WO2011023304A2 - Novel antiparasitic combination of active substances - Google Patents

Abstract

The invention relates to the combined use of substituted benzimidazoles and heterocyclically substituted 1,2,4-triazine diones for fighting against parasitic protozoa, in particular coccidia.

Description

 New antiparasitic combination of drugs

The present invention relates to the combined use of substituted benzimidazoles len and of heterocyclic substituted 1,2,4-triazinediones against parasitic protozoa, in particular coccidia. Substituted benzimidazoles and their use as insecticides, fungicides and herbicides have already become known (EP 0 087 375, 0 152 360, 0 181 826, 0 239 508, 0 260 744, 0 266 984, US 3 418 318, 3 472 865, 3 576 818, 3 728 994). Halogenated benzimidazoles and their action as anthelmintics, coccidiostats and pesticides are also known (DE 2 047 369, EP 0 597 304A1). The substituted benzimidazoles preferably used according to this invention are described in WO 00/04022 and WO 00/68225.

Mixtures of nitrosubstituted benzimidazoles and polyether antibiotics have become known as cocci diosemittel (US 5,331,003). Mixtures of substituted benzimidazoles with polyether antibiotics or synthetic coccidiosis agents as agents for controlling parasitic protozoa are known from WO 96/38140. Diseases caused by parasitic protozoa, such as coccidioses, are common infections in animals; such as e.g. subclinical infections caused by protozoa of the genera Coccidia, Sarcosporidia and Toxoplasma spread worldwide in the pig. As a further example, Isospora suis infections are mentioned, which have only been recognized in recent years as the cause of follicular diarrhea and intensively researched. Triazine compounds such as toltrazuril or diclazuril have long been known as anti-coccidiosis agents. However, after many years of use and use, resistances have formed that limit or make impossible the use of existing products.

A group of heterocyclic substituted 1,2,4-triazinediones which are suitable for controlling coccidia is described in EP 0 330 041A2. Further applications of these compounds are disclosed in EP 0 353 526 A2 and EP 0 377 904 A2.

WO 2006/024428 discloses combinations of diclazuril and similar 1,2,4-triazinediones with substituted benzimidazoles active against parasitic protozoa. Of the 1, 2,4-triazinediones described there, however, the heterocyclic substituted 1,2,4-triazinediones which are important for the present invention differ in their structure and also in their mode of action. The excellent combination of substituted benzimidazoles with 1,2,4-triazines for controlling parasitic protozoa has not previously been described.

Diseases caused by parasitic protozoa, such as coccidiosis, are of considerable importance, above all in livestock farming. The emergence of resistance to the known means of implementation leads to serious problems shortly after the funds are introduced. There is therefore a need for new coccidiosis agents, in particular combinations having an improved action, with which preferably polyresistant parasite strains can also be controlled.

The invention therefore relates to products containing in each case at least one substituted benzimidazole active against parasitic protozoa or its physiologically tolerated salt and a heterocyclically substituted 1,2,4-triazinedione of the formula (I)

in which

R ^{1 represents} carbon-linked heteroaromatic radicals which are optionally substituted,

X is O, S, SO or SO ₂ ,

R ^{2 is} one or more identical or different radicals of the group hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy and haloalkylthio,

R ^{3 is} hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aralkyl, or its physiologically acceptable salt.

Preferred benzimidazoles are those of the formula (II)

in which

Z is hydrogen or the radical -CHR ² R ³ ,

R ^{1 is} fluoroalkyl, R ^{2 is} hydrogen or alkyl,

R ^{3 is} a radical of the formula

or for a remainder of the formula

R ° O

-N- -OR ⁰ is R ^{4 is} alkyl,

R ^{5 is} alkyl or substituted phenyl, R ^{6 is} alkyl,

X ', X ² , X ³ and X ⁴ independently of one another are hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulfonyl, or X ² and X ³ or X ³ and X ⁴ together represent a dioxyhaloalkylene radical.

The substituted benzimidazoles according to the invention are generally defined by the formula (II). In formula (II), the radicals have the following preferred meanings: - A -

R ¹ is preferably C ¹ -C 4 -fluoroalkyl,

R 1 is preferably hydrogen or C 1 -C 4 -alkyl,

R ⁴ is preferably C 1 -C ⁴ -alkyl,

R ^ preferably represents Ci _-6 -alkyl or phenyl which is optionally substituted one or more times with substi- ated is

Halogen, nitro, Ci _-4 -alkoxy, C _M haloalkoxy or optionally mono- or polysubstituted with halogen lendioxy substituted methylene or ethylene.

