WO2003002115A2 - Substituted benzimidazoles for controlling endoparasites - Google Patents

Abstract

The invention relates to the use of substituted benzimidazoles for the control of endoparasites, more particularly endoparasitic worms (helminthes).

Description

Substituted benzimidazoles for the control of endoparasites

The present invention relates to the use of substituted benzimidazoles for controlling endoparasites, in particular endoparasitic worms (helminths).

Substituted benzimidazoles and their use as insecticides, fungicides and herbicides have already been disclosed (EP-OS 87 375, 152 360, 181 826, 239 508, 260 744, 266 984, US Pat. No. 3,418,318, 3,472,865, 3,576 818, 3 728 994).

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).

In particular, WO 00/68225 describes substituted benzimidazoles which can be used as agents against parasitic protozoa, in particular against coccidiosis and toxoplasmosis.

It has now surprisingly been found that the compounds described in WO 00/68 225 also have endoparasiticidal, in particular anthelmintic, effects.

The invention therefore relates to the use of compounds of the formula (I)

in which

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,

or

X ² and X ³ or X ³ and X ⁴ together represent dioxyhaloalkylene,

for the production of anthelmintic agents.

The benzimidazoles of the formula (I)

in which

R ¹ , R ² , R ³ , X ¹ to X ^{4 have} the meanings given above,

can be made by 1 H-benzimidazoles of the formula (II)

in which

R ¹ and X ¹ to X ^{4 have} the meaning given above,

with an alkylating agent of formula (III)

in which

A stands for a suitable leaving group,

R ² and R ^{3 have} the meaning given above,

if appropriate in the presence of diluents and / or reaction auxiliaries.

The compounds of formula (I) may optionally, depending on the

Type and number of substituents as geometric and / or optical isomers or regioisomers or their isomer mixtures in different compositions available. Both the pure isomers and the isomer mixtures can be used according to the invention.

Formula (I) provides a general definition of the substituted benzimidazoles used in accordance with the invention. Compounds of are preferably used

Formula (I) in which

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.

Compounds of the formula (I) in which

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- ,

The meanings of the individual radicals are very particularly preferably given below. Preferred embodiments result from combination with the meanings given above for the other radicals.

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.

Furthermore, 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.

If, for example, 4-bromo-2,6-bis-trifluoromethylbenzimidazole is used to carry out the process according to the invention for the preparation of compounds of the formula (I), the 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. In this formula (II) R to R ³ and X ¹ to X ⁴ preferably represent those radicals which are already in the

In connection with the description of the compounds of formula (I) according to the invention were mentioned as preferred for these substituents.

The 1H-benzimidazoles of the formula (II) are known or can be obtained in analogy to known processes (see, for example, J. Amer. Chem. Soc. 75, 1292 [1953] US patent

3576818).

Formula (III) provides a general definition of the alkylating agents which are furthermore required as starting products for carrying out the production process. In this formula (III), 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.

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, N-methylpyrrolidone or hexamethylphosphoric triamide; Esters such as methyl acetate or ethyl acetate or bases such as pyridine or organic acids such as formic acid or acetic acid.

The production process is preferably carried out in the presence of 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. -butylate, sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium acetate, potassium acetate, calcium acetate, ammonium acetate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate or ammonium carbonate, 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).

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. Examples of such catalysts are: tetrabutylammonium iodide, tetra-butylammonium bromide, tetrabutylammonium chloride, tributyl-methylphosphonium bromide, trimethyl-Cι / 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, methyltrioctylammonium chloride, trimethylbenzylammonium chloride, 15-crown-5, 18-crown-6 or tris- [ 2- (2-methoxyethoxy) -ethyl] -amine.

The 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.

To carry out the preparation process, 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.

The reaction is carried out, worked up and isolated by known processes (see also the preparation examples). The 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).

With favorable warm-blood toxicity, 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,

Honey, etc.) can be reduced, so that the use of the active ingredients enables more economical and easier animal husbandry. Pathogenic endoparasites include cestodes, trematodes, nematodes, acantocephals in particular:

From the order of the Pseudophyllidea, for example: Diphyllobothrium spp., Spirometra spp.,

Schistocephalus spp., Ligula spp., Bothridium spp., Diphlogonoporus spp.

