EP1789038A1

EP1789038A1 - Combination of substituted benzimidazoles and triazine derivatives with antiparasitic action

Info

Publication number: EP1789038A1
Application number: EP05777588A
Authority: EP
Inventors: Gisela Greif
Original assignee: Bayer Healthcare AG
Current assignee: Bayer AG
Priority date: 2004-09-02
Filing date: 2005-08-23
Publication date: 2007-05-30
Also published as: DE102004042958A1; NO20071324L; PE20060443A1; CA2578184A1; GT200500236A; SV2007002216A; ZA200701819B; TW200621239A; BRPI0515353A; US20070232609A1; WO2006024428A1; JP2008511567A; MX2007002471A; AU2005279361A1; AR050722A1

Abstract

The invention relates to the combined use of substituted benzimidazoles and 1,2,4-triazine compounds against parasitic protozoa, in particular, Coccidia.

Description

COMBINATION OF SUBSTITUTED BENZIMIDAZOLES AND TRIAZINE DERIVATIVES WITH ANTIPARASITIC EFFECT

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

Substituted benzimidazoles and _. their use as insecticides, fungicides and herbicides has already become known (EP-OS 87 375, 152 360, 181 826, 239 508, 260 744, 266 984, US-P 3 418 318, 3 472 865, 3 576 818, 3 728 994). Halogenated benzimidazoles and their action as anthelmintics, coccidiostats and pesticides have become known (DE-OS 2,047,369, EP 597 304 Al). 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-P 5,331,003). Mixtures of substituted benzimidazoles with polyether antibiotics or synthetic coccidia agents as agents for controlling parasitic protozoa are known from WO 96/38140.

The excellent combination of substituted benzimidazoles with 1,2,4-triazines for controlling parasitic protozoa has not previously been described.

An important example of a disease caused by unicellular parasites (protozoa) is coccidiosis. It can cause large losses, especially in poultry rearing. To avoid this, the stocks are treated prophylactically with Coccidiosemitteln. The development of resistance to the funds used leads to serious problems shortly after the funds are introduced. On the other hand, the use of completely new coccidiosis agents, in particular combinations, makes it possible to control polyresistant parasite strains.

The invention therefore relates to:

Products containing in each case at least one active against parasitic protozoa substituted benzimidazole and 1,2,4-triazine derivative.

Preferred benzimidazoles are those of the formula (I)

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 ⁵ O - N - C - OR ⁶ _stands

R ^{4 is} alkyl,

R ^{5 is} alkyl or substituted phenyl,

R ^{6 is} alkyl,

χ 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 a dioxyhaloalkylene radical. The substituted benzimidazoles according to the invention are generally defined by the formula (I).

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

R 2 is preferably hydrogen or C 1 -C 4 -alkyl,

R.4 is preferably C 1 -C 4 -alkyl,

R-> is preferably Ci-β-alkyl or phenyl, which is optionally mono- or polysubstituted substitu¬ ated with Ci- ₄ alkyl, d- ₄ haloalkyl, halo, nitro, Ci _-4 alkoxy, Q ^ - Haloalkoxy or optionally one or more times halogen-substituted methylene or ethylenedioxy.

R ⁶ is preferably C _1-4 -alkyl

χl, X ^, χ3 and X ^ are preferably each independently hydrogen, F, Cl, Br, C 1 -C 4 -haloalkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -haloalkylthio, C 1 -C 4 -halogenoalkylsulfonyl, or

X.sup.1 and X.sup.2 or X.sup.1 and X.sup.2 together represent, according to a further preferred embodiment, a dioxyhalo-C 1 -C 4 -alkylene radical.

R ¹ particularly preferably stands for CF3, CHF2 or CHF.

R 1 particularly preferably represents hydrogen, methyl, ethyl, n-propyl or isopropyl.

R4 particularly preferably represents methyl, ethyl, n-propyl or isopropyl.

R5 is particularly preferably Ci _-6 alkyl.

R ^ is particularly preferably methyl or ethyl.

χl, X ^, X ^ and X ^ are more preferably independently of one another 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.sup.1 and X.sup.2 or X.sup.1 and X.sup.2, according to a further embodiment, particularly preferably also together represent 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-CClF-CClF-O-, -O-CHF-O-, -O-CHF-CHF-O- or -O-CC1F-O-.