R ⁶ is preferably C _M alkyl

X ^, X ^, X 3 and X ⁴ are preferably independently of one another are hydrogen, F, CI, Br, _C] -C4 haloalkyl, Cj-C ^ haloalkoxy, _C] -C4-haloalkylthio, Ci-C4-halo- alkylsulfonyl, or

X ^ and X ^ or X * and X ⁴ in accordance with a further preferred embodiment together represent a _Dioxyhalo-C] -C4-alkylene.

R ¹ particularly preferably represents CF ₃ , CHF ₂ or CHF. R 1 particularly preferably represents hydrogen, methyl, ethyl, n-propyl or isopropyl.

R ⁴ particularly preferably represents methyl, ethyl, n-propyl or isopropyl.

R ^ is particularly preferably Ci. _6- alkyl.

R "particularly preferably represents methyl or ethyl. Χ 1, X 1, X 1 and X ⁴ particularly preferably independently of one another represent hydrogen, F, Cl, 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.

X ^ and X ^ X ^ or and X ⁴ according to a further embodiment particularly preferably also together a radical -0-CF ₂ -O-, -0-CF ₂ -CF ₂ -O-, -0-CF ₂ - CF ₂ -CF ₂ -O-, -O-CF ₂ -CHF-O-, -O-CCIF-CCIF-O-, -O-CHF-O-, -O-CHF-CHF-O- or -O -CCIF-O-. In a most preferred embodiment, R 1 is a radical of the formula

According to a further very particularly preferred embodiment, R ^{3 is} a radical of the formula

R 'is most preferably -CF3.

R 2 is very particularly preferably hydrogen. R ^ is most preferably methyl. X 1 very particularly preferably represents Cl or Br. X 1 very particularly preferably represents hydrogen. X.sup.1 and X.sup.2 most preferably together represent -OCF.sub.2-CF.sub.2-O-.

In one embodiment, Z in formula (II) is hydrogen and the other substituents may have the meanings given above, including the preferred and particularly preferred meanings. Compounds of the formula (II) in which Z is hydrogen are described in the prior art mainly as intermediates in the preparation of benzimidazole active compounds. However, the compounds of the formula (II) in which Z is hydrogen, have themselves excellent activity against parasitic protozoa (as explained in more detail below). According to a further embodiment of this invention, compounds of the formula (II) in which Z is hydrogen can therefore be used. Preferred and particularly preferred compounds of the formula (II) in which Z is hydrogen are those in which the other substituents have the preferred and particularly preferred meanings given above. The preparation of such compounds is known or can be carried out analogously to known methods, see e.g. WO 00/04022, WO 00/68225 and EP 597 304 Al and the literature cited therein.

As a preferred example of this embodiment, the compound of the formula (II-A) (see WO00 / 04022) may be mentioned:

According to a preferred further embodiment, Z in formula (II) is the radical -CHR ^ R.3 and the other substituents may have the meanings given above, including the preferred and particularly preferred meanings. Preferred examples of this embodiment are the compound of the formula (H-B) (see WO00 / 04022) and in particular the compound of the formula (II-C) (see WO00 / 68225):

Heterocyclic substituted 1, 2,4-triazines with activity against parasitic protozoa are known per se. Heterocyclically substituted 1, 2,4-triazines of the formula (I) are used according to the invention.

in which R ^{1 represents} carbon-linked heteroaromatic radicals which are optionally substituted,

X is O, S, SO or SO ₂ , R ^{2 is} one or more identical or different radicals of the group hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy and haloalkylthio,

R ^{3 is} hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aralkyl, optionally in the form of their physiologically acceptable salts.

Preferred compounds of the formula (I) are compounds in which

R ^{1 is} optionally halogen, alkyl, cyano, nitro, o-alkyl, s-alkyl, haloalkyl, substituted thiazolyl, oxazolyl, benzthiazolyl or benzoxazolyl;

X stands for O, S

R ^{2 is} halogen or C 1-6 -alkyl R ^{3 is} hydrogen or C 1-4 -alkyl, in particular methyl.