From the order of the 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.

From the subclass of Monogenea e.g. Gyrodactylus spp., Dactylogyrus spp.,

Polystoma spp. From the subclass of Digenea, for example: Diplostomum spp., Posthodiplostomum spp Schistosoma spp., Trichobilharzia spp., Ornithobilharzia spp., Austrobilharzia spp., Leucochloridium spp., Brachylaima spp., Echinostphium sppas. Echinop. Sppas spp., Fasciola spp

Fasciolides spp., Fasciolopsis spp., Cyclocoelum spp., Typhlocoelum spp Paramphistomum spp., Calicophoron spp-, Cotylophoron spp., Gigantocotyle spp Fischoederius spp., Gastrothylacus spp., Notocotatususpppp., Cat. Spp., Cat. Spp., Cat ., Dicrocoelium spp., Eurytrema spp., Troglotrema spp., Paragonimus spp., Collyriclum spp., Nanophyetus spp., Opisthorchis spp., Clonorchis spp. Metorchis spp., Heterophyes spp., Metagonimus

SOUTH.

From the order of the Enoplida, for example: Trichuris spp., CapiUaria spp., Trichomosoides spp. , Trichinella spp.

From the order of the Rhabditia, for example: Micronema spp., Strongyloides spp.

From the order of the Strongylida, for example: Stronylus spp., Triodontophorus spp., Oesophagodontus spp., Trichonema spp., Gyalocephalus spp., Cylindropharynx spp.,

Poteriostomum spp., Cyclococercus spp., Cylicostephanus spp., Oesophagostomum spp., Chabertia spp., Stephanurus spp., Ancylostoma spp., Uncinaria spp., Bunostomum 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.

From the order of the Oxyurida, for example: Oxyuris spp., Enterobius spp., Passalurus spp., Syphacia spp., Aspiculuris spp., Heterakis spp.

From the order of Ascaridia, for example: Ascaris spp., Toxascaris spp., Toxocara spp., Parascaris spp., Anisakis spp., Ascaridia spp.

From the order of the Spirurida, for example: Gnathostoma spp., Physaloptera spp., Thelazia spp., Gongylonema spp., Habronema spp., Parabronema spp., Draschia spp., Dracunculus spp.

From the order of the Filariida, for example: Stephanofilaria spp., Parafilaria spp., Setaria spp., Loa spp., Dirofilaria spp., Litomosoides spp., Brugia spp., Wuchereria spp.,

Onchocerca spp.

From the order of the Gigantorhynchida, for example: Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

As already described in WO 00/68 225, 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 (Flagellata) 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 (Rhizopoda) such as Entamoebidae e.g. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.

Apicomplexa (Sporozoa) 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. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E. magna, E. maxima, E. media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec, E. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec, Hammon dia heyderni, Isospora belli, I. canis, I. felis, I. ohioensis, I. rivolta, I. spec, I. suis, Neospora spec, Neospora carinum, Neospora hugesi, Neospora caninum, Cystisospora spec., Cryptosporidium spec. such as Toxoplasmadidae e.g.

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.

Hepatozoon canis, H. spec.

Furthermore Myxospora and Microspora e.g. Glugea spec. Nosema spec.

Furthermore Pneumocystis carinii, as well as Ciliophora (Ciliata) such as e.g. Balantidium coli,

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

Farm and ornamental fish.

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,

Plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthread seabream (Sparas auratus), Tilapia spp. Chichlid species such as Plagioscion, Channel catfish. The agents according to the invention are particularly suitable for the treatment of fish fry, e.g. Carp of

2 to 4 cm body length. 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

(pour-on and spot-on) and powdering. 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;

Formulations in which the active ingredient is processed in an ointment base or in an oil in water or water in oil emulsion base;

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. The following may be mentioned as 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.

If appropriate, the active compounds can also be dissolved in physiologically tolerable vegetable or synthetic oils which are suitable for injection.

The following may be mentioned as 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.

It may be advantageous to add thickeners during manufacture. 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.

The following may be mentioned as 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.

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.

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.