In a most preferred embodiment, R-> is a radical of the formula

According to another particularly preferred embodiment, K? for a remainder of the formula

RI very particularly preferably represents -CF3.

R ^ is very particularly preferably hydrogen.

R4 is very particularly preferably methyl.

X * is most preferably Cl or Br.

X 1 is very particularly preferably hydrogen.

and

Most preferably, XP and X ^ together are -OCF2-CF2-O-.

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. Methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl.

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; Preference is given to perfluoroalkyl radicals, for example 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 is a straight-chain or branched alkylthio radical having 1 to 8, preferably 1 to 6, more preferably 1 to 4, carbon atoms in which one or more, in particular 1 to 3, hydrogen atoms are replaced by a halogen atom, in particular fluorine, chlorine or bromine were replaced; 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.

In one embodiment, Z in formula (I) is hydrogen and the other substituents may have the meanings given above, including the preferred and particularly preferred meanings. As a preferred example of this embodiment, the compound of the formula (I-A) (see WO00 / 04022) may be mentioned:

According to a preferred further embodiment, Z in formula Q) is the radical -CHR 2 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 (IB) (see WO00 / 04022) and in particular the compound of the formula (IC) (see WO00 / 68225):

Compounds of formula (I) in which Z is hydrogen have hitherto been known as intermediates in the preparation of active benzimidazole drugs. Surprisingly, it has now been found that the compounds of the formula (I) in which Z is hydrogen themselves have excellent activity against parasitic protozoa (as explained in more detail below). According to a further aspect, this invention therefore relates to the use of compounds of the formula (I) in which Z is hydrogen, for controlling parasitic proteins, in particular in animal husbandry and animal breeding. Preferred and particularly preferred compounds of the formula (I) in which Z is hydrogen are those in which the other substituents have the preferred and particularly preferred meanings given above. As a particularly preferred example, reference is made to the compound of formula (I-A). 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.

1,2,4-triazines with activity against parasitic protozoa are known. Preferred 1,2,4-triazines are represented by formula (IT):

embedded image in which R ¹ and R ² independently of one another represent hydrogen or Cl and

R ^{3 is} fluorine or chlorine.

Particularly preferred examples are:

Clazuril (R ¹ = Cl, R ² = H, R ³ = Cl in formula ^" (II))

Letrazuril (R ¹ = Cl, R ² = Cl, R ³ = F in formula (IT)) and

Diclazuril (R ¹ = Cl, R ² = Cl, R ³ = Cl in formula (IT)).

Of these 1,2,4-triazines, diclazuril is most preferred.

Depending on the nature and number of the substituents, the abovementioned active compounds may optionally be present as geometric and / or optical isomers or regioisomers or their isomer mixtures in different compositions. Both the pure isomers and the isomer mixtures can be used according to the invention.

Insofar as the active compounds can form salts, the use in the form of pharmaceutically acceptable salts is also suitable.

Furthermore, if appropriate, the use of hydrates or other solvates of the active substances or their salts comes into question.

The active ingredients are suitable for favorable toxicity to warm-blooded animals for the control of parasitic protozoa, which occur in livestock and livestock in livestock, breeding, zoo, laboratory, experimental and hobby animals. They are active against all or individual stages of development of the pests and against resistant and normally sensitive strains. By controlling the parasitic protozoa disease, deaths and reductions in performance (eg in the Pro¬ production of meat, milk, wool, hides, eggs, honey, etc.) are to be reduced, so that through the use of active ingredients a more economical and easier animal husbandry possible is.

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. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L tropica, such as Trichomonadidae eg Giardia lamblia, G. canis. Sarcomastigophora (Rhizopoda) such as Entamoebidae eg Entamoeba histolytica, 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 clupeamm, 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. 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. 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. spec., Theileria parva, Theileria spec such as Adeleina e.g. Hepatozoon canis, H. spec

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 proteases which occur as parasites in insects. As such, parasites of the strain Microsporida, in particular of the genus Nosema, may be mentioned. Particular mention may be made of Nosema apis in the honeybee.

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 such as 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 yellowtaü (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream ( Pagurus major), Seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthread seabream (Sparus auratus), Tilapia spp., Chichlid species such as Plagioscion, Channel catfish. Particularly suitable are the inventive means for the treatment of fish fry, for example carp of 2 to 4 cm Körper¬ length. The remedies are also very suitable in the eel mast.