Particular preference is given to compounds of the formula (I) in which X is O,

R ^{1 represents} thiazolyl, benzthiazolyl or benzoxazolyl which is optionally substituted by C _M alkyl, in particular methyl; C 1 -haloalkyl, especially trifluoromethyl; Halogen, in particular

Chlorine, bromine, fluorine; Nitro, CN, amino, C, _M -amino, C]. ₄ -Halogenalkylamino, Acyla- mino, Ci _-4 -alkoxy, in particular methoxy; C ₁ -haloalkoxy, in particular trifluoromethoxy;

especially methylthio; C _M haloalkylthio in particular

Trifluoromethylthio, Ci-4-alkylsulfonyl, in particular methylsulfonyl and Ci _-4 - haloalkylsulfonyl, in particular trifluoromethylsulfonyl are substituted, stands,

R2 especially methyl is one or more radicals of the group comprising hydrogen or halogen, in particular chlorine, bromine, C _M alkyl, R3 is hydrogen.

Very particular preference is given to compounds of the formula (I) in which X is O,

R ^{1 represents} thiazolyl or benzthiazolyl optionally substituted by chlorine or methyl or trifluoromethyl,

R ^{2 is} one or more radicals of the group hydrogen, methyl or chlorine, R ^{3 is} hydrogen.

Among the very particularly preferred compounds of the formula (I), the following substituent meanings are emphasized: R ¹ is benzthiazolyl which is optionally substituted by chlorine, methyl or trifluoromethyl,

R ² is a methyl radical.

As a preferred single compound, the following compound (I-A) may be mentioned:

The compounds of the formula (I) are described in EP 330 041 A2 and can be prepared by the processes described therein. Substituent definitions of the general formulas (I) and (II) are explained in more detail below:

Alkyl is a straight-chain or branched hydrocarbon radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. Alkoxy represents an -O-alkyl radical in which alkyl is as defined above. Alkylthio is an -S-alkyl radical in which alkyl is as defined above.

Alkylene represents a straight-chain or branched hydrocarbon radical having 1 to 4, preferably 1 to 3, particularly preferably 1 to 2, carbon atoms which is linked via two different positions.

Haloalkyl is an alkyl radical as defined above in which one or more, in particular 1 to 3, hydrogen atoms have been replaced by a halogen atom, in particular fluorine, chlorine or bromine.

Accordingly, fluoroalkyl represents an alkyl group in which 1 until all hydrogens have been replaced by fluorine atoms; preferred are perfluoroalkyl radicals, e.g. Trifluoromethyl or pentafluoroethyl.

Haloalkoxy represents a straight-chain or branched alkoxy radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 4, carbon atoms in which one or more, in particular 1 to 3, hydrogen atoms have been replaced by a halogen atom, in particular fluorine, chlorine or bromine; eg -OCF ₃ .

Haloalkylthio represents a straight-chain or branched alkylthio radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 4, carbon atoms in which one or more, in particular 1 to 3, hydrogen atoms have been replaced by a halogen atom, in particular fluorine, chlorine or bromine ; eg CF ₃ S-. Haloalkylsulfonyl is a straight-chain or branched alkylsulfonyl radical having 1 to 8, preferably 1 to 6, particularly preferably 1 to 4 carbon atoms, in the alkyl part of which one or more, in particular 1 to 3, hydrogen atoms have been replaced by a halogen atom, in particular fluorine, chlorine or bromine.

Alkenyl is a straight-chain or branched hydrocarbon radical having 2 to 8, preferably 2 to 6, more preferably 2 to 4 carbon atoms and one or more double bonds, very particularly preferably having 2 to 3 carbon atoms and one double bond. Examples which may be mentioned by way of example and preferably include vinyl, allyl, n-prop-1-en-1-yl and n-but-2-en-1-yl.

Alkynyl represents a straight-chain or branched hydrocarbon radical having 2 to 8, preferably 2 to 6, more preferably 2 to 4 carbon atoms and one or more triple bonds, very particularly preferably having 2 to 3 carbon atoms and a triple bond. Aryl is preferably an aromatic radical having 6 to 10 carbon atoms. Preferred aryl radicals are naphthyl or especially phenyl.

Aralkyl is an aryl radical bound via an alkyl radical as defined above, for example naphthylmethyl, phenylethyl or benzyl.

Heteroaromatic radical (heteroaryl) in the context of the invention generally represents an aromatic, mono- or bicyclic radical, preferably having 5 to 10 ring atoms and up to 5 heteroatoms from the series S, O and / or N. Preferred are 5-6 heteroaryls with up to 4 heteroatoms. The heteroaryl radical may be bonded via a carbon or heteroatom. Examples which may be mentioned are thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl. Optionally substituted radicals carry one or more further substituents, preferably these are 1 to 3, particularly preferably a substituent. These further substituents are preferably selected from: alkyl, alkoxy, haloalkyl, alkylthio, halogen, aryl, aralkyl, cyano, nitro, amino, alkylamino and dialkylamino. Most preferably, the substituents are selected from halogen and alkyl.