They are produced by dissolving the active ingredient either in the hydrophobic or in the hydrophilic phase and this with the aid of suitable emulsifiers and, if appropriate, other auxiliaries such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers and viscosity-increasing agents

Substances homogenized with the solvent of the other phase.

The following are mentioned as hydrophobic phase (oils): 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

Chain length Cg_i2 or other specially selected natural fatty acids, partial glyceride mixtures of saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of Cg / Cjo 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-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids such as Oleic acid and its mixtures.

The following can be mentioned as the hydrophilic phase:

Water, alcohols such as e.g. Propylene glycol, glycerin, sorbitol and their mixtures.

The following may be mentioned as emulsifiers: nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated

Sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ether;

ampholytic surfactants such as di-Na-N-lauryl-β-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.

The following may be mentioned as further auxiliaries:

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).

Further additives mentioned are those mentioned above.

Semi-solid preparations can be administered orally or dermally. They differ from the suspensions and emulsions described above only in their higher viscosity.

To prepare solid preparations, the active ingredient is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.

All physiologically compatible solid inert substances may be mentioned as carriers. All of these serve inorganic and organic substances. 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.

Other suitable 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.

The active substances can also be present in the preparations as a mixture with synergists or with other active substances.

Mixtures of the compounds according to the invention are particularly emphasized

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.

In general, it has proven advantageous to administer amounts of about 0.5 to about 50 mg, preferably 1 to 20 mg, of active ingredient per kg of body weight per day in order to achieve effective results.

The 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

Contains 20% by weight of an active ingredient in a mixture with an edible organic or inorganic carrier with conventional feed. 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. The premix obtained in this way can then be completely

Feed must be added to the animals before they are fed.

An example of use in coccidiosis is:

For the treatment of individual animals, e.g. in the case of the treatment of coccidiosis in mammals or toxoplasmosis, 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

Animal species and its individual response to the active ingredient or the type of formulation and the time or interval at which it is administered. In some cases it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the above upper limit must be exceeded. When administering larger quantities, it may be advisable to divide them into several individual administrations during the day.

The effectiveness of the compounds according to the invention can be demonstrated, for example, in cage experiments using the following experimental arrangement, in which the animals are treated with the respective individual components and with the mixtures of the individual components.

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.

If 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. The premix thus obtained can then be added to the whole poultry feed prior to administration.

The following composition is an example of the use of the substances according to the invention in poultry feed.

52.00% feed grain meal, namely: 40% corn, 12% wheat

17.00% soybean meal extr.

5.00% corn gluten feed

5.00% wheat feed flour

3.00% fish meal

3.00% mineral mixture

3.00% alfalfa grass green flour

2.50% vitamin premix

2.00% wheat germ, crushed

2.00% soybean oil

2.00% meat bone meal

1.50% whey powder

1.00% molasses

1.00% brewer's yeast, bound to beer spent grains

100.00%

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 of compounds of the formula (T)

example 1

3.3 g (10 mmol) of 4-bromo-2,6-bis-trifluoromethylbenzimidazole are placed in 100 ml of methylene chloride and 1.73 ml (12.5 mmol) of triethylamine are added at 20 ° C. 2.4 g (12.5 mmol) of 4-bromomethyl-5-methyl-1,3-dioxol-2-one in 10 ml of methylene chloride are then added dropwise at 20 ° C. and the mixture is refluxed for 24 hours. The methylene chloride solution is washed 3 times with 30 ml of water each time, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel (35-70 μm) with cyclohexane / ethyl acetate (3: 1). 1.5 g (34% of theory) of the above compound are obtained. Mp: 141-143 ° C.

Examples 2 to 28 were obtained analogously to Example 1 and in accordance with the general information on the preparation.

Preparation of the starting compound for Example 14

Example a)

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.

Yield: 1 540 g (80% of theory), KplO: 70-74 ° C (GC: 99%).

Example b)

350 g (1.2 mol) of 6-bromo-2,3-tetrafluoro-1,4-benzodioxane are added dropwise at 20 ° C. in 75 min to 273 ml (98%) nitric acid and 293 ml conc. Sulfuric acid, stirring for 1 h at 20 ° C and 3 h at 40 ° C. The mixture is poured onto ice, extracted with methylene chloride, the organic phase is washed with water, with aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The organic phase is evaporated and further converted as a crude product.