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, potions, granules, drenches, boiled egg, 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. The parenteral application 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, 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.

Suitable solvents include: Physiologically acceptable solvents such as water, alcohols such as ethanol, butanol, benzyl alcohol, glycerol, hydrocarbons, propylene glycol, polyethylene glycols, N-methylpyrrolidone, and mixtures thereof.

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

Solubilizers which may promote the dissolution of the active ingredient in the main solvent or prevent it from precipitating may be mentioned as solubilizers. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

Preservatives are: benzyl alcohol, trichlorobutanol, p-hydroxybenzoic acid ester, n-butanol.

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 dripped, brushed, rubbed, sprayed on, sprinkled 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 thickening agents in the preparation. Thickeners are: inorganic thickeners such as bentonites, colloidal silicic acid, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.

Gels are applied to or painted on or placed in body cavities. Gels were prepared by adding solutions prepared as described for the injection solutions with thickening agent sufficient to give a clear mass of ointment-like consistency. The thickeners used are the thickening agents specified above. Pour-on formulations are poured or sprayed onto limited areas of the skin, the active ingredient either penetrating the skin and acting systemically or being distributed on the body surface.

Pour-on formulations are prepared by dissolving, suspending or emulsifying the active ingredient in suitable skin-compatible solvents or solvent mixtures. If appropriate, further auxiliaries such as dyes, absorption-promoting substances, antioxidants, light stabilizers, adhesives are added.

The following may be mentioned as solvents: water, alkanols, glycols, polyethylene glycols, polypropylene glycols, glycerol, 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 ether, ketones such as Acetone, methyl ethyl ketone, aromatic and / or aliphatic hydrocarbons, vegetable or synthetic oils, DMF, dimethylacetamide, N-methylpyrrolidone, 2-dimethyl-4-oxy-methylene-l, 3-dioxolane.

Dyes are all animal-approved dyes that may be dissolved or suspended.

Absorption promoting 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, butylhydroxytoluene, butylhydroxyanisole, tocopherol.

Sunscreen agents are e.g. 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 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, Antioxi¬ danties, light stabilizers, viscosity-increasing substances, with the solvent of others Homogenized phase. A hydrophobic phase (oils) may be mentioned: 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 of chain length Cg_i 2 or other specially selected natural fatty acids, partial glyceride mixtures saturated or unsaturated, possibly also hydroxyl-containing fatty acids, mono- and diglycerides of Cg / C \ _Q fatty acids.

Fatty acid esters such as ethyl stearate, di-n-butyryl adipate, hexyl laurate, dipropylene glycol pelargonate, esters of a branched fatty acid of medium chain length with saturated fatty alcohols of chain length C _j gC _j g, isopropyl myristate, isopropyl palmitate, caprylic / capric esters of saturated fatty alcohols of chain length C ^ -C j g, isopropyl stearate, oleic acid esters, oleic acid decyl esters, ethyl oleate, ethyl lactate, waxy fatty acid esters such as dibutyl phthalate, diisopropyl adipate, the latter related ester mixtures, inter alia fatty alcohols such as isotridecyl alcohol, 2-octyldodecanol, cetylstearyl alcohol, oleyl alcohol.

Fatty acids, e.g. Oleic acid and its mixtures.

As hydrophilic phase may be mentioned:

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

As emulsifiers may be mentioned:

nonionic surfactants, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethyl stearate, alkylphenol polyglycol ethers;

ampholytic surfactants such as di-Na-N-lauryl-β-iminodipropionate or lecithin;

anionic surfactants, such as Na lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt;

cationic surfactants such as cetyltrimethylammonium chloride.

As further auxiliaries may be mentioned:

Viscosity-increasing and emulsion-stabilizing substances such as carboxymethylcellulose, methylcellulose and other cellulose and starch derivatives, polyacrylates, alginates, gelatin, gum arabic, polyvinylpyrrolidone, polyvinyl alcohol, copolymers of methyl vinyl ether and maleic anhydride, polyethylene glycols, waxes, colloidal Silica or mixtures of the listed substances. 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 excipients, such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants, light stabilizers.