However, the general or preferred radical definitions or explanations given above can also be combined with one another as desired, ie between the respective ranges and preferred ranges.

Depending on the nature and number of the substituents, the compounds of the formula (I) or (II) may optionally be used as geometric and / or optical isomers (for example enantiomers) or regioisomers or their isomer mixtures (for example racemates) in different composition. Both the use of the pure isomers and the isomer mixtures are claimed according to the invention.

If appropriate, the active compounds can also be used in the form of their salts, solvates and solvates of the salts

As salts physiologically acceptable salts of the active ingredients are preferred in the context of the present invention.

Physiologically acceptable salts of the active compounds comprise acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of chlorine, depending on the structure of the active substance. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid, etc. Physiologically acceptable salts of the active compounds optionally also include Salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium and potassium salts), alkaline earth salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and preferably ethylamine, Diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine, N-methylpiperidine and choline.

Solvates in the context of the invention are those forms of the active ingredients which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.

If appropriate, prodrugs of the active compounds may also be used in the context of the invention. The term "prodrugs" encompasses compounds which themselves may be biologically active or inactive, but are converted to the actual active substance during their residence time in the body (for example metabolically or hydrolytically) The products according to the invention are suitable for combating parasitic protozoa in the case of favorable warm-blooded toxicity. They are used in livestock and livestock breeding in livestock, breeding, zoo, laboratory, experimental and hobby animals and are effective against all or individual stages of development of the pests and against resistant and normally sensitive strains by controlling the parasitic protozoa The aim is to reduce illness, death and reduced performance (eg in the production of meat, milk, wool, hides, eggs, honey, etc.) so that the use of the active ingredients makes it possible to achieve more economical and easier animal husbandry.

The parasitic protozoa include:

Mastigophora (Flagellata) such as Trypanosomatidae eg Trypanosoma b. brucei, Tb gambiense, Tb rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. equiperdum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L Donovani, L. tropica, such as, for example, Trichomonadae T. fetus, Tritrichomonas suis, Trichomitus rotunda, Tetratrichomonas buttreyi, Giardia duodenalis (G. intestinalis, G. lamblia, G. bovis, G. caprae), G. canis , Sarcomastigophora (Rhizopoda) such as Entamoebidae eg Entamoeba histolytica, E. bovis, E. ovis, E. dilimani, Hartmanellidae eg 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. chinchilla- e, E Clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E. dispersa, E. ellipsoidales, E. falciformis, 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. neodebliecki, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. perminuta, E. phasani, E. piriformis, E. polita, E. porci, E. praecox, E. residua, E. scabra, E. spinosa, E. spec. stiedai, E. suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec., Hammondia heydorni, 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 parvum. such as Toxoplasmadidae e.g. Toxoplasma gondii, such as Sarcocystidae, e.g. Sarcocystis bovicanis, S. bovihominis, S. cruzi, S. hirsuta, S. hominis, S. miescheriana, S. neurona, S. ovicanis, S. ovifelis, S. spec., S. suihominis such as Leucozoidae e.g. Leucocytosis 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. divergens, B. bigemina, B. trautmanni, B. perroncitoi, B. spec., Theileria parva, T. annulata, T. lawrencei, Theileria spec., Such as Adeleina e.g. Hepatozoon canis, H. spec. Also Besnoitia besnoiti, B. tarandi, B. caprae. Further Myxospora and Microspora e.g. Glugea spec. Nosema spec

Furthermore, Pneumocystis carinii, as well as Ciliophora (Ciliata), e.g. Balantidium coli, Ichthiophthirius spec, Trichodina spp., Epistylis spec

The active compounds or active compound combinations according to the invention are also active against protozoa which occur as parasites in insects. As such, parasites of the strain Microsporida, in particular of the genus Nosema, may be mentioned. Nosema apis is especially named in the honey bee.

The livestock and breeding animals include mammals such as e.g. Cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, fallow deer, reindeer, fur animals such as e.g. Mink, chinchilla, raccoon, birds, e.g. Chickens, geese, turkeys, ducks, pigeons, bird species for home and zoo keeping. It also includes farmed and ornamental fish.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

Hobby animals include dogs and cats. The fish include farmed, farmed, aquarium and ornamental fish of all ages, living in fresh and salt water. The farmed and farmed fish include, for example, carp, eel, trout, whitefish, 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, Gilthead seabream (Sparus auratus), Tilapia spp., Chilli species such as Plagioscion, Channel catfish. Particularly suitable are the agents according to the invention for the treatment of fish fry, eg carp of 2 to 4 cm body length. The remedies are also very suitable in the eel mast.