Yield: 396 g (98% of theory), (crude, GC: 99.1%), Kpl6: 121-124 ° C, nD: 1.5065 at 20 ° C. Example c

396 g (1.2 mol) of 6-bromo-7-nitro-2,3-tetrafluoro-1,4-benzodioxane are placed in 1,400 ml of ethanol, 253 g (4.5 mol) of Fe powder are added and heated to reflux. Then 29 g of conc. Hydrochloric acid and stirring for 1 h, 43 ml of water are added dropwise at the boil and stirring is continued for 2 h. The mixture is cooled, the precipitate is filtered off with suction and washed with ethanol. The mother liquor is made alkaline and evaporated. The residue is taken up in methylene chloride and washed twice with water and dried over sodium sulfate. The organic phase is evaporated.

Yield: 313 g (87% of theory), (GC: 95.3%).

Example d)

313 g (1.04 mol) of 7-amino-6-bromo-2,3-tetrafluoro-1,4-benzodioxane are placed in 1250 ml of toluene and 500 g (4.4 mol) of trifluoroacetic acid and added in portions at 20 to 25 ° C to 188 g (1.3 mol) of phosphorus pentoxide. The approach becomes lumpy.

The mixture is heated at 80 ° C. for 1 h (not stirrable). 500 ml of water are added and the mixture is stirred at 80 ° C. for 1 h. After cooling, the organic phase is separated off and dried over sodium sulfate. The evaporated residue (340 g) still contains 50% educt (GC). Therefore, the residue (340 g, 50%) again with 1250 ml of toluene and 500 g

(4.4 mol) of trifluoroacetic acid are added, then 188 g (1.3 mol) of phosphorus pentoxide are added in portions and the mixture is heated at 80 ° C. for 5 h. The organic phase is decanted off, washed twice with water, dried over sodium sulfate and evaporated.

Yield: 273 g (66% of theory), mp: 79-81 ° C. (GC: 98%)

The lumpy reaction residue is mixed with water, the organic portion is separated off, dried over sodium sulfate and evaporated.

Yield: 56 g (14%), (GC 87%).

Example e)

273 g (0.7 mol) of 6-bromo-7-trifluoromethylcarbonylamino-2,3-tetrafluoro-1,4-benzodioxane are placed in 2047 ml of conc. Sulfuric acid and drips in 15 min at 0 ° C

300 g of mixed acid and add 1000 ml to the thick slurry at 0 to 20 ° C

Methylene chloride. The solution is then stirred at 40 ° C for 2 h. The cooled contents of the flask are poured onto ice water and the precipitate is isolated. The organic

Phase is separated from the mother liquor and dried over sodium sulfate. The evaporated residue and the isolated precipitate are combined.

Yield: 269 g (88% of theory), mp: 158-159 ° C. (GC: 100%). Example f

347 g (0.8 mol) of 6-bromo-8-nitro-7-trifluoromethylcarbonylamino-2,3-tetrafluoro-l, 4-benzodioxane are placed in 1735 ml of ethanol and 183 g (3.3 mol) of Fe- Chips and 183 g (3.3 mol) of Fe powder. 38.5 ml of hydrochloric acid are added dropwise under reflux, stirring is continued for 1 h, then 58 ml of water are added dropwise and the mixture is refluxed for 15 hours. The cooled batch is suctioned off, the mother liquor is made alkaline and evaporated. The residue is taken up in methylene chloride, washed twice with water, dried over sodium sulfate and evaporated. The residue (170 g) is chromatographed on 1 kg of silica gel (35-70 μm) with cyclohexane / ethyl acetate (5: 1).

Yield: 125 g (40% of theory), mp 162-164 ° C.

Biological examples

Example A:

Anthelmintic effectiveness in sheep in the egg reduction test

Example B

Anthelmintic effectiveness in vitro

Compound from Example 15

Claims

claims

Use of compounds of the formula (I)

in which

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,

or

X ² and X ³ or X ³ and X ³ together represent dioxyhaloalkylene,

for the production of anthelmintic agents.

2. Use of the compounds of formula (I) defined in claim 1 for the preparation of agents for the simultaneous control of helminths and parasitic protozoa.