As carrier liquids, all homogeneous solvents and solvent mixtures may be mentioned.

Suitable wetting agents (dispersants) are the surfactants specified above.

As further auxiliaries mentioned above.

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

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.

Suitable carriers are all physiologically compatible solid inert substances. All such den¬ nen inorganic and organic substances. Inorganic substances are e.g. Common salt, carbonates such as calcium carbonate, bicarbonates, aluminas, silicas, clays, precipitated or colloidal silica, phosphates.

Organic substances are e.g. Sugar, cellulose, food and feed such as milk powder, animal meals, cereal flours and meals, starches.

Adjuvants are preservatives, antioxidants, dyes which have already been mentioned above.

Other suitable excipients are lubricants and lubricants such as e.g. Magnesium stearate, stearic acid, talc, bentonites, disintegrants such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.

The active ingredients may be present in combination with synergists or with other active ingredients.

As further active ingredients in particular polyether antibiotics come into question, such as:

Amprolium, z.T. in combination with folic acid antagonists

robenidine

monensin

salinomycin Lasalocid Narasin

Semduramicin and especially maduramicin.

Ready-to-use preparations contain the active compounds in each case in concentrations of 0.005 ppm to 50 ppm, preferably from 0.1 to 10 ppm.

In general, it has proven to be advantageous to administer amounts of about 0.05 to about 50 mg, preferably 0.1 to 20 mg, of active ingredient per kg of body weight per day to achieve effective results.

In the mixture with other Coccidiosemitteln or polyether antibiotics erfindungs¬ the active compounds in the ratio 1 to 0.01 - 50 to 1 to 1 - 50 before. Preferably, the ratio is I to 25.

The active ingredients can also be administered together with the feed 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 takes place by mixing a concentrate or a 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 feed ¬ average. 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 obtained in this case can 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 coccidiosis in poultry, especially chickens,

Ducks, geese and turkeys, 0.005 to 100 ppm, preferably 0.05 to 100 ppm of an active ingredient are mixed with a suitable edible material, eg a nutritious feed. 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, e.g. in the case of treatment of mammalian coccidiosis or toxoplasmosis, preferably amounts of active ingredient of from 0.05 to 100 mg / kg of body weight are administered daily in order to obtain the desired results. Nevertheless, it may be necessary at times to deviate from the stated amounts, in particular as a function of the body weight of the test animal or the type of administration method, but also because of the animal genus and its individual reaction to the active substance or the type of formulation and time or the distance to which it 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 expedient to divide them into several individual administrations during the course of the day.

The effectiveness 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 and 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 a premix is to be prepared, which is to be finally diluted in the feed to the values mentioned in the experiment, generally about 1 to 30%, preferably about 10 to 20 wt .-% active ingredient with an edible organic or anorgani¬ 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 - II

3.00% mineral mixture

3.00% alfalfa grass green flour

2.50% Vitaminvortnischung

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.

Cage trial of coccidiosis / chicks

Coccidium-free 8 to 12-day-old male chickens (eg LSL Brinkschulte / Senden) receive the compounds according to the invention from 3 days before (day -3) of infection (= ai) to 8 (9) days after infection (= pi) (Test substances) in the concentration indicated 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 gavage directly into the crop with about 100 000 sporulated oocysts of Eimeria acervulina and each with about 30 000 sporulated oocysts of E. maxima and 40 000 sporulated oocysts of E. tenella. These are highly virulent strains. The exact dose of infection is adjusted so that as many as one of three experimentally infected untreated chicks dies due to infection. The following criteria are taken into account for the evaluation of the efficacy: weight increases from the beginning of the test to the end of the experiment, infection-related mortality, macroscopic assessment of the faeces with regard to diarrhea and blood excretion on days 5 and 7 pi (evaluation 0 to 6), macroscopic assessment of the intestinal mucosa , in particular the caeca (rating 0 to 6) and the oocyst excretion as well as the proportion (in%) of the oocysts sporulating within 24 hours. The number of oocysts in the faeces was determined with the aid of the McMaster counting chamber (see Engelbrecht and co-workers "Parasitological Work 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 evaluation is calculated (see A. Haberkorn (1986) pp. 263 to 270 in Research in Avian Coc. cidiosis ed. LR McDougald, LP Joyner, PL Long Proceedings of the Georgia Coccidiosis Conference Nov, 18.-20. 1985 Athens / Georgia USA).