According to a preferred embodiment, the products according to the invention are used in pigs. An example of a particularly important pathogen in pigs is called Isospora suis.

According to a further preferred embodiment, the products according to the invention are used in cattle. So examples of particularly important pathogens in cattle are called Eimeria bovis, Neospora caninum and Besnoitia besnoitii.

According to another particularly preferred embodiment, the active ingredients are used in poultry, such as. As in ducks, geese, turkeys and especially chickens.

The application can be both prophylactic and therapeutic.

The use of the active ingredients is carried out directly or in the form of suitable preparations enteral, parenteral, dermal, nasal.

Enteral administration of the drugs is e.g. orally in the form of powders, suppositories, tablets, capsules, pastes, infusions, granules, drenches, boii, medicated feed or drinking water. The dermal application is e.g. in the form of diving (dipping), spraying, bathing, washing, pour-on and spot-on and powdering. Parenteral administration is e.g. in the form of injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or by implants.

Suitable preparations are: solutions such as injectable solutions, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or in body cavities, infusion formulations, gels; Emulsions and suspensions for oral or dermal application and for injection; Semi-solid preparations;

Formulations in which the active substance 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, extrudates, granules, pellets, tablets, tablets, capsules; Aerosols and inhalants, active substance-containing moldings.

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 bottled.

Oral solutions are applied directly. Concentrates are administered orally after prior dilution to the concentration of use. Oral solutions and concentrates are prepared as described above for the injection solutions, whereby sterile work can be dispensed with. Solutions for use on the skin are dribbled, brushed, rubbed, sprayed, sprayed on or applied by dipping, bathing or washing. These solutions are prepared as described above for the injection solutions. It may be advantageous to add thickening agents in the preparation.

Gels are applied to or painted on or placed in body cavities. Gels are made by adding solutions that have been prepared as described in the injection solutions with enough thickening agents to form a clear mass with an ointment-like consistency.

Pour-on formulations are poured or sprayed onto limited areas of the skin, whereby the active ingredient either penetrates the skin and acts systemically or spreads over the body surface.

Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. Optionally, further adjuvants such as dyes, absorption-promoting substances, antioxidants, light stabilizers, adhesives are added. Emulsions can be used orally, dermally or as injections. Emulsions are either water-in-oil type or oil-in-water type.

They are prepared by dissolving the active ingredients either in the hydrophobic or in the hydrophilic phase and these with the aid of suitable emulsifiers and optionally other auxiliaries such as dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers, viscosity regulators, with the solvent of others Homogenized phase.

Suspensions may be administered orally, dermally or as an injection. They are prepared by suspending the active ingredient in a carrier liquid optionally with the addition of further auxiliaries, such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers.

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

Extrudates are semi-solid to solid forms, preferably administered orally. Extrudates can be prepared by mixing the active ingredient with suitable excipients and then extruding the mixture under pressure, usually at elevated temperature through nozzles. The mixture can z. B. contain adjuvants for adjusting the viscosity, the humidity and the melting behavior.

For the preparation of solid preparations, the active compounds are mixed with suitable excipients, if appropriate with the addition of auxiliaries, and brought into the desired form. These may optionally contain further active ingredients and / or synergists.

The use in combination means either that the benzimidazole and the 1, 2,4-triazine of the formula (I) are formulated in a common preparation and applied together accordingly. However, the products may also comprise separate preparations for each active substance. If more than two active substances are to be used, correspondingly all active substances can be formulated in a common preparation or all active substances can be formulated in separate formulations; mixed forms are also conceivable in which a part of the active ingredients is formulated together and some of the active ingredients are formulated separately.

Separate formulations allow separate or sequential use of the respective active ingredients.

Aπwendungsfertigige preparations contain the active ingredients in each case in concentrations of 0.05 to 40% m / V (or m / m in the case of solid preparation forms). Preference is given to preparations with a content of the active ingredients of in each case from 0.05 to 15% m / V (or m / m in the case of solid preparation forms). Under m / V is the concentration in mass of drug / volume of the preparation form given in g / 100 ml to understand.

In general, it has been found advantageous to administer amounts of about 0.05 to about 100 mg, preferably 0.1 to 50 mg, of active ingredient per kg of body weight per day to achieve effective results.

