002115A2 (fr)

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DE10131149A DE10131149A1 (de) 2001-06-28 2001-06-28 Substituierte Benzinmidazole zur Bekämpfung von Endoparasiten
DE10131149.4 2001-06-28

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WO2003002115A2 true WO2003002115A2 (fr) 2003-01-09
WO2003002115A3 WO2003002115A3 (fr) 2003-04-10

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DE102004042958A1 (de) * 2004-09-02 2006-03-09 Bayer Healthcare Ag Neue antiparasitäre Kombination von Wirkstoffen

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NL264338A (fr) * 1960-05-04
US3357884A (en) * 1961-05-25 1967-12-12 Merck & Co Inc Anthelmintic compositions containing benzimidazole derivatives
FR1450478A (fr) * 1965-03-29 1966-06-24 Chimetron Sarl Nouveaux benzimidazoliums quaternaires
FR1476529A (fr) * 1965-04-24 1967-04-14 Chimetron Sarl Nouveaux dérivés benzimidazole-sulfoniques et sulfamides correspondants
FR1476531A (fr) * 1965-04-26 1967-04-14 Chimetron Sarl Nouvelles cétones halogénées dérivées du benzimidazole
FR1476568A (fr) * 1965-09-07 1967-04-14 Chimetron Sarl Benzimidazolylpyridiniums et composés apparentés
DE1904288A1 (de) * 1969-01-29 1970-08-13 Glanzstoff Ag Vorrichtung zum Schneiden von auf Spulen aufgewickelten Faeden zu Stapelfasern
NL7013343A (fr) * 1969-09-26 1971-03-30
US3749789A (en) * 1970-02-27 1973-07-31 Merck & Co Inc Anthelmintic compositions containing benzimidazoles and method of use
DE3010041C2 (de) * 1980-03-15 1985-01-03 A. Nattermann & Cie GmbH, 5000 Köln Arzneimittel zur Behandlung von parasitärem Wurmbefall
DE3705227A1 (de) * 1987-02-19 1988-09-01 Bayer Ag Anthelminthische wirkstoffkombinationen
DE4237617A1 (de) * 1992-11-06 1994-05-11 Bayer Ag Verwendung von substituierten Benzimidazolen
DE19920551A1 (de) * 1999-05-05 2000-11-09 Bayer Ag Substituierte Benzimidazole, ihre Herstellung und ihre Verwendung als Mittel gegen parasitäre Protozoen

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DE10131149A1 (de) 2003-01-16

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