Experimental results with combinations according to the invention are shown by way of example in the following table. The increased efficacy of the combinations in comparison to the individual components is particularly evident in the reduction of oocyst excretion and in the findings of infection.

In the following tables, the column "Treatment" indicates n.inf.contr. = Uninfected control group inf.contr. = Infected control group (I-A) = benzimidazole of formula (I-A).

In the column "ppm", the concentration of active ingredient used in the feed in ppm angege¬ ben.

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.

table

treatment ppm mortality weight in% dropping lesion oocysts in% effica- of not inf. score score% of inf. cy

% n control control not infec- 0 0 .0 / 6 100 0 0 0.3 100 ted control infected 0 33,3 2/6 30,5 6 6 100 0 control

(1-A) * 1 0 0/3 16 6 6 36.0 15.7

(1-A) * 2.5 0 0/3 41 6 6 80.7 12.3

Diclazu 0.05 0 0/3 86 0 0 17.0 69.3 ril

Diclazu- 0.1 0 0/3 92 0-2 0 14.0 77.0 ril

QrA) * + 1 0 0/3 85 0 0 6.0 78.3

Diclazu +0.05 ril

Q-A) * + 1 +0,1 0 0/3 71 0-1 0 5,7 67,3 Diclazu- ril

QrA) * + 2.5 + 0, 0 0/3 85 0 0 6,0 76,7

Diclazu-05 ril

(I-A) + 2.5 0 0/3> 100 0 0 3.7 91, Diclazu +0.1 ril

(1-A) * 1 +1 0 0/3 95 0 0 0 100 Diclazu-ril

* contains about 23% compound of formula (I-C)

Claims

Patentansprflche

1. Products containing in each case at least one effective against parasitic protozoa sub¬ stituted benzimidazole and 1,2,4-triazine derivative.

2. Products according to claim 1 for simultaneous, separate or time-phased use against parasitic protozoa in humans or animals.

3. A product according to any one of the preceding claims, wherein the substituted benzimidazole active against parasitic proteases is a compound of formula (T) or a salt thereof, optionally in the form of a hydrate or solvate

in which

Z represents 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 ° N C OFT stands

R ^{4 is} alkyl, R ^ is alkyl or substituted phenyl,

R ^{6 is} alkyl,

χl, X ^, X ^ and X ^ independently represent hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulfonyl,

or

X ^ and X ^ or X ³ and X ^ together represent a dioxyhaloalkylene radical.

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

5. Products according to one of the preceding claims, wherein the 1,2,4-triazine derivative is a compound of the formula (II) or a salt thereof, optionally in the form of a hydrate or solvate

worm

R ¹ and R ² independently of one another represent hydrogen or Cl and

R ^{3 is} fluorine or chlorine.

Products according to claim 4, in which the 1,2,4-triazine derivative is clazuril, letrazuril or diclazuril.

7. Use of at least one substituted benzimidazole and benzamidazole active against parasitic protozoa 1,2,4-triazine derivative for the production of products for combating parasitic protozoa.

8. Use of a compound of the formula (I) in which

Z is hydrogen,

R 1 is fluoroalkyl,

or

X ^ and X ^ or X ^ and X ^ together represent a dioxyhaloalkylene radical,

or a salt thereof, if appropriate in the form of a hydrate or solvate for the production of products for controlling parasitic protozoa.

9. A method for controlling parasitic protozoa in humans or animals, wherein the human or animal in each case at least one against parasitic protozoa Wirka¬ mes substituted benzimidazole and 1,2,4-Triazmderivat in an effective amount appli¬.

10. A method for controlling parasitic protozoa in humans or animals, wherein the human or animal in each case at least one against parasitic protozoa wirka¬ mes substituted benzimidazole of the formula (T)

in which

stands for hydrogen, R * is fluoroalkyl,

χ 1, X 1, χ 3 and X 1 independently of one another represent hydrogen, halogen, haloalkyl, haloalkoxy, haloalkylthio or haloalkylsulphonyl,

or

X ^ and X ^ or X ^ and X ^ together represent a dioxyhaloalkylene radical,

or a salt thereof optionally applied in the form of a hydrate or solvate in an effective amount.