In the products, the substituted benzimidazoles and the heterocyclic substituted 1,2,4-triazinediones are usually present in mixing ratios (by weight) of 1: 0.01-50 to 1: 1-50. Preferably, the ratio is 1 to 10. The active ingredients may also be administered together with the food or drinking water of the animals.

Feed and food contain 0.005 to 250 ppm, preferably 0.05 to 100 ppm of the active ingredient in combination with a suitable edible material.

Such food and food can be used both for curative purposes and for prophylactic purposes.

The preparation of such a feed or foodstuff is carried out by mixing a concentrate or premix containing 0.5 to 30%, preferably 1 to 20% by weight of an active ingredient in admixture with an edible organic or inorganic carrier with conventional feeds. Edible carriers are e.g. Corn flour or corn and soybean meal or mineral salts, preferably containing a small amount of an edible dust control oil, e.g. Corn oil or soybean oil. The premix thus obtained may then be added to the complete feed before it is fed to the animals.

The use in coccidiosis may be mentioned as an example:

For the healing and prophylaxis of, for example, coccidiosis in poultry, particularly chickens, ducks, geese and turkeys, 0.005 to 100 ppm, preferably 0.05 to 100 ppm of an active ingredient is mixed with a suitable edible material, e.g. a nutritious feed, mixed. If desired, these amounts can be increased, especially if the active ingredient is well tolerated by the recipient. Accordingly, the administration can be done via the drinking water.

For the treatment of individual animals, for example in the case of treatment of coccidiosis in mammals or toxoplasmosis, it is preferable to administer amounts of active compound of from 0.05 to 100 mg / kg of body weight daily in order to obtain the desired results. Nevertheless, it can It may be necessary to derogate from the quantities mentioned, in particular depending on the body weight of the test animal or the method of administration, but also on the animal species and its individual response to the active substance or the nature of the formulation and the time or interval to which it is added is administered. Thus, in some cases, it may be sufficient to make do with less than the minimum quantity mentioned above, while in other cases the said upper limit must be exceeded. When administering larger amounts, it may be appropriate to divide them into several individual administrations during the course of the day.

The activity of the compounds of the invention can be e.g. in caged experiments with the following test arrangement, in which the animals are treated with the respective individual components as well as with the mixtures of the individual components.

A medicated feed is prepared so that the required amount of active ingredient is supplemented with a nutritionally balanced animal feed, e.g. with the chick chow specified under, is thoroughly mixed. When a concentrate or premix is to be prepared which is ultimately to be diluted in feed to the levels specified in the experiment, generally from about 1 to 30%, preferably from about 10 to 20%, by weight of active ingredient with an edible organic or inorganic carrier , eg Corn and soybean meal or mineral salts containing a small amount of an edible de-oiling oil, e.g. Corn oil or soybean oil, mixed. The resulting premix can then be added to the whole poultry feed prior to administration.

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

52.00% cereal meal, namely: 40% corn, 12% wheat

 17,00% soybean meal extr.

 5.00% corn gluten feed

 5.00% wheat flour

 3.00% fishmeal

 3.00% mineral mixture

 3.00% alfalfa grass green flour

 2.50% vitamin premix

 2.00% wheat germ, minced

 2.00% soybean oil

2,00% meat bone meal 1, 50% whey powder

 1, 00% molasses

 1,00% brewer's yeast, bound to brewer's grains

 100.00%

Such feed contains 18% crude protein, 5% crude fiber, 1% Ca, 0.7% P and 1 kg 1200 i.E. Vitamin A, 1200 i.E. Vitamin D3, 10 mg Vitamin E, 20 mg Zinc bacitracin.

Biological Examples A. Eimeria falciformis mouse model

Eimeria falciformis develops in the caecum and especially in the upper colon of the 15-18 g SPF mice (strain CFW). It is infected by gavage with 18,000 sporulated oocysts. The test substances are suspended with Cremophor EL (BASF) in water (0.2%) and the animals according to their current body weight (mg / kg) per os by gavage on days 1, 2, 3, 6, 7, 8 post infection (pi) administered. To assess the efficacy, the parameters of infection-related mortality, weight development, diarrhea, macroscopic and microscopic findings and oocyst excretion are used. A high E. falciformis efficacy is, according to the experience in our laboratory, a fairly reliable indication of a broad spectrum of activity, in particular in relation to other mammalian coccidia. Haberkorn and G. Greif (1999): Animal Mode of Coccidia Infection Chapter 99: 821-838, In: Handbook of Anim Models of Infection, Academic Press. The results are summarized in Table 1.

Tab. 1: Efficacy of combinations of the compounds of the formulas (H-C) and (I-A) against E. falciformis (synergism)

 Application mg / kg was carried out p.o. on study days 1 -3 & 7-8 p.i.

* KO = uninfected control group

** Ki = infected control group

B. Coccidiosis / chick cage experiment

Coccidium-free 8 to 12-day-old male chickens (eg LSL Brinkschulte / Senden) receive the test substances from 3 days before (day -3) of infection (= ai) to 8 (9) days after infection (= pi) the concentration in ppm with the feed. In each cage, 3 animals are kept. One to several such groups are used per dosage. The infection is carried out by means of a gavage directly into the crop with about 50,000 sporulated oocysts of the field strain RIJ 070320-1. It is a highly virulent feldiolate resistant to toltrazuril. The exact dose of infection is adjusted so that as many as one of three experimentally infected untreated chicks dies due to infection. For the assessment of efficacy, the following criteria are considered: Weight gain from the start of the experiment to the end of the experiment, infection-related mortality, macroscopic assessment of faeces with regard to diarrhea and blood excretion on days 5 and 7 pi (scores 0 to 6), macroscopic evaluation of the intestinal mucosa, especially the caeca (score 0 to 6) and the oocyst excretion as well as the proportion (in%) oocysts sporadic within 24 hours. The number of oocysts in the faeces was determined using the McMaster counting chamber (see Engelbrecht and co-workers "Parasitological Methods in Medicine and Veterinary Medicine, Akademie-Verlag, Berlin (1965)). The individual findings are set in relation to the untreated uninfected control groups and an overall score is calculated (vG G. Haberkorn and G. Greif (1999): Animal Mode of Coccidial Infection, Chapter 99: 821-838, In: Handbook of Animal Models of Infection, Academic Press.)

Test results with combinations according to the invention are listed by way of example in the following table. The increased efficacy of the combinations compared to the individual components is particularly evident in the reduction of oocyst excretion.

In the following tables, in column "Treatment", the indication n.inf.contr. = Uninfected control group

inf.contr. = infected control group

The column "dose" indicates the concentration of the active substance in the feed in ppm.

In the column "mortality" is given below% of the percentage of dead animals and under n the number of dead animals / animals used in the experiment.

In the column "weight% of not inf. control "is the ratio of the weight of the treated animals to the weight of the uninfected control group.

 In the columns "dropping scores", "lesion score" and "oocyst control" individual details will be made effective.

In the column "% efficacy" the overall rating is scored, 0% means no effect, 100% means full effect. Tab. 2: Efficacy of combinations of the compounds of the formulas (HC) and (IA) against the toltrazuril-resistant field strain RIJ 070320-1

C. Ground keeping Coccidiosis / turkey

 Coccidium-free 8 to 1 day old male turkey chicks (eg BIG 6 / Moorgut Karzfehn) receive from 3 days before (day -3) the infection (= ai) to 8 (9) days after infection (= pi) Test substances in the concentration specified in ppm with the feed. 5-10 animals are kept in each holding facility for keeping the ground. One to several such groups are used per dosage. The infection is carried out by means of a gavage directly into the goiter with about 65,000 sporulated oocysts of each field isolate. These are highly virulent, toltrazuril-resistant strains. For the evaluation of the efficacy the following criteria are taken into account: Weight increase from the beginning of the test until the end of the experiment, infection-related mortality rate, macroscopic assessment of the faeces with regard to diarrhea and blood excretion on day 7 p.i. (Rating 0 to 4), macroscopic assessment of the intestinal mucosa, especially the caeca and small intestine (scores 0 to 4) and oocyst excretion. The number of oocysts in the faeces was determined using the McMaster counting chamber (see Engelbrecht and co-workers "Parasitological Methods in Medicine and Veterinary Medicine, Akademie-Verlag, Berlin (1965)). The individual findings are set in relation to the untreated uninfected control groups and an overall score is calculated (see A. Haberkorn and G. Greif (1999): Animal Models of Coccidial Infection Chapter 99: 821-838, In: Handbook of Animal Models of Infection, Academic Press.)

Experimental results with erfϊndungsgemäßen combinations are listed in the following Tables 3 and 4 for two different field strains.

In the following tables, in column "Treatment", the indication n.inf.contr. = Uninfected control group

inf.contr. = infected control group

In the column "dose", the concentration of the active substance in the feed is given in ppm, in the column "mortality", the percentage of animals died is given as% and, under n, the number of animals died / animals used in the experiment.

In the column "weight% of not inf. control "is the ratio of the weight of the treated animals to the weight of the uninfected control group.

In the columns "dropping scores", "lesion score" and "oocyst control" individual details will be made effective. In the column "% efficacy" the overall rating is scored, 0% means no effect, 100% means full effect.

Tab. 3: Effectiveness of combinations of the compounds of the formulas (II-C) and (1-A) against the toltrazuril-resistant field strain BAL 060810 D

Tab. 4: Effectiveness of combinations of the compounds of the formulas (II-C) and (IA) against the toltrazuril-resistant field strain LVL 080918 D

Example of an application: Cremophor suspension

The active substance (s) are mixed with 200 μl of Cremophor EL® (a polyethoxylated rhizinic oil, BASF), then a suspension is prepared by adding 3 ml of water.

Used active ingredients:

a) 100 mg of Vbdg (I-A)

b) 50 mg of Vbdg (I-A)

c) 100 mg of Vbdg (II-C)

d) 50 mg of bis (II-C)

e) 50 mg Vbdg (I-A) and 50 mg Vbdg (II-C)

f) 100 mg of Vbdg (I-A) and 100 mg of Vbdg (II-C)

Claims

claims

1. Products containing in each case at least one active against parasitic protozoa substituted benzimidazole or its physiologically acceptable salt and a heterocyclically substituted 1, 2,4-triazinedione of the formula (I)

 in which

R ^{1 represents} carbon-linked heteroaromatic radicals which are optionally substituted,

X is O, S, SO or SO ₂ ,

R ^{2 is} one or more identical or different radicals of the group hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy and haloalkyl

(I) kylthio stands,

R ^{3 is} hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aralkyl, or its physiologically acceptable salt.

2. Products according to claim 1 for simultaneous, separate or graduated in time

Use against parasitic protozoa in humans or animals.

3. A product according to any one of the preceding claims, wherein the parasitic protozoal substituted benzimidazole is a compound of formula (II) or a physiologically acceptable salt thereof

in which Z is hydrogen or the radical -CHR ² R ³ , R ^{1 is} fluoroalkyl,

R ^{2 is} hydrogen or alkyl,

R ^ is a radical of the formula

or for a remainder of the formula

R ⁵ O

- N- C- OR ⁶ _is

R ^{4 is} alkyl,

R ^ is alkyl or substituted phenyl,

R ⁶ is alkyl, χl, X ^2, X ⁴ χ3 _U nd logenalkoxy independently hydrogen, halo, haloalkyl, Ha-, haloalkylthio or haloalkylsulfonyl stand, or

X ² and X ^ or X ^ and X ⁴ together represent a dioxyhaloalkylene radical.

4. Products according to claim 3, characterized in that Z is the radical -CHR ² R ^.

5. Products according to one of the preceding claims, wherein the as against parasitic

Protozoa effective substituted benzimidazole the compound of formula (IIa)

(IIa) or their physiologically acceptable salt.

Products according to any one of the preceding claims, wherein the 1,2,4-triazine derivative is a compound of formula (Ia)

 or their salt is.

7. Use in combination in each case of at least one substituted benzimidazole active against parasitic protozoa and at least one heterocyclic substituted 1, 2,4-triazinedione of the formula (I)

R ^{1 represents} heteroaromatic radicals bonded via carbon, which are optionally substituted,

X is O, S, SO or SO ₂ ,

R ^{2 is} one or more identical or different radicals of the group hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy and haloalkylthio,

R ^{3 is} hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aralkyl,

or of their physiologically acceptable salts for the production of products for controlling parasitic protozoa.

8. A method for controlling parasitic protozoa in humans or animals, wherein at least one substituted benzimidazole effective against parasitic protozoa and a heterocyclic substituted 1, 2,4-triazinedione of the formula (I)

 in which

R ^{1 represents} carbon-linked heteroaromatic radicals which are optionally substituted,

X is O, S, SO or SO ₂ ,

R ^{2 is} one or more identical or different radicals of the group hydrogen, halogen, nitro, alkyl, alkoxy, alkylthio, haloalkyl, haloalkoxy and haloalkylthio,

R ^{3 is} hydrogen, optionally substituted alkyl, alkenyl, alkynyl, aralkyl, or its physiologically acceptable salt is applied in combination in an effective amount.

9. Use of a product according to the preceding claims for the manufacture of a medicament for combating parasitic protozoal diseases in